WO2021167006A1 - Antitumor effect enhancing agent containing uracil derivative compound - Google Patents

Abstract

Provided is a method which is for treating a tumor and by which a remarkably excellent antitumor effect is exhibited and side effects are few.　This antitumor effect enhancing agent for 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor contains, as an active ingredient, (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

Description

Antitumor effect enhancer containing uracil derivative compound

The present invention relates to an antitumor effect enhancer and an antitumor agent using a uracil derivative compound having a deoxyuridine triphosphatase (dUTPase) inhibitory action.

It is known to block not only a single target in vivo but also multiple targets simultaneously to treat a tumor. In order to inhibit a plurality of targets at the same time, it is often carried out by taking a plurality of compounds that inhibit different targets in combination, or by providing a mixture in which such compounds are combined in advance. However, at present, where there are an infinite number of combinations of multiple compounds, many of them have enhanced toxicity and side effects, are not suitable for treating tumors, and must be abandoned during research and development.
Furthermore, when there are two or more different compounds that inhibit the same target, and when they are combined with compounds that inhibit other targets, the effects and side effects are between the two or more different compounds. It is no exaggeration to say that they usually show different behaviors that cannot be inferred from each other. Therefore, it is very difficult to take a combination of compounds having an antitumor effect or to provide a mixture.

DNA methylation is known as one of the gene expression regulation mechanisms that suppress gene expression. Further, in tumors, suppression of expression of genes that originally suppress tumor growth is observed by advanced DNA methylation, and inhibition of DNA methylation is expected to be useful for tumor treatment.
DNA methyltransferase (DNMT) is a protein involved in DNA methylation, and its inhibition will suppress DNA methylation. Therefore, treatment of tumors with a DNA methyltransferase inhibitor (DNMTi) is expected. DNA methyltransferase inhibitors include 5-fluoro-2'-deoxycytidine (FdCyd), 5-aza-2'-deoxycytidine (decitabine; 5-AZA-CdR), and zebularine as having a cytidine skeleton. , Guadecitabine (SGI-110), azacitidine (Azacitidine) and the like are known, and procaineamide, RG-108, SGI-1027 and the like are known as those having no cytidine skeleton (Non-Patent Document 1). Drugs that inhibit these DNA methyltransferases are hematopoietic tumors (acute myelogenous leukemia (AML), myelogenous dysplasia syndrome (MDS), multiple myelogenous tumors (MM), chronic myelogenous leukemia (CML), acute lymphocytic). Treatment effect for leukemia (ALL), etc.), solid cancer (breast cancer, lung cancer, colon cancer, liver cancer, pancreatic cancer, prostate cancer, esophageal cancer, head and neck cancer, renal cancer, skin cancer, bone / soft tumor, etc.) (Non-Patent Document 2), some compounds have been clinically tested, and some have been approved as pharmaceuticals (Non-Patent Document 3).

However, a DNA methyltransferase inhibitor having a cytidine skeleton is easily transformed into a uridine skeleton by the enzymatic activity of cytidine deaminase (CDA) and easily inactivates the DNA methyltransferase inhibitory activity (Non-Patent Document 4). Therefore, when a DNA methyltransferase inhibitor having a cytidine skeleton is used in the treatment of tumors, it has been proposed to target cytidine deaminase as a further therapeutic target at the same time, and a combination of the DNA methyltransferase inhibitor and the cytidine deaminase inhibitor (CDAi) has been proposed. It has been proposed to use it. Known examples of cytidine deaminase inhibitors include tetrahydrouridine (THU), sedazuridine (CDZ), deoxy THU, ER-876437, and ER-876400 (Non-Patent Document 1). Currently, clinical trials such as a combination of decitabine and sedazlydin (ASTX727) and a combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine are being conducted.

However, even if the DNA methyltransferase inhibitor, which is the main antitumor agent, escapes degradation in the body by the cytidine deaminase inhibitor and reaches the tumor, it is a transporter involved in the uptake of the DNA methyltransferase inhibitor itself into tumor cells. It has been suggested that (ENT1) and the subsequent decrease in deoxycytidine kinase (DCK), which controls activation, and further increase in cytidine deaminase are simultaneously induced to reduce the effect of the drug itself that inhibits DNA methyltransferase (). Non-Patent Documents 5 and 6). In fact, many clinical studies of DNA methyltransferase inhibitors alone and combined use of DNA methyltransferase inhibitors and cytidine deaminase inhibitors have been conducted, but their clinical effects are limited (Non-Patent Document 7). .. In clinical trials of azacitidine, nausea, vomiting, diarrhea, and hepatotoxicity were observed (Non-Patent Document 8), and in addition, 5-fluoro-2'-deoxycitidine was observed. In clinical trials using tetrahydrouridine in combination, colitis, malaise with elevations in liver enzymes, thrombocytopenia, and leukopenia were performed early from the start of the study. -Thrombocytopenia with gastrointestinal hepatotoxicities has been recognized as dose-limiting toxicity (Non-Patent Document 9), and such side effects are the exposure required for the clinical effect of DNA methyltransferase inhibitors. It has become a clinical issue, hindering its continuation.

On the other hand, (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propane -1-Sulfonamide (hereinafter also referred to as "Compound 1") or a pharmaceutically acceptable salt thereof, also called TAS-114, inhibits deoxyuridine triphosphatase and, as a result, is one of the nucleic acid antimetabolites. It is known as a compound that enhances the antitumor effect of one FU antitumor agent (Patent Document 1).
However, so far, the combined use of a uracil derivative compound having a deoxyuridine triphosphatase inhibitory activity and a DNA methyl transferase inhibitor can also be used in combination with a uracil derivative compound having a deoxyuridine triphosphatase inhibitory activity, a DNA methyl transferase inhibitor and citidine deaminase. There is no literature that explicitly or suggests the combined use with inhibitors.

International Publication No. 2011/0655441

Biomolecules. 2017; 7: 3 Biomark Res. 2017; 5: 1 Br J Cancer. 2018; 118: 1062-1073 Anticancer Research Res. 2013; 33: 2989-2996 Oncol Lett. 2015; 10: 761-767 PLoS One. 2011; 6 (8): e23372 Epigenomics. 2010; 2 (1): 71-86 Pharmaceuticals 2010, 3, 2022-2044 Cancer Chemother Pharmacol. 2015; 75: 537-546

An object of the present invention is to provide a method for treating a tumor which exhibits a remarkably excellent antitumor effect and has few side effects.

As a result of diligent studies to solve the above problems, the present inventor has introduced compound 1, which is a uracil derivative having deoxyuridine triphosphatase inhibitory activity, into 5-fluoro-, which is a DNA methyl transferase inhibitor having a cytidine skeleton. It has been found that when used in combination with 2'-deoxycytidine and a cytidine deaminase inhibitor, the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor is enhanced, and at the same time, side effects are suppressed. The present invention has been completed.

That is, the present invention provides the following inventions [1] to [6].
[1] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) An effect enhancer of an antitumor agent in which 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination, which comprises propane-1-sulfonamide or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) An antitumor agent comprising a combination of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor.
[3] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A kit formulation for combined administration with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors containing propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and instructions for use.
The instructions for use include (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-) for patients to whom it should be applied. Dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor are administered in combination. The kit formulation that is described.
[4] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) An antitumor agent consisting of a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[5] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) An antitumor agent containing a cytidine deaminase inhibitor for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine.
[6] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) An antitumor agent containing 5-fluoro-2'-deoxycytidine for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor.

The present invention also provides the following inventions [7] to [15].
[7] The agent according to any one of [1] to [6], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[8] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The agent according to any one of [1] to [7], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered.
[9] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. The agent according to [8].
[10] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The agent according to [8], which is 7.5 to 75.
[11] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The agent according to [8], which is 0.42 to 4.2.
[12] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection to any of [1] to [7]. The agent described.
[13] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. The agent according to [12].
[14] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The agent according to [12], which is 1.5 to 15.
[15] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The agent according to [12], which is 0.11 to 1.1.

The present invention also provides the following inventions [16] to [20].
[16] (R) -N- (1- (3- (cyclopentyloxy) phenyl) for the production of an effect enhancer of an antitumor agent in which 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination. ) Ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[17] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) for producing an antitumor agent in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor. Use of -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[18] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Use of a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor to produce an antitumor agent for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[19] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Use of a cytidine deaminase inhibitor to produce an antitumor agent for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine.
[20] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Use of 5-fluoro-2'-deoxycytidine to produce an antitumor agent for administration in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor.

The present invention also provides the following inventions [21] to [29].
[21] The use according to any one of [16] to [20], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[22] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The use according to any one of [16] to [21], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered.
[23] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. There is a use according to [22].
[24] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: Use according to [22], which is 7.5 to 75.
[25] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The use according to [22], which is 0.42 to 4.2.
[26] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection to any of [16] to [21]. Use of description.
[27] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. There is a use according to [26].
[28] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The use according to [26], which is 1.5 to 15.
[29] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The use according to [26], which is 0.11 to 1.1.

The present invention also provides the following inventions [30] to [39].
[30] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl)-for use in enhancing the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor. 3-((2,4-Dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[31] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-) according to [30], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. 3,4-Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[32] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) (R) -N- (1- (3- (Cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or its pharmacy Tolerable salt.
[33] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to 5-fluoro-2'-deoxycytidine to a cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) according to [32]. ) Methylene) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[34] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: 7.5-75 according to [32] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[35] The citidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-). The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlidine is 1: 0.046 to 0. 46: 0.42 to 4.2 (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) according to [32]. -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[36] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) (R) according to [30] or [31], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycitidine and citidine deaminase inhibitor are administered by injection. ) -N- (1- (3- (Cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfon Amide or a pharmaceutically acceptable salt thereof.
[37] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to 5-fluoro-2'-deoxycytidine to a cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) according to [36]. ) Methylene) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[38] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: 1.5 to 15 of (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) according to [36]. -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[39] The citidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-). The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlidine is 1: 0.012 to 0. 12: 0.11 to 1.1 according to [36] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

The present invention also provides the following inventions [40] to [49].
[40] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) for use in the treatment of tumors A combination of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor.
[41] The combination according to [40], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[42] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The combination according to [40] or [41], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered.
[43] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A combination according to [42].
[44] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The combination according to [42], which is 7.5 to 75.
[45] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The combination according to [42], which is 0.42 to 4.2.
[46] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The combination according to [40] or [41], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection.
[47] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A combination according to [46].
[48] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The combination according to [46], which is 1.5 to 15.
[49] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The combination according to [46], which is 0.11 to 1.1.

The present invention also provides the following inventions [50] to [59].
[50] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for use in the treatment of tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.
[51] The combination according to [50], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[52] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The combination according to [50] or [51], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered.
[53] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A combination according to [52].
[54] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The combination according to [52], which is 7.5 to 75.
[55] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The combination according to [52], which is 0.42 to 4.2.
[56] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The combination according to [50] or [51], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection.
[57] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A combination according to [56].
[58] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The combination according to [56], which is 1.5 to 15.
[59] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The combination according to [56], which is 0.11 to 1.1.

The present invention also provides the following inventions [60] to [69].
[60] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A cytidine deaminase inhibitor used in the treatment of tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine.
[61] The cytidine deaminase inhibitor according to [60], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[62] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The cytidine deaminase inhibitor according to [60] or [61], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered.
[63] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. [62] The cytidine deaminase inhibitor according to the above.
[64] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The cytidine deaminase inhibitor of [62], which is 7.5 to 75.
[65] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin is 1: 0.046 to 0. 46: The cytidine deaminase inhibitor according to [62], which is 0.42 to 4.2.
[66] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The cytidine deaminase according to [60] or [61], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection. Inhibitor.
[67] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. [66] The cytidine deaminase inhibitor according to the above.
[68] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The cytidine deaminase inhibitor according to [66], which is 1.5 to 15.
[69] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin is 1: 0.012 to 0. 12: The cytidine deaminase inhibitor according to [66], which is 0.11 to 1.1.

The present invention also provides the following inventions [70] to [79].
[70] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) 5-Fluoro-2'-deoxycytidine for use in the treatment of tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor.
[71] The 5-fluoro-2'-deoxycytidine according to [70], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[72] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) 5-Fluoro-2'described in [70] or [71], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered. -Deoxycytidine.
[73] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor have a molar ratio of 1: 0.0001 to 10000: 0.0001 to 10000. A 5-fluoro-2'-deoxycytidine according to [72].
[74] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: 5-fluoro-2'-deoxycytidine according to [72], which is 7.5 to 75.
[75] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The 5-fluoro-2'-deoxycytidine according to [72], which is 0.42 to 4.2.
[76] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) 5-Fluoro-2'-deoxycytidine and cytidine deaminase inhibitors are administered orally with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors are administered by injection [70] or [71]. Fluoro-2'-deoxycytidine.
[77] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor have a molar ratio of 1: 0.0001 to 10000: 0.0001 to 10000. A 5-fluoro-2'-deoxycytidine according to [76].
[78] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The 5-fluoro-2'-deoxycytidine according to [76], which is 1.5 to 15.
[79] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazulidine is 1: 0.012 to 0. 12: The 5-fluoro-2'-deoxycytidine according to [76], which is 0.11 to 1.1.

The present invention also provides the following inventions [80] to [84].
[80] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Antitumor of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors, including administering an effective amount of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject in need thereof. Effect enhancement method.
[81] A method for treating tumors, which is required for subjects, includes (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-). Effectiveness of 3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor A method comprising administering an amount.
[82] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A method of treating tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, for subjects in need of it, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors. A method comprising administering an effective amount of.
[83] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A method of treating tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof in combination with 5-fluoro-2'-deoxycytidine, which is a cytidine deaminase inhibitor for subjects who require it. A method comprising administering an effective amount of.
[84] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) A method of treating tumors in combination with propane-1-sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor, and for subjects in need of it, 5-fluoro-2'-deoxycytidine. A method comprising administering an effective amount of.

The present invention also provides the following inventions [85] to [93].
[85] The method according to any one of [80] to [84], wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine.
[86] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The method according to any one of [80] to [85], wherein propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered.
[87] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A method according to [86].
[88] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46: The method according to [86], which is 7.5 to 75.
[89] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.046 to 0. 46: The method according to [86], which is 0.42 to 4.2.
[90] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection to any of [80] to [85]. The method described.
[91] (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) The molar ratio of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. A method according to [90].
[92] The cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine). The molar ratio of -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012 to 0.12: The method according to [90], which is 1.5 to 15.
[93] The cytidine deaminase inhibitor is sedazlidine, and (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-) The molar ratio of 1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlidine is 1: 0.012 to 0. 12: The method according to [90], which is 0.11 to 1.1.

When the above compound 1 is used in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor while suppressing the onset of side effects, when 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination. Enhances the antitumor effect of. Therefore, according to the present invention, it is possible to treat a tumor having a high antitumor effect.

It is a figure which shows the combined effect of compound 1 and 5-fluoro-2'-deoxycytidine and tetrahydrouridine. It is a figure which shows the body weight change when compound 1 and 5-fluoro-2'-deoxycytidine and tetrahydrouridine are used in combination. It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human hematopoietic tumor cell line K562). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human hematopoietic tumor cell line MM1S). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human hematopoietic tumor cell line Molt4). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human hematopoietic tumor cell line MV-4-11). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human hematopoietic tumor cell line HT). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human brain tumor cell line A172). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human ovarian cancer cell line ES-2). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human colorectal cancer cell line Lovo). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human gastric cancer cell line SNU5). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human pancreatic cancer cell line AsPC1). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human uterine cancer cell line RL95-2). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human lung cancer cell line SHP77). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazlydin by compound 1 (human prostate cancer cell line PC3). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human breast cancer cell line AU565). It is a figure which shows the enhancing effect of the antitumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or sedazuridine by compound 1 (human renal cancer cell line ACHN). It is a figure which shows the combined effect of compound 1 and 5-fluoro-2'-deoxycytidine and sedazuridine. It is a figure which shows the effect on the body weight when the compound 1 and 5-fluoro-2'-deoxycytidine and sedazlysin are used in combination.

In the present invention, compound 1 is represented by the following formula.

Compound 1 or a pharmaceutically acceptable salt thereof is a known compound having excellent deoxyuridine triphosphatase inhibitory activity, and is, for example, according to the method described in Patent Document 1 (International Publication No. 2011/065541). Can be synthesized.

Examples of the pharmaceutically acceptable salt of Compound 1 include a base addition salt and an acid addition salt.
Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine. Examples thereof include salts, triethanolamine salts, procaine salts, organic amine salts such as N, N'-dibenzylethylenediamine salts and the like.
Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.

Compound 1 or a salt thereof may be amorphous or crystalline, and may be a single crystal form or a polymorphic mixture, and may be a pharmaceutically acceptable salt thereof of Compound 1 of the present invention or a salt thereof. Included. Crystals can be produced by crystallization by applying a known crystallization method.

Compound 1 or its pharmaceutically acceptable salt also includes its prodrug. The prodrug is a compound that is converted into the compound of the present invention or a pharmaceutically acceptable salt thereof by a reaction with an enzyme, gastric acid, etc. under physiological conditions in the living body, that is, enzymatically undergoes oxidation, reduction, hydrolysis, etc. A compound that changes to the compound of the invention or a pharmaceutically acceptable salt thereof, or a compound that undergoes hydrolysis or the like due to gastric acid or the like to change to the compound of the present invention or a pharmaceutically acceptable salt thereof. In addition, it changes to the compound of the present invention or a pharmaceutically acceptable salt thereof under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. You may.

In the present invention, 5-fluoro-2'-deoxycytidine (hereinafter, also referred to as "FdCyd") is an inhibitor of DNA methyltransferase represented by the following formula.

5-Fluoro-2'-deoxycytidine is described in the literature (eg, Visser, Gerard WM, J Chem Soc, Perkin Trans 1: Organic and Bio-Organic Chemistry, 1972-1999; 1988 (9): 25). ) Can be obtained by the method described in.

In the present invention, 5-fluoro-2'-deoxycytidine also includes its pharmaceutically acceptable salt. Examples of such salts include base-added salts and acid-added salts.
Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine. Examples thereof include salts, triethanolamine salts, procaine salts, organic amine salts such as N, N'-dibenzylethylenediamine salts and the like.
Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.

In the present invention, the cytidine deaminase inhibitor refers to an agent that inhibits the enzymatic activity of cytidine deaminase. Examples of the cytidine deaminase inhibitor include tetrahydrouridine (hereinafter, also referred to as “THU”), sedazulysin (hereinafter, also referred to as “CDZ”), and deoxy THU.
Tetrahydrouridine is obtained by the method described in the literature (eg, Hanze, AR, JAm Chem Soc. 1967; 89: 6720), and sedazulysin is obtained by the method described in US Pat. No. 8,268,800. be able to.

In the present invention, tetrahydrouridine and sedazuridine also include pharmaceutically acceptable salts thereof. Examples of such salts include base-added salts and acid-added salts.
Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt and diethanolamine. Examples thereof include salts, triethanolamine salts, procaine salts, organic amine salts such as N, N'-dibenzylethylenediamine salts and the like.
Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; acetates, formates, maleates, fumarates, tartrates and citrates. , Organic acid salts such as ascorbate and trifluoroacetate; sulfonates such as methanesulfonate, ISEthionate, benzenesulfonate, p-toluenesulfonate and the like.

As shown in Examples below, Compound 1 can be used in combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors, and by further concomitant use, with respect to 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors. Enhances the antitumor effect of the combination.
On the other hand, when compound 1 is further used in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, weight loss due to the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, etc. The occurrence of side effects is suppressed.

Therefore, in one embodiment, an antitumor effect enhancer in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor containing Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient is provided. NS.
In other embodiments, an antitumor agent comprising a combination of Compound 1 or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor in combination is provided. ..
In the present invention, the antitumor effect can be evaluated as, for example, a decrease in tumor volume, a stagnation in tumor growth, an extension of survival time, and the like.

In the present invention, the enhancement of the antitumor effect means to enhance the antitumor effect of another antitumor agent, and the effect enhancer of the antitumor effect exerts the enhancement of the antitumor effect of another antitumor agent. A drug that is used.
The effect enhancer of the antitumor effect often accompanies the enhancement of side effects, but preferably the enhancement of side effects is mild, more preferably the enhancement of side effects is not accompanied, and more preferably. , With reduction of side effects.

The tumor to be treated by the medicament of the present invention is not particularly limited, and examples thereof include carcinomas, sarcomas, brain tumors, and hematopoietic tumors.
The cancer is not particularly limited, but head and neck cancer (oral cancer, pharyngeal cancer, laryngeal cancer, nasal cavity cancer, sinus cancer, salivary adenocarcinoma, thyroid cancer, etc.), gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, etc.) Liver cancer, biliary tract cancer (biliary sac / bile duct cancer, etc.), pancreatic cancer, colon cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesenteric cancer, etc.), breast cancer, reproductive organ cancer ( Examples include ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), urinary cancer (renal cancer, bladder cancer, prostate cancer, testicular tumor, etc.), skin cancer, and the like.
The sarcoma is not particularly limited, and examples thereof include bone tumors and soft tissue tumors.
The hematopoietic tumor is not particularly limited, and examples thereof include leukemia, malignant lymphoma, and multiple myeloma.
Leukemia is not particularly limited, and examples thereof include acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, myelodysplastic syndrome, and hairy cell leukemia. The malignant lymphoma is not particularly limited, and examples thereof include Hodgkin lymphoma and non-Hodgkin lymphoma, and examples of the non-Hodgkin lymphoma include B cell-derived lymphoma, T / NK cell-derived lymphoma, and lymphoblastic lymphoma.
Brain tumors are not particularly limited, but include, for example, metastatic brain tumors (for example, brain tumors such as lung cancer, breast cancer, gastric cancer, colorectal cancer, bladder cancer, biliary tract cancer, and germinoma), hairy cell astrocytoma, Diffuse astrocytoma, oligoastrocytoma / oligoastrocytoma, osteogenic astrocytoma / oligoastrocytoma, oligoastrocytoma, gligodendroglioma, coat tumor, degeneration Sexual coat tumor, ganglion glioma, central neurocytoma, medullary blastoma, germinoma, central nervous system malignant lymphoma, meningeal tumor, nerve sheath tumor, GH-producing pituitary adenoma, PRL-producing pituitary adenoma , ACTH-producing pituitary adenomas, non-functional pituitary adenomas, cranio-pharyngeal tumors, spinal cord tumors, hemangioblastomas, epitheliomas and the like.

Here, the tumor includes not only the primary tumor but also a tumor that has metastasized to other organs (liver, etc.). Further, even if the antitumor agent of the present invention is used for postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, it is performed in advance for surgical removal of the tumor. It may be preoperative adjuvant chemotherapy.

When compound 1 or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are used as pharmaceuticals, a pharmaceutical carrier may be added as necessary, depending on the prophylactic or therapeutic purpose. Various administration forms can be adopted.
Examples of the dosage form include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, and the like. Oral preparations and injection preparations are preferable. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

Pharmaceutical carriers include various general-purpose pharmaceutical carriers such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, etc. Examples thereof include pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

The administration schedule of the drug of the present invention is appropriately selected within the range of exerting the effect of enhancing the antitumor effect, and each active ingredient is administered simultaneously or separately at intervals. When administered separately, either may be administered first.

The medicament of the present invention may be formulated by dividing each active ingredient into a plurality of dosage forms based on the administration form and administration schedule of each active ingredient, or may be formulated collectively in one dosage form. In addition, each preparation may be manufactured and sold in a single package suitable for combined administration, or each preparation may be manufactured and sold in separate packages.

The administration or compounding ratio of compound 1 or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is not particularly limited as long as it exerts an effect of enhancing the antitumor effect.
When compound 1 and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered, the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor while suppressing the onset of side effects. From the viewpoint of enhancing, the amount of 5-fluoro-2'-deoxycytidine may be 0.0001 to 10000 mol, preferably 0.001 per 1 mol of compound 1 or a pharmaceutically acceptable salt thereof. To 1000 mol, more preferably 0.01 to 100 mol, still more preferably 0.015 to 1.5 mol, particularly preferably 0.046 to 0.46 mol, most preferably 0.06 to 0.18 mol. do it.
From the same viewpoint, the amount of the cytidine deaminase inhibitor may be 0.0001 to 10000 mol with respect to 1 mol of Compound 1 or a pharmaceutically acceptable salt thereof. In the case of THU, it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, further preferably 2.3 to 230 mol, particularly preferably 7.5 to 75 mol, and most preferably 18 to 54 mol. And it is sufficient. In the case of CDZ, it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, still more preferably 0.15 to 15 mol, particularly preferably 0.42 to 4.2 mol, and most preferably 0. It may be 56 to 1.7 mol.

In addition, when compound 1 is orally administered and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered while suppressing the onset of side effects. From the viewpoint of enhancing the antitumor effect of the combined use, the amount of 5-fluoro-2'-deoxycytidine may be 0.0001 to 10000 mol with respect to 1 mol of compound 1 or a pharmaceutically acceptable salt thereof. , Preferably 0.001 to 1000 mol, more preferably 0.005 to 50 mol, still more preferably 0.006 to 0.6 mol, particularly preferably 0.012 to 0.12 mol, most preferably 0.015 mol. It may be ~ 0.045 mol.
From the same viewpoint, the amount of the cytidine deaminase inhibitor may be 0.0001 to 10000 mol with respect to 1 mol of Compound 1 or a pharmaceutically acceptable salt thereof. In the case of THU, it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, still more preferably 0.45 to 45 mol, particularly preferably 1.5 to 15 mol, most preferably 3.8 to It may be 11.4 mol. In the case of CDZ, it is preferably 0.001 to 1000 mol, more preferably 0.01 to 100 mol, further preferably 0.04 to 4 mol, particularly preferably 0.11 to 1.1 mol, and most preferably 0. It may be 17 to 0.51 mol.

In the medicament of the present invention, the dose of each active ingredient can be appropriately selected depending on the usage, age of the patient, gender and other conditions, degree of disease and the like.
For example, when compound 1 and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered, the daily dose of compound 1 or a pharmaceutically acceptable salt thereof per human is 0. It is 3 to 30,000 mg / m ² / day. From the viewpoint of enhancing the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor ^{, it is preferably 1 to 10000 mg / m 2} / day, and more preferably 3 to 3000 mg / m ² /. It is a day, more preferably 10 to 1000 mg / m ² / day, particularly preferably 60 to 600 mg / m ² / day, and most preferably 90 to 270 mg / m ² / day.
The dose of 5-fluoro-2'-deoxycytidine is 0.1-10000 mg / m ² / day. From the viewpoint of exerting an antitumor effect and suppressing the onset of side effects ^{, it is preferably 0.3 to 3000 mg / m 2} / day, more preferably 0.6 to 600 mg / m ² / day, and further preferably. Is 1 to 100 mg / m ² / day, particularly preferably 3 to 30 mg / m ² / day, and most preferably 4 to 12 mg / m ² / day.
The dose of the cytidine deaminase inhibitor is 0.1 to 200,000 mg / m ² / day. From the viewpoint of exerting an antitumor effect and suppressing the onset of side effects, in the case of THU, it is preferably 2 to 20000 mg / m ² / day, more preferably 18 to 18000 mg / m ² / day, and further preferably. is a 150 ~ 15000mg / m ² / day, particularly preferably at 500 ~ 5000mg / m ² / day, most preferably 1200 ~ 3600mg / m ² / day. For CDZ, or preferably 1 ~ 10000mg / m ² / day, more preferably 3 ~ 3000mg / m ² / day, more preferably not more 10 ~ 1000mg / m ² / day, particularly preferably 30 ~ 300 mg / M ² / day, most preferably 40-120 mg / m ² / day.

When compound 1 is orally administered and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection, the daily dose of compound 1 or a pharmaceutically acceptable salt thereof per human is determined. It is 0.3 to 30,000 mg / m ² / day. From the viewpoint of enhancing the antitumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor ^{, it is preferably 1 to 10000 mg / m 2} / day, and more preferably 3 to 3000 mg / m ² /. It is a day, more preferably 10 to 1000 mg / m ² / day, particularly preferably 60 to 600 mg / m ² / day, and most preferably 90 to 270 mg / m ² / day.
The dose of 5-fluoro-2'-deoxycytidine is 0.1-10000 mg / m ² / day. From the viewpoint of exerting an antitumor effect and suppressing the onset of side effects ^{, it is preferably 0.2 to 2000 mg / m 2} / day, more preferably 0.3 to 300 mg / m ² / day, and even more preferably. Is 0.4 to 40 mg / m ² / day, particularly preferably 0.8 to 8 mg / m ² / day, and most preferably 1 to 3 mg / m ² / day.
The dose of the cytidine deaminase inhibitor is 0.01 to 30,000 mg / m ² / day. From the viewpoint of suppressing the exhibit antitumor effects, the onset of side effects, in the case of THU, preferably at 1 ~ 10000mg / m ² / day, more preferably 5 ~ 5000mg / m ² / day, more preferably Is 30 to 3000 mg / m ² / day, particularly preferably 100 to 1000 mg / m ² / day, and most preferably 250 to 750 mg / m ² / day. In the case of CDZ, it is preferably 0.6 to 6000 mg / m ² / day, more preferably 1 to 1000 mg / m ² / day, still more preferably 3 to 300 mg / m ² / day, and particularly preferably 8 It is -80 mg / m ² / day, most preferably 12-36 mg / m ² / day.
This can be administered once a day or in several divided doses.

The present invention also presents compound 1 or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof for cancer patients, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibition. The present invention relates to a kit formulation containing instructions for administration in combination with the drug. Here, the "instruction manual" may be any one in which the above-mentioned dose is described, regardless of whether or not it is legally binding, but the one in which the above-mentioned dose is recommended is preferable. Specifically, package inserts, pamphlets and the like are exemplified. In addition, the kit formulation including the instruction manual means that the instruction manual is printed and attached to the package of the kit formulation, but the instruction manual is enclosed with the antitumor agent in the package of the kit formulation. It may be a thing.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 in vitro test-1
The human hematopoietic tumor cell line MV-4-11 was suspended in medium, seeded in each well of a multi-well plate, and cultured in an incubator. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega.

The cell viability was calculated from the following formula, and the concentration of the compound (IC50 (μM)) that inhibits cell viability by 50% was determined.
Cell viability (%) = (T / C) x 100
T: Emission intensity of wells with compound added C: Emission intensity of wells without compound added

In addition, as an index of the combined effect, the rate of change of IC50 (μM) depending on the presence or absence of combined use of compound 1 (10 μM) (combination effect by compound 1) was determined by the following formula, and the enhancing effect of compound 1 on FdCid + THU (THU: 10 μM). Asked.

Combined effect of compound 1 = IC50 (μM) when compound 1 is not used in combination / IC50 (μM) when compound 1 is used in combination

As a result, Compound 1 enhanced the antitumor effect of FdCyd in the presence of THU by 10 times or more.

Example 2 in vivo test-1
The human hematopoietic tumor cell line MV-4-11 was transplanted into the right chest of BALB / cA Jcl-nu / nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, the tumor volume (TV) is calculated by the following formula, and then mice are placed in each group so that the average TV in each group is even. The day when the allocation and grouping were carried out was set as Day 0.

TV (mm ³ ) = (major axis x minor axis ² ) / 2

Administration was started from Day 1, the Control group was a 0.5% hypromellose (HPMC) aqueous solution, the FdCyd + THU administration group was 1 + 100 mg / kg / day FdCyd + THU, and the Compound 1 administration group was 600 mg / kg / day Compound 1. In the FdCyd + THU + compound 1 administration group, 1 + 100 + 600 mg / kg / day of FdCyd + THU + compound 1 was orally administered to Day 1-14 once a day every day. As an index of antitumor effect and toxicity, the relative tumor volume (reactive tumor volume: RTV) and body weight change (BWC) with respect to Day 0 were obtained from the TV and body weight (BW) of each group by the following formula. And compared the changes over time of RTV and BWC in each group.

RTV = (TV on evaluation date) / (TV on Day 0)
BWC (%) = (BW at BW-Day 0 on the evaluation date) / (BW at Day 0) × 100

As a result, as shown in FIGS. 1 and 2, Compound 1 showed an extremely excellent effect of enhancing the antitumor effect of FdCyd + THU, while suppressing the weight loss caused by FdCid + THU.

Example 3 in vitro test-2
Various cell lines derived from human hematopoietic tumors shown in Table 1 below were suspended in a medium, seeded in each well of a multi-well plate, and cultured. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega.

The cell viability is calculated from the following formula, and the concentration that inhibits the cell viability of FdCid, Decitabine, SGI-110, Azacytide and Cytarabine (cytarabine) in the presence of THU or CDZ (THU: 10 μM, CDZ: 10 μM) by 50%. (IC50 (μM)), as well as concentrations of 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FdUrd) that inhibit cell survival by 50% (IC50 (μM)), compound 1 (10 μM). ) With and without combination.
Cell viability (%) = (T / C) x 100
T: Emission intensity of wells with compound added C: Emission intensity of wells without compound added

As an index of the combined effect of compound 1, the combined effect of compound 1 was determined by the following formula.
The results are shown in FIGS. 3 to 7.

Combined effect of compound 1 = IC50 (μM) when compound 1 is not used in combination / IC50 (μM) when compound 1 is used in combination

As a result, as shown in FIGS. 3 to 7, compound 1 was found to have an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ in cell lines derived from various types of hematopoietic tumors. rice field. It is compared to the antitumor effect of compound 1 on other DNA methyltransferase inhibitors in the presence of THU or CDZ (eg, Decitabine, SGI-110, Azacitidine) and Cytarabine, which also has a cytidine skeleton. Remarkably strong. In addition, it exceeded the enhancing effect of Compound 1 on the antitumor effect of 5-FU and FdUrd.
The enhancing effect of FdCyd on the antitumor effect of FdCyd in the presence of THU or CDZ on hematopoietic tumors is specific as compared with other compounds having a pyrimidine skeleton, which is a surprising result.

Example 4 in vitro test-3
Various cell lines derived from human carcinoma, sarcoma and brain tumor shown in Table 2 below were suspended in a medium, seeded in each well of a multi-well plate, and cultured. The compound solution was added the day after the start of culturing, and the cells were further cultured for 3 days. The number of cells was measured using Celtitagro (manufactured by Promega) based on the protocol recommended by Promega.
As for the rest, the combined effect of Compound 1 was determined in the same manner as in Example 3.
The results are shown in FIGS. 8 to 17.

As a result, as shown in FIGS. 8 to 17, Compound 1 has an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ in cell lines derived from various types of carcinomas, sarcomas and brain tumors. Admitted. It exceeded the enhancing effect of Compound 1 on the antitumor effect of 5-FU and FdUrd. This is a surprising result.
In the first place, the antitumor effect of a DNA methyltransferase inhibitor on carcinoma, sarcoma and brain tumor is considered to be limited regardless of the combined use of a cytidine deaminase inhibitor. In contrast, Compound 1 was found to have an enhancing effect on the antitumor effect of FdCyd in the presence of THU or CDZ. This is an even more surprising result.

Example 5 in vivo test-2
The human hematopoietic tumor cell line MV-4-11 was transplanted into the right chest of BALB / cA Jcl-nu / nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, the tumor volume (TV) is calculated by the following formula, and then mice are placed in each group so that the average TV in each group is even. The day when the allocation and grouping were carried out was set as Day 0.

TV (mm ³ ) = (major axis x minor axis ² ) / 2

Administration was started from Day 1, Control group (0.5% hypromellose (HPMC) aqueous solution as a medium), Compound 1 administration group (600 mg / kg / day), FdCyd + CDZ administration group (1 + 100 mg / kg / day), FdCyd + CDZ + compound 1 The administration group (1 + 100 + 600 mg / kg / day) was orally administered to Day 1-14 once a day every day. In order to evaluate the antitumor effect and toxicity, the TV and body weight (BW) of each group on Day 15 on the day after the final day of administration were determined.
The TV is shown in FIG. 18 and the BW is shown in FIG. In addition, a significant difference test (t test) was performed using a TV to evaluate the effect of enhancing the antitumor effect (p <0.001 (***)).

As a result, as shown in FIGS. 18 and 19, when Compound 1 was used in combination with FdCyd + CDZ, its antitumor effect was observed to enhance its antitumor effect, although its effect on body weight was limited.

Claims (93)

(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -An effect enhancer of an antitumor agent in which 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination, which comprises a sulfonamide or a pharmaceutically acceptable salt thereof as an active ingredient. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 An antitumor agent comprising a combination of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -A kit formulation for combined administration with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors containing sulfonamide or a pharmaceutically acceptable salt thereof and instructions for use.
The instructions for use include (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-) for patients to whom it should be applied. Dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a cytidine deaminase inhibitor are administered in combination. The kit formulation that is described. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -An antitumor agent consisting of a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for administration in combination with sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -An antitumor agent containing a cytidine deaminase inhibitor for administration in combination with sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -An antitumor agent containing 5-fluoro-2'-deoxycytidine for administration in combination with sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor. The agent according to any one of claims 1 to 6, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The agent according to any one of claims 1 to 7, wherein -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. The agent according to 8. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The agent according to claim 8, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The agent according to claim 8, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The agent according to any one of claims 1 to 7, wherein -sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. .. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. The agent according to 12. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The agent according to claim 12, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The agent according to claim 12, which is 11.11 to 1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) for the production of an effect enhancer of an antitumor agent in which 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are used in combination. Use of -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3- for producing an antitumor agent in combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor. ((2,4-Dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Use of propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -Use of a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor to produce an antitumor agent for administration in combination with sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 Use of a cytidine deaminase inhibitor to produce an antitumor agent for administration in combination with sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -Use of 5-fluoro-2'-deoxycytidine to produce antitumor agents for administration in combination with sulfonamides or pharmaceutically acceptable salts thereof and cytidine deaminase inhibitors. The use according to any one of claims 16 to 20, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The use according to any one of claims 16 to 21, wherein a sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 22 Use. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The use according to claim 22, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The use according to claim 22, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The use according to any one of claims 16 to 21, wherein a sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are administered by injection. .. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. Use of 26. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The use according to claim 26, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. .. Use according to claim 26, which is 11-1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-(for use in enhancing the antitumor effect of the combination of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor (2,4-Dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) according to claim 30, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 (R) -N- (1- (1).-(R) -N- (1- (1). 3- (Cyclopentyloxy) Phenyl) Ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or pharmaceutically acceptable thereof Salt. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 Claim that the molar ratio of a sulfonamide or a pharmaceutically acceptable salt thereof to 5-fluoro-2'-deoxycytidine to a cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 32. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. The citidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : 7.5-75 (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) according to claim 32. -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof. The citidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) according to claim 32, which is .42 to 4.2. -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -(R) -N- (R) -N- (according to claim 30 or 31), wherein sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycitidine and citidine deaminase inhibitor are administered by injection. 1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) propan-1-sulfonamide or its pharmaceuticals Tolerable salt. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 Claim that the molar ratio of a sulfonamide or a pharmaceutically acceptable salt thereof to 5-fluoro-2'-deoxycytidine to a cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 36. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. The citidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : 1.5 to 15 (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) according to claim 36. -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof. The citidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycitidine, and sedazlidine have a molar ratio of 1: 0.012-0.12: 0. .11-1.1 (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine) according to claim 36. -1 (2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)) for use in the treatment of tumors ) -Il) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and a combination of a cytidine deaminase inhibitor. The combination according to claim 40, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The combination according to claim 40 or 41, wherein a sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 42 The combination described. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The combination according to claim 42, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The combination according to claim 42, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The combination according to claim 40 or 41, wherein sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 46 The combination described. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The combination according to claim 46, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The combination according to claim 46, which is 11.11 to 1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -A combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for use in the treatment of tumors in combination with sulfonamides or pharmaceutically acceptable salts thereof. The combination according to claim 50, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The combination according to claim 50 or 51, wherein a sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 52 The combination according to description. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The combination according to claim 52, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The combination according to claim 52, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The combination according to claim 50 or 51, wherein the sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and the 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 56 The combination described. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The combination according to claim 56, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The combination according to claim 56, which is 11.11 to 1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -A cytidine deaminase inhibitor used in the treatment of tumors in combination with sulfonamide or a pharmaceutically acceptable salt thereof and 5-fluoro-2'-deoxycytidine. The cytidine deaminase inhibitor according to claim 60, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The cytidine deaminase inhibitor according to claim 60 or 61, wherein the sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and the cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 62. The cytidine deaminase inhibitor. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The cytidine deaminase inhibitor according to claim 62, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The cytidine deaminase inhibitor according to claim 62, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The cytidine deaminase inhibitor according to claim 60 or 61, wherein the sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and the 5-fluoro-2'-deoxycytidine and the cytidine deaminase inhibitor are administered by injection. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 66. The cytidine deaminase inhibitor. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The cytidine deaminase inhibitor according to claim 66, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The cytidine deaminase inhibitor according to claim 66, which is 11.11 to 1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -5-Fluoro-2'-deoxycytidine for use in the treatment of tumors in combination with sulfonamides or pharmaceutically acceptable salts thereof and cytidine deaminase inhibitors. The 5-fluoro-2'-deoxycytidine according to claim 70, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The 5-fluoro-2'-deoxycytidine according to claim 70 or 71, wherein the sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 Claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 72. 5-Fluoro-2'-deoxycytidine. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : 7.5-75. 5-Fluoro-2'-deoxycytidine according to claim 72. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The 5-fluoro-2'-deoxycytidine according to claim 72, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -The 5-fluoro-2'- according to claim 70 or 71, wherein sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. Deoxycytidine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 Claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 76. 5-Fluoro-2'-deoxycytidine. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The 5-fluoro-2'-deoxycytidine according to claim 76, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The 5-fluoro-2'-deoxycytidine according to claim 76, which is 11.11 to 1.1. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -Method for enhancing the antitumor effect of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors, which comprises administering an effective amount of sulfonamide or a pharmaceutically acceptable salt thereof to a subject in need thereof. .. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4) is a treatment method for tumors and requires it. -Dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and an effective amount of a cytidine deaminase inhibitor are administered. Methods, including doing. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -An effective amount of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor for subjects who treat tumors in combination with sulfonamides or pharmaceutically acceptable salts thereof. Methods, including administration of. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -A method of treating tumors in combination with sulfonamide or a pharmaceutically acceptable salt thereof in combination with 5-fluoro-2'-deoxycytidine, an effective amount of a cytidine deaminase inhibitor for subjects in need of it. Methods, including administration of. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 -A method of treating tumors in combination with sulfonamide or a pharmaceutically acceptable salt thereof and a cytidine deaminase inhibitor, in which an effective amount of 5-fluoro-2'-deoxycytidine is given to the subject in need of it. Methods, including administration of. The method according to any one of claims 80 to 84, wherein the cytidine deaminase inhibitor is tetrahydrouridine or sedazuridine. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The method according to any one of claims 80 to 85, wherein a sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor are orally administered. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 86 The method according to description. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.046 to 0.46. : The method according to claim 86, which is 7.5 to 75. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.046 to 0.46: 0. The method according to claim 86, which is .42 to 4.2. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The method according to any one of claims 80 to 85, wherein -sulfonamide or a pharmaceutically acceptable salt thereof is orally administered, and 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. .. (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) methoxy) Propane-1 The claim that the molar ratio of -sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor is 1: 0.0001 to 10000: 0.0001 to 10000. 90. The method according to description. The cytidine deaminase inhibitor is tetrahydrouridine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2,4-dioxo-3,4-dihydropyrimidine-1). The molar ratio of 2H) -yl) methoxy) propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and tetrahydrouridine is 1: 0.012-0.12. : The method according to claim 90, which is 1.5 to 15. The cytidine deaminase inhibitor is sedazlidine, which is (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)). ) -Il) methoxy) Propan-1-sulfonamide or a pharmaceutically acceptable salt thereof, 5-fluoro-2'-deoxycytidine, and sedazlysin have a molar ratio of 1: 0.012-0.12: 0. The method according to claim 90, which is 11.11 to 1.1.

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