Combination drug of temozolomide and mutant IDH1 enzyme inhibitor

Abstract

To provide combination medicines with excellent effects on cancers with IDH1 gene mutations that can reduce the dose of temozolomide without reducing the antitumor effect.SOLUTION: The present invention is completed by finding that the combination of temozolomide and a mutant IDH1 enzyme inhibitor can reduce the dose of temozolomide without reducing the antitumor effect.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a combination drug of temozolomide and a mutant IDH1 enzyme inhibitor, which has excellent antitumor activity. [Background technology]

[0002] Temozolomide is an antitumor drug classified as an alkylating agent and is used to treat brain tumors, particularly gliomas. In brain tumor treatment, the administered drug must cross the blood-brain barrier. However, because many anticancer drugs used for trunk tumors cannot cross the blood-brain barrier, very few drugs are effective against brain tumors. Temozolomide is a drug that has been shown to be effective against various malignant gliomas, including glioblastoma, the most malignant type of glioma.

[0003] Grade II and grade III malignant gliomas grow more slowly than glioblastomas, and their prognosis from initial diagnosis is relatively long. Even for these low-grade gliomas, radiation therapy or chemoradiotherapy is typically performed after surgical removal to prevent recurrence. However, this does not eradicate the microscopic cancer cells that have infiltrated into the normal brain, and they eventually recur. At recurrence, the tumor often transforms into a more malignant tumor, and the prognosis after recurrence is as poor as that of glioblastoma. Temozolomide is used for initial or recurrent treatment, but because it is an alkylating agent, it has been reported to carry a dose-dependent risk of developing secondary cancers, and long-term administration of large doses is considered inappropriate (Non-Patent Document 1).

[0004] Isocitrate dehydrogenases (IDHs) are metabolic enzymes that convert isocitrate to α-ketoglutarate (α-KG), and there are three types: IDH1, IDH2, and IDH3. IDH1 and IDH2 use nicotinamide adenine dinucleotide phosphate (NADP+) as a coenzyme and produce reduced NADPH during the reaction. IDH3 uses nicotinamide adenine dinucleotide (NAD+) as a coenzyme and is part of the tricarboxylic acid cycle (TCA cycle).

[0005] Point mutations in the IDH1 gene have been observed in a variety of tumors, including brain tumors such as gliomas, acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, peripheral T-cell lymphoma, chondrosarcoma, osteosarcoma, cholangiocarcinoma, primitive neuroectodermal tumors, B-lymphoblastic lymphoma, malignant melanoma, prostate cancer, colorectal cancer, and thyroid cancer. Among these, missense mutations at arginine 132 (R132), such as substitution with histidine (R132H) or cysteine ​​(R132C), are frequently observed. Mutant IDH1 enzymes exhibit reduced activity and acquire a new function: converting α-KG to 2-hydroxyglutarate (2-HG). Indeed, tumor cells with IDH1 gene mutations exhibit significantly elevated levels of 2-HG. High concentrations of 2-HG are known to inhibit α-KG-dependent dioxygenases, such as DNA and histone demethylases, resulting in epigenetic changes, such as increased DNA methylation, which are thought to have a significant impact on tumor progression. Mutant IDH1 enzyme inhibitors include, for example, (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid (Patent Document 1), ivosidenib (Patent Document 2), AG-881, BAY1436032, IDH305, FT-2102, and LY3410738, as well as pharmaceutically acceptable salts of these compounds. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2016 / 052697 [Patent Document 2] WO2013 / 107291 [Non-patent literature]

[0007] [Non-Patent Document 1] Momota S,et.al.,Neuro Oncol.15:1445-1450,(2013) Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a combination drug that has excellent efficacy against cancers with IDH1 gene mutations, and that allows the dose of temozolomide to be reduced without reducing the antitumor effect. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the problems. As a result, they have found that by combining temozolomide with a mutant IDH1 enzyme inhibitor, the dosage of temozolomide can be reduced without reducing the antitumor effect, and have completed the present invention. The present invention relates to the following (1) to (32).

[0010] (1) A pharmaceutical composition for use in the treatment of cancer, comprising a mutant IDH1 enzyme inhibitor, which is administered in combination with temozolomide. (2) The pharmaceutical composition according to (1), which is administered simultaneously or at different times with temozolomide. (3) Mutant IDH1 enzyme inhibitors (i) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof, and (vi) FT-2102 or a pharmaceutically acceptable salt thereof; The pharmaceutical composition according to (1) or (2), which is any one of the following: (4) The pharmaceutical composition according to any one of (1) to (3), wherein the mutant IDH1 enzyme inhibitor is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. (5) The pharmaceutical composition according to any one of (1) to (3), wherein the mutant IDH1 enzyme inhibitor is a tert-butylamine salt of the compound represented by formula (I) above. (6) The pharmaceutical composition according to any one of (1) to (5), wherein the cancer is a cancer with an IDH1 gene mutation. (7) The pharmaceutical composition according to any one of (1) to (6), wherein the cancer is a brain tumor. (8) The pharmaceutical composition according to (7), wherein the brain tumor is a glioma. (9) A pharmaceutical composition for use in the treatment of cancer, comprising administering a mutant IDH1 enzyme inhibitor and temozolomide in combination. (10) The pharmaceutical composition according to (9), wherein the mutant IDH1 enzyme inhibitor and temozolomide are administered simultaneously or at different times. (11) A mutant IDH1 enzyme inhibitor, (i) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0013] [ka]

[0014] (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof, and (vi) FT-2102 or a pharmaceutically acceptable salt thereof; The pharmaceutical composition according to (9) or (10), wherein the pharmaceutical composition is any one of the following: (12) The pharmaceutical composition according to any one of (9) to (11), wherein the mutant IDH1 enzyme inhibitor is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. (13) The pharmaceutical composition according to any one of (9) to (11), wherein the mutant IDH1 enzyme inhibitor is a tert-butylamine salt of the compound represented by formula (I). (14) The pharmaceutical composition according to any one of (9) to (13), wherein the cancer is a cancer with an IDH1 gene mutation. (15) The pharmaceutical composition according to any one of (9) to (14), wherein the cancer is a brain tumor. (16) The pharmaceutical composition according to (15), wherein the brain tumor is a glioma. (17) A method for treating cancer, comprising administering a mutant IDH1 enzyme inhibitor and temozolomide in combination. (18) The method for treating cancer according to (17), characterized in that a mutant IDH1 enzyme inhibitor and temozolomide are administered simultaneously or at different times. (19) A mutant IDH1 enzyme inhibitor, (i) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0015] [ka]

[0016] (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof; (vi) FT-2102 or a pharmaceutically acceptable salt thereof, and (vii) LY3410738 or a pharmaceutically acceptable salt thereof; The method for treating cancer according to (17) or (18), wherein the cancer is one of the following: (20) The method for treating cancer according to any one of (17) to (19), wherein the mutant IDH1 enzyme inhibitor is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. (21) The method for treating cancer according to any one of (17) to (20), wherein the mutant IDH1 enzyme inhibitor is a tert-butylamine salt of the compound represented by formula (I) above. (22) The method for treating cancer according to any one of (17) to (21), wherein the cancer is a cancer having an IDH1 gene mutation. (23) The method for treating cancer according to any one of (17) to (22), wherein the cancer is a brain tumor. (24) The method for treating cancer according to (23), wherein the brain tumor is a glioma. (25) A pharmaceutical composition for treating cancer, comprising a mutant IDH1 enzyme inhibitor and temozolomide. (26) A pharmaceutical composition for use in the treatment of cancer, which is a combination of a pharmaceutical composition containing a mutant IDH1 enzyme inhibitor and a pharmaceutical composition containing temozolomide. (27) A mutant IDH1 enzyme inhibitor is (i) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0017] [ka]

[0018] (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof; (vi) FT-2102 or a pharmaceutically acceptable salt thereof, and (vii) LY3410738 or a pharmaceutically acceptable salt thereof; The pharmaceutical composition according to (25) or (26), wherein the pharmaceutical composition is any one of the following: (28) The pharmaceutical composition according to any one of (25) to (27), wherein the mutant IDH1 enzyme inhibitor is a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. (29) The pharmaceutical composition according to any one of (25) to (27), wherein the mutant IDH1 enzyme inhibitor is a tert-butylamine salt of the compound represented by formula (I). (30) The pharmaceutical composition according to any one of (25) to (29), wherein the cancer is a cancer having an IDH1 gene mutation. (31) The pharmaceutical composition according to any one of (25) to (30), wherein the cancer is a brain tumor. (32) The pharmaceutical composition according to (31), wherein the brain tumor is a glioma. [Effects of the Invention]

[0019] According to the present invention, by combining temozolomide with a mutant IDH1 enzyme inhibitor, it is possible to reduce the dose of temozolomide while enhancing the antitumor effect, thereby providing a therapeutic agent that is highly effective against cancers with IDH1 gene mutations. [Brief explanation of the drawings]

[0020] [Figure 1] The antitumor effects of each drug when used alone and in combination are shown. DETAILED DESCRIPTION OF THE INVENTION

[0021] The pharmaceutical composition of the present invention is characterized by the administration of a mutant IDH1 enzyme inhibitor and temozolomide in combination. In this invention, "administration in combination" includes administering the active ingredients, a mutant IDH1 enzyme inhibitor and temozolomide, in the form of their respective individual formulations simultaneously or at different times, by the same route or by different routes. Furthermore, the administration frequency of each ingredient may be the same or different. Therefore, the pharmaceutical composition of the present invention may be a combination drug containing two active ingredients in a single composition, or a combination drug containing two active ingredients in separate compositions.

[0022] In the present invention, the "mutant IDH1 enzyme inhibitor" is not particularly limited as long as it is a compound that inhibits the activity of the mutant IDH1 enzyme. Evaluation of the inhibition of mutant IDH1 enzyme activity can be performed by those skilled in the art using known methods (e.g., a method disclosed in WO2016 / 052697 in which the inhibitory effect on the conversion of 2-oxoglutarate and NADPH to D-2-hydroxyglutarate and NADP+ by the mutant IDH1 enzyme is detected by WST-8 assay).

[0023] Examples of the "mutant IDH1 enzyme inhibitor" according to the present invention include the following. (i) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0024] [ka]

[0025] (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof; (vi) FT-2102 or a pharmaceutically acceptable salt thereof; (vii) LY3410738 or a pharmaceutically acceptable salt thereof.

[0026] The compound of the present invention represented by formula (I) is also known as (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid. The compound of formula (I) can be prepared, for example, by the method described in WO2016 / 052697. WO2016 / 052697 is incorporated herein by reference in its entirety.

[0027] The most preferred pharmaceutically acceptable salt of the compound of formula (I) of the present invention is (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid tert-butylamine salt (hereinafter referred to as the "test compound"). It is also known as mono(2-methylpropan-2-ammonium)(2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoate.

[0028] In the present invention, "Ivosidenib" is (2S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorodichlorobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. A drug containing ivosidenib as an active ingredient is sold under the trade name "Tibsovo." Ivosidenib can be produced, for example, according to the method described in WO2013 / 107291. WO2013 / 107291 is incorporated herein by reference in its entirety.

[0029] In the present invention, "AG881" refers to 6-(6-chloropyridin-2-yl)-2-N,4-N-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine. AG-881 is also known as vorasidenib. AG-881 can be produced, for example, by the method described in WO2015 / 003640. WO2015 / 003640 is incorporated herein by reference in its entirety.

[0030] In the present invention, "BAY1436032" is 3-(2-((4-(trifluoromethoxy)phenyl)amino)-1-((1R,5R)-3,3,5-trimethylcyclohexyl)-1H-benzo[d]imidazol-5-yl)propanoic acid. BAY1436032 can be produced, for example, according to the methods described in WO2015 / 121210 and WO2017 / 016992. WO2015 / 121210 and WO2017 / 016992 are incorporated herein by reference in their entirety.

[0031] In the present invention, "IDH305" is (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2'-(trifluoromethyl)-[3,4'-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolin-2-one. IDH305 can be produced, for example, according to the method described in WO2014 / 141104. WO2014 / 141104 is incorporated herein by reference in its entirety.

[0032] In the present invention, "FT2102" can be produced, for example, according to the method described in WO2016 / 044787, which is incorporated herein by reference in its entirety.

[0033] In the present invention, "LY3410738" is a drug undergoing clinical trials in Japan, the United States, etc. (clinical research information portal site clinical research implementation plan number: jRCT2031200178, ClinicalTrials.gov Identifier: NCT04603001).

[0034] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is not significantly toxic and can be used in pharmaceutical compositions. Compounds having an acidic substituent can be converted into salts by reacting them with a base. Examples of the salt include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; amine salts such as tert-butylamine salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts.

[0035] Compounds having basic substituents can be converted into salts by reaction with acids. Examples of such salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; C1-C6 alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate.

[0036] In the present invention, (i) a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof; (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof (vi) FT-2102 or a pharmaceutically acceptable salt thereof, and (vii) LY3410738 or a pharmaceutically acceptable salt thereof may incorporate water molecules to form a hydrate upon exposure to air or upon recrystallization, and such hydrates are also encompassed by the present invention.

[0037] In the present invention, (i) a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof; (ii) Ivosidenib or a pharmaceutically acceptable salt thereof, (iii) AG-881 or a pharmaceutically acceptable salt thereof; (iv) BAY1436032 or a pharmaceutically acceptable salt thereof; (v) IDH305 or a pharmaceutically acceptable salt thereof; (vi) FT-2102 or a pharmaceutically acceptable salt thereof, and (vii) LY3410738 or a pharmaceutically acceptable salt thereof may absorb a certain type of solvent when left in a solvent or when recrystallized, and may become a solvate. Such solvates are also encompassed by the present invention.

[0038] As used herein, "cancer" refers to all malignant tumors.

[0039] As used herein, "glioma" refers to a brain tumor that arises from glial cells, which are supportive tissue for brain nerve cells. Gliomas are also called gliomas.

[0040] The pathological diagnosis and classification of the disease are as follows: For example, the 3rd edition of the procedure for removing tumors and ulcers (Kanahara Publishing Co., Ltd.), the 4th edition of the WHO classification (WHO2007), the 4th edition of the WHO classification (WHO2007), and the 3rd edition of the standard classification of tumors. The main classification is A. Astrocytic tumors: Pilocytic astrocytoma, Pilomyxoid astrocytoma, Subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, Diffuse astrocytoma, Fibrillary astrocytoma, Gemistocytic astrocytoma, Protoplasmic astrocytoma, Anaplastic astrocytoma, Glioblastoma, Giant cell glioma. B. Glioblastoma, Gliosarcoma, Gliomatosis cerebri; C. Oligodendroglial tumors: Oligodendroglioma, Anaplastic oligoastrocytoma, Oligoastrocytoma, Anaplastic oligoastrocytoma; D. Epiendymal tumors: Subependymoma, Myxopapillary ependymoma, Epiendymoma, Cellular, Papillary, Clear cell, Tanycytic, Anaplastic ependymoma)などがあげられる.

[0041] They are also classified into four grades (WHO Grades) according to their clinical malignancy. Grade I tumors include, for example, subependymal giant cell astrocytoma, pilocytic astrocytoma, subependymoma, and myxopapillary ependymoma. Grade II tumors include, for example, pilomyxoid astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma. Grade III tumors include, for example, anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligoastrocytoma, anaplastic ependymoma, etc. Grade IV tumors include, for example, glioblastoma, giant cell glioblastoma, gliosarcoma, etc.

[0042] IDH1 gene mutations in gliomas are rare in primary glioblastomas, but are frequently found in approximately 80% of WHO grade II and III gliomas and secondary glioblastomas. It has also been revealed that IDH1 mutations occur at an early stage in gliomas with IDH1 gene mutations, and are thought to play an important role in tumor development and the subsequent accumulation of genetic abnormalities.

[0043] Examples of mutations in the "mutant IDH1" of the present invention include, but are not limited to, a mutation of arginine at position 132 of IDH1 (hereinafter referred to as R132), a mutation of glycine at position 97 (hereinafter referred to as G97), a mutation of arginine at position 100 (hereinafter referred to as R100), a mutation of histidine at position 133 (hereinafter referred to as H133), and a mutation of alanine at position 134 (hereinafter referred to as A134). Examples of mutations at R132 include, but are not limited to, a mutation to histidine (R132H), a mutation to cytosine (R132C), a mutation to leucine (R132L), a mutation to serine (R132S), a mutation to glycine (R132G), and a mutation to valine (R132V). The compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof is particularly suitable as an inhibitor of the R132 mutant of IDH1.

[0044] The amino acid sequence of a typical wild-type IDH1 from a human is described in Genebank as NP_005887.2 and UniprotKB as O75874.

[0045] The presence or absence of an IDH1 gene mutation can be confirmed by analyzing a patient's test tissue (e.g., collected by blood sampling, biopsy, etc.) using Western blot, ELISA, DNA chip, FISH assay, tissue immunostaining, other known genetic analysis methods (e.g., Sanger sequencing, next-generation DNA sequencing (NGS), PCR, ligase chain reaction (LCR), strand displacement amplification (SDA), nucleic acid sequence-based amplification (NASBA), isothermal and chineric primer-initiated amplification (ICAN), loop-mediated isothernal amplification (LAMP), etc.), or by known methods such as pathological techniques.

[0046] "Temozolomide" as used herein is an anticancer drug classified as an alkylating agent, also known as 3-methyl-4-oxo-3,4-dihydromidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide. It is used around the world under the trade name "Temodar."

[0047] As used herein, the term "alkylating agent" refers to a substance that acts as an anticancer agent by alkylating the DNA of cancer cells and inhibiting cell proliferation.

[0048] In the present invention, in addition to temozolomide and mutant IDH1 enzyme inhibitors, other antitumor agents or other treatments (eg, radiation therapy, immunotherapy) may be used in combination.

[0049] In the present invention, when a mutant IDH1 enzyme inhibitor and / or temozolomide is formulated as a pharmaceutical composition, pharmaceutically acceptable carriers used include, but are not limited to, sterile water, physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, fragrance, excipient, vehicle, preservative, binder, diluent, isotonicity agent, soothing agent, bulking agent, disintegrant, buffer, coating agent, lubricant, colorant, sweetener, thickener, flavoring agent, solubilizer, or other additive. The compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated in various forms, such as tablets, powders, granules, capsules, and liquids, depending on the therapeutic purpose. It can also be administered in the form of a liposome delivery system. The liposome can also be loaded with the above-mentioned auxiliary moieties (e.g., antibodies, ligands, etc.) that enhance useful therapeutic properties.

[0050] The present invention also relates to a method for treating cancer, which comprises administering a mutant IDH1 enzyme inhibitor in combination with temozolomide.

[0051] "Patients" who are candidates for administration of a mutant IDH1 enzyme inhibitor in combination with temozolomide include not only individuals with cancer, but also individuals who are undergoing or have undergone treatment for cancer (e.g., individuals at risk of cancer recurrence).

[0052] Administration to a patient can be oral or parenteral, including, for example, intravenous, intraarterial, intramuscular, intrathoracic, intraperitoneal, or direct administration to a target site (e.g., a tumor).

[0053] The dosage is not particularly limited as long as it is an amount effective for treating the target disease, and may be appropriately selected depending on the patient's age, body weight, symptoms, health condition, and progression of the disease. The frequency of administration is also not particularly limited and may be appropriately selected depending on the purpose. For example, the daily dosage may be administered once a day or in divided doses. When the agent of the present invention is administered to humans, the dosage range of each active ingredient is usually about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 100 mg / kg body weight per day. When administered to humans, it is preferably administered once a day or in divided doses 2 to 4 times a day, and is preferably repeated at appropriate intervals. Furthermore, in the present invention, by administering temozolomide in combination with a mutant IDH1 enzyme inhibitor, the dose of temozolomide can be reduced to preferably 1 / 5 to 4 / 5, more preferably 1 / 4 to 3 / 4, even more preferably 1 / 3 to 2 / 3, and more preferably about 1 / 2 (e.g., 2 / 5 to 3 / 5, 1 / 2) of that used in normal use (administration alone).

[0054] In the present invention, "treatment" includes not only complete recovery from cancer, but also inhibition of cancer progression (inhibition of cancer tissue proliferation, reduction of cancer tissue, etc.), inhibition of cancer occurrence (inhibition of secondary cancer occurrence, inhibition of cancer recurrence, etc.), and alleviation of cancer-related symptoms.

[0055] Furthermore, the compositions of the present invention can be used not only in the form of pharmaceutical compositions described above, but also as reagents. In the present invention, when a mutant IDH1 enzyme inhibitor and / or temozolomide is prepared as a reagent, other components acceptable for reagents, such as sterile water, physiological saline, a buffer, a preservative, etc., can be included as needed. The reagent can be administered to a subject (e.g., cells, fractions thereof, tissues, laboratory animals, etc.) at a dosage appropriate for the purpose, thereby inhibiting mutant IDH1, inhibiting 2-HG production, and suppressing tumor growth, for example. [Example]

[0056] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0057] (Example) Measurement of antitumor activity in a mouse model transplanted with glioblastoma A1074 derived from a human patient with IDH1 R132H mutation Ninety-six NSG mice (Charles River Japan) were subcutaneously transplanted with 4 mm-sized pieces of human patient-derived glioblastoma A1074 carrying the IDH1 R132H mutation into the right axilla. Tumor masses were measured using calipers as needed, and tumor volumes (mm 3 ) to (long diameter) x (short diameter) 2 The calculated value was calculated using the formula / 2 and used to confirm tumor growth and drug efficacy.

[0058] On day 24 after transplantation, mice were divided into five groups based on tumor volume: diet (CRF-1 (Oriental Yeast Co., Ltd.)) + injectable water group, diet + temozolomide aqueous solution (0.75 mg / kg) group, diet + temozolomide aqueous solution (1.5 mg / kg) group, test compound formulated feed (test compound mixed at a ratio of 0.34% (weight ratio) based on CRF-1) + injectable water group, and test compound formulated feed + temozolomide aqueous solution (0.75 mg / kg) group, with 12 mice in each group. Injectable water or temozolomide aqueous solution was administered orally for five consecutive days after group allocation. The test compound was administered in test compound formulated feed for 40 days. The compound (mutant IDH1 enzyme inhibitor) used in this test was, as described above, (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid tert-butylamine salt, synthesized by the method described in [Example 168] of WO2016 / 052697.

[0059] The tumor growth inhibition rate (%) was calculated using the following formula. Tumor growth inhibition rate (%) = {1 - (tumor volume in each treatment group at each time point) ÷ (tumor volume in the feed + water for injection group)} × 100.

[0060] The tumor volumes over 40 days after group division are shown in Table 1 and Figure 1. By combining the test compound with temozolomide, a stronger tumor growth inhibitory effect was observed, even though the dose of temozolomide was reduced.

[0061] [Table 1] [Industrial Applicability]

[0062] As described above, according to the present invention, by combining temozolomide with a mutant IDH1 enzyme inhibitor, it is possible to reduce the dosage of temozolomide without reducing the antitumor effect. Furthermore, this can also reduce the risk of developing temozolomide dose-dependent secondary cancers. Therefore, the present invention can be used in the medical field as a combination drug that is particularly effective against cancers with IDH1 gene mutations.

Claims

1. It is characterized by being administered in combination with temozolomide, A pharmaceutical composition for use in treating cancer, comprising a mutant IDH1 enzyme inhibitor, wherein the mutant IDH1 enzyme inhibitor is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (provided that temozolomide-resistant cancer is excluded from the cancers): 【Chemistry 1】

2. The pharmaceutical composition according to claim 1, which is administered simultaneously or at different times with temozolomide.

3. The pharmaceutical composition described in claim 1, characterized in that it is administered simultaneously with temozolomide.

4. The pharmaceutical composition described in claim 1, characterized in that it is administered at different times from temozolomide.

5. The pharmaceutical composition according to claim 1, wherein the mutant IDH1 enzyme inhibitor is a tert-butylamine salt of a compound represented by the following formula (I): 【Chemistry 2】

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein the cancer is a cancer having an IDH1 gene mutation.

7. The pharmaceutical composition according to claim 6, wherein the IDH1 gene mutation is a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to histidine (R132H), a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to cysteine ​​(R132C), a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to leucine (R132L), a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to serine (R132S), a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to glycine (R132G), or a gene mutation in which the 132nd amino acid in IDH1 is substituted from arginine to valine (R132V).

8. The pharmaceutical composition described in claim 6, wherein the IDH1 gene mutation is a gene mutation (R132H) in which the 132nd amino acid in IDH1 is replaced from arginine to histidine.

9. A pharmaceutical composition described in any one of claims 1 to 8, wherein the cancer is a brain tumor.

10. The pharmaceutical composition described in claim 9, wherein the brain tumor is a glioma.

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