CN104710489A - 5`-脱氧-5-氟-n-｛4–[双(2-氯乙基)氨基]苯丁酰基｝胞苷及其制备方法和应用 - Google Patents
5`-脱氧-5-氟-n-｛4–[双(2-氯乙基)氨基]苯丁酰基｝胞苷及其制备方法和应用 Download PDFInfo
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- CN104710489A CN104710489A CN201410426100.0A CN201410426100A CN104710489A CN 104710489 A CN104710489 A CN 104710489A CN 201410426100 A CN201410426100 A CN 201410426100A CN 104710489 A CN104710489 A CN 104710489A
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- deoxidation
- cytidine
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
本发明公开了具有式Ⅰ结构的药物分子：5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷及其制备方法。本发明所述化合物具有良好的抗癌活性，可用于制备治疗白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、胰腺癌、结肠癌、直肠癌、非小细胞肺癌、膀胱癌、胃癌、肝癌、肉瘤、皮肤癌或胶质瘤的药物。
Description
技术领域
本发明涉及核苷类似物5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷及其制备方法、制剂以及作为抗肿瘤药物的应用。
背景技术
肿瘤是一类严重危害人类生命健康的疾病，是机体在致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的异常病变。表现为细胞过度增殖、分化异常,目前癌症已成为人类第一死因,对人类生存构成最严重的威胁。药物治疗在治疗肿瘤方面起作重要作用,抗肿瘤药物品种繁多，作用机理不同。多数抗肿瘤药物的作用机制主要是阻止脱氧核糖核酸(DNA)、核糖核酸(RNA)或蛋白质的合成，或直接对这些大分子发生作用，从而抑制肿瘤细胞的分裂增殖，使之死亡。有些药物也可以通过改变体内激素平衡而抑制肿瘤生长。目前抗肿瘤药物主要分为6大类:①抗代谢药；②烷化剂；③细胞毒素类抗生素；④植物生物碱和其他天然药；⑤抗肿瘤激素类；⑥铂类及其他抗肿瘤药。
核苷类似物是一类抗代谢药抗肿瘤药物，是利用生物电子等排原理，将DNA复制中所需的嘌呤核苷、嘧啶核苷等单元物质的结构作化学修饰而得，经细胞内三磷酸化后，通过抑制脱氧核苷三磷酸(dNTPs)的合成、掺入DNA或RNA分子中干扰细胞复制、竞争性抑制DNA聚合酶等作用，特异性干扰核酸的代谢，阻止细胞的分裂和繁殖，最终导致肿瘤细胞死亡.核苷类类抗肿瘤药物包括:1)鸟苷类似物,如鸟嘌呤核苷类药物奈拉滨(nelarabine)；2)腺苷类似物，如氟达拉滨(fludarabine)、克拉屈滨(cladribine)和氯法拉滨(clofarabine)；3)嘌呤类似物，如巯嘌呤(mercaptopurine，6-MP)、硫鸟嘌呤(tioguanine，6-TG)和硫唑嘌呤(azathioprine)；4)尿嘧啶及尿苷类似物，如氟尿嘧啶(5-FU，fluorouracil)、替加氟(tegafur)、卡培他滨(capecitabine)和5-乙炔基尿嘧啶(5-ethynyluracil)；5)胞苷类似物，如阿糖胞苷(cytarabine，ara-C)、吉西他滨(gemcitabine)、阿扎胞苷(azacitidine，5-AC)和地西他滨(decitabine)。核苷类抗肿瘤药物在治疗肿瘤方面起作重要作用。
发明内容
本发明的目的在于提供一种核苷类似物抗肿瘤药物：5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)，具有式Ⅰ的化学结构：
本发明的另一目的在于提供所述核苷类似物抗肿瘤药物XBB-009(式Ⅰ)的合成方法。
上述化合物Ⅰ可通过以下方法制备：
(1)将4-[双(2-氯乙基)氨基]苯丁酸与酰氯化试剂反应生成4-[双(2-氯乙基)氨基]苯丁酰氯。
上述酰氯化试剂为本领域常规使用的酰氯化试剂，优选SOCl2或(COCl)2或POCl3，反应条件为常规酰氯化反应条件，一个优选的实施方案为氮气保护下，无水甲苯作为溶剂，无水DMF催化下，4-[双(2-氯乙基)氨基]苯丁酸与氯化亚砜在室温下反应2-10小时得到4-[双(2-氯乙基)氨基]苯丁酰氯。
(2)5’-脱氧-5-氟胞苷与羟基保护试剂氯硅烷反应，在咪唑(imidazol)的作用下，生成2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷(2’,3’-bis-O-(tert-butyldimethylsilyl)-5’-deoxy-5-fluorocytidine)。
上述羟基保护试剂氯硅烷优选叔丁基二甲基氯硅烷。反应条件为本领域常规使用的反应条件，一个优选的实施方案为无水DMF作为反应溶剂，加入5’-脱氧-5-氟胞苷溶解后，再加入叔丁基二甲基氯硅烷，在咪唑作用下，室温搅拌，反应过夜至反应完成。可进一步将反应生成的2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷进行柱层析纯化，使用硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗液，得纯化的2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷。
(3)将步骤(1)得到的4-[双(2-氯乙基)氨基]苯丁酰氯与步骤(2)得到的2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷反应，在碱的作用下生成N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷；
上述碱为有机碱或无机碱，有机碱优选三乙胺、吡啶、4-二甲氨基吡啶(DMAP)等，无机碱优选碳酸钠、碳酸钾、碳酸铯等，一个优选的实施方案为以4-二甲氨基吡啶(DMAP)为碱，将2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷与4-[双(2-氯乙基)氨基]苯丁酰氯在DMAP的作用下，室温搅拌，反应过夜至反应完成。
可进一步将反应生成的N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷使用柱层析分离纯化，更优选的，用硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗剂，得到纯化的N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷。
(4)将步骤(3)得到的N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷与四丁基氟化铵反应得到5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)。
上述反应的一个优选的实施方案为氮气保护下，将N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷在四丁基氟化铵催化下，室温反应，得到5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)。
可进一步将5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)使用柱层析分离，更优选的，用硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗液，得纯化的5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)。
本发明所述反应路线示意图如下图所示：
本发明的另一目的在于提供所述核苷类似物抗肿瘤药物5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)在制备抗癌药物中的应用。所述癌症包括但不限于(1)血液系统的癌症，如白血病、淋巴瘤、骨髓瘤；(2)非血液癌症，如实体瘤癌(如乳腺癌、卵巢癌、胰腺癌、结肠癌、直肠癌、非小细胞肺癌、膀胱癌、胃癌、肝癌等)、肉瘤、皮肤癌和胶质瘤等。
上述应用中，所述的药物包括有效治疗量的XBB-009以及药学上可接受的药物载体。可以为注射剂、口服制剂或外用制剂。优选乳剂、微乳剂、胶束剂、脂质体、片剂或胶囊剂、膏剂。
本发明的化合物XBB-009分子中同时含有可使DNA碱基交叉联结的双氯乙胺烷化基团和可抑制脱氧胸苷酸合成酶的5-氟尿嘧啶前体结构，预期分子本身或其代谢产物以两种机制作用于癌细胞，从而产生协同作用效果抑制并杀死癌细胞，以提高疗效和降低毒副作用。
本发明还涉及所述的新的抗癌药物的制剂配方，包括乳剂或微乳液剂、胶束剂、脂质体剂、片剂、胶囊剂和膏剂配方。乳剂包括新发明的抗癌药物化合物、一种或多种表面活性剂、油相(亲脂性介质)和水相。乳剂可以是水包油型或油包水型。胶束剂包括新发明的抗癌药物化合物、助溶剂和一种或多种表面活性剂和水相。脂质体剂包括新发明的抗癌药物化合物、磷脂(最具有代表性的是卵磷脂、磷脂酰胆碱)、胆固醇和水相。片剂包括新发明的抗癌药物化合物和辅料。胶囊剂包括新发明的抗癌药物化合物和辅料。膏剂配方包括新发明的抗癌药物化合物和基质。
采用的技术方案为，一种所述的抗癌药物化合物的乳剂或微乳剂，其成分包括：
1)油相，包括：
a)抗癌药物化合物XBB-009；
b)生物相容的亲脂性介质；
2)表面活性剂和助溶剂；
3)水相。
或者，一种所述的抗癌药物化合物胶束剂，其成分包括：
1)抗癌药物化合物XBB-009；
2)表面活性剂；
3)助溶剂；
4)水相。
或者，一种所述的抗癌药物化合物脂质体制剂，其成分包括：
1)抗癌药物化合物XBB-009；
2)磷脂；
3)胆固醇；
4)水相。
或者，一种所述的抗癌药物化合物的片剂，其成分包括：
1)抗癌药物化合物XBB-009；
2)辅料。
常用的辅料包括：(1)稀释剂(Diluents)，如淀粉、糖粉、糊精、乳糖、预胶化淀粉(Pregelatinized starch)、微晶纤维素(Microcrystalline cellulose，MCC)、无机钙盐，如硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇；(2)粘合剂(Adhesives)，如蒸馏水、乙醇、淀粉浆、羧甲基纤维素钠(carboxymethylcellulose sodium，CMC-Na)、羟丙基纤维素(hydroxypropylcellulose，HPC)、甲基纤维素和乙基纤维素(Methylcellulose，MC；Ethylcellulose，EC)、羟丙甲纤维素(Hydroxypropylmethyl cellulose，HPMC)、其它粘合剂(5％～20％的明胶溶液，50％～70％的蔗糖溶液，3％～5％的聚乙烯毗咯烷酮(PVP)的水溶液或醇溶液)；(3)崩解剂(Disintegrants)，如干淀粉、羧甲基淀粉钠(Carboxymethylstarch sodium，CMS-Na)、低取代羟丙基纤维素(L-HPC)、交联聚乙烯比咯烷酮(Cross-linked polyvinyl pyrrolidone，亦称交联PVP)、交联羧甲基纤维素钠(Croscarmellosesodium，CCNa是交联化的纤维素羧甲基醚(大约有70％的羧基为钠盐型)；(4)润滑剂(Lubricants)，如硬脂酸镁、氢化植物油、聚乙二醇、月挂醇硫酸镁、微粉硅胶(Aerosil)、滑石粉；(5)着色剂；(6)矫味剂等。无论加入何种辅料，都应符合药用的要求，都不能与主药发生反应，也不应妨碍主药的溶出和吸收。
片剂可采用湿法制粒压片、干法制粒压片和直接压片制备。
或者，一种所述的抗癌药物化合物的胶囊剂，包括硬胶囊和软胶囊。其成分包括：
1)抗癌药物化合物XBB-009；
2)辅料。
硬胶囊剂的常用辅料包括但不限于：(1)稀释剂：用于改善内容物的物理特性和增加体积，往往具有一定的可压性。常用的稀释剂有甘露醇、微晶纤维素、乳糖、预胶化淀粉1500、玉米淀粉等。(2)润滑剂：以防止粉末与金属材料的黏附。常用有硬脂酸镁、单硬脂酸甘油酯、硬脂酸、滑石粉等。(3)助流剂：改善内容物的流动性。常用有微粉硅胶和滑石粉等。(4)崩解剂：保证内容物的崩解。常见有交联纤维素、玉米淀粉、交联聚维酮、预胶化淀粉1500、甘氨酰基淀粉钠、海藻酸等。(5)润湿剂：增加药物与溶出介质的润湿性，保证制剂的效能。常见有吐温80、十二烷基硫酸钠等。
软胶囊剂内容物中的辅料包括但不限于油性分散或PEG分散，内容物可以是溶液、混悬液、乳剂、半固体等。油性分散(亲脂性)内容物辅料包括：(1)油性载体：大豆油、蓖麻油、中链脂肪酸等；(2)用于调节粘度的半固体包括氢化蓖麻油、蜂蜡等；(3)表面活性剂如磷脂可以改善混悬液的混悬稳定性。也可添加其它稳定剂如抗氧剂BHT等。PEG分散(亲水性)内容物辅料通常为PEG400和600，半固体的可以同时使用低分子量的PEG200、300和高分子的PEG4000-10000。
硬胶囊壳与软胶囊壳相似，主要含明胶、阿拉伯胶、水、增塑剂(如甘油，也可以加入适量丙二醇和聚乙二醇200，甘露醇或山梨醇可以替代甘油作为胶皮的增塑剂)、防腐剂(如山梨酸钾、尼泊金等)、遮光剂和色素等，其中水的作用是溶剂。
或者，一种所述的抗癌药物化合物的膏剂，其成分包括：
1)抗癌药物化合物XBB-009；
2)基质。
常用的基质包括：烃类(如凡士林、固体石蜡、液体石蜡、硅酮)、类脂类(如羊毛脂、蜂蜡与鲸蜡、二甲硅油)、油脂类(如动植物高级脂肪酸甘油脂及其混合物)。
本发明的抗癌药物化合物可溶于亲脂性介质中。亲脂性介质(或载体)可以是任何一种的生物相容的亲脂性介质，具有代表性的生物相容的亲脂性介质包括：
1)可作为亲脂性介质的油脂，包括不同链长的脂肪酸及酯，它们大多是直链的，但也可以是支链的，例如癸酸、辛酸、己酸、月桂酸、肉豆蔻、硬脂酸、油酸、亚油酸、以及其它饱和或不饱和脂肪酸及酯类。
2)脂溶性的维生素E及衍生物。维生素E是指以天然或人工合成的维生素E系列，它们通常称为生育酚和生育三烯酚(tocopherols和tocotrienols)，生育酚包括α-生育酚(D型、DL型、L型)、β-生育酚(D型、DL型、L型)、γ-生育酚(D型、DL型、L型)和δ-生育酚(D型、DL型、L型)。生育三烯酚在结构上与生育酚相似，但生育三烯酚在碳-2的侧链植基(phytyl)上有三个双键。生育三烯酚包括α-生育三烯酚(D型、DL型、L型)、β-生育三烯酚(D型、DL型、L型)、γ-生育三烯酚(D型、DL型、L型)和δ-生育三烯酚(D型、DL型、L型)。维生素E衍生物包括所有生育酚和生育三烯酚的衍生物，如维生素E琥珀酸酯，维生素E醋酸酯等。
3)脂肪酸与甘油酯化反应所形成的甘油单酯、甘油二酯或甘油三酯，无论它们是合成的还是天然的，都可作为亲脂性介质，例如，甘油酯，如豆油，棉籽油，菜籽油，鱼油，乙酰化单甘酯，甘油单油酸酯，三醋酸甘油酯，和双乙酰酒石酸酯，单甘酯，蓖麻油等。
4)脂肪醇，如苄醇、硬脂醇、月桂醇等，或是它们的酯或醚，如苯甲酸苄酯。
具有代表性的表面活性剂包括：
1)聚乙二醇表面活性剂，如聚氧乙烯蓖麻油EL(Cremophor EL)、吐温系列表面活性剂等。
2)磷脂表面活性剂(phospholipids)，如卵磷脂(lecithin)、聚乙二醇磷脂(pegylatedphospholipids)。
3)聚乙二醇维生素E衍生物，如维生素E琥珀酸酯聚乙二醇(d-α-tocopherolpolyethylene glycol 1000succinate,TPGS)。
4)聚氧乙烯聚氧丙烯嵌段共聚物：POLOXAMERS或PLURONICS的嵌段共聚物(H(OCH2CH2)a(OCH2CH2CH2)b(OCH2CH2)aOH)。
具有代表性的有机助溶剂包括：
乙醇、聚乙二醇、丙二醇、甘油、N-甲基吡咯烷酮等。聚乙二醇(PEG)是亲水性的，重复单元的化学结构组成为-CH2CH2O-，通式为H-(CH2CH2)n-OH，分子量范围一般从200至10000。例如，聚乙二醇200、PEG-300、聚乙二醇400等。
本发明的乳剂、微乳剂、胶束剂和脂质体剂、片剂、胶囊剂和膏剂。配方中都包含本发明的抗癌药物化合物。
此处使用的“乳剂”是指在表面活性剂的作用下，一相液体以液滴状态分散于另一相液体中形成的非均相液体分散体系，如油和水所形成的液滴，其直径一般在0.1至3.0微米。
所述的乳剂可以形成稳定的微乳剂。“微乳”一词是指两个不混溶的液体形成一个热力学稳定的各向同性、透明或半透明的分散体系，如油和水的微乳分散体系是被表面活性剂分子形成的界面膜所稳定。微乳平均液滴直径小于200nm，一般10至50纳米。
乳剂或微乳剂中包括油相和水相。乳剂或微乳剂可以是水包油型乳化或油包水型。
在没有水的情况下，由油相、非离子型表面活性剂和助乳化剂混合所形成的均一透明并包含药物的溶液被称为自乳化释药系统(self-emulsifying drug delivery system：SEDDS)，自发乳化形成粒径在100nm至500nm的乳剂，可用于提高亲脂性药物溶解度和口服吸收度。
所述的乳剂或微乳剂中，抗癌药物化合物在制剂配方中所占的重量百分比为0.005％至5.0％；优选抗癌药物化合物在制剂配方中所占的重量百分比为0.01％至2.5％；更优选的方案中，抗癌药物化合物在制剂配方中所占的重量百分比为0.1％至1.5％。
所述的乳剂或微乳剂中，亲脂性介质在制剂配方中所占的重量百分比为2％至20％；优选亲脂性介质在制剂配方中所占的重量百分比为4％至12％；更优选的方案中，亲脂性介质在制剂配方中所占的重量百分比为6％至10％。
在一个乳剂或微乳剂的实施方案中，亲脂性介质包括豆油，水相介质是水。在另一个乳剂和微乳剂的实施方案中，亲脂性介质包括油溶性维生素E。在另一个乳剂或微乳剂的实施方案中，亲脂性介质包括油溶性维生素E衍生物。
除了本发明的抗癌药物化合物，乳剂或微乳剂配方中还可以包括药物乳剂和微乳剂中常用的其他的成分，这些成分包括表面活性剂和助溶剂。具有代表性的表面活性剂包括非离子表面活性剂，如聚氧乙烯蓖麻油EL(Cremophor EL)、吐温80(Tween 80)、聚乙二醇维生素E衍生物表面活性剂及其它表面活性剂聚合物。
合适的聚乙二醇维生素E衍生物表面活性包括维生素E琥珀酸聚乙二醇衍生物(例如维生素E聚乙二醇琥珀酸酯)，在维生素E衍生物分子中，聚乙二醇是由琥珀酸与维生素E的羟基连接而成，这些维生素E的聚乙二醇衍生物中的聚乙二醇包括具有各种分子量(例如，200、300、400、600、1000等)的聚乙二醇。此处的“维生素E聚乙二醇琥珀酸酯”包括维生素E聚乙二醇琥珀酸酯(如D-α生育酚聚乙二醇1000琥珀酸酯，TPGS，一种非离子型表面活性剂(HLB＝16-18))和维生素E聚乙二醇的各种酯和醚衍生物。
所述的乳剂或微乳剂中，表面活性剂在配方中的重量百分含量约为1至10％，优选2-6％，更优选4-5％。
所述的乳剂或微乳剂中，助溶剂约占配方重量的0％至20％。
在另一个方面，本发明还提供了一种所述的抗癌药物化合物的胶束制剂包括本发明的抗癌药物化合物、一种或多种表面活性剂、一种或多种助溶剂和水相。
在所述的抗癌药物化合物的胶束剂中，药物化合物在配方中重量百分含量约为0.005％至3.0％，优选药物化合物在配方中重量百分含量约为0.01％至2.5％；更优选，药物化合物在配方中重量百分含量约为0.1％至1.0％。
合适的表面活性剂在本发明的胶束剂配方中的重量百分含量约为1至10％，优选2-6％，更优选4-5％。
胶束剂配方还包括其它的成份，如上面提到的助溶剂。在一个实施例中，胶束剂配方中包含聚乙二醇和较低的烷基醇(如乙醇)。所述的胶束剂中，助溶剂约占配方重量的1％至20％。
在另一个方面，本发明还提供了一种所述的抗癌药物化合物的脂质体剂包括本发明的抗癌药物化合物、一种或多种磷脂(包括PEG化磷脂)、一种或多种亲脂性介质(如胆固醇)和水相。
在所述的抗癌药物化合物的脂质体剂中，药物化合物在配方中重量百分含量约为0.005％至5.0％，优选药物化合物在配方中的重量百分含量约为0.01％至2.5％；更优选，药物化合物在配方中重量百分含量约为0.1％至1.5％。
合适的磷脂在本发明的脂质体剂配方中的重量百分含量约为1至10％，优选2-6％，更优选4-5％。
脂质体剂配方还包括其它的成份，如上面提到的亲脂性介质(如胆固醇)。在一个实施例中，脂质体剂配方中包含胆固醇或维生素E。所述的脂质体剂中，胆固醇或维生素E约占配方重量的0.1％至20％。
乳剂、微乳剂、胶束剂和脂质体剂配方中包含水相。在一个实施例中，水相包括去离子水。在另一个实施例中，水相包括生理盐水。在另一个实施例中，水相中含一种酸的如琥珀酸、柠檬酸、磷酸)缓冲液。
在另一个方面，本发明还提供了一种所述的抗癌药物化合物的片剂包括本发明的抗癌药物化合物和辅料。所述的抗癌药物化合物的在每片中的含量可为1毫克至1000毫克，优选的方案中抗癌药物化合物在每片中的含量为10毫克至500毫克；更优选的方案中，抗癌药物化合物在每片中的含量为20毫克至250毫克。
在另一个方面，本发明还提供了一种所述的抗癌药物化合物的胶囊剂包括本发明的抗癌药物化合物和辅料。所述的抗癌药物化合物的在每颗胶囊中的含量可为1毫克至1000毫克，优选的方案中抗癌药物化合物在每颗胶囊中的含量为10毫克至500毫克；更优选的方案中，抗癌药物化合物在每颗中的含量为20毫克至250毫克。
在另一个方面，本发明还提供了一种所述的抗癌药物化合物的膏剂包括本发明的抗癌药物化合物、一种或多种基质。
在所述的抗癌药物化合物的膏剂中的重量百分含量约为0.01％至30％，优选药物化合物在配方中的重量百分含量约为0.05％至20％；更优选，药物化合物在配方中重量百分含量约为0.1％至10％。
本发明还提供了新发明的药物化合物的应用，即所述的抗癌药物化合物在制备抗癌药物中的应用。
例如，本发明的药物化合物用于制备治疗癌症的药物。本发明的药物化合物可用于治疗包括血液系统的癌症，如白血病，淋巴瘤，骨髓瘤；和非血液癌症，如实体瘤癌(如乳腺癌、卵巢癌、胰腺癌、结肠癌、直肠癌、非小细胞肺癌、膀胱癌、胃癌、肝癌等)，肉瘤、皮肤癌和胶质瘤等。
本发明的药物化合物的疗效和毒性用体外细胞或体内动物实验来确定，例如，ED50(50％effective dose，半数有效量：50％实验对象出现阳性反应时的药量)、LD50(50％lethaldose，半数致死量，杀死一半试验对象的剂量)和GI50(concentration of the anti-cancer drugthat inhibits the growth of cancer cells by 50％，抑制50％的实验对象生长的药物浓度)。通常将半数致死量(LD50)/半数有效量(ED50)的比值称为治疗指数，用以表示药物的安全性。治疗指数大的药物相对治疗指数小的药物更安全。
新发明的抗癌药物化合物旨在提高治疗指数和药物的安全性，同时也提高治疗效果。从体外细胞实验和体内动物实验获得的药物剂量可以用来制定用于人体的剂量范围。这种化合物的剂量最好在很少或根本没有毒性的ED50范围内。剂量变化通常取决于采用的剂型、病人的敏感性和给药途径等。通常可用相同或类似药物，如伊立替康和拓扑替康的常规剂量做参考。例如拓扑替康的常规剂量为0.2-1.5mg/m2、伊立替康的常规剂量为100mg-350mg/m2。
本发明的药物化合物可以单独使用，也可与一个或多个其它的治疗药物一起使用。例如，在癌症的治疗时，这些药物化合物可与以下治疗药物一起使用，包括但不限于：雄激素抑制剂，如氟他胺(flutamide)和鲁珀若利得(luprolide)；抗雌激素，如他莫昔芬(tomoxifen)；抗代谢药物和细胞毒性药物，如道诺红菌素(daunorubicin)、五氟脲嘧啶(fluorouracil)、氟尿苷(floxuridine)、α-干扰素(interferon alpha)、甲氨蝶呤(methotrexate)、光神霉素(plicamycin)、硫基嘌呤(mecaptopurine)、硫鸟嘌呤(thioguanine)、阿霉素(adriamycin)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、阿糖胞苷(cytarabine)、环磷酰胺(cyclophosphamide)、阿霉素(doxorubicin)、雌莫司汀(estramustine)、六甲蜜胺(altretamine)、羟基脲(hydroxyurea)、异环磷酰胺(ifosfamide)、甲基苄肼(procarbazine)、突变霉素(mutamycin)、白消安(busulfan)、米托蒽醌(mitoxantrone)、卡铂carboplatin)、顺铂(cisplatin)、链脲佐菌素(streptozocin)、博莱霉素(bleomycin)、放线菌素(dactinomycin)、和依达比星(idamycin)；激素，如甲孕酮(medroxyprogesterone)、炔雌二醇(ethinyl estradiol)、雌二醇(estradiol)、亮丙瑞林(leuprolide)、甲地孕酮(megestrol)、奥曲肽(octreotide)、己烯雌酚(diethylstilbestrol)、氯烯雌醚(chlorotrianisene)、足叶乙甙(etoposide)、鬼臼毒素(podophyllotoxin)和戈舍瑞林(goserelin)；氮芥衍生物，如苯丙酸氮芥(melphalan)、苯丁酸氮芥(chlorambucil)和塞替派(thiotepa)；类固醇，如倍他米松(betamethasone)；和其他抗肿瘤药物，如活牛分枝杆菌(live Mycobacterium bovis)、达卡巴嗪(dicarbazine)、天冬酰胺酶(asparaginase)、甲酰四氢叶酸(leucovorin)、米托坦(mitotane)、长春新碱(vincristine)、长春碱(vinblastine)和多西紫杉醇(taxotere)等。
附图说明
图1为5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)核磁共振氢谱图。
图2为5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)质谱图。
图3为5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)的液相色谱图。
具体实施方式
下面以实施例说明本发明的新抗癌药物化合物的合成、制剂和体外细胞实验等。所述的实施例有助于对本发明的理解和实施，并不构成对于本发明的限制，保护范围由权利要求加以界定。
实施例1.5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)的合成
(1)2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷的合成
反应式如下式所示：
实验步骤：
向100mL圆底烧瓶中，加入0.980g(4mmol)5’-脱氧-5-氟胞苷和25mL无水DMF，搅拌使其溶解。向溶液中加入2.000g(13.26mmol)叔丁基二甲基氯硅烷，然后加入2.000g(29.37mmol)咪唑，室温搅拌，反应过夜至反应完成。向反应液中加入200mL乙酸乙酯，搅拌15分钟，转移至分液漏斗中，混合液分别用100mL食盐水洗三次，有机相用20g无水硫酸镁干燥1小时，过滤除去硫酸镁，旋转蒸发除去溶剂乙酸乙酯。柱层分离，用100-200目硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗液，得白色固体1.802g，产率95.0％。.
MS(Positive Ion mode ESI):m/z＝969.5(2M+Na)+,MS(Negtive Ion Mode ESI):m/z＝472.2(M-H)-。
1H NMR(500MHz,CDCl3):δppm:7.5658-7.5532(d,J＝5Hz,1H)，5.5271(s,1H),4.2494-4.2206(t,J＝5Hz,1H),4.1914-4.1850(d,J＝3.2Hz,1H),3.4715-3.4476(m,1H),1.8499(s,1H),1.4102-1.3976(d,J＝6.3Hz,1H),0.9206(s,9H),0.8939(s,9H),0.2380(s,3H),0.1214(s,3H),0.0578(s,3H),0.0519(s,3H)。
2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷的液相色谱分析结果：纯度：99.07％；色谱条件：色谱柱：C18柱(5μm,150mm×5mm)；流动相：CH3CN：IPA:HAc(95:5:0.1)；检测波长：254nm；流速：1.0ml/min；进样量：5μL；柱温：40℃。
(2)N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷的合成
反应式如下式所示：
实验步骤：
向100mL圆底烧瓶中加入0.625g(2.00mmol)4-[对双(2-氯乙基)胺基]苯丁酸、30mL无水甲苯、1000μL亚硫酰氯(氯化亚砜)和2滴无水DMF，氮气保护，室温搅拌6小时，减压旋转蒸发掉过量的亚硫酰氯和无水甲苯，然后加入10mL三氯甲烷溶解剩余物，得溶液A。
称取0.715g(1.50mmol)2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷、0.244g(2.00mmol)4-二甲氨基吡啶(DMAP)，加入到另一个100mL的圆底烧瓶中，加入30mL氯仿，搅拌使其溶解。向上述溶液经滴液漏斗慢慢滴加溶液A，60分钟滴加完毕，室温搅拌，反应过夜至反应完成，旋转蒸发掉溶剂，柱层分离，用100-200目硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗剂，产物真空干燥，得淡黄色固体0.447g，产率39.2％。
MS(Positive Ion mode ESI):m/z＝781.5(M+Na)+。
1H NMR(300MHz,CDCl3):δppm:7.7810-7.7609(d,J＝9.12Hz,1H),7.1498-7.1218(d,J＝14Hz,1H),6.7667-6.7394(d,J＝13.7Hz,1H),5.5209(s,1H),4.3047-4.2563(t,J＝6Hz,1H),4.2216-4.2099(d,J＝3Hz,1H),3.7009-3.6322(m,8H),3.4580-3.4175(m,1H),3.0685-3.0221(t,J＝6Hz,2H),2.6634-2.6119(t,J＝7.5Hz,2H),2.0117-1.9379(m,2H),1.4321-1.4110(d,J＝6Hz,1H),0.9344(s,9H),0.8956(s,9H),0.2654(s,3H),0.1451(s,3H),0.0606(s,3H),0.0533(s,3H)。
(3)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)的合成
反应式如下式所示：
实验步骤：
向20mL圆底烧瓶中加0.416g(0.54mmol)N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷、7mL四丁基氟化铵，氮气保护，室温搅拌1小时，减压旋转蒸发掉四丁基氟化铵，然后加入10mL三氯甲烷溶解剩余物，柱层分离，用100-200目硅胶为固定相，二氯甲烷和乙酸乙酯混合液为淋洗液，得淡黄色固体0.189g，产率64.7％。
5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷的核磁共振氢谱图如图1所示，质谱图如图2所示。
5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷的液相色谱图如图3所示，纯度：99.34％；色谱条件：色谱柱：C18柱(5μm,150mm×5mm)；流动相：乙腈：水(50:50)；检测波长：254nm；流速：1.0ml/min；进样量：5uL；柱温40℃。
MS(Positive Ion mode ESI):m/z＝553.1(M+Na)+,MS(Negtive Ion Mode ESI):m/z＝529.1(M-H)-。
1H NMR(500MHz,CDCl3):δppm:7.9533-7.9416(d,J＝5Hz，1H),7.1197-7.1028(d,J＝5Hz,2H)，6.6954-6.6786(d,J＝5Hz,2H),5.6481-5.6392(d,J＝4.45Hz,1H),4.4078-4.3882(m,1H),4.2153-4.1958(t,J＝4.88Hz,1H),3.9567-3.9398(m,1H),3.7142-3.6867(t,J＝6.88Hz,4H),3.6366-3.6097(t,J＝6.73Hz,4H),3.0304-3.0023(t,J＝7.03Hz,2H),2.6535-2.6231(t,J＝7.6Hz,2H),2.0257-1.9667(m,2H),1.3871-1.3738(d,J＝3.33Hz,3H)。
实施例2.抗癌药物化合物的制剂，包括乳剂、胶束剂、脂质体剂、片剂、胶囊剂和膏剂配方
本实施例中，包括抗癌药物化合物的乳剂、胶束剂、脂质体剂、片剂、胶囊剂和膏剂配方。乳剂、胶束剂、脂质体剂、片剂、胶囊剂和膏剂配方中含有本发明的抗癌药物化合物，配方中的药物化合物可用本发明的其它抗癌药物化合物替换。
1)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)乳剂XBB-009溶解于豆油、吐温80和聚乙二醇PEG(200)的混合物中，再加入去离子水(DIwater)，然后搅拌和超声乳化或用均质机乳化，所生产的乳剂的组成如下：
制成的乳剂药品通过一个孔径0.2微米的过滤器过滤，再装入无菌的玻璃瓶。
2)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)乳剂
XBB-009溶解于D-α-生育酚乙酸酯、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)和聚乙二醇PEG(200)的混合物中，再加入去离子水(DI water)，然后搅拌和超声乳化或用均质机乳化，所生产的乳剂的组成如下：
制成的乳液药品通过一个孔径0.2微米的过滤器过滤，再装入无菌的玻璃瓶。
3)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)的胶束剂XBB-009溶解于D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)、乙醇和聚乙二醇PEG(200)的混合物中得到一透明的液体，使用前再加入适量的生理盐水，然后搅拌和超声搅拌，得一澄清液体，所生产的胶束剂的组成如下：
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤，备用。
4)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)胶束剂XBB-009溶解于聚氧乙烯蓖麻油EL(Cremophor EL)、乙醇和聚乙二醇PEG(200)的混合物中得到透明的液体，使用前再加入适量的去离子水(DI water)，然后搅拌和超声搅拌，得一澄清液体，所生产的胶束剂的组成如下：
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤，备用
5)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)胶束剂XBB-009溶解于聚氧乙烯蓖麻油EL(Cremophor EL)、乙醇和聚乙二醇PEG(200)的混合物中得到透明的液体，使用前再加入适量的去离子水(DI water)，然后搅拌和超声搅拌，得一澄清液体，所生产的胶束剂的组成如下：
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤，备用
6)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)脂质体剂在一个圆底烧瓶中，将0.01mmol XBB-009和0.5mmol磷脂(卵磷脂、磷脂酰胆碱)溶解于15mL的氯仿(CHCl3)，慢慢加热至40℃，用旋转蒸发仪减压蒸发溶剂，形成一层薄的脂质膜，真空干燥过夜，进一步除去脂质膜中的氯仿，加入10mL蒸馏水，然后搅拌和超声搅拌，所得脂质体液通过一个孔径0.2微米的过滤器过滤，再装入无菌的玻璃瓶，用干冰和丙酮冷冻，然后冷冻干燥24小时，得5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷的脂质体剂。
7)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)胶囊剂((湿法制粒)
处方量的XBB-009与处方量的羟基乙酸淀粉钠混合后，加入处方量的吐温80水溶液后进行湿法制粒，制得的湿材料在流化床、干燥盘或其它适当干燥器中干燥，将干燥后的颗粒碾磨至合适的粒径分布，再与处方量的其它组分混合，最后将混合物装入两片硬明胶胶囊壳体中。
| 组分 | 每颗胶囊的含量(mg) | 每组分的百分含量(％) |
| XBB-009 | 100 | 40 |
| 吐温80 | 5 | 2 |
| 乳糖 | 50 | 20 |
| 硬脂酸镁 | 5 | 2 |
| 羟基乙酸淀粉钠 | 90 | 36 |
| 每颗胶囊总重量 | 250 |
1)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)片剂(湿法制粒)
处方量的十二烷基硫酸钠水溶液与处方量的XBB-009、淀粉甘醇酸钠和微晶纤维素制粒，制得的湿材料在流化床、干燥盘或其它适当干燥器中干燥，干燥后的颗粒碾磨至所需的粒径分布，然后将混合物压制成片。
| 组分 | 每片的含量(mg) | 每组分的百分含量(％) |
| XBB-009 | 300 | 50 |
| 十二烷基硫酸钠 | 12 | 2 |
| 乳糖 | 42 | 7 |
| 硬脂酸镁 | 6 | 1 |
| 羟基乙酸淀粉钠 | 120 | 20 |
| 微晶纤维素 | 120 | 20 |
| 每颗胶囊总重量 | 600 |
2)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)片剂(干法制粒)
首先将XBB-009原料粉碎过筛，控制粒径小于80μm，再将处方量的XBB-009与微粉硅胶混匀，加入处方量的淀粉、蔗糖、交联羧甲基纤维素钠，混匀，干法制粒，制粒后，加入处方量的硬脂酸镁，混匀，压片，包薄膜衣。
| 组分 | 每片的含量(mg) | 每组分的百分含量(％) |
| XBB-009 | 100 | 50 |
| 淀粉 | 52 | 26 |
| 蔗糖 | 15 | 7.5 |
| 交联羧甲基纤维素钠 | 15 | 7.5 |
| 微粉硅胶 | 15 | 7.5 |
| 硬脂酸镁 | 3 | 1.5 |
| 每颗胶囊总重量 | 200 |
3)5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷(XBB-009)膏剂取适量XBB-009、硬脂酸、单硬脂酸甘油酯、液体石蜡、聚乙二醇200(PEG 200)、吐温-80加热熔化；另取适量甘油、水加热至70-80℃，在搅拌下加入至油相中，继续搅拌至成型，所生产的膏剂的组成如下：
实施例6.抗癌药物化合物XBB-009的体外细胞毒性实验
将处于对数生长期的细胞(人胃癌细胞株BGC-823，人肝癌细胞株HepG2，人非小细胞肺癌A549，人结肠癌细胞HCT-116，人乳腺癌细胞MCF-7)，用0.02％EDTA消化，制成细胞悬液，以适当的细胞浓度加入96孔酶标板内100μl/孔，设三复孔，置37℃5％CO2孵箱内培养24h左右，再分别加入终浓度为1×10-7～1×10-4mol/L的药物100μl/孔，作用48h后加5mg/ml MTT溶液20μl/孔，继续培养4h，弃去全部上清，加入DMSO 100μl/孔，微型振荡器上振5min，使结晶完全溶解，用酶联仪570nm波长处测定吸光度值(A)，计算细胞抑制率。
根据改进寇氏法计算半数抑制浓度(IC50)。
表1.XBB-009对体外培养细胞株的生长抑制率IC50(μM)的对比(48小时)
| 药物 | A549 | BGC-823 | HepG2 | MCF-7 | HCT-116 |
| XBB-009 | 5.86 | 25.1 | 42.8 | 45.6 | 42.5 |
MTT细胞增殖抑制实验表明，不同浓度的XBB-009作用于细胞48h后，对于体外培养5种细胞株均有明显的生长抑制作用，并呈现剂量依赖性。
实施例7.抗癌药物化合物XBB-009对动物移植性S180肉瘤的抑制作用实验
7.1实验方法
取ICR小鼠，按移植性肿瘤研究法，接种实体型瘤(在无菌操作下取瘤块，称重，用玻璃组织匀浆器研磨，磨匀后放入无菌容器内，加生理盐水稀释成1:3的细胞悬液，容器置冰块上，用空针抽吸，每次抽吸前将细胞混匀，每只小鼠右前肢腋窝皮下接种0.2ml)，接种后24小时称鼠重，并随机分为4组，每组10只。各给药组于接种24小时后(d1)第一次给药，尾静脉给药，两天给药一次，共给药4次。给药体积均为0.2ml/20g。于接种后第9天(d8)处死荷瘤小鼠称重，并分离瘤块称重，所得数据进行统计学处理(t检验)。
剂量设置：共设4组
7.3实验结果：
表2.XBB-009药物对小鼠移植瘤S180抑制作用
*P<0.05**P<0.01与空白组比较
7.4实验结论
结果表明，与模型对照组相比，待测药XBB-009(30mg/kg，15mg/kg)，阳性对照组5-氟尿嘧啶(5-FU,30mg/kg)，对S180肿瘤生长具有极显著的抑制作用(P<0.01),同等剂量下，XBB-009抑瘤率高于5-FU。XBB-009对实验鼠体重影响高于阳性对照药5-FU(30mg/kg)对实验鼠体重的影响。
实施例8.抗癌药物化合物XBB-009对动物移植性肝肿瘤的抑制作用实验
8.1、实验方法
取ICR小鼠，按移植性肿瘤研究法，接种实体型瘤(在无菌操作下取瘤块，称重，用玻璃组织匀浆器研磨，磨匀后放入无菌容器内，加生理盐水稀释成1:3的细胞悬液，容器置冰块上，用空针抽吸，每次抽吸前将细胞混匀，每只小鼠右前肢腋窝皮下接种0.2ml)，接种后24小时称鼠重，并随机分为4组，每组10只。各给药组于接种24小时后(d1)第一次给药，待测药XBB-009(20mg/ml)尾静脉给药，给药体积0.2ml/20g；待测药XBB-009(100mg/ml)、阳性对照组卡培他滨(800mg/ml)灌胃给药，给药体积均为0.4ml/20g。两天给药一次，共给药4次。于接种后第8天(d9)处死荷瘤小鼠称重，并分离瘤块称重，所得数据进行统计学处理(t检验)。
8.2剂量设置：共设5组
8.3实验结果
表3.XBB-009药物对小鼠移植瘤Heps抑制作用
*P<0.05**P<0.01与空白组比较
8.4实验结论
结果表明，与模型对照组相比，阳性对照药卡培他滨、待测药XBB-009(20mg/kg)尾静脉给药、XBB-009(10、20、40mg/kg)灌胃给药各组，对Heps肿瘤生长具有极显著的抑制作用(P<0.01)。
给药后，待测药XBB-009(20mg/kg)尾静脉给药以及XBB-009(40mg/kg)灌胃给药，对实验鼠体重有极显著影响(P<0.01)；XBB-009(20mg/kg和10mg/kg)灌胃给药，对实验鼠体重无显著影响。
Claims (8)
1.具有式Ⅰ分子结构的5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷：
2.根据权利要求1所述的5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷的制备方法，其特征在于包括如下步骤：
(1)将4-[双(2-氯乙基)氨基]苯丁酸与酰氯化试剂反应生成4-[双(2-氯乙基)氨基]苯丁酰氯；
(2)5’-脱氧-5-氟胞苷与羟基保护试剂氯硅烷反应，在咪唑的作用下，生成2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷；
(3)将步骤(1)得到的4-[双(2-氯乙基)氨基]苯丁酰氯与步骤(2)得到的2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷反应，在碱的作用下生成N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷；
(4)将步骤(3)得到的N-{4-[双(2-氯乙基)氨基]苯丁酰基-2’,3’-双-O-(叔丁基二甲基硅烷基)-5’-脱氧-5-氟胞苷与四丁基氟化铵反应得到5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷。
3.根据权利要求1所述的5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷在制备抗癌药物中的应用。
4.根据权利要求3所述的应用，其特征在于所述癌症包括血液系统的癌症、实体瘤癌、肉瘤或胶质瘤。
5.根据权利要求4所述的应用，其特征在于所述癌症包括白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、胰腺癌、结肠癌、直肠癌、非小细胞肺癌、膀胱癌、胃癌、肝癌、肉瘤、皮肤癌或胶质瘤。
6.根据权利要求3所述的应用，其特征在于所述药物包括有效治疗量的5'-脱氧-5-氟-N-{4–[双(2-氯乙基)氨基]苯丁酰基}胞苷以及药学上可接受的药物载体。
7.根据权利要求6所述的应用，其特征在于所述药物为注射剂、口服制剂或外用制剂。
8.根据权利要求7所述的应用，其特征在于所述药物为乳剂、微乳剂、胶束剂、脂质体、片剂、胶囊剂或膏剂。
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