TW202140018A - Antitumor effect enhancing agent containing uracil derivative compound - Google Patents

Antitumor effect enhancing agent containing uracil derivative compound Download PDF

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TW202140018A
TW202140018A TW110105559A TW110105559A TW202140018A TW 202140018 A TW202140018 A TW 202140018A TW 110105559 A TW110105559 A TW 110105559A TW 110105559 A TW110105559 A TW 110105559A TW 202140018 A TW202140018 A TW 202140018A
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fluoro
deoxycytidine
pharmaceutically acceptable
propane
sulfonamide
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田中望
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日商大鵬藥品工業股份有限公司
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    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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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

含有尿嘧啶衍生物化合物之抗腫瘤效果增強劑Anti-tumor effect enhancer containing uracil derivative compound

本發明係關於一種使用具有去氧尿苷三磷酸酶(dUTPase)阻礙作用之尿嘧啶衍生物化合物之抗腫瘤效果增強劑及抗腫瘤劑。The present invention relates to an antitumor effect enhancer and an antitumor agent using a uracil derivative compound with deoxyuridine triphosphatase (dUTPase) inhibitory effect.

為了治療腫瘤，已知不僅要阻礙活體內之單一靶標，亦要同時阻礙複數個靶標。為了同時阻礙複數個靶標，多藉由組合複數種阻礙不同靶標之化合物服用，或提供預先組合此種化合物而成之合劑進行。但是，現狀為複數種化合物之組合方法存在無限種，並且其大多數會使毒性、副作用增強，不適於腫瘤之治療，而不得不於研究開發之過程中放棄。 進而，於存在兩種以上不同之阻礙相同靶標之化合物時，於將該等分別與阻礙其他靶標之化合物組合之情形時，可以說其效果或副作用通常於兩種以上不同之化合物之間顯示無法相互類推之行為。因此，實際狀況為組合具有抗腫瘤效果之化合物服用或提供合劑非常困難。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.

已知DNA甲基化為抑制基因表現之基因表現調節機制之一。又，關於腫瘤，確認了藉由高度之DNA甲基化來抑制原先腫瘤之增殖之基因表現抑制，期待DNA甲基化之阻礙對於腫瘤之治療有用。 DNA甲基轉移酶(DNMT)係參與DNA之甲基化之蛋白，其阻礙會抑制DNA之甲基化。因此，期待利用DNA甲基轉移酶阻礙劑(DNMTi)來治療腫瘤。關於DNA甲基轉移酶阻礙劑，作為具有胞苷骨架者，已知5-氟-2'-去氧胞苷(FdCyd)、5-氮雜-2'-去氧胞苷(地西他濱(Decitabine)；5-AZA-CdR)、4-去氧尿苷(Zebularine)、鳥地西他濱(Guadecitabine；SGI-110)、阿紮胞苷(Azacytidine)等，作為不具有胞苷骨架者，已知普魯卡因胺、RG-108、SGI-1027等(非專利文獻1)。期待該等阻礙DNA甲基轉移酶之藥劑對造血系統腫瘤(急性骨髓性白血病(AML)、骨髓化生不良症候群(MDS)、多發性骨髓瘤(MM)、慢性骨髓性白血病(CML)、急性淋巴球性白血病(ALL)等)、實體癌(乳癌、肺癌、大腸癌、肝癌、胰臟癌、***癌、食管癌、頭頸癌、腎癌、皮膚癌、骨腫瘤、軟組織腫瘤等)等之治療效果(非專利文獻2)，一些化合物實施了臨床試驗，一些化合物已作為醫藥品獲得了承認(非專利文獻3)。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).

但是，具有胞苷骨架之DNA甲基轉移酶阻礙劑容易因胞苷去胺酶(CDA)之酵素活性而變為尿苷骨架，而使DNA甲基轉移酶阻礙活性失活(非專利文獻4)。因此，於腫瘤之治療中，於使用具有胞苷骨架之DNA甲基轉移酶阻礙劑時，提倡同時將胞苷去胺酶作為進一步之治療靶標，提出組合DNA甲基轉移酶阻礙劑及胞苷去胺酶阻礙劑(CDAi)使用。作為胞苷去胺酶阻礙劑，已知四氫尿苷(Tetrahydrouridine；THU)、西屈嘧啶(Cedazuridine；CDZ)、去氧THU、ER-876437、ER-876400等(非專利文獻1)。目前，已經實施了併用地西他濱及西屈嘧啶(ASTX727)、併用5-氟-2'-去氧胞苷及四氫尿苷等之臨床試驗。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.

但是，提示：作為抗腫瘤性主劑之DNA甲基轉移酶阻礙劑即便藉由胞苷去胺酶阻礙劑避免於體內分解而到達腫瘤，亦會同時誘導DNA甲基轉移酶阻礙劑本身被帶入至腫瘤細胞相關之轉運體(ENT1)及掌管之後之活化之去氧胞苷激酶(DCK)之減少、進而胞苷去胺酶之上升，而使阻礙DNA甲基轉移酶之藥劑自身之效果降低(非專利文獻5及6)。實際上，已經實施了許多DNA甲基轉移酶阻礙劑之單獨之臨床試驗、併用DNA甲基轉移酶阻礙劑及胞苷去胺酶阻礙劑之臨床試驗，但其臨床效果有限(非專利文獻7)。又，於阿紮胞苷之臨床試驗中觀察到噁心(nausea)、嘔吐(vomiting)、下痢(diarrhea)、肝毒性(hepatotoxicity)(非專利文獻8)，此外於併用5-氟-2'-去氧胞苷及四氫尿苷之臨床試驗中，試驗開始早期便確認到結腸炎(colitis)、伴隨肝酵素上升(elevations in liver enzymes)之倦怠感(fatigue)、血小板減少(thrombocytopenia)、白血球減少(leukopenia)、伴隨消化道損傷(gastrointestinal toxicities)之嗜中性球減少(neutropenia)等作為劑量限制毒性(非專利文獻9)，該等副作用阻止了DNA甲基轉移酶阻礙劑之臨床效果所需之暴露或其持續，成為臨床上之課題。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.

另一方面，(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺(以下，亦稱為「化合物1」)或其藥學上容許之鹽亦被稱為TAS-114，可阻礙去氧尿苷三磷酸酶，其結果，作為對核酸代謝拮抗劑之一之FU(Fluorouracil，氟尿嘧啶)系抗腫瘤劑增強其抗腫瘤效果之化合物而為人所知(專利文獻1)。 但是，此前並不存在明示或者暗示併用具有去氧尿苷三磷酸酶阻礙活性之尿嘧啶衍生物化合物及DNA甲基轉移酶阻礙劑，以及併用具有去氧尿苷三磷酸酶阻礙活性之尿嘧啶衍生物化合物、DNA甲基轉移酶阻礙劑及胞苷去胺酶阻礙劑的文獻。 [先前技術文獻] [專利文獻]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]

[專利文獻1]國際公開第2011/065541號 [非專利文獻][Patent Document 1] International Publication No. 2011/065541 [Non-Patent Literature]

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

[發明所欲解決之問題][The problem to be solved by the invention]

本發明之課題在於提供一種表現明顯優異之抗腫瘤效果，且副作用較少之腫瘤之治療方法。 [解決問題之技術手段]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]

本發明人為了解決上述問題，反覆進行銳意研究，結果發現，若將作為具有去氧尿苷三磷酸酶阻礙活性之尿嘧啶衍生物之化合物1與具有胞苷骨架之DNA甲基轉移酶阻礙劑中之5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑併用，則可增強併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果，同時抑制副作用，從而完成了本發明。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.

即，本發明提供以下之發明[1]～[6]。 [1]一種抗腫瘤劑之效果增強劑，該抗腫瘤劑併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑，且該抗腫瘤劑之效果增強劑以(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽作為有效成分。 [2]一種抗腫瘤劑，其係組合(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑而成。 [3]一種套組製劑，其係用於與5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑併用投予者，包括(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及使用說明書，且 該使用說明書中記載有對於應當應用之患者，併用投予(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑。 [4]一種抗腫瘤劑，其係組合5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑而成，用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽併用投予。 [5]一種含胞苷去胺酶阻礙劑之抗腫瘤劑，其用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及5-氟-2'-去氧胞苷併用投予。 [6]一種含5-氟-2'-去氧胞苷之抗腫瘤劑，其用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及胞苷去胺酶阻礙劑併用投予。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.

又，本發明提供以下之發明[7]～[15]。 [7]如[1]至[6]中任一項所記載之劑，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [8]如[1]至[7]中任一項所記載之劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [9]如[8]所記載之劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [10]如[8]所記載之劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [11]如[8]所記載之劑，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [12]如[1]至[7]中任一項所記載之劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [13]如[12]所記載之劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [14]如[12]所記載之劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [15]如[12]所記載之劑，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.012～0.12：0.11～1.1。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.

又，本發明提供以下之發明[16]～[20]。 [16]一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽之用途，用於製造併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤劑之效果增強劑。 [17]一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽之用途，用於製造與5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑組合而成之抗腫瘤劑。 [18]一種5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之組合之用途，用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽併用投予之抗腫瘤劑。 [19]一種胞苷去胺酶阻礙劑之用途，用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及5-氟-2'-去氧胞苷併用投予之抗腫瘤劑。 [20]一種5-氟-2'-去氧胞苷之用途，用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及胞苷去胺酶阻礙劑併用投予之抗腫瘤劑。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.

又，本發明提供以下之發明[21]～[29]。 [21]如[16]至[20]中任一項所記載之用途，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [22]如[16]至[21]中任一項所記載之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [23]如[22]所記載之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [24]如[22]所記載之用途，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [25]如[22]所記載之用途，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [26]如[16]至[21]中任一項所記載之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [27]如[26]所記載之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [28]如[26]所記載之用途，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [29]如[26]所記載之用途，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.012～0.12：0.11～1.1。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.

又，本發明提供以下之發明[30]～[39]。 [30]一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其用於與5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑併用來增強抗腫瘤效果。 [31]如[30]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [32]如[30]或[31]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [33]如[32]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [34]如[32]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [35]如[32]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [36]如[30]或[31]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [37]如[36]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [38]如[36]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [39]如[36]所記載之(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為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.

又，本發明提供以下之發明[40]～[49]。 [40]一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之組合，其用於治療腫瘤。 [41]如[40]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [42]如[40]或[41]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [43]如[42]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [44]如[42]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [45]如[42]所記載之組合，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [46]如[40]或[41]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [47]如[46]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [48]如[46]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [49]如[46]所記載之組合，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為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.

又，本發明提供以下之發明[50]～[59]。 [50]一種5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之組合，其用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽併用來治療腫瘤。 [51]如[50]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [52]如[50]或[51]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [53]如[52]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [54]如[52]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [55]如[52]所記載之組合，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [56]如[50]或[51]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [57]如[56]所記載之組合，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [58]如[56]所記載之組合，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [59]如[56]所記載之組合，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為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.

又，本發明提供以下之發明[60]～[69]。 [60]一種胞苷去胺酶阻礙劑，其用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及5-氟-2'-去氧胞苷併用來治療腫瘤。 [61]如[60]所記載之胞苷去胺酶阻礙劑，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [62]如[60]或[61]所記載之胞苷去胺酶阻礙劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [63]如[62]所記載之胞苷去胺酶阻礙劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [64]如[62]之胞苷去胺酶阻礙劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [65]如[62]所記載之胞苷去胺酶阻礙劑，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [66]如[60]或[61]所記載之胞苷去胺酶阻礙劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [67]如[66]所記載之胞苷去胺酶阻礙劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [68]如[66]所記載之胞苷去胺酶阻礙劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [69]如[66]所記載之胞苷去胺酶阻礙劑，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為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.

又，本發明提供以下之發明[70]～[79]。 [70]一種5-氟-2'-去氧胞苷，其用於與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及胞苷去胺酶阻礙劑併用來治療腫瘤。 [71]如[70]所記載之5-氟-2'-去氧胞苷，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [72]如[70]或[71]所記載之5-氟-2'-去氧胞苷，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [73]如[72]所記載之5-氟-2'-去氧胞苷，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [74]如[72]所記載之5-氟-2'-去氧胞苷，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [75]如[72]所記載之5-氟-2'-去氧胞苷，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [76]如[70]或[71]所記載之5-氟-2'-去氧胞苷，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [77]如[76]所記載之5-氟-2'-去氧胞苷，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [78]如[76]所記載之5-氟-2'-去氧胞苷，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [79]如[76]所記載之5-氟-2'-去氧胞苷，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為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.

又，本發明提供以下之發明[80]～[84]。 [80]一種5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果增強方法，其包括向需要投予之對象投予(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽之有效量。 [81]一種腫瘤之治療方法，其包括向需要投予之對象投予(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之有效量。 [82]一種治療腫瘤之方法，其係與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽併用來治療腫瘤之方法，包括向需要投予之對象投予5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之有效量。 [83]一種治療腫瘤之方法，其係與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及5-氟-2'-去氧胞苷併用來治療腫瘤之方法，包括向需要投予之對象投予胞苷去胺酶阻礙劑之有效量。 [84]一種治療腫瘤之方法，其係與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及胞苷去胺酶阻礙劑併用來治療腫瘤之方法，包括向需要投予之對象投予5-氟-2'-去氧胞苷之有效量。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.

又，本發明提供以下之發明[85]～[93]。 [85]如[80]至[84]中任一項所記載之方法，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶。 [86]如[80]至[85]中任一項所記載之方法，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。 [87]如[86]所記載之方法，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [88]如[86]所記載之方法，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。 [89]如[86]所記載之方法，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.046～0.46：0.42～4.2。 [90]如[80]至[85]中任一項所記載之方法，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。 [91]如[90]所記載之方法，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。 [92]如[90]所記載之方法，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。 [93]如[90]所記載之方法，其中胞苷去胺酶阻礙劑為西屈嘧啶，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶之莫耳比為1：0.012～0.12：0.11～1.1。 [發明之效果]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]

上述化合物1藉由與5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑併用，從而阻礙副作用發病，且增強併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑時之抗腫瘤效果。因此，根據本發明，能夠進行起到較高之抗腫瘤效果的腫瘤之治療。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.

於本發明中，化合物1用下述式表示。In the present invention, Compound 1 is represented by the following formula.

[化1]

Figure 02_image001
[化1]
Figure 02_image001

化合物1或其藥學上容許之鹽為具有優異之去氧尿苷三磷酸酶阻礙活性之公知之化合物，例如可依據專利文獻1(國際公開第2011/065541號)所記載之方法進行合成。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).

作為化合物1之藥學上容許之鹽，可例舉鹼加成鹽或酸加成鹽。 作為鹼加成鹽，例如可例舉：鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽；銨鹽；三甲胺鹽、三乙胺鹽、二環己胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普魯卡因鹽、N,N'-二苄基乙二胺鹽等有機胺鹽等。 作為酸加成鹽，例如可例舉：鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽等無機酸鹽；乙酸鹽、甲酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、三氟乙酸鹽等有機酸鹽；甲磺酸鹽、羥乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等磺酸鹽等。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.

化合物1或其鹽不論為非晶質或結晶，晶形不論單一或為多晶型混合物，均包含於本發明化合物1或其藥學上容許之鹽。結晶可藉由應用公知之結晶法進行結晶化來製造。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.

化合物1或其藥學上容許之鹽亦包含其前驅藥。前驅藥係指於活體內之生理條件下藉由利用酵素或胃酸等之反應而轉化成本發明化合物或其藥學上容許之鹽的化合物，即藉由酵素產生氧化、還原、水解等而變成本發明化合物或其藥學上容許之鹽的化合物、藉由胃酸等產生水解等而變成本發明化合物或其藥學上容許之鹽的化合物。又，亦可為於如廣川書店1990年刊「醫藥品之開發」第7卷分子設計163頁至198頁所記載之生理條件下變成本發明化合物或其藥學上容許之鹽的化合物。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.

於本發明中，5-氟-2'-去氧胞苷(以下，亦稱為「FdCyd」)為下述式所表示之DNA甲基轉移酶之阻礙藥。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]

Figure 02_image003
[化2]
Figure 02_image003

5-氟-2'-去氧胞苷可藉由文獻(例如Visser, Gerard W. M., J Chem Soc, Perkin Trans 1: Organic and Bio-Organic Chemistry, 1972 - 1999; 1988 (9): 2547 - 54)所記載之方法而獲得。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.

於本發明中，5-氟-2'-去氧胞苷亦包含其藥學上容許之鹽。作為此種鹽，可例舉鹼加成鹽或酸加成鹽。 作為鹼加成鹽，例如可例舉：鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽；銨鹽；三甲胺鹽、三乙胺鹽、二環己胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普魯卡因鹽、N,N'-二苄基乙二胺鹽等有機胺鹽等。 作為酸加成鹽，例如可例舉：鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽等無機酸鹽；乙酸鹽、甲酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、三氟乙酸鹽等有機酸鹽；甲磺酸鹽、羥乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等磺酸鹽等。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.

於本發明中，胞苷去胺酶阻礙劑係指阻礙胞苷去胺酶之酵素活性之藥劑。作為胞苷去胺酶阻礙劑，例如可例舉：四氫尿苷(以下，亦稱為「THU」)、西屈嘧啶(以下，亦稱為「CDZ」)、去氧THU等。 四氫尿苷可藉由文獻(例如Hanze, A. R., J Am Chem Soc. 1967; 89: 6720)所記載之方法而獲得，又，西屈嘧啶可藉由美國專利第8268800號說明書所記載之方法而獲得。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.

於本發明中，四氫尿苷或西屈嘧啶亦包含其藥學上容許之鹽。作為此種鹽，可例舉鹼加成鹽或酸加成鹽。 作為鹼加成鹽，例如可例舉：鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽；銨鹽；三甲胺鹽、三乙胺鹽、二環己胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普魯卡因鹽、N,N'-二苄基乙二胺鹽等有機胺鹽等。 作為酸加成鹽，例如可例舉：鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽等無機酸鹽；乙酸鹽、甲酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、三氟乙酸鹽等有機酸鹽；甲磺酸鹽、羥乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等磺酸鹽等。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.

如下述實施例所示，藉由在5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之併用時進一步併用化合物1，從而增強併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果。 另一方面，若在5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之併用時進一步併用化合物1，則阻礙由於併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑所導致之體重減少等副作用之產生。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.

因此，於一實施方式中，提供一種5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之併用之抗腫瘤效果增強劑，其以化合物1或其藥學上容許之鹽作為有效成分。 又，於另一實施方式中，提供一種組合化合物1或其藥學上容許之鹽、及5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之併用而成之抗腫瘤劑。 於本發明中，抗腫瘤效果例如可以腫瘤體積減少、腫瘤生長停滯或存活時間延長等形式評估。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.

於本發明中，抗腫瘤效果之增強係指使其他抗腫瘤劑之抗腫瘤效果增強，抗腫瘤效果之效果增強劑係指發揮使其他抗腫瘤劑之抗腫瘤效果增強之作用的藥劑。 抗腫瘤效果之效果增強劑往往伴隨副作用增強，較佳為副作用輕度增強，更佳為不伴隨副作用增強，進而較佳為伴隨副作用減輕。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.

本發明之醫藥之治療對象之腫瘤並無特別限制，可例舉：癌、肉瘤、腦腫瘤、造血系統腫瘤等。 癌並無特別限制，可例舉：頭頸癌(口腔癌、咽癌、喉頭癌、鼻腔癌、鼻竇癌、唾液腺癌、甲狀腺癌等)、消化系統癌(食道癌、胃癌、十二指腸癌、肝臟癌、膽道癌(膽囊癌、膽管癌等)、胰臟癌、大腸癌(結腸癌、直腸癌等))、肺癌(非小細胞肺癌、小細胞肺癌、間皮瘤等)、乳癌、生殖器癌(卵巢癌、子宮癌(子宮頸癌、子宮體癌等)等)、泌尿器官癌(腎癌、膀胱癌、***癌、睾丸瘤等)、皮膚癌等。 肉瘤並無特別限制，可例舉：骨腫瘤、軟組織腫瘤等。 造血系統腫瘤並無特別限制，可例舉：白血病、惡性淋巴瘤、多發性骨髓瘤等。 白血病並無特別限制，可例舉：急性骨髓性白血病、慢性骨髓性白血病、急性淋巴球性白血病、慢性淋巴球性白血病、成人T細胞白血病、骨髓化生不良症候群、毛細胞白血病等。惡性淋巴瘤並無特別限制，可例舉霍奇金淋巴瘤、非霍奇金淋巴瘤，作為非霍奇金淋巴瘤，可例舉：源自B細胞之淋巴瘤、源自T/NK細胞之淋巴瘤、淋巴胚細胞性淋巴瘤等。 腦腫瘤並無特別限制，例如可例舉：轉移性腦腫瘤(例如，肺癌、乳癌、胃癌、結腸直腸癌、膀胱癌、膽道癌、子宮癌等之腦轉移)、毛細胞性星狀細胞瘤、彌漫性星狀細胞瘤、寡樹突神經膠細胞瘤/寡樹突星狀細胞瘤、退行性星狀細胞瘤/退行性寡樹突神經膠細胞瘤、退行性寡樹突星狀細胞瘤、神經膠母細胞瘤、室管膜瘤、退行性室管膜瘤、神經節膠質瘤、中樞性神經細胞瘤、神經管胚細胞瘤、胚細胞瘤(germinoma)、中樞神經系統惡性淋巴瘤、腦膜瘤、神經鞘瘤、GH(Growth Hormone，生長激素)分泌型垂體腺瘤、PRL(Prolactin，泌乳素)分泌型垂體腺瘤、ACTH(Adrenocorticotropic Hormone，促腎上腺皮質激素)分泌型垂體腺瘤、非功能性垂體腺瘤、顱咽管瘤、脊索瘤、血管母細胞瘤、表皮樣囊腫等。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.

再者，此處之腫瘤不僅包含原發病灶，亦包含轉移至其他器官(肝臟等)之腫瘤。又，本發明之抗腫瘤劑可用於在外科摘除腫瘤後用以防止復發而進行之術後輔助化學療法，亦可用於為了外科摘除腫瘤而事先進行之術前輔助化學療法。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.

於將化合物1或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑用作醫藥時，可視需要調配藥學載體，根據預防或治療目的採用各種投予形態。 作為劑型，例如可例示：經口劑(錠劑、被覆錠劑、散劑、顆粒劑、膠囊劑、液劑等)、注射劑、栓劑、貼附劑、軟膏劑等。較佳為經口劑、注射劑。該等投予形態可藉由各業者公知慣用之製劑方法進行製造。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.

作為藥學載體，可例示通常之藥劑所通用之各種載體，例如，賦形劑、黏合劑、崩解劑、潤滑劑、稀釋劑、溶解助劑、懸浮劑、等張劑、pH值調整劑、緩衝劑、穩定劑、著色劑、矯味劑、矯臭劑等。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.

本發明之醫藥之投予排程能夠於發揮抗腫瘤效果之增強效果之範圍內適當選擇，各有效成分可同時投予或空開間隔分別投予。於分別投予之情形時，無先後之分。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.

本發明之醫藥基於各有效成分之投予形態或投予排程，可將各有效成分分成複數種劑型進行製劑化，亦可統一為一種劑型進行製劑化。又，可將各製劑彙總至一個適於併用投予之包裝內製造販賣，又，亦可將各製劑分成不同之包裝來製造販賣。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.

化合物1或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之投予或調配比率只要為發揮抗腫瘤效果之增強效果之範圍則並無特別限制。 於經口投予化合物1、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之情形時，就阻礙副作用發病，並且使併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果增強之觀點而言，相對於化合物1或其藥學上容許之鹽1莫耳，5-氟-2'-去氧胞苷設為0.0001～10000莫耳即可，較佳為設為0.001～1000莫耳即可，更佳為設為0.01～100莫耳即可，進而較佳為設為0.015～1.5莫耳即可，特佳為設為0.046～0.46莫耳即可，最佳為設為0.06～0.18莫耳即可。 就相同之觀點而言，相對於化合物1或其藥學上容許之鹽1莫耳，胞苷去胺酶阻礙劑設為0.0001～10000莫耳即可。於THU之情形時，較佳為設為0.001～1000莫耳即可，更佳為設為0.03～300莫耳即可，進而較佳為設為2.3～230莫耳即可，特佳為設為7.5～75莫耳即可，最佳為設為18～54莫耳即可。於CDZ之情形時，較佳為設為0.001～1000莫耳即可，更佳為設為0.03～300莫耳即可，進而較佳為設為0.15～15莫耳即可，特佳為設為0.42～4.2莫耳即可，最佳為設為0.56～1.7莫耳即可。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.

又，於經口投予化合物1，注射投予5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之情形時，就阻礙副作用發病，且使併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果增強之觀點而言，相對於化合物1或其藥學上容許之鹽1莫耳，5-氟-2'-去氧胞苷設為0.0001～10000莫耳即可，較佳為設為0.001～1000莫耳即可，更佳為設為0.005～50莫耳即可，進而較佳為設為0.006～0.6莫耳即可，特佳為設為0.012～0.12莫耳即可，最佳為設為0.015～0.045莫耳即可。 就相同之觀點而言，相對於化合物1或其藥學上容許之鹽1莫耳，胞苷去胺酶阻礙劑設為0.0001～10000莫耳即可。於THU之情形時，較佳為設為0.001～1000莫耳即可，更佳為設為0.03～300莫耳即可，進而較佳為設為0.45～45莫耳即可，特佳為設為1.5～15莫耳即可，最佳為設為3.8～11.4莫耳即可。於CDZ之情形時，較佳為設為0.001～1000莫耳即可，更佳為設為0.01～100莫耳即可，進而較佳為設為0.04～4莫耳即可，特佳為設為0.11～1.1莫耳即可，最佳為設為0.17～0.51莫耳即可。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.

於本發明之醫藥中，各有效成分之投予量可根據用法、患者之年齡、性別、其他條件、疾病之程度等適當選擇。 例如，於經口投予化合物1、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之情形時，一個人平均一天之化合物1或其藥學上容許之鹽之投予量為0.3～30000 mg/m2 /天。就使併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果增強之觀點而言，較佳為1～10000 mg/m2 /天，更佳為3～3000 mg/m2 /天，進而較佳為10～1000 mg/m2 /天，特佳為60～600 mg/m2 /天，最佳為90～270 mg/m2 /天。 5-氟-2'-去氧胞苷之投予量為0.1～10000 mg/m2 /天。就發揮抗腫瘤效果，以及抑制副作用發病之觀點而言，較佳為0.3～3000 mg/m2 /天，更佳為0.6～600 mg/m2 /天，進而較佳為1～100 mg/m2 /天，特佳為3～30 mg/m2 /天，最佳為4～12 mg/m2 /天。 胞苷去胺酶阻礙劑之投予量為0.1～200000 mg/m2 /天。就發揮抗腫瘤效果，以及抑制副作用發病之觀點而言，於THU之情形時，較佳為2～20000 mg/m2 /天，更佳為18～18000 mg/m2 /天，進而較佳為150～15000 mg/m2 /天，特佳為500～5000 mg/m2 /天，最佳為1200～3600 mg/m2 /天。於CDZ之情形時，較佳為1～10000 mg/m2 /天，更佳為3～3000 mg/m2 /天，進而較佳為10～1000 mg/m2 /天，特佳為30～300 mg/m2 /天，最佳為40～120 mg/m2 /天。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.

於經口投予化合物1，注射投予5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之情形時，一個人平均一天之化合物1或其藥學上容許之鹽之投予量為0.3～30000 mg/m2 /天。就使併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤效果增強之觀點而言，較佳為1～10000 mg/m2 /天，更佳為3～3000 mg/m2 /天，進而較佳為10～1000 mg/m2 /天，特佳為60～600 mg/m2 /天，最佳為90～270 mg/m2 /天。 5-氟-2'-去氧胞苷之投予量為0.1～10000 mg/m2 /天。就發揮抗腫瘤效果，以及抑制副作用發病之觀點而言，較佳為0.2～2000 mg/m2 /天，更佳為0.3～300 mg/m2 /天，進而較佳為0.4～40 mg/m2 /天，特佳為0.8～8 mg/m2 /天，最佳為1～3 mg/m2 /天。 胞苷去胺酶阻礙劑之投予量為0.01～30000 mg/m2 /天。就發揮抗腫瘤效果，以及抑制副作用發病之觀點而言，於THU之情形時，較佳為1～10000 mg/m2 /天，更佳為5～5000 mg/m2 /天，進而較佳為30～3000 mg/m2 /天，特佳為100～1000 mg/m2 /天，最佳為250～750 mg/m2 /天。於CDZ之情形時，較佳為0.6～6000 mg/m2 /天，更佳為1～1000 mg/m2 /天，進而較佳為3～300 mg/m2 /天，特佳為8～80 mg/m2 /天，最佳為12～36 mg/m2 /天。 其可一天投予一次或分成數次左右進行投予。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.

又，本發明係關於一種包含化合物1或其藥學上容許之鹽及使用說明書之套組製劑，上述使用說明書記載了對癌症患者併用投予化合物1或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑。此處，「使用說明書」只要記載上述投予量即可，較佳為推薦上述投予量，但並不問有無法律約束力。具體而言，可例示附件、說明書等。又，包含使用說明書之套組製劑可為套組製劑之包裝上印刷、隨附使用說明書者，亦可為套組製劑之包裝中附有抗腫瘤劑及使用說明書者。 [實施例]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]

以下，例舉實施例進一步具體地說明本發明，但本發明並不受該等任何限定。Hereinafter, examples will be given to further specifically illustrate the present invention, but the present invention is not limited in any way.

實施例1 試管內(in vitro)試驗-1 使人類造血系統腫瘤細胞株MV-4-11懸浮於培養基中，接種至多孔板之各孔中，於培養器中進行培養。於培養開始第二天添加化合物溶液，進而培養3天。細胞數之測量使用CellTiter-Glo(Promega公司製造)，基於Promega公司推薦之操作流程進行。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.

藉由以下算式算出細胞存活率，求出將細胞存活阻礙了50%之化合物之濃度(IC50(μM))。 細胞存活率(%)＝(T/C)×100 T：添加有化合物之孔之發光強度 C：未添加化合物之孔之發光強度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

又，作為併用效果之指標，藉由以下算式求出由有無併用化合物1(10 μM)引起之IC50(μM)之變化率(化合物1之併用效果)，求出化合物1對FdCyd＋THU(THU：10 μM)之增強效果。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.

化合物1之併用效果＝未併用化合物1時之IC50(μM)/併用化合物1時之IC50(μM)The combined effect of compound 1 = IC50 (μM) when compound 1 is not combined / IC50 (μM) when compound 1 is combined

結果，化合物1使THU存在下之FdCyd之抗腫瘤效果增強10倍以上。As a result, Compound 1 enhanced the anti-tumor effect of FdCyd in the presence of THU by more than 10 times.

實施例2 活體內試驗-1 將人類造血系統腫瘤細胞株MV-4-11移植至BALB/cA Jcl-nu/nu小鼠之右側胸部。於腫瘤移植後測定腫瘤之長徑(mm)及短徑(mm)，藉由下式算出腫瘤體積(tumor volume：TV)後，以各組之平均TV均等之方式將小鼠分配至各組，將實施分組之日作為Day0。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(mm3 )＝(長徑×短徑2 )/2TV(mm 3 )=(long diameter×short diameter 2 )/2

自Day1開始投予，對照組投予作為介質之0.5%羥丙甲纖維素(HPMC)水溶液，FdCyd＋THU投予組投予1＋100 mg/kg/day之FdCyd＋THU，化合物1投予組投予600 mg/kg/day之化合物1，FdCyd＋THU＋化合物1投予組投予1＋100＋600 mg/kg/day之FdCyd＋THU＋化合物1，其等均於Day1-14以1天1次之方式連續經口投予。作為抗腫瘤效果及毒性之指標，根據各組之TV及體重(body weight：BW)，藉由下式求出相對於Day0之相對腫瘤體積(relative tumor volume：RTV)及體重變化(body weight change：BWC)而繪圖，比較各組之RTV及BWC之經日變遷。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＝(評估日之TV)/(Day0之TV) BWC(%)＝(評估日之BW－Day0之BW)/(Day0之BW)×100RTV = (TV of Evaluation Day)/(TV of Day0) BWC(%)=(BW on the evaluation day－BW on Day0)/(BW on Day0)×100

結果，如圖1及圖2所示，化合物1表現出使FdCyd＋THU之抗腫瘤效果增強，另一方面抑制由FdCyd＋THU所導致之體重減少的極其優異之作用。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.

實施例3 試管內試驗-2 使下述表1所示之源自人類造血系統腫瘤之各種細胞株懸浮於培養基中，接種至多孔板之各孔進行培養。於培養開始第二天添加化合物溶液，進而培養3天。細胞數之測量使用CellTiter-Glo(Promega公司製造)，依據Promega公司推薦之操作流程進行。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.

[表1] 種類 細胞株 人類白血病 K562 人類多發性骨髓瘤 MM1S 人類白血病 Molt4 人類白血病 MV-4-11 人類淋巴瘤 HT [Table 1] type Cell line Human leukemia K562 Human multiple myeloma MM1S Human leukemia Molt4 Human leukemia MV-4-11 Human lymphoma HT

藉由以下算式算出細胞存活率，分別求出於有無併用化合物1(10 μM)之情況下，THU或CDZ存在下(THU：10 μM，CDZ：10 μM)之FdCyd、地西他濱、SGI-110、阿紮胞苷及阿糖胞苷(Cytarabine)將細胞存活阻礙了50%之濃度(IC50(μM))，以及5-氟尿嘧啶(5-FU)、5-氟-2'-去氧尿苷(FdUrd)將細胞存活阻礙了50%之濃度(IC50(μM))。 細胞存活率(%)＝(T/C)×100 T：添加有化合物之孔之發光強度 C：未添加化合物之孔之發光強度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

作為化合物1之併用效果之指標，藉由以下算式求出化合物1之併用效果。 將結果示於圖3～圖7。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.

化合物1之併用效果＝未併用化合物1時之IC50(μM)/併用化合物1時之IC50(μM)The combined effect of compound 1 = IC50 (μM) when compound 1 is not combined / IC50 (μM) when compound 1 is combined

其結果，如圖3～圖7所示，於各種源自造血系統腫瘤之細胞株中確認到化合物1具有THU或CDZ存在下之FdCyd之抗腫瘤效果之增強作用。其明顯強於由化合物1產生之THU或CDZ存在下之其他DNA甲基轉移酶阻礙劑(例如，地西他濱、SGI-110、阿紮胞苷)或同樣具有胞苷骨架之阿糖胞苷之抗腫瘤效果之增強作用。又，其超出由化合物1產生之5-FU及FdUrd之抗腫瘤效果之增強作用。 針對造血系統腫瘤之由化合物1產生之THU或CDZ存在下之FdCyd之抗腫瘤效果之增強作用與其他具有嘧啶骨架之化合物相比有特異性，這一結果令人驚訝。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.

實施例4 試管內試驗-3 使下述表2所示之源自人類癌、肉瘤及腦腫瘤之各種細胞株懸浮於培養基中，接種至多孔板之各孔進行培養。於培養開始第二天添加化合物溶液，進而培養3天。細胞數之測量使用CellTiter-Glo(Promega公司製造)，基於Promega公司推薦之操作流程進行。 其餘與實施例3同樣地求出化合物1之併用效果。 將結果示於圖8～圖17。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.

[表2] 種類 細胞株 人類腦腫瘤 A172 人類卵巢癌 ES-2 人類大腸癌 Lovo 人類胃癌 SNU5 人類胰臟癌 AsPC1 人類子宮癌 RL95-2 人類肺癌 SHP77 人類***癌 PC3 人類乳癌 AU565 人類腎癌 ACHN [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

其結果，如圖8～圖17所示，於各種源自癌症、肉瘤及腦腫瘤之細胞株中確認到化合物1具有THU或CDZ存在下之FdCyd之抗腫瘤效果之增強作用。其超出由化合物1產生之5-FU、FdUrd之抗腫瘤效果之增強作用。這一結果令人驚訝。 原本認為無論是否與胞苷去胺酶阻礙劑併用，DNA甲基轉移酶阻礙劑對癌症、肉瘤及腦腫瘤之抗腫瘤效果有限。與此相對，確認了化合物1具有THU或CDZ存在下之FdCyd之抗腫瘤效果之增強作用。這一結果更令人驚訝。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.

實施例5 活體內試驗-2 將人類造血系統腫瘤細胞株MV-4-11移植至BALB/cA Jcl-nu/nu小鼠之右側胸部。於腫瘤移植後測定腫瘤之長徑(mm)及短徑(mm)，藉由下式算出腫瘤體積(tumor volume：TV)後，以各組之平均TV均等之方式將小鼠分配至各組，將實施分組之日作為Day0。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(mm3 )＝(長徑×短徑2 )/2TV(mm 3 )=(long diameter×short diameter 2 )/2

自Day1開始投予，於Day1-14以1天1次之方式連續經口投予對照組(作為介質之0.5% 羥丙甲纖維素(HPMC)水溶液)、化合物1投予組(600 mg/kg/day)、FdCyd＋CDZ投予組(1＋100 mg/kg/day)、FdCyd＋CDZ＋化合物1投予組(1＋100＋600 mg/kg/day)。為了評估抗腫瘤效果及毒性，求出投予最後一天之第二天即Day15之各組之TV及體重(body weight：BW)。 將TV示於圖18，將BW示於圖19。又，為了評估抗腫瘤效果之增強作用，使用TV進行有意義差檢定(t檢定)(p＜0.001(***))。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 (***)).

其結果，如圖18及圖19所示，化合物1若與FdCyd＋CDZ併用，則對體重之影響有限，而且觀察到其抗腫瘤效果之增強作用。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.

圖1係表示化合物1、5-氟-2'-去氧胞苷及四氫尿苷之併用效果之圖。 圖2係表示併用化合物1、5-氟-2'-去氧胞苷及四氫尿苷時之體重變化之圖。 圖3係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類造血系統腫瘤細胞株K562)。 圖4係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類造血系統腫瘤細胞株MM1S)。 圖5係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類造血系統腫瘤細胞株Molt4)。 圖6係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類造血系統腫瘤細胞株MV-4-11)。 圖7係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類造血系統腫瘤細胞株HT)。 圖8係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類腦腫瘤細胞株A172)。 圖9係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類卵巢癌細胞株ES-2)。 圖10係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類大腸癌細胞株Lovo)。 圖11係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類胃癌細胞株SNU5)。 圖12係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類胰臟癌細胞株AsPC1)。 圖13係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類子宮癌細胞株RL95-2)。 圖14係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類肺癌細胞株SHP77)。 圖15係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類***癌細胞株PC3)。 圖16係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類乳癌細胞株AU565)。 圖17係表示由化合物1產生之四氫尿苷或西屈嘧啶存在下之5-氟-2'-去氧胞苷之抗腫瘤效果之增強效果的圖(人類腎癌細胞株ACHN)。 圖18係表示併用化合物1、5-氟-2'-去氧胞苷及西屈嘧啶之效果之圖。 圖19係表示於併用化合物1、5-氟-2'-去氧胞苷及西屈嘧啶時對體重之影響之圖。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)

一種抗腫瘤劑，其係組合(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑而成。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. 如請求項1之抗腫瘤劑，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶(Cedazuridine)。The antitumor agent of claim 1, wherein the cytidine deaminase inhibitor is tetrahydrouridine or Cedazuridine. 如請求項1或2之抗腫瘤劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。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. 如請求項3之抗腫瘤劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。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. 如請求項3之抗腫瘤劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。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. 如請求項3之抗腫瘤劑，其中胞苷去胺酶阻礙劑為西屈嘧啶(Cedazuridine)，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶(Cedazuridine)之莫耳比為1：0.046～0.46：0.42～4.2。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. 如請求項1或2之抗腫瘤劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。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. 如請求項7之抗腫瘤劑，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。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. 如請求項7之抗腫瘤劑，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。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. 如請求項7之抗腫瘤劑，其中胞苷去胺酶阻礙劑為西屈嘧啶(Cedazuridine)，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶(Cedazuridine)之莫耳比為1：0.012～0.12：0.11～1.1。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. 一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽之用途，係用於製造併用5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之抗腫瘤劑之效果增強劑。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. 一種(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽之用途，係用於製造與5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑組合而成之抗腫瘤劑。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. 一種5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之組合之用途，係用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽併用投予之抗腫瘤劑。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. 一種胞苷去胺酶阻礙劑之用途，係用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及5-氟-2'-去氧胞苷併用投予之抗腫瘤劑。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. 一種5-氟-2'-去氧胞苷之用途，係用於製造用以與(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽及胞苷去胺酶阻礙劑併用投予之抗腫瘤劑。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. 如請求項11至15中任一項之用途，其中胞苷去胺酶阻礙劑為四氫尿苷或西屈嘧啶(Cedazuridine)。The use according to any one of claims 11 to 15, wherein the cytidine deaminase inhibitor is tetrahydrouridine or Cedazuridine. 如請求項11至15中任一項之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係經口投予。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. 如請求項17之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。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. 如請求項17之用途，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.046～0.46：7.5～75。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. 如請求項17之用途，其中胞苷去胺酶阻礙劑為西屈嘧啶(Cedazuridine)，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶(Cedazuridine)之莫耳比為1：0.046～0.46：0.42～4.2。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. 如請求項11至15中任一項之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽係經口投予，5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑係注射投予。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. 如請求項21之用途，其中(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及胞苷去胺酶阻礙劑之莫耳比為1：0.0001～10000：0.0001～10000。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. 如請求項21之用途，其中胞苷去胺酶阻礙劑為四氫尿苷，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及四氫尿苷之莫耳比為1：0.012～0.12：1.5～15。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. 如請求項21之用途，其中胞苷去胺酶阻礙劑為西屈嘧啶(Cedazuridine)，且(R)-N-(1-(3-(環戊氧基)苯基)乙基)-3-((2,4-二側氧基-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺或其藥學上容許之鹽、5-氟-2'-去氧胞苷及西屈嘧啶(Cedazuridine)之莫耳比為1：0.012～0.12：0.11～1.1。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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