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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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
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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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    • 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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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080214557A1 (en) * 2005-09-01 2008-09-04 Eisai R&D Management Co., Ltd. Method for preparation of pharmaceutical composition having improved disintegratability and pharmaceutical composition manufactured by same method
US20080214604A1 (en) * 2004-09-17 2008-09-04 Hisao Furitsu Medicinal Composition
US20090171112A1 (en) * 2003-11-11 2009-07-02 Toshihiko Naito Urea derivative and process for preparing the same
US20090247576A1 (en) * 2005-11-22 2009-10-01 Eisai R & D Management Co., Ltd. Anti-tumor agent for multiple myeloma
US20090264464A1 (en) * 2006-08-28 2009-10-22 Eisai R & D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US20100048620A1 (en) * 2007-01-29 2010-02-25 Yuji Yamamoto Composition for treatment of undifferentiated gastric cancer
US20100105031A1 (en) * 2005-08-01 2010-04-29 Esai R & D Management Co., Ltd. Method for prediction of the efficacy of vascularization inhibitor
US20100197911A1 (en) * 2000-10-20 2010-08-05 Eisai R&D Management Co., Ltd. Nitrogen-Containing Aromatic Derivatives
US20100324087A1 (en) * 2008-01-29 2010-12-23 Eisai R&D Management Co., Ltd. Combined use of angiogenesis inhibitor and taxane
US20110207756A1 (en) * 2006-05-18 2011-08-25 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US20130123274A1 (en) * 2010-06-25 2013-05-16 Eisai R&D Management Co., Ltd. Antitumor Agent Using Compounds Having Kinase Inhibitory Effect in Combination
US8759530B2 (en) 2011-03-29 2014-06-24 Eisai R&D Management Co., Ltd. Method for producing phenoxypyridine derivative
US8815241B2 (en) 2005-11-07 2014-08-26 Eisai R&D Management Co., Ltd. Use of combination of anti-angiogenic substance and c-kit kinase inhibitor
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US20160000913A1 (en) * 2012-02-29 2016-01-07 University Hospitals Cleveland Medical Center Targeted treatment of anerobic cancer
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US10525152B2 (en) 2009-10-09 2020-01-07 Signablok, Inc. Methods and compositions for targeted imaging
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11542259B2 (en) * 2018-01-26 2023-01-03 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11673897B2 (en) 2018-01-26 2023-06-13 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1604665B1 (en) 2003-03-10 2011-05-11 Eisai R&D Management Co., Ltd. C-kit kinase inhibitor
US20100150884A1 (en) * 2005-02-10 2010-06-17 Oncolys Biopharma Inc. Anticancer Agent to Be Combined with Telomelysin
CN101723894B (zh) * 2009-12-03 2011-12-28 南京大学 N-喹啉酰胺类衍生物及其制法与用途
CA2915005C (en) 2013-06-26 2021-12-28 Eisai R&D Management Co., Ltd. Use of eribulin and lenvatinib as combination therapy for treatment of cancer
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RU2718048C2 (ru) * 2015-08-20 2020-03-30 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Противоопухолевое терапевтическое средство
WO2017090157A1 (ja) * 2015-11-26 2017-06-01 大和薬品株式会社 血管新生抑制剤
CN106496116A (zh) * 2016-10-21 2017-03-15 沈阳药科大学 含双芳基脲结构的喹啉类化合物及其用途
CN108530455B (zh) 2017-03-01 2021-01-12 北京赛特明强医药科技有限公司 脲取代的芳环连二噁烷并喹唑啉类化合物或药用盐或水合物及作为酪氨酸激酶抑制剂的应用
CA3090829C (en) 2018-02-11 2023-05-09 Beijing Scitech-Mq Pharmaceuticals Limited Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof

Citations (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526988A (en) * 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US4742003A (en) * 1984-02-17 1988-05-03 Genentech, Inc. Human transforming growth factor
US4764454A (en) * 1985-12-20 1988-08-16 Fuji Photo Film Co., Ltd. Color photographic material with color forming ligand compounds and a method of processing
US5180818A (en) * 1990-03-21 1993-01-19 The University Of Colorado Foundation, Inc. Site specific cleavage of single-stranded dna
US5464826A (en) * 1984-12-04 1995-11-07 Eli Lilly And Company Method of treating tumors in mammals with 2',2'-difluoronucleosides
US5487889A (en) * 1992-06-03 1996-01-30 The Metrohealth System Bandage for continuous application of biologicals
US5624937A (en) * 1995-03-02 1997-04-29 Eli Lilly And Company Chemical compounds as inhibitors of amyloid beta protein production
US5650376A (en) * 1994-11-07 1997-07-22 International Superconductivity Technology Center (Nd, Ba)3 Cu3 O7-d superconductor film
US5656454A (en) * 1994-10-04 1997-08-12 President And Fellows Of Harvard College Endothelial cell-specific enhancer
US5658374A (en) * 1995-02-28 1997-08-19 Buckman Laboratories International, Inc. Aqueous lecithin-based release aids and methods of using the same
US5733913A (en) * 1994-11-14 1998-03-31 Blankley; Clifton John 6-Aryl pyrido 2,3-d! pyrimidines and naphthyridines for inhibiting protein tyrosine kinase mediated cellular proliferation
US5747651A (en) * 1991-04-02 1998-05-05 The Trustees Of Princeton University Antibodies against tyrosine kinase receptor flk-1
US5750376A (en) * 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
US5770599A (en) * 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
US5792783A (en) * 1995-06-07 1998-08-11 Sugen, Inc. 3-heteroaryl-2-indolinone compounds for the treatment of disease
US5891996A (en) * 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US6156522A (en) * 1997-06-30 2000-12-05 University Of Maryland Baltimore Heparin binding--epidermal growth factor-like growth factor in the diagnosis of Interstitial Cystitis
US6217866B1 (en) * 1988-09-15 2001-04-17 Rhone-Poulenc Rorer International (Holdings), Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US20020010203A1 (en) * 1999-12-22 2002-01-24 Ken Lipson Methods of modulating c-kit tyrosine protein kinase function with indolinone compounds
US6346398B1 (en) * 1995-10-26 2002-02-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor
US20020040127A1 (en) * 2000-06-09 2002-04-04 Yuqiu Jiang Compositions and methods for the therapy and diagnosis of colon cancer
US6476040B1 (en) * 1999-03-31 2002-11-05 Pfizer Inc. Processes and intermediates for preparing anti-cancer compounds
US6524583B1 (en) * 1999-04-28 2003-02-25 Board Of Regents, The University Of Texas System Antibody methods for selectively inhibiting VEGF
US6534535B1 (en) * 1999-08-12 2003-03-18 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US20030087907A1 (en) * 2001-04-27 2003-05-08 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives having azolyl group
US20030113713A1 (en) * 2001-09-10 2003-06-19 Meso Scale Technologies, Llc Methods and apparatus for conducting multiple measurements on a sample
US20030215523A1 (en) * 2000-10-31 2003-11-20 Yoichi Ozawa Medicinal compositions for concomitant use as anticancer agent
US20040009965A1 (en) * 2002-06-14 2004-01-15 Agouron Pharmaceuticals, Inc. Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use
US20040034026A1 (en) * 2000-11-22 2004-02-19 Wood Jeannette M Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity
US20040053908A1 (en) * 2000-10-20 2004-03-18 Yasuhiro Funahashi Nitrogen-containing aromatic derivatives
US20040132727A1 (en) * 1999-12-24 2004-07-08 Teruyuki Sakai Quinoline and quinazoline derivatives and drugs containing the same
US20040152759A1 (en) * 2002-11-15 2004-08-05 Sugen, Inc. Combination administration of an indolinone with a chemotherapeutic agent for cell proliferation disorders
US6797823B1 (en) * 1999-01-22 2004-09-28 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives
US20040191254A1 (en) * 2001-10-09 2004-09-30 Fagin James Alexander Method of treatment of thyroid cancer
US6811779B2 (en) * 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
US20040242506A1 (en) * 2001-08-09 2004-12-02 Barges Causeret Nathalie Claude Marianne Paroxetine glycyrrhizinate
US20040253205A1 (en) * 2003-03-10 2004-12-16 Yuji Yamamoto c-Kit kinase inhibitor
US20050014727A1 (en) * 2003-03-05 2005-01-20 Muller George W. Diphenylethylene compounds and uses thereof
US20050049264A1 (en) * 2001-10-17 2005-03-03 Kirin Beer Kabushiki Kaisha Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
US20050119303A1 (en) * 2002-03-05 2005-06-02 Eisai Co., Ltd Antitumor agent comprising combination of sulfonamide-containing heterocyclic compound with an angiogenesis inhibitor
US20050176802A1 (en) * 2000-02-15 2005-08-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20050187236A1 (en) * 2002-08-30 2005-08-25 Akihiko Tsuruoka Nitrogen-containing aromatic derivatives
US20050272688A1 (en) * 2004-06-03 2005-12-08 Brian Higgins Combined treatment with gemcitabine and an epidermal growth factor receptor kinase inhibitor
US20050277652A1 (en) * 2004-02-27 2005-12-15 Eisai Co., Ltd. Novel pyridine derivative and pyrimidine derivative
US20060004017A1 (en) * 1999-02-10 2006-01-05 Astrazeneca Ab Quinazoline derivatives as angiogenesis inhibitors
US7005430B2 (en) * 1999-12-24 2006-02-28 Kyowa Hakko Kogyo Co., Ltd. Fused purine derivatives
US20060057195A1 (en) * 2002-10-16 2006-03-16 Takeda Pharmaceutical Company Limited Stable solid preparations
US20060079494A1 (en) * 2004-09-27 2006-04-13 Santi Daniel V Specific kinase inhibitors
US20060135486A1 (en) * 2004-09-13 2006-06-22 Eisai Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
US20070004773A1 (en) * 2005-06-23 2007-01-04 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chiloro-4-(cycloproplylaminocarbonyl)aminophenoxy)-7-method-6-quinolinecarboxamide and process for preparing the same
US20070032521A1 (en) * 2003-08-15 2007-02-08 Ab Science Use of c-kit inhibitors for treating type II diabetes
US20070037849A1 (en) * 2003-11-11 2007-02-15 Toshihiko Naito Urea derivative and process for producing the same
US20070078159A1 (en) * 2003-12-25 2007-04-05 Tomohiro Matsushima A crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amin ophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same
US20070117842A1 (en) * 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
US20070214604A1 (en) * 2006-03-20 2007-09-20 Samsung Electronics Co., Ltd Portable electronic device having triaxial hinge structure
US20080214604A1 (en) * 2004-09-17 2008-09-04 Hisao Furitsu Medicinal Composition
US20080241835A1 (en) * 1999-11-01 2008-10-02 Genentech, Inc. Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
US7435590B2 (en) * 2003-03-14 2008-10-14 Taisho Pharmaceutical Co., Ltd. Monoclonal antibody and hybridoma producing the same
US20090047278A1 (en) * 2005-02-28 2009-02-19 Eisai R & D Management Co., Ltd. Novel Combinational Use of Sulfonamide Compound
US20090047365A1 (en) * 2005-02-28 2009-02-19 Eisai R & D Management Co., Ltd. Novel Concomitant Use of Sulfonamide Compound with Anti-Cancer Agent
US20100092490A1 (en) * 2005-08-02 2010-04-15 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4582789A (en) 1984-03-21 1986-04-15 Cetus Corporation Process for labeling nucleic acids using psoralen derivatives
US4563417A (en) 1984-08-31 1986-01-07 Miles Laboratories, Inc. Nucleic acid hybridization assay employing antibodies to intercalation complexes
US5143854A (en) 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
DE69132843T2 (de) 1990-12-06 2002-09-12 Affymetrix, Inc. (N.D.Ges.D.Staates Delaware) Identifizierung von Nukleinsäuren in Proben
GB9105677D0 (en) 1991-03-19 1991-05-01 Ici Plc Heterocyclic compounds
US6027880A (en) 1995-08-02 2000-02-22 Affymetrix, Inc. Arrays of nucleic acid probes and methods of using the same for detecting cystic fibrosis
US6156501A (en) 1993-10-26 2000-12-05 Affymetrix, Inc. Arrays of modified nucleic acid probes and methods of use
US5948438A (en) 1995-01-09 1999-09-07 Edward Mendell Co., Inc. Pharmaceutical formulations having improved disintegration and/or absorptivity
PT817775E (pt) 1995-03-30 2002-01-30 Pfizer Derivados de quinazolina
US6057100A (en) 1996-06-07 2000-05-02 Eos Biotechnology, Inc. Oligonucleotide arrays
JP3040486U (ja) 1997-02-13 1997-08-19 有限会社ザップ フィッシングジャケット
JP3270834B2 (ja) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク 抗がん剤として有用なヘテロ芳香族二環式誘導体
JP2000328080A (ja) 1999-03-12 2000-11-28 Shin Etsu Chem Co Ltd シートベルト用低摩擦化処理剤
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
JP2001131071A (ja) 1999-10-29 2001-05-15 Meiji Seika Kaisha Ltd 非晶質および非晶質を含有する医薬組成物
AU784338B2 (en) 1999-11-01 2006-03-16 Curagen Corporation Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
JP3657203B2 (ja) 2000-04-21 2005-06-08 エーザイ株式会社 銅クロロフィリン塩含有液剤組成物
US7101663B2 (en) 2001-03-02 2006-09-05 University of Pittsburgh—of the Commonwealth System of Higher Education PCR method
EP1379545A2 (de) 2001-04-19 2004-01-14 Gesellschaft für biotechnologische Forschung mbH (GBF) Verfahren zur herstellung stabiler, regenerierbarer antikörper-arrays
JP3602513B2 (ja) 2001-04-27 2004-12-15 麒麟麦酒株式会社 アゾリル基を有するキノリン誘導体およびキナゾリン誘導体
JP2003026576A (ja) 2001-05-09 2003-01-29 Eisai Co Ltd 味覚改善製剤
US6812341B1 (en) 2001-05-11 2004-11-02 Ambion, Inc. High efficiency mRNA isolation methods and compositions
CZ299756B6 (cs) 2001-05-16 2008-11-12 Novartis Ag Kombinace s obsahem N-{5-[4-(4-methyl-piperazino-methyl)benzoylamido]-2-methylfenyl}-4-(3-pyridyl)-2-pyrimidin-aminu k lécení proliferativních onemocnení
DE60233736D1 (de) 2001-06-22 2009-10-29 Kirin Pharma K K Chinolinderivat und chinazolinderivat, die die selbstphosphorylierung des hepatocytus-proliferator-rezeptors hemmen, und diese enthaltende medizinische zusammensetzung
US20030013208A1 (en) 2001-07-13 2003-01-16 Milagen, Inc. Information enhanced antibody arrays
US20040266779A1 (en) 2001-09-27 2004-12-30 Anderson Kenneth C. Use of c-kit inhibitors for the treatment of myeloma
GB0201508D0 (en) * 2002-01-23 2002-03-13 Novartis Ag Organic compounds
WO2003079020A2 (en) * 2002-03-20 2003-09-25 Dana-Farber Cancer Institute Inc. Methods and compositions for the identification, assessment, and therapy of small cell lung cancer
WO2003093238A1 (fr) 2002-05-01 2003-11-13 Kirin Beer Kabushiki Kaisha Derives de quinoleine et derives de quinazoline inhibiteurs de l'autophosphorylation du recepteur du facteur stimulant la proliferation des macrophages
EP1509219A1 (en) * 2002-05-13 2005-03-02 Beth Israel Deaconess Medical Center Methods and compositions for the treatment of graft failure
US7252976B2 (en) 2002-08-28 2007-08-07 Board Of Regents The University Of Texas System Quantitative RT-PCR to AC133 to diagnose cancer and monitor angiogenic activity in a cell sample
JP4749660B2 (ja) 2002-10-16 2011-08-17 武田薬品工業株式会社 安定な固形製剤
WO2004039782A1 (ja) 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha Ｆｌｔ３自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物
DE10250711A1 (de) 2002-10-31 2004-05-19 Degussa Ag Pharmazeutische und kosmetische Zubereitungen
US7399866B2 (en) 2003-01-14 2008-07-15 Cytokinetics, Inc. Compounds, compositions, and methods
JP2005008534A (ja) 2003-06-17 2005-01-13 Soc De Conseils De Recherches & D'applications Scientifiques (Scras) 抗癌剤及び癌の治療方法
KR20120093411A (ko) 2003-07-10 2012-08-22 아스트라제네카 아베 백금 화합물 및 임의적으로 이온화 방사능과 조합된 퀴나졸린 유도체 ｚｄ6474의 혈관신생 및/또는 증가된 혈관 투과성 관련 질환 치료 용도
CN1852905A (zh) 2003-08-21 2006-10-25 Osi制药公司 具有n－取代的苯并咪唑基的c－kit抑制剂
KR20060115346A (ko) 2003-08-21 2006-11-08 오에스아이 파마슈티컬스, 인코포레이티드 Ｎ―치환된 피라졸릴-아미딜-벤즈이미다졸릴 ｃ―ｋｉｔ억제제
US7485658B2 (en) 2003-08-21 2009-02-03 Osi Pharmaceuticals, Inc. N-substituted pyrazolyl-amidyl-benzimidazolyl c-Kit inhibitors
JP2007505938A (ja) * 2003-09-23 2007-03-15 ノバルティス アクチエンゲゼルシャフト Ｖｅｇｆ受容体阻害剤と化学療法剤の組み合わせ
WO2006030941A1 (ja) 2004-09-13 2006-03-23 Eisai R & D Management Co., Ltd. スルホンアミド含有化合物の血管新生阻害物質との併用
CN101233111A (zh) 2005-06-23 2008-07-30 卫材R&D管理有限公司 4-（3-氯-4-（环丙基氨基羰基）氨基苯氧基）-7-甲氧基-6-喹啉羧酸酰胺的无定形盐及其制备方法
WO2007000347A2 (en) 2005-06-29 2007-01-04 Roselli, Patrizia Agonistic and antagonistic peptide mimetics of the vegf alpha-helix binding region for use in therapy
WO2007015569A1 (ja) 2005-08-01 2007-02-08 Eisai R & D Management Co., Ltd. 血管新生阻害物質の効果を予測する方法
PT1889836E (pt) 2005-08-24 2013-08-28 Eisai R&D Man Co Ltd Novo derivado de piridina e derivado de pirimidina (3)
US20090053236A1 (en) 2005-11-07 2009-02-26 Eisai R & D Management Co., Ltd. USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR
EP1964837A4 (en) 2005-11-22 2010-12-22 Eisai R&D Man Co Ltd Antitumor agent against multiple myeloma
AR059066A1 (es) 2006-01-27 2008-03-12 Amgen Inc Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf)
EP2062886B1 (en) 2006-08-23 2011-11-30 Eisai R&D Management Co., Ltd. Salt of phenoxypyridine derivative or crystal thereof and process for producing the same
WO2008026748A1 (fr) 2006-08-28 2008-03-06 Eisai R & D Management Co., Ltd. Agent antitumoral pour cancer gastrique non différencié
CA2675736A1 (en) 2007-01-19 2008-07-24 Eisai R&D Management Co., Ltd. Composition for treatment of pancreatic cancer
KR101445892B1 (ko) 2007-01-29 2014-09-29 에자이 알앤드디 매니지먼트 가부시키가이샤 미분화형 위암 치료용 조성물
JPWO2008111441A1 (ja) 2007-03-05 2010-06-24 協和発酵キリン株式会社 医薬組成物
WO2008108386A1 (ja) 2007-03-05 2008-09-12 Kyowa Hakko Kirin Co., Ltd. 医薬組成物
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
JP2009132660A (ja) 2007-11-30 2009-06-18 Eisai R & D Management Co Ltd 食道癌治療用組成物
MX2010008187A (es) 2008-01-29 2010-08-10 Eisai R&D Man Co Ltd Uso combinado de inhibidor de angiogenesis y taxano.
WO2009111648A1 (en) 2008-03-05 2009-09-11 Vicus Therapeutics, Llc Compositions and methods for mucositis and oncology therapies
CA2723617A1 (en) 2008-05-14 2009-11-19 Amgen Inc. Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer
CN102470133B (zh) 2009-08-19 2013-08-28 卫材R&D管理有限公司 含有喹啉衍生物的药物组合物
WO2011022335A1 (en) 2009-08-21 2011-02-24 Mount Sinai School Of Medicine Of New York University Methods of using cd44 fusion proteins to treat cancer
EP2680886B1 (en) 2011-02-28 2016-08-10 Calitor Sciences, LLC Substituted quinoline compounds
EP2741784B1 (en) 2011-03-02 2017-05-17 Board Of Regents, The University Of Texas System Tusc2 therapies
CN103476943A (zh) 2011-03-10 2013-12-25 普罗维克图斯药品公司 用于增强治疗癌症的局部和全身性免疫调节疗法的组合

Patent Citations (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5891996A (en) * 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
US4526988A (en) * 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US4742003A (en) * 1984-02-17 1988-05-03 Genentech, Inc. Human transforming growth factor
US5464826A (en) * 1984-12-04 1995-11-07 Eli Lilly And Company Method of treating tumors in mammals with 2',2'-difluoronucleosides
US4764454A (en) * 1985-12-20 1988-08-16 Fuji Photo Film Co., Ltd. Color photographic material with color forming ligand compounds and a method of processing
US6217866B1 (en) * 1988-09-15 2001-04-17 Rhone-Poulenc Rorer International (Holdings), Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US5180818A (en) * 1990-03-21 1993-01-19 The University Of Colorado Foundation, Inc. Site specific cleavage of single-stranded dna
US5747651A (en) * 1991-04-02 1998-05-05 The Trustees Of Princeton University Antibodies against tyrosine kinase receptor flk-1
US5750376A (en) * 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
US5487889A (en) * 1992-06-03 1996-01-30 The Metrohealth System Bandage for continuous application of biologicals
US6811779B2 (en) * 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
US5656454A (en) * 1994-10-04 1997-08-12 President And Fellows Of Harvard College Endothelial cell-specific enhancer
US5650376A (en) * 1994-11-07 1997-07-22 International Superconductivity Technology Center (Nd, Ba)3 Cu3 O7-d superconductor film
US5733913A (en) * 1994-11-14 1998-03-31 Blankley; Clifton John 6-Aryl pyrido 2,3-d! pyrimidines and naphthyridines for inhibiting protein tyrosine kinase mediated cellular proliferation
US5658374A (en) * 1995-02-28 1997-08-19 Buckman Laboratories International, Inc. Aqueous lecithin-based release aids and methods of using the same
US5624937A (en) * 1995-03-02 1997-04-29 Eli Lilly And Company Chemical compounds as inhibitors of amyloid beta protein production
US5770599A (en) * 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
US5792783A (en) * 1995-06-07 1998-08-11 Sugen, Inc. 3-heteroaryl-2-indolinone compounds for the treatment of disease
US6346398B1 (en) * 1995-10-26 2002-02-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US6156522A (en) * 1997-06-30 2000-12-05 University Of Maryland Baltimore Heparin binding--epidermal growth factor-like growth factor in the diagnosis of Interstitial Cystitis
US20070027318A1 (en) * 1999-01-22 2007-02-01 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives
US6797823B1 (en) * 1999-01-22 2004-09-28 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives
US7169789B2 (en) * 1999-01-22 2007-01-30 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives
US20060004017A1 (en) * 1999-02-10 2006-01-05 Astrazeneca Ab Quinazoline derivatives as angiogenesis inhibitors
US6476040B1 (en) * 1999-03-31 2002-11-05 Pfizer Inc. Processes and intermediates for preparing anti-cancer compounds
US6524583B1 (en) * 1999-04-28 2003-02-25 Board Of Regents, The University Of Texas System Antibody methods for selectively inhibiting VEGF
US6676941B2 (en) * 1999-04-28 2004-01-13 Board Of Regents, The University Of Texas System Antibody conjugate formulations for selectively inhibiting VEGF
US6534535B1 (en) * 1999-08-12 2003-03-18 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US20080241835A1 (en) * 1999-11-01 2008-10-02 Genentech, Inc. Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
US20020010203A1 (en) * 1999-12-22 2002-01-24 Ken Lipson Methods of modulating c-kit tyrosine protein kinase function with indolinone compounds
US7135466B2 (en) * 1999-12-24 2006-11-14 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives and drugs containing the same
US7005430B2 (en) * 1999-12-24 2006-02-28 Kyowa Hakko Kogyo Co., Ltd. Fused purine derivatives
US20040132727A1 (en) * 1999-12-24 2004-07-08 Teruyuki Sakai Quinoline and quinazoline derivatives and drugs containing the same
US20050176802A1 (en) * 2000-02-15 2005-08-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20020040127A1 (en) * 2000-06-09 2002-04-04 Yuqiu Jiang Compositions and methods for the therapy and diagnosis of colon cancer
US20060160832A1 (en) * 2000-10-20 2006-07-20 Yosuhiro Funahashi Nitrogen-containing aromatic derivatives
US20040053908A1 (en) * 2000-10-20 2004-03-18 Yasuhiro Funahashi Nitrogen-containing aromatic derivatives
US7612092B2 (en) * 2000-10-20 2009-11-03 Eisai R & D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7253286B2 (en) * 2000-10-20 2007-08-07 Eisai Co., Ltd Nitrogen-containing aromatic derivatives
US20030215523A1 (en) * 2000-10-31 2003-11-20 Yoichi Ozawa Medicinal compositions for concomitant use as anticancer agent
US20040034026A1 (en) * 2000-11-22 2004-02-19 Wood Jeannette M Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity
US20030087907A1 (en) * 2001-04-27 2003-05-08 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives having azolyl group
US6821987B2 (en) * 2001-04-27 2004-11-23 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives having azolyl group
US20040242506A1 (en) * 2001-08-09 2004-12-02 Barges Causeret Nathalie Claude Marianne Paroxetine glycyrrhizinate
US20030113713A1 (en) * 2001-09-10 2003-06-19 Meso Scale Technologies, Llc Methods and apparatus for conducting multiple measurements on a sample
US20040191254A1 (en) * 2001-10-09 2004-09-30 Fagin James Alexander Method of treatment of thyroid cancer
US20050049264A1 (en) * 2001-10-17 2005-03-03 Kirin Beer Kabushiki Kaisha Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
US7495104B2 (en) * 2001-10-17 2009-02-24 Kirin Beer Kabushiki Kaisha Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
US20050119303A1 (en) * 2002-03-05 2005-06-02 Eisai Co., Ltd Antitumor agent comprising combination of sulfonamide-containing heterocyclic compound with an angiogenesis inhibitor
US20040009965A1 (en) * 2002-06-14 2004-01-15 Agouron Pharmaceuticals, Inc. Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use
US20060004029A1 (en) * 2002-08-30 2006-01-05 Akihiko Tsuruoka Nitrogen-containing aromatic derivatives
US20050187236A1 (en) * 2002-08-30 2005-08-25 Akihiko Tsuruoka Nitrogen-containing aromatic derivatives
US20060057195A1 (en) * 2002-10-16 2006-03-16 Takeda Pharmaceutical Company Limited Stable solid preparations
US20040152759A1 (en) * 2002-11-15 2004-08-05 Sugen, Inc. Combination administration of an indolinone with a chemotherapeutic agent for cell proliferation disorders
US20050014727A1 (en) * 2003-03-05 2005-01-20 Muller George W. Diphenylethylene compounds and uses thereof
US20040253205A1 (en) * 2003-03-10 2004-12-16 Yuji Yamamoto c-Kit kinase inhibitor
US7435590B2 (en) * 2003-03-14 2008-10-14 Taisho Pharmaceutical Co., Ltd. Monoclonal antibody and hybridoma producing the same
US20070117842A1 (en) * 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
US20070032521A1 (en) * 2003-08-15 2007-02-08 Ab Science Use of c-kit inhibitors for treating type II diabetes
US20070037849A1 (en) * 2003-11-11 2007-02-15 Toshihiko Naito Urea derivative and process for producing the same
US20070078159A1 (en) * 2003-12-25 2007-04-05 Tomohiro Matsushima A crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amin ophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same
US7612208B2 (en) * 2003-12-25 2009-11-03 Eisai R&D Management Co., Ltd. Crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same
US20050277652A1 (en) * 2004-02-27 2005-12-15 Eisai Co., Ltd. Novel pyridine derivative and pyrimidine derivative
US20050272688A1 (en) * 2004-06-03 2005-12-08 Brian Higgins Combined treatment with gemcitabine and an epidermal growth factor receptor kinase inhibitor
US20060135486A1 (en) * 2004-09-13 2006-06-22 Eisai Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
US20080214604A1 (en) * 2004-09-17 2008-09-04 Hisao Furitsu Medicinal Composition
US20060079494A1 (en) * 2004-09-27 2006-04-13 Santi Daniel V Specific kinase inhibitors
US20090047278A1 (en) * 2005-02-28 2009-02-19 Eisai R & D Management Co., Ltd. Novel Combinational Use of Sulfonamide Compound
US20090047365A1 (en) * 2005-02-28 2009-02-19 Eisai R & D Management Co., Ltd. Novel Concomitant Use of Sulfonamide Compound with Anti-Cancer Agent
US20070004773A1 (en) * 2005-06-23 2007-01-04 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chiloro-4-(cycloproplylaminocarbonyl)aminophenoxy)-7-method-6-quinolinecarboxamide and process for preparing the same
US20100092490A1 (en) * 2005-08-02 2010-04-15 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US20070214604A1 (en) * 2006-03-20 2007-09-20 Samsung Electronics Co., Ltd Portable electronic device having triaxial hinge structure

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110118470A1 (en) * 2000-10-20 2011-05-19 Yasuhiro Funahashi Nitrogen-containing aromatic derivatives
US8372981B2 (en) 2000-10-20 2013-02-12 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US20100197911A1 (en) * 2000-10-20 2010-08-05 Eisai R&D Management Co., Ltd. Nitrogen-Containing Aromatic Derivatives
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US20090171112A1 (en) * 2003-11-11 2009-07-02 Toshihiko Naito Urea derivative and process for preparing the same
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
US20080214604A1 (en) * 2004-09-17 2008-09-04 Hisao Furitsu Medicinal Composition
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US9504746B2 (en) 2004-09-17 2016-11-29 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide
US20100105031A1 (en) * 2005-08-01 2010-04-29 Esai R & D Management Co., Ltd. Method for prediction of the efficacy of vascularization inhibitor
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US20080214557A1 (en) * 2005-09-01 2008-09-04 Eisai R&D Management Co., Ltd. Method for preparation of pharmaceutical composition having improved disintegratability and pharmaceutical composition manufactured by same method
US8815241B2 (en) 2005-11-07 2014-08-26 Eisai R&D Management Co., Ltd. Use of combination of anti-angiogenic substance and c-kit kinase inhibitor
US20090247576A1 (en) * 2005-11-22 2009-10-01 Eisai R & D Management Co., Ltd. Anti-tumor agent for multiple myeloma
US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US20110207756A1 (en) * 2006-05-18 2011-08-25 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US20090264464A1 (en) * 2006-08-28 2009-10-22 Eisai R & D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
US20100048620A1 (en) * 2007-01-29 2010-02-25 Yuji Yamamoto Composition for treatment of undifferentiated gastric cancer
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US20100324087A1 (en) * 2008-01-29 2010-12-23 Eisai R&D Management Co., Ltd. Combined use of angiogenesis inhibitor and taxane
US10525152B2 (en) 2009-10-09 2020-01-07 Signablok, Inc. Methods and compositions for targeted imaging
US20130123274A1 (en) * 2010-06-25 2013-05-16 Eisai R&D Management Co., Ltd. Antitumor Agent Using Compounds Having Kinase Inhibitory Effect in Combination
US9012458B2 (en) * 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
AU2011270165B2 (en) * 2010-06-25 2015-12-24 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
US8759530B2 (en) 2011-03-29 2014-06-24 Eisai R&D Management Co., Ltd. Method for producing phenoxypyridine derivative
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US9918950B2 (en) 2012-02-29 2018-03-20 University Hospitals Cleveland Medical Center Targeted treatment of anerobic cancer
US20160000913A1 (en) * 2012-02-29 2016-01-07 University Hospitals Cleveland Medical Center Targeted treatment of anerobic cancer
US9480745B2 (en) * 2012-02-29 2016-11-01 University Hospitals Cleveland Medical Center Targeted treatment of anerobic cancer
US9334239B2 (en) 2012-12-21 2016-05-10 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10407393B2 (en) 2014-08-28 2019-09-10 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US12083112B2 (en) 2015-03-04 2024-09-10 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist and a VEGFR/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US10487091B2 (en) 2015-10-05 2019-11-26 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11261199B2 (en) 2015-10-05 2022-03-01 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
US11230558B2 (en) 2015-10-05 2022-01-25 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11008341B2 (en) 2015-10-05 2021-05-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US10865214B2 (en) 2015-10-05 2020-12-15 The Trustees of Columbia University in they City of New York Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies
US11542259B2 (en) * 2018-01-26 2023-01-03 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders
US11673897B2 (en) 2018-01-26 2023-06-13 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders

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