WO2020059705A1 - キノリンカルボキサミド誘導体を用いるがん併用療法 - Google Patents
キノリンカルボキサミド誘導体を用いるがん併用療法 Download PDFInfo
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Definitions
- the present invention relates to a cancer combination therapy using a quinolinecarboxamide derivative.
- Transcription factor STAT (Signal Transducers and Activators of Transcription) is a DNA-binding protein, and its activity is regulated by stimulation of various cytokines (IL-6, interferon, etc.) or growth factors (EGF, PDGF, etc.). ing. STATs activated by forming a dimer translocate into the nucleus, specifically recognize and bind to a specific DNA sequence in a gene promoter region, and induce transcription of many genes. That is, STAT is an essential mediator in a pathway for transmitting a signal from the cell surface to the nucleus, and is deeply involved in cell proliferation and differentiation.
- cytokines IL-6, interferon, etc.
- EGF growth factor
- STATs activated by forming a dimer translocate into the nucleus, specifically recognize and bind to a specific DNA sequence in a gene promoter region, and induce transcription of many genes. That is, STAT is an essential mediator in a pathway for transmitting a signal from the cell surface to
- STAT3 Seven different members of STAT are known, of which STAT3 is expressed in most cell types, and its constitutive activation and overexpression is associated with lung cancer, skin cancer, and pancreas. Cancer, ovarian, myeloma, breast, prostate, brain, head and neck, melanoma, leukemia lymphoma, and multiple myeloma. It is thought that proliferation and invasion depend on STAT3.
- STAT3 is considered to be useful as a target molecule for these cancer types, and its inhibitor is expected as an anticancer agent.
- a specific quinolinecarboxamide derivative has excellent STAT3 inhibitory activity and has antitumor activity against various cancers (Patent Document 1).
- the present invention relates to providing a method of using a STAT3 inhibitor having a high antitumor effect and few side effects.
- the present inventors have conducted repeated studies to further enhance the antitumor effect of the quinolinecarboxamide derivative represented by the following formula (I). It was found that an antitumor effect was obtained.
- the present invention relates to the following inventions 1) to 24).
- An antitumor agent comprising a combination of one or more cancer molecular targeted drugs selected from BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors.
- An antitumor agent according to 1) which is a combination drug.
- the cancer molecular targeted drug is one or more selected from crizotinib, alectinib, ceritinib, osimertinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, dabrafenib, trametinib, imatinib and dasatinib 1) to 10) Antitumor agent.
- the cancer molecular targeted drug is one or more selected from crizotinib, alectinib, ceritinib, osimertinib, sorafenib, bandetanib, lembatinib, everolimus, dabrafenib, trametinib, imatinib and dasatinib, 1) to 10) Antitumor agent.
- the cancer is at least one selected from non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, endometrial cancer, melanoma and leukemia 1) to 12) Any of the antitumor agents.
- At least one cancer molecule targeting drug selected from ALK inhibitors, EGFR inhibitors, Multikinase inhibitors, HER2 / EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors;
- An antitumor agent comprising, as an active ingredient, a quinolinecarboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, which is administered in combination.
- ALK inhibitor, EGFR inhibitor, Multikinase inhibitor, HER2 / EGFR inhibitor comprising a quinolinecarboxamide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:
- An antitumor effect enhancer of one or more cancer molecule-targeted drugs selected from mTOR inhibitors, BRAF inhibitors, MEK inhibitors, and BCR-ABL inhibitors.
- ALK inhibitor In the treatment of tumor, one or more selected from ALK inhibitor, EGFR inhibitor, Multikinase inhibitor, HER2 / EGFR inhibitor, mTOR inhibitor, BRAF inhibitor, MEK inhibitor and BCR-ABL inhibitor
- a method for treating a tumor comprising administering to a patient a therapeutically effective amount of one or more cancer molecule-targeted drugs selected from BRAF inhibitors, MEK inhibitors, and BCR-ABL inhibitors.
- one or more cancer molecule-targeted drugs selected from ALK inhibitors, EGFR inhibitors, Multikinase inhibitors, HER2 / EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors;
- ALK inhibitors EGFR inhibitors
- Multikinase inhibitors HER2 / EGFR inhibitors
- mTOR inhibitors mTOR inhibitors
- BRAF inhibitors MEK inhibitors
- BCR-ABL inhibitors BCR-ABL inhibitors
- one or more cancer molecule targeted drugs selected from ALK inhibitors, EGFR inhibitors, Multikinase inhibitors, HER2 / EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors
- ALK inhibitor, EGFR inhibitor, Multikinase inhibitor, HER2 / EGFR wherein a quinolinecarboxamide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in a therapeutically effective amount.
- one or more cancer molecule-targeted drugs selected from ALK inhibitors, EGFR inhibitors, Multikinase inhibitors, HER2 / EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors Use of a quinolinecarboxamide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof for producing an antitumor effect enhancer for enhancing an antitumor effect.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, COOR 7 (Wherein, R 7 represents a substituted or unsubstituted alkyl group) or OR 8 (wherein, R 8 represents a substituted or unsubstituted alkyl group).
- the antitumor agent of the present invention it is possible to carry out a cancer treatment exhibiting a high antitumor effect while suppressing the occurrence of side effects, and thus prolong the survival of patients.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group.
- examples of the substituent in the alkyl group include a halogen atom and a hydroxy group.
- R a to R w may be the same or different and may represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or the like.
- the number of these substituents may be the same or different and up to the number of hydrogen atoms present in each group, but is preferably 1 to 10, more preferably 1 to 5.
- each group defined in the general formula (I) represents all possible position isomers.
- the alkyl moiety of the alkyl group and the alkoxy group include linear or branched alkyl having 1 to 12 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
- cycloalkyl group examples include a 3 to 12-membered cycloalkyl group which may have a saturated or partially unsaturated bond, and a monocyclic or a plurality of the monocyclic cycloalkyl groups or an aryl group or an aromatic group. It may be a polycyclic fused cycloalkyl group fused with a group heterocyclic group.
- the monocyclic cycloalkyl group for example, a monocyclic cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclo Hexenyl and the like.
- the polycyclic cycloalkyl group include, for example, a polycyclic cycloalkyl having 5 to 12 carbon atoms, specifically, pinanyl, adamantyl, bicyclo [3.3.1] octyl, bicyclo [3.1.1] heptyl and the like.
- alkenyl group examples include linear or branched alkenyl having 2 to 12 carbon atoms, specifically, vinyl, allyl, 1-propenyl, isopropenyl, methacryl, butenyl, 1,3-butadienyl, crotyl, pentenyl , Hexenyl, heptenyl, decenyl, dodecenyl and the like.
- alkynyl group examples include straight-chain or branched alkynyl having 2 to 12 carbon atoms, specifically ethynyl, propargyl, 1-propynyl, isopropynyl, 2-butynyl, pentynyl, 2-penten-4-ynyl , Hexynyl, heptynyl, decynyl, dodecynyl and the like.
- aryl group examples include aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl, phenanthryl and the like.
- the aromatic heterocyclic group may be the same or different and includes a 5- or 6-membered aromatic heterocyclic group containing at least one or more heteroatoms, for example, nitrogen, oxygen, sulfur and the like. Or a monocyclic or a polycyclic fused aromatic heterocyclic group in which the monocyclic heterocyclic group is fused with a plurality or an aryl group, for example, a bicyclic or tricyclic heterocyclic group.
- monocyclic aromatic heterocyclic group examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
- polycyclic fused aromatic heterocyclic groups such as benzofuryl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, carbazolyl, purinyl, quinolyl, and isoquinolyl.
- halogen atom examples include fluorine, chlorine, bromine, and iodine atoms.
- quinolinecarboxamide derivatives represented by the formula (I) a compound in which R 1 and R 2 are the same or different and are a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group is preferable, and an aryl group
- R 1 and R 2 are the same or different and are a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group
- an aryl group A preferred example is a phenyl group or a naphthyl group, and a preferred example of the aromatic heterocyclic group is a furyl group or a thienyl group.
- R 1 is a furyl group and R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted furyl group or a substituted or unsubstituted thienyl group is more preferable, and the substituent of the substituted phenyl group is methyl.
- a substituted or unsubstituted alkoxy group such as a methoxy group, a difluoromethoxy group or the like, a halogen atom such as a fluorine atom or a chlorine atom, a hydroxy group, an alkoxycarbonyl group such as tert-butoxycarbonyl, an amino group, a nitro group
- Preferable examples include a cyano group and the like
- examples of a substituent of the substituted furyl group and the substituted thienyl group include an alkyl group such as a methyl group and a halogen atom such as a chlorine atom.
- a compound in which R 3 , R 5 and R 6 are hydrogen atoms and R 4 is OR 8 (preferably, a methoxy group or a trifluoromethoxy group) is more preferable.
- these compounds (I) include, for example, N- [5- (2-furyl) -1,3,4-oxadiazol-2-yl] -2-phenyl-4-quinolinecarboxamide, -[5- (3-furyl) -1,3,4-oxadiazol-2-yl] -2-phenyl-4-quinolinecarboxamide, 2-phenyl-N- (5-phenyl-1,3,4 -Oxadiazol-2-yl) -4-quinolinecarboxamide, N- [5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl] -2-phenyl-4-quinolinecarboxamide, N- [5- (4-nitrophenyl) -1,3,4-oxadiazol-2-yl] -2-phenyl-4-quinolinecarboxamide, 2-phenyl-N- [5- (3-pyridyl) -1,3,4-o Sadiazol-2-yl] -4-quinolinecarboxamide,
- Pharmaceutically acceptable salts of the quinolinecarboxamide derivative represented by the formula (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
- Pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and formic acid, acetic acid, propionic acid, and fumaric acid as organic acids.
- Examples include carboxylic acids such as acid, malonic acid, succinic acid, maleic acid, tartaric acid, citric acid and benzoic acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid.
- Pharmacologically acceptable metal salts include lithium, sodium, potassium and other alkali metal salts, magnesium, calcium and other alkaline earth metal salts, aluminum and zinc, and other metal salts.
- Acceptable ammonium salts include ammonium and tetramethylammonium salts
- pharmacologically acceptable organic amine salts include triethylamine, piperidine, morpholine, and toluidine salts.
- Examples of the amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.
- the quinolinecarboxamide derivative represented by the formula (I) of the present invention or a salt thereof is described in Japanese Patent No. 5650529 (the aforementioned Patent Document 1) as a STAT3 inhibitor, and can be produced by the method described in the same. It is known that the quinolinecarboxamide derivative or a salt thereof inhibits STAT3 dimerization and exhibits an antitumor effect.
- the cancer molecule-targeted drug of the present invention suppresses the growth of tumor cells by targeting molecules involved in tumor cell growth, invasion, and metastasis, and inhibits the progression of tumors, thereby suppressing only the primary tumor. In addition, it is a drug developed for the purpose of suppressing tumor metastasis.
- the cancer molecule-targeted drug of the present invention is selected from ALK inhibitors, EGFR inhibitors, Multikinase inhibitors, HER2 / EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors, and BCR-ABL inhibitors.
- One or more hereinafter, referred to as "cancer molecular targeted drug of the present invention").
- ALK inhibitor refers to a substance that inhibits tyrosine kinase of anaplastic lymphoma kinase (ALK)
- EGFR inhibitor inhibits T790M gene mutation and activating mutation of epidermal growth factor receptor (EGFR)
- Multikinase inhibitors include RAFs involved in tumor cell growth and angiogenesis, vascular endothelial growth factor (VEGFR), platelet-derived growth factor receptor (PDGFR), Inhibits multiple tyrosine kinases such as Rearranged during Transfection (RET),
- HER2 / EGFR inhibitors are those that inhibit both EGFR and HER2 (EGFR2) of the EGFR family
- MTOR inhibitors are those that inhibit mammalian target of rapamycin (mTOR)
- BRAF inhibitors are those that inhibit the kinase activity of mutant BRAF (V600E, V600K and V600D mutation positive)
- MEK inhibitors are those that inhibit the kinase activity
- ALK inhibitors include crizotinib (Crizotinib), alectinib (Alectinib), ceritinib (Ceritinib), lorlatinib (Lorlatinib), brigatinib (Brigatinib), and entrectinib (Entrectinib); (Osimertinib), gefitinib (Gefitinib), erlotinib (Erlotinib), afatinib (Afatinib), dacomitinib (Dacomitinib), cetuximab (Cetuximab), panitumumab (Panitumabib) ), Lenvatinib, Legorafenib (Regorafenib), Sunitinib (Sunitinib), Axitinib (Axitinib), Pazopanib (Pazopanib), Cabozantinib (C
- Preferred cancer molecular targeted drugs include alectinib, crizotinib, ceritinib, osimertinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, dabrafenib, trametinib, imatinib, and dasatinib.
- the cancer molecular targeted drug includes ALK inhibitor, EGFR inhibitor, Multikinase inhibitor, mTOR inhibitor, BRAF inhibitors, MEK inhibitors, and BCR-ABL inhibitors are preferred, and ALK inhibitors and Multi @ kinase inhibitors are more preferred.
- alectinib preferably as a cancer molecular targeted drug, alectinib, crizotinib, ceritinib, osimertinib, sorafenib, vandetanib, lembatinib, everolimus, dabrafenib, trametinib, imatinib, imatinib, dasatinib, more preferably alectinib, crizotinib, crizotinib, crizotinib It is.
- cytotoxic activity was determined by the combination effect evaluation (combination index: CI) calculated by the median-effect method (Pharmacol Rev 58: 621-681, 2006) using the combination effect analysis software CalcuSyn (HULINKS). Indicates a synergistic effect of 0.9 or less.
- the combination of the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof and the cancer molecule-targeted drug of the present invention is useful as an antitumor agent.
- the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof is useful as an antitumor agent to be administered in combination with the cancer molecule-targeting drug of the present invention.
- the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof is used as an antitumor effect enhancer of the cancer molecule-targeted drug of the present invention, and the cancer molecule-targeted drug of the present invention is represented by the formula (I)
- the quinolinecarboxamide derivative or a salt thereof is useful as an antitumor effect enhancer.
- the cancer that can be treated by the antitumor agent of the present invention is not particularly limited, and examples thereof include non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, and uterine body. Cancer, melanoma, leukemia, etc., preferably non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular carcinoma, ovarian cancer, endometrial cancer.
- the antitumor agent of the present invention obtained by combining the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof with a cancer molecule-targeted drug is used as a combination drug in the quinolinecarboxamide derivative represented by the above formula (I) or a derivative thereof. Even if the effective amount of each of the salt and the cancer molecular targeted drug is formulated into one dosage form at an appropriate mixing ratio (single dosage form), each of the above components can be used simultaneously or separately at intervals. It may be a single preparation of a drug containing each effective amount (two-part form).
- the dosage form of the above preparation is not particularly limited and may be appropriately selected depending on the purpose of the treatment. Specifically, oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories , Patches, ointments and the like.
- the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof and the cancer molecule-targeted drug may be in different dosage forms or in the same dosage form.
- the preparation containing the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof according to the present invention and / or the cancer molecule-targeting drug of the present invention can be prepared by using a pharmacologically acceptable carrier, and then preparing a known drug. It can be prepared by a method.
- a pharmacologically acceptable carrier include those commonly used in ordinary pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH Examples include adjusting agents, buffering agents, stabilizers, coloring agents, flavoring agents, flavoring agents, and the like.
- lactose sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica Acids, methylcellulose, glycerin, sodium alginate, gum arabic and mixtures thereof.
- the lubricant include purified talc, stearate, borax, polyethylene glycol, and a mixture thereof.
- binder examples include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, water, ethanol, potassium phosphate, and mixtures thereof.
- Disintegrators include, for example, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and mixtures thereof Is mentioned.
- Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof.
- Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures thereof.
- Examples of the tonicity agent include sodium chloride, boric acid, glucose, glycerin, and mixtures thereof.
- Examples of the pH adjuster and the buffer include sodium citrate, citric acid, sodium acetate, sodium phosphate, and a mixture thereof.
- Examples of the soothing agent include procaine hydrochloride, lidocaine hydrochloride, and mixtures thereof.
- the amounts of the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention in the above-mentioned preparation can be appropriately set.
- the represented quinolinecarboxamide derivative or salt thereof is 0.001 to 5000 mg, preferably 0.1 to 1000 mg, more preferably 1 to 500 mg.
- the cancer molecule-targeted drug is appropriately set within a range permitted for each drug. For example, 150 to 600 mg for alectinib and 200 to 800 mg for sorafenib.
- the antitumor agent of the present invention When used as a kit, the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof formulated as described above and a drug comprising the cancer molecule-targeted drug of the present invention are used.
- Each can be packaged separately and designed for use by removing each pharmaceutical formulation from each package at the time of administration.
- each pharmaceutical preparation can be packaged in a form suitable for single combined administration.
- the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof, and the dose of the cancer molecule-targeted drug of the present invention are determined according to the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof, and There is no particular limitation as long as the cancer molecule-targeted drug exerts an antitumor effect synergistically and can effectively treat cancer.
- the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof may be appropriately set depending on the presence or absence of other antitumor agent or the like, and the quinolinecarboxamide derivative represented by the formula (I) is 0.001 to It is 5000 mg / day, preferably 0.1-1000 mg / day, more preferably 1-500 mg.
- the cancer molecular targeted drug is appropriately set within a range permitted for each drug. For example, 150 to 600 mg / day for alectinib, and 200
- the administration order and administration interval of the quinolinecarboxamide derivative represented by the formula (I) or a salt thereof of the present invention and the cancer molecule-targeting drug of the present invention are not particularly limited as long as a synergistic effect can be obtained.
- a single preparation may be administered at the same time or at an interval.
- Cell culture NCI-H2228, NCI-H1975, SK-BR-3, Hep3B, MCF-7, Caov-3, A2058, K562 and SUP-B15 from American Type Culture Collection, SAS and HuH-7 from national research K1, FTC-133 and Ishikawa were purchased from the European Collection of Authenticated Cell Cultures.
- Cells were subcultured in the medium of Table 1 containing 100 U / mL penicillin and 100 ⁇ g / mL streptomycin (Thermo Fisher Scientific, Cat. No. 15140-122) under the conditions of 5% CO 2 and 37 ° C. Used for the experiment.
- Fetal bovine serum (hereinafter abbreviated as FBS) and MCDB 105 medium were obtained from Sigma Aldrich (Cat. No. 172012 and 117-500), RMPI1640 medium, DMEM medium, Ham's F-12 medium, MEM medium and IMDM medium were Thermo Fisher It was purchased from Scientific (Cat. No. A1049101, 11995-065, 11765-054, 11095-080 and 12440-053).
- @Crizotinib, everolimus, and trametinib were purchased from LC Laboratories (Cat. No. C-7900, E-4040, V-2800 and T-8123).
- Alectinib, osimertinib, and lenvatinib were purchased from Selleckchem.com (Cat. No. S2762, S7297 and S1164), and ceritinib was purchased from Active Biochem (Cat. No. A-1189).
- Sorafenib is from Cayman Chemical (Cat. No. 10009644), vandetanib, lapatinib and lapatinib and dabrafenib are from Santa Cruz Biotechnology (Cat. No.
- Imatinib was purchased from Cell Signaling Technology (Cat. No. 9084), and dasatinib was purchased from Bio Vision (Cat. No. 1586). All drugs were dissolved in dimethyl sulfoxide (hereinafter abbreviated as DMSO).
- DMSO dimethyl sulfoxide
- Example 1 Evaluation of Drug Combination Effect (1) Setting of Reference Dose Each cell was seeded in a 96-well plate at the density shown in Table 2, and cultured under conditions of 5% CO 2 and 37 ° C. Each drug was added alone the day after seeding. DMSO was added to the control group to a final concentration of 0.05%. Subsequently, the cells were cultured under the conditions of 5% CO 2 and 37 ° C. for the time described in Table 2, and the number of viable cells was evaluated by the WST-8 assay. That is, 10 ⁇ L of a WST-8 kit solution (Kishida Chemical, Cat. No. 260-96162) was added to each well, and the cells were cultured for 1-2 hours under conditions of 5% CO 2 and 37 ° C.
- a WST-8 kit solution Korean Chemical, Cat. No. 260-96162
- the absorbance at 450 nm of water-soluble formazan generated by mitochondrial enzymatic activity in cells was measured using a microplate reader (Molecular Devices, model SpectraMax Plus). This was evaluated as the number of viable cells was calculated 50% cytostatic concentration (hereinafter, abbreviated as IC 50).
- IC 50 50% cytostatic concentration
- CI combination index
- STX-1159 was added alone or in combination to a final concentration of 5 ⁇ M, or alectinib to a final concentration of 0.01 or 0.1 ⁇ M.
- DMSO was added to the control group to a final concentration of 0.1%.
- the cells were cultured for 24 hours under conditions of 5% CO 2 and 37 ° C., and then the cells were collected. The cells were washed once with ice-cold PBS, and RIPA to which a protease inhibitor cocktail (Nacalai Tesque, Inc., Cat. No. 25955-11) and a phosphatase inhibitor cocktail (Nacalai Tesque, Inc., Cat. No. 07574) were added.
- Buffer 25 mM Tris-HCl, pH 7.6, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS, 0.15M NaCl
- the lysate was subjected to electrophoresis, and the proteins in the acrylamide gel were transferred to Immobilon PVDF membrane using a semi-dry transfer device. After transcription, the membrane is blocked, and the primary antibody (anti-phosphorylated STAT3 (Y705) antibody: Cell Signaling Technology, Cat. No. CST9131, anti-STAT3 antibody: Cell Signaling Technology, Cat. No. CST4904, phosphorylated ALK (Y1278 / Y1282 / Y1283) Antibody: Cell Signaling Technology, Cat. No.
- Example 3 Evaluation of Combination Effect of STX-1159 and mTOR Inhibitor (1) Setting of Reference Dose 2.5 ⁇ 10 3 each of human breast cancer cell line MDA-MB-231 cells or MDA-MB-468 (in the case of Rapamycin) / 100 [mu] L / well or were seeded in 96-well plate at 1.0 ⁇ 10 3 / 100 ⁇ L / well , and cultured under the conditions of 5% CO 2, 37 °C. On the day after the seeding, each drug listed in Table 7 was added alone. DMSO was added to the control group to a final concentration of 0.05%. Subsequently, after culturing under conditions of 5% CO 2 and 37 ° C.
- the number of surviving cells was evaluated by the WST-8 assay. That is, 10 ⁇ L of a WST-8 kit solution (Kishida Chemical, Cat. No. 260-96162) was added to each well, and the cells were cultured for 1-2 hours under conditions of 5% CO 2 and 37 ° C. The absorbance at 450 nm of water-soluble formazan generated by mitochondrial enzyme activity in cells was measured using a microplate reader (Molecular Devices, model SpectraMax Plus). This was evaluated as the number of viable cells was calculated 50% cytostatic concentration (hereinafter, abbreviated as IC 50). The reference dose for each drug was set based on the IC 50 (Table 6).
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Abstract
Description
1)下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を組み合わせてなる抗腫瘍剤。
2)式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を含有してなる薬剤と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を含有してなる薬剤からなるキットである1)の抗腫瘍剤。
3)配合剤である1)の抗腫瘍剤。
4)式(I)におけるR1及びR2が、同一又は異なって、置換若しくは非置換アリール基又は置換若しくは非置換芳香族複素環基である、1)~3)のいずれかの抗腫瘍剤。
5)式(I)におけるR3、R4、R5及びR6の少なくとも一つの基が、水素原子以外の基である、4)の抗腫瘍剤。
6)式(I)におけるR1及びR2におけるアリール基がフェニル基、芳香族複素環基がフリル基である、1)~5)のいずれかの抗腫瘍剤。
7)式(I)におけるR1がフリル基、R2が置換又は非置換フェニル基である、1)~5)のいずれかの抗腫瘍剤。
8)R3、R4、R5及びR6の少なくとも一つの基は、トリフルオロメトキシ基である、1)~7)のいずれかの抗腫瘍剤。
9)R4がトリフルオロメトキシ基である、1)~7)のいずれかの抗腫瘍剤。
10)式(I)で表されるキノリンカルボキサミド誘導体が、N-[5-(2-フリル)-1,3,4-オキサジアゾール-2-イル]-2-フェニル-6-トリフルオロメトキシ-4-キノリンカルボキサミドである、1)~9)のいずれかの抗腫瘍剤。
11)がん分子標的薬が、クリゾチニブ、アレクチニブ、セリチニブ、オシメルチニブ、ソラフェニブ、バンデタニブ、レンバチニブ、ラパチニブ、エベロリムス、ダブラフェニブ、トラメチニブ、イマチニブ及びダサチニブから選ばれる1以上である、1)~10)のいずれかの抗腫瘍剤。
12)がん分子標的薬が、クリゾチニブ、アレクチニブ、セリチニブ、オシメルチニブ、ソラフェニブ、バンデタニブ、レンバチニブ、エべロリムス、ダブラフェニブ、トラメチニブ、イマチニブ及びダサチニブから選ばれる1以上である、1)~10)のいずれかの抗腫瘍剤。
13)がんが、非小細胞肺がん、舌がん、甲状腺がん、肝細胞がん、乳がん、卵巣がん、子宮体がん、メラノーマ及び白血病から選ばれる1以上である1)~12)のいずれかの抗腫瘍剤。
14)ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と併用投与されることを特徴とする、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を有効成分とする抗腫瘍剤。
15)下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を有効成分とする、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果増強剤。
16)キノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を含有する医薬組成物。
17)腫瘍の治療に使用するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩とALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の組み合わせ。
18)腫瘍の治療において、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と組み合わせて使用するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩。
19)下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を患者に治療有効量投与する腫瘍の治療方法。
20)抗腫瘍剤を製造するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の組み合わせの使用。
21)ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と併用投与される抗腫瘍剤を製造するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩の使用。
22)ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果を増強するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩。
23)下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を患者に治療有効量投与する、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果増強方法。
24)ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果を増強する抗腫瘍効果増強剤を製造するための、下記式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩の使用。
ここで、アルキル基における置換基としては、ハロゲン原子、ヒドロキシ基等が挙げられる。また、アリール基、芳香族複素環基における置換基としては、炭素数1~6のアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アラルキル基、ORa、NRbRc、S(O)qRd(式中、qは、0、1又は2を表す)、CORe、COORf、OCORg、CONRhRi、NRjCORk、NRlCOORm、NRnSO2Ro、C(=NRp)NRqRr、NRsSO2NRtRu、SO2NRvRw、ニトロ基、シアノ基及びハロゲン原子等から適宜選択される。ここで、Ra~Rwは、同一又は異なって、水素原子、アルキル基、アルケニル基、アルキニル基、シクロアルキル基等を表してもよい。
これら置換基の置換数としては、同一又は異なって、最大各基に存在する水素原子の数まで可能であるが、好ましくは1~10、より好ましくは1~5である。
アルキル基及びアルコキシ基のアルキル部分としては、例えば、直鎖又は分岐状の炭素数1~12のアルキル、具体的には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル等が挙げられる。
またさらに、R3、R5及びR6が水素原子で、R4がOR8(好ましくは、メトキシ基又はトリフルオロメトキシ基)である化合物がより好ましい。
本発明のがん分子標的薬としては、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上が挙げられる(以降、「本発明のがん分子標的薬」と称する)。
ここで、「ALK阻害剤」は、未分化リンパ腫キナーゼ(Anaplastic lymphoma kinase:ALK)のチロシンキナーゼを阻害するもの、
「EGFR阻害剤」は、上皮増殖因子受容体(Epidermal Growth Factor Receptor:EGFR)のT790M遺伝子変異及び活性化変異を阻害するもの、
「Multi kinase阻害剤」は、腫瘍細胞増殖と血管新生に関わるRAF、血管内皮増殖因子受容体(Vascular endothelial growth factor:VEGFR)、血小板由来増殖因子受容体(Platelet-derived growth factor Receptor:PDGFR)、Rearranged during Transfection(RET)などの複数のチロシンキナーゼを阻害するもの、
「HER2/EGFR阻害剤」は、EGFRファミリーのEGFRとHER2(EGFR2)の両者を阻害するもの、
「mTOR阻害剤」は、哺乳類ラパマイシン標的蛋白質(mammalian target of rapamycin:mTOR)を阻害するもの、
「BRAF阻害剤」は、変異型BRAF(V600E、V600K及びV600D変異陽性)のキナーゼ活性を阻害するもの、
「MEK阻害剤」は、マイトジェン活性化細胞外シグナル関連キナーゼ(Mitogen-activated extracellular signal-regulated kinase:MEK)1/MEK2のキナーゼ活性を阻害するもの、
「BCR-ABL阻害剤」は、Breakpoint cluster region-abelson(Bcr-Abl)、KIT、PDGFRのチロシンキナーゼを阻害するもの、である。
したがって、式(I)で表されるキノリンカルボキサミド誘導体又はその塩と本発明のがん分子標的薬の組み合わせは抗腫瘍剤として有用である。また、式(I)で表されるキノリンカルボキサミド誘導体又はその塩は、本発明のがん分子標的薬と併用投与される抗腫瘍剤として有用である。また、式(I)で表されるキノリンカルボキサミド誘導体又はその塩は、本発明のがん分子標的薬の抗腫瘍効果増強剤として、また本発明のがん分子標的薬は、式(I)で表されるキノリンカルボキサミド誘導体又はその塩の抗腫瘍効果増強剤として有用である。
1. 細胞培養
NCI-H2228、NCI-H1975、SK-BR-3、Hep3B、MCF-7、Caov-3、A2058、K562及びSUP-B15はAmerican Type Culture Collectionから、SAS及びHuH-7は国立研究開発法人医薬基盤・健康・栄養研究所から、K1、FTC-133及びIshikawaはEuropean Collection of Authenticated Cell Culturesから購入した。細胞は100 U/mL penicillin、100 μg/mL streptomycin(Thermo Fisher Scientific, Cat. No. 15140-122)を含む表1の培地にて、5%CO2、37℃の条件下で継代培養し、実験に用いた。Fetal bovine serum(以下、FBSと略す)及びMCDB 105培地はSigma Aldrich(Cat. No. 172012及び117-500)から、RMPI1640培地、DMEM培地、Ham's F-12培地、MEM培地及びIMDM培地はThermo Fisher Scientific(Cat. No. A1049101、11995-065、11765-054、11095-080及び12440-053)から購入した。
下記式で示される、N-[5-(2-フリル)-1,3,4-オキサジアゾール-2-イル]-2-フェニル-6-トリフルオロメトキシ-4-キノリンカルボキサミド(以下、「STX-1159」と称する)は、特許文献1に記載の方法に準じて合成した。
(1)基準用量の設定
各細胞を表2に記載した密度となるように96ウェルプレートに播種し、5%CO2、37℃の条件下で培養した。播種した翌日に各薬剤を単独で添加した。コントロール群にはDMSOを最終濃度0.05%になるように添加した。引き続き表2に記載した時間を5%CO2、37℃の条件下で培養した後、生存細胞数をWST-8アッセイにより評価した。即ち、WST-8キット溶液(キシダ化学、Cat. No. 260-96162)を各ウェルに10μLずつ添加し、1-2時間、5%CO2、37℃の条件下で培養した。細胞内のミトコンドリアの酵素活性により生成した水溶性ホルマザンの450nmの吸光度をマイクロプレートリーダー(Molecular Devices, 機種SpectraMax Plus)を用いて測定した。これを生存細胞数として評価し、50%細胞増殖抑制濃度(以下、IC50と略す)を算出した。各薬剤の基準用量は、IC50をもとに設定した(表3)。
各細胞を表2に記載した密度となるように96ウェルプレートに播種し、5%CO2、37℃の条件下で培養した。播種した翌日に単独群ではSTX-1159と各薬剤を基準用量の1/4、1/2、1、2及び4倍の最終濃度になるように添加し、併用群ではSTX-1159と各薬剤が基準用量の1/4倍同士、1/2倍同士、1倍同士、2倍同士及び4倍同士が組み合わさった最終濃度になるように添加した。コントロール群にはDMSOを最終濃度0.1%になるように添加した。引き続き表2に記載した時間を5%CO2、37℃の条件下で培養した後、WST-8アッセイにより生存細胞数を測定した。次式からfraction affected(以下、faと略す)を算出した。
fa = 1-(薬剤曝露群の生存細胞数)/(コントロール群の生存細胞数)
併用効果解析用ソフトウェアCalcuSyn(HULINKS)を用いたmedian-effect法により、STX-1159と各薬剤をそれぞれ単独又は併用で曝露した際のfaからcombination index(以下、CIと略す)を算出した。併用効果の評価は、表4のCIによるグレード分けに従った。なお、CIの算出に当たっては、同様に実施した2回以上の実験値の平均値を採用した。
STX-1159と各薬剤との併用効果をmedian-effect法を用いて評価した結果、STX-1159とクリゾチニブ、アレクチニブ、セリチニブ、オシメルチニブ、ソラフェニブ、バンデタニブ、レンバチニブ、ラパチニブ、エベロリムス、ダブラフェニブ、トラメチニブ、イマチニブ又はダサチニブとの併用は相乗効果を示した(表5)。この結果から、STX-1159とこれらの薬剤との組み合わせはいずれも、併用薬物療法として有効であることが示唆された。
(1)ウェスタンブロッティング法による評価
NCI-H2228細胞の増殖に対して相乗的に抑制作用を示したSTX-1159とアレクチニブとの併用が、細胞内のSTAT3又はALKを阻害していることを確認する目的で、両薬剤がNCI-H2228細胞におけるリン酸化STAT3、リン酸化ALK、survivin及びc-mycのタンパク質量に及ぼす作用をウェスタンブロッティング法により検討した。
NCI-H2228細胞を2 x 105cells/ウェルとなるように6ウェルプレートに播種し、5%CO2、37℃の条件下で培養した。播種した翌日にSTX-1159を最終濃度が5μMになるように、又はアレクチニブを最終濃度が0.01又は0.1μMになるように、単独又は併用で添加した。コントロール群にはDMSOを最終濃度0.1%になるように添加した。薬剤を添加してから5%CO2、37℃の条件下で24時間培養後に細胞を回収した。細胞を氷冷PBSで1回洗浄し、プロテアーゼ阻害剤カクテル(ナカライテスク株式会社, Cat. No. 25955-11)及びホスファターゼ阻害剤カクテル(ナカライテスク株式会社, Cat. No. 07574)を添加したRIPA Buffer(25mM Tris-HCl, pH7.6、1%NP-40、1%デオキシコール酸ナトリウム、0.1%SDS、0.15M NaCl)を加えて細胞を溶解した。この溶解液について電気泳動を実施し、アクリルアミドゲル内のタンパク質を、セミドライ型転写装置を用いてイモビロンPVDFメンブランに転写した。転写後、メンブランをブロッキングし、1次抗体(抗リン酸化STAT3(Y705)抗体:Cell Signaling Technology, Cat. No. CST9131 、抗STAT3抗体:Cell Signaling Technology, Cat. No. CST4904、リン酸化ALK(Y1278/Y1282/Y1283)抗体:Cell Signaling Technology, Cat. No. CST3983 、抗ALK抗体:Cell Signaling Technology, Cat. No. CST3633、抗survivin抗体:R&D Systems, Cat. No. AF886、抗c-myc抗体:Cell Signaling Technology, Cat. No. CST9402及び抗β-actin抗体:Sigma Aldrich, Cat. No. A5316)溶液に4℃で一晩浸した。さらに2次抗体溶液に室温で1時間浸した後、ECL select(GEヘルスケアジャパン株式会社, Cat. No. RPN2235)を用いてメンブラン上の目的タンパク質を検出した。
ウエスタンブロッティングの結果を図1に示す。
STX-1159とアレクチニブの併用が細胞内のSTAT3又はALKを阻害しているかを検討した。STX-1159単独によるリン酸化STAT3、survivin及びc-mycの減少、また、アレクチニブ単独によるリン酸化ALK、リン酸化STAT3及びc-mycの減少が認められた。リン酸化STAT3及びc-myc(STAT3経路及びALK経路の下流因子)は各単剤に比べ、両薬剤を併用することにより更なる減少が認められた。この結果から、STX-1159とアレクチニブの併用は、STAT3経路を重複して阻害することで、相乗的に細胞増殖抑制作用を発揮すると考えられた。
(1)基準用量の設定
ヒト乳がん細胞株MDA-MB-231細胞またはMDA-MB-468(Rapamycinの場合)を各々2.5×103/100μL/wellまたは1.0×103/100μL/wellとなるように96ウェルプレートに播種し、5%CO2、37℃の条件下で培養した。播種した翌日に表7に記載の各薬剤を単独で添加した。コントロール群にはDMSOを最終濃度0.05%になるように添加した。引き続き48時間で5%CO2、37℃の条件下で培養した後、生存細胞数をWST-8アッセイにより評価した。即ち、WST-8キット溶液(キシダ化学、Cat. No. 260-96162)を各ウェルに10μLずつ添加し、1-2時間、5%CO2、37℃の条件下で培養した。細胞内のミトコンドリアの酵素活性により生成した水溶性ホルマザンの450 nmの吸光度をマイクロプレートリーダー(Molecular Devices, 機種SpectraMax Plus)を用いて測定した。これを生存細胞数として評価し、50%細胞増殖抑制濃度(以下、IC50と略す)を算出した。各薬剤の基準用量は、IC50をもとに設定した(表6)。
ヒト乳がん細胞株MDA-MB-231細胞またはMDA-MB-468(Rapamycinの場合)を各々2.5×103/100μL/wellまたは1.0×103/100μL/wellとなるように96ウェルプレートに播種した。37℃のCO2インキュベータ内でインキュベートし、24hr後、上清を捨て、80μLのAssay用培地を添加した。段階希釈した10μLのmTOR阻害剤溶液(表7に記載のもの)を添加し、次に段階希釈した10μLのSTX-1159溶液を添加した。CO2インキュベータ内で48時間静置後に上清を除去し、PBS(-)100μLで1回洗浄した。Assay用培地で10倍希釈したWST-8溶液を100μL/well添加し、プレートリーダーで波長450nmの吸光度を測定した。測定値より、CIを算出した。
STX-1159とmTOR阻害剤の併用効果はCalcusyn ソフトウェア (BIOSOFT、Cambridge、UK)を用いて解析した。CIによる併用効果のグレード分けについては、実施例1の表4と同様の基準を用いた。結果を表7に示す。
STX-1159と表7に記載のmTOR阻害剤との併用は相乗効果を示した(表7)。この結果から、STX-1159とこれらの薬剤との組合せはいずれも、併用薬物療法として有効であることが示唆された。
Claims (24)
- 式(I)で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を含有してなる薬剤と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を含有してなる薬剤からなるキットである請求項1記載の抗腫瘍剤。
- 配合剤である請求項1記載の抗腫瘍剤。
- 式(I)におけるR1及びR2が、同一又は異なって、置換若しくは非置換アリール基又は置換若しくは非置換芳香族複素環基である、請求項1~3のいずれか1項記載の抗腫瘍剤。
- 式(I)におけるR3、R4、R5及びR6の少なくとも一つの基が、水素原子以外の基である、請求項4記載の抗腫瘍剤。
- 式(I)におけるR1及びR2におけるアリール基がフェニル基、芳香族複素環基がフリル基である、請求項1~5のいずれか1項記載の抗腫瘍剤。
- 式(I)におけるR1がフリル基、R2が置換又は非置換フェニル基である、請求項1~5のいずれか1項記載の抗腫瘍剤。
- R3、R4、R5及びR6の少なくとも一つの基は、トリフルオロメトキシ基である、請求項1~7のいずれか1項記載の抗腫瘍剤。
- R4がトリフルオロメトキシ基である、請求項1~7のいずれか1項記載の抗腫瘍剤。
- 式(I)で表されるキノリンカルボキサミド誘導体が、N-[5-(2-フリル)-1,3,4-オキサジアゾール-2-イル]-2-フェニル-6-トリフルオロメトキシ-4-キノリンカルボキサミドである、請求項1~9のいずれか1項記載の抗腫瘍剤。
- がん分子標的薬が、クリゾチニブ、アレクチニブ、セリチニブ、オシメルチニブ、ソラフェニブ、バンデタニブ、レンバチニブ、ラパチニブ、エベロリムス、ダブラフェニブ、トラメチニブ、イマチニブ及びダサチニブから選ばれる1以上である、請求項1~10のいずれか1項記載の抗腫瘍剤。
- がん分子標的薬が、クリゾチニブ、アレクチニブ、セリチニブ、オシメルチニブ、ソラフェニブ、バンデタニブ、レンバチニブ、エべロリムス、ダブラフェニブ、トラメチニブ、イマチニブ及びダサチニブから選ばれる1以上である、請求項1~10のいずれか1項記載の抗腫瘍剤。
- がんが、非小細胞肺がん、舌がん、甲状腺がん、肝細胞がん、乳がん、卵巣がん、子宮体がん、メラノーマ及び白血病から選ばれる1以上である請求項1~12のいずれか1項記載の抗腫瘍剤。
- ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と併用投与されることを特徴とする、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を有効成分とする抗腫瘍剤。 - 腫瘍の治療に使用するための、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩とALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の組み合わせ。 - 腫瘍の治療において、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と組み合わせて使用するための、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩。 - 下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬を患者に治療有効量投与する腫瘍の治療方法。 - 抗腫瘍剤を製造するための、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩と、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の組み合わせの使用。 - ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬と併用投与される抗腫瘍剤を製造するための、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩の使用。 - 下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩を患者に治療有効量投与する、ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果増強方法。 - ALK阻害剤、EGFR阻害剤、Multi kinase阻害剤、HER2/EGFR阻害剤、mTOR阻害剤、BRAF阻害剤、MEK阻害剤及びBCR-ABL阻害剤から選ばれる1以上のがん分子標的薬の抗腫瘍効果を増強する抗腫瘍効果増強剤を製造するための、下記式(I):
で表されるキノリンカルボキサミド誘導体又はそれらの薬理学的に許容される塩の使用。
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JP2018504418A (ja) * | 2015-02-05 | 2018-02-15 | ティルノーヴォ リミテッド | 癌を治療するためのirs/stat3二重修飾因子と抗癌剤の組み合わせ |
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GB201514760D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds and method of use |
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- 2019-09-17 KR KR1020217008052A patent/KR20210063332A/ko unknown
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EP3854397A4 (en) | 2022-07-13 |
US20220008409A1 (en) | 2022-01-13 |
AU2019341976A1 (en) | 2021-04-15 |
KR20210063332A (ko) | 2021-06-01 |
EP3854397A1 (en) | 2021-07-28 |
CN112703001A (zh) | 2021-04-23 |
JPWO2020059705A1 (ja) | 2021-08-30 |
CA3113408A1 (en) | 2020-03-26 |
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