CN104557544A - C-10甲氧基紫杉烷类衍生物及其肿瘤多药耐药逆转剂的用途 - Google Patents

C-10甲氧基紫杉烷类衍生物及其肿瘤多药耐药逆转剂的用途 Download PDF

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CN104557544A
CN104557544A CN201310488098.5A CN201310488098A CN104557544A CN 104557544 A CN104557544 A CN 104557544A CN 201310488098 A CN201310488098 A CN 201310488098A CN 104557544 A CN104557544 A CN 104557544A
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japanese yew
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戴均贵
陈晓光
谢丹
张翼
尹大力
梅梅
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Abstract

本发明公开了一类新的通式（I）所述的C-10为甲氧基取代的新型紫杉烷类化合物，其制备方法，含有该类化合物的药物组合物，及其作为药物，尤其是作为肿瘤多药耐药逆转剂与抗肿瘤药物合用提高肿瘤细胞对抗肿瘤药物的敏感性，从而治疗发生多药耐药的肿瘤的新用途。

Description

C-10甲氧基紫杉烷类衍生物及其肿瘤多药耐药逆转剂的用途
发明领域：
本发明涉及C-10位为甲氧基取代的新型紫杉烷类化合物，其制备方法，含有该类化合物的药物组合物，及其作为药物，尤其是作为肿瘤多药耐药逆转剂与抗肿瘤药物合用治疗发生多药耐药的肿瘤，提高肿瘤细胞对抗肿瘤药物的敏感性的新用途。
背景技术：
目前全世界肿瘤发病率及死亡率都处于较高的水平，尽管随着现代癌症研究的深入和科技的进步，临床治疗手段不断提高，药物化学家也一直致力于开发新的、高效低毒的抗肿瘤药物，但随之出现的肿瘤多药耐药性(multi-drug resistance,MDR)却成为癌症治疗的最大障碍。[Bruce C Baguley.Multiple drug resistance mechanisms in cancer.Molecular Biotechnology.2010;46(3):308–316.]肿瘤细胞的多药耐药是指肿瘤细胞接触化疗药物后，一旦对某一特定的化疗药物产生耐受性，通常会对许多结构各异、机理不同的药物产生交叉耐药，导致药物疗效降低甚至失去治疗作用，从而导致肿瘤化疗失败。[Michael M.Gottesman;Ira Pastan.Biochemistryof multidrug resistance mediated by the multidrug transporter.Annual Review Biochemistry.1993,62,385–427.]
目前针对肿瘤多药耐药的治疗途径，主要有以下三种：1、研究新的靶点，开发新型结构的抗肿瘤药物；2、通过对原抗肿瘤药物的结构改造，开发能够抗耐药的抗肿瘤药物；3、开发多药耐药逆转剂，与抗肿瘤药物联合使用，增强耐药细胞对抗肿瘤药物的敏感性。多药耐药逆转剂是指能够全部或者部分恢复耐药的肿瘤细胞对某种或某类化疗药物敏感的一类化合物。比较理想的多药耐药逆转剂一般要求剂量有一定的耐受性，能够重复给药以保持所需的药物浓度，能完全逆转MDR，且副作用较小。应用多药耐药逆转剂克服肿瘤临床耐药、提高化疗效果一直是国内外的研究热点。[James M Ford;William N Hait.Pharmacology of drugs thatalter multidrug resistance in cancer.Pharmacological Reviews.1990,42,155–199.]
研究表明，肿瘤多药耐药产生的机制非常复杂。在诸多MDR机制中，P-gp的过量表达引起抗肿瘤药物外排，被认为是引起MDR的经典机制，研究也最为透彻。因此，MDR逆转剂的研究主要以P-gp逆转剂为主。这些逆转剂通过竞争性占据P-gp的结合位点，减少P-gp对抗肿瘤药物的外排，增加抗肿瘤药物在细胞内的累积水平，从而克服肿瘤多药耐药。[TakashiTsuruo;Iida,Harumi;Shigeru Tsukagoshi;Sakurai Yoshio.Overcoming of vincristine resistance inP388leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine byverapamil.Cancer Research.1981,41,1967–1972.]
最早作为逆转剂的药物如Verapamil,Cyclosporine A和Quinidine等，由于它们作为MDR逆转剂使用时出现较大的毒副作用，实际上未能在临床化疗中应用。目前，针对P-gp进行开发的逆转剂已经发展到了第三代。但是从临床研究结果来看，这些药物都存在特异性不强、具有剂量依耐性毒副作用或者显著改变抗肿瘤药物的药代动力学以及机制方面的不足。迄今为止，尚无多药耐药逆转剂应用于临床。
因此，开发具有全新结构的新型化合物，寻找活性强、毒性低、广谱、对抗肿瘤药物代谢影响小的新型MDR逆转剂仍然是肿瘤研究领域的主要方向之一。
发明内容:
为了克服现有技术的不足，本发明的主要目的之一在于提供一种新的化合物及其衍生物；
本发明的另一目的在于提供一种本发明所述化合物的制备方法；
本发明的再一目的在于提供一种含有本发明所述化合物及其药用组合物作为肿瘤多药耐药逆转剂的应用；
本发明一方面涉及药物组合物，其包括作为活性成分的通式（I）的化合物及其异构体及制药领域中常用的载体；
本发明再一方面涉及的是通式（I）化合物或含有它的药物组合物与以P-gp为底物的抗肿瘤药物包括紫杉烷类、长春碱类、蒽环类，以及米托蒽醌、放线菌素D、丝裂霉素C联合用药用于具有抗P-gp糖蛋白过度表达的内在多药耐药性以及获得性多药耐药性实体肿瘤和血液系统肿瘤的用途。
本发明涉及通式（I）的化合物或其立体异构体及其药学上可接受的盐：
其中，
R1、R2、R3代表氢；卤素；羟基；氨基；硝基；芳香基C1-8烷基酰氧基；杂环基C1-8烷基酰氧基；
上述取代的芳香基是指含有1-3个取代基的芳香环，
上述取代的杂环基是指含有1-3个取代基的杂环，这些杂环可以为含有N、O、S等杂原子取代的五元或六元饱和或不饱和杂环如吡啶、呋喃、噻吩等；
上述“C1-8的烷基酰氧基”中的“C1-8的烷基”是指1-8个碳的直链或支链的烷基，这些烷基取代基可以为氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、新戊基、己基、庚基、辛基等；在C1-8烷基上可以有1个或2个相同或不同的取代基，取代基还可以是卤素、羟基、硝基、氨基、甲氧基、甲酰基等；条件是取代基不在同一位置上；
R4R5为氢，或R4R5为=O。
但是不包括：
根据本发明，优选通式（Ia）化合物或其立体异构体包括：
其中：
R1、R2代表氢；卤素；羟基；氨基；硝基；芳香基C1-8烷基酰氧基；杂环基C1-8烷基酰氧基；
上述取代的芳香基是指含有1-3个取代基的芳香环，
上述取代的杂环基是指含有1-3个取代基的杂环，这些杂环可以为含有N、O、S等杂原子取代的五元或六元饱和或不饱和杂环如吡啶、呋喃、噻吩等；
R3为氢。
但是不包括：
根据本发明，优选通式（Ib）化合物或其立体异构体包括：
其中：
R1、R2、R3代表氢；卤素；羟基；氨基；硝基；芳香基C1-8烷基酰氧基；杂环基C1-8烷基酰氧基；
上述取代的芳香基是指含有1-3个取代基的芳香环，
上述取代的杂环基是指含有1-3个取代基的杂环，这些杂环可以为含有N、O、S等杂原子取代的五元或六元饱和或不饱和杂环如吡啶、呋喃、噻吩等。
但是不包括：
应当明白的是，上述通式Ia、Ib化合物或其立体异构体是本发明通式（I）化合物的特例或其亚类，通式Ia、Ib化合物均包括在本发明通式（I）化合物的范围内。
本发明中的术语“芳香基C1-8烷基酰氧基”中的“C1-8烷酰氧基”是指含1-8个碳原子的烷酰氧基，如甲酰氧基，乙酰氧基，丙酰氧基，异丙酰氧基，丁酰氧基，异丁酰氧基等，戊酰氧基，含支链的戊酰氧基，己酰氧基，含支链的己酰氧基等；在C1-8烷基上可以有1个或2个相同或不同的取代基，取代基还可以是卤素、羟基、硝基、氨基、甲氧基、甲酰基等；条件是取代基不在同一位置上；优选的是苯丙烯酰氧基；3,5-二甲氧基苯丙酰氧基。
根据本发明，本发明化合物可以以异构体的形式存在，而且通常所述的“本发明化合物”包括该化合物的异构体。
本发明化合物可以存在双键的反异构体，不对称中心具有R构型或S构型，本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。如果存在顺/反异构体，本发明涉及顺式形式和反式形式以及这些形式的混合物，如果需要单一异构体可以根据常规分离或通过立体选择性合成制备。
根据本发明的实施方案，所述的本发明化合物还包括其药效学上可接受的盐、盐的水合物、酯或前体药物。
根据本发明还涉及制备本发明化合物的方法，用C-10含甲氧基的C-5、C-9或C-14位为羟基的新杉素A类似物或C-13位羰基的新杉素A类似物为底物，采用化学方法，在有机溶剂中与相应的羧酸或酰卤进行缩合反应而制备的。缩合反应在合适的缩合剂、催化剂存在的条件下发生。优选的缩合剂选自1,3-二环己基碳酰二亚胺(DCC)、二吡啶碳酸酯(2-DPC)、1-(3-二甲胺丙基)-3-乙基碳酰亚胺盐酸盐(EDCI)、1,3-二异丙基碳酰亚胺(DIPC)等。更优选的缩合剂是1,3-二环己基碳酰二亚胺(DCC)、1-(3-二甲胺丙基)-3-乙基碳酰亚胺盐酸盐(EDCI)。优选的催化剂选自三级胺。优选的三级胺选自4-二甲氨基吡啶(DMAP)、4-吡咯烷基吡啶(4-PP)、三乙胺。更优选的三级胺选自4-二甲氨基吡啶(DMAP)。反应的温度在0℃～100℃之间，优选的温度是20℃～30℃，更优选的温度是室温。反应在适宜的溶剂下进行，优选的溶剂为无水的非质子性溶剂，更优选的是吡啶、甲苯、卤代烷、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)等。最优选的为二氯甲烷。
本发明还涉及上述通式(I)化合物或其立体异构体在制备抗恶性肿瘤药物，尤其是治疗多药耐药肿瘤的药物和逆转多药耐药肿瘤的耐药性药物中的用途。
根据本发明，药学上可接受的盐包括但不局限于与下列酸形成的酸加成盐：盐酸、硫酸、磷酸、氢溴酸、乙酸、三氟乙酸、柠檬酸、酒石酸、乳酸、丙酮酸、马来酸、苯磺酸、琥珀酸、富马酸。
本发明再一方面还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂（包括真溶液和胶体溶液）、乳剂（包括o/w型、w/o型和复乳）、混悬剂、注射剂（包括水针剂、粉针剂和输液）、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂（包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片）、胶囊剂（包括硬胶囊、软胶囊、肠溶胶囊）、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气（粉）雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
具体实施方式：
为了进一步理解本发明，下面的实施例以及药理实验仅仅用来进一步说明本发明，但并不意味着对本发明的任何限制。
制备例
(1)化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯的制备：将新杉素A：2α,5α,10β,14β-四乙酰氧基-4(20),11-紫杉二烯(5.0g,10mmol)溶于甲醇150ml中，在10MKOH溶液(14.0ml,139.0mmol)中，-10℃下搅拌反应20min，即可得到全水解的新杉素A：2α,5α,10β,14β-四羟基-4(20),11-紫杉二烯3.2g，收率约85%。全水解的新杉素A(1.0g,2.97mmol)在50ml吡啶溶剂中，加入乙酸酐(5ml,50mmol)进行酰化反应，60℃下搅拌反应6h，可得到2α,5α,14β-三乙酰氧基-10β-甲氧基-4(20),11-紫杉二烯0.8g,收率约65%。
利用2α,5α,14β-三乙酰氧基-10β-甲氧基-4(20),11-紫杉二烯，制备化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯的方法参考文献[张猛，尹大力，刘红岩，郭积玉，梁晓天。紫杉烷类多药耐药逆转剂的合成及其逆转耐药活性。药学学报，2003，38，424-429。]中制备2α,10β-二乙酰氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯的方法。
(2)化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯的制备：将2α,5α,14β-三乙酰氧基-10β-甲氧基-4(20),11-紫杉二烯(4.6g,10mmol)溶于甲醇150ml中，0℃加入4mol/l碳酸钾溶液，室温下搅拌3h。加入1M盐酸调pH值至7，过滤，滤液减压浓缩，得到的残余物用乙酸乙酯萃取三次，合并有机相，依次以饱和碳酸氢钠溶液，饱和食盐水洗，无水硫酸钠干燥。减压浓缩得到粗产物用硅胶柱色谱纯化，石油醚–丙酮10:1(v/v)洗脱，得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯3.0g，收率60%。
1H NMR(CDCl3,300MHz)δppm:5.40(dd,1H,J=2.1,6.0,H-2),5.25(s,2H,H-20a,H-5),4.89(s,1H,H-20b),4.61(dd,1H,J=5.4,12.0,H-10),4.12(dd,1H,J=4.8,9.2,H-14),3.28(s,3H,10-OCH 3),2.87(d,1H,J=6.0,H-3),2.63(dd,1H,J=9.2,19.2,H-13a),2.56(dd,1H,J=4.8,19.2,H-13b),2.28(dd,1H,J=12.0,15.0,H-9a),2.14(s,3H,COCH 3),2.07(s,3H,COCH 3),2.01(s,3H,18-H),2.03(s,3H,COCH 3),2.01(s,3H,COCH 3),1.88(m,1H,H-9b),1.73(s,1H,H-1),1.62(s,3H,16-H),1.80-1.60(m,3H,H-6a,b,H-7a),1.23(s,3H,17-H),1.18(br s,1H,H-7b),0.82(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.06(CH3 CO),170.51(CH3 CO),142.49(C-4),137.13(C-11),134.60(C-12),116.82(C-20),78.46(C-14),75.96(C-10),71.19(C-2),70.67(C-5),59.33(10-OCH3),55.64(C-1),45.27(C-8),42.26(C-3),39.93(C-13),39.55(C-15),37.37(C-9),33.99(C-17),31.77(C-7),28.95(C-6),24.45(C-18),22.55(C-16),21.77(CH3CO),21.55(CH3CO),19.88(C-19)。
ESI-MS m/z:457.22[M+Na]+。
(3)化合物2α,14β-二乙酰氧基-5α-羟基-10β-甲氧基-4(20),11-紫杉二烯的制备：将新杉素A(2α,5α,10β,14β-四乙酰氧基-4(20),11-紫杉二烯5.0g,10mmol)溶于甲醇150ml中，在10MKOH溶液(14.0ml,139.0mmol),中，-10℃下搅拌反应20min，可得到全水解的新杉素A(2α,5α,10β,14β-四羟基-4(20),11-紫杉二烯)，产率为85%。将全水解的新杉素A(2.3g,6.8mmol)溶于吡啶溶剂中，加入乙酸酐(5ml,50mmol)进行酰化，室温下反应16h，可得到2α,14β-二乙酰氧基-5α-羟基-10β-甲氧基-4(20),11-紫杉二烯，两步收率约30%。
1H NMR(CDCl3,300MHz)δppm:5.33(dd,1H,J=1.8,6.0,H-2),5.09(s,1H,H-20a),5.04(dd,1H,J=4.8,9.3,H-14),4.78(s,1H,H-20b),4.65(dd,1H,J=5.4,11.7,H-10),4.18(s,1H,H-5),3.28(s,3H,10-OCH 3),3.21(d,1H,J=6.0,H-3),2.77(dd,1H,J=9.3,19.2,H-13a),2.37(dd,1H,J=4.5,19.2,H-13b),2.23(dd,1H,J=11.7,14.7,H-9a),2.04(s,3H,COCH 3),2.03(s,3H,COCH 3),1.99(s,3H,18-H),1.83(s,1H,H-1),1.72-1.63(m,2H,H-6a,b),1.62(s,3H,16-H),1.60(m,1H,H-9b),1.26(m,1H,H-7a),1.17(s,3H,17-H),1.10(m,1H,H-7b),0.80(s,3H,19-H)。
13C NMR(CDCl3,125MHz)δppm:170.25(CH3 CO),169.92(CH3 CO),147.91(C-11),136.15(C-4),135.62(C-12),113.42(C-20),76.43(C-5),76.05(C-10),71.09(C-2),70.82(C-14),59.07(10-OCH3),55.19(C-1),45.11(C-18),40.06(C-3),39.87(C-13),39.56(C-8),37.37(C-15),33.19(C-9),31.63(C-6),30.82(C-7),24.94(C-17),22.27(C-16),21.53(CH3CO),21.49(CH3CO),20.85(C-19)。
HR-ESI-MS m/z:435.2720[M+H]+(calcd for C31H42NO7435.2746)。
实施例
实施例1.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙烯酰氧基-4(20),11-紫杉二烯
(1)化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(24mg,0.062mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(64mg,0.31mmol),苯丙烯酸(80mg,0.54mmol),DMAP(70mg,0.57mmol)。室温26℃搅拌反应5h，加入1ml甲醇终止反应，减压浓缩，乙酸乙酯溶解，过滤除去反应体系中的白色不溶物，2倍体积乙酸乙酯稀释，依次用1mol/l稀盐酸水溶液、饱和碳酸氢钠溶液、饱和食盐水洗，无水硫酸钠干燥，减压浓缩，硅胶柱色谱初步分离，石油醚–丙酮=5:2(v/v)洗脱，得到初产物经乙酸乙酯溶解过滤，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙烯酰氧基-4(20),11-紫杉二烯(tR16min,27mg,产率84%)。
1H NMR(CDCl3,400MHz)δppm:7.77(d,2H,J=7.6,H-25,H-29),7.64(d,1H,J=15.6,H-23),7.40(m,3H,H-26,27,28),6.46(d,1H,J=15.6,H-22),5.48(d,1H,J=6.4,H-2),5.32(s,1H,H-5),5.27(s,1H,H-20a),4.79(s,1H,H-20b),4.72(dd,1H,J=5.6,11.6,H-10),3.31(s,3H,10-OMe),3.34(d,1H,J=6.4,H-3),2.85(dd,1H,J=7.2,20.0,H-14a),2.45(d,1H,J=20.0,H-14b),2.39(dd,1H,J=11.6,14.8,H-9a),2.17(d,1H,J=7.2,H-1),2.14(s,3H,COCH 3),2.06(s,3H,18-H),1.96-1.85(m,3H,H-6a,b,H-7a),1.79(dd,1H,J=5.6,14.8,H-9b),1.69(s,3H,16-H),1.26(m,1H,H-7b),1.22(s,3H,17-H),0.91(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:198.7(C-13CO),170.0(CH3 CO),169.6(CH3 CO),166.3(C21-CO),154.1(C-11),144.6(C-22),142.3(C-4),138.0(C-12),134.2(C-23),130.3(C-24),128.9(C-25,C-29),128.1(C-26,C-28),118.5(C-27),116.9(C-20),82.8(C-1),76.4(C-5),69.9(C-2),56.51(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),38.9(C-14),38.2(C-9),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.1(C-16),21.4(CH3CO),21.2(CH3CO),17.2(C-18),14.0(C-19)。
HR-ESI-MS m/z:543.2718[M+Na]+(calcd for C32H40O6Na543.2722)。
实施例2.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-L-脯氨酰氧基-4(20),11-紫杉二烯
1）L-脯氨酸(100mg，0.869mmol)溶于12ml NaOH/NaHCO3(1:2)混合溶液中，呈黄色乳浊液，缓慢滴加二碳酸二叔丁酯(Boc)2O(300mg,1.375mmol)的1,4-二氧六环溶液10ml入反应器中，使pH>10，室温搅拌过夜，溶液浑浊，生成大量乳白色沉淀。待反应完成后，溶液澄清，终止反应，反应液静置15min后分层，下层为白色固体不溶物，上层澄清。将反应液倾入分液漏斗中，石油醚萃取(50ml×3)，除掉多余的Boc酸酐。下层水相在0℃下，加1mol/lHCl调节pH=2～3，有大量白色沉淀析出，抽滤，母液反复洗涤，干燥后得到产物N-Boc-L-脯氨酸，白色粉末140mg,收率98%备用。
2）化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(20mg,0.051mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(90mg,0.44mmol),N-Boc-L-脯氨酸(70mg,0.35mmol),DMAP(60mg,0.50mmol)。室温26℃搅拌反应3h，加入1ml甲醇终止反应，后处理过程同实施例1，得到的粗产物未经纯化，溶于二氯甲烷中，缓慢滴加三氟乙酸。室温下搅拌1h，至TLC显示原料完全消失。减压除去二氯甲烷和三氟乙酸，多次加入无水乙醚再减压蒸除，残余物用乙酸乙酯溶解。溶液依次用水、饱和碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩除去溶剂，正相半制备HPLC纯化，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-L-脯氨酰氧基-4(20),11-紫杉二烯(tR16min,20mg,两步产率81%)。
1H NMR(CDCl3,400MHz)δppm:5.46(d,1H,J=6.0,H-2),5.26(s,1H,H-5),5.22(s,1H,H-20a),4.80(s,1H,H-20b),4.68(dd,1H,J=5.6,11.6,H-10),3.61(dd,1H,J=6.8,13.6,H-22),3.31(s,3H,10-OMe),3.15(d,1H,J=6.0,H-3),3.08(m,2H,H-25a,b),2.79(dd,1H,J=7.2,20.0,H-14a),2.38(dd,1H,J=11.6,14.8,H-9a),2.32(d,1H,J=20.0,H-14b),2.20(m,2H,H-23a,b),2.14(d,1H,J=7.2,H-1),2.08(s,3H,COCH 3),2.05(s,3H,18-H),1.85(m,3H,H-6a,b,H-7a),1.80-1.60(m,2H,H-24a,b),1.76(dd,1H,J=5.6,14.8,H-9b),1.67(s,3H,16-H),1.25(m,1H,H-7b),1.18(s,3H,17-H),0.88(s,3H,19-H)。
HR-ESI-MS m/z:511.2900[M+Na]+(calcd for C28H42NO6Na511.2909)
实施例3.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(20mg,0.051mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(90mg,0.44mmol),苯丙酸(75mg,0.50mmol),DMAP(61mg,0.50mmol)。室温26℃搅拌反应3h，加入1ml甲醇终止反应，后处理过程同实施例1，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙酰氧基-4(20),11-紫杉二烯(tR15min,24mg,产率90%)。
1H NMR(CDCl3,400MHz)δppm:7.28(m,3H,H-26,27,28),7.20(m,2H,H-25,H-29),5.44(d,1H,J=6.4,H-2),5.24(s,1H,H-20a),5.20(s,1H,H-5),4.79(s,1H,H-20b),4.68(dd,1H,J=5.6,11.6,H-10),3.31(s,3H,10-OMe),3.12(d,1H,J=6.4,H-3),2.92(t,2H,J=7.6,H-23a,b),2.79(dd,1H,J=6.8,20.0,H-14a),2.55(t,2H,J=7.6,H-22),2.37(dd,1H,J=11.6,14.8,H-9a),2.30(d,1H,J=20.0,H-14b),2.12(d,1H,J=6.8,H-1),2.08(s,3H,COCH 3),2.06(s,3H,18-H),1.75(m,4H,H-6a,b,H-7a,H-9b),1.67(s,3H,16-H),1.23(m,1H,H-7b),1.19(s,3H,17-H),0.87(s,3H,19-H)。
13C NMR(CDCl3,125MHz)δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),165.2(C21-CO),154.1(C-11),149.4(C-24),142.3(C-4),138.0(C-12),137.3(C-27),130.2(C-25,C-29),129.3(C-26,C-28),116.9(C-20),82.8(C-1),76.4(C-5),69.9(C-2),57.2(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),37.1(C-15),36.5(C-9),36.1(C-17),35.6(C-22),30.2(C-23),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:5445.2845[M+Na]+(calcd for C32H42O6Na545.2879)。
实施例4.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-2-呋喃甲酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(15mg,0.038mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(80mg,0.38mmol),2-呋喃甲酸(50mg,0.45mmol),DMAP(50mg,0.41mmol)。室温26℃搅拌反应5h，加入1ml甲醇终止反应，后处理过程同实施例1，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-2-呋喃甲酰氧基-4(20),11-紫杉二烯(tR13min,17mg,产率91%)。
1H NMR(CDCl3,400M Hz)δppm:7.68(s,1H,H-23),7.15(d,1H,J=3.6,H-25),6.54(t,1H,J=1.6,H-24),5.48(d,1H,J=6.8,H-2),5.38(s,1H,H-5),5.31(s,1H,H-20a),4.76(s,1H,H-20b),4.67(dd,1H,J=5.2,11.6,H-10),3.30(s,3H,10-OMe),3.25(d,1H,J=6.8,H-3),2.78(dd,1H,J=7.2,20.0,H-14a),2.45(dd,1H,J=11.6,14.8,H-9a),2.40(d,1H,J=20.0,H-14b),2.17(d,1H,J=7.2,H-1),2.04(s,6H,COCH 3,18-H),1.95(m,3H,H-6a,b,H-7a),1.78(dd,1H,J=5.2,14.8,H-9b),1.68(s,3H,16-H),1.30(m,1H,H-7b),1.17(s,3H,17-H),0.92(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),157.7(C21-CO),154.1(C-11),146.3(C-25),142.3(C-4),138.0(C-12),117.0(C-22),116.9(C-20),115.8(C-23),110.9(C-24),82.8(C-1),76.4(C-5),69.9(C-2),59.5(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),38.4(C-9),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:507.2352[M+Na]+(calcd for C28H36O7Na507.2358)。
实施例5.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-4-苯丁酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(17mg,0.044mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(85mg,0.41mmol),4-苯基丁酸(62mg,0.38mmol),DMAP(62mg,0.50mmol)。室温26℃搅拌反应10h，加入1ml甲醇终止反应，后处理过程同实施例1，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-4-苯丁酰氧基-4(20),11-紫杉二烯(tR13min,16mg,产率68%)。
1H NMR(CDCl3,400MHz)δppm:7.30(m,3H,H-26,28,30),7.20(t,2H,J=7.2,H-27,H-29),5.46(d,1H,J=6.0,H-2),5.26(s,1H,H-20a),5.23(s,1H,H-5),4.81(s,1H,H-20b),4.71(dd,1H,J=5.6,11.6,H-10),3.33(s,3H,10-OMe),3.16(d,1H,J=6.0,H-3),2.80(dd,1H,J=6.8,20.0,H-14a),2.70(m,2H,H-24a,b),2.42-2.22(m,4H,H-22a,b,H-14b,H-9a),2.14(d,1H,J=6.8,H-1),2.08(s,3H,COCH 3),2.06(s,3H,18-H),2.00-1.90(m,2H,H-23a,b),1.88-1.75(m,4H,H-6a,b,H-7a,H-9b),1.69(s,3H,16-H),1.26(m,1H,H-7b),1.21(s,3H,17-H),0.89(s,3H,19-H)。
HR-ESI-MS m/z:559.3012[M+Na]+(calcd for C33H44O6Na559.3035)。
实施例6.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(16mg,0.041mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(74mg,0.36mmol),3-吡啶甲酸(62mg,0.50mmol),DMAP(62mg,0.50mmol)。室温26℃搅拌反应3h，加入1ml甲醇终止反应，后处理过程同实施例1，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯(tR16min,17mg,产率84%)。
1H NMR(CDCl3,400MHz)δppm:9.10(s,1H,H-27),8.83(d,1H,J=4.4,H-25),8.02(d,1H,J=7.6,H-23),7.54(dd,1H,J=4.8,7.6,H-24),5.50(dd,1H,J=1.6,6.8,H-2),5.37(s,2H,H-20a,H-5),4.86(s,1H,H-20b),4.64(dd,1H,J=5.6,11.6,H-10),3.29(s,3H,10-OMe),3.14(d,1H,J=6.8,H-3),2.81(dd,1H,J=7.2,20.0,H-14a),2.43(dd,1H,J=11.6,14.8,H-9a),2.38(d,1H,J=20.0,H-14b),2.17(d,1H,J=7.2,H-1),2.08(s,3H,COCH 3),1.98(s,3H,18-H),1.95-1.76(m,4H,H-6a,b,H-7a,H-9b),1.68(s,3H,16-H),1.24(m,1H,H-7b),1.16(s,3H,17-H),0.93(s,3H,19-H)。
13C NMR(CDCl3,100MHz):δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),164.6(C21-CO),154.1(C-11),149.2(C-23),148.8(C-22),142.3(C-4),138.0(C-12),137.0(C-25),126.7(C-26),125.4(C-27),116.9(C-20),82.8(C-1),76.4(C-5),69.9(C-2),56.5(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),39.2(C-9),37.9(C-14),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:518.2510[M+Na]+(calcd for C29H37NO7Na518.2518).
实施例7.2α-乙酰氧基-10β-甲氧基-13-羰基-5α-环己烷乙酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(20mg,0.051mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(90mg,0.44mmol),环己烷乙酸(71mg,0.50mmol),DMAP(60mg,0.50mmol)。室温26℃搅拌反应5h，加入1ml甲醇终止反应，后处理过程同实施例1，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得2α-乙酰氧基-10β-甲氧基-13-羰基-5α-环己烷乙酰氧基-4(20),11-紫杉二烯(tR14min,22mg,产率84%)。
1H NMR(CDCl3,400MHz)δppm:5.44(d,1H,J=6.0,H-2),5.24(s,1H,H-20a),5.21(s,1H,H-5),4.79(s,1H,H-20b),4.69(dd,1H,J=5.6,11.6,H-10),3.31(s,3H,10-OMe),3.13(d,1H,J=6.0,H-3),2.77(dd,1H,J=6.8,20.0,H-14a),2.37(dd,1H,J=11.6,14.8,H-9a),2.29(d,1H,J=20.0,H-14b),2.21(d,1H,J=6.8,H-1),2.12-2.06(m,2H,H-22),2.10(s,3H,COCH 3),2.04(s,3H,18-H),1.87-1.68(m,11H,H-6a,b,H-7a,H-9b,H-23a,b,25a,b,26a,b,27a,b),1.62(s,3H,16-H),1.24(m,5H,H-7b,H-24a,b,28a,b),1.18(s,3H,17-H),0.87(s,3H,19-H)。
HR-ESI-MS m/z:537.3180[M+Na]+(calcd for C31H46O6Na537.3192).
实施例8.2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙烯酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14-羰基-4(20),11-紫杉二烯(30mg,0.090mmol)[该化合物的制备参考文献：Jian-Hua Zou,Huixia Du,Yi Zhang,Jungui Dai,Dali Yin,Xiaoguang Chen.Biotransformation and tumor multidrug resistance reversal potency of polyoxygenated taxadienes.Journal of Molecular Catalysis B:Enzymatic.2008,55,12–18.]，溶于10ml干燥的二氯甲烷中，依次加入DCC(170mg,0.89mmol),苯丙烯酸(174mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙烯酰氧基-4(20),11-紫杉二烯(tR10min,42mg,产率91.3%)。
1H NMR(CDCl3,500MHz)δppm:7.73(d,1H,J=16,H-23),7.55-7.53(m,2H,H-25,29),7.38-7.37(m,3H,H-26,27,28),6.47(d,1H,J=16,H-22),5.90(d,1H,J=9.5,H-10),5.56(dd,1H,J=2,7,H-2),5.31(s,1H,H-20a),5.24(s,1H,H-5),4.83(s,1H,H-20b),4.61(d,1H,J=9.5,H-9),3.27(s,3H,10-OCH 3),3.26(d,1H,J=6.5,H-3),2.80(dd,1H,J=7,20,H-14b),2.32(d,1H,J=19.5,H-14a),2.15(s,3H,2-COCH 3),2.04(s,3H,5-COCH 3),1.99(s,3H,18-H),1.88-1.82(m,2H,H-9b,H-1,H-7a),1.79(s,3H,16-H),1.74-1.66(m,2H,H-6a,b),1.28-1.22(m,1H,H-7b),1.20(s,3H,17-H),0.92(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),165.9(C21-CO),154.1(C-11),144.7(C-22),142.3(C-4),138.0(C-12),134.4(C-23),130.3(C-24),128.8(C-25,C-29),128.0(C-26,C-28),118.4(C-27),116.9(C-20),82.8(C-1),78.4(C-9),76.4(C-5),69.9(C-2),56.5(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:601.2755[M+Na]+(calcd for C34H42O8Na601.2777)。
实施例9.2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14-羰基-4(20),11-紫杉二烯(33mg,0.094mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(170mg,0.89mmol),苯丙酸(174mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙酰氧基-4(20),11-紫杉二烯(tR10min,40mg,产率84.2%)。
1H NMR(CDCl3,500MHz)δppm:7.27(t,1H,J=7,H-26,28),7.22(d,2H,J=7.5,H-25,29),7.18(t,1H,J=7.5,H-27),5.76(d,1H,J=10,H-9),5.50(dd,1H,J=1.5,6.5,H-2),5.29(s,1H,H-20a),5.21(s,1H,H-5),4.81(s,1H,H-20b),4.50(d,1H,J=9.5,H-10),3.24(s,3H,10-OCH 3),3.20(d,1H,J=6,H-3),2.99(t,2H,J=8,H-23),2.79(dd,1H,J=7.5,20,H-14b),2.69(dd,2H,J=8,15.5,H-22),2.30(d,1H,J=20,H-14a),2.19-2016(m,1H,H-1),2.13(s,3H,2-COCH 3),2.03(s,3H,5-COCH 3),1.97(s,3H,18-H),1.78-1.76(m,1H,H-7a),1.74(s,3H,16-H),1.68-1.60(m,2H,H-6a,b),1.25-1.22(m,1H,H-7b),1.19(s,3H,17-H),0.77(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),165.9(C21-CO),154.1(C-11),142.3(C-4),138.0(C-12),130.3(C-24),128.8(C-25,C-29),128.0(C-26,C-28),118.4(C-27),116.9(C-20),82.8(C-1),78.4(C-9),76.4(C-5),69.9(C-2),56.5(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),37.1(C-15),36.1(C-17),35.6(C-22),33.2(C-23),28.7(C-6),26.4(C-7),25.0(C-16),22.0(CH3CO),21.4(CH3CO),17.8(C-18),15.2(C-19)。
HR-ESI-MS m/z:603.2952[M+Na]+(calcd for C34H44O8Na603.2933)。
实施例10.2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-呋喃丙烯酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14-羰基-4(20),11-紫杉二烯(33mg,0.094mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(170mg,0.89mmol),呋喃丙烯酸(174mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-呋喃丙烯酰氧基-4(20),11-紫杉二烯(tR10min,40mg,产率85.7%)。
1H NMR(CDCl3,500MHz)δppm:7.48(s,1H,H-25),7.46(d,1H,J=15.5,H-23),6.63(d,1H,J=3.5,H-27),6.47(dd,1H,J=2,3,H-26),5.87(d,1H,J=9.5,H-10),5.56(dd,1H,J=2,6.5,H-2),5.30(s,1H,H-20a),5.23(s,1H,H-5),4.82(s,1H,H-20b),4.59(d,1H,J=10,H-9),3.26(s,3H,10-OCH 3),3.25(d,1H,J=6.5,H-3),2.80(dd,1H,J=7,19.5,H-14b),2.31(d,1H,J=19.5,H-14a),2.19(d,1H,J=7.0,H-1),2.16(s,3H,2-COCH 3),2.04(s,3H,5-COCH 3),1.98(s,3H,18-H),1.88-1.80(m,1H,H-7a),1.77(s,3H,16-H),1.72-1.67(m,2H,H-6a,b),1.27-1.22(m,1H,H-7b),1.20(s,3H,17-H),0.90(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),165.9(C21-CO),154.1(C-11),150.7(C-22),142.3(C-4),138.0(C-12),134.4(C-23),130.3(C-24),128.8(C-25),128.0(C-26),118.4(C-27),116.9(C-20),82.8(C-1),78.4(C-9),76.4(C-5),69.9(C-2),56.5(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:591.2528[M+Na]+(calcd for C32H40O9Na591.2570)。
实施例11.2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-2-吡啶甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14-羰基-4(20),11-紫杉二烯(32mg,0.093mmol)溶于10ml干燥的二氯甲烷中，依次加入DCC(170mg,0.89mmol),2-吡啶甲酸(114mg,0.90mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-2-吡啶甲酰氧基-4(20),11-紫杉二烯(tR10min,41mg,产率86.2%)。
1H NMR(CDCl3,500MHz)δppm:9.24(s,1H,H-26),8.79(d,1H,J=4.5,H-23),8.34(d,1H,J=8,H-25),7.43(dd,1H,J=4.5,8,H-24),6.04(d,1H,J=9.5,H-9),5.58(dd,1H,J=2,7,H-2),5.33(s,1H,H-20a),5.25(s,1H,H-5),4.85(s,1H,H-20b),4.70(d,1H,J=9.5,H-10),3.30(d,1H,J=6.5,H-3),3.23(s,3H,10-OCH 3),2.82(dd,1H,J=7,20,H-14a),2.34(d,1H,J=20,H-14b),2.21(dd,1H,J=2,7,H-1),2.18(s,3H,2-COCH 3),2.05(s,3H,5-COCH 3),2.00(s,3H,18-H),1.96-1.82(m,3H,H-6a,b,H-7),1.79(s,3H,16-H),1.21(s,3H,17-H),1.17-1.12(m,1H,H-7b),0.95(s,3H,19-H)。
13C NMR(CDCl3,100MHz):δppm:199.1(C-13CO),170.2(CH3 CO),169.6(CH3 CO),165.3(C21-CO),154.1(C-11),149.3(C-24),148.8(C-22),142.3(C-4),138.0(C-12),137.0(C-25),126.8(C-26),125.5(C-27),116.9(C-20),82.8(C-1),78.4(C-9),76.4(C-5),69.9(C-2),56.51(10-OCH3),48.6(C-1),42.8(C-3),44.1(C-8),37.9(C-14),37.1(C-15),36.1(C-17),28.7(C-6),26.4(C-7),25.0(C-16),21.4(CH3CO),21.4(CH3CO),17.4(C-18),14.0(C-19)。
HR-ESI-MS m/z:554.2744[M+H]+(calcd for C31H40NO8554.2753)。
实施例12.2α,5α-二乙酰氧基-10β-甲氧基-14β-苯甲酰氧基-4(20),11-紫杉二烯
(1)化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(38mg,0.087mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(170mg,0.89mmol),苯甲酸(112mg,0.92mmol),DMAP(110mg,0.90mmol)。室温25℃搅拌反应15h,终止反应，减压浓缩，乙酸乙酯溶解，过滤除去反应体系中的白色不溶物，2倍体积乙酸乙酯稀释，依次用1mol/l稀盐酸水溶液、饱和碳酸氢钠溶液、饱和食盐水洗，无水硫酸钠干燥，减压浓缩，硅胶柱色谱初步分离，石油醚–丙酮=5:2(v/v)洗脱，得到初产物经乙酸乙酯溶解过滤，正相半制备HPLC分离，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-苯甲酰氧基-4(20),11-紫杉二烯(tR6min,43mg,产率90%)。
1H NMR(CDCl3,300MHz)δppm:8.00(d,2H,J=7.5,H-23,27),7.56(t,1H,J=7.5,H-25),7.44(t,2H,J=7.5,H-24,26),5.40(br d,1H,J=6.3,H-2),5.28(m,3H,H-20a,H-14,H-5),4.87(s,1H,H-20b),4.64(dd,1H,J=5.1,12.0,H-10),3.31(s,3H,10-OCH 3),3.00(d,1H,J=5.4,H-3),2.94(dd,1H,J=9.0,19.2,H-13a),2.61(dd,1H,J=4.8,19.2,H-13b),2.30(dd,1H,J=12.0,15.0,H-9a),2.22(s,3H,COCH 3),2.07(s,1H,H-1),2.03(s,3H,COCH 3),2.00(s,3H,18-H),1.90(m,1H,H-9b),1.68(s,3H,16-H),1.70-1.50(m,2H,H-6a,b),1.31(s,3H,17-H),1.24(m,2H,H-7a,b),0.85(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.06(CH3 CO),169.56(CH3 CO),164.20(C21-CO),142.49(C-4),137.13(C-11),134.60(C-12),132.92(C-25),130.53(C-22),129.46(C-23,C-27),128.40(C-24,C-26),116.82(C-20),78.46(C-14),75.96(C-10),71.19(C-2),70.67(C-5),59.33(10-OCH3),55.32(C-1),45.27(C-8),42.26(C-3),39.93(C-13),39.55(C-15),37.37(C-9),33.99(C-17),31.77(C-7),28.95(C-6),24.95(C-18),22.55(C-16),21.97(CH3CO),21.50(CH3CO),21.04(C-19)。
HR-ESI-MS m/z:561.2815[M+Na]+(calcd for C32H42O7Na561.2828)。
实施例13.2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(45mg,0.103mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(190mg,0.10mmol),1-萘甲酸(177mg,0.10mmol),DMAP(122mg,0.10mmol).室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘甲酰氧基-4(20),11-紫杉二烯(tR6.7min,60mg,产率98%)。
1H NMR(CDCl3,300MHz)δppm:8.95(d,1H,J=8.4,H-25),8.12(d,1H,J=8.4,H-27),8.02(d,1H,J=8.4,H-30),7.88(d,1H,J=8.4,H-23),7.65-7.47(m,3H,H-26,H-28,H-29),5.50-5.34(m,3H,H-14,H-5,H-2),5.31(s,1H,H-20a),4.90(s,1H,H-20b),4.65(dd,1H,J=5.4,12.0,H-10),3.32(s,3H,10-OCH 3),3.10-3.00(m,2H,H-3,H-13a),2.67(dd,1H,J=4.8,19.2,H-13b),2.38(dd,1H,J=12.0,15.0,H-9a),2.22(s,3H,COCH 3),2.07(s,1H,H-1),2.06(s,3H,18-H),2.04(s,3H,COCH 3),1.90(m,1H,H-9b),1.70(s,3H,16-H),1.54(m,2H,H-6a,b),1.34(s,3H,17-H),1.25(m,2H,H-7a,b),0.87(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:169.92(CH3 CO),166.36(CH3 CO),158.60(C21-CO),142.54(C-22),137.20(C-4),134.63(C-11),133.84(C-12),133.35(C-23),131.44(C-24),129.97(C-28,C-29),128.55(C-25),127.73(C-26),126.24(C-27),125.72(C-30),124.51(C-31),116.86(C-20),78.48(C-14),75.97(C-10),71.29(C-2),70.77(C-5),59.38(10-OCH3),55.33(C-1),45.31(C-8),42.34(C-3),40.00(C-13),39.59(C-15),37.47(C-9),34.03(C-17),31.84(C-7),28.99(C-6),25.00(C-18),22.60(C-16),22.03(CH3CO),21.53(CH3CO),21.09(C-19)。
HR-ESI-MS m/z:611.2972[M+Na]+(calcd for C36H44O7Na611.2984)。
实施例14.2α,5α-二乙酰氧基-10β-甲氧基-14β-4-甲氧基苯甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(40mg,0.092mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(175mg,0.92mmol),4-甲氧基苯甲酸(140mg,0.92mmol),DMAP(112mg,0.92mmol)。室温25℃搅拌反应14h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-4-甲氧基苯甲酰氧基-4(20),11-紫杉二烯(tR6min,41mg,产率78%)。
1H NMR(CDCl3,300MHz)δppm:7.95(d,2H,J=8.4,H-24,26),6.91(d,2H,J=8.4,H-23,27),5.40(br d,1H,J=6.3,H-2),5.31(s,1H,H-5),5.24(m,2H,H-20a,H-14),4.87(s,1H,H-20b),4.64(dd,1H,J=5.4,12.0,H-10),3.86(s,3H,25-OCH 3),3.31(s,3H,10-OCH 3),3.00(d,1H,J=6.3,H-3),2.94(dd,1H,J=9.0,19.2,H-13a),2.56(dd,1H,J=4.8,19.2,H-13b),2.31(dd,1H,J=12.0,15.0,H-9a),2.22(s,3H,COCH 3),2.07(s,1H,H-1),2.03(s,3H,COCH 3),2.00(s,3H,18-H),1.90-1.50(m,3H,H-6a,b,H-9b),1.68(s,3H,16-H),1.30(s,3H,17-H),1.22(m,2H,H-7a,b),0.85(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.08(CH3 CO),169.85(CH3 CO),165.27(C21-CO),163.36(C-25),142.50(C-4),137.06(C-11),134.71(C-12),131.46(C-24,C-26),122.97(C-22),116.79(C-20),113.65(C-23,C-27),78.44(C-14),75.96(C-10),70.82(C-2),70.71(C-5),55.44(10-OCH3),55.31(C-1),45.29(C-8),42.26(C-3),40.04(C-13),39.54(C-15),37.38(C-9),33.99(C-17),31.77(C-7),28.95(C-6),24.97(C-18),22.57(C-16),21.97(CH3CO),21.51(CH3CO),21.05(C-19)。
HR-ESI-MS m/z:591.2923[M+Na]+(calcd for C33H44O7Na591.2933)。
实施例15.2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘乙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(45mg,0.103mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(192mg,0.10mmol),1-萘乙酸(191mg,0.10mmol),DMAP(124mg,0.10mmol)。室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘乙酰氧基-4(20),11-紫杉二烯(tR6.3min,58mg,产率94%)。
1H NMR(CDCl3,300MHz)δppm:8.00(d,1H,J=7.2,H-25),7.85(d,1H,J=8.4,H-30),7.77(d,1H,J=7.2,H-31),7.55-7.37(m,4H,H-24,H-26,H-28,H-29),5.26-5.19(m,3H,H-20a,H-5,H-2),5.00(dd,1H,J=4.5,9.0,H-14),4.75(s,1H,H-20b),4.53(dd,1H,J=5.4,12.0,H-10),4.03(s,2H,H-22a,b),3.23(s,3H,10-OCH 3),2.85(d,1H,J=6.3,H-3),2.75(dd,1H,J=9.0,19.2,H-13a),2.32-2.18(m,2H,H-13b,H-9a),2.12(s,3H,COCH 3),2.07(s,1H,H-1),1.92(s,3H,18-H),1.81(s,3H,COCH 3),1.74-1.55(m,3H,H-9b,H-6a,b),1.52(s,3H,16-H),1.20(m,2H,H-7a,b),0.87(s,3H,17-H),0.79(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.42(CH3 CO),169.79(CH3 CO),169.78(C21-CO),142.39(C-23),137.01(C-4),134.32(C-27),133.83(C-11),132.02(C-32),130.71(C-12),128.74(C-24),127.99(C-25),127.94(C-26),126.35(C-28),125.80(C-29),125.49(C-30),123.76(C-31),116.69(C-20),78.34(C-14),75.84(C-10),71.21(C-2),70.44(C-5),59.11(10-OCH3),55.22(C-1),45.20(C-8),42.15(C-3),39.78(C-22),39.53(C-13),39.44(C-15),37.12(C-9),33.92(C-17),31.13(C-7),28.92(C-6),24.81(C-18),22.51(C-16),21.90(CH3CO),21.21(CH3CO),20.92(C-19)。
HR-ESI-MS m/z:625.3129[M+Na]+(calcd for C37H46O7Na625.3141)。
实施例16.2α,5α-二乙酰氧基-10β-甲氧基-14β-3-氯苯甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(37mg,0.085mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(172mg,0.92mmol),3-氯苯甲酸(144mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应8h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-3-氯苯甲酰氧基-4(20),11-紫杉二烯(tR5min,51mg,产率99%)。
1H NMR(CDCl3,300MHz)δppm:7.95(s,1H,H-23),7.88(d,1H,J=7.5,H-25),7.53(d,1H,J=7.5,H-27),7.38(t,1H,J=7.5,H-26),5.39(br d,1H,J=4.8,H-2),5.31-5.25(m,3H,H-20a,H-14,H-5),4.88(s,1H,H-20b),6.04(dd,1H,J=5.4,12.0,H-10),3.31(s,3H,10-OMe),2.99(d,1H,J=5.4,H-3),2.92(dd,1H,J=9.0,19.2,H-13a),2.61(dd,1H,J=4.8,19.2,H-13b),2.40(dd,1H,J=12.0,15.0,H-9a),2.21(s,3H,COCH 3),2.13(s,1H,H-1),2.03(s,3H,COCH 3),2.02(s,3H,18-H),2.00-1.60(m,3H,H-9b,H-6a,b),1.68(s,3H,16-H),1.29(s,3H,17-H),1.23(m,2H,H-7a,b),0.85(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.42(CH3 CO),169.79(CH3 CO),169.78(C21-CO),137.70(C-22),139.23(C-4),135.32(C-23),133.83(C-11),132.74(C-24),131.71(C-12),129.90(C-25),129.68(C-26),127.78(C-27),117.69(C-20),78.34(C-14),75.84(C-10),71.21(C-2),70.44(C-5),59.11(10-OCH3),57.55(C-1),45.20(C-8),42.15(C-3),39.53(C-13),37.44(C-15),37.12(C-9),32.22(C-17),28.39(C-7),27.92(C-6),25.81(C-18),21.80(C-16),21.90(CH3CO),21.21(CH3CO),20.92(C-19)。
HR-ESI-MS m/z:595.2431[M+Na]+(calcd for C32H41ClO7Na595.2438)。
实施例17.2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘氧乙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(41mg,0.094mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(162mg,0.82mmol),1-萘氧乙酸(200mg,0.95mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘氧乙酰氧基-4(20),11-紫杉二烯(tR7min,44mg,产率86%)。
1H NMR(CDCl3,300MHz)δppm:8.32(t,1H,J=5.4,H-29),7.79(t,1H,J=5.4,H-30),7.51-7.46(m,3H,H-26,H-28,H-31),7.35(t,1H,J=7.5,H-25),6.69(d,1H,J=7.5,H-24),5.33(d,1H,J=6.3,H-2),5.28(m,1H,H-5),5.25(s,1H,H-20a),5.18(dd,1H,J=4.5,9.0,H-14),4.85(s,1H,H-20b),4.80(s,2H,H-22),4.58(dd,1H,J=5.4,12.0,H-10),3.25(s,3H,10-OCH 3),2.91(d,1H,J=6.3,H-3),2.82(dd,1H,J=9.0,19.2,H-13a),2.48(dd,1H,J=4.8,19.2,H-13b),2.25(dd,1H,J=12.0,15.0,H-9a),2.17(s,3H,COCH 3),2.06(s,1H,H-1),2.03(s,3H,COCH 3),1.98(s,3H,18-H),1.94-1.55(m,3H,H-9b,H-6a,b),1.57(s,3H,16-H),1.22(m,2H,H-7a,b),0.97(s,3H,17-H),0.82(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:169.87(CH3 CO),167.89(CH3 CO),153.63(C21-CO),142.39(C-26),137.23(C-4),134.59(C-11),134.11(C-12),127.40(C-29),126.65(C-30),125.51(C-28,C-31),125.36(C-27,C-32),122.07(C-24),121.41(C-25),116.84(C-20),104.75(C-23),78.44(C-14),75.85(C-10),71.96(C-2),70.51(C-5),65.87(C-22),59.09(10-OCH3),55.29(C-1),45.19(C-8),42.21(C-3),39.50(C-13),39.44(C-15),37.21(C-9),33.93(C-17),31.22(C-7),28.92(C-6),24.83(C-18),22.51(C-16),21.93(CH3CO),21.47(CH3CO),20.96(C-19)。
HR-ESI-MS m/z:641.3093[M+Na]+(calcd for C37H46O8Na641.3090)。
实施例18.2α,5α-二乙酰氧基-10β-甲氧基-14β-3,4,5-三甲氧基苯甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(42mg,0.095mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(182mg,0.95mmol),3,4,5-三甲氧基苯甲酸(195mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应15h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-3,4,5-三甲氧基苯甲酰氧基-4(20),11-紫杉二烯(tR8.6min,48mg,产率75%)。
1H NMR(CDCl3,300MHz)δppm:7.26(s,2H,H-23,27),5.41(br d,1H,J=5.4,H-2),5.32-5.24(m,3H,H-20a,H-14,H-5),4.88(s,1H,H-20b),4.64(dd,1H,J=5.4,12.0,H-10),3.89(s,9H,24,25,26-OCH 3),3.31(s,3H,10-OCH 3),3.00(d,1H,J=6.0,H-3),2.94(dd,1H,J=9.0,19.2,H-13a),2.56(m,1H,H-13b),2.32(dd,1H,J=12.0,15.0,H-9a),2.22(s,3H,COCH 3),2.07(s,1H,H-1),2.03(s,3H,18-H),2.02(s,3H,COCH 3),1.90-1.60(m,3H,H-6a,b,H-9b),1.69(s,3H,16-H),1.31(s,3H,17-H),1.22(m,2H,H-7a,b),0.85(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:169.81(CH3 CO),167.60(CH3 CO),152.94(C21-CO),142.45(C-4),134.64(C-23,C-27),134.20(C-11),129.79(C-12),119.32(C-22),116.83(C-20),106.65(C-24,C-25,C-26),78.44(C-14),75.95(C-10),71.22(C-2),70.61(C-5),59.21(10-OCH3),56.17(24-OCH3,25-OCH3,26-OCH3),55.33(C-1),45.24(C-8),42.21(C-3),39.96(C-13),39.56(C-15),37.25(C-9),33.50(C-17),31.74(C-7),28.93(C-6),24.92(C-18),22.55(C-16),21.99(CH3CO),21.57(CH3CO),21.05(C-19)。
HR-ESI-MS m/z:651.3132[M+Na]+(calcd for C31H42O7Na651.3145)。
实施例19.2α,5α-二乙酰氧基-10β-甲氧基-14β-2-萘氧乙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(45mg,0.10mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(192mg,0.10mmol),2-萘氧乙酸(195mg,0.95mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-2-萘氧乙酰氧基-4(20),11-紫杉二烯(tR9min,56mg,产率91%)。
1H NMR(CDCl3,300MHz)δppm:7.76(dd,2H,J=2.7,7.5,H-25,H-27),7.70(d,1H,J=8.1,H-24),7.45(t,1H,J=7.5,H-28),7.35(t,1H,J=7.5,H-29),7.18(dd,1H,J=2.7,6.3,H-30),7.05(d,1H,J=2.7,H-32),5.33(d,1H,J=4.2,H-2),5.28(m,1H,H-5),5.24(s,1H,H-20a),5.16(dd,1H,J=4.5,9.0,H-14),4.84(s,1H,H-20b),4.72(s,2H,H-22),4.58(dd,1H,J=5.4,12.0,H-10),3.25(s,3H,10-OCH 3),2.90(d,1H,J=6.0,H-3),2.83(dd,1H,J=9.0,19.2,H-13a),2.47(dd,1H,J=4.8,19.2,H-13b),2.28(dd,1H,J=12.0,15.0,H-9a),2.16(s,3H,COCH 3),1.98(s,3H,18-H),1.96(s,3H,COCH 3),1.87(s,1H,H-1),1.80-1.50(m,3H,H-9b,H-6a,b),1.60(s,3H,16-H),1.22(m,2H,H-7a,b),1.06(s,3H,17-H),0.82(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:180.32(C21-CO),169.73(CH3 CO),167.20(CH3 CO),142.38(C-26),137.26(C-4),134.12(C-11),134.05(C-12),129.79(C-29),128.11(C-30),127.71(C-28,C-31),126.81(C-27,C-32),126.59(C-24),124.12(C-23),118.54(C-25),116.90(C-20),106.93(C-23),78.46(C-14),75.86(C-10),72.18(C-2),70.55(C-5),65.65(C-22),59.10(10-OCH3),55.31(C-1),45.25(C-8),42.26(C-3),39.54(C-13,C-15),37.27(C-9),33.98(C-17),31.35(C-7),28.91(C-6),24.89(C-18),22.56(C-16),21.97(CH3CO),21.43(CH3CO),21.03(C-19)。
HR-ESI-MS m/z:641.3077[M+Na]+(calcd for C37H46O8Na641.3090)。
实施例20.2α,5α-二乙酰氧基-10β-甲氧基-14β-3,5-二甲氧基苯甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(43mg,0.10mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(175mg,0.92mmol),3,5-二甲氧基苯甲酸(167mg,0.92mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应15h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-3,5-二甲氧基苯甲酰氧基-4(20),11-紫杉二烯(tR7min,52mg,产率86%)。
1H NMR(CDCl3,300MHz)δppm:7.15(s,2H,H-23,27),6.66(s,1H,H-25),5.41(br d,1H,J=5.7,H-2),5.32-5.24(m,3H,H-20a,H-14,H-5),4.89(s,1H,H-20b),4.63(dd,1H,J=5.4,12.0,H-10),3.83(s,6H,24,26-OCH 3),3.31(s,3H,10-OCH 3),3.00(d,1H,J=5.7,H-3),2.94(dd,1H,J=9.0,19.2,H-13a),2.56(m,1H,H-13b),2.32(dd,1H,J=12.0,15.0,H-9a),2.23(s,3H,COCH 3),2.08(s,1H,H-1),2.04(s,3H,18-CH 3),2.02(s,3H,COCH 3),1.90-1.70(m,3H,H-6a,b,H-9b),1.69(s,3H,16-CH 3),1.31(s,3H,17-CH 3),1.22(m,2H,H-7a,b),0.86(s,3H,19-CH 3。
HR-ESI-MS m/z:621.3035[M+Na]+(calcd for C34H46O9Na621.3039)。
实施例21.2α,5α-二乙酰氧基-10β-甲氧基-14β-2-呋喃甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(42mg,0.99mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(177mg,0.93mmol),2-呋喃甲酸(110mg,0.10mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-2-呋喃甲酰氧基-4(20),11-紫杉二烯(tR9.7min,45mg,产率86%)。
1H NMR(CDCl3,300MHz)δppm:7.58(s,1H,H-23),7.10(d,1H,J=3.3,H-25),6.50(dd,1H,J=1.8,3.3,H-24),5.39(dd,1H,J=2.1,6.0,H-2),5.31(m,1H,H-5),5.27(s,1H,H-20a),5.23(dd,1H,J=4.8,9.0,H-14),4.86(s,1H,H-20b),4.64(dd,1H,J=5.7,12.0,H-10),3.30(s,3H,10-OCH 3),2.97(d,1H,J=6.0,H-3),2.90(dd,1H,J=9.0,19.2,H-13a),2.60(dd,1H,J=4.8,19.2,H-13b),2.30(dd,1H,J=12.0,15.0,H-9a),2.20(s,3H,COCH 3),2.07(s,1H,H-1),2.03(s,3H,COCH 3),2.02(s,3H,18-H),1.80-1.50(m,3H,H-9b,H-6a,b),1.66(s,3H,16-H),1.26(s,3H,17-H),1.22(m,2H,H-7a,b),0.85(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:170.08(CH3 CO),169.82(CH3 CO),157.79(C21-CO),146.37(C-25),142.44(C-4),137.18(C-11),134.40(C-12),117.57(C-20),116.99(C-22),116.84(C-23),111.74(C-24),78.42(C-14),75.94(C-10),71.40(C-2),70.57(C-5),59.10(10-OCH3),55.32(C-1),45.25(C-8),42.25(C-3),39.74(C-13),39.54(C-15),37.32(C-9),33.97(C-17),31.65(C-7),28.95(C-6),24.93(C-18),22.56(C-16),21.91(CH3CO),21.53(CH3CO),21.02(C-19)。
HR-ESI-MS m/z:551.2618[M+Na]+(calcd for C30H40O8Na551.2621)。
实施例22.2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(38mg,0.087mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(170mg,0.90mmol),2-吲哚甲酸(148mg,0.92mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应11h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯(tR7min,8mg,产率16%)。
1H NMR(CDCl3,300MHz)δppm:8.77(br s,1H,NH-23),7.68(d,1H,J=8.1,H-28),7.42(t,1H,J=7.2,H-27),7.33(t,1H,J=7.2,H-26),7.15(d,2H,J=6.0,H-25,H-30),5.40(d,1H,J=6.0,H-2),5.31(m,3H,H-20a,H-14,H-5),4.88(s,1H,H-20b),4.65(dd,1H,J=5.4,12.0,H-10),3.31(s,3H,10-OCH 3),3.00(d,1H,J=6.0,H-3),2.93(dd,1H,J=9.0,19.2,H-13a),2.66(dd,1H,J=4.8,19.2,H-13b),2.33(dd,1H,J=12.0,15.0,H-9a),2.22(s,3H,COCH 3),2.14(s,1H,H-1),2.04(s,3H,COCH 3),2.02(s,3H,18-H),1.90-1.70(m,3H,H-9b,H-6a,b),1.70(s,3H,16-H),1.32(s,3H,17-H),1.26(m,2H,H-7a,b),0.85(s,3H,19-H)。
HR-ESI-MS m/z:600.2930[M+Na]+(calcd for C34H43NO7Na600.2937)。
实施例23.2α,5α-二乙酰氧基-10β-甲氧基-14β-4-苯基丁酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(37mg,0.085mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(170mg,0.90mmol),2-吲哚甲酸(148mg,0.92mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应6h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-4-苯基丁酰氧基-4(20),11-紫杉二烯(tR7min,43mg,产率86%)。
1H NMR(CDCl3,300MHz)δppm:7.30(d,2H,J=7.5,H-26,H-30),7.17(t,3H,J=7.5,H-27,H-28,H-29),5.35(dd,1H,J=2.1,6.6,H-2),5.28(br s,1H,H-5),5.25(s,1H,H-20a),5.01(dd,1H,J=4.8,9.0,H-14),4.84(s,1H,H-20b),4.60(dd,1H,J=5.4,12.0,H-10),3.28(s,3H,10-OCH 3),2.92(d,1H,J=6.3,H-3),2.83(dd,1H,J=9.0,19.2,H-13a),2.63(t,2H,J=7.5,H-22a,b),2.40(dd,1H,J=4.8,19.2,H-13b),2.26(t,2H,J=7.5,H-24a,b),2.20(m,1H,H-9a),2.18(s,3H,COCH 3),2.09(s,1H,H-1),2.01(s,3H,COCH 3),1.93(s,3H,18-H),1.90(t,2H,J=7.5,H-23),1.70-1.60(m,3H,H-9b,H-6a,b),1.62(s,3H,16-H),1.22(m,2H,H-7a,b),1.17(s,3H,17-H),0.82(s,3H,19-H)。
HR-ESI-MS m/z:603.3291[M+Na]+(calcd for C35H48O7Na603.3297)。
实施例24.2α,5α-二乙酰氧基-10β-甲氧基-14β-2,5-二甲氧基苯乙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(41mg,0.096mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(176mg,0.92mmol),2,5-二甲氧基苯乙酸(180mg,0.92mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-2,5-二甲氧基苯乙酰氧基-4(20),11-紫杉二烯(tR9min,40mg,产率68%)。
1H NMR(CDCl3,300MHz)δppm:6.49(br s,3H,H-25,H-26,H-28),5.05(dd,1H,J=2.1,6.3,H-2),5.00(br s,1H,H-5),4.96(s,1H,H-20a),4.75(dd,1H,J=4.5,9.0,H-14),4.56(s,1H,H-20b),4.32(dd,1H,J=5.7,12.0,H-10),3.49(s,6H,24-OCH 3,27-OCH 3),3.29(s,2H,H-22a,b),3.00(s,3H,10-OCH 3),2.63(d,1H,J=6.3,H-3),2.53(dd,1H,J=9.0,19.2,H-13a),2.16(dd,1H,J=4.8,19.2,H-13b),2.00(dd,1H,J=12.0,15.0,H-9a),1.88(s,3H,COCH 3),1.80(s,1H,H-1),1.74(s,3H,COCH 3),1.73(s,3H,18-H),1.70-1.30(m,3H,H-9b,H-6a,b),1.32(s,3H,16-H),0.96(m,2H,H-7a,b),0.75(s,3H,17-H),0.55(s,3H,19-H)。
13C NMR(CDCl3,100MHz)δppm:169.97(CH3 CO),169.80(CH3 CO),153.38(C21-CO),145.60(C-23),142.66(C-4),137.08(C-11),135.40(C-12),123.56(C-24),117.14(C-20),112.56(C-25),111.25(C-26),108.54(C-28),78.37(C-14),75.89(C-10),70.77(C-2),70.56(C-5),59.09(10-OCH3),55.93and55.69(24-OCH3and27-OCH3),55.23(C-1),45.22(C-8),42.14(C-3),39.60(C-13),39.45(C-15),37.16(C-22),36,67(C-9),33.93(C-17),31.33(C-7),28.91(C-6),24.92(C-18),22.52(C-16),21.92(CH3CO),21.39(CH3CO),20.97(C-19)。
HR-ESI-MS m/z:635.3202[M+Na]+(calcd for C35H48O9Na635.3196)。
实施例25.2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(39mg,0.090mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(175mg,0.92mmol),2-吲哚乙酸(161mg,0.92mmol),DMAP(110mg,0.92mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯(tR12min,28mg,产率53%)。
1H NMR(CDCl3,300MHz)δppm:8.05(br s,1H,NH-24),7.60(d,1H,J=7.8,H-26),7.36(t,1H,J=7.8,H-29),7.20(m,3H,H-27,H-28,H-31),5.28(m,2H,H-5,H-2),5.21(s,1H,H-20a),4.99(dd,1H,J=4.5,9.0,H-14),4.77(s,1H,H-20b),4.58(dd,1H,J=5.4,12.0,H-10),3.73(s,2H,H-22a,b),3.26(s,3H,10-OCH 3),2.89(d,1H,J=6.0,H-3),2.88(dd,1H,J=9.0,19.2,H-13a),2.41(dd,1H,J=4.8,19.2,H-13b),2.26(dd,1H,J=12.0,15.0,H-9a),2.15(s,3H,COCH 3),2.05(s,1H,H-1),1.96(s,3H,18-H),1.84(s,3H,COCH 3),1.59(s,3H,16-H),1.26(m,3H,H-9b,H-6a,b),1.32(s,3H,17-H),0.86(m,2H,H-7a,b),0.81(s,3H,19-H)。
HR-ESI-MS m/z:614.3088[M+Na]+(calcd for C35H45NO7Na614.3093)。
实施例26.2α,5α-二乙酰氧基-10β-甲氧基-14β-3-吲哚丙酰氧基-4(20),11-紫杉二烯
化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-羟基-4(20),11-紫杉二烯(39mg,0.090mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(170mg,0.89mmol),3-吲哚丙酸(174mg,0.92mmol),DMAP(100mg,0.82mmol)。室温25℃搅拌反应12h,终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,5α-二乙酰氧基-10β-甲氧基-14β-3-吲哚丙酰氧基-4(20),11-紫杉二烯(tR10min,42mg,产率77%)。
1H NMR(CDCl3,300MHz)δppm:8.77(br s,1H,NH-26),7.58(d,1H,J=7.5,H-31),7.35(d,1H,J=8.1,H-28),7.19(t,1H,J=8.1,H-29),7.13(t,1H,J=7.5,H-30),6.98(s,1H,H-25),5.28(m,2H,H-5,H-2),5.25(s,1H,H-20a),5.03(dd,1H,J=4.5,9.3,H-14),4.84(s,1H,H-20b),4.58(dd,1H,J=4.8,12.0,H-10),3.26(s,3H,10-OCH 3),3.08(t,2H,J=7.5,H-23a,b),2.90(d,1H,J=6.0,H-3),2.77(dd,1H,J=9.3,19.2,H-13a),2.68(t,2H,J=7.5,H-22a,b),2.40(dd,1H,J=4.8,19.2,H-13b),2.25(dd,1H,J=12.0,15.0,H-9a),2.17(s,3H,COCH 3),2.06(d,1H,J=3.9,H-1),1.99(s,3H,COCH 3),1.97(s,3H,18-H),1.90-1.60(m,3H,H-9b,H-6a,b),1.58(s,3H,16-H),1.21(m,2H,H-7a,b),1.00(s,3H,17-H),0.82(s,3H,19-H)。
HR-ESI-MS m/z:628.3225[M+Na]+(calcd for C36H47NO7Na628.3250)。
实施例27.2α,14β-二乙酰氧基-10-甲氧基-5α-2-吡啶甲酰氧基-4(20),11-紫杉二烯
(1)化合物2α,14β-二乙酰氧基-10β-甲氧基-5α-羟基-4(20),11-紫杉二烯(29mg,0.067mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(125mg,0.65mmol),2-吡啶甲酸(80mg,0.71mmol),DMAP(76mg,0.62mmol)。室温25℃搅拌反应6h，终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,14β-二乙酰氧基-10-甲氧基-5α-2-吡啶甲酰氧基-4(20),11-紫杉二烯(tR10min,33mg,产率39%)。
1H NMR(CDCl3,300MHz)δppm:8.77(d,1H,J=4.8,H-24),8.20(d,1H,J=7.6,H-27),7.91(t,1H,J=7.8,H-26),7.49(t,1H,J=7.6,H-25),5.44(br s,1H,H-5),5.38(m,2H,H-20a,H-2),5.00(dd,1H,J=4.8,9.3,H-14),4.88(s,1H,H-20b),4.58(dd,1H,J=5.4,12.0,H-10),3.25(s,3H,10-OCH 3),3.01(d,1H,J=6.3,H-3),2.95(dd,1H,J=9.3,19.2,H-13a),2.31(dd,1H,J=4.8,19.2,H-13b),2.24(m,1H,H-9a),2.14(m,1H,H-6a),2.05(s,3H,COCH 3),1.99(s,3H,COCH 3),1.89(d,1H,J=2.1,H-1),1.82(s,3H,18-H),1.70-1.50(m,2H,H-6b,H-9b),1.63(s,3H,16-H),1.24(m,2H,H-7a,b),1.15(s,3H,17-H),0.88(s,3H,19-H)。
13C NMR(CDCl3,100MHz):δppm:170.07(CH3 CO),169.82(CH3 CO),165.35(C21-CO),149.32(C-24),148.79(C-22),142.42(C-4),137.03(C-25),136.09(C-11),135.41(C-12),126.76(C-26),125.47(C-27),117.37(C-20),80.65(C-2),75.76(C-14),70.99(C-10),70.80(C-5),59.33(10-OCH3),55.18(C-1),45.45(C-8),42.69(C-3),39.54(C-13),38.64(C-9),37.16(C-15),34.14(C-17),31.54(C-7),28.71(C-6),25.04(C-18),22.79(C-16),21.53(CH3CO),21.47(CH3CO),20.57(C-19)。
HR-ESI-MS m/z:540.2825[M+H]+(calcd for C31H42NO7540.2961),562.2637[M+Na]+(calcdfor C31H41NO7Na562.2780)。
实施例28.2α,14β-二乙酰氧基-10-甲氧基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯
化合物2α-乙酰氧基-10β-甲氧基-13-羰基-5α-羟基-4(20),11-紫杉二烯(25mg,0.058mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(110mg,0.57mmol),3-吡啶甲酸(82mg,0.71mmol),DMAP(87mg,0.71mmol)。室温25℃搅拌反应6h，终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,14β-二乙酰氧基-10-甲氧基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯(tR10min,30mg,产率96%)。
1H NMR(CDCl3,300MHz)δppm:9.26(s,1H,H-23),8.82(d,1H,J=4.8,H-25),8.40(d,1H,J=7.8,H-27),7.50(dd,1H,J=4.8,7.8,H-26),5.40(br s,2H,H-20a,H-2),5.33(s,1H,H-5),5.00(dd,1H,J=5.4,9.3,H-14),4.87(s,1H,H-20b),4.54(dd,1H,J=5.4,12.0,H-10),3.24(s,3H,10-OCH 3),2.91(d,1H,J=6.6,H-3),2.55(dd,1H,J=9.3,19.2,H-13a),2.30(m,2H,H-13b,H-9a),2.12(m,1H,H-6a),2.05(s,3H,COCH 3),2.02(s,3H,COCH 3),1.92(m,1H,H-1),1.70(s,3H,18-H),1.60(m,2H,H-6b,H-9b),1.63(s,3H,16-H),1.27(m,2H,H-7a,b),1.15(s,3H,17-H),0.88(s,3H,19-H)。
13C NMR(CDCl3,100MHz):δppm:170.18(CH3 CO),170.02(CH3 CO),165.41(C21-CO),150.38(C-22),150.29(C-23),141.87(C-4),137.26(C-11),134.04(C-12),135.52(C-24),134.40(C-25),129.57(C-26),117.85(C-20),81.67(C-2),75.64(C-14),70.75(C-10),70.69(C-5),59.30(10-OCH3),55.25(C-1),45.49(C-8),42.96(C-3),39.51(C-13),39.48(C-9),37.38(C-15),34.21(C-17),31.19(C-7),28.52(C-6),25.13(C-18),22.80(C-16),21.49(CH3CO),21.34(CH3CO),20.84(C-19)。
HR-ESI-MS m/z:540.2827[M+H]+(calcd for C31H42NO7540.2961),562.2626[M+Na]+(calcd forC31H41NO7Na562.2780)。
实施例29.2α,14β-二乙酰氧基-10-甲氧基-5α-4-吡啶甲酰氧基-4(20),11-紫杉二烯
化合物2α,14β-二乙酰氧基-10β-甲氧基-5α-羟基-4(20),11-紫杉二烯(25mg,0.058mmol)溶于10ml干燥的二氯甲烷中，依次加入EDCI(100mg,0.52mmol),4-吡啶甲酸(60mg,0.50mmol),DMAP(61mg,0.50mmol)。室温25℃搅拌反应5h，终止反应，后处理过程同实施例1，流动相正己烷–乙酸乙酯=4:1(v/v),流速：4ml/min,得化合物2α,14β-二乙酰氧基-10-甲氧基-5α-4-吡啶甲酰氧基-4(20),11-紫杉二烯(tR11min,31mg,产率99%)。
1H NMR(CDCl3,300MHz)δppm:8.85(d,2H,J=5.4,H-24,26),7.92(d,2H,J=5.4,H-23,27),5.40(m,2H,H-20a,H-2),5.31(s,1H,H-5),5.01(dd,1H,J=5.4,9.3,H-14),4.87(s,1H,H-20b),4.53(dd,1H,J=5.7,12.0,H-10),3.23(s,3H,10-OCH 3),2.89(d,1H,J=6.6,H-3),2.55(dd,1H,J=9.3,19.2,H-13a),2.33(dd,1H,J=12.0,15.0,H-9a),2.30(m,1H,H-13b),2.05(s,3H,COCH 3),2.04(s,3H,COCH 3),1.92(m,1H,H-6a),1.91(br s,1H,H-1),1.70(m,2H,H-9b,H-6b),1.64(s,6H,18-H,16-H),1.26(m,2H,H-7a,b),1.15(s,3H,17-H),0.88(s,3H,19-H)。
13C NMR(CDCl3,100MHz):δppm:170.01(CH3 CO),169.88(CH3 CO),165.41(C21-CO),150.38(C-24,C-26),141.87(C-4),137.26(C-11),134.04(C-12),123.23(C-23,C-27),117.85(C-20),81.67(C-2),75.64(C-14),70.75(C-10),70.69(C-5),59.30(10-OCH3),55.25(C-1),45.49(C-8),42.96(C-3),39.51(C-13),39.48(C-9),37.38(C-15),34.21(C-17),31.19(C-7),28.52(C-6),25.13(C-18),22.82(C-16),21.49(CH3CO),21.34(CH3CO),20.91(C-19)。
HR-ESI-MS m/z:540.2850[M+H]+(calcd for C31H42NO7540.2961),562.2635[M+Na]+(calcd forC31H41NO7Na562.2780)。
药理实验：
为了进一步理解本发明，下面的药理实验仅仅用来进一步说明本发明，但并不意味着对本发明的任何限制。
实施例30.紫杉烷类化合物对耐药细胞株抗肿瘤药物的体外逆转活性评价
实验材料和方法：
1、耐药肿瘤细胞株：
选用三种不同的肿瘤获得性耐药细胞株作为体外肿瘤细胞模型，人肺腺癌A549/Taxol为紫杉醇获得性耐药细胞株，中国医学科学院药物研究所药理室建立；乳腺癌MCF-7/DOX为多柔比星获得性耐药的乳腺癌细胞株和MX-1/Taxol为紫杉醇获得性耐药的乳腺癌细胞株，中国医学科学院药物研究所药理室建立。
2、体外耐药筛选步骤：
在体外筛选实验中，首先选用紫杉醇获得性耐药的人肺腺癌细胞株A549/Taxol作为获得性多药耐药的体外肿瘤细胞模型，将待检测的肿瘤细胞以一定的细胞浓度接种于96孔板中，37℃，5%CO2培养24h后，依次加入4个浓度的紫杉醇（10-6,10-7,10-8,10-9mol/l）和10μmol/l的紫杉烷逆转剂后，继续培养72h。然后用MTT法测定肿瘤细胞存活率，获得单独用药和联合用药时紫杉醇的IC50，以了解紫杉醇与多药耐药逆转化合物联合用药后其对敏感肿瘤细胞的抑制作用。通过检测此耐药细胞株在单独应用不同浓度的紫杉醇(10-6,10-7,10-8,10-9mol/l)和联合使用紫杉醇与逆转剂后，其对紫杉醇抑制细胞生长的影响，并通过公式分别计算各化合物的逆转倍数(reversal fold,RF)。筛选时采用维拉帕米作为阳性对照药，所有逆转剂和维拉帕米的浓度均为10μmol/l。
3、MTT法测定肿瘤细胞存活率
将对数生长期的人肺腺癌A549/Taxol、人乳腺癌MCF-7/DOX和MX-1/Taxol各耐药细胞株，用0.25%胰酶/EDTA消化后，配制成1×104细胞/毫升的单细胞悬液，根据细胞生长速度的差异，按800-2000个/孔接种于96孔板，每孔加入细胞悬液100μl。24h后，加入含不同浓度药物及相应溶剂对照的新鲜培养基，每孔加100μl（DMSO终浓度<0.1%），每种受试化合物设5～7个剂量组，每组至少设三个平行孔，于37℃继续培养72h后，弃上清，每孔加入100μl新鲜配制的含0.5mg/mL MTT的无血清培养基，继续培养4h，弃上清后，每孔加入150μl DMSO溶解MTT甲簪沉淀，随后每孔加入25μl Sorensen氏缓冲液，微型振荡器振荡混匀后，酶标仪在参考波长450nm，检测波长570nm条件下测定光密度值(OD)，以溶剂对照处理的肿瘤细胞为对照组，用以下公式计算药物对肿瘤细胞的抑制率，并按中效方程计算IC50。
逆转倍数(RF)=单用抗肿瘤药物时IC50/合用逆转剂时IC50。
具体结果见表1，表2
表1紫杉烷化合物联合Taxol对肺腺癌耐药细胞株A549/Taxol耐Taxol的逆转作用a
a紫杉醇浓度为10-6,10-7,10-8,10-9mol/l，实施例化合物和维拉帕米的浓度均为10μmol/l
表2紫杉烷化合物联合Taxol对乳腺癌耐药细胞株MCF-7/DOX和MX-1/Taxol耐Taxol的逆转作用a
a紫杉醇浓度为10-6,10-7,10-8,10-9mol/l，实施例化合物和维拉帕米的浓度均为10μmol/l
表1结果显示，实施例1-26化合物中除实施例21以外，联合紫杉醇对人肺腺癌耐紫杉醇的细胞株A549/Taxol均具有一定的体外耐药逆转作用，其中实施例4,7,8,10,11,18化合物显示出比阳性对照药维拉帕米更强的逆转作用。其余化合物逆转作用与维拉帕米相当或接近。表2结果显示，实施例28化合物联合紫杉醇对多柔比星获得性耐药的乳腺癌细胞株MCF-7/DOX和紫杉醇获得性耐药的乳腺癌细胞株MX-1/Taxol两种乳腺癌细胞株均具有较强的体外耐药逆转作用，实施例27仅对MX-1/Taxol表现出较强的逆转作用，实施29仅对MCF-7/DOX表现出一定的逆转作用。
实施例31.新杉素衍生物对耐紫杉醇的人乳腺癌MX-1/T裸鼠异体移植性肿瘤的耐药逆转作用
1、受试药物：
名称：实施例20化合物，紫杉醇(Taxol)，均为白色粉末
配制方法：Taxol采用北京协和药厂提供的注射用溶液配制成所需浓度，实施例20化合物以0.5%CMC配成所需浓度的混悬液。
2、实验动物
动物来源：中国医学科学院实验动物研究所动物繁育场
种属：BALB/c(nu/nu)裸小鼠
合格证号：京动许017号
体重：14-17g
性别：♀
各组动物数：对照组8只，实验组每组4-5只
饲养环境：SPF级
3、实验步骤：
动物经1周适应后，无菌条件下将裸鼠耐药肿瘤（MX-1耐Taxol）剥离取出，用玻璃匀浆器研磨后采用生理盐水配制为一定浓度的混悬液接种于裸鼠腋窝皮下，由于逆转剂需在给予Taxol时给予，因此将在接种24小时后动物按体重随机分组，设置单用Taxol组和实施例20化合物100mg/kg、200mg/kg和400mg/kg剂量组，并同时给予Taxol。待肿瘤体积至100-200mm3时，Taxol组和实施例20化合物组各组均腹腔给予Taxol，30mg/kg/次，每3天腹腔注射给药一次，共给药2次，实施例20化合物为口服给药；每日称量体重并用游标卡尺测量肿瘤的长度（a）和宽度（b），按照公式V=a×b2/2计算出肿瘤的体积。于接种后第13天，将裸鼠脱臼处死并拍照，然后剥离肿瘤，称重并拍照。最后计算相对瘤体积RTV和肿瘤增殖速率T/C%。
4、结果：
MX-1耐Taxol体内模型具有很强的耐药作用，单独给予2次30mg/kg的Taxol后对耐Taxol的人乳腺癌肿瘤的生长无抑制作用，对动物的体重也无影响。实施例20化合物具有良好的逆转MX-1耐Taxol体内耐药模型的耐药活性。在100mg/kg、200mg/kg和400mg/kg剂量组与Taxol同时应用时，均显示了较强的逆转Taxol的耐药作用，以200mg/kg为最强。即恢复了Taxol对人乳腺癌MX-1/T裸鼠异体移植瘤的生长抑制作用。
表3和表4结果显示，单用Taxol对耐Taxol的人乳腺癌MX-1/T裸鼠异体移植性肿瘤的生长无明显的抑制作用。实施例20化合物在100mg/kg、200mg/kg和400mg/kg剂量组与Taxol同时应用时，可显著逆转Taxol的耐药，即恢复Taxol对人乳腺癌MX-1/T裸鼠异体移植瘤的生长抑制作用。

Claims (12)

1.一种如通式（I）化合物：
其中，
R1选自氢；卤素；羟基；氨基；硝基；芳香基C1-8烷基酰氧基；杂环基C1-8烷基酰氧基；上述取代的芳香基是指含有1-3个取代基的芳香环，上述取代的杂环基是指含有1-3个取代基的杂环，这些杂环可以为含有N、O、S等杂原子取代的五元或六元饱和或不饱和杂环如吡啶、呋喃、噻吩等，上述C1-8的烷基是指1-8个碳的直链或支链的烷基，这些烷基取代基可以为氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、新戊基、己基、庚基、辛基等；在C1-8烷基上可以有1个或2个相同或不同的取代基，取代基还可以是卤素、羟基、硝基、氨基、甲氧基、甲酰基等；条件是取代基不在同一位置上；
R2的定义和R1相同；
R3的定义和R1相同；
R4R5为氢，或R4R5为=O。
但是不包括：
2 -->
2.根据权利要求1所述的化合物，其特征在于该化合物包括以下通式（Ia）所示的化合物：
其中：
R1、R2如权利要求1所定义；
R3为氢；
但是不包括：
3.根据权利要求1所述的化合物，其特征在于该化合物包括以下通式（Ib）所示的化合物：
其中：
R1、R2、R3如权利要求1所定义；
但是不包括：
4 -->
4.根据权利要求1所述的化合物，其特征在于该化合物选自：
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙烯酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-L-脯氨酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-苯丙酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-2-呋喃甲酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-4-苯丁酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯
2α-乙酰氧基-10β-甲氧基-13-羰基-5α-环己烷乙酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙烯酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-苯丙酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-呋喃丙烯酰氧基-4(20),11-紫杉二烯
6 -->
2α,5α-二乙酰氧基-10β-甲氧基-13-羰基-9α-2-吡啶甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-苯甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-4-甲氧基苯甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘乙酰氧基-4(20),11-紫杉二烯
7 -->
2α,5α-二乙酰氧基-10β-甲氧基-14β-3-氯苯甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-1-萘氧乙酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-3,4,5-三甲氧基苯甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-2-萘氧乙酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-3,5-二甲氧基苯甲酰氧基-4(20),11-紫杉二烯
8 -->
2α,5α-二乙酰氧基-10β-甲氧基-14β-2-呋喃甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-4-苯基丁酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-2,5-二甲氧基苯乙酰氧基-4(20),11-紫杉二烯
2α,5α-二乙酰氧基-10β-甲氧基-14β-2-吲哚甲酰氧基-4(20),11-紫杉二烯
9 -->
2α,5α-二乙酰氧基-10β-甲氧基-14β-3-吲哚丙酰氧基-4(20),11-紫杉二烯
2α,14β-二乙酰氧基-10-甲氧基-5α-2-吡啶甲酰氧基-4(20),11-紫杉二烯
2α,14β-二乙酰氧基-10-甲氧基-5α-3-吡啶甲酰氧基-4(20),11-紫杉二烯
2α,14β-二乙酰氧基-10-甲氧基-5α-4-吡啶甲酰氧基-4(20),11-紫杉二烯
5.权利要求1的紫杉烷衍生物，其药学上可接受的盐是通式（I）化合物与下列酸形成的盐：盐酸、硫酸、磷酸、氢溴酸、乙酸、三氟乙酸、柠檬酸、酒石酸、乳酸、丙酮酸、马来酸、苯磺酸、琥珀酸、戊二酸、富马酸。
6.制备如权利要求1─5的任一所述的化合物，其特征在于：以新杉素A(2α,5α,10β,14β-四乙酰氧基-4(20),11-紫杉二烯)为底物，采用生物转化或化学合成的方法，得到C-5、C-9或C-14位为羟基（或2个位置上同时为羟基）的化合物；采用化学方法，合成得到C-13位为羰基的化合物；进一步在有机溶剂中与相应的羧酸或酰氯缩合反应，制备相应的化合物。
7.一种药物组合物，其特征在于：含有治疗有效剂量的如权利要求1─5所述的任一化合物或其药学上可接受的盐，以及药学上可接受的载体。
8.根据权利要求1─5中任一所述的化合物作为肿瘤多药耐药逆转剂的应用。
9.根据权利要求8的应用，其特征在于：所述化合物与抗肿瘤药物联用。
10.根据权利要求9的应用，其特征在于：所述的抗肿瘤药物包括为P-gp(P-糖蛋白)底物的抗肿瘤药物。
11.根据权利要求10的应用，其特征在于：所述的P-gp底物的抗肿瘤药物包括紫杉烷类、长春碱类、蒽环类，以及米托蒽醌、放线菌素D、丝裂霉素C。
12.根据权利要求8的应用，其特征在于：所述的肿瘤包括具有P-gp过度表达的内在多药耐药性以及获得性多药耐药性实体肿瘤和血液系统肿瘤。
CN201310488098.5A 2013-10-17 2013-10-17 C-10甲氧基紫杉烷类衍生物及其肿瘤多药耐药逆转剂的用途 Pending CN104557544A (zh)

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Application publication date: 20150429