Combination therapy for antitumor agent

Abstract

Provided is a combination therapy for an antitumor agent that exhibits a high antitumor effect using a pyridone carboxylic acid derivative.　An antitumor agent characterized by being administered in combination with other antitumor agents, and comprising, as an active ingredient, a compound represented by the formula (1) (in the formula, the wavy line represents the steric configuration being the R configuration or the S configuration) or a salt thereof, wherein the other antitumor agents are one or more types selected from cytarabine, venetoclax, azacitidine, gilteritinib, birabresib, vorinostat, GSK126, MK-8776, AZD7762, rabusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin, and AZD5991.

Description

Combination antitumor therapy

[0001] The present invention relates to a combination antitumor drug therapy using pyridonecarboxylic acid derivatives.

[0002] Certain pyridonecarboxylic acid derivatives are known to have antitumor and anticancer activities, and for example, it has been reported that pyridonecarboxylic acid derivatives having a 2-thiazolyl group have antitumor effects (Patent Document 1 and Patent Document 2). Of these, 1,4-dihydro-7-(3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, described in Patent Document 1, has been confirmed to have excellent antitumor effects against human cancer cells in vitro and in vivo (Non-Patent Documents 1 and 2), and it has also been reported that in a phase III trial, when used in combination with cytarabine, it showed a significant therapeutic effect against relapsed / refractory acute myeloid leukemia in patients 60 years of age or older compared to the placebo group (Non-Patent Document 3).

[0003] The present applicant has also found that pyridonecarboxylic acid compounds having a substituted azetidinyl group at the 7-position have excellent antitumor activity and are useful as antitumor agents (Patent Document 3). Among these, 5-methyl-7-{3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl}-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid has excellent growth inhibitory activity against acute myeloid leukemia (AML) cells, non-small cell lung cancer, prostate cancer cells, etc.

[0004] Japanese Patent No. 5079612 International Publication No. 2011 / 056566 International Publication No. 2018 / 174266

[0005] Journal of Medicinal Chemistry 47, 2097 (2004)Cancer Chemotherapy and Pharmacology 64, 53 (2009)Expert Review of Hematology 9, 529 (2016)

[0006] The present invention relates to providing a combination therapy with antitumor agents that uses a pyridonecarboxylic acid derivative and exhibits a high antitumor effect.

[0007] The present inventors have conducted extensive research to further enhance the antitumor effect of 5-methyl-7-{3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl}-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and have found that an excellent antitumor effect can be achieved by using this compound in combination with a specific antitumor agent.

[0008] That is, the present invention relates to the following inventions 1) to 15): 1) An antitumor agent containing, as an active ingredient, a compound represented by the following formula (1) or a salt thereof, which is administered in combination with another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazolinone, ... (4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５2) An agent for enhancing the antitumor effect of another antitumor agent, comprising a compound represented by the following formula (1) or a salt thereof as an active ingredient: 、 Other antitumor agents include cytarabine, venetoclax, azacitidine, gilteritinib, virabresol, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazoline, 1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin, and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５3) The agent according to 1) or 2), wherein the compound represented by formula (1) is 5-methyl-7-(3-{[(2R)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid. 4) The agent according to any one of 1) to 3), wherein the other antitumor agent is one or more selected from cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, and vorinostat. 5) The agent according to 4) for treating or preventing acute myeloid leukemia or myelodysplastic syndrome. 6) The other antitumor agent is 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] The agent according to any one of 1) to 3), wherein the compound represented by formula (1) or a salt thereof and the other antitumor agent are one or more selected from the group consisting of octadecane-1(36), 4(38), 6,11,14,16,18,20,23,29(37), 30,32,34-tridecaene-23-carboxylic acid. 7) The agent according to 6), for treating or preventing colorectal cancer, kidney cancer, ovarian cancer, breast cancer, bladder cancer, malignant melanoma, lung cancer, or fibrosarcoma. 8) The agent according to any one of 1) to 7), wherein the compound represented by formula (1) or a salt thereof and the other antitumor agent are administered to a patient simultaneously or separately with an interval between them. 9) The agent according to any one of 1) to 8), wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is administered at a daily dose of 0.1 mg to 4000 mg as the compound represented by formula (1). 10) Use of a compound represented by the following formula (1) or a salt thereof for the manufacture of an antitumor agent to be administered in combination with other antitumor agents, wherein the other antitumor agents are cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole) 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1] ... ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] Octatriacontara 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid, or one or more selected from the group consisting of octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid. 11) Use of a compound represented by the following formula (1) or a salt thereof for producing an antitumor effect enhancer that enhances the antitumor effect of another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazin-3-yl)methyl ... (3R)-piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] Octatriacontara 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid, or one or more selected from the group consisting of octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid. 12) A compound represented by the following formula (1) or a salt thereof for administration in combination with another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)- 5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin, and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] A compound or a salt thereof, which is one or more selected from octatriaconta-1(36),4(38),6,11,14,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid. 13) A compound represented by the following formula (1) or a salt thereof for enhancing the antitumor effect of another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)- )-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] A compound or a salt thereof, which is one or more selected from octatriaconta-1(36),4(38),6,11,14,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid. 14) An anticancer therapy comprising administering to a patient a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof and another antitumor agent, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole-4-yl)methyl 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, rabsertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin, and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５] Octatriacontara 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid. 15) A method for enhancing the antitumor effect of another antitumor agent, comprising administering to a patient a therapeutically effective amount of a compound represented by the following formula (1) or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazole- 4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５ ] Octatriacontara 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.

[0009] [In the formula, the wavy line indicates that the configuration is R or S.]

[0010] The antitumor agent of the present invention makes it possible to perform cancer treatment that exhibits a high antitumor effect while suppressing the onset of side effects, thereby resulting in long-term survival of patients.

[0011] The compound of the present invention represented by formula (1) is a pyridonecarboxylic acid derivative named 5-methyl-7-{3-[(oxan-2-ylmethyl)carbamoyl]azetidin-1-yl}-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Patent Document 3, Compound 078), and has excellent growth inhibitory activity against various tumor cells such as acute myeloid leukemia (AML) cells, non-small cell lung cancer, and prostate cancer cells. In particular, it is effective against acute myeloid leukemia (AML) cells, and is therefore useful as a therapeutic agent for acute myeloid leukemia (AML).

[0012] The compound represented by formula (1) includes stereoisomers of 5-methyl-7-(3-{[(2R)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (referred to as "(R)-WAC-224"), in which the steric configuration of the oxan-2-ylmethyl group is the R configuration, and 5-methyl-7-(3-{[(2S)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, in which the steric configuration of the oxan-2-ylmethyl group is the S configuration. In the present invention, either of these may be used, or a mixture of both (referred to as "WAC-224") may be used, but the 2R isomer ((R)-WAC-224) is preferred.

[0013] The compound represented by formula (1) can be produced, for example, according to the method described in Patent Document 3.

[0014] The compound represented by formula (1) can form a base addition salt. This salt also includes a chelate salt with a boron compound. Examples of base addition salts include (A) salts with alkali metals such as sodium and potassium, (B) salts with alkaline earth metals such as calcium and magnesium, (C) ammonium salts, (D) trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, 2-aminoethane-1-ol, N-methylaminoethanol, N,N-dimethylaminoethanol, 1,1,3,3-tetramethyl-2-methyl-3-methyl-2 ... Examples of the boron compound include salts with nitrogen-containing organic bases such as methylguanidine, diethanolamine, triethanolamine, dicyclohexylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, glucamine, N-methylglucamine, 1-carbamimidamido-N,N-dimethylmethanimidamide, and salts with basic amino acids such as (E) arginine, lysine, ornithine, etc. Examples of the boron compound include boron halides such as boron fluoride, and lower acyloxyborons such as acetoxyboron.

[0015] The compound of the present invention or a salt thereof can exist not only in an unsolvated form but also as a hydrate or solvate. Therefore, the compound of the present invention or a salt thereof encompasses all crystal forms and hydrates or solvates thereof.

[0016] In the present invention, the other antitumor agent means a drug (also referred to as a "concomitant drug") having an antitumor effect different from the compound represented by formula (1), and examples thereof include cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide (GSK126), 6-bromo-3-(1-methyl-1H-pyrazole-4 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide (AZD7762), rabsertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin, and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ .0 １１，１５ .0 １６，２１ .0 ２０，２４ .0 ３０，３５ ] and one or more selected from the group consisting of octadecane-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid (AZD5991). These compounds may form salts with pharmaceutically acceptable acids or bases, provided that they are used as antitumor agents. Substance information on these agents is shown in Tables 1-1 and 1-2 below, and all of these agents are commercially available as pharmaceuticals or reagents.

[0017]

[0018]

[0019] Here, cytarabine is a DNA polymerase inhibitor, venetoclax is a BCL-2 (B-cell / CLL lymphoma-2) inhibitor, azacitidine is a DNA methyltransferase inhibitor, gilteritinib is an FLT3 (FMS-like tyrosine kinase 3) inhibitor, virabresib is a BRD (bromodomain-containing protein) 2,3,4 inhibitor, and vorinostat is an HDAC (histone deacetylase) inhibitor, and of these, cytarabine, venetoclax, azacitidine, and gilteritinib are considered standard therapeutic drugs for AML. GSK126 is an EZH2 (Enhancer of zeste homolog 2) inhibitor, MK-8776, AZD7762, and ravsertib are CHK1 (Checkpoint kinase 1) inhibitors, dabrafenib and vemurafenib are BRAF (B-Raf) V600E inhibitors, olaparib is a PARP (Poly(ADP-ribose) polymerases) 1,2 inhibitor, adavosertib is a Wee1 inhibitor, alisertib is an Aurora Kinase A inhibitor, decitabine is a DNA demethylating agent, midostaurin is a multikinase inhibitor, and AZD5991 is an MCL1 (Myeloid cell leukemia 1) inhibitor.

[0020] As described in the Examples below, the combined administration of the compound represented by formula (1) and another antitumor agent exhibits a significantly stronger cell proliferation inhibitory effect (cytotoxic activity) than when the compound is administered alone. This cell proliferation inhibitory effect is evaluated by the isobologram method (Cancer Chemother Pharmacol 31:259-264, 1993), where the combination index (CI) is a synergistic effect with a CI of 0.9 or less. Therefore, combined administration of the compound represented by formula (1) or a salt thereof with another antitumor agent of the present invention is useful as an excellent anticancer therapy, and the compound represented by formula (1) or a salt thereof is useful as an antitumor agent administered in combination with the other antitumor agent in anticancer therapy. Furthermore, the compound represented by formula (1) or a salt thereof is useful as an antitumor effect enhancer for enhancing the antitumor effect of the other antitumor agent in anticancer therapy.

[0021] Cancers that can be treated or prevented by the antitumor agent of the present invention are not particularly limited, and examples thereof include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples include neuroblastoma, intestinal cancers such as rectal cancer, colon cancer, familial polyposis coli cancer and hereditary non-polyposis, colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, malignant adenoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, head and neck cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, bladder cancer, malignant melanoma, brain tumors such as glioblastoma, These include astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia-lymphoma, diffuse large B-cell lymphoma (DLBCL), myelodysplastic syndrome (MDS), hepatocellular carcinoma, gallbladder cancer, bronchial asthma cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma, as well as cancer of unknown primary origin. Among these, in terms of the combined effects, the antitumor agent of the present invention is suitable for the treatment or prevention of leukemia, colon cancer, kidney cancer, ovarian cancer, breast cancer, bladder cancer, malignant melanoma, lung cancer, fibrosarcoma, etc., and is particularly suitable for the treatment or prevention of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), particularly acute myeloid leukemia (AML) resistant to treatment with venetoclax and myelodysplastic syndrome (MDS) resistant to treatment with venetoclax. Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of cancerous myeloblasts in the bone marrow. While remission can be achieved with treatment, some patients experience relapse and become refractory, making it a poor prognosis disease. Furthermore, myelodysplastic syndrome (MDS) is a disease in which abnormalities occur in hematopoietic stem cells, which are the source of blood cells, resulting in the inability to produce normal blood cells. It is an refractory disease with a low remission rate with chemotherapy, which is known to progress to leukemia in some patients.

[0022] In the antitumor agent of the present invention, examples of other antitumor agents to be used together with the compound represented by formula (1) or a salt thereof include: 1) when the purpose is to treat or prevent acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), it is preferable to use one or more selected from cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, decitabine, midostaurin, and AZD5991; 2) when the purpose is to treat or prevent colorectal cancer, it is preferable to use one or more selected from dabrafenib, vemurafenib, adavosertib, alisertib, and vorinostat; 3) when the purpose is to treat or prevent ovarian cancer, it is preferable to use one or more selected from GSK126, ravusertib, MK-8776, and olaparib; and 4) when the purpose is to treat or prevent lung cancer. 5) when the purpose is the treatment or prevention of malignant melanoma, it is preferable to use one or more selected from dabrafenib, vemurafenib, and alisertib; 6) when the purpose is the treatment or prevention of kidney cancer, it is preferable to use one or more selected from ravusertib and MK-8776; 7) when the purpose is the treatment or prevention of bladder cancer, it is preferable to use one or more selected from AZD7762 and ravusertib; 8) when the purpose is the treatment or prevention of fibrosarcoma, it is preferable to use one or more selected from adavosertib and vorinostat; and 9) when the purpose is the treatment or prevention of breast cancer, it is preferable to use one or more selected from olaparib, adavosertib, alisertib, and vorinostat.

[0023] The antitumor agent of the present invention may be a combination drug in which effective amounts of the compound represented by formula (1) or a salt thereof and another antitumor agent are formulated in a single dosage form at an appropriate blending ratio (single-dose form), or may be a single drug formulation containing effective amounts of each of the above components so that they can be used simultaneously or separately at intervals (multiple-dose form).

[0024] The dosage form of the above-mentioned preparation is not particularly limited and can be appropriately selected depending on the purpose of treatment, and specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquid preparations, etc.), injections, suppositories, patches, ointments, etc. The compound represented by formula (1) or a salt thereof and the other antitumor agent may be in different dosage forms or the same dosage form.

[0025] Preparations containing the compound represented by formula (1) or a salt thereof and / or other antitumor agents of the present invention can be prepared by commonly known methods using pharmacologically acceptable carriers. Examples of such carriers include various carriers commonly used in conventional pharmaceutical preparations, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odor-correcting agents.

[0026] Examples of excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof. Examples of lubricants include purified talc, stearates, borax, polyethylene glycol, and mixtures thereof. Examples of binders include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures thereof. Disintegrants include, for example, dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and mixtures thereof. Diluents include, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Stabilizers include, for example, sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures thereof. Isotonicity agents include, for example, sodium chloride, boric acid, glucose, glycerin, and mixtures thereof. pH adjusters and buffers include, for example, sodium citrate, citric acid, sodium acetate, sodium phosphate, and mixtures thereof. Examples of the soothing agent include procaine hydrochloride, lidocaine hydrochloride, and mixtures thereof.

[0027] The amounts of the compound represented by formula (1) or a salt thereof and other antitumor agents in the above preparations can be appropriately determined, but generally, the compound represented by formula (1) or a salt thereof in the preparation is administered in an amount of 0.1 to 4000 mg / m per day in terms of the compound represented by formula (1).２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area). The dose of other antitumor agents is appropriately determined within the range permitted for each agent. For example, in the case of cytarabine, the dose is 0.1 to 4000 mg / m per day. ２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area), and in the case of azacitidine, 0.1 to 4000 mg / m per day ２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area), for venetoclax, it is 0.1 to 4000 mg per day, preferably 1 to 2000 mg, more preferably 10 to 800 mg.

[0028] When the antitumor agent of the present invention is formulated as a multi-dose form, the agent containing the compound represented by formula (1) or a salt thereof formulated as described above and the other antitumor agent can be packaged separately, and each pharmaceutical preparation can be taken out of its respective package at the time of administration. Alternatively, each pharmaceutical preparation can be packaged in a form suitable for single combined administration.

[0029] The dose of the antitumor agent of the present invention is not particularly limited as long as the compound represented by formula (1) or a salt thereof and the other antitumor agent can synergistically exert antitumor effects to effectively treat cancer. The dose is appropriately determined depending on the patient's age, type of cancer, stage of disease, presence or absence of metastasis, treatment history, presence or absence of other drugs, etc., but the compound represented by formula (1) or a salt thereof is administered in an amount equivalent to the compound represented by formula (1) of 0.1 to 4000 mg / m per day. ２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area). The dose of other antitumor agents is appropriately determined within the range permitted for each agent. For example, in the case of cytarabine, the dose is 0.1 to 4000 mg / m per day.２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area), and in the case of azacitidine, 0.1 to 4000 mg / m per day ２ (body surface area), preferably 1 to 1000 mg / m ２ (body surface area), more preferably 10 to 400 mg / m ２ (body surface area), for venetoclax, examples include 0.1 to 4000 mg per day, preferably 1 to 2000 mg, and more preferably 10 to 800 mg.

[0030] The order and interval of administration of the compound represented by formula (1) or a salt thereof and the other antitumor agent in the present invention are not particularly limited as long as a synergistic effect can be obtained. In addition, when a multiple-dose formulation is used, each individual formulation may be administered simultaneously or at intervals.

[0031] <Materials and Experimental Methods> 1. Cell culture and preparation of cell suspension 1-1. Preparation of human-derived acute myeloid leukemia (AML) cell line Human-derived acute myeloid leukemia (AML) cell lines HEL92.1.7, TF-1, KG-1, HL-60, MV4-11, and MOLM13 (Table 2 below) were used. HEL92.1.7 and MOLM13 were cultured in RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS) (GIBCO), TF-1 in RPMI-1640 medium containing 10% fetal bovine serum and 2 ng / mL recombinant human GM-CSF (BioLegend), KG-1 and HL-60 in IMDM medium containing 20% ​​FBS (Fujifilm Wako Pure Chemical Industries, Ltd.), and MV4-11 in IMDM medium containing 10% FBS to prepare cell suspensions.

[0032]

[0033] 1-2. Preparation of Tumor Cell Lines (Other Than AML Cell Lines) The following cell lines were used: UM-UC-3, a bladder cancer cell line; 786-O, a kidney cancer cell line; SK-OV-3, an ovarian cancer cell line; A375, SK-MEL5, and SK-MEL28, which are malignant melanoma cell lines; RKO and HCT116, which are colon cancer cells; MDA-MB-462, MDA-MB-436, and MDA-MB-468, which are breast cancer cell lines; NCI-H460, which is a lung cancer cell line; and HT1080, which is a fibrosarcoma cell line (Table 3 below).

[0034] UM-UC-3, A375, SK-MEL5, SK-MEL28, RKO, MDA-MB-436, MDA-MB-468, and HT1080 were cultured in 10% FBS-containing DMEM medium (Fujifilm Wako Pure Chemical Industries, Ltd.), 786-O and NCI-H460 in 10% FBS-containing RPMI-1640 medium, and SK-OV-3 and HCT116 in 10% FBS-containing McCoy's 5a medium (ThermoFisher Scientific) to prepare cell suspensions.

[0035]

[0036] 1-3. Preparation of venetoclax-resistant human-derived acute myeloid leukemia (AML) cell lines The venetoclax-resistant human acute myeloid leukemia (AML) cell lines used were HEL92.1.7, TF-1, KG-1, HL-60, MV4-11, and MOLM13 (Table 2 above). EC values ​​for venetoclax were measured using RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS) (GIBCO) for HEL92.1.7 and MOLM13, RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum and 2 ng / mL recombinant human GM-CSF (BioLegend) for TF-1, IMDM medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 20% ​​FBS for KG-1 and HL-60, and IMDM medium containing 10% FBS for MV4-11. ５０Culture was initiated in venetoclax-containing medium with initial concentrations of (HEL92.1.7: 5 μM, TF-1: 5 μM, KG-1: 1.5 μM, HL-60: 0.02 μM, MV4-11: 0.02 μM, MOLM13: 0.02 μM), and the concentrations were gradually increased over long-term culture to obtain resistant clones (Table 4 below). ５０ All of these were elevated compared to the venetoclax-untreated group (hereinafter referred to as the parent line), demonstrating reduced susceptibility to venetoclax. The obtained resistant lines are hereafter referred to as VR (venetoclax resistance) at the end of their cell names, and subsequent cultures were performed under the same conditions as the parent line to prepare cell suspensions.

[0037]

[0038] 2. Drugs (1) "(R)-WAC-224" (5-methyl-7-(3-{[(2R)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid), "WAC-224" (5-methyl-7-(3-{[(2R)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid), A mixture of so-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 5-methyl-7-(3-{[(2S)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid) was synthesized in accordance with the method described in Patent Document 3 and used.

[0039] (2) Comparative Compound “Vosaroxin” (1,4-dihydro-7-(3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid) was synthesized according to the method described in Patent Document 1 and used.

[0040] (3) Concomitant medications: cytarabine (Fujifilm Wako Pure Chemical Industries, Ltd.), venetoclax (Combi-Blocks), azacitidine (Fujifilm Wako Pure Chemical Industries, Ltd.), gilteritinib (Medchemexpress), decitabine (Angened), midostaurin (BLD The following drugs were purchased and used: AZD5991 (MCE), virabresib (Chemexpress), vorinostat (Abcam), AZD7762 (Funakoshi), ravsertib (Funakoshi), MK-8776 (Cosmo Bio), dabrafenib (Selleck), vemurafenib (ChemieTek), olaparib (Selleck), adavosertib (ChemieTek), alisertib (adooq bio), and vorinostat (Abcam).

[0041] Example 1 Evaluation of the tumor cell proliferation inhibitory effect of drug combinations Cell suspensions were seeded into a 96-well plate at 25,000 to 50,000 cells / well for AML cells, including venetoclax-resistant cells, and at 4,000 to 5,000 cells / well for other cells. Drug solutions adjusted to the concentrations shown in (1) to (5) below were added to the cell culture medium. The maximum concentrations of each compound when used alone or in combination were 40 μmol / L for (R)-WAC-224, 200 μmol / L for cytarabine, 40 μmol / L for venetoclax, 200 μmol / L for azacitidine, 0.08 μmol / L for gilteritinib, 160 μmol / L for decitabine, 2 μmol / L for midostaurin, 16 μmol / L for AZD5991, 16 μmol / L for virabresive, 1.6 μmol / L for vorinostat, and 8 μmol / L for vorinostat. The compound solutions used were 1 μmol / L for AZD7762, 6.5 μmol / L for rabuseritib, 13 μmol / L for SCH900776, 3.2 μmol / L for dabrafenib, 11 μmol / L for vemurafenib, 50 μmol / L for olaparib, 16 μmol / L for adavosertib, 8 μmol / L for alisertib, and 20 μmol / L for vorinostat, with concentrations in a 1.33-, 2-, or 4-fold dilution series, respectively.

[0042] 37°C, 5% CO ２After 72 hours of incubation under these conditions, 10 μL of Cell Counting Kit-8 reagent (Dojindo Laboratories) was added to each well. After 2 hours of incubation, absorbance at a wavelength of 450 nm was measured using a plate reader (TECAN), and the EC ５０ The values ​​were calculated using Kyplot Software (KyensLab). For example, the combination index (CI) value of (R)-WAC-224 and the concomitant drug was calculated using the following formula: (Equation 1) CI = (EC of (R)-WAC-224 when used in combination) ５０ / EC of (R)-WAC-224 as a single agent ５０ ) + (EC ５０ / EC of single agent and combination compound ５０ )

[0043] The combined effect was evaluated according to the grading system based on the CI value shown below. A CI value of <0.9 indicates a synergistic effect, and the lower the value, the stronger the synergistic effect. <0.1: Very strong synergistic effect 0.1-0.3: Strong synergistic effect 0.3-0.7: Synergistic effect 0.7-0.85: Mild synergistic effect 0.85-0.9: Slight synergistic effect 0.9-1.1: Additive effect >1.1: Antagonistic effect

[0044] (1) Growth inhibitory effect on AML cells <1> (R)-WAC-224 and an AML therapeutic drug (standard AML therapeutic drug) were dissolved in DMSO and mixed under the conditions shown in Tables 5-1 and 5-2 below. When used alone, the same concentration as when used in combination was used as a single agent, and when used in combination, the drugs were mixed to achieve the indicated concentration.

[0045]

[0046]

[0047] <Results> The results are shown in Table 6.

[0048]

[0049] 1) In the combined use of (R)-WAC-224 and cytarabine, the CI values ​​for MOLM13 and HL-60 were 0.47 and 0.58, respectively, confirming that the effect obtained by the combination was a synergistic effect; the CI values ​​for KG-1 and HEL-92.1,7 were 0.73 and 0.77, respectively, confirming that the effect obtained by the combination was a mild synergistic effect; and the CI value for MV4-11 was 0.87, confirming that the effect obtained by the combination was a slight synergistic effect. 2) In the combined use of (R)-WAC-224 and venetoclax, the CI value for MOLM13 was 0.25, indicating that the effect obtained by the combination was a strong synergistic effect; the CI values ​​for TF-1 and KG-1 were 0.34 and 0.69, respectively, indicating that the effect obtained by the combination was a synergistic effect; and the CI values ​​for MV4-11 and HL-60 were 0.73 and 0.76, respectively, indicating that the effect obtained by the combination was a mild synergistic effect. 3) In the combined use of (R)-WAC-224 and azacitidine, the CI value for MV4-11 was 0.62, confirming that the effect obtained by the combination was a synergistic effect; the CI values ​​for HEL-92.1.7, KG-1, and MOLM13 were 0.80, 0.85, and 0.85, respectively, confirming that the effect obtained by the combination was a mild synergistic effect; and the CI value for TF-1 was 0.86, confirming that the effect obtained by the combination was a slight synergistic effect. 4) In the combined use of (R)-WAC-224 and gilteritinib, the CI value for MOLM13 was 0.61, confirming that the effect obtained by the combination was a synergistic effect; and the CI value for MV4-11 was 0.72, confirming that the effect obtained by the combination was a mild synergistic effect. 5) In the combined use of (R)-WAC-224 and decitabine, the CI value for KG-1 was 0.76, confirming that the effect obtained by the combination was a synergistic effect. The CI values ​​for MOLM13 and HEL-92.1.7 were 0.76 and 0.71, respectively, confirming that the effect obtained by the combination was a mild synergistic effect.6) In the combined use of (R)-WAC-224 and midostaurin, the CI value for MV4-11 was 0.88, confirming that the effect obtained by the combined use was a slight synergistic effect, and the CI value for MOLM13 was 1.05, confirming that the effect obtained by the combined use was an additive effect.

[0050] (2) Growth inhibitory effect on AML cells <2> Vosaroxin (comparative compound) and an AML therapeutic agent were dissolved in DMSO and mixed under the conditions shown in Table 7. When used alone, the same concentration as when used in combination was used as a single agent, and when used in combination, the agents were mixed to achieve the indicated concentrations.

[0051]

[0052] <Results> The results are shown in Tables 8-1 and 8-2.

[0053]

[0054]

[0055] (R)-WAC-224 exhibited a synergistic effect in tumor cell proliferation inhibition compared to vosaroxin.

[0056] (3) Growth inhibitory effect on AML cells <3> (R)-WAC-224 and an AML therapeutic drug (non-standard AML therapeutic drug) were mixed under the conditions shown in Table 9 below. When used alone, the same concentration as when used in combination was used as a single agent, and when used in combination, the drugs were mixed to achieve the indicated concentration.

[0057]

[0058] <Results> The results are shown in Table 10.

[0059]

[0060] 1) In the combined use of (R)-WAC-224 and villabresib, the CI value for KG-1 was 0.39, confirming that the effect obtained by the combination was a synergistic effect, and the CI value for HL-60 was 0.78, confirming that the effect obtained by the combination was a mild synergistic effect. 2) In the combined use of (R)-WAC-224 and vorinostat, the CI values ​​for MV4-11 and KG-1 were 0.70 and 0.72, respectively, confirming that the effect obtained by the combination was a mild synergistic effect.

[0061] (4) Growth inhibitory effect on various tumor cells WAC-224 and other antitumor agents were mixed under the conditions shown in Tables 11-1, 11-2, and 11-3 below. When used alone, the same concentration as when used in combination was used as a single agent, and when used in combination, the agents were mixed to the indicated concentration.

[0062]

[0063]

[0064]

[0065] <Results> The results are shown in Tables 12-1, 12-2, and 12-3.

[0066]

[0067] 1) In the combined use of WAC-224 and AZD7762, the CI value for UM-UC-3 was 0.83, confirming that the combined effect against bladder cancer was a mild synergistic effect. 2) In the combined use of WAC-224 and ravsertib, the CI value for 786-O was 0.68, confirming that the combined effect against kidney cancer was a synergistic effect. The CI value for UM-UC-3 was 0.75, confirming that the combined effect against bladder cancer was a mild synergistic effect. The CI value for SK-OV-3 was 0.87, confirming that the combined effect against ovarian cancer was a slight synergistic effect. 3) In the combined use of WAC-224 and MK-8776, the CI values ​​for 786-O and SK-OV-3 were 0.73 and 0.78, respectively, confirming that the combined effect against kidney cancer and ovarian cancer was a mild synergistic effect.

[0068]

[0069] 1) In the combined use of WAC-224 and dabrafenib, the CI values ​​for SK-MEL5 and RKO were 0.18 and 0.17, respectively, confirming a strong synergistic effect against malignant melanoma and colorectal cancer. The CI values ​​for SK-MEL28 and A375 were 0.69 and 0.85, respectively, confirming a mild synergistic effect against malignant melanoma. 2) In the combined use of WAC-224 and vemurafenib, the CI value for SK-MEL5 was 0.29, confirming a strong synergistic effect against malignant melanoma. The CI value for RKO was 0.43, confirming a synergistic effect against colorectal cancer. The CI value for SK-MEL28 was 0.77, confirming a mild synergistic effect against malignant melanoma. 3) In the combined use of WAC-224 and olaparib, the CI value for MDA-MB-462 was 0.61, confirming that the combined effect against ovarian cancer was a synergistic effect, and the CI value for SK-OV-3 was 0.77, confirming that the combined effect against breast cancer was a mild synergistic effect.

[0070]

[0071] 1) In the combined use of WAC-224 and adavosertib, the CI values ​​for HT1080 and MDA-MB-436 were 0.55 and 0.62, respectively, confirming that the effect of the combination against fibrosarcoma and breast cancer was synergistic. The CI values ​​for HCT116 and NCI-H460 were 0.71 and 0.75, respectively, confirming that the effect of the combination against colon cancer and lung cancer was mildly synergistic. 2) In the combined use of WAC-224 and alisertib, the CI values ​​for HCT116 and A375 were 0.17 and 0.21, respectively, confirming that the effect of the combination against colon cancer and malignant melanoma was strong synergistic. The CI value for MDA-MB-436 was 0.55, confirming that the effect of the combination against breast cancer was synergistic. 3) In the combined use of WAC-224 and vorinostat, the CI values ​​for HT1080, MDA-MB-468, and NCI-H460 were 0.33, 0.57, and 0.68, respectively, confirming that the combined effect against fibrosarcoma, breast cancer, and lung cancer was a synergistic effect. The CI value for HCT116 was 0.81, confirming that the combined effect against colorectal cancer was a mild synergistic effect.

[0072] (5) Growth inhibitory effect on venetoclax-resistant AML cells (R)-WAC-224 and an AML therapeutic drug (standard AML therapeutic drug) were dissolved in DMSO and mixed under the conditions shown in Tables 13-1 to 13-2 below. When used alone, the same concentration as when used in combination was used as a single agent, and when used in combination, the drugs were mixed to achieve the indicated concentration.

[0073]

[0074]

[0075] <Results> The results are shown in Table 14.

[0076]

[0077] 1) In the combined use of (R)-WAC-224 and cytarabine, the CI values ​​for KG-1-VR, MV4-11-VR, and HL-60-VR were 0.45, 0.65, and 0.63, respectively, confirming that the effect obtained by the combination was synergistic. 2) In the combined use of (R)-WAC-224 and venetoclax, the CI value for MOLM13-VR was 0.20, confirming that the effect obtained by the combination was a strong synergistic effect; the CI values ​​for MV4-11-VR, HEL-92.1.7-VR, and HL-60-VR were 0.37, 0.58, and 0.58, respectively, confirming that the effect obtained by the combination was synergistic; and the CI value for TF-1-VR was 1.03, confirming that the effect obtained by the combination was an additive effect. 3) In the combined use of (R)-WAC-224 and azacitidine, the CI values ​​for MV4-11-VR, HEL-92.1.7-VR, and HL-60-VR were 0.70, 0.30, and 0.31, respectively, confirming that the effect obtained by the combination was a synergistic effect; the CI value for TF-1-VR was 0.85, confirming that the effect obtained by the combination was a mild synergistic effect; the CI value for MOLM13-VR was 0.86, confirming that the effect obtained by the combination was a slight synergistic effect; and the CI value for KG-1-VR was 1.02, confirming that the effect obtained by the combination was an additive effect. 4) In the combined use of (R)-WAC-224 and gilteritinib, the CI value for MV4-11-VR was 0.69, confirming that the effect obtained by the combination was a synergistic effect, and the CI value for MOLM13-VR was 0.79, confirming that the effect obtained by the combination was a mild synergistic effect. 5) In the combined use of (R)-WAC-224 and AZD5991, the CI value for MV4-11-VR was 0.45, confirming that the effect obtained by the combination was a synergistic effect, the CI value for MOLM13-VR was 0.79, confirming that the effect obtained by the combination was a mild synergistic effect, and the CI value for KG-1-VR was 0.98, confirming that the effect obtained by the combination was an additive effect.

Claims

1. A compound of the formula (1) below, which is administered in combination with another antitumor agent: [wherein the wavy line represents an R or S configuration] or a salt thereof as an active ingredient, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R -piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ]An antitumor agent which is one or more selected from octatriacin-1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.

2. The following formula (1): (wherein the wavy line represents an R or S configuration) or a salt thereof as an active ingredient, an agent for enhancing the antitumor effect of another antitumor agent, wherein the other antitumor agent is selected from the group consisting of cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-methyl- -[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, rabsertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ]An antitumor effect enhancer, which is one or more selected from octatriacinth 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.

3. The agent according to claim 1 or 2, wherein the compound represented by formula (1) is 5-methyl-7-(3-{[(2R)-oxan-2-ylmethyl]carbamoyl}azetidin-1-yl)-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.

4. The agent according to any one of claims 1 to 3, wherein the other antitumor agent is one or more selected from cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, and vorinostat.

5. The agent according to claim 4 for treating or preventing acute myeloid leukemia or myelodysplastic syndrome.

6. Other antitumor agents include 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3 -(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ] Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid, the agent according to any one of claims 1 to 3.

7. The agent according to claim 6 for treating or preventing colorectal cancer, kidney cancer, ovarian cancer, breast cancer, bladder cancer, malignant melanoma, lung cancer or fibrosarcoma.

8. The agent according to any one of claims 1 to 7, wherein the compound represented by formula (1) or a salt thereof and the other antitumor agent are administered to a patient simultaneously or separately with an interval therebetween.

9. The agent according to any one of claims 1 to 8, wherein the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof is administered in an amount of 0.1 mg to 4000 mg per day as the compound represented by formula (1).

10. For producing an antitumor agent to be administered in combination with other antitumor agents, a compound of the following formula (1): (wherein the wavy line represents an R or S configuration) or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-4-yl]- [0036] pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ] Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid or more.

11. For producing an antitumor effect enhancer that enhances the antitumor effect of another antitumor agent, a compound represented by the following formula (1): (wherein the wavy line represents an R or S configuration) or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidin-4-yl]- [0036] pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ] Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid or more.

12. A compound of the formula (1) below for co-administration with other antitumor agents: [wherein the wavy line represents an R or S configuration] or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidine 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, rabsertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ]Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid or a salt thereof.

13. A compound represented by the following formula (1) for enhancing the antitumor effect of another antitumor agent: [wherein the wavy line represents an R or S configuration] or a salt thereof, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-[(3R)-piperidine 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, rabsertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ]Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid or a salt thereof.

14. The following formula (1): [wherein the wavy line represents an R or S configuration] or a salt thereof and another antitumor agent are administered to a patient in a therapeutically effective amount, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)- 5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ] Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.

15. The following formula (1): (wherein the wavy line represents an R or S configuration) or a salt thereof is administered to a patient in a therapeutically effective amount, wherein the other antitumor agent is cytarabine, venetoclax, azacitidine, gilteritinib, virabresib, vorinostat, 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)- )-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide, ravusertib, dabrafenib, vemurafenib, olaparib, adavosertib, alisertib, decitabine, midostaurin and 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1 ４，７ . 0 １１，１５ . 0 １６，２１ . 0 ２０，２４ . 0 ３０，３５ ] Octatriacontour 1 (36), 4 (38), 6, 11, 14, 16, 18, 20, 23, 29 (37), 30, 32, 34-tridecaene-23-carboxylic acid.

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