# Patent

## Title
Combination of anti-angiogenic substance and anti-tumor platinum complex

## Abstract

The problems of the present invention are to find a pharmaceutical composition and a method for treating cancer that exhibit excellent anti-tumor effect. Excellent anti-tumor effect is achieved when 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy- 6 quinolinecarboxamide or an analogous compound thereof, a pharmacologically acceptable salt thereof or a solvate thereof is used in combination with an anti-tumor platinum complex.

## Background
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition and a kit comprising a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof (hereinafter, also referred to as the “compound of the invention”) used in combination with an anti-tumor platinum complex, to a method for treating cancer characterized by administering an effective amount of the pharmaceutical composition to a patient, to use of a compound of the invention for producing the pharmaceutical composition, and to a compound of the invention for the pharmaceutical composition, etc.
BACKGROUND OF THE INVENTION
Examples of substances conventionally used as chemotherapeutic agents for cancer include alkylating agents such as cyclophosphamide, antimetabolites such as methotrexate and fluorouracil, antibiotics such as adriamycin, mitomycin and bleomycin, plant-derived agents such as paclitaxel, vincristine and etoposide and metal complexes such as a platinum formulation. None of them, however, have satisfactory anti-tumor effect and thus there has been a strong need for development of a novel anti-tumor agent.
Formulations comprising an anti-tumor platinum complex as an active element are known as platinum formulations. Examples of such anti-tumor platinum complexes include cisplatin, carboplatin, nedaplatin, zeniplatin, enloplatin, lobaplatin, ormaplatin, loboplatin, sebriplatin, oxaliplatin, miboplatin and spiroplatin. Such platinum formulations have been approved and developed for application to testicular tumor, bladder cancer, renal pelvic/ureteral tumor, prostate cancer, ovarian cancer, head and neck cancer, non-small-cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, small cell lung cancer, malignant lymphoma, hepatocellular carcinoma or the like. In addition, combination therapy for various cancers has also been approved or developed by combining a platinum formulation including an anti-tumor platinum complex with various drugs, for example, with paclitaxel for non-small-cell lung cancer and with gemcitabine for non-small-cell lung cancer.
In a test by Abratt et al., a median survival period obtained with combined use of vinorelbine and carboplatin was 8.6 months while a median survival period obtained with combined use of vinorelbine and gemcitabine was 11.5 months. These results showed that combination therapy without a platinum formulation was better than combination therapy with a platinum formulation. That is to say that even if a platinum formulation has anti-tumor effect, the effect is not necessarily enhanced by simply combining with other drugs, and that selection of drugs for anti-tumor effect enhancement is yet unobvious (Non-patent references 1-9)
Furthermore, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is known as a VEGF receptor kinase inhibitory substance (Patent References 1-2).
However, there is no report as to whether or not pharmaceutical compositions comprising these substances in combination have any anti-tumor effect.
[Patent Reference 1] International Publication No. WO2002/32872
[Patent Reference 2] International Publication No. WO2005/063713
[Non-Patent Reference 1] Paclitaxel+carboplatin: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial (J. Clin Oncol., 14(7), 2054-2060, 1996)
[Non-Patent Reference 2] Paclitaxel+cisplatin: Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. (J. Clin Oncol., 18(19), 3390-3399, 2000)
[Non-Patent Reference 3] Vinorelbine+cisplatin: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. (J. Clin Oncol., 16(7), 2459-65, 1998)
[Non-Patent Reference 4] Gemcitabine+cisplatin: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. (J. Clin Oncol., 18(1)), 122-130, 2000)
[Non-Patent Reference 5] Gemcitabine+carboplatin: Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer. (Cancer Chemother Pharmacol., 60 (4), 601-607, 2007)
[Non-Patent Reference 6] CPT-11 (Irinotecan)+cisplatin: A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy. (Cancer, 107(4), 799-805, 2006) [Non-Patent Reference 7] J. Clin Oncol. 24(3):419-430, 2006
[Non-Patent Reference 8] Other: Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. (Ann Oncol., 18(2), 317-323, 2006) [Non-Patent Reference 9] Lung Cancer 2005, Vol. 49, No2, pp. 233-240
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
The present invention was achieved regarding the circumstances described above and the problems to be solved by the invention are to find a pharmaceutical composition and a kit that show excellent anti-tumor effect and a method for treating cancer.
Means for Solving the Problems
In order to solve the above-mentioned problems, the present inventors have gone through keen research and found that an angiogenesis inhibitory substance such as 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide shows excellent anti-tumor effect when combined with an anti-tumor platinum complex.
Thus, the present invention relates to the followings.
(1) A pharmaceutical composition comprising a compound represented by General Formula (1), a pharmacologically acceptable salt thereof or a solvate thereof in combination with an anti-tumor platinum complex.
(2) A kit comprising:
(a) at least one selected from the group consisting of a packaging container, an instruction and a package insert describing use of a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof in combination with an anti-tumor platinum complex; and
(b) a pharmaceutical composition comprising a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof
(3) A kit characterized by comprising a set of a formulation containing a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and a formulation containing an anti-tumor platinum complex.
(4) A pharmaceutical composition comprising a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof that is simultaneously or separately administered to a patient with an anti-tumor platinum complex.
(5) A method for treating cancer characterized by simultaneously or separately administering effective amounts of a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and an anti-tumor platinum complex to a patient.
(6) Use of a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof for producing a pharmaceutical composition in combination with an anti-tumor platinum complex.
(7) A compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof for a pharmaceutical composition in combination with an anti-tumor platinum complex.
The compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof is as follows:




[wherein, R1 represents a group represented by Formula —V1—V2—V3 (wherein, V1 represents an optionally substituted C1-6 alkylene group; V2 represents a single bond, an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, a group represented by Formula —CONR6—, a group represented by Formula —SO2NR6—, a group represented by Formula —NR6SO2—, a group represented by Formula —NR6CO— or a group represented by Formula —NR6— (wherein, R6 represents a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-8 cycloalkyl group); V3 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group);

    R2 represents a cyano group, an optionally substituted C1-6 alkoxy group, a carboxyl group, an optionally substituted C2-7 alkoxycarbonyl group or a group represented by Formula —CONVa11V12 (wherein, Van represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group; Va12 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group, an optionally substituted 3-10-membered nonaromatic heterocyclic group, a hydroxyl group, an optionally substituted C1-6 alkoxy group or an optionally substituted C3-8 cycloalkoxy group);
    Y1 represents a group represented by either one of the following formulae






(wherein, R7 and R8 each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C1-6 alkylthio group, a formyl group, an optionally substituted C2-7 acyl group, an optionally substituted C2-7 alkoxycarbonyl group or a group represented by Formula —CONVd1Vd2 (wherein, Vd1 and Vd2 each independently represent a hydrogen atom or an optionally substituted C1-6 alkyl group);

    W1 and W2 each independently represent an optionally substituted carbon atom or nitrogen atom);
    R3 and R4 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C2-7 acyl group or an optionally substituted C2-7 alkoxycarbonyl group; and
    R5 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-5 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group],

a pharmacologically acceptable salt thereof or a solvate thereof.



The anti-tumor platinum complex is, for example, cisplatin, carboplatin, nedaplatin, zeniplatin, enloplatin, lobaplatin, ormaplatin, loboplatin, sebriplatin, oxaliplatin, miboplatin or spiroplatin
Furthermore, the present invention preferably relates to the followings.
(8) A pharmaceutical composition comprising 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof in combination with cisplatin or carboplatin.
(9) A kit comprising:
(a) at least one selected from the group consisting of a packaging container, an instruction and a package insert describing use of 4-(3-chloro-4-(cyclopropylaminocarbonyliaminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof in combination with cisplatin or carboplatin; 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
(10) A kit characterized by 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 cisplatin or carboplatin.
(11) A pharmaceutical composition comprising 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof that is simultaneously or separately administered to a patient with cisplatin or carboplatin.
(12) A method for treating cancer characterized by simultaneously or separately administering effective amounts of 4-(3-chloro-4-(cyclopropylaminocarbonyliaminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof, and cisplatin or carboplatin to a patient.
(13) Use of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof for producing a pharmaceutical composition in combination with cisplatin or carboplatin.
(14) 4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof for a pharmaceutical composition in combination with cisplatin or carboplatin.
Effect of the Invention
The present invention provides a pharmaceutical composition and a kit that exhibit excellent anti-tumor effect. Specifically, the present invention provides a pharmaceutical composition and a kit comprising a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof in combination with an anti-tumor platinum complex. The pharmaceutical composition and the kit of the invention can be used for the treatment of cancer.



BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows the effect of combination use of E7080 and cisplatin on subcutaneous transplanted (in vivo) models of non-small-cell lung cancer cell lines (A549). In FIG. 1, E7080 represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
FIG. 2 shows the effect of combination use of E7080 and cisplatin on subcutaneous transplanted (in vivo) models of non-small-cell lung cancer cell lines (A549). In FIG. 2, E7080 represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
FIG. 3 shows the effect of combination use of E7080 and cisplatin on subcutaneous transplanted (in vivo) models of non-small-cell lung cancer cell lines (A549). In FIG. 3, E7080 represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
FIG. 4 shows the effect of combination use of E7080 and carboplatin on subcutaneous transplanted (in vivo) models of non-small-cell lung cancer cell lines (A549). In FIG. 4, E7080 represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
FIG. 5 shows the effect of combination use of E7080 and carboplatin on subcutaneous transplanted (in vivo) models of non-small-cell lung cancer cell lines (A549). In FIG. 5, E7080 represents 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.



BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, embodiments of the present invention will be described. The following embodiments are examples provided for illustrating the present invention, and the present invention is not intended to be limited thereto. The present invention may be carried out in various embodiments without departing from the spirit of the invention.
The publications, laid-open patent publications, patent publications and other patent documents cited herein are entirely incorporated herein by reference. The present specification incorporates the content of the specification of U.S. provisional application No. 60/986,641 (filed on 9 Nov., 2007) based on which the present application claims priority.
1. Compound
As used herein, a “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Preferable examples of a “halogen atom” include a fluorine atom and a chlorine atom.
As used herein, a “C1-6 alkyl group” refers to a linear or branched alkyl group with a carbon number of 1-6, specific examples including a methyl group, an ethyl group, a 1-propyl group (n-propyl group), a 2-propyl group (i-propyl group), a 2-methyl-1-propyl group (1-butyl group), a 2-methyl-2-propyl group (t-butyl group), a 1-butyl group (n-butyl group), a 2-butyl group (s-butyl group), a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-1-butyl group, a 3-methyl-1-butyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 2,2-dimethyl-1-propyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a 3-methyl-1-pentyl group, a 4-methyl-1-pentyl group, a 2-methyl-2-pentyl group, a 3-methyl-2-pentyl group, a 4-methyl-2-pentyl group, a 2-methyl-3-pentyl group, a 3-methyl-3-pentyl group, a 2,3-dimethyl-1-butyl group, a 3,3-dimethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, a 2-ethyl-1-butyl group, a 3,3-dimethyl-2-butyl group and a 2,3-dimethyl-2-butyl group.
Preferable examples of a “C1-6 alkyl group” include a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-butyl group and a 2-butyl group.
As used herein, a “C1-6 alkylene group” refers to a divalent group derived from a “C1-6 alkyl group” defined above by removing any one hydrogen atom therefrom, specific examples including a methylene group, a 1,2-ethylene group, a 1,1-ethylene group, a 1,3-propylene group, a tetramethylene group, a pentamethylene group and a hexamethylene group.
As used herein, a “C2-6 alkenyl group” refers to a linear or branched alkenyl group having one double bond and a carbon number of 2-6, specific examples including an ethenyl group (vinyl group), a 1-propenyl group, a 2-propenyl group (allyl group), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a pentenyl group and a hexenyl group.
As used herein, a “C2-6 alkynyl group” refers to a linear or branched alkynyl group having one triple bond and a carbon number of 2-6, specific examples including an ethinyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a pentynyl group and a hexynyl group.
As used herein, a “C3-8 cycloalkyl group” refers to a monocyclic or bicyclic saturated aliphatic hydrocarbon group with a carbon number of 3-8, specific examples including a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a bicyclo[2.1.0]pentyl group, a bicyclo[3.1.0]hexyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[4.1.0]heptyl group, a bicyclo[2.2.1]heptyl group (norbornyl group), a bicyclo[3.3.0]octyl group, a bicyclo[3.2.1]octyl group and a bicyclo[2.2.2]octyl group.
Preferable examples of a “C3-8 cycloalkyl group” include a cyclopropyl group, a cyclobutyl group and a cyclopentyl group.
As used herein, a “C6-10 aryl group” refers to an aromatic hydrocarbon cyclic group with a carbon number of 6-10, specific examples including a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an indenyl group and an azulenyl group.
A preferable example of a “C6-10 aryl group” includes a phenyl group.
As used herein, a “heteroatom” refers to a nitrogen atom, an oxygen atom or a sulfur atom.
As used herein, a “5-10-membered heteroaryl group” refers to an aromatic cyclic group having 5-10 atoms forming the ring and 1-5 heteroatoms included in the atoms forming the ring, specific examples including a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, a furazanyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a triazinyl group, a purinyl group, a pteridinyl group, a quinolyl group, an isoquinolyl group, a naphthiridinyl group, a quinoxalinyl group, a cinnolinyl group, a quinazolinyl group, a phthalazinyl group, an imidazopyridyl group, an imidazothiazolyl group, an imidazoxazolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a pyrrolopyridyl group, a thienopyridyl group, a furopyridyl group, a benzothiadiazolyl group, a benzoxadiazolyl group, a pyridopyrimidinyl group, a benzofuryl group, a benzothienyl group and a thienofuryl group.
Preferable examples of a “5-10-membered heteroaryl group” include a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, an isothiazolyl group, a pyridyl group and a pyrimidinyl group.
As used herein, a “3-10-membered nonaromatic heterocyclic group”:
(a) has 3-10 atoms forming the ring;
(b) has 1-2 heteroatoms included in the atoms forming the ring;
(c) may include 1-2 double bonds in the ring;
(d) may include 1-3 carbonyl groups, sulfinyl groups or sulfonyl groups in the ring; and
(e) refers to a nonaromatic monocyclic or bicyclic group, where when a nitrogen atom is included in the atoms forming the ring, the nitrogen atom may have a bond.
Specific examples include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, an azocanyl group, a piperazinyl group, a diazepanyl group, a diazocanyl group, a diazabicyclo[2.2.1]heptyl group, a morpholinyl group, a thiomorpholinyl group, a 1,1-dioxothiomorpholinyl group, an oxiranyl group, an oxetanyl group, a tetrahydrofuryl group, a dioxoranyl group, a tetrahydropyranyl group, a dioxanyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, an oxazolidinyl group and a thiazolidinyl group.
Preferable examples of a “3-10-membered nonaromatic heterocyclic group” include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, a piperazinyl group, a diazepanyl group, a morpholinyl group, a thiomorpholinyl group, a 1,1-dioxothiomorpholinyl group, a tetrahydrofuryl group and a tetrahydropyranyl group.
As used herein, a “C1-6 alkoxy group” refers to a group in which an oxygen atom is bound to the terminal of a “C1-6 alkyl group” defined above, specific examples including a methoxy group, an ethoxy group, a 1-propoxy group (n-propoxy group), a 2-propoxy group (1-propoxy group), a 2-methyl-1-propoxy group (1-butoxy group), a 2-methyl-2-propoxy group (t-butoxy group), a 1-butoxy group (n-butoxy group), a 2-butoxy group (s-butoxy group), a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-1-butoxy group, a 3-methyl-1-butoxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group, a 2,2-dimethyl-1-propoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, a 3-methyl-1-pentyloxy group, a 4-methyl-1-pentyloxy group, a 2-methyl-2-pentyloxy group, a 3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a 2-methyl-3-pentyloxy group, a 3-methyl-3-pentyloxy group, a 2,3-dimethyl-1-butoxy group, a 3,3-dimethyl-1-butoxy group, a 2,2-dimethyl-1-butoxy group, a 2-ethyl-1-butoxy group, a 3,3-dimethyl-2-butoxy group and a 2,3-dimethyl-2-butoxy group.
Preferable examples of a “C1-6 alkoxy group” include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 2-methyl-1-propoxy group, a 2-methyl-2-propoxy group, a 1-butoxy group and a 2-butoxy group.
As used herein, a “C1-6 alkylthio group” refers to a group in which a sulfur atom is bound to the terminal of a “C1-6 alkyl group” defined above, specific examples including a methylthio group, an ethylthio group, a 1-propylthio group (n-propylthio group), a 2-propylthio group (i-propylthio group), a 2-methyl-1-propylthio group (1-butylthio group), a 2-methyl-2-propylthio group (t-butylthio group), a 1-butylthio group (n-butylthio group), a 2-butylthio group (s-butylthio group), a 1-pentylthio group, a 2-pentylthio group, a 3-pentylthio group, a 2-methyl-1-butylthio group, a 3-methyl-1-butylthio group, a 2-methyl-2-butylthio group, a 3-methyl-2-butylthio group, a 2,2-dimethyl-1-propylthio group, a 1-hexylthio group, a 2-hexylthio group, a 3-hexylthio group, a 2-methyl-1-pentylthio group, a 3-methyl-1-pentylthio group, a 4-methyl-1-pentylthio group, a 2-methyl-2-pentylthio group, a 3-methyl-2-pentylthio group, a 4-methyl-2-pentylthio group, a 2-methyl-3-pentylthio group, a 3-methyl-3-pentylthio group, a 2,3-dimethyl-1-butylthio group, a 3,3-dimethyl-1-butylthio group, a 2,2-dimethyl-1-butylthio group, a 2-ethyl-1-butylthio group, a 3,3-dimethyl-2-butylthio group and a 2,3-dimethyl-2-butylthio group.
Preferable examples of a “C1-6 alkylthio group” include a methylthio group, an ethylthio group, a 1-propylthio group (n-propylthio group), a 2-propylthio group (1-propylthio group), a 2-methyl-1-propylthio group (1-butylthio group), a 2-methyl-2-propylthio group (t-butylthio group), a 1-butylthio group (n-butylthio group) and a 2-butylthio group (s-butylthio group).
As used herein, a “C3-8 cycloalkoxy group” refers to a group in which an oxygen atom is bound to the terminal of a “C3-8 cycloalkyl group” defined above, specific examples including a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, a bicyclo[2.1.0]pentyloxy group, a bicyclo[3.1.0]hexyloxy group, a bicyclo[2.1.1]hexyloxy group, a bicyclo[4.1.0]heptyloxy group, a bicyclo[2.2.1]heptyloxy group (norbornyloxy group), a bicyclo[3.3.0]octyloxy group, a bicyclo[3.2.1]octyloxy group and a bicyclo[2.2.2]octyloxy group.
Preferable examples of a “C3-8 cycloalkoxy group” include a cyclopropoxy group, a cyclobutoxy group and a cyclopentyloxy group.
As used herein, a “mono-C1-6 alkylamino group” refers to a group in which one hydrogen atom in an amino group is substituted with a “C1-6 alkyl group” defined above, specific examples including a methylamino group, an ethylamino group, a 1-propylamino group (n-propylamino group), a 2-propylamino group (i-propylamino group), a 2-methyl-1-propylamino group (1-butylamino group), a 2-methyl-2-propylamino group (t-butylamino group), a 1-butylamino group (n-butylamino group), a 2-butylamino group (s-butylamino group), a 1-pentylamino group, a 2-pentylamino group, a 3-pentylamino group, a 2-methyl-1-butylamino group, a 3-methyl-1-butylamino group, a 2-methyl-2-butylamino group, a 3-methyl-2-butylamino group, a 2,2-dimethyl-1-propylamino group, a 1-hexylamino group, a 2-hexylamino group, a 3-hexylamino group, a 2-methyl-1-pentylamino group, a 3-methyl-1-pentylamino group, a 4-methyl-1-pentylamino group, a 2-methyl-2-pentylamino group, a 3-methyl-2-pentylamino group, a 4-methyl-2-pentylamino group, a 2-methyl-3-pentylamino group, a 3-methyl-3-pentylamino group, a 2,3-dimethyl-1-butylamino group, a 3,3-dimethyl-1-butylamino group, a 2,2-dimethyl-1-butylamino group, a 2-ethyl-1-butylamino group, a 3,3-dimethyl-2-butylamino group and a 2,3-dimethyl-2-butylamino group.
As used herein, a “di-C1-6 alkylamino group” refers to a group in which two hydrogen atoms in an amino group are substituted with identical or different “C1-6 alkyl groups” defined above, specific examples including a N,N-dimethyl amino group, a N,N-diethylamino group, a N,N-di-n-propylamino group, a N,N-di-1-propylamino group, a N,N-di-n-butylamino group, a N,N-di-1-butylamino group, a N,N-di-s-butylamino group, a N,N-di-t-butylamino group, a N-ethyl-N-methylamino group, a N-n-propyl-N-methylamino group, a N-1-propyl-N-methylamino group, a N-n-butyl-N-methylamino group, a N-1-butyl-N-methylamino group, a N-s-butyl-N-methylamino group and a N-t-butyl-N-methylamino group.
As used herein, a “C2-7 acyl group” refers to a carbonyl group bound with a “C1-6 alkyl group” defined above, specific examples including an acetyl group, a propionyl group, an isopropionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group and a pivaloyl group.
As used herein, a “C2-7 alkoxycarbonyl group” refers to a carbonyl group bound with a “C1-6 alkoxy group” defined above, specific examples including a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propyloxycarbonyl group, a 2-propyloxycarbonyl group, a 2-methyl-2-propoxy group and a 2-methyl-2-propoxycarbonyl group.
As used herein, “that may have a substituent (optionally substituted)” means “that may have one or more substituents in any combination at substitutable positions”, and specific examples of the substituent include a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a formyl group, a carboxyl group, an amino group, a silyl group, a methanesulfonyl group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5-10-membered heteroaryl group, a 3-10-membered nonaromatic heterocyclic group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C3-8 cycloalkoxy group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a C2-7 acyl group and a C2-7 alkoxycarbonyl group. In this case, the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group, the C3-8 cycloalkyl group, the C6-10 aryl group, the 5-10-membered heteroaryl group, the 3-10-membered nonaromatic heterocyclic group, the C1-6 alkoxy group, the C1-6 alkylthio group, the C3-8 cycloalkoxy group, the mono-C1-6 alkylamino group, the di-C1-6 alkylamino group, the C2-7 acyl group and the C2-7 alkoxycarbonyl group may each independently have 1-3 groups selected from the group consisting of the following substituent groups.
<Substituent Groups>
A halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5-10-membered heteroaryl group, a 3-10-membered nonaromatic heterocyclic group, a C1-6 alkoxy group and a C1-6 alkylthio group.
(A) Compound of the Invention
According to the present invention, a compound represented by General Formula (I) is as follows.




(i) R1 
R1 represents a group represented by Formula —V1—V2—V3 (wherein, V1 represents an optionally substituted C1-6 alkylene group; V2 represents a single bond, an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, a group represented by Formula —CONR6—, a group represented by Formula —SO2NR6—, a group represented by Formula —NR6SO2—, a group represented by Formula —NR6CO— or a group represented by Formula —NR6— (wherein, R6 represents a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-8 cycloalkyl group); V3 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group).
A preferable example of R1 includes a C1-6 alkyl group provided that R1 may have a substituent selected from a 3-10-membered nonaromatic heterocyclic group, a hydroxyl group, a C1-6 alkoxy group, an amino group, a mono-C1-6 alkylamino group and a di-C1-6 alkylamino group which may have a C1-6 alkyl group.
More preferable examples of R1 include a methyl group and a group represented by any one of the following formulae




(wherein, Ra3 represents a methyl group; Ra1 represents a hydrogen atom or a hydroxyl group; Ra2 represents a methoxy group, an ethoxy group, a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, a dimethylamino group or a diethylamino group).

Still more preferable examples of R1 include a methyl group and a 2-methoxyethyl group.
(ii) R2 
R2 represents a cyano group, an optionally substituted C1-6 alkoxy group, a carboxyl group, an optionally substituted C2-7 alkoxycarbonyl group or a group represented by Formula —CONVa11Va12 (wherein, Va11 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group; Va12 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group, an optionally substituted 3-10-membered nonaromatic heterocyclic group, a hydroxyl group, an optionally substituted C1-6 alkoxy group or an optionally substituted C3-8 cycloalkoxy group).
Preferable examples of R2 include a cyano group or a group represented by Formula —CONVa11Va12 (wherein, Va11 and Va12 have the same meaning as defined above).
More preferable examples of R2 include a cyano group or a group represented by Formula —CONHVa16 (wherein, Va16 represents a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group or a C3-8 cycloalkoxy group, provided that Va16 may have a substituent selected from a halogen atom, a cyano group, a hydroxyl group and a C1-6 alkoxy group).
A still more preferable example of R2 includes a group represented by Formula —CONHVa17 (wherein, Va17 represents a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group).
The most preferable example of R2 includes a group represented by Formula —CONHVa18 (wherein, Va18 represents a hydrogen atom, a methyl group or a methoxy group).
(iii) Y1 
Y1 represents a group represented by the following formula




(wherein, R7 and R8 each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C1-6 alkylthio group, a formyl group, an optionally substituted C2-7 acyl group, an optionally substituted C2-7 alkoxycarbonyl group or a group represented by Formula —CONVd1Vd2 (wherein, Vdl and Vd2 each independently represent a hydrogen atom or an optionally substituted C1-6 alkyl group);

W1 and W2 each independently represent an optionally substituted carbon atom or nitrogen atom).
A preferable example of Y1 includes a group represented by the following formula




(wherein, R71 represents a hydrogen atom or a halogen atom).

(iv) R3 and R4 
R3 and R4 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C2-7 acyl group or an optionally substituted C2-7 alkoxycarbonyl group.
A preferable example of R3 and R4 includes a hydrogen atom.
(v) R5 
R5 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5-10-membered heteroaryl group or an optionally substituted 3-10-membered nonaromatic heterocyclic group.
Preferable examples of R5 include a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group and a C6-10 aryl group (provided that R5 may have a substituent selected from a halogen atom and a methanesulfonyl group).
More preferable examples of R5 include a methyl group, an ethyl group and a cyclopropyl group.
Moreover, preferable examples of the compound represented by General Formula (I) include:
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea;
N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea;
N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea;
N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea;
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide;
N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;

    4-(3-fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide;


4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide;
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide;
4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide;
4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide;
N-(2-fluoro-4-((6-carbamoyl-7-methoxy-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea;
N6-(2-hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino)ethoxy)-6-quinolinecarboxamide;
4-(3-chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-((2R)tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide;
N6-methyl-4-(3-chloro-4-(((ethylamino) carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide;
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea;
N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea;
4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-(2-ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(4-(3-ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylic acid (2-cyanoethyl)amide; and
N-(4-(6-(2-cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea.
More preferable examples of the compound represented by General Formula (I) include:
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide; and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.
A still more preferable example of the compound represented by General Formula (I) includes 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (see Formula (II)).




The most preferable example of the compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof includes methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
A compound represented by General formula (I) may be produced by a known method such as methods described in International Publication Nos. 02/32872 (WO02/32872) and 2005/063713 (WO2005/063713).
(B) Anti-Tumor Platinum Complex
According to the present invention, an anti-tumor platinum complex (a platinum complex having anti-tumor effect) is, for example, cisplatin, carboplatin, nedaplatin, zeniplatin, enloplatin, lobaplatin, ormaplatin, loboplatin, sebriplatin, oxaliplatin, miboplatin or spiroplatin, preferably cisplatin or carboplatin, and particularly preferably carboplatin.
These anti-tumor platinum complexes may be produced according to a known method.
These anti-tumor platinum complexes are also available by purchasing commercially-available products. For example, cisplatin is commercially available under the trade names of Randa (Registered Trademark) from Nippon Kayaku Co., Ltd., Platosin (Registered Trademark) from Pfizer Japan Inc., Cisplamerck (Registered Trademark) from Merck Japan and Briplatin (Registered Trademark) from Bristol-Myers Squibb. Carboplatin is commercially available under the trade names of Paraplatin (Registered Trademark) from Bristol-Myers Squibb and Carbomerck (Registered Trademark) from Merck Japan. Nedaplatin is commercially available under a trade name of Aqupla (Registered Trademark) from Shionogi & Co., Ltd. Oxaliplatin is commercially available under the trade names of Elplat (Registered Trademark) or Eloxatin (Registered Trademark) from Yakult Honsha, Co., Ltd. Miboplatin is commercially available as miboplatin hydrochloride or under a trade name of Lobaplatin (Registered Trademark) from Chugai Pharmaceutical Co., Ltd.
According to the present invention, the compound represented by General Formula (I), and/or the anti-tumor platinum complex may form a pharmacologically acceptable salt with acid or base. The compound of the invention comprises these pharmacologically acceptable salts. Examples of salts formed with acids include inorganic acid salts such as hydrochloride salts, hydrobromate salts, sulfate salts and phosphate salts, 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. Examples of salts formed with bases 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 salts.
Furthermore, according to the present invention, the compound represented by General Formula (I) and/or an anti-tumor platinum complex also comprise, if any, a solvate or an optical isomer thereof. Examples of solvates include hydrates and nonhydrates, preferably hydrates. Examples of solvents include water, alcohols (for example, methanol, ethanol and n-propanol) and dimethylformamide.
Moreover, according to the present invention, the compound of the invention and/or an anti-tumor platinum complex may be crystalline or amorphous. If a crystalline polymorph is present, it may exist as one type of any crystalline or mixture thereof.
According to the present invention, the compound of the invention and/or an anti-tumor platinum complex also comprises compounds that generate the compound of the invention and/or an anti-tumor platinum complex by undergoing metabolism such as oxidation, reduction and hydrolysis in vivo.
2. Pharmaceutical Composition, Kit and Method for Treating Cancer
The present invention relates to a pharmaceutical composition, a kit, a method for treating cancer and the like, characterized in that a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof (compound of the invention) is combined with an anti-tumor platinum complex.
According to the present invention, the term “combination” refers to a combination of compounds for combination use, and includes both modes where separate substances are used in combination upon administration or where they are provided as a mixture (compounding agent). According to the present invention, “combination use” does not only refer to exactly the same administration timing of the compound of the invention and an anti-tumor platinum complex. As long as the compound of the invention and the anti-tumor platinum complex are administered during a single administration schedule, both simultaneous and separate administrations thereof can be referred to as “combination use” When they are administered separately, the anti-tumor platinum complex may be administered after the compound of the invention. Alternatively, the compound of the invention may be administered after the anti-tumor platinum complex.
A pharmaceutical composition and/or a kit of the invention is useful as a pharmaceutical composition and/or a kit for treating cancer.
A pharmaceutical composition and/or a kit of the invention may be used as a therapeutic agent for cancer.
According to the present invention, a therapeutic agent for cancer comprises those that contain an anti-tumor drug, a drug for improving prognosis of cancer, a drug for preventing cancer recurrence, and an antimetastatic drug or the like. Pleferably, an anti-tumor drug can be used.
The effect of cancer treatment can be confirmed by observation of X-ray pictures, CT or the like, histopathologic diagnosis by biopsy, tumor marker value or the like.
A pharmaceutical composition and/or a kit of the invention may be administered to mammals (e.g., human, rat, rabbit, sheep, pig, cattle, cat, dog or monkey).
Examples of the types of cancers targeted by the therapeutic agent for cancer include, but not limited to, brain tumors (including hypophysial adenoma and glioma), head and neck cancer, cervical cancer, jaw cancer, maxillary cancer, submandibular gland cancer, oral cancers (including tongue cancer, mouth floor cancer, gingival cancer, buccal mucosa cancer and hard palate cancer), salivary gland cancer, sublingual gland cancer, parotid gland cancer, nasal cavity cancer, paranasal sinus cancers (including maxillary sinus cancer, frontal sinus cancer, ethmoid sinus cancer and sphenoid sinus cancer), pharyngeal cancers (including supraglottic cancer, glottic cancer and subglottic cancer), esophageal cancer, lung cancers (including bronchogenic cancer, non-small-cell lung cancers (including lung adenocarcinoma, squamous cell carcinoma and large cell lung cancer), small cell lung cancers (including oat cell (lymphoid) and intermediate cell types) and mixed small/large cell lung cancers), breast cancer, pancreas cancers (including pancreatic duct cancer), gastric cancers (including scirrhous gastric cancer and undifferentiated gastric cancer), biliary tract cancers (including bile duct cancer and gallbladder cancer), small intestinal or duodenal cancer, colorectal cancers (including colon cancer, rectal cancer, cecal cancer, sigmoid colon cancer, ascending colon cancer, transverse colon cancer and descending colon cancer), bladder cancer, renal cancers (including renal cell cancer), hepatic cancers (including hepatocellular cancer and intrahepatic bile duct cancer), prostate cancer, uterine cancers (including uterine cervix cancer and uterine body cancer), ovarian cancer, thyroid gland cancer, pharyngeal cancers (including nasopharyngeal cancer, oropharyngeal cancer and hypopharyngeal cancer), sarcomas (e.g., osteosarcoma, chondrosarcoma, Kaposi's sarcoma, myosarcoma, angiosarcoma, fibrosarcoma, etc.), malignant lymphomas (including Hodgkin's lymphoma and non-Hodgkin's lymphoma), leukemias (e.g., chronic myelocytic leukemia (CML), acute myelocytic leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), lymphoma, multiple myeloma (MM) and myelodysplastic syndrome), skin cancers (basal cell cancer, squamous cell carcinoma, malignant melanoma, mycosis fungoides, Sezary's syndrome, solar keratosis, Bowen's disease and Paget's disease) and melanoma.
The pharmaceutical composition and/or the kit of the invention may be administered orally or parenterally. Upon use of the pharmaceutical composition and/or the kit of the invention, the dosage 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 type of the pharmaceutical formulation and the type of the active ingredient. Usually, but without limitation, the dosage is 0.1-1000 mg/day, preferably 0.5-100 mg/day and more preferably 1-30 mg/day for an adult (weight 60 kg), which may be administered usually once to three times a day.
An anti-tumor platinum complex may be administered according to known clinical practice. The dosage and dosing schedule may be altered according to a specific symptom or all symptoms of the patient's disease. The dosage may appropriately be reduced according to age, symptoms or incidence of side effects. Upon use of the pharmaceutical composition and/or the kit of the invention, an anti-tumor platinum complex may usually, but not limited, be administered for 10-2000 mg/m2/day, preferably 50-1000 mg/m2/day and more preferably 100-500 mg/m2/day for an adult, which may be administered usually once to three times a day. The dosage needs to be reduced if undue toxicity occurs in the patient. The dosage and dosing schedule may be altered when one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosing schedule may be determined by the physician in charge of the treatment of the specific patient.
The amount of the compound of the invention used is not particularly limited, and differs depending on the individual combination with the anti-tumor platinum complex. For example, the amount of the compound of the invention is about 0.0001-10000 times (weight ratio), more preferably about 0.001-1000 times (weight ratio) of the amount of the anti-tumor platinum complex.
More specifically, when the compound of the invention is combined with cisplatin, the dosage of the compound of the invention is not particularly limited and may be administered, for example, for 0.1-1000 mg/day, preferably 0.5-100 mg/day and more preferably 1-30 mg/day for an adult (60 kg) and cisplatin may be administered for 10-2000 mg/m2/day, preferably 50-1000 mg/m2/day and more preferably 100-500 mg/m2/day for an adult (60 kg) while the dosage of the compound of the invention is set to about 0.0001-10000 times (weight ratio), more preferably about 0.001-1000 times (weight ratio) of that of cisplatin.
Furthermore, when the compound of the invention is combined with carboplatin, the dosage of the compound of the invention is not particularly limited and may be administered, for example, for 0.1-1000 mg/day, preferably 0.5-100 mg/day and more preferably 1-30 mg/day for an adult (60 kg) and carboplatin may be administered for 10-2000 mg/m2/day, preferably 50-1000 mg/m2/day and more preferably 100-500 mg/m2/day for an adult (60 kg) while the dosage of the compound of the invention is set to about 0.0001-10000 times (weight ratio), more preferably about 0.001-1000 times (weight ratio) of that of carboplatin.
The pharmaceutical composition of the invention may be made into a solid oral formulation, an injection or the like.
Furthermore, the compound of the invention and the anti-tumor platinum complex included in the kit of the invention may each be made into a solid oral formulation, an injection or the like.
The 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 anti-tumor platinum complex.
In order to prepare a solid oral formulation, the principal agent may be added with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent or the like, and then made into a tablet, a coated tablet, granule, subtle granule, powder, a capsule or the like according to a conventional method.
Examples of excipients used include lactose, cornstarch, sucrose, glucose, sorbit, crystalline cellulose and silicon dioxide; examples of binders used include polyvinyl alcohol, ethyl cellulose methyl cellulose, gum arabic, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; examples of lubricants include magnesium stearate, talc and silica; examples of colorants include those that are allowed to be added to pharmaceutical preparations; examples of flavoring agents include cocoa powder, menthol, aromatic acid, peppermint oil, camphor and cinnamon powder. Of course, if necessary, these tablets and granule may be coated appropriately with sugar coating, gelatin coating or else.
When an injection is to be prepared, if necessary, the principal agent may be added with a pH adjuster, a buffer, a suspending agent, a solubilizing aid, a stabilizer, an isotonizing agent, a preservative or the like, and may be made into an injectable form for an intravenous, subcutaneous or intramuscular injection by a conventional technique. In this case, if necessary, it may be prepared into a lyophilized form by a conventional technique.
Examples of suspending agents may include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, powdered tragacanth, sodium carboxy methyl cellulose and polyoxyethylene sorbitan monolaurate.
Examples of solubilizing aids may include polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotine acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and ethyl ester of castor oil fatty acid.
Examples of stabilizers may include sodium sulfite and sodium metasulfite; and examples of preservatives may include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
In the kit of the invention, the compound of the invention or a formulation containing the compound of the invention may be mixed with a formulation containing the anti-tumor platinum complex, or they may be kept separately and packed together. The order of administrations of the above formulations is not particularly limited, and they may be administered simultaneously or one after the other.
In addition to the compound of the invention and the anti-tumor platinum complex, the pharmaceutical composition and/or the kit of the invention can also comprise a packaging container, an instruction, a package insert or the like. The packaging container, the instruction, the package insert or the like may be printed with description of a combination for using the substances in combination, and description of usage and dose for using separate substances in combination upon administration or for use of them as a mixture. The usage and dose may be described by referring to the related description above.
The kit of the invention may comprise. (a) at least one selected from the group consisting of a packaging container, an instruction and a package insert describing combination use of the compound of the invention with the anti-tumor platinum complex; and (b) a pharmaceutical composition comprising the compound of the invention. This kit is useful for treating cancer. The pharmaceutical composition comprising the compound of the invention is useful for treating cancer. The packaging container, the instruction, the package insert of the like may be printed with description for using the compounds in combination, and description of usage and dose for using separate substances in combination upon administration or for use of them as a mixture. The usage and dose may be described by referring to the related description above.
The present invention also comprises use of a compound of the invention for producing a pharmaceutical composition in combination with an anti-tumor platinum complex. According to the use of the invention, the pharmaceutical composition is useful for treating cancer.
The present invention also comprises a compound of the invention for a pharmaceutical composition in combination with an anti-tumor platinum complex. The pharmaceutical composition is useful for treating cancer. The present invention also comprises a compound of the invention for preventing or treating cancer in combination with an anti-tumor platinum complex. The route and the method for administering the compound of the invention and the anti-tumor platinum complex are not particularly limited but reference may be made to the description of the pharmaceutical composition and/or kit of the invention above.
The present invention also comprises a method for preventing or treating cancer comprising simultaneously or separately administering effective amounts of a compound of the invention and an anti-tumor platinum complex to a patient. According to the method of the invention for preventing or treating cancer, the route and the method for administering the compound of the invention and the anti-tumor platinum complex are not particularly limited but reference may be made to the description of the pharmaceutical composition and/or kit of the invention above.
The present invention also comprises a pharmaceutical composition comprising a compound of the invention which is simultaneously or separately administered with an anti-tumor platinum complex to a patient. For the pharmaceutical composition of the invention, the route and the method for administering the compound of the invention and the anti-tumor platinum complex are not particularly limited but reference may be made to the description of the pharmaceutical composition and/or kit of the invention above.
EXAMPLES
Hereinafter, the present invention will be illustrated by way of specific examples, although the invention should not be limited thereto.
Example 1
Combination Use of E7080 and Cisplatin in Subcutaneous Transplanted Models (In Vivo) of Non-Small-Cell Lung Cancer Cell Line (A549)
Human non-small-cell lung cancer cell line A549 (purchased from Dainippon Sumitomo Pharma Co., Ltd) was cultured in RPMI1640 (containing 10% FBS) in a 5% carbon dioxide gas incubator at 37° C. to about 80% confluence, and then the cells were collected with trypsin-EDTA. A 1×108 cells/mL suspension was prepared with a phosphate buffer, which was further added with matrigel matrix (purchased from Becton, Dickinson and Co.) to give a 5×107 cells/mL suspension, and each 0.2 mL of the resulting cell suspension was subcutaneously transplanted to a nude mouse at the side of its body. Eleven days after the transplantation, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (hereinafter, also referred to as “E7080”) was orally administered for 3, 10 or 30 mg/kg, once a day for four weeks, while 10 mg/kg of cisplatin was administered into the tail vein once a day. The major and minor axes of tumors were measured with Digimatic caliper (Mitsutoyo Corporation), 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(mm2)/2

Relative Tumor Volume (RTV)=Tumor volume on measurement day/Tumor volume on the first administration day.

Synergistic effect was determined to be present in the combination group when a statistically significant (p<0.05) interaction was observed in two-way ANOVA analysis. In addition, even if synergistic effect was not observed, additive effect was determined to be present when higher anti-tumor effect than that obtained upon administration of E7080 or cisplatin alone was observed.
As a result, E7080 showed additive or synergistic effect when used in combination with cisplatin, and their combination use showed a superior anti-tumor effect as compared with those obtained with E7080 or cisplatin alone (Tables 1, 2 and 3, and FIGS. 1, 2 and 3).









TABLE 1






Relative tumor volume



Administered
on Day 29
Two-way


compound
Average ± standard deviation
ANOVA







Control (untreated)
10.07 ± 2.22 



E7080 3 mg/kg
2.24 ± 0.34


Cisplatin 10 mg/kg
7.99 ± 0.88


E7080 3 mg/kg +
1.45 ± 0.41
p = 0.142


Cisplatin 10 mg/kg

Additive effect


















TABLE 2






Relative tumor volume



Administered
on Day 29
Two-way


compound
Average ± standard deviation
ANOVA







Control (untreated)
10.07 ± 2.22 



E7080 10 mg/kg
1.81 ± 0.29


Cisplatin 10 mg/kg
7.99 ± 0.88


E7080 10 mg/kg +
0.81 ± 0.28
p = 0.00205


Cisplatin 10 mg/kg

Synergistic effect


















TABLE 3






Relative tumor volume



Administered
on Day 29
Two-way


compound
Average ± standard deviation
ANOVA







Control (untreated)
10.07 ± 2.22 



E7080 30 mg/kg
1.20 ± 0.21


Cisplatin 10 mg/kg
7.99 ± 0.88


E7080 30 mg/kg +
0.65 ± 0.17
p = 0.0272


Cisplatin 10 mg/kg

Synergistic effect









Tables 1, 2 and 3 show anti-tumor effects obtained by the use of E7080 alone, the use of cisplatin alone and the combination use of E7080 and cisplatin in subcutaneous transplanted A549 models. The first day of administration was considered Day 1.
According to the obtained results, the combination of E7080 and cisplatin can provide a pharmaceutical composition and a kit that show a remarkable anti-tumor activity, which may be used for treating cancer.
Example 2
Combination Use of E7080 and Carboplatin in Subcutaneous Transplanted Models (In Vivo) of Non-Small-Cell Lung Cancer Cell Line (A549)
Human non-small-cell lung cancer cell line A549 (purchased from Dainippon Sumitomo Pharma Co., Ltd) was cultured in RPMI1640 (containing 10% FBS) in a 5% carbon dioxide gas incubator at 37° C. to about 80% confluence, and then the cells were collected with trypsin-EDTA. A 1×108 cells/mL suspension was prepared with a phosphate buffer, which was further added with matrigel matrix (purchased from Becton, Dickinson and Co.) to give a 5×107 cells/mL suspension, and each 0.2 mL of the resulting cell suspension was subcutaneously transplanted to a nude mouse at the side of its body. Eleven days after the transplantation, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (E7080) was orally administered for 3 or 10 mg/kg, once a day for four weeks, while 100 mg/kg of carboplatin was administered into the tail vein on the first day. The major and minor axes of tumors were measured with Digimatic caliper (Mitsutoyo Corporation), 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(mm2)/2

Relative Tumor Volume (RTV)=Tumor volume on measurement day/Tumor volume on the first administration day.

Synergistic effect was determined to be present in the combination group when a statistically significant (p<0.05) interaction was observed in two-way ANOVA analysis. In addition, even if synergistic effect was not observed, additive effect was determined to be present when higher anti-tumor effect than that obtained upon administration of E7080 or carboplatin alone was observed.
As a result, E7080 showed additive or synergistic effect when used in combination with carboplatin, and their combination use showed a superior anti-tumor effect as compared with those obtained with E7080 or carboplatin alone (Tables 4 and 5, and FIGS. 4 and 5).









TABLE 4






Relative tumor volume



Administered
on Day 29
Two-way


compound
Average ± standard deviation
ANOVA







Control (untreated)
10.07 ± 2.22 



E7080 3 mg/kg
2.24 ± 0.34


Carboplatin 100 mg/kg
7.87 ± 1.05


E7080 3 mg/kg +
1.59 ± 0.25
p = 0.417


Carboplatin 100 mg/kg

Additive effect


















TABLE 5






Relative tumor volume



Administered
on Day 29
Two-way


compound
Average ± standard deviation
ANOVA







Control (untreated)
10.07 ± 2.22 



E7080 10 mg/kg
1.81 ± 0.29


Carboplatin 100 mg/kg
7.87 ± 1.05


E7080 10 mg/kg +
0.68 ± 0.23
p = 0.000715


Carboplatin 100 mg/kg

Synergistic effect









Tables 4 and 5 show anti-tumor effects obtained by the use of E7080 alone, the use of carboplatin alone and the combination use of E7080 and carboplatin in subcutaneous transplanted A549 models. The first day of administration was considered Day 1.
According to the obtained results, the combination of E7080 and carboplatin can provide a pharmaceutical composition and a kit that show a remarkable anti-tumor activity, which may be used for treating cancer,
Reference Example
Hereinafter, a method for producing a formulation of one of the compounds represented by General Formula (I), i.e., 4-(3-chloro-4-(cyclopropylaminocarbonyliaminophenoxy)-7-methoxy-6-quinolinecarboxamide, will be described as a reference example.
(Production of Pharmaceutical Composition)
(1) 1 mg Tablet
24 g of crystal (C) of methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (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 AEROSIL (Registered Trademark) 200, Nippon Aerosil Co., Ltd.) were mixed with 20 L Super Mixer, and then 1236 g of D-mannitol (excipient, Towa-Kasei Co., Ltd.), 720 g of crystalline cellulose (excipient sold under the trade name of Avicel PH101, Asahi Kasei Corporation) and 72 g of hydroxypropylcellulose (binder sold under the trade name of HPC-L, Nippon Soda Co., Ltd.) were further added and mixed together. Subsequently, a suitable amount of anhydrous ethanol was added to obtain a granulated body containing crystal (C). 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 and mixed together in a 20 L tumbler mixer, and molded with a tablet machine to obtain tablets with a total mass of 100 mg per tablet. Furthermore, the tablets were coated using aqueous 10% Opadry yellow (OPADRY 03F42069 YELLOW, Colorcon Japan) solution as a coating solution with a tablet coating machine, thereby obtaining coated tablets with a total mass of 105 mg per tablet.
(2) 10 mg Tablet
Sixty grams of crystal (C) and 192 g of light anhydrous silicic acid (antigelling agent sold under the trade name of AEROSIL (Registered Trademark) 200, Nippon Aerosil Co., Ltd.) were mixed with 20 L Super Mixer, and then 1200 g of D-mannitol (excipient, Towa-Kasei Co., Ltd.), 720 g of crystalline cellulose (excipient sold under the trade name of Avicel PH101, Asahi Kasei Corporation) and 72 g of hydroxypropylcellulose (binder sold under the trade name of HPC-L, Nippon Soda Co., Ltd.) were further added and mixed together. Subsequently, a suitable amount of anhydrous ethanol was added to obtain a granulated body containing crystal (C). 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 and mixed together in a 20 L tumbler mixer, and molded with a tablet machine to obtain tablets with a total mass of 400 mg per tablet. Furthermore, the tablets were coated using aqueous 10% Opadry yellow (OPADRY 03F42069 YELLOW, Colorcon Japan) solution as a coating solution with a tablet coating machine, thereby obtaining coated tablets with a total mass of 411 mg per tablet.
(3) 100 mg Tablet
31.4 g of crystal (C) and 4 g of light anhydrous silicic acid (antigelling agent sold under the trade name of AEROSEL (Registered Trademark) 200, Nippon Aerosil Co., Ltd.) were mixed with 1 L Super Mixer, and then 40.1 g of anhydrous calcium hydrogen phosphate (excipient, Kyowa Chemical Industry Co., Ltd.), 10 g of low substituted hydroxypropylcellulose (binder sold under the trade name of L-HPC (LH-21), Shin-Etsu Chemical Co., Ltd.) and 3 g of hydroxypropylcellulose (binder sold under the trade name of HPC-L, Nippon Soda Co., Ltd.) were further added and mixed together.
Subsequently, a suitable amount of anhydrous ethanol was added to obtain a granulated body containing crystal (C). This granulated body was dried in a rack dryer (60° C.), and then granulated using PowerMILL to obtain granules. Together with the granules, 10 g of croscarmellose sodium (disintegrant sold under the trade name of Ac-Di-Sol, FMC International Inc.) and 1.5 g of sodium stearyl fumarate (lubricant, JRS Pharma LP) were mixed and molded with a tablet machine to obtain tablets with a total mass of 400 mg per tablet.
INDUSTRIAL APPLICABILITY
According to the present invention, there is provided a pharmaceutical composition and a kit that exhibit excellent anti-tumor effect. Specifically, the present invention provides a pharmaceutical composition and/or a kit comprising a compound represented by General Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof in combination with an anti-tumor platinum complex, which can be used for the treatment of cancer.

## Claims

1. A pharmaceutical composition comprising a combination of:
(i) 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof; and
(ii) cisplatin or carboplatin.

2. The pharmaceutical composition according to claim 1, wherein the 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, pharmacologically acceptable salt thereof or solvate thereof is a methanesulfonate of 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

3. A pharmaceutical composition comprising:
4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof that is simultaneously or separately administered to a patient with an anti-tumor platinum complex selected from the group consisting of cisplatin or carboplatin.

4. The pharmaceutical composition according to claim 3, wherein the 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, pharmacologically acceptable salt thereof or solvate thereof is a methanesulfonate of 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

5. A method for treating lung cancer characterized by simultaneously or separately administering, to a patient in need thereof, an effective amount of:
(i) 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof; and
(ii) an anti-tumor platinum complex selected from the group consisting of cisplatin or carboplatin.

6. A method according to claim 5, wherein the 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, pharmacologically acceptable salt thereof or solvate thereof is a methanesulfonate of 4-(3-chloro-4-(cyclopropyloaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.