TW202140018A - 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

Anti-tumor effect enhancer containing uracil derivative compound

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

In order to treat tumors, it is known not only to block a single target in the living body, but also to block multiple targets at the same time. In order to block multiple targets at the same time, it is usually carried out by combining multiple compounds that block different targets, or providing a mixture of such compounds in advance. However, the current situation is that there are infinite ways of combining multiple compounds, and most of them will increase toxicity and side effects, and are not suitable for tumor treatment, and have to be abandoned in the process of research and development. Furthermore, when there are two or more different compounds that inhibit the same target, when these are combined with compounds that inhibit other targets, it can be said that the effects or side effects are usually not shown between two or more different compounds. Act of analogy to each other. Therefore, the actual situation is that it is very difficult to combine a compound with anti-tumor effect to take or provide a mixture.

It is known that DNA methylation is one of gene expression regulation mechanisms that inhibit gene expression. In addition, with regard to tumors, it has been confirmed that the gene expression inhibition of the proliferation of the original tumor by high DNA methylation is confirmed, and it is expected that the inhibition of DNA methylation will be useful for the treatment of tumors. DNA methyltransferase (DNMT) is a protein involved in DNA methylation, and its hindrance will inhibit DNA methylation. Therefore, it is expected to use DNA methyltransferase inhibitors (DNMTi) to treat tumors. Regarding DNA methyltransferase inhibitors, as those having a cytidine backbone, 5-fluoro-2'-deoxycytidine (FdCyd), 5-aza-2'-deoxycytidine (decitabine) are known (Decitabine); 5-AZA-CdR), 4-deoxyuridine (Zebularine), Guadecitabine (Guadecitabine; SGI-110), Azacytidine (Azacytidine), etc., as those without a cytidine skeleton Procainamide, RG-108, SGI-1027, etc. are known (Non-Patent Document 1). It is expected that these drugs that block DNA methyltransferase will affect hematopoietic system tumors (acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma (MM), chronic myelogenous leukemia (CML), acute Lymphocytic leukemia (ALL, etc.), solid cancers (breast cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer, skin cancer, bone tumors, soft tissue tumors, etc.), etc. Therapeutic effect (Non-Patent Document 2), some compounds have been clinically tested, and some compounds have been approved as pharmaceuticals (Non-Patent Document 3).

However, a DNA methyltransferase inhibitor having a cytidine backbone is likely to become a uridine backbone due to the enzymatic activity of cytidine deaminase (CDA), thereby inactivating the DNA methyltransferase inhibitory activity (Non-Patent Document 4) ). Therefore, in the treatment of tumors, when using a DNA methyltransferase inhibitor with a cytidine backbone, cytidine deaminase is advocated as a further therapeutic target at the same time, and a combination of a DNA methyltransferase inhibitor and cytidine is proposed. Deaminase inhibitor (CDAi) is used. As cytidine deaminase inhibitors, Tetrahydrouridine (THU), Cedazuridine (CDZ), deoxy THU, ER-876437, ER-876400, etc. are known (Non-Patent Document 1). At present, clinical trials of combined use of decitabine and cedrocil (ASTX727), combined use of 5-fluoro-2'-deoxycytidine and tetrahydrouridine, etc. have been implemented.

However, it is suggested that the DNA methyltransferase inhibitor, which is the main antitumor agent, can also induce the DNA methyltransferase inhibitor itself to be carried by the cytidine deaminase inhibitor to avoid decomposition in the body and reach the tumor. Into the tumor cell-related transporter (ENT1) and the activated deoxycytidine kinase (DCK) after taking charge of the decrease, and then the increase of cytidine deaminase, so that the effect of the drug itself that inhibits DNA methyltransferase Decrease (Non-Patent Documents 5 and 6). In fact, many separate clinical trials of DNA methyltransferase inhibitors and clinical trials of DNA methyltransferase inhibitors and cytidine deaminase inhibitors have been implemented, but their clinical effects are limited (Non-Patent Document 7 ). In addition, nausea, vomiting, diarrhea, and hepatotoxicity were observed in clinical trials of azacitidine (Non-Patent Document 8). In addition, 5-fluoro-2'- In clinical trials of deoxycytidine and tetrahydrouridine, colitis, fatigue associated with elevations in liver enzymes, thrombocytopenia, and white blood cells were confirmed early in the trial. Leukopenia, neutropenia associated with gastrointestinal toxicities, etc. are used as dose-limiting toxicities (Non-Patent Document 9). These side effects prevent the clinical effects of DNA methyltransferase inhibitors. The required exposure or its continuation becomes a clinical issue.

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 its pharmaceutically acceptable salt is also called TAS-114, which can inhibit deoxyuridine As a result, triphosphatase is known as a compound that enhances its antitumor effect on FU (Fluorouracil), which is one of the antagonists of nucleic acid metabolism, as an antitumor agent (Patent Document 1). However, there has been no explicit or suggestion that the combined use of uracil derivative compounds with deoxyuridine triphosphatase inhibitory activity and DNA methyltransferase inhibitors, and the combined use of uracil with deoxyuridine triphosphatase inhibitory activity Literature on derivative compounds, DNA methyltransferase inhibitors, and cytidine deaminase inhibitors. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2011/065541 [Non-Patent Literature]

[Non-Patent Document 1] Biomolecules. 2017; 7: 3 [Non-Patent Document 2] Biomark Res. 2017; 5: 1 [Non-Patent Document 3] Br J Cancer. 2018; 118: 1062-1073 [Non-Patent Document 4] Anticancer Res. 2013; 33: 2989-2996 [Non-Patent Document 5] Oncol Lett. 2015; 10: 761-767 [Non-Patent Document 6]PLoS One. 2011; 6 (8): e23372 [Non-Patent Document 7] Epigenomics. 2010; 2 (1): 71-86 [Non-Patent Document 8] Pharmaceuticals 2010, 3, 2022-2044 [Non-Patent Document 9] Cancer Chemother Pharmacol. 2015; 75: 537-546

[The problem to be solved by the invention]

The subject of the present invention is to provide a method for the treatment of tumors that exhibits significantly excellent anti-tumor effects and fewer side effects. [Technical means to solve the problem]

In order to solve the above-mentioned problems, the present inventors have conducted intensive research and found that if compound 1 as a uracil derivative with deoxyuridine triphosphatase inhibitory activity and a DNA methyltransferase inhibitor with a cytidine backbone are combined The combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor can enhance the anti-tumor effect of the combined use of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor , While suppressing side effects, thus completing the present invention.

That is, the present invention provides the following inventions [1] to [6]. [1] An effect enhancer of an antitumor agent, the antitumor agent uses 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor in combination, and the effect enhancer of the antitumor agent is (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 used as an active ingredient. [2] An anti-tumor agent, which is a combination of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3 ,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase Obstructing agent. [3] A kit preparation for use in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, including (R)-N-(1-(3- (Cyclopentyloxy)phenyl)ethyl)-3-((2,4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfon Amide or its pharmaceutically acceptable salt and instructions for use, and The instruction manual states that for patients who should be used, (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral Oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytosine Glycoside deaminase inhibitor. [4] An anti-tumor agent, which is a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, which is used in combination with (R)-N-(1-(3-(cyclic Pentyloxy)phenyl)ethyl)-3-((2,4-di-pendoxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide Or its pharmaceutically acceptable salt is administered in combination. [5] An antitumor agent containing a cytidine deaminase inhibitor, which is used in combination with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and 5-fluoro-2'- Concomitant administration of deoxycytidine. [6] An antitumor agent containing 5-fluoro-2'-deoxycytidine, which is used in combination with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)- 3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and cytidine Aminase inhibitors are administered in combination.

In addition, the present invention 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 cedrocil. [8] The agent as described in any one of [1] to [7], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'- Deoxycytidine and cytidine deaminase inhibitors were administered orally. [9] The agent as described in [8], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diposide oxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [10] The agent according to [8], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 The molar ratio of -fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [11] The agent as described in [8], wherein the cytidine deaminase inhibitor is cedrolidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.046~0.46:0.42~4.2. [12] The agent according to any one of [1] to [7], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5- The fluoro-2'-deoxycytidine and cytidine deaminase inhibitors were administered by injection. [13] The agent as described in [12], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diendoxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [14] The agent according to [12], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -The molar ratio of fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [15] The agent as described in [12], wherein the cytidine deaminase inhibitor is cedripyrimidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [16] to [20]. [16] A (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine- The use of 1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, for the manufacture and inhibition of 5-fluoro-2'-deoxycytidine and cytidine deaminase The effect enhancer of the anti-tumor agent. [17] A (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine- The use of 1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is used in the manufacture and inhibition of 5-fluoro-2'-deoxycytidine and cytidine deaminase An anti-tumor agent formed by a combination of agents. [18] The use of a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor in the manufacture of a combination with (R)-N-(1-(3-(cyclopentoxy Yl)phenyl)ethyl)-3-((2,4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or A pharmaceutically acceptable salt is used in combination with the administered antitumor agent. [19] The use of a cytidine deaminase inhibitor for the manufacture of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2 , 4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and 5-fluoro-2'-to Oxycytidine is administered in combination with an antitumor agent. [20] A use of 5-fluoro-2'-deoxycytidine in the manufacture of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3 -((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and cytidine deamine Enzyme inhibitors are used in combination with the administered antitumor agents.

In addition, the present invention 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 cedrocil. [22] The use as described in any one of [16] to [21], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'- Deoxycytidine and cytidine deaminase inhibitors were administered orally. [23] The use as described in [22], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diendoxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [24] The use as described in [22], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 The molar ratio of -fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [25] The use as described in [22], wherein the cytidine deaminase inhibitor is cedripyrimidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.046~0.46:0.42~4.2. [26] The use as described in any one of [16] to [21], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5- The fluoro-2'-deoxycytidine and cytidine deaminase inhibitors were administered by injection. [27] The use as described in [26], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxon -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [28] The use as described in [26], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -The molar ratio of fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [29] The use as described in [26], wherein the cytidine deaminase inhibitor is cedripyrimidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [30] to [39]. [30] A (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine- 1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, which is used in combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor To enhance the anti-tumor effect. [31] As described in [30] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the cytidine deaminase inhibitor is tetrahydrouridine or cedrocil. [32] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxon) as described in [30] or [31] Yl-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein (R)-N-(1-(3-( (Cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The amine or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered orally. [33] As described in [32] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein (R)-N-(1-(3-(cyclopentyloxy) )Phenyl)ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The molar ratio of the permitted salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [34] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) The molar ratio of methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [35] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the cytidine deaminase inhibitor is cydridine, and (R)- N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)methyl The molar ratio of oxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.046~0.46:0.42~4.2. [36] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxon) as described in [30] or [31] Yl-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein (R)-N-(1-(3-( (Cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The amine or its pharmaceutically acceptable salt is administered orally, and the 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors are administered by injection. [37] As described in [36] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein (R)-N-(1-(3-(cyclopentyloxy) )Phenyl)ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The molar ratio of the permitted salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [38] As described in [36] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3, 4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R) -N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) The molar ratio of methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [39] (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dipontoxy-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, wherein the cytidine deaminase inhibitor is cydridine, and (R)- N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)methyl The molar ratio of oxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [40] to [49]. [40] A (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidine- 1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, a combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for use For the treatment of tumors. [41] The combination as described in [40], wherein the cytidine deaminase inhibitor is tetrahydrouridine or cedrocil. [42] The combination as described in [40] or [41], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4- Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine And the cytidine deaminase inhibitor is administered orally. [43] The combination as described in [42], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral oxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [44] The combination as described in [42], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 The molar ratio of -fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [45] The combination as described in [42], wherein the cytidine deaminase inhibitor is cedaridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.046~0.46:0.42~4.2. [46] The combination as described in [40] or [41], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4- Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5-fluoro-2' -Deoxycytidine and cytidine deaminase inhibitors are administered by injection. [47] The combination as described in [46], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diposide oxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [48] The combination as described in [46], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -The molar ratio of fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [49] The combination as described in [46], wherein the cytidine deaminase inhibitor is cedripyrimidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [50] to [59]. [50] A combination of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor for use with (R)-N-(1-(3-(cyclopentyloxy)phenyl )Ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable Salt is also used to treat tumors. [51] The combination as described in [50], wherein the cytidine deaminase inhibitor is tetrahydrouridine or cedrocil. [52] The combination as described in [50] or [51], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4- Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine And the cytidine deaminase inhibitor is administered orally. [53] The combination as described in [52], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dipontoxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [54] The combination as described in [52], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 The molar ratio of -fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [55] The combination as described in [52], wherein the cytidine deaminase inhibitor is cedaridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.046~0.46:0.42~4.2. [56] The combination as described in [50] or [51], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4- Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5-fluoro-2' -Deoxycytidine and cytidine deaminase inhibitors are administered by injection. [57] The combination as described in [56], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diposide oxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [58] The combination as described in [56], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -The molar ratio of fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [59] The combination as described in [56], wherein the cytidine deaminase inhibitor is cedripyrimidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [60] to [69]. [60] A cytidine deaminase inhibitor for use with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-di Pendant oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and 5-fluoro-2'-deoxycytidine in combination To treat tumors. [61] The cytidine deaminase inhibitor as described in [60], wherein the cytidine deaminase inhibitor is tetrahydrouridine or cedrocil. [62] The cytidine deaminase inhibitor as described in [60] or [61], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3- ((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2 '-Deoxycytidine and cytidine deaminase inhibitors are administered orally. [63] The cytidine deaminase inhibitor as described in [62], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2, 4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxy The molar ratio of cytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [64] The cytidine deaminase inhibitor of [62], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)benzene Yl)ethyl)-3-((2,4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable The molar ratio of the salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046～0.46:7.5～75. [65] The cytidine deaminase inhibitor as described in [62], wherein the cytidine deaminase inhibitor is cydridine, and (R)-N-(1-(3-(cyclopentyloxy) (Phenyl) ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The molar ratio of permissible salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.046~0.46:0.42~4.2. [66] The cytidine deaminase inhibitor as described in [60] or [61], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3- ((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5-Fluoro-2'-deoxycytidine and cytidine deaminase inhibitors were administered by injection. [67] The cytidine deaminase inhibitor as described in [66], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2, 4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxy The molar ratio of cytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [68] The cytidine deaminase inhibitor as described in [66], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy) )Phenyl)ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The molar ratio of the permitted salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [69] The cytidine deaminase inhibitor as described in [66], wherein the cytidine deaminase inhibitor is cydridine, and (R)-N-(1-(3-(cyclopentyloxy) (Phenyl) ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The molar ratio of permissible salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.012～0.12:0.11～1.1.

In addition, the present invention provides the following inventions [70] to [79]. [70] A 5-fluoro-2'-deoxycytidine used in combination with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2 ,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and cytidine deaminase inhibitor To treat tumors. [71] The 5-fluoro-2'-deoxycytidine as described in [70], wherein the cytidine deaminase inhibitor is tetrahydrouridine or cedrocil. [72] 5-fluoro-2'-deoxycytidine as described in [70] or [71], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -Fluoro-2'-deoxycytidine and cytidine deaminase inhibitors are administered orally. [73] 5-Fluoro-2'-deoxycytidine as described in [72], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3- ((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2 The molar ratio of'-deoxycytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [74] The 5-fluoro-2'-deoxycytidine as described in [72], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-( (Cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The molar ratio of amine or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [75] The 5-fluoro-2'-deoxycytidine as described in [72], wherein the cytidine deaminase inhibitor is cydridine, and (R)-N-(1-(3-(cyclic Pentyloxy)phenyl)ethyl)-3-((2,4-di-pendoxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The molar ratio of its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.046~0.46:0.42~4.2. [76] 5-fluoro-2'-deoxycytidine as described in [70] or [71], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt Oral administration, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection. [77] 5-Fluoro-2'-deoxycytidine as described in [76], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3- ((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2 The molar ratio of'-deoxycytidine and cytidine deaminase inhibitor is 1:0.0001～10000:0.0001～10000. [78] The 5-fluoro-2'-deoxycytidine as described in [76], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-( (Cyclopentyloxy)phenyl)ethyl)-3-((2,4-dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The molar ratio of the amine or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [79] The 5-fluoro-2'-deoxycytidine as described in [76], wherein the cytidine deaminase inhibitor is cydridine, and (R)-N-(1-(3-(cyclic Pentyloxy)phenyl)ethyl)-3-((2,4-di-pendoxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide The molar ratio of its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cedaridine is 1:0.012~0.12:0.11~1.1.

In addition, the present invention provides the following inventions [80] to [84]. [80] A method for enhancing the antitumor effect of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, which comprises administering (R)-N-(1-( 3-(Cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1 -The effective amount of sulfonamide or its pharmaceutically acceptable salt. [81] A method for the treatment of tumors, which comprises administering (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2, 4-di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxy The effective amount of cytidine and cytidine deaminase inhibitor. [82] A method of treating tumors, which is combined with (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 and used to treat tumors, including administering 5 to a subject in need of administration -The effective amount of fluoro-2'-deoxycytidine and cytidine deaminase inhibitor. [83] A method for the treatment of tumors, which is combined with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo- 3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and 5-fluoro-2'-deoxycytidine and used to treat tumors The method includes administering an effective amount of a cytidine deaminase inhibitor to a subject in need of administration. [84] A method for the treatment of tumors, which is combined with (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo- 3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salts and cytidine deaminase inhibitors are used to treat tumors, including An effective amount of 5-fluoro-2'-deoxycytidine is administered to a subject who needs to be administered.

In addition, the present invention 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 cedrocil. [86] The method according to any one of [80] to [85], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'- Deoxycytidine and cytidine deaminase inhibitors were administered orally. [87] The method described in [86], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dipontoxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [88] The method described in [86], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 The molar ratio of -fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. [89] The method as described in [86], wherein the cytidine deaminase inhibitor is cedaridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.046~0.46:0.42~4.2. [90] The method according to any one of [80] to [85], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-(( 2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5- The fluoro-2'-deoxycytidine and cytidine deaminase inhibitors were administered by injection. [91] The method as described in [90], wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diposide oxy -3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine The molar ratio of the aminase inhibitor is 1:0.0001～10000:0.0001～10000. [92] The method described in [90], wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl )-3-((2,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5 -The molar ratio of fluoro-2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. [93] The method as described in [90], wherein the cytidine deaminase inhibitor is cedrolidine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and cedrocil is 1:0.012～0.12:0.11～1.1. [Effects of Invention]

The above compound 1 is used in combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors to prevent the onset of side effects, and the combined use of 5-fluoro-2'-deoxycytidine and cytidine to remove The anti-tumor effect of an aminase inhibitor. Therefore, according to the present invention, the treatment of tumors with high anti-tumor effects can be performed.

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

[化1]

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

The pharmaceutically acceptable salt of Compound 1 may be a base addition salt or an acid addition salt. Examples of base addition salts 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 Organic amine salts such as salt, diethanolamine salt, triethanolamine salt, procaine salt, N,N'-dibenzylethylenediamine salt, etc. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; acetate, formate, maleate, and fumarate. Organic acid salts such as diacid salt, tartrate, citrate, ascorbate, and trifluoroacetate; sulfonate such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

Whether compound 1 or its salt is amorphous or crystalline, whether its crystal form is single or a mixture of polymorphs, it is included in compound 1 of the present invention or a pharmaceutically acceptable salt thereof. Crystals can be produced by crystallization by applying a known crystallization method.

Compound 1 or its pharmaceutically acceptable salt also includes its prodrug. A prodrug refers to a compound that is converted into the compound of the invention or a pharmaceutically acceptable salt thereof by the reaction of enzymes or gastric acid under physiological conditions in the living body, that is, the compound of the invention is transformed into the present invention by the oxidation, reduction, hydrolysis, etc. of the enzyme A compound or a pharmaceutically acceptable salt thereof, or a compound that is hydrolyzed by gastric acid or the like to become the compound of the present invention or a pharmaceutically acceptable salt thereof. In addition, it may also be a compound that becomes the compound of the present invention or a pharmaceutically acceptable salt thereof under physiological conditions as described in the "Development of Pharmaceuticals" Vol. 7, Molecular Design, pages 163 to 198 of Guangchuan Bookstore, 1990.

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.

[化2]

5-Fluoro-2'-deoxycytidine can be found in the literature (e.g. Visser, Gerard WM, J Chem Soc, Perkin Trans 1: Organic and Bio-Organic Chemistry, 1972-1999; 1988 (9): 2547-54) Obtained by the recorded method.

In the present invention, 5-fluoro-2'-deoxycytidine also includes its pharmaceutically acceptable salts. As such a salt, a base addition salt or an acid addition salt can be mentioned. Examples of base addition salts 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 Organic amine salts such as salt, diethanolamine salt, triethanolamine salt, procaine salt, N,N'-dibenzylethylenediamine salt, etc. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; acetate, formate, maleate, and fumarate. Organic acid salts such as diacid salt, tartrate, citrate, ascorbate, and trifluoroacetate; sulfonate such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

In the present invention, the cytidine deaminase inhibitor refers to an agent that inhibits the enzyme activity of cytidine deaminase. As the cytidine deaminase inhibitor, for example, tetrahydrouridine (hereinafter also referred to as "THU"), cedrolidine (hereinafter also referred to as "CDZ"), deoxy THU, and the like can be mentioned. Tetrahydrouridine can be obtained by the method described in the literature (for example, Hanze, AR, J Am Chem Soc. 1967; 89: 6720), and cedrocil can be obtained by the method described in the specification of U.S. Patent No. 8268800 And get.

In the present invention, tetrahydrouridine or cedrocil also includes its pharmaceutically acceptable salts. As such a salt, a base addition salt or an acid addition salt can be mentioned. Examples of base addition salts 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 Organic amine salts such as salt, diethanolamine salt, triethanolamine salt, procaine salt, N,N'-dibenzylethylenediamine salt, etc. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; acetate, formate, maleate, and fumarate. Organic acid salts such as diacid salt, tartrate, citrate, ascorbate, and trifluoroacetate; sulfonate such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

As shown in the following examples, by using compound 1 in combination with 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, the combined use of 5-fluoro-2'-deoxycyt Anti-tumor effects of glycosides and cytidine deaminase inhibitors. On the other hand, if compound 1 is further used in combination with a 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, it will be hindered due to the combined use of 5-fluoro-2'-deoxycytidine and cytidine Side effects such as weight loss caused by glycodeaminase inhibitors.

Therefore, in one embodiment, there is provided an anti-tumor effect enhancer for the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, which uses compound 1 or a pharmaceutically acceptable salt thereof as Active ingredients. Furthermore, in another embodiment, there is provided an antitumor agent comprising the combination of compound 1 or a pharmaceutically acceptable salt thereof, and 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor . In the present invention, the anti-tumor effect can be evaluated in the form of reduced tumor volume, tumor growth arrest, or prolonged survival time, for example.

In the present invention, the enhancement of the antitumor effect refers to the enhancement of the antitumor effect of other antitumor agents, and the effect enhancer of the antitumor effect refers to the agent that exerts the effect of enhancing the antitumor effect of other antitumor agents. The effect enhancer of the anti-tumor effect is often accompanied by enhanced side effects, preferably mildly enhanced side effects, more preferably not accompanied by enhanced side effects, and more preferably accompanied by reduced side effects.

There is no particular limitation on the tumor to be treated by the medicine of the present invention, and examples include cancer, sarcoma, brain tumor, hematopoietic system tumor, and the like. Cancer is not particularly limited. Examples include: head and neck cancer (oral cancer, pharyngeal cancer, laryngeal cancer, nasal cavity cancer, paranasal sinus cancer, salivary gland cancer, thyroid cancer, etc.), digestive system cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, etc.) , Biliary tract cancer (gallbladder cancer, cholangiocarcinoma, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (Ovarian cancer, uterine cancer (cervix cancer, uterine body cancer, etc.), etc.), urinary organ cancer (kidney cancer, bladder cancer, prostate cancer, testicular cancer, etc.), skin cancer, etc. Sarcoma is not particularly limited, and examples include bone tumors and soft tissue tumors. Tumors of the hematopoietic system are not particularly limited, and examples include leukemia, malignant lymphoma, and multiple myeloma. Leukemia is not particularly limited, and examples include acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, myelodysplastic syndrome, hairy cell leukemia, and the like. Malignant lymphomas are not particularly limited. Examples include Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Examples of non-Hodgkin’s lymphoma include: lymphoma derived from B cells, lymphoma derived from T/NK cells Lymphoma, lymphoblastic lymphoma, etc. Brain tumors are not particularly limited. Examples include: metastatic brain tumors (for example, brain metastases from lung cancer, breast cancer, stomach cancer, colorectal cancer, bladder cancer, biliary tract cancer, uterine cancer, etc.), hairy stellate cells Tumor, diffuse astrocytoma, oligodendritic glioma/oligodendritic astrocytoma, degenerative astrocytoma/degenerative oligodendritic glioma, degenerative oligodendritic stellate cell Tumor, glioblastoma, ependymoma, degenerative ependymoma, ganglione glioma, central neurocytoma, neuroblastoma, germinoma, malignant lymphoma of the central nervous system , Meningioma, schwannoma, GH (Growth Hormone) secreting pituitary adenoma, PRL (Prolactin) secreting pituitary adenoma, ACTH (Adrenocorticotropic Hormone, adrenocorticotropic hormone) secreting pituitary adenoma , Non-functional pituitary adenoma, craniopharyngioma, chordoma, hemangioblastoma, epidermoid cyst, etc.

Furthermore, the tumor here includes not only the primary lesion, but also tumors that have metastasized to other organs (liver, etc.). In addition, the antitumor agent of the present invention can be used for postoperative adjuvant chemotherapy to prevent recurrence after surgical removal of tumors, and can also be used for preoperative adjuvant chemotherapy for surgical removal of tumors.

When compound 1 or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are used as medicine, a pharmaceutical carrier may be formulated as needed, and various administrations may be adopted according to the purpose of prevention or treatment. I form. Examples of dosage forms include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, and the like. Preferably, it is oral or injection. These dosage forms can be manufactured by well-known and customary formulation methods by various industries.

As the pharmaceutical carrier, various carriers commonly used in general pharmaceuticals can be exemplified, such as excipients, binders, disintegrants, lubricants, diluents, dissolution aids, suspending agents, isotonic agents, pH adjusters, Buffer, stabilizer, coloring agent, flavoring agent, flavoring agent, etc.

The administration schedule of the medicine of the present invention can be appropriately selected within the range of enhancing the anti-tumor effect, and each active ingredient can be administered at the same time or separately administered at intervals. In the case of separate voting, there is no priority.

The medicine of the present invention can be divided into multiple dosage forms for preparation based on the dosage form or schedule of each active ingredient, or can be unified into one dosage form for preparation. In addition, the preparations can be manufactured and sold in a package suitable for combined administration, or they can be manufactured and sold by dividing the preparations into different packages.

Compound 1 or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine, and cytidine deaminase inhibitor are administered or formulated in a ratio that is within the scope of enhancing the anti-tumor effect. limit. When compound 1, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered orally, the onset of side effects is prevented, and 5-fluoro-2'-deoxycytidine is used in combination From the viewpoint of enhancing the anti-tumor effect of cytidine deaminase inhibitors, 5-fluoro-2'-deoxycytidine is set to 0.0001～10000 moles relative to 1 mole of compound 1 or its pharmaceutically acceptable salt. Ears are sufficient, preferably 0.001 to 1000 mols, more preferably 0.01 to 100 mols, more preferably 0.015 to 1.5 mols, particularly preferably 0.046 ~0.46 mol is sufficient, preferably 0.06～0.18 mol. From the same viewpoint, the cytidine deaminase inhibitor may be 0.0001 to 10,000 mol relative to 1 mol of compound 1 or its pharmaceutically acceptable salt. In the case of THU, it is preferably 0.001-1000 mol, more preferably 0.03-300 mol, more preferably 2.3-230 mol, particularly preferably It is 7.5-75 mol, the best is 18-54 mol. In the case of CDZ, it is preferably 0.001 to 1000 mol, more preferably 0.03 to 300 mol, more preferably 0.15 to 15 mol, particularly preferably It is only 0.42 to 4.2 mol, and the best is 0.56 to 1.7 mol.

In addition, when compound 1 is administered orally, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection, the onset of side effects is prevented, and 5-fluoro-2' is used in combination. -From the viewpoint of enhanced anti-tumor effect of deoxycytidine and cytidine deaminase inhibitors, compared with 1 mole of compound 1 or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine is designed It is 0.0001 to 10000 mol, preferably 0.001 to 1000 mol, more preferably 0.005 to 50 mol, and more preferably 0.006 to 0.6 mol. It is preferably 0.012 to 0.12 mol, and most preferably 0.015 to 0.045 mol. From the same viewpoint, the cytidine deaminase inhibitor may be 0.0001 to 10,000 mol relative to 1 mol of compound 1 or its pharmaceutically acceptable salt. In the case of THU, it is preferably 0.001-1000 mol, more preferably 0.03-300 mol, more preferably 0.45-45 mol, particularly preferably It is only 1.5 to 15 mol, and the best is 3.8 to 11.4 mol. In the case of CDZ, it is preferably 0.001 to 1000 mol, more preferably 0.01 to 100 mol, and still more preferably 0.04 to 4 mol, particularly preferably It is only required to be 0.11 to 1.1 mol, and it is best to set it to 0.17 to 0.51 mol.

In the medicine of the present invention, the dosage of each active ingredient can be appropriately selected according to the usage, the age, sex of the patient, other conditions, the degree of the disease, and the like. For example, in the case of oral administration of compound 1, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor, the dosage of compound 1 or its pharmaceutically acceptable salt per person per day It is 0.3～30000 mg/m ² /day. From the viewpoint of enhancing the anti-tumor effect of the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, it is preferably 1 to 10000 mg/m ² /day, more preferably 3 to 3000 mg/m ² /day, more preferably 10 to 1000 mg/m ² /day, particularly preferably 60 to 600 mg/m ² /day, most preferably 90 to 270 mg/m ² /day. The dosage of 5-fluoro-2'-deoxycytidine is 0.1～10000 mg/m ² /day. From the viewpoint of exerting an anti-tumor 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 still more preferably 1 to 100 mg/day m ² /day, particularly ^{preferably 3-30 mg/m 2} /day, most preferably 4-12 mg/m ² /day. The dosage of cytidine deaminase inhibitor is 0.1～200,000 mg/m ² /day. From the viewpoint of exerting an anti-tumor 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 even more preferably It is 150～15000 mg/m ² /day, particularly preferably is 500～5000 mg/m ² /day, and most preferably is 1200～3600 mg/m ² /day. In the case of CDZ, it is preferably 1 to 10000 mg/m ² /day, more preferably 3 to 3000 mg/m ² /day, still more preferably 10 to 1000 mg/m ² /day, particularly preferably 30 ~300 mg/m ² /day, preferably 40 ~ 120 mg/m ² /day.

When compound 1 is administered orally, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor are administered by injection, the administration of compound 1 or its pharmaceutically acceptable salt per person per day The amount is 0.3～30000 mg/m ² /day. From the viewpoint of enhancing the anti-tumor effect of the combined use of 5-fluoro-2'-deoxycytidine and a cytidine deaminase inhibitor, it is preferably 1 to 10000 mg/m ² /day, more preferably 3 to 3000 mg/m ² /day, more preferably 10 to 1000 mg/m ² /day, particularly preferably 60 to 600 mg/m ² /day, most preferably 90 to 270 mg/m ² /day. The dosage of 5-fluoro-2'-deoxycytidine is 0.1～10000 mg/m ² /day. From the viewpoint of exerting an anti-tumor 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 still more preferably 0.4 to 40 mg/day m ² /day, particularly ^{preferably 0.8-8 mg/m 2} /day, most preferably 1-3 mg/m ² /day. The dosage of cytidine deaminase inhibitor is 0.01-30000 mg/m ² /day. From the viewpoint of exerting an anti-tumor effect and suppressing the onset of side effects, in the case of THU, it is preferably 1 to 10000 mg/m ² /day, more preferably 5 to 5000 mg/m ² /day, and even more preferably It is 30-3000 mg/m ² /day, particularly ^{preferably 100-1000 mg/m 2} /day, and most preferably 250-750 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, particularly preferably 8 ～80 mg/m ² /day, the best is 12～36 mg/m ² /day. It can be administered once a day or divided into several times.

In addition, the present invention relates to a kit containing compound 1 or its pharmaceutically acceptable salt and instructions for use. The instructions for use describe the combined administration of compound 1 or its pharmaceutically acceptable salt, 5-fluoro- for cancer patients. 2'-deoxycytidine and cytidine deaminase inhibitor. Here, the "instruction manual" only needs to record the above-mentioned dosage, and it is preferable to recommend the above-mentioned dosage, but it does not matter whether it is legally binding or not. Specifically, attachments, manuals, etc. can be exemplified. In addition, the kit preparation containing the instructions for use may be those printed on the package of the kit preparation and accompanied by the instructions for use, or the package of the kit preparations may be accompanied by the antitumor agent and the instructions for use. [Example]

Hereinafter, examples will be given to further specifically illustrate the present invention, but the present invention is not limited in any way.

Example 1 In vitro test-1 The human hematopoietic system tumor cell line MV-4-11 was suspended in a culture medium, inoculated into each well of a multi-well plate, and cultured in an incubator. The compound solution was added on the second day of the culture, and the culture was continued for 3 days. The cell count was measured using CellTiter-Glo (manufactured by Promega), based on the operating procedure recommended by Promega.

The cell survival rate was calculated by the following formula, and the concentration of the compound that inhibited cell survival by 50% (IC50 (μM)) was determined. Cell survival rate (%)=(T/C)×100 T: Luminous intensity of holes with compound added C: Luminous intensity of holes without compound added

In addition, as an indicator of the combined effect, the rate of change of IC50 (μM) caused by the presence or absence of combined use of compound 1 (10 μM) (the combined use effect of compound 1) was obtained by the following formula, and the effect of compound 1 on FdCyd+THU (THU: 10 μM) enhanced effect.

The combined effect of compound 1 = IC50 (μM) when compound 1 is not combined / IC50 (μM) when compound 1 is combined

As a result, Compound 1 enhanced the anti-tumor effect of FdCyd in the presence of THU by more than 10 times.

Example 2 In vivo test-1 The human hematopoietic system tumor cell line MV-4-11 was transplanted into the right chest of BALB/cA Jcl-nu/nu mice. After tumor transplantation, the long diameter (mm) and short diameter (mm) of the tumor were measured, and the tumor volume (TV) was calculated by the following formula, and the mice were assigned to each group with the average TV of each group equal , Set the day of grouping as Day0.

TV(mm ³ )=(long diameter×short diameter ² )/2

Administration started on Day 1, the control group was given 0.5% hypromellose (HPMC) aqueous solution as the medium, the FdCyd+THU administration group was given 1+100 mg/kg/day FdCyd+THU, and the compound 1 administration group was given 600 mg/day Compound 1 kg/day, FdCyd+THU+Compound 1 administration group was given 1+100+600 mg/kg/day FdCyd+THU+Compound 1, all of which were continuously orally administered once a day on Day 1-14. As an indicator of anti-tumor effect and toxicity, according to the TV and body weight (BW) of each group, the relative tumor volume (RTV) and body weight change (body weight change) relative to Day 0 are calculated by the following formula : BWC) and drawing to compare the changes of RTV and BWC in each group.

RTV = (TV of Evaluation Day)/(TV of Day0) BWC(%)=(BW on the evaluation day－BW on Day0)/(BW on Day0)×100

As a result, as shown in Figs. 1 and 2, Compound 1 exhibited an extremely excellent effect of enhancing the anti-tumor effect of FdCyd+THU, and on the other hand, inhibiting the weight loss caused by FdCyd+THU.

Example 3 Test in test tube-2 Various cell lines derived from human hematopoietic tumors shown in Table 1 below were suspended in a culture medium and inoculated into each well of a multi-well plate for culture. The compound solution was added on the second day of the culture, and the culture was continued for 3 days. CellTiter-Glo (manufactured by Promega) was used to measure the number of cells, according to the operating procedure recommended by Promega.

[Table 1] type Cell line Human leukemia K562 Human multiple myeloma MM1S Human leukemia Molt4 Human leukemia MV-4-11 Human lymphoma HT

Calculate the cell survival rate by the following formula, and find the FdCyd, decitabine, and SGI in the presence of THU or CDZ (THU: 10 μM, CDZ: 10 μM) in the presence or absence of compound 1 (10 μM) in combination with or without the following formula -110, azacitidine and Cytarabine (Cytarabine) inhibit cell survival at a concentration (IC50 (μM)), as well as 5-fluorouracil (5-FU), 5-fluoro-2'-deoxy Uridine (FdUrd) inhibits cell survival at a concentration of 50% (IC50(μM)). Cell survival rate (%)=(T/C)×100 T: Luminous intensity of holes with compound added C: Luminous intensity of holes without compound added

As an indicator of the combined use effect of the compound 1, the combined use effect of the compound 1 was obtained by the following formula. The results are shown in Figs. 3 to 7.

The combined effect of compound 1 = IC50 (μM) when compound 1 is not combined / IC50 (μM) when compound 1 is combined

As a result, as shown in Figs. 3-7, it was confirmed that Compound 1 has the effect of enhancing the antitumor effect of FdCyd in the presence of THU or CDZ in various cell lines derived from hematopoietic tumors. It is significantly stronger than other DNA methyltransferase inhibitors (for example, decitabine, SGI-110, azacitidine) in the presence of THU or CDZ produced by compound 1, or arabinocytes that also have a cytidine backbone Enhance the anti-tumor effect of glycosides. In addition, it exceeds the anti-tumor effect of 5-FU and FdUrd produced by compound 1. The anti-tumor effect of FdCyd in the presence of THU or CDZ produced by compound 1 against hematopoietic tumors is more specific than other compounds with pyrimidine backbone. This result is surprising.

Example 4 Test in test tube-3 Various cell lines derived from human cancers, sarcomas, and brain tumors shown in Table 2 below were suspended in a culture medium, and inoculated into each well of a multi-well plate for culture. The compound solution was added on the second day of the culture, and the culture was continued for 3 days. The cell count was measured using CellTiter-Glo (manufactured by Promega), based on the operating procedure recommended by Promega. Otherwise, in the same manner as in Example 3, the combined effect of compound 1 was determined. The results are shown in Figs. 8-17.

[Table 2] type Cell line Human brain tumor A172 Human ovarian cancer ES-2 Human colorectal cancer Lovo Human stomach cancer SNU5 Human pancreatic cancer AsPC1 Human Uterine Cancer RL95-2 Human lung cancer SHP77 Human prostate cancer PC3 Human breast cancer AU565 Human Kidney Cancer ACHN

As a result, as shown in Figs. 8-17, it was confirmed that compound 1 has the antitumor effect of FdCyd in the presence of THU or CDZ in various cell lines derived from cancer, sarcoma and brain tumor. It is beyond the enhancement of 5-FU and FdUrd's anti-tumor effect produced by compound 1. This result is surprising. It was originally thought that the anti-tumor effect of DNA methyltransferase inhibitors on cancer, sarcoma and brain tumors is limited regardless of whether it is used in combination with a cytidine deaminase inhibitor. On the contrary, it was confirmed that Compound 1 has the effect of enhancing the antitumor effect of FdCyd in the presence of THU or CDZ. This result is even more surprising.

Example 5 In vivo test-2 The human hematopoietic system tumor cell line MV-4-11 was transplanted into the right chest of BALB/cA Jcl-nu/nu mice. After tumor transplantation, the long diameter (mm) and short diameter (mm) of the tumor were measured, and the tumor volume (TV) was calculated by the following formula, and the mice were assigned to each group with the average TV of each group equal , Set the day of grouping as Day0.

TV(mm ³ )=(long diameter×short diameter ² )/2

The administration started on Day 1, and the control group (0.5% hypromellose (HPMC) aqueous solution as the medium) and the compound 1 administration group (600 mg/ kg/day), FdCyd＋CDZ administration group (1＋100 mg/kg/day), FdCyd＋CDZ＋Compound 1 administration group (1＋100＋600 mg/kg/day). In order to evaluate the anti-tumor effect and toxicity, the TV and body weight (body weight: BW) of each group on Day 15 on the second day of the last day of administration were obtained. The TV is shown in FIG. 18, and the BW is shown in FIG. 19. In addition, in order to evaluate the enhancement of the anti-tumor effect, a meaningful difference test (t test) was performed using TV (p<0.001 (***)).

As a result, as shown in Figs. 18 and 19, if Compound 1 is used in combination with FdCyd+CDZ, the effect on body weight is limited, and the enhancement of its anti-tumor effect is observed.

Fig. 1 is a graph showing the combined effect of compound 1, 5-fluoro-2'-deoxycytidine and tetrahydrouridine. Figure 2 is a graph showing changes in body weight when compound 1, 5-fluoro-2'-deoxycytidine and tetrahydrouridine were used in combination. Figure 3 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human hematopoietic tumor cell line K562). Figure 4 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human hematopoietic tumor cell line MM1S). Figure 5 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human hematopoietic tumor cell line Molt4). Figure 6 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human hematopoietic tumor cell line MV-4) -11). Figure 7 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human hematopoietic tumor cell line HT). Figure 8 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human brain tumor cell line A172). Figure 9 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human ovarian cancer cell line ES-2) . Figure 10 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human colorectal cancer cell line Lovo). Figure 11 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human gastric cancer cell line SNU5). Figure 12 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human pancreatic cancer cell line AsPC1). Figure 13 is a graph showing the anti-tumor effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or cedaridine produced by compound 1 (human uterine cancer cell line RL95-2) . Figure 14 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human lung cancer cell line SHP77). Figure 15 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human prostate cancer cell line PC3). Figure 16 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human breast cancer cell line AU565). Figure 17 is a graph showing the enhancement effect of 5-fluoro-2'-deoxycytidine in the presence of tetrahydrouridine or 5-fluoro-2'-deoxycytidine produced by compound 1 (human renal cancer cell line ACHN). Fig. 18 is a graph showing the effect of the combined use of compound 1, 5-fluoro-2'-deoxycytidine and cedrocil. Figure 19 is a graph showing the effect on body weight when compound 1, 5-fluoro-2'-deoxycytidine and cedaridine are used in combination.

Claims (24)

An anti-tumor agent, which is a combination of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-diside oxy-3,4- Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor and become. The antitumor agent of claim 1, wherein the cytidine deaminase inhibitor is tetrahydrouridine or Cedazuridine. The anti-tumor agent of claim 1 or 2, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo- 3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salts, 5-fluoro-2'-deoxycytidine and cytidine deamine The enzyme inhibitor is administered orally. The anti-tumor agent of claim 3, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibition The molar ratio of the agent is 1:0.0001～10000:0.0001～10000. The antitumor agent according to claim 3, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3 -((2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro- The molar ratio of 2'-deoxycytidine and tetrahydrouridine is 1:0.046~0.46:7.5~75. The antitumor agent according to claim 3, wherein the cytidine deaminase inhibitor is Cedazuridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and Cedazuridine is 1:0.046～0.46:0.42～4.2. The anti-tumor agent of claim 1 or 2, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo- 3,4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5-fluoro-2'-deoxycytidine And cytidine deaminase inhibitor is administered by injection. The anti-tumor agent according to claim 7, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxo-3, 4-Dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibition The molar ratio of the agent is 1:0.0001～10000:0.0001～10000. The antitumor agent according to claim 7, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3 -((2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro- The molar ratio of 2'-deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. The antitumor agent according to claim 7, wherein the cytidine deaminase inhibitor is Cedazuridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl) -3-((2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5- The molar ratio of fluoro-2'-deoxycytidine and Cedazuridine is 1:0.012～0.12:0.11～1.1. One (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-di-side oxy-3,4-dihydropyrimidine-1(2H )-(Yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is used in the manufacture of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitors The effect enhancer of anti-tumor agent. One (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-di-side oxy-3,4-dihydropyrimidine-1(2H )-(Yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is used in the manufacture of combination with 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor It is an anti-tumor agent. A combination of 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor is used in the manufacture of (Phenyl) ethyl)-3-((2,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmacy The permitted salt is used in combination with the administered antitumor agent. The use of a cytidine deaminase inhibitor is used in the manufacture of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4 -Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and 5-fluoro-2'-deoxycell Glycoside is used in combination with the administered anti-tumor agent. A use of 5-fluoro-2'-deoxycytidine, which is used in the manufacture of (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-( (2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt and cytidine deaminase inhibition Concomitant use of the administered anti-tumor agent. The use according to any one of claims 11 to 15, wherein the cytidine deaminase inhibitor is tetrahydrouridine or Cedazuridine. Such as the use of any one of claims 11 to 15, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxon 3-,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salts, 5-fluoro-2'-deoxycytidine and cytidine Deaminase inhibitors are administered orally. Such as the use of claim 17, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-di-side oxy-3,4- One of dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor The molar ratio is 1:0.0001～10000:0.0001～10000. Such as the use of claim 17, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-( (2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2' -The molar ratio of deoxycytidine and tetrahydrouridine is 1:0.046～0.46:7.5～75. Such as the use of claim 17, wherein the cytidine deaminase inhibitor is Cedazuridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3 -((2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro- The molar ratio of 2'-deoxycytidine and Cedazuridine is 1:0.046～0.46:0.42～4.2. Such as the use of any one of claims 11 to 15, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-dioxon 3-,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt is administered orally, 5-fluoro-2'-deoxy Cytidine and cytidine deaminase inhibitors were administered by injection. Such as the use of claim 21, wherein (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-((2,4-di-side oxy-3,4- One of dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2'-deoxycytidine and cytidine deaminase inhibitor The molar ratio is 1:0.0001～10000:0.0001～10000. Such as the use of claim 21, wherein the cytidine deaminase inhibitor is tetrahydrouridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3-( (2,4-Dilateral oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro-2' -The molar ratio of deoxycytidine and tetrahydrouridine is 1:0.012～0.12:1.5-15. Such as the use of claim 21, wherein the cytidine deaminase inhibitor is Cedazuridine, and (R)-N-(1-(3-(cyclopentyloxy)phenyl)ethyl)-3 -((2,4-Di-side oxy-3,4-dihydropyrimidine-1(2H)-yl)methoxy)propane-1-sulfonamide or its pharmaceutically acceptable salt, 5-fluoro- The molar ratio of 2'-deoxycytidine and Cedazuridine is 1:0.012～0.12:0.11～1.1.

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