CN108117580A - 菝葜皂苷元衍生物及其制备方法和用途 - Google Patents
菝葜皂苷元衍生物及其制备方法和用途 Download PDFInfo
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- CN108117580A CN108117580A CN201611077848.XA CN201611077848A CN108117580A CN 108117580 A CN108117580 A CN 108117580A CN 201611077848 A CN201611077848 A CN 201611077848A CN 108117580 A CN108117580 A CN 108117580A
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- furostane
- oxo
- benzyloxy
- methoxycarbonyl
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Abstract
本发明属于药物化学技术领域，具体涉及菝葜皂苷元衍生物及其制备方法和用途。该类化合物具有式Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅵ和Ⅶ所示结构，通过分子水平实验、细胞水平实验以及APP转基因小鼠定位航行和空间探索实验证明该类化合物可以提高模型小鼠的空间学习记忆能力，具有良好的治疗神经系统退行性疾病的效果。
Description
技术领域
本发明属于药物化学技术领域，具体涉及菝葜皂苷元衍生物,以其为活性成分的药物组合物，它们的制备方法及其在治疗神经退行性疾病中的应用。
背景技术
神经退行性疾病是由神经元或其髓鞘的丧失所致，随着年龄老化而恶化，最终导致功能障碍，如阿尔茨海默病(AD)、帕金森氏病(PD)、肌肉萎缩性侧索硬化症(ALS)和亨廷顿舞蹈症(HD)等。神经退行性疾病主要影响患者的认知和运动功能，致残、致死率极高，给患者家庭和社会带来极大的心理和经济负担.然而，由于病因不明确、发病机制复杂，目前的一些治疗药物和手段,仅能暂时改善症状,尚缺乏长期有效的、特别是能够阻断甚至逆转病程的治疗方法。
阿尔茨海默病(俗称老年痴呆，Alzheimer’s disease)是一种进行性发展的致死性神经退行性疾病，临床表现为认知和记忆功能不断恶化，日常生活能力进行性减退，并有各种神经精神症状和行为障碍，导致患者不能独立生活。随着社会人口老龄化，阿尔茨海默病发病率有逐年增加的趋势。目前我国超过60岁的老人约有1.29亿，占总人口的10.15％，从而使我国提前进入老龄化社会。据不完全统计到2025年，世界范围内人老年性痴呆的患病人口将达到220万。在我国，老年痴呆症多发生于65岁以上老人，约占4％～5％，75岁以上的约占10％，85岁以上约占20％，提示老年人年龄每增加10岁，痴呆的患病率增加1倍。因此，研究和开发治疗阿尔茨海默病的药物有重要的临床和社会意义。
帕金森病(Parkinsong disease PD)是第二大中枢神经退行性疾病，常见于老年人。其最主要的临床表现是静止性震颤、肌强直、运动迟缓和姿势不稳等运动症状。PD的病因和发病机制尚不完全清楚，目前认为PD可能是遗传、环境、老龄化等因素共同作用的结果，具体机制涉及线粒体功能障碍、氧化应激、神经炎症、兴奋性毒性损伤等。由于病因不清、发病机制复杂导致PD的治疗依旧是一个亟待解决的问题。现国内外应用较多的PD药物主要分为以下几类：(1)左旋多巴-外周多巴胺脱羧酶抑制剂；(2)多巴胺激动剂；(3)单胺氧化酶B抑制剂(MAOBIs)；(4)儿茶酚一氧位一甲基转移酶抑制剂(COMTIs)；(5)抗胆碱能药物；(6)金刚烷胺等。
然而，由于阿尔茨海默病的发病机制复杂，到目前为止，阿尔茨海默病的发病病因和机制尚未完全阐明，至今没有较好的根治或逆转病程的药物，研究表明，对于阿尔茨海默病的病因主要有以下几种学说：其一、胆碱能学说：研究认为胆碱能神经元功能的下降，导致乙酰胆碱(ACh)合成、储存和释放减少，进而引起学习、记忆和识别功能障碍。其二、β-淀粉样蛋白(β-amyloid protein,Aβ)学说：该学说的核心是Aβ在脑内聚集，会形成老年斑，从而进一步引起一系列病理症状的产生。其三、阿尔茨海默病的发生与衰老引起的生理、生化改变有密切的关系。钙平衡失调、自由基增多等都可导致神经元的损害。研究较多的是胆碱能学说和β-淀粉样蛋白学说，对阿尔茨海默病已有的治疗药物主要为乙酰胆碱酯酶抑制剂如他克林，加兰他敏，多奈哌齐，石杉碱甲等，这些药物在一定程度上缓解了阿尔茨海默病的发病进程，并不能根治该病，同时这些药物也伴随着严重的肝毒性和胃肠反应等副作用，这些都严重影响了药效的发挥。因此，寻找针对AD病因的新的有效治疗药物和方法，成为当今研究的热点。
目前以β-淀粉样蛋白(β-amyloid protein,Aβ)学说为发病机制引起了科研工作者极大的关注，该学说的核心是Aβ在脑内聚集，会形成老年斑，从而进一步引起一系列病理症状的产生，Aβ是形成老年痴呆症的主要原因。因此减少Aβ的产生对改善AD的认知和记忆障碍有理论依据，寻找能够防止脑内Aβ过度沉积，促进Aβ的降解，保护神经元细胞，促进神经元细胞再生的化合物，将是今后对阿尔茨海默病研究的重要方向。
本发明的菝葜皂苷元衍生物前体为菝葜皂苷元(结构式如下)，其是中药知母中总皂苷水解后脱去结合糖基的产物。药效实验证明菝葜皂苷元衍生物是一种新型的治疗神经系统退行性病变药物，它不仅能够抑制胆碱酯酶，同时还能抑制β-淀粉样蛋白的过度聚集，防止老年斑的形成，并且对神经元细胞具有保护作用，改善APP转基因小鼠的学习记忆能力。因而，对阿尔茨海默病及帕金森病具有很好的治疗作用。迄今为止，还没有关于它及其衍生物治疗神经系统退行性病变的报道。本发明首次公开其治疗阿尔茨海默病及帕金森病等神经系统退行性病变以及它的制备方法和用途。
菝葜皂苷元结构式
发明内容
本发明第一个目的在于公开了具有如下结构式的菝葜皂苷元衍生物及其药学上可接受的盐，由于菝葜皂苷元极性小，水溶性不好，成药性差，对皂苷元结构修饰引入含氮基团，解决药物水溶性的问题，增加其生物利用度，可以达到更好的治疗效果。
本发明对菝葜皂苷元进行了一系列的结构改造工作。用于神经系统退行性病变药物的制造,如用于治疗帕金森病(Parkinson’s disease,PD)、阿尔茨海默病(Alzheimer’sdisease,AD)、亨廷顿病(Huntington disease，HD)、肌萎缩侧索硬化症(amyotrophiclateral sclerosis.ALS)等。本发明是通过如下技术方案实现的：
菝葜皂苷元衍生物结构通式如下：
其中，
R1为H、取代或未取代的苄基，所述取代基为卤素、C1-C4烷基、C1-C4烷氧基；
优选地，R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基；R2为OH、卤素、-NH2、-NR’R″、取代或未取代的5-12元含氮杂环或含氮芳杂环(其中氮原子位置为1位、1,3位、1,4位，所述取代基为卤素、C1-C4烷基、C1-C4烷氧基)、含氮生物碱及其盐、R取代的氨基酸酯及其相应的氨基酸，所述的R为H、C1-C4烷基(其中烷基链中氢原子可以由苯基、甲硫基、甲氧甲酰基所取代)，R’、R”为CnH2n+1，n＝1、2、3、4；优选地，R2为OH、卤素、-NH2、-NR’R”、 含氮生物碱及其盐、及其相应的氨基酸；
R为H、-CH3、 R’、R”为CnH2n+1，n＝1、2、3、4；
R3为C1-C4烷基；
R4为C1-C4烷基、取代或未取代的苄基，所述取代基为：卤素、C1-C4烷基、C1-C4烷氧基。进一步地，
式Ⅰ中，当3位为α或β构型时，R1为苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R2为OH、Cl、-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅱ中，R2为OH、Cl、-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅲ中，R2为OH、Cl、-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅳ中，当3位为α或β构型时，R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R2为OH、Cl、-NH2、-NR’R”、 含氮生物碱及其盐和(R为H、-CH3、 )和及其相应的氨基酸。
式Ⅴ中，当3位为α或β构型时，R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R3为甲基、乙基；
式Ⅵ中，R2为OH、Cl、-NH2、-NR’R”、 含氮生物碱及其盐和(R为H、-CH3、 )和及其相应的氨基酸；
式Ⅶ中，当3位为α或β构型时，R1为苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R4为甲基、乙基、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基。
注：R’、R”为CnH2n+1，n＝1、2、3、4。
菝葜皂苷元衍生物的合成包括以下步骤：
A.a的制备：在三颈瓶中加入菝葜皂苷元、NaH，DMF室温搅拌状态下加入溴化苄或氯化苄，搅拌至反应完全，放冷，然后加入蒸馏水，抽滤，重结晶得白色固体a。
B.b的合成：将a加入反应器中，加入DCM，冰醋酸，搅拌下分次加入NaBH3CN，室温搅拌至反应完全。用饱和NaCl水溶液萃取，向二氯甲烷层中缓慢滴加饱和碳酸钠溶液中和至pH＞9，搅拌10min，分出有机层，用水洗涤，加入无水硫酸钠干燥，过滤浓缩得白色固体，用正庚烷进行重结晶，得白色固体b。
C.c的制备：在三颈瓶中加入NCS或NBS，偶氮二异丁腈，干燥氯仿，氮气或氩气保护下滴Ph3P，室温搅拌，然后滴加b，室温下搅拌至反应完毕。减压蒸出有机溶剂得粗样，经硅胶柱色谱纯化得白色固体c。
D.Ⅰ的合成：将c加入到反应器中，加入DMA或乙腈，反应试剂，NaI，置换氮气，升温至90-92℃反应至原料点基本消失。搅拌下冷却至室温,缓慢加入约无水甲醇，继续冷却至-5℃，抽滤，甲醇淋洗，得白色固体，用水打浆1h，过滤淋洗，干燥得白色固体Ⅰ。
E.d的合成：在三颈瓶中加入c，Pt/C，无水乙醇、二氯甲烷或者二者的混合溶剂，氢气下回流搅拌至反应完全。放冷，过滤浓缩得白色固体d。
F.e的合成：在三颈瓶中加入d，PDC，少量活化的分子筛，DMF、DMA、DCM、DMSO等有机溶剂，氮气保护下，室温搅拌至反应完全，放冷，加入蒸馏水，氯仿萃取，干燥，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体f。
G.f的合成：在三颈瓶中加入d，DMF、DMA、DCM、DMSO等有机溶剂，50-80℃下一次性加入IBX，搅拌下反应至完全，放冷，加入等体积水，乙醚萃取，干燥，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体e。
H.g的合成：在三颈瓶中加入b，DCM、丙酮、THF等做溶剂，室温搅拌下滴加Jones试剂至无原料剩余，将反应液减压蒸干，经硅胶柱色谱纯化得白色固体g。
I.h的合成：将g溶解于干燥的CH2Cl2中，加入CDI，搅拌反应2-4h后将溶剂蒸干，加入已制备的酰肼，于DMF溶液中室温搅拌过夜。反应结束后，向反应液中加入等体积水，分出有机层，干燥过滤得白色固体，经硅胶柱色谱纯化得白色固体h。
J.Ⅳ的合成：在三颈瓶中加入g，DCM，草酰氯，1滴DMF，室温搅拌至反应完全，将反应液蒸干，直接投下一步反应。于反应瓶中加入干燥DCM，Na2CO3冷却至0℃，缓慢滴加反应试剂，滴加完毕。逐渐升温至室温，搅拌反应至原料点基本消失停止反应。将反应液减压浓缩，经硅胶柱色谱纯化得白色固体Ⅳ。
K.Ⅴ的合成：在三颈瓶中加入h、POCl3，回流反应2h，反应完毕后，降至室温，将反应液缓慢倒入冰水中，加入饱和碳酸氢钠，析出白色固体，过滤，干燥，经硅胶柱色谱纯化得白色固体Ⅴ。
L.i的合成：在三颈瓶中加入Ⅳ，Pt/C，无水乙醇、二氯甲烷或者二者的混合溶剂，氢气下回流搅拌至反应完全。放冷，过滤浓缩得白色固体i。
M.Ⅵ的合成：在三颈瓶中加入i，Jones试剂，THF，室温搅拌至反应完全，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体Ⅵ。
N.J的合成：将中间体g溶于二氯甲烷中，加入炔丙胺，搅拌5min，再加入TBTU和二异丙基乙胺，室温搅拌至反应完全。依次用水、饱和食盐水萃取，分出有机层，干燥，过滤，浓缩得淡黄色固体，经硅胶柱色谱纯化得白色固体J。
O.Ⅶ的合成：将中间体J和含有不同取代基的叠氮化合物溶于二氯甲烷和水(等体积)混合溶液中，加入五水硫酸铜和维生素C钠，室温搅拌至反应完全。依次用水、饱和食盐水萃取，分出有机层，干燥，过滤，浓缩得固体，经硅胶柱色谱纯化得目标产物Ⅶ。
本发明所述的菝葜皂苷元衍生物的药理特性良好。它不仅能够抑制胆碱酯酶，同时对β淀粉样蛋白的形成具有强效抑制作用，减少APP沉淀，还对模型动物表现出高效低毒的行为学特性，这是菝葜皂苷元以及目前其它市售药物所不具备的。
为了实现上述目的，本发明提供了一种用于治疗或预防神经系统退行性病变的药物组合物，它是其药效学上可接受的盐、盐的水合物、溶剂化物或前体药物与药学上可接受的载体制备而成的制剂，其中，所述的制剂是片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂以及各种微粒给药系统。
本发明具有操作简便，原料易得(制备方法见本课题组已授权专利CN101768202B)，易于实现工业化的特点。
综上所述，本发明具有以下优点：本发明反应过程基本上十分稳定，各步反应步骤的独立性较好，可有多条路线供选择，而且操作简便利于工业化。改造后的菝葜皂苷元衍生物药理特性良好。
附图说明
图1为总蛋白含量测定的标准曲线；
图2为实施例128的实验目标蛋白；
图3为分子对接实验结果。
具体实施方式
下面将通过实施例对本发明作进一步的描述，这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解，对本发明的技术特征所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。本发明的典型化合物包括如下化合物或它们药学上可接受的盐，但不限于这些：
实施例1：(22R,25S)-3β-苄氧基-26-哌啶基-5β-呋甾烷(ZA-3-6)的合成
A.a的合成：250mL茄形瓶中加入菝葜皂苷元(4.16g，0.01mol)，NaH(0.48g，0.02mol)，40mL DMF室温搅拌状态下加入溴化苄(3.42g，0.02mol)，40℃搅拌反应至反应完全。反应完全后放冷，然后加约10倍量的水，搅拌，抽滤，得固体，乙醇重结晶得白色固体ZA-1(3.8g，产率为75％)。1H NMR(300MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.28(m,1H,H-4'),4.51(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.40(m,1H,H-16),3.96(dd,J＝2.6,11.0Hz,1H,H-26),3.71(br.s,1H,H-3),3.30(d,J＝11.0Hz,1H,H-26),1.08(d,J＝7.1Hz,3H,27-CH3),0.99(d,J＝6.8Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.76(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.6,128.4,128.4,127.4,127.4,127.3,109.8,81.2,74.0,69.6,65.3,62.2,56.6,42.2,40.8,40.5,40.2,37.1,35.5,35.3,31.9,30.9,30.6,27.2,26.9,26.7,26.1,25.9,24.8,24.0,21.0,16.6,16.2,14.5.ESI-HRMS:m/z 507.3823[M+H]+(Calcd for C34H51O3,507.3833).
B.b的合成：将a(3.04g，6mmol)加入反应器中，加入25mL DCM，12mL冰醋酸，搅拌下分次加入NaBH3CN(0.76g，12mmol)，约1h加完，室温搅拌至反应完全。用25mL饱和NaCl水溶液萃取，向二氯甲烷层中缓慢滴加碳酸钠溶液中和至pH＞9，搅拌10min，分出有机层，再用水洗涤，加入无水硫酸钠干燥，过滤浓缩得白色固体，用20mL正庚烷进行重结晶，得白色固体ZA-2(2.70g，88.5％)。1H NMR(300MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.51(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.29(td,J＝5.2,7.8Hz,1H,H-16),3.70(br.s,1H,H-3),3.51(dd,J＝5.5,10.6Hz,1H,26-H),3.45(dd,J＝6.1,10.6Hz,1H,26-H),3.31(m,1H,H-22),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.93(d,J＝6.6Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.7,128.5,128.5,127.5,127.5,127.4,90.7,83.5,74.0,69.7,68.2,65.6,57.2,41.3,40.3,40.2,38.1,37.2,36.2,35.7,35.3,32.4,31.0,30.9,30.7,30.3,26.9,26.7,24.9,24.1,20.9,19.2,17.0,16.8.ESI-HRMS:m/z 509.3979[M+H]+(Calcd forC34H53O3,509.3989).
C.c的合成：50mL茄型瓶中加入NCS(0.6g，4.5mmol)，0.05g偶氮二异丁腈，5mL干燥CH2Cl2，氮气保护下滴加5mL干燥CH2Cl2溶解的Ph3P(1.18g，4.5mmol)，滴加完毕室温搅拌0.5h，然后滴加10mL干燥CH2Cl2溶解的b(1.5g，3mmol)，室温下搅拌反应6h至反应完毕。反应完毕后减压蒸出二氯甲烷得粗样，样品硅胶拌样上硅胶柱，石油醚：乙酸乙酯(80:1)冲产品得白色固体ZA-3(1.51g，产率约87.7％)。1H NMR(400MHz,CDCl3,δ):7.35(dd,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,J＝12.2Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.29(td,J＝5.2,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.51(dd,J＝4.9,10.6Hz,1H,26-H),3.39(dd,J＝6.6,10.6Hz,1H,26-H),3.30(m,1H,H-22),1.02(d,J＝6.6Hz,3H,21-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.97(s,3H,19-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.7,128.5,128.5,127.5,127.5,127.4,90.3,83.5,74.0,69.7,65.7,57.2,51.3,41.4,40.4,40.2,38.1,37.2,35.9,35.7,35.3,32.4,31.3,31.0,30.7,26.9,26.7,24.9,24.1,21.0,19.3,17.9,16.8.ESI-HRMS:m/z 549.3457[M+Na]+(Calcd for C34H51ClNaO2,549.3470).
D.Ⅰ的合成：将c(0.53g,1mmol)加入到反应器中，NaI(0.23g,1.5mmol)，加入8mLDMA或乙腈，六氢吡啶(0.26g,3mmol)，置换氮气，升温至90-92℃反应至原料点基本消失。搅拌下冷却至室温，缓慢加入约8mL无水甲醇，继续冷却至-5℃，抽滤，甲醇淋洗，得白色固体，用水打浆1h，过滤淋洗，干燥得白色粉末ZA-3-6(0.37g,63.5％)。1H-NMR(300MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.27(m,1H,H-4′),4.48(d,2H,J＝1.65Hz,O-CH2),4.28(1H,m,H-16),3.70(br.s,1H,H-3),3.29(m,1H,H-22),2.30(d,4H,J＝14.19Hz,N-CH2),0.99(d,3H,J＝6.75Hz,21-CH3),0.97(s,3H,19-CH3),0.90(d,3H,J＝6.42Hz,27-CH3),0.78(s,3H,18-CH3).HR-ESI-MS:m/z576.4779[M+H]+(Calcd for C39H62NO2,576.4776).
实施例2：(22R,25S)-3β-苄氧基-26-二乙氨基-5β-呋甾烷(ZA-3-2)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为二乙胺，得油状物ZA-3-2(0.34g，60.6％)。1H NMR(300MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,J＝12.3Hz,1H,Ar-CH2),4.45(d,J＝12.3Hz,1H,Ar-CH2),4.28(td,J＝7.7&5.0Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.46(m,4H,N-CH2),1.00(s,3H,19-CH3),0.97(m,9H,3×CH3),0.90(d,J＝6.3Hz,3H,27-CH3),0.79(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,65.6,60.2,57.0,47.6,47.6,41.1,40.2,40.0,37.9,37.1,35.5,35.1,32.3,31.8,31.0,30.8,30.5,26.7,26.5,24.7,23.9,20.8,19.2,18.5,16.6,11.7,11.7.ESI-HRMS:m/z 564.4765[M+H]+(Calcd for C38H62NO2,564.4775).
实施例3：(22R,25S)-3β-苄氧基-26-二正丙氨基-5β-呋甾烷(ZA-3-3)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为二正丙胺，得油状物ZA-3-3(0.43g，73.2％)。1H NMR(400MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,J＝12.2Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.29(td,J＝5.1,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.32(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.90(d,J＝6.4Hz,3H,27-CH3),0.86(t,J＝7.3Hz,6H,2×CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.2,73.8,69.5,65.6,61.6,57.0,56.8,56.8,41.1,40.2,40.0,37.8,37.0,35.5,35.1,32.2,32.1,31.8,30.9,30.8,30.5,26.7,26.5,24.7,23.9,20.8,20.1,20.1,19.2,18.4,16.6,12.0,12.0.ESI-HRMS:m/z 592.5095[M+H]+(Calcd for C40H66NO2,592.5088).
实施例4：(22R,25S)-3β-苄氧基-26-二正丁氨基-5β-呋甾烷(ZA-3-4)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为二丁丙胺，得油状物ZA-3-4(0.47g，75.8％)。1H NMR(400MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,J＝12.2Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.29(td,J＝5.1,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.27(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.90(m,9H,3×CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.2,73.8,69.5,65.6,61.6,57.0,54.5,54.5,41.1,40.2,40.0,37.8,37.0,35.5,35.1,32.2,32.1,31.8,30.9,30.8,30.5,29.3,29.3,26.7,26.5,24.7,23.9,20.8,20.7,20.7,19.2,18.4,16.6,14.1,14.1.ESI-HRMS:m/z620.5395[M+H]+(Calcd for C42H70NO2,620.5401).
实施例5：(22R,25S)-3β-苄氧基-26-吡咯基-5β-呋甾烷(ZA-3-5)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为四氢吡咯，得白色固体ZA-3-5(0.39g，68.7％)。1H NMR(300MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.28(td,J＝5.0,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.47(br.s,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.95(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,65.4,63.2,57.0,54.5,54.5,41.1,40.1,40.0,38.0,37.0,35.5,35.1,32.5,32.2,32.0,30.9,30.8,30.5,26.7,26.5,24.7,23.9,23.4,23.4,20.7,19.0,18.5,16.6.ESI-HRMS:m/z562.4611[M+H]+(Calcd for C38H60NO2,562.4619).
实施例6：(22R,25S)-3β-苄氧基-26-哌嗪基-5β-呋甾烷(ZA-3-7)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为无水哌嗪，得白色粉末ZA-3-7(0.30g，53.6％)。1H NMR(300MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.51(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.28(m,1H,H-22),3.13(m,4H,N-CH2),2.64(m,4H,N-CH2),2.15(m,1H,H-26),0.99(d,J＝6.7Hz,3H,21-CH3),0.98(s,3H,19-CH3),0.89(d,3H,J＝6.5Hz,27-CH3),0.79(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,66.1,65.5,57.0,54.7,54.7,45.9,45.9,41.1,40.1,37.9,37.0,35.5,35.1,32.3,32.2,31.0,30.7,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.3,16.6.ESI-HRMS:m/z 577.4725[M+H]+(Calcd for C38H61N2O2,577.4728).
实施例7：(22R,25S)-3β-苄氧基-26-(N-甲基哌嗪基)-5β-呋甾烷(ZA-3-8)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为N-甲基哌嗪，得白色粉末ZA-3-8(0.43g，72.6％)。1H NMR(300MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.51(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.29(m,1H,H-22),2.43(br.s,8H,N-CH2),2.28(s,3H,N-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.90(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,65.6,65.5,57.0,55.3,55.3,53.6,53.6,46.1,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.4,32.2,31.0,30.7,30.5,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.3,16.6.ESI-HRMS:m/z 591.4885[M+H]+(Calcd forC39H63N2O2,591.4884).
实施例8：(22R,25S)-3β-苄氧基-26-吗啉基-5β-呋甾烷(ZA-3-9)的合成
制备步骤同实施例1，仅将步骤D中反应试剂更换为吗啡啉，得白色粉末ZA-3-9(0.40g，69.1％)。1H NMR(300MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.51(d,J＝12.3Hz,1H,Ar-CH2),4.46(d,J＝12.3Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.69(m,4H,O-CH2),3.69(br.s,1H,H-3),3.29(m,1H,H-22),2.37(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.91(d,J＝6.3Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,67.1,67.1,66.0,65.5,57.0,54.2,54.2,41.1,40.2,40.0,37.9,37.0,35.5,35.1,32.3,32.3,31.0,30.8,30.5,30.2,26.7,26.5,24.7,23.9,20.8,19.2,18.3,16.6.ESI-HRMS:m/z578.4568[M+H]+(Calcd for C38H60NO3,578.4568).
实施例9：(22R,25S)-3β-(4’-氟苄氧基)-26-二甲氨基-5β-呋甾烷(ZB-3-1)的合成
将实施例1步骤A中反应试剂换为对氟溴苄，将步骤D中所述反应溶剂换为乙腈，反应试剂换为二甲胺盐酸盐，得到了化合物ZB-3-1(0.32g，75.8％).1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝8.4,5.7Hz,H-2′,6′),7.00(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.1,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.30(m,1H,H-22),2.18(s,6H,N-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):163.3,135.1,129.0,128.9,115.2,115.0,90.4,83.2,73.9,68.9,67.1,65.6,57.0,46.0,46.0,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.4,32.2,31.4,31.0,30.7,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.2,16.6；ESI-HRMS:m/z 554.4344[M+H]+(Calcd forC36H57FNO2,554.4368).
实施例10：(22R,25S)-3β-(4’-氟苄氧基)-26-二乙氨基-5β-呋甾烷(ZB-3-2)的合成
将实施例1步骤A中反应试剂换为对氟溴苄，将步骤D中所述反应溶剂换为乙腈，反应试剂换为二乙胺，得到了化合物ZB-3-2(0.32g，68.9％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.7,8.4Hz,H-2′,6′),7.00(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.69(s,1H,H-3),3.30(m,1H,H-22),2.50(m,4H,N-CH2),1.00(m,9H,3×CH3),0.99(m,3H,19-CH3),0.93(d,J＝6.3Hz,3H,27-CH3),0.81(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):163.5,135.2,129.0,128.9,115.2,115.0,90.4,83.2,73.9,68.9,67.1,65.5,57.0,47.5,47.5,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.3,32.2,31.4,30.9,30.7,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.5,16.6,11.1,11.1.ESI-HRMS:m/z 582.4686[M+H]+(Calcd for C38H61FNO2,582.4681).
实施例11：(22R,25S)-3β-(4’-氟苄氧基)-26-二正丙氨基-5β-呋甾烷(ZB-3-3)的合成
将实施例1步骤A中反应试剂换为对氟溴苄，将步骤D中所述反应溶剂换为乙腈，反应试剂换为二正丙胺，得到了化合物ZB-3-3(0.50g，81.8％).1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.7,8.5Hz,H-2′,6′),7.01(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.1,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.30(m,1H,H-22),2.36(m,4H,N-CH2),1.00(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.92(d,J＝6.4Hz,3H,27-CH3),0.87(t,J＝7.3Hz,6H,2×CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):163.5,135.1,129.0,128.9,115.2,115.0,90.2,83.4,73.9,68.9,68.1,65.2,59.0,59.0,56.9,41.1,40.1,39.9,38.0,37.0,35.5,35.1,32.6,32.2,30.7,30.5,30.4,30.2,29.4,29.4,26.7,26.5,24.6,23.9,20.7,18.9,18.8,16.6,11.2,11.2.ESI-HRMS:m/z 610.5010[M+H]+(Calcd for C40H65FNO2,610.4994).
实施例12：(22R,25S)-3β-(4’-氟苄氧基)-26-二正丁氨基-5β-呋甾烷(ZB-3-4)的合成
将实施例1步骤A中反应试剂换为对氟溴苄，将步骤D中所述反应溶剂换为乙腈，反应试剂换为二正丁胺，得到了化合物ZB-3-4(0.49g，76.9％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.7,8.6Hz,H-2′,6′),7.00(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.69(s,1H,H-3),3.30(m,1H,H-22),2.50(m,4H,N-CH2),1.00(m,9H,3×CH3),0.99(m,3H,19-CH3),0.93(d,J＝6.3Hz,3H,27-CH3),0.81(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):163.3,135.2,129.0,128.9,115.2,115.0,90.4,83.2,73.9,68.9,67.1,65.5,57.0,54.2,54.2,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.2,32.2,31.4,30.8,30.7,30.5,28.5,28.5,26.7,26.5,24.7,23.9,20.7,20.6,20.6,19.1,18.5,16.6,14.0,14.0.ESI-HRMS:m/z 638.5305[M+H]+(Calcd for C42H69FNO2,638.5307).
实施例13：(22R,25S)-3β-(4’-氟苄氧基)-26-吡咯基-5β-呋甾烷(ZB-3-5)的合成
制备步骤同实施例1，仅将步骤A中反应试剂换为对氟溴苄，步骤D中所述反应溶剂换为乙腈，反应试剂更换为四氢吡咯，得到白色固体ZB-3-5(0.46g，79.3％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.7,8.4Hz,H-2′,6′),7.00(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.27(td,J＝5.5,7.6Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(m,1H,H-22),2.60(m,4H,N-CH2),0.98(m,9H,3×CH3),0.77(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):163.5,135.2,129.0,128.9,115.2,115.0,90.4,83.2,73.9,68.9,65.5,63.5,57.0,54.5,54.5,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.6,32.4,32.2,31.0,30.7,30.5,26.7,26.5,24.7,23.9,23.4,23.4,20.7,19.1,18.5,16.6.ESI-HRMS:m/z580.4516[M+H]+(Calcd for C38H59FNO2,580.4524).
实施例14：(22R,25S)-3β-(4’-氟苄氧基)-26-吡啶基-5β-呋甾烷(ZB-3-6)的合成
制备步骤同实施例1，仅将步骤A中反应试剂换为对氟溴苄，步骤D中所述反应溶剂换为乙腈，反应试剂更换为六氢吡啶，得到白色固体ZB-3-6(0.44g，74.1％)。1H NMR(400MHz,CDCl3,δ):7.31(dd,2H,J＝5.7,8.4Hz,H-2′,6′),7.01(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.5,7.6Hz,1H,H-16),3.69(br.s,1H,H-3),3.29(m,1H,H-22),2.30(m,4H,N-CH2),0.99(s,3H,21-CH3),0.97(m,3H,27-CH3),0.90(d,J＝6.5Hz,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):163.3,135.2,129.0,128.9,115.2,115.0,90.5,83.2,73.9,68.9,66.4,65.6,57.0,55.1,55.1,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.5,32.3,31.0,30.7,30.6,30.5,26.7,26.5,26.0,24.7,24.6,23.9,20.7,19.2,18.5,16.6.ESI-HRMS:m/z594.4704[M+H]+(Calcd for C39H61FNO2,594.4681).
实施例15：(22R,25S)-3β-(4’-氟苄氧基)-26-哌嗪基-5β-呋甾烷(ZB-3-7)的合成
制备步骤同实施例1，仅将步骤A中反应试剂换为对氟溴苄，步骤D中所述反应溶剂换为乙腈，反应试剂更换为无水哌嗪，得到白色固体ZB-3-7(0.42g，69.4％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝8.4,5.7Hz,H-2′,6′),7.01(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝7.7,5.2Hz,1H,H-16),3.69(br.s,1H,H-3),3.29(m,1H,H-22),2.89(m,4H,N-CH2),2.35(m,4H,N-CH2),2.17(s,1H,NH),2.15(m,1H,H-26),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(d,3H,J＝6.5Hz,18-CH3),0.78(s,3H,27-CH3).13C NMR(400MHz,CDCl3,δ):162.9,135.2,129.0,128.9,115.1,115.0,90.4,83.2,73.9,68.8,66.0,65.5,56.9,54.6,54.6,45.9,45.9,41.1,40.1,39.9,37.9,37.0,35.5,35.1,32.3,32.2,30.9,30.7,30.5,30.3,26.7,26.5,24.6,23.9,20.7,19.2,18.3,16.6；ESI-HRMS:m/z595.4638[M+H]+(Calcd for C38H60F1N2O2,595.4633).
实施例16：(22R,25S)-3β-(4’-氟苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷(ZB-3-8)的合成
制备步骤同实施例1，仅将步骤A中反应试剂换为对氟溴苄，步骤D中所述反应溶剂换为乙腈，反应试剂更换为N-甲基哌嗪，得到白色固体ZB-3-8(0.43g，70.3％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.6,8.5Hz,H-2′,6′),7.01(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.3,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.29(m,1H,H-22),2.43(br.s,8H,N-CH2),2.28(s,3H,N-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(d,3H,J＝6.5Hz,18-CH3),0.78(s,3H,27-CH3).13C NMR(100MHz,CDCl3,δ):163.4,135.1,129.0,128.9,115.2,115.0,90.5,83.2,73.9,68.9,65.5,65.4,57.0,55.2,55.2,53.5,53.5,46.1,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.4,32.2,31.0,31.0,30.7,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.3,16.6.ESI-HRMS:m/z 609.4812[M+H]+(Calcd for C39H62FN2O2,609.4790).
实施例17：(22R,25S)-3β-(4’-氟苄氧基)-26-吗啡啉基-5β-呋甾烷(ZB-3-9)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对氟溴苄，步骤D中反应试剂更换为吗啡啉，得到白色固体ZB-3-7(0.42g，51.4％)。1H NMR(400MHz,CDCl3,δ):7.30(dd,2H,J＝5.7,8.4Hz,H-2′,6′),7.01(m,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.1,7.7Hz,1H,H-16),3.69(m,4H,O-CH2),3.69(br.s,1H,H-3),3.29(m,1H,H-22),2.37(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.97(s,3H,19-CH3),0.91(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3)；13C NMR(400MHz,CDCl3,δ):163.3,135.1,129.0,128.9,115.2,115.0,90.4,83.2,73.9,68.9,66.7,66.7,65.8,65.5,57.0,54.0,54.0,41.1,40.1,40.0,38.0,37.0,35.5,35.1,32.3,32.2,31.0,30.7,30.5,30.0,26.7,26.5,24.7,23.9,20.7,19.1,18.3,16.6；ESI-HRMS:m/z596.4478[M+H]+(Calcdfor C38H59FNO3,596.4473).
实施例18：(22R,25S)-3β-(4’-溴苄氧基)-26-二甲氨基-5β-呋甾烷(ZC-3-1)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为二甲胺盐酸盐，得白色固体ZC-3-1(0.40g，65.0％)。1H-NMR(400MHz,CDCl3,δ):7.45(d,J＝8.3Hz,2H,H-2′,6′),7.22(d,J＝8.3Hz,2H,H-3′,5′),4.43(d,J＝12.5Hz,1H,Ar-CH2),4.40(d,J＝12.5Hz,1H,Ar-CH2),4.28(m,1H,H-16),3.68(br.s,1H,H-3),3.29(m,1H,H-22),2.22(br.s,6H,N-CH3),1.02(d,J＝6.6Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z614.3710[M+H]+(Calcd forC36H59BrNO2,616.3724).
实施例19：(22R,25S)-3β-(4’-溴苄氧基)-26-二乙氨基-5β-呋甾烷(ZC-3-2)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为二乙氨，得白色固体ZC-3-2(0.77g，73.0％)。1H-NMR(400MHz,CDCl3,δ):7.45(d,J＝8.3Hz,2H,Ar-H),7.22(d,J＝8.2Hz,2H,Ar-H),4.43(d,J＝12.6Hz,1H,Ar-CH2),4.40(d,J＝12.6Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.8Hz,1H,H-16),3.80(s,3H,OCH3),3.68(br.s,1H,H-3),3.30(td,J＝7.9,4.2Hz,1H,H-22),2.49(m,4H,N-CH2),0.99(d,J＝6.3Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.3Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z644.4050[M+H]+.
实施例20：(22R,25S)-3β-(4’-溴苄氧基)-26-二正丙氨基-5β-呋甾烷(ZC-3-3)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为二正丙氨，得白色固体ZC-3-2(0.54g，80.0％)。1H-NMR(400MHz,CDCl3,δ):1H-NMR(400MHz,CDCl3):δ7.45(d,J＝8.3Hz,2H,Ar-H),7.22(d,J＝8.3Hz,2H,Ar-H),4.43(d,J＝12.7Hz,1H,Ar-CH2),4.40(d,J＝12.7Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.8Hz,1H,H-16),3.68(br.s,1H,H-3),3.28(m,1H,H-22),2.28(m,4H,N-CH2),2.68(m,1H,H-25),2.33(s,3H,Ar-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(d,J＝6.3Hz,3H,27-CH3),0.86(m,J＝7.4Hz,6H,N-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z 672.4335[M+H]+.
实施例21：(22R,25S)-3β-(4’-溴苄氧基)-26-二正丁氨基-5β-呋甾烷(ZC-3-4)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为二正丁氨，得白色固体ZC-3-2(0.60g，86.0％)。1H-NMR(400MHz,CDCl3,δ):1H-NMR(400MHz,CDCl3):δ7.45(d,J＝8.3Hz,2H,Ar-H),7.22(d,J＝8.3Hz,2H,Ar-H),4.44(d,J＝12.6Hz,1H,Ar-CH2),4.40(d,J＝12.7Hz,1H,Ar-CH2),4.28(td,J＝5.3,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.30(td,J＝4.5,7.6Hz,1H,H-22),2.32(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(d,J＝7.2Hz,3H,27-CH3),0.86(m,J＝7.4Hz,6H,N-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z 698.4646[M+H]+.
实施例22：(22R,25S)-3β-(4’-溴苄氧基)-26-吡咯基-5β-呋甾烷(ZC-3-5)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为吡咯烷，得白色固体ZC-3-5(0.34g，83.0％)。1H-NMR(400MHz,CDCl3,δ):7.44(d,J＝8.3Hz,2H,H-2′,6′),7.21(d,J＝8.3Hz,2H,H-3′,5′),4.43(d,J＝12.6Hz,1H,Ar-CH2),4.39(d,J＝12.6Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(td,J＝3.9,8.3Hz,1H,H-22),2.27(m,2H,26-H),2.44(m,4H,N-CH2),0.98(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.94(d,J＝6.5Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 642.3901[M+H]+(Calcd for C38H61BrNO2,642.3880).
实施例23：(22R,25S)-3β-(4’-溴苄氧基)-26-哌啶基-5β-呋甾烷(ZC-3-6)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为哌啶，得白色固体ZC-3-6(0.54g，82.2％)。1H-NMR(400MHz,CDCl3,δ):7.45(d,J＝8.3Hz,2H,H-2′,6′),7.22(d,J＝8.3Hz,2H,H-3′,5′),4.43(d,J＝12.5Hz,1H,Ar-CH2),4.40(d,J＝12.5Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(td,J＝4.5,7.8Hz,1H,H-22),2.01(m,2H,26-H),2.29(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3)；ESI-HRMS:m/z656.3912.
实施例24：(22R,25S)-3β-(4’-溴苄氧基)-26-哌嗪基-5β-呋甾烷(ZC-3-7)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为无水哌嗪，得白色固体ZC-3-7(0.55g，85.0％)。1H-NMR(400MHz,CDCl3,δ):7.44(d,J＝8.3Hz,2H,Ar-H),7.21(d,J＝8.3Hz,2H,Ar-H),4.43(d,J＝12.6Hz,1H,Ar-CH2),4.39(d,J＝12.6Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(td,J＝3.9,8.3Hz,1H,H-22),2.27(m,2H,26-H),2.44(m,4H,N-CH2),0.98(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.94(d,J＝6.5Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z642.3901[M+H]+.
实施例25：(22R,25S)-3β-(4’-溴苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷(ZC-3-8)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为N-甲基哌嗪，得白色固体ZC-3-8(0.54g，81.0％)。1H-NMR(400MHz,CDCl3,δ):7.44(d,J＝8.3Hz,2H,Ar-H),7.21(d,J＝8.3Hz,2H,Ar-H),4.43(d,J＝12.5Hz,1H,Ar-CH2),4.40(d,J＝12.6Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(td,J＝4.0,7.8Hz,1H,H-22),2.43(m,8H,N-CH2),2.27(s,3H,N-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.89(d,J＝6.5Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 671.4173[M+H]+.
实施例26：(22R,25S)-3β-(4’-溴苄氧基)-26-吗啉基-5β-呋甾烷(ZC-3-9)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对溴溴苄，步骤D中反应试剂更换为吗啡啉，得白色固体ZC-3-9(0.55g，83.2％)。1H-NMR(400MHz,CDCl3,δ):7.45(d,J＝8.3Hz,2H,Ar-H),7.22(d,J＝8.3Hz,2H,Ar-H),4.43(d,J＝12.6Hz,1H,Ar-CH2),4.40(d,J＝12.6Hz,1H,Ar-CH2),4.28(td,J＝5.3,7.7Hz,1H,H-16),3.68(br.s,5H,H-3,O-CH2),3.29(td,J＝4.0,8.0Hz,1H,H-22),2.38(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z 658.3842[M+H]+。
实施例27：(22R,25S)-3β-(4’-甲基苄氧基)-26-二甲氨基-5β-呋甾烷(ZD-3-1)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为二甲胺盐酸盐，得白色固体ZC-3-1(0.38g，70.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.14(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝11.9Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(s,1H,H-3),3.30(m,1H,H-22),2.25(s,6H,N-CH3),2.33(s,3H,Ar-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.95(d,J＝6.8Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z550.4619[M+H]+.
实施例28：(22R,25S)-3β-(4’-甲基苄氧基)-26-二乙氨基-5β-呋甾烷(ZD-3-2)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为二乙胺，得白色固体ZD-3-2(0.43g，74.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.13(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(s,1H,H-3),3.30(m,1H,H-22),2.81(m,4H,N-CH2),2.33(s,3H,Ar-CH3),1.06(d,J＝6.0Hz,3H,21-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.96(s,3H,19-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 578.4930[M+H]+.
实施例29：(22R,25S)-3β-(4’-甲基苄氧基)-26-二正丙氨基-5β-呋甾烷(ZD-3-3)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为二正丙胺，得白色固体ZD-3-3(0.52g，86.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.13(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(s,1H,H-3),3.30(m,1H,H-22),2.41(m,4H,N-CH2),2.33(s,3H,Ar-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.93(d,J＝5.7Hz,3H,27-CH3),0.87(t,J＝7.3Hz,6H,N-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 606.5248[M+H]+.
实施例30：(22R,25S)-3β-(4’-甲基苄氧基)-26-二正丁氨基-5β-呋甾烷(ZD-3-4)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为二正丁胺，得白色固体ZD-3-4(0.56g，88.0％)。1H-NMR(400MHz,CDCl3,δ):7.24(d,J＝7.9Hz,2H,H-2′,6′),7.14(d,J＝7.9Hz,2H,H-3′,5′),4.46(d,J＝12.0Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.29(td,J＝5.2,7.8Hz,1H,H-16),3.68(s,1H,H-3),3.30(td,J＝3.4,8.0Hz,1H,H-22),2.33(s,3H,Ar-CH3),1.02(d,J＝6.6Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 634.5558[M+H]+.
实施例31：(22R,25S)-3β-(4’-甲基苄氧基)-26-吡咯基-5β-呋甾烷(ZD-3-5)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为四氢吡咯，得白色固体ZD-3-2(0.51g，88.0％)。1H-NMR(400MHz,CDCl3,δ):7.22(d,J＝7.9Hz,2H,H-2′,6′),7.12(d,J＝7.9Hz,2H,H-3′,5′),4.44(d,J＝11.9Hz,1H,Ar-CH2),4.40(d,J＝11.9Hz,1H,Ar-CH2),4.26(td,J＝5.1,7.7Hz,1H,H-16),3.67(br.s,1H,H-3),3.29(td,J＝2.8,8.3Hz,1H,H-22),2.82(m,2H,26-H),2.12(m,4H,N-CH2),2.32(s,3H,Ar-CH3),1.19(d,J＝6.6Hz,3H,21-CH3),0.95(s,3H,19-CH3),0.98(d,J＝6.6Hz,3H,27-CH3),0.75(s,3H,18-CH3).ESI-HRMS:m/z 576.4788[M+H]+.
实施例32：(22R,25S)-3β-(4’-甲基苄氧基)-26-哌啶基-5β-呋甾烷(ZD-3-6)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为哌啶，得白色固体ZD-3-6(0.34g，57.2％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,H-2′,6′),7.13(d,J＝7.9Hz,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.30(m,1H,H-22),2.57(m,4H,N-CH2),2.33(s,3H,Ar-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.95(d,J＝6.8Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z590.4935[M+H]+(Calcd for C40H64NO2,590.4932).
实施例33：(22R,25S)-3β-(4’-甲基苄氧基)-26-哌嗪基-5β-呋甾烷(ZD-3-7)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为无水哌嗪，得白色固体ZD-3-7(0.53g，89.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.14(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.1Hz,1H,Ar-CH2),4.28(td,J＝5.1,7.7Hz,1H,H-16),3.64(m,1H,H-3),3.30(m,1H,H-22),2.56(m,4H,N-CH2),2.33(s,3H,Ar-CH3),0.98(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.89(s,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 591.4886[M+H]+.
实施例34：(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷(ZD-3-8)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为N-甲基哌嗪，得白色固体ZD-3-8(0.51g，85.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝8.0Hz,2H,Ar-H),7.14(d,J＝7.8Hz,2H,Ar-H),4.45(d,J＝11.7Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.28(m,1H,H-16),3.69(br.s,1H,H-3),3.30(m,1H,H-22),2.86(m,4H,N-CH2),2.33(s,3H,Ar-CH3),1.25(s,3H,N-CH3),0.98(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.88(d,J＝6.7Hz,3H,27-CH3),0.76(s,3H,18-CH3).ESI-HRMS:m/z605.4992[M+H]+.
实施例35：(22R,25S)-3β-(4’-甲基苄氧基)-26-吗啉基-5β-呋甾烷(ZD-3-9)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲基溴苄，步骤D中反应试剂更换为吗啡啉，得白色固体ZD-3-9(0.50g，85.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.14(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝11.9Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.69(m,4H,O-CH2),3.29(td,J＝3.8,7.9Hz,1H,H-22),2.39(m,4H,N-CH2),2.33(s,3H,Ar-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.1Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 592.4726[M+H]+.
实施例36：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二甲氨基-5β-呋甾烷(ZE-3-1)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对对甲氧基溴苄，步骤D中反应试剂更换为二甲胺盐酸盐，得白色固体ZE-3-1(0.40g，71.6％)。1H NMR(400MHz,CDCl3,δ):7.27(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.28(dt,J＝7.8,5.1Hz,1H,H-16),3.80(s,3H,O-CH3),3.68(br.s,1H,H-3),3.30(m,1H,H-22),2.20(br.s,6H,N-CH3),1.02(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.4,83.2,73.5,69.1,67.1,65.5,57.0,55.3,46.0,46.0,41.1,40.1,40.0,38.0,37.0,35.5,35.1,32.4,32.2,31.4,31.0,30.8,30.5,26.7,26.5,24.7,23.9,20.7,19.1,18.2,16.6.ESI-HRMS:m/z566.4563[M+H]+(Calcd for C37H60NO3,566.4568).
实施例37：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二乙氨基-5β-呋甾烷(ZE-3-2)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为二乙胺，得白色固体ZE-3-2(0.45g，75.2％)。1H NMR(400MHz,CDCl3,δ):7.26(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.43(d,J＝11.8Hz,1H,Ar-CH2),4.38(d,J＝11.8Hz,1H,Ar-CH2),4.27(td,J＝7.7,5.4Hz,1H,H-16),3.80(s,3H,O-CH3),3.68(br.s,1H,H-3),3.30(m,1H,H-22),3.02(m,4H,N-CH2),1.02(d,J＝6.6Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,27-CH3),0.76(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.4,83.2,73.5,69.1,67.1,65.5,57.0,55.3,46.0,46.0,41.1,40.1,40.0,38.0,37.0,35.5,35.1,32.4,32.2,31.4,31.0,30.8,30.5,26.7,26.5,24.7,23.9,20.7,19.1,18.2,16.6.ESI-HRMS:m/z594.4887[M+H]+(Calcd for C39H64NO3,594.4881).
实施例38：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二正丙氨基-5β-呋甾烷(ZE-3-3)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为二正丙胺。得白色固体ZE-3-3(0.32g，51.8％)。1H NMR(400MHz,CDCl3,δ):7.24(d,J＝8.4Hz,2H,H-2′,6′),6.84(d,J＝8.4Hz,2H,H-3′,5′),4.40(d,J＝11.7Hz,1H,Ar-CH2),4.36(d,J＝11.7Hz,1H,Ar-CH2),4.26(dt,J＝7.7,5.3Hz,1H,H-16),3.80(s,3H,O-CH3),3.66(br.s,1H,H-3),3.28(m,1H,H-22),2.40(m,4H,N-CH2),0.97(d,J＝6.7Hz,3H,21-CH3),0.94(s,3H,19-CH3),0.92(d,J＝6.5Hz,3H,27-CH3),0.86(t,J＝7.3Hz,6H,2×CH3),0.76(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.5,83.2,73.5,69.1,65.6,61.6,57.0,56.8,56.8,55.3,41.1,40.1,40.0,37.8,37.0,35.5,35.1,32.2,32.1,31.8,30.9,30.8,30.5,26.7,26.5,24.7,23.9,20.7,20.2,20.2,19.2,18.4,16.6,12.0,12.0.ESI-HRMS:m/z622.5173[M+H]+(Calcd for C41H68NO3,622.5194).
实施例39：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二正丁氨基-5β-呋甾烷(ZE-3-4)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为二正丁胺。得白色固体ZE-3-4(0.42g，64.1％)。1H NMR(400MHz,CDCl3,δ):7.26(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.42(d,J＝11.7Hz,1H,Ar-CH2),4.39(d,J＝11.7Hz,1H,Ar-CH2),4.28(td,J＝7.7,5.1Hz,1H,H-16),3.80(s,3H,O-CH3),3.68(br.s,1H,H-3),3.30(m,1H,H-22),2.35(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(m,9H,3×CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.5,83.2,73.5,69.1,65.6,61.5,57.0,55.3,54.5,54.5,41.1,40.1,40.0,37.8,37.0,35.5,35.1,32.2,32.1,31.8,30.9,30.8,30.5,29.2,29.2,26.7,26.5,24.7,23.9,20.7,20.7,20.7,19.2,18.4,16.6,14.1,14.1.ESI-HRMS:m/z650.5510[M+H]+(Calcd for C43H72NO3,650.5507).
实施例40：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吡咯基-5β-呋甾烷(ZE-3-5)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为吡咯烷。得白色固体ZE-3-5(0.49g，82.8％)。1H NMR(400MHz,CDCl3,δ):7.26(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.42(d,J＝11.7Hz,1H,Ar-CH2),4.39(d,J＝11.7Hz,1H,Ar-CH2),4.28(td,J＝7.7,5.2Hz,1H,H-16),3.80(s,3H,O-CH3),3.68(s,1H,H-3),3.29(m,1H,H-22),2.45(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.95(m,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.5,83.2,73.5,69.1,65.6,60.2,57.0,55.3,47.6,47.6,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.3,32.3,31.8,30.8,30.5,26.7,26.5,24.7,23.9,20.7,19.2,18.5,16.6,11.7,11.7.ESI-HRMS:m/z592.4724[M+H]+(Calcdfor C39H62NO3,592.4724).
实施例41：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吡啶基-5β-呋甾烷(ZE-3-6)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为六氢吡啶。得白色固体ZE-3-7(0.51g，85.0％)。1H-NMR(400MHz,CDCl3):δ7.26(d,J＝8.6Hz,2H,Ar-H),6.87(d,J＝8.7Hz,2H,Ar-H),4.42(d,J＝11.7Hz,1H,Ar-CH2),4.39(d,J＝11.7Hz,1H,Ar-CH2),4.28(td,J＝5.2,7.7Hz,1H,H-16),3.80(s,3H,OCH3),3.68(s,1H,H-3),3.29(td,J＝4.6,7.8Hz 1H,H-22),2.27(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.90(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z606.4880[M+H]+.
实施例42：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-哌嗪基-5β-呋甾烷(ZE-3-7)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为哌嗪，得白色固体ZE-3-8(0.52g，86.4％)。1H NMR(400MHz,CDCl3,δ):7.26(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.42(d,J＝11.7Hz,1H,Ar-CH2),4.38(d,J＝11.7Hz,1H,Ar-CH2),4.27(td,J＝7.7,5.3Hz,1H,H-16),3.80(s,3H,O-CH3),3.68(s,1H,H-3),3.20(m,1H,H-22),2.70(m,4H,N-CH2),2.20(m,4H,N-CH2),0.98(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.88(d,J＝5.8Hz,3H,27-CH3),0.77(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.4,83.3,73.5,69.1,65.8,65.5,57.0,55.3,53.8,53.8,45.5,45.5,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.3,32.3,30.9,30.8,30.5,30.4,26.7,26.5,24.7,23.9,20.7,19.2,18.3,16.6.ESI-HRMS:m/z607.4838[M+H]+(Calcd for C39H63N2O3,607.4833).
实施例43：(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吗啉基-5β-呋甾烷(ZE-3-9)的合成
制备步骤同实施例1，仅将步骤A中反应试剂更换为对甲氧基溴苄，步骤D中反应试剂更换为吗啡啉，得白色固体ZE-3-9(0.53g，87.2％)。1H NMR(400MHz,CDCl3,δ):7.26(d,J＝8.6Hz,2H,H-2′,6′),6.87(d,J＝8.6Hz,2H,H-3′,5′),4.42(d,J＝11.7Hz,1H,Ar-CH2),4.38(d,J＝11.7Hz,1H,Ar-CH2),4.28(td,J＝7.8,5.2Hz,1H,H-16),3.79(s,3H,O-CH3),3.69(br.s,1H,H-3),3.68(m,4H,O-CH2),3.29(m,1H,H-22),2.37(m,4H,N-CH2),0.99(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.5Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):158.9,131.5,128.9,128.9,113.7,113.7,90.4,83.3,73.5,69.1,67.1,67.1,65.9,65.5,57.0,55.3,54.1,54.1,41.1,40.1,40.0,37.9,37.0,35.5,35.1,32.3,32.2,30.9,30.7,30.5,30.2,26.7,26.5,24.7,23.9,20.7,19.2,18.2,16.6.ESI-HRMS:m/z608.4674[M+H]+(Calcd for C39H62NO4,608.4673).
实施例44：(22R,25S)-3-氧代-26-二甲氨基-5β-呋甾烷(ZF-3-1)的合成
A.c的制备同实施例1，其他步骤如下：
B.d的制备：在三颈瓶中加入c(1.05g,2mmol)，Pt/C(0.1g)，20mL无水乙醇,氢气下回流搅拌至反应完全。放冷，过滤浓缩得白色固体d(0.82g,产率约94.2％)。
C.f的制备：在三颈瓶中加入d(0.8g,1.8mmol)，PDC(1.38g，3.6mmol)，少量活化的分子筛，8mL DCM，氮气保护下，室温搅拌至反应完全，放冷，加入蒸馏水，氯仿萃取，干燥，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体f(0.62g，产率约79％)。
D.在三颈瓶中加入f(0.5g,1.15mmol),5mL THF，二甲胺盐酸盐，回流反应20h至反应完全，放冷，浓缩，得白色固体，硅胶柱，石油醚：丙酮(1:2)加三乙胺冲产品，得白色粉末ZF-3-1(0.37g，84.3％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝5.1,7.7Hz,1H,H-16),3.30(m,1H,H-22),2.69(m,1H,H-26),2.33(m,1H,H-26),2.18(s,6H,N-CH3),1.03(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.81(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):213.2,90.5,83.1,67.1,65.5,56.7,46.0,46.0,44.2,42.3,41.1,40.9,39.8,38.0,37.2,37.0,35.4,35.0,32.4,32.2,31.3,31.0,26.5,26.0,22.7,20.8,19.2,18.2,16.6；ESI-HRMS:m/z444.3849[M+H]+(Calcd for C29H50NO2,444.3836).
实施例45：(22R,25S)-3-氧代-26-二乙氨基-5β-呋甾烷(ZF-3-2)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为二乙胺，得黄色油状物ZF-3-2(0.36g，75.8％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.30(m,1H,H-22),2.54(m,4H,N-CH2),1.00(m,12H,4×CH3),0.92(d,J＝6.3Hz,3H,27-CH3),0.80(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.3,90.3,83.2,65.3,58.8,56.7,47.4,47.4,44.2,42.3,41.1,40.9,39.7,38.0,37.2,37.0,35.3,35.0,32.5,32.1,30.7,30.4,26.5,26.0,22.7,20.8,19.0,18.7,16.6,9.60,9.60.ESI-HRMS:m/z472.4168[M+H]+(Calcd for C31H54NO2,472.4149).
实施例46：(22R,25S)-3-氧代-26-吡咯基-5β-呋甾烷(ZF-3-3)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为四氢吡咯，得白色粉末ZF-3-3(0.29g，61.7％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.30(m,1H,H-22),2.59(br.s,4H,N-CH2),1.03(m,12H,4×CH3),1.00(d,J＝6.3Hz,3H,27-CH3),0.80(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.2,90.0,83.3,65.1,62.3,56.7,54.6,54.6,44.2,42.3,41.1,40.8,39.7,38.0,37.1,37.0,35.3,35.0,32.3,32.1,31.1,30.5,26.5,25.9,23.3,22.7,20.8,18.8,18.4,16.6.ESI-HRMS:m/z470.3980[M+H]+(Calcd for C31H52NO2,470.3993).
实施例47：(22R,25S)-3-氧代-26-吡啶基-5β-呋甾烷(ZF-3-4)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为六氢吡啶，得白色粉末ZF-3-4(0.28g，58.1％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.29(m,1H,H-22),2.42(br.s,4H,N-CH2),0.99(m,9H,3×CH3),0.80(s,3H,18-CH3).ESI-HRMS:m/z484.4182[M+H]+(Calcd for C32H54NO2,484.4149).
实施例48：(22R,25S)-3-氧代-26-哌嗪基-5β-呋甾烷(ZF-3-5)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为无水哌嗪，得白色粉末ZF-3-5(0.26g，54.7％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.29(m,1H,H-22),2.90(m,4H,N-CH2),2.40(m,4H,N-CH2),2.17(s,1H,NH),1.02(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.88(d,3H,J＝6.5Hz,27-CH3),0.80(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.3,90.5,83.2,65.6,65.5,57.0,57.0,52.8,51.6,45.0,45.0,44.3,42.4,41.2,40.9,39.8,38.0,37.2,37.1,35.4,35.0,32.2,31.0,30.5,26.6,26.0,22.7,20.9,19.2,18.3,16.6.ESI-HRMS:m/z485.4104[M+H]+(Calcd forC31H53N2O2,485.4102).
实施例49：(22R,25S)-3-氧代-26-(N-甲基哌嗪基)-5β-呋甾烷(ZF-3-6)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为N甲基哌嗪(0.35g，5.2mmol)，得白色粉末ZF-3-6(0.33g，65.6％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.30(m,1H,H-22),2.43(br.s,8H,NH2),2.30(m,1H,N-H),2.28(s,3H,N-CH3),1.03(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.89(d,J＝6.4Hz,3H,27-CH3),0.80(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.2,90.5,83.1,65.5,65.4,56.7,56.7,55.2,53.5,53.5,46.1,44.2,42.3,41.1,40.8,39.8,38.0,37.2,37.0,35.4,35.0,32.4,32.2,31.0,30.5,26.5,26.0,22.7,20.8,19.2,18.3,16.6.ESI-HRMS:m/z499.4251[M+H]+(Calcd for C32H55N2O2,499.4258).
实施例50：(22R,25S)-3-氧代-26-吗啉基-5β-呋甾烷(ZF-3-7)的合成
制备步骤同实施例44，将D步骤中所用溶剂更换为乙腈，反应试剂更换为吗啡啉，得白色粉末ZF-3-7(0.37g，76.8％)。1H NMR(400MHz,CDCl3,δ):4.29(td,J＝7.7,5.1Hz,1H,H-16),3.30(m,1H,H-22),2.69(m,1H,N-H),2.33(m,1H,N-H),2.18(s,6H,N-CH3),1.03(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.81(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.2,90.5,83.1,67.1,67.1,66.0,65.4,56.7,54.1,54.1,44.2,42.3,41.1,40.8,39.7,38.0,37.2,37.0,35.3,35.0,32.3,32.2,31.0,30.1,26.5,26.0,22.7,20.8,19.2,18.3,16.6.ESI-HRMS:m/z486.3941[M+H]+(Calcd forC31H52NO3,486.3942).
实施例51：(22R,25S)-3-氧代-26-咪唑基-5β-呋甾烷(ZF-3-8)的合成
制备步骤同实施例44，仅将步骤D中反应试剂更换为咪唑，得白色固体ZF-3-8(0.35g，60.4％)。1H NMR(400MHz,CDCl3,δ):7.42(s,1H,N＝CH),7.03(s,1H,C＝CH),6.86(s,1H,C＝CH),4.28(td,J＝5.1,7.7Hz,1H,H-16),3.88(dd,J＝5.7,13.8Hz,1H,H-26),3.67(dd,J＝5.7,13.8Hz,1H,H-26),3.27(m,1H,H-22),1.02(s,3H,19-CH3),0.97(d,J＝6.8Hz,3H,21-CH3),0.85(d,J＝6.6Hz,3H,27-CH3),0.78(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.1,137.5,129.2,119.4,90.0,83.2,65.2,56.7,53.2,44.2,42.3,41.1,40.8,39.7,37.9,37.2,37.0,35.3,35.1,35.0,32.1,31.2,30.7,26.5,25.9,22.7,20.8,19.0,17.3,16.6.ESI-HRMS:m/z467.3631[M+H]+(Calcd for C30H47N2O2,467.3632).
实施例52：(22R,25S)-3-氧代-26-(苯并咪唑基)-5β-呋甾烷(ZF-3-9)的合成
制备步骤同实施例44，仅将步骤D中反应试剂更换为苯并咪唑(0.48g,3.34mmol)，得白色固体ZF-3-9(0.35g，60.4％)。1H NMR(400MHz,CDCl3,δ):7.87(s,1H,N＝CH),7.80(dd,1H,J＝3.2,6.5Hz,Ar-H),7.40(dd,1H,J＝3.2,6.5Hz,Ar-H),7.28(m,2H,Ar-H),4.29(td,J＝5.1,7.7Hz,1H,H-16),4.15(dd,J＝5.7,14.2Hz,1H,H-26),3.89(dd,J＝5.7,14.2Hz,1H,H-26),3.30(m,1H,H-22),1.03(s,3H,19-CH3),0.99(d,J＝6.7Hz,3H,21-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.81(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):213.2,143.7,143.5,134.1,122.8,122.0,109.9,90.0,83.3,65.2,56.7,51.3,44.2,42.3,41.1,40.8,39.7,37.8,37.2,37.0,35.3,35.0,34.0,32.1,31.6,31.0,26.5,26.0,22.7,20.8,18.9,17.7,16.6.ESI-HRMS:m/z517.3774[M+H]+(Calcd for C34H49N2O2,517.3789).
实施例53：(22R,25S)-26-二乙氨基-3-氧代-4-烯-呋甾烷(ZG-1-2)的合成
A.d的制备同实施例44，其他操作步骤如下：
B.e的制备：在三颈瓶中加入d(0.5g，1.2mmol)，5mL DMF，70℃下一次性加入IBX(0.77g，2.76mmol)，搅拌下反应至完全，放冷，加入等体积水，二氯甲烷萃取，干燥，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体e(0.27g,55％)。
C.在三颈瓶中加入e(0.2g,0.46mmol)，1mL DMA，二乙胺(0.1g,1.38mmol)，回流反应20h至反应完全，放冷，浓缩，得白色固体，硅胶柱，石油醚：丙酮(2:1)加三乙胺冲产品，淡黄色油状物ZG-1-2(0.14g，65.4％)。1H NMR(400MHz,CDCl3,δ):5.72(s,1H,HC＝C),4.29(td,J＝5.1,7.7Hz,1H,H-16),3.30(m,1H,H-22),2.50(m,4H,NH2),1.19(s,3H,19-CH3),0.99(m,9H,3×CH3),0.90(d,J＝6.4Hz,3H,27-CH3),0.83(s,3H,18-CH3)；ESI-HRMS:m/z470.3990[M+H]+(Calcd for C31H52NO2,470.3993).
实施例54：(22R,25S)-26-哌啶基-3-氧代-4-烯-呋甾烷(ZG-1-4)的合成
制备步骤同实施例53，仅将步骤C中反应试剂更换为乙腈，反应试剂更换为哌啶，得淡黄色油状物(0.13g，58.6％)。1H NMR(400MHz,CDCl3,δ):5.72(s,1H,HC＝C),4.29(td,J＝5.1,7.7Hz,1H,H-16),3.30(m,1H,H-22),2.30(m,4H,NH2),1.20(s,3H,19-CH3),1.00(d,J＝6.7Hz,3H,21-CH3),0.90(d,J＝6.4Hz,3H,27-CH3),0.84(s,3H,18-CH3).ESI-HRMS:m/z482.4006[M+H]+(Calcd for C32H52NO2,482.3993).
实施例55：(22R,25S)-26-苯并咪唑基-3-氧代-4-烯-呋甾烷(ZG-1-9)的合成
制备步骤同实施例53，仅将步骤C中反应试剂更换为苯并咪唑，得淡黄色油状物(0.17g，70.1％)。1H NMR(400MHz,CDCl3,δ):7.99(s,1H,N＝CH),7.82(dd,1H,J＝3.2,6.5Hz,H-3′),7.41(dd,1H,J＝3.2,6.5Hz,H-6′),7.30(m,2H,H-4′,5′),δ5.72(s,1H,HC＝C),4.30(td,J＝5.1,7.7Hz,1H,H-16),4.16(dd,J＝5.8,14.2Hz,1H,H-26),3.92(m,1H,H-26),3.30(m,1H,H-22),1.19(s,3H,19-CH3),0.96(d,J＝6.7Hz,3H,21-CH3),0.91(d,J＝6.4Hz,3H,27-CH3),0.81(s,3H,18-CH3)；ESI-HRMS:m/z515.3631[M+H]+(Calcd forC34H47N2O2,515.3632).
实施例56：(22R,25S)-3β-苄氧基-26-二甲氨基-26-氧代-5β-呋甾烷(ZH-1-1)的合成
A.a，b的制备同实施例1。
B.g的制备：将b(2.54g,5mmol)加入50mL反应器，10mLTHF，室温搅拌下滴加Jones试剂至无原料剩余，将反应液减压蒸干，经硅胶柱色谱纯化得白色固体(2.09g，产率为80％)。
C.将g(0.261g,0.5mmol)加入25mL反应器，加入干燥2mL DCM，草酰氯(0.19g,1.5mmol)，1滴DMF，反应2-4h，TLC(PE:EA＝4:1)监测原料基本消失后，将反应液蒸干，直接投下一步反应。于反应瓶中加入干燥2mL DCM，Na2CO3(0.37g,2mmol)冷却至0℃，缓慢滴加二甲胺盐酸盐(0.122g,1.5mmol)，滴加完毕。逐渐升温至室温，搅拌反应3h，TLC(PE:EA＝4:1)原料点基本消失停止反应。将反应液减压浓缩，经硅胶柱色谱，PE:EA＝30:1冲柱，得白色固体ZH-1-1(0.193g，70.2％)。1H-NMR(400MHz,CDCl3,δ):8.04(d,J＝7.3Hz,2H,H-2′,6′),7.54(t,J＝7.4Hz,1H,H-4′),7.43(t,J＝7.6Hz,2H,H-3′,5′),4.50(d,J＝13.1Hz,1H,Ar-CH2),4.46(d,J＝12.9Hz,1H,Ar-CH2),4.26(m,1H,H-16),3.69(br.s,1H,H-3),3.30(m,1H,H-22),2.99(br.s,6H,N-CH3),1.03(m,3H,21-CH3),0.96(s,3H,19-CH3),0.97(m,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 550.4286[M+H]+(Calcd for C36H56NO3,550.4255).
实施例57：(22R,25S)-3β-苄氧基-26-二乙胺基-26-氧代-5β-呋甾烷(ZH-1-2)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为二乙胺，得到白色固体ZH-1-2(0.42g，73％)。1H-NMR(300MHz,CDCl3,δ):8.02(d,J＝7.3Hz,2H),7.52(t,J＝7.4Hz,1H),7.41(t,J＝7.6Hz,2H),4.47(d,J＝12.2Hz,1H,Ar-CH2),4.44(d,J＝12.2Hz,1H,Ar-CH2),4.26(td,J＝5.2,7.7Hz,1H,H-16),3.44(br.s,1H,H-3),3.29(m,1H,H-22),2.65(m,1H,H-25),2.18(m,4H,N-CH2),1.09(m,9H,21-CH3,N-CH3),1.01(s,3H,19-CH3),0.96(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 578.4568[M+H]+.
实施例58：(22R,25S)-3β-苄氧基-26-二正丙胺基-26-氧代-5β-呋甾烷(ZH-1-3)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为二正丙胺，得到白色固体ZH-1-3(0.42g，70％)。1H-NMR(300MHz,CDCl3,δ):8.04(d,J＝7.3Hz,2H),7.52(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),4.49(d,J＝12.2Hz,1H,Ar-CH2),4.45(d,J＝12.2Hz,1H,Ar-CH2),4.26(td,J＝5.2,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.28(m,1H,H-22),3.17(m,4H,N-CH2),2.68(m,1H,H-25),1.10(d,J＝6.7Hz,3H,21-CH3),0.96(m,6H,N-CH3),0.92(m,3H×2,19-CH3,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 606.4881[M+H]+.
实施例59：(22R,25S)-3β-苄氧基-26-二正丁胺基-26-氧代-5β-呋甾烷(ZH-1-4)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为二正丁胺，得到白色固体ZH-1-4(0.47g，75％)。1H-NMR(300MHz,CDCl3):δ8.03(d,J＝7.3Hz,2H),7.54(t,J＝7.4Hz,1H),7.43(t,J＝7.6Hz,2H),4.49(d,J＝12.1Hz,1H,Ar-CH2),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.28(td,J＝5.4,7.7Hz,1H,H-16),3.65(br.s,1H,H-3),3.28(m,1H,H-22),3.17(m,4H,N-CH2),2.67(m,1H,H-25),1.11(d,J＝6.7Hz,3H,21-CH3),1.02(s,3H,19-CH3),0.97(d,J＝6.7Hz,3H,27-CH3),0.92(m,J＝7.3Hz,6H,N-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z634.5206[M+H]+。
实施例60：(22R,25S)-3β-苄氧基-26-吡咯基-26-氧代-5β-呋甾烷(ZH-1-5)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为四氢吡咯，得到白色固体ZH-1-5(0.19g，65.3％)。1H-NMR(400MHz,CDCl3,δ):8.05(d,J＝7.3Hz,2H,H-2′,6′),7.55(t,J＝7.4Hz,1H,H-4′),7.44(t,J＝7.6Hz,2H,H-3′,5′),4.48(d,J＝12.2Hz,1H,Ar-CH2),4.45(d,J＝12.2Hz,1H,Ar-CH2),4.27(td,J＝7.6,5.2Hz,1H,H-16),3.68(br.s,1H,H-3),3.28(m,1H,H-22),3.42(m,4H,N-CH2),2.56(m,1H,H-25),1.10(d,J＝6.8Hz,3H,21-CH3),1.02(s,3H,19-CH3),0.97(d,J＝6.7Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z576.4416[M+H]+(Calcd for C38H58NO3,576.4411).
实施例61：(22R,25S)-3β-苄氧基-26-吡啶基-26-氧代-5β-呋甾烷(ZH-1-6)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为六氢吡啶，得到白色固体ZH-1-6(0.41g，69.6％)。1H-NMR(300MHz,CDCl3):δ8.05(d,J＝7.3Hz,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),4.50(d,J＝12.2Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.27(td,J＝5.2,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.30(td,J＝8.1,6.4Hz,1H,H-22),3.45(m,4H,N-CH2),2.75(m,1H,H-25),1.10(d,J＝6.8Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝5.0Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 590.4529[M+H]+.
实施例62：(22R,25S)-3β-苄氧基-26-哌嗪基-26-氧代-5β-呋甾烷(ZH-1-7)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为无水哌嗪，得到白色固体ZH-1-7(0.20g，67.5％)。1H-NMR(400MHz,CDCl3,δ):8.05(d,J＝7.3Hz,2H,H-2′,6′),7.55(t,J＝7.4Hz,1H,H-4′),7.44(t,J＝7.6Hz,2H,H-3′,5′),4.50(d,J＝12.2Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.28(td,J＝7.4,5.6Hz,1H,H-16),3.63(br.s,1H,H-3),3.30(m,1H,H-22),3.61(m,4H,N-CH2),2.76(m,1H,H-25),1.13(d,J＝6.6Hz,3H,21-CH3),0.98(s,3H,19-CH3),1.03(d,J＝7.3Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z591.4529[M+H]+(Calcd for C38H59N2O3,591.4520).
实施例63：(22R,25S)-3β-苄氧基-26-(N-甲基哌嗪基)-26-氧代-5β-呋甾烷(ZH-1-8)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为N-甲基哌嗪，得到白色固体ZH-1-8(0.41g，68.3％)。1H-NMR(400MHz,CDCl3,δ):8.03(d,J＝7.2Hz,2H),7.54(t,J＝7.4Hz,1H),7.43(t,J＝7.6Hz,2H),4.48(d,J＝12.2Hz,1H,Ar-CH2),4.44(d,J＝12.2Hz,1H,Ar-CH2),4.27(td,J＝5.2,7.5Hz,1H,H-16),3.63(br.s,1H,H-3),3.30(m,1H,H-22),3.53(m,4H,N-CH2),2.73(m,1H,H-25),2.36(m,4H,N-CH2),2.29(s,3H,N-CH3),1.09(d,J＝6.8Hz,3H,21-CH3),1.02(s,3H,19-CH3),0.97(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 605.4664[M+H]+.
实施例64：(22R,25S)-3β-苄氧基-26-吗啡基-26-氧代-5β-呋甾烷(ZH-1-9)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为吗啡啉，得到白色固体ZH-1-9(0.43g，73.5％)。1H-NMR(400MHz,CDCl3,δ):8.04(d,J＝7.2Hz,2H),7.54(t,J＝7.4Hz,1H),7.43(t,J＝7.6Hz,2H),4.49(d,J＝12.2Hz,1H,Ar-CH2),4.45(d,J＝12.2Hz,1H,Ar-CH2),4.27(td,J＝5.2,7.6Hz,1H,H-16),3.64(br.s,1H,H-3),3.29(td,J＝4.1,7.7Hz,1H,H-22),3.53(m,8H,N-CH2,O-CH2),2.71(m,1H,H-25),1.11(d,J＝6.8Hz,3H,21-CH3),1.02(s,3H,19-CH3),0.97(d,J＝6.7Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z592.4362[M+H]+.
实施例65：(22R,25S)-3β-苄氧基-26-[N-(4-甲基苯基)]-26-氧代-5β-呋甾烷(ZH-1-10)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为对甲基苯胺，得到白色固体ZH-1-10(0.42g，68.2％)。1H-NMR(400MHz,CDCl3,δ):8.05(d,J＝8.5Hz,2H,Ar-H),7.41(d,J＝8.4Hz,2H,Ar-H),7.45(d,J＝7.8Hz,2H,Ar-H),7.10(d,J＝8.3Hz,2H,Ar-H),6.96(d,J＝8.1Hz,1H,Ar-H),4.50(d,J＝12.1Hz,1H,Ar-CH2),4.46(d,J＝12.2Hz,1H,Ar-CH2),4.32(td,J＝5.4,7.7Hz,1H,H-16),3.65(br.s,1H,H-3),3.37(m,1H,H-22),2.46(m,1H,H-25),2.33(s,3H,Ar-CH3),1.22(d,J＝6.8Hz,3H,21-CH3),1.04(s,3H,19-CH3),0.98(d,J＝6.7Hz,3H,27-CH3),0.79(s,3H,18-CH3).ESI-HRMS:m/z 612.4415[M+H]+.
实施例66：(22R,25S)-3β-苄氧基-26-(N-甲基苯基)-26-氧代-5β-呋甾烷(ZH-1-11)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为N-甲基苯胺，得到白色固体ZH-1-11(0.48g，78.3％)。1H-NMR(400MHz,CDCl3,δ):8.04(d,J＝7.1Hz,2H),7.17(d,J＝7.3Hz,2H),7.55(d,J＝7.4Hz,1H),7.44(d,J＝7.8Hz,2H),7.39(d,J＝7.8Hz,2H),7.32(d,J＝7.4Hz,1H),4.49(d,J＝12.3Hz,1H,Ar-CH2),4.45(d,J＝12.2Hz,1H,Ar-CH2),4.22(td,J＝5.5,7.6Hz,1H,H-16),3.65(br.s,1H,H-3),3.21(m,1H,H-22),3.24(s,3H,N-CH3),2.40(m,1H,H-25),1.03(d,J＝6.7Hz,3H,21-CH3),1.02(s,3H,19-CH3),0.96(d,J＝6.7Hz,3H,27-CH3),0.75(s,3H,18-CH3).ESI-HRMS:m/z 612.4424[M+H]+.
实施例67：(22R,25S)-3β-苄氧基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZH-1-12)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为丙氨酸甲酯盐酸盐，得到白色固体ZH-1-12(0.21g，70.6％)。1H NMR(400MHz,CDCl3,δ):7.36(m,2H,H-2′,6′),7.34(m,2H,H-3′,5′),7.28(m,1H,H-4′),6.17(d,1H,-NH-),4.48(d,1H,J＝12.2,Ar-CH2),4.47(d,1H,J＝12.2,Ar-CH2),4.59(q,1H,J＝4.7Hz,-CH-),4.28(dt,1H,J＝5.53,7.81Hz,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),3.72(s,3H,O-CH3),2.35(m,1H,-CH-),1.17(d,3H,J＝6.9Hz,2″-CH3),0.99(d,3H,J＝6.35Hz,21-CH3),0.99(s,3H,19-CH3),0.91(d,3H,J＝6.3Hz,27-CH3),0.79(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.2,172.7,139.5,128.3,127.3,127.2,89.8,83.3,73.8,69.5,65.2,57.0,56.1,52.0,41.2,40.1,40.0,37.9,37.3,37.0,35.5,35.1,32.2,31.0,30.8,30.5,30.4,26.7,26.5,25.2,24.7,23.9,20.7,18.8,17.9,16.6,15.5,11.6.ESI-HRMS:m/z 608.4312[M+Na]+(Calcd forC38H58N1O5,608.4310).
实施例68：(22R,25S)-3β-苄氧基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZH-1-13)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为亮氨酸甲酯盐酸盐，得到白色固体ZH-1-13(0.20g，68.9％)。1H NMR(400MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),6.03(d,1H,-NH-),4.48(d,1H,J＝12.2,Ar-CH2),4.47(d,1H,J＝12.2,Ar-CH2),4.62(m,1H,J＝4.76Hz,-CH-),4.28(dt,1H,J＝5.41,7.89Hz,H-16),3.70(br.s,1H,H-3),3.34(m,1H,H-22),3.71(s,3H,O-CH3),2.34(m,1H,-CH-),1.17(d,3H,J＝6.9Hz,27-CH3),0.99(d,3H,J＝6.35Hz,21-CH3),0.99(s,3H,19-CH3),0.96(d,6H,J＝7.23Hz,2″′-CH3),0.76(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.2,173.7,139.5,128.3,127.3,127.2,89.8,83.3,73.8,69.5,65.2,56.9,52.2,50.4,41.7,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,32.2,31.0,30.8,30.5,30.4,29.1,26.7,26.5,24.9,24.7,23.9,22.9,21.9,20.7,18.8,18.7,17.8,16.6.ESI-HRMS:m/z 650.4775[M+H]+(Calcd for C41H64N1O5,650.4779).
实施例69：(22R,25S)-3β-苄氧基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZH-1-14)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为异亮氨酸甲酯盐酸盐，得到白色固体ZH-1-14(0.21g，65.3％)。1H NMR(400MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),6.15(d,1H,-NH-),4.48(d,1H,J＝12.2,Ar-CH2),4.47(d,1H,J＝12.2,Ar-CH2),4.58(m,1H,J＝4.76Hz,-CH-),4.28(dt,1H,J＝5.30,7.69Hz,H-16),3.70(br.s,1H,H-3),3.33(m,1H,H-22),3.71(s,3H,O-CH3),2.32(m,1H,-CH-),1.14(d,3H,J＝6.82Hz,27-CH3),0.99(d,3H,J＝6.35Hz,21-CH3),0.99(s,3H,19-CH3),1.40(d,3H,J＝7.15Hz,1″′-CH3),1.25(t,3H,-CH3),0.76(s,3H,18-CH3).ESI-HRMS:m/z 650.4782[M+H]+(Calcd for C41H64N1O5,650.4779).
实施例70：(22R,25S)-3β-苄氧基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷(ZH-1-15)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为甘氨酸甲酯盐酸盐，得到白色固体ZH-1-15(0.39g，65.8％)。1H NMR(400MHz,CDCl3,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5'′),7.26(m,1H,H-4′),6.14(t,1H,-NH-),4.50(d,1H,J＝12.15,Ar-CH2),4.46(d,1H,J＝12.15,Ar-CH2),4.28(dt,1H,J＝5.45,7.61Hz,H-16),4.04(d,2H,J＝5.17Hz,-CH2-),3.76(s,3H,O-CH3),3.7(br.s,1H,H-3),3.33(m,1H,H-22),2.36(m,1H,-CH-),1.16(d,3H,J＝6.90Hz,27-CH3),0.97(d,3H,J＝6.44Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.6,170.6,139.5,128.3,128.3,127.3,127.3,127.2,89.7,83.3,73.8,69.5,65.3,56.9,52.3,41.2,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,32.2,30.9,30.8,30.5,30.5,26.7,26.5,24.7,23.9,20.7,18.9,17.6,16.6.ESI-HRMS:m/z 616.3988[M+Na]+(Calcd for C37H55NO5Na,616.3972).
实施例71：(22R,25S)-3β-苄氧基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZH-1-16)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为缬氨酸甲酯盐酸盐，得到白色固体ZH-1-16(0.44g，68.9％)。1H NMR(400MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.32(m,2H,H-3',5'),7.26(m,1H,H-4′),6.13(d,1H,-NH-),4.56(m,1H,J＝8.77Hz,-CH-),4.49(d,1H,J＝12.21,Ar-CH2),4.46(d,1H,J＝12.21,Ar-CH2),4.28(dt,1H,J＝5.33,7.44Hz,H-16),3.72(s,3H,O-CH3),3.70(br.s,1H,H-3),3.33(m,1H,H-22),2.38(m,1H,-CH-),1.16(d,3H,J＝6.90Hz,27-CH3),0.97(d,3H,J＝6.44Hz,21-CH3),0.97(s,3H,19-CH3),0.93(d,3H,J＝6.90Hz,2″-CH3),0.90(d,3H,J＝6.90Hz,-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,172.7,139.4,128.3,128.3,127.3,127.3,127.2,89.7,83.3,73.8,69.5,65.2,56.9,56.7,52.0,41.2,41.1,40.1,40.0,37.3,37.0,35.5,35.1,32.2,31.2,31.0,30.7,30.5,30.3,26.7,26.5,24.7,23.9,20.7,19.0,18.8,18.0,17.8,16.6.ESI-HRMS:m/z658.4415[M+Na]+(Calcd for C40H61NO5Na,658.4442).
实施例72：(22R,25S)-3β-苄氧基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷(ZH-1-17)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为脯氨酸甲酯盐酸盐，得到白色固体ZH-1-17(0.46g，74.6％)。1H NMR(400MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d,1H,J＝12.30,Ar-CH2),4.46(d,1H,J＝12.30,Ar-CH2),4.28(dt,1H,J＝5.16,7.74Hz,H-16),3.70(s,3H,O-CH3),3.55(m,1H,H-3),3.33(m,1H,H-22),1.25(m,2H,-CH2-),1.11(d,3H,J＝6.58Hz,27-CH3),0.99(d,3H,J＝6.58Hz,21-CH3),0.97(s,3H,19-CH3),0.78(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.6,172.9,139.5,128.3,128.3,127.3,127.3,127.2,89.7,83.3,73.8,69.5,65.4,58.8,57.0,52.1,46.9,41.2,40.1,40.0,37.5,37.4,37.0,35.5,35.1,32.2,30.8,30.5,30.3,29.1,26.7,26.5,24.9,24.7,23.9,20.7,18.9,18.8,17.0,16.6.ESI-HRMS:m/z 656.4288[M+Na]+(Calcd for C40H59NO5Na,656.4285).
实施例73：(22R,25S)-3β-苄氧基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZH-1-18)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为苯丙氨酸甲酯盐酸盐，得到白色固体ZH-1-18(0.50g，72.6％)。1H NMR(400MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.25(m,1H,H-4′),7.25(m,3H,H-3′,5′,4′),7.09(d,2H,J＝6.79Hz,H-2′,6′),6.11(d,1H,J＝7.65Hz,-NH-),4.87(m,1H,-CH-),4.49(d,1H,J＝12.17,Ar-CH2),4.46(d,1H,J＝12.17,Ar-CH2),4.26(dt,1H,J＝5.20,7.80Hz,H-16),3.71(s,3H,O-CH3),3.70(br.s,1H,H-3),3.33(m,1H,H-22),3.15(dd,1H,J＝5.81,J＝13.85,Ar-CH2),3.07(dd,1H,J＝5.99,J＝13.85,Ar-CH2),2.26(m,1H,-CH-),1.08(d,3H,J＝6.74Hz,27-CH3),0.96(s,3H,19-CH3),0.94(d,3H,J＝7.03Hz,21-CH3),0.75(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.0,172.3,139.6,136.1,129.4,129.4,128.6,128.6,128.4,128.4,127.4,127.4,127.3,127.2,89.7,83.4,73.9,69.6,65.4,57.0,52.9,52.3,41.2,41.1,40.2,40.1,38.0,37.5,37.1,35.6,35.2,32.3,30.9,30.9,30.6,30.5,26.8,26.6,24.8,24.0,20.8,18.9,17.8,16.7.ESI-HRMS:m/z 706.4439[M+Na]+(Calcd for C40H61NO5Na,706.4442).
实施例74：(22R,25S)-3β-苄氧基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZH-1-19)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为蛋氨酸甲酯盐酸盐，得到白色固体ZH-1-19(0.46g，68.6％)。1H NMR(400MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),6.34(d,1H,-NH-),4.70(dt,1H,J＝5.31,J＝7.41Hz,-CH-),4.50(d,1H,J＝12.10,Ar-CH2),4.46(d,1H,J＝12.10,Ar-CH2),4.28(dt,1H,J＝5.35,7.74Hz,H-16),3.75(s,3H,O-CH3),3.70(br.s,1H,H-3),3.34(m,1H,H-22),2.50(m,2H,-CH2-),2.36(m,1H,-CH-),2.09(s,3H,-CH3),1.15(d,3H,J＝6.80Hz,27-CH3),0.97(d,3H,J＝6.28Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,172.6,139.4,128.3,128.3,127.3,127.3,127.2,89.7,83.3,73.7,69.5,65.2,56.9,52.4,51.3,41.1,41.0,40.1,39.9,37.4,37.0,35.5,35.1,32.2,31.7,30.9,30.7,30.5,30.4,30.0,26.7,26.5,24.6,23.9,20.7,18.8,17.8,16.6,15.5.ESI-HRMS:m/z690.4160[M+Na]+(Calcd for C40H61NO5NaS,690.4163).
实施例75：(22R,25S)-3β-苄氧基-26-(1,2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZH-1-20)的合成
制备步骤同实施例56，仅将步骤C中反应试剂更换为天冬氨酸甲酯盐酸盐，得到白色固体ZH-1-20(0.47g，70.3％)。1H NMR(400MHz,CDCl3,δ):7.34(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.26(m,1H,H-4′),6.57(d,1H,-NH-),4.88(m,1H,-CH-),4.50(d,1H,J＝12.27Hz,Ar-CH2),4.46(d,1H,J＝12.27Hz,Ar-CH2),4.28(dt,1H,J＝5.39,7.62Hz,H-16),3.75(s,3H,O-CH3),3.69(s,3H,O-CH3),3.70(br.s,1H,H-3),3.34(m,1H,H-22),3.03(dd,1H,-CH2-),2.83(dd,1H,-CH2-),2.33(m,1H,-CH-),2.00(m,1H,-CH-),1.14(d,3H,J＝6.81Hz,27-CH3),0.97(d,3H,J＝6.28Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.3,170.6,170.3,138.4,127.2,127.2,126.3,126.3,126.2,88.7,82.3,72.8,68.5,64.3,55.9,51.7,51.0,47.2,40.1,40.0,39.1,39.0,36.5,36.0,35.1,34.5,34.1,31.1,29.8,29.7,29.5,29.4,25.7,25.5,23.7,22.9,19.7,17.8,16.6,15.6.ESI-HRMS:m/z 688.4184[M+Na]+(Calcd for C40H59NO7Na,688.4184).
实施例76：(22R,25S)-3β-(4’-甲基苄氧基)-26-二甲氨基-26-氧代-5β-呋甾烷(ZI-1-1)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为二甲胺盐酸盐。得白色固体ZI-1-1(0.17g，60.7％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,H-2′,6′),7.13(d,J＝7.9Hz,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.26(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.29(td,J＝4.9,7.1Hz,1H,H-22),2.99(br.s,6H,N-CH3),2.33(s,3H,Ar-CH3),1.10(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝7.1Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 564.4455[M+H]+(Calcd for C37H58NO3,564.4411).
实施例77：(22R,25S)-3β-(4’-甲基苄氧基)-26-二乙胺基-26-氧代-5β-呋甾烷(ZI-1-2)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为二乙胺盐酸盐。得白色固体ZI-1-2(0.40g，67.7％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.13(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.27(td,J＝5.2,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.28(td,J＝4.9,7.1Hz,1H,H-22),3.27(m,4H,N-CH2),2.66(m,1H,H-25),2.33(s,3H,Ar-CH3),1.11(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝6.9Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 592.4725[M+H]+.
实施例78：(22R,25S)-3β-(4’-甲基苄氧基)-26-二丙胺基-26-氧代-5β-呋甾烷(ZI-1-3)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为二正丙胺盐酸盐。得白色固体ZI-1-3(0.41g，65.9％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.13(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.27(td,J＝5.4,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.28(m,1H,H-22),3.17(m,4H,N-CH2),2.68(m,1H,H-25),2.33(s,3H,Ar-CH3),1.11(d,J＝6.7Hz,3H,21-CH3),0.95(s,3H,19-CH3),0.96(d,J＝6.1Hz,3H,27-CH3),0.86(m,J＝7.4Hz,6H,N-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 620.5038[M+H]+.
实施例79：(22R,25S)-3β-(4’-甲基苄氧基)-26-二丁胺基-26-氧代-5β-呋甾烷(ZI-1-4)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为二正丁胺盐酸盐。得白色固体ZI-1-4(0.49g，75.2％)。1H-NMR(400MHz,CDCl3,δ):7.22(d,J＝7.8Hz,2H,Ar-H),7.12(d,J＝7.8Hz,2H,Ar-H),4.44(d,J＝12.0Hz,1H,Ar-CH2),4.40(d,J＝12.1Hz,1H,Ar-CH2),4.26(td,J＝7.6,5.6Hz,1H,H-16),3.67(br.s,1H,H-3),3.28(m,1H,H-22),3.16(m,4H,N-CH2),2.66(m,1H,H-25),2.32(s,3H,Ar-CH3),1.09(d,J＝6.7Hz,3H,21-CH3),0.95(s,3H,19-CH3),0.96(d,J＝6.9Hz,3H,27-CH3),0.89(m,J＝7.4Hz,6H,N-CH3),0.76(s,3H,18-CH3).ESI-HRMS:m/z 648.5351[M+H]+.
实施例80：(22R,25S)-3β-(4’-甲基苄氧基)-26-吡咯基-26-氧代-5β-呋甾烷(ZI-1-5)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为四氢吡咯，得白色固体ZI-1-5(0.20g，70.0％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.7Hz,2H,H-2′,6′),7.13(d,J＝7.7Hz,2H,H-3′,5′),4.45(d,J＝12.1Hz,1H,Ar-CH2),4.41(d,J＝12.1Hz,1H,Ar-CH2),4.26(td,J＝5.3,7.5Hz,1H,H-16),3.67(br.s,1H,H-3),3.29(td,J＝5.1,7.2Hz,1H,H-22),3.44(m,4H,N-CH2),2.56(m,1H,H-25),2.33(s,3H,Ar-CH3),1.11(d,J＝6.7Hz,3H,21-CH3),0.95(s,3H,19-CH3),0.96(d,J＝6.9Hz,3H,27-CH3),0.77(s,3H,18-CH3)；ESI-HRMS:m/z 590.4567[M+H]+(Calcd for C39H60NO3,590.4568).
实施例81：(22R,25S)-3β-(4’-甲基苄氧基)-26-吡啶基-26-氧代-5β-呋甾烷(ZI-1-6)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为六氢吡啶。得白色固体ZI-1-6(0.36g，60.2％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.14(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.27(td,J＝5.3,7.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.30(td,J＝6.2,7.7Hz,,1H,H-22),3.47(m,4H,N-CH2),2.75(m,1H,H-25),2.33(s,3H,Ar-CH3),1.10(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝7.3Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 604.4721[M+H]+.
实施例82：(22R,25S)-3β-(4’-甲基苄氧基)-26-哌嗪基-26-氧代-5β-呋甾烷(ZI-1-7)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为哌嗪。得白色固体ZI-1-7(0.17g，58.7％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,H-2′,6′),7.14(d,J＝7.9Hz,2H,H-3′,5′),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.26(td,J＝5.3,7.8Hz,1H,H-16),3.68(br.s,1H,H-3),3.30(m,1H,H-22),3.61(m,4H,N-CH2),2.76(m,1H,H-25),2.33(s,3H,Ar-CH3),2.01(m,4H,N-CH2),1.12(d,J＝6.7Hz,3H,21-CH3),1.25(s,3H,19-CH3),0.97(d,J＝6.0Hz,3H,27-CH3),0.78(s,3H,18-CH3)；ESI-HRMS:m/z 605.4679[M+H]+(Calcd for C39H61N2O3,605.4677).
实施例83：(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基哌嗪基)-26-氧代-5β-呋甾烷(ZI-1-8)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为N-甲基哌嗪。得白色固体ZI-1-8(0.37g，59.9％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝8.0Hz,2H,Ar-H),7.13(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝12.0Hz,1H,Ar-CH2),4.41(d,J＝12.0Hz,1H,Ar-CH2),4.26(td,J＝5.2,7.7Hz,1H,H-16),3.66(br.s,1H,H-3),3.29(td,J＝4.5,7.5Hz,1H,H-22),3.61(m,4H,N-CH2),2.74(m,1H,H-25),2.39(m,4H,N-CH2),2.31(s,3H,N-CH3),2.33(s,3H,Ar-CH3),1.10(d,J＝6.8Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝7.6Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 619.4836[M+H]+.
实施例84：(22R,25S)-3β-(4’-甲基苄氧基)-26-吗啡基-26-氧代-5β-呋甾烷(ZI-1-9)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为吗啡啉。得白色固体ZI-1-9(0.45g，74.4％)。1H-NMR(400MHz,CDCl3,δ):7.23(d,J＝7.9Hz,2H,Ar-H),7.14(d,J＝7.9Hz,2H,Ar-H),4.45(d,J＝11.9Hz,1H,Ar-CH2),4.42(d,J＝11.9Hz,1H,Ar-CH2),4.26(td,J＝5.2,7.8Hz,1H,H-16),3.66(br.s,1H,H-3),3.29(td,J＝4.1,7.4Hz,1H,H-22),3.61(m,8H,N-CH2,O-CH2),2.72(m,1H,H-25),2.33(s,3H,Ar-CH3),1.12(d,J＝6.8Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝8.3Hz,3H,27-CH3),0.77(s,3H,18-CH3).ESI-HRMS:m/z 606.4515[M+H]+.
实施例85：(22R,25S)-3β-(4’-甲基苄氧基)-26-[N-(4-甲基苯基)]-26-氧代-5β-呋甾烷(ZI-1-10)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为对甲基苯胺。得白色固体ZI-1-10(0.40g，64.6％)。1H-NMR(400MHz,CDCl3,δ):7.40(d,J＝8.4Hz,2H,Ar-H),7.10(d,J＝8.4Hz,2H,Ar’-2H),7.23(d,J＝7.9Hz,2H,Ar-3H),7.14(d,J＝7.9Hz,2H,Ar-1H),4.46(d,J＝12.0Hz,1H,Ar-CH2),4.42(d,J＝12.0Hz,1H,Ar-CH2),4.31(td,J＝7.8,5.7Hz,1H,H-16),3.68(br.s,1H,H-3),3.39(m,1H,H-22),2.45(m,1H,H-25),2.33(s,3H,Ar-CH3),2.30(s,3H,Ar’-CH3),1.21(d,J＝6.8Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.97(d,J＝6.6Hz,3H,27-CH3),0.78(s,3H,18-CH3).ESI-HRMS:m/z626.4549[M+H]+.
实施例86:(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基苯基)-26-氧代-5β-呋甾烷(ZI-1-11)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为4-甲基溴苄，步骤C中反应试剂更换为N-甲基苯胺。得白色固体ZI-1-11(0.43g，69.5％)。1H-NMR(400MHz,CDCl3,δ):7.40(t,J＝7.5Hz,2H),7.17(d,J＝7.3Hz,2H),7.33(t,J＝7.3Hz,1H),7.23(d,J＝7.9Hz,2H),7.13(d,J＝7.8Hz,2H),4.45(d,J＝12.0Hz,1H),4.41(d,J＝12.0Hz,1H),4.21(td,J＝5.5,7.6Hz,1H,H-16),3.67(br.s,1H,H-3),3.21(m,1H,H-22),3.24(s,3H,N-CH3),2.39(m,1H,H-25),2.33(s,3H,Ar-CH3),1.03(d,J＝6.7Hz,3H,21-CH3),0.95(s,3H,19-CH3),0.95(d,J＝6.5Hz,3H,27-CH3),0.74(s,3H,18-CH3).ESI-HRMS:m/z 626.4569[M+H]+.
实施例87：(22R,25S)-3β-苄氧基-26-(5-乙基-1,3,4-恶二唑-2-基)-5β-呋甾烷(ZJ-1-1)
h的合成：将g(2g,3.8mmol)溶解于干燥的10mL CH2Cl2中，加入草酰氯(0.57g,8.4mmol)，1滴DMF，反应2-4h，将其滴入乙酰肼的二氯甲烷溶液，室温搅拌过夜。反应结束后，向反应液中加入10mL水，分出有机层，干燥过滤得白色固体，经硅胶柱色谱纯化得白色固体h(1.64g,75.0％)。
ZJ-1-1的合成：在三颈瓶中加入h(1g,1.7mmol)，5mL POCl3，回流反应2h，反应完毕后，降至室温，将反应液缓慢倒入冰水中，加入饱和碳酸氢钠，析出白色固体，过滤，干燥，经硅胶柱色谱纯化得白色固体ZJ-1-1(0.66g,68.2％)。
实施例88：(22R,25S)-3氧代-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZK-1-1)的合成
A.a、b、g的制备同实施例56。
B.ZH-1-12的制备同实施例67。
C.i的制备：在三颈瓶中加入ZH-1-12(1g,1.65mmol)，10％Pt/C，无水乙醇、二氯甲烷或者二者的混合溶剂10mL，氢气下回流搅拌至反应完全。放冷，过滤浓缩得白色固体i(0.8g,1.5mmol)。
D.在三颈瓶中加入i(0.8g,1.5mmol)，8mL THF，1mL Jones试剂，室温搅拌至反应完全，过滤浓缩得粗品，经硅胶柱色谱纯化得白色固体ZK-1-1(0.48g,60.0％)。1H-NMR(400MHz,CDCl3,δ):6.14(d,J＝7.15Hz,1H,-NH-),4.60(m,1H,J＝7.2Hz,-CH-),4.30(dt,1H,J＝5.30,7.63Hz,H-16),3.33(m,1H,H-22),3.78(s,3H,O-CH3),2.66(m,1H,-CH-),1.39(d,3H,J＝7.11Hz,27-CH3),1.14(d,3H,J＝6.86Hz,2″-CH3),1.02(s,3H,19-CH3),0.97(d,3H,J＝6.66Hz,21-CH3),0.79(s,3H,18-CH3).ESI-HRMS:m/z 538.4529[M+Na]+(Calcd forC31H49NNaO5,538.3503).
实施例89：(22R,25S)-3氧代-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZK-1-2)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为亮氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-2(0.46g，55.0％)。1H-NMR(400MHz,CDCl3,δ):5.99(d,J＝8.22Hz,1H,-NH-),4.62(m,1H,-CH-),4.30(dt,1H,J＝5.32,7.85Hz,H-16),3.33(m,1H,H-22),3.72(s,3H,O-CH3),2.67(m,1H,-CH-),1.15(d,3H,J＝6.87Hz,27-CH3),1.03(s,3H,19-CH3),0.98(d,3H,J＝6.68Hz,21-CH3),0.93(d,6H,J＝6.00Hz,3″-CH3),0.79(s,3H,18-CH3).ESI-HRMS:m/z 580.3969[M+Na]+(Calcd forC34H55NNaO5,580.3972).
实施例90：(22R,25S)-3氧代-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZK-1-3)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为异亮氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，得到白色固体ZK-1-3(0.49g，58.2％)。1H-NMR(400MHz,CDCl3,δ):6.13(d,J＝8.54Hz,1H,-NH-),4.59(m,1H,-CH-),4.30(dt,1H,J＝7.74,5.27Hz,H-16),3.35(m,1H,H-22),3.72(s,3H,O-CH3),2.67(m,1H,-CH-),1.15(d,3H,J＝6.80Hz,27-CH3),1.03(s,3H,19-CH3),0.97(d,3H,J＝6.71Hz,21-CH3),0.91(t,3H,J＝7.49Hz,-CH3),0.89(d,3H,J＝6.92Hz,2″-CH3),0.79(s,3H,18-CH3).ESI-HRMS:m/z 580.3984[M+Na]+(Calcdfor C34H55NNaO5,580.3972).
实施例91：(22R,25S)-3氧代-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷(ZK-1-4)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为甘氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-4(0.31g，62.5％)。1HNMR(400MHz,CDCl3,δ):6.14(t,1H,-NH-),4.30(dt,1H,J＝5.24,7.74Hz,H-16),4.04(d,2H,J＝5.24Hz,-CH2-),3.76(s,3H,O-CH3),3.35(m,1H,H-22),2.68(t,1H,-CH-),2.36(m,1H,-CH-),1.17(d,3H,J＝6.98Hz,27-CH3),1.04(s,3H,19-CH3),0.98(d,3H,J＝6.60Hz,21-CH3),0.80(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):213.2,176.6,170.6,89.7,83.2,65.2,56.7,52.3,44.2,42.3,41.2,41.1,41.0,40.9,39.7,37.5,37.2,37.0,35.3,35.0,32.1,30.9,30.5,26.5,26.0,22.7,20.8,18.8,17.6,16.6.ESI-HRMS:m/z 524.3355[M+Na]+(Calcd for C30H47NO5Na,524.3346).
实施例92：(22R,25S)-3氧代-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZK-1-5)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为缬氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-5(0.32g，59.7％)。1HNMR(400MHz,CDCl3,δ):6.11(d,1H,J＝8.77,-NH-),4.57(dd,1H,J＝4.76,8.52Hz,-CH-),4.31(dt,1H,J＝5.20,7.70Hz,H-16),3.74(s,3H,O-CH3),3.36(m,1H,H-22),2.68(m,1H,-CH-),1.17(d,3H,J＝6.91Hz,27-CH3),1.04(s,3H,19-CH3),0.98(d,3H,J＝6.69Hz,21-CH3),0.94(d,3H,J＝6.91Hz,2″-CH3),0.90(d,3H,J＝6.80Hz,3″-CH3),0.80(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):212.2,175.3,171.7,88.8,82.2,64.1,55.7,55.7,51.0,43.2,41.3,40.2,40.1,39.8,38.7,36.4,36.1,36.0,34.3,34.0,31.1,30.2,30.0,29.4,25.5,25.0,21.7,19.8,18.0,17.8,17.0,16.8,15.5.ESI-HRMS:m/z 566.3816[M+Na]+(Calcd for C33H53NO5Na,566.3816).
实施例93：(22R,25S)-3氧代-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷(ZK-1-6)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为脯氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-6(0.34g，63.6％)。1HNMR(400MHz,CDCl3,δ):4.48(dd,1H,J＝4.56,8.65Hz,-CH-),4.30(dt,1H,J＝5.03,7.86Hz,H-16),3.71(s,3H,O-CH3),3.56(m,1H,H-3),3.34(m,1H,H-22),2.66(m,2H,2-CH-),1.11(d,3H,J＝6.76Hz,27-CH3),1.04(s,3H,19-CH3),1.01(d,3H,J＝6.76Hz,21-CH3),0.81(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):212.3,174.5,171.9,88.7,82.2,64.3,57.7,55.7,51.0,45.9,43.2,41.3,40.2,39.9,38.7,36.5,36.4,36.1,36.0,34.3,34.0,31.1,29.5,29.2,28.1,25.5,25.0,23.9,21.7,19.8,17.9,16.0,15.6.ESI-HRMS:m/z542.3844[M+H]+(Calcd for C33H52N1O5,542.3840).
实施例94：(22R,25S)-3氧代-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZK-1-7)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为苯丙氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-7(0.38g，65.0％)。1H NMR(400MHz,CDCl3,δ):7.29(m,2H,H-3',5'),7.24(m,1H,H-4'),7.09(d,2H,H-2',6'),6.00(d,1H,J＝7.59,-NH-),4.89(m,1H,-CH-),4.28(dt,1H,J＝5.27,7.64Hz,H-16),3.73(s,3H,O-CH3),3.32(m,1H,H-22),3.16(dd,1H,J＝5.74,13.69Hz,Ar-CH2),3.08(dd,1H,J＝5.92,13.69Hz,Ar-CH2),2.67(m,1H,-CH-),1.10(d,3H,J＝6.85Hz,27-CH3),1.03(s,3H,19-CH3),0.96(d,3H,J＝6.66Hz,21-CH3),0.79(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):213.3,175.9,172.2,135.9,129.3,129.3,128.5,128.5,127.1,89.7,83.2,65.2,56.7,52.8,52.3,44.2,42.3,41.1,41.0,40.8,39.7,37.9,37.4,37.2,37.0,35.3,35.0,32.1,30.8,30.4,26.5,26.0,22.7,20.8,18.8,17.7,16.6.ESI-HRMS:m/z 592.3996[M+H]+(Calcd for C37H54NO5,592.3997).
实施例95：(22R,25S)-3氧代-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZK-1-8)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为蛋氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-8(0.34g，58.4％)。1HNMR(400MHz,CDCl3,δ):6.30(d,1H,J＝7.84Hz,-NH-),4.70(dt,1H,J＝5.35,7.34Hz,-CH-),4.30(dt,1H,J＝5.22,7.84Hz,H-16),3.76(s,3H,O-CH3),3.35(m,1H,H-22),2.67(m,1H,-CH-),2.50(m,2H,-CH2-),2.10(s,3H,-CH3),1.16(d,3H,J＝6.87Hz,27-CH3),1.04(s,3H,19-CH3),0.98(d,3H,J＝6.77Hz,21-CH3),0.80(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):213.2,176.3,172.6,89.8,83.2,65.2,56.7,52.5,51.3,44.2,42.3,41.2,41.1,40.9,39.7,37.5,37.2,37.0,35.3,35.0,32.1,31.7,30.9,30.5,30.0,26.5,26.0,22.7,20.8,18.8,17.8,16.6,15.5.ESI-HRMS:m/z 598.3546[M+Na]+(Calcd for C33H53NO5NaS,598.3537).
实施例96：(22R,25S)-3氧代-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZK-1-9)的合成
制备步骤同实施例88，仅将步骤B中反应试剂更换为天冬氨酸甲酯盐酸盐，步骤C中反应溶剂换为无水甲醇，步骤D中溶剂换为丙酮，得到白色固体ZK-1-9(0.37g，64.7％)。1H NMR(400MHz,CDCl3,δ):6.56(d,1H,J＝8.19Hz,-NH-),4.88(m,1H,-CH-),4.30(dt,1H,J＝5.26,7.78Hz,H-16),3.76(s,3H,O-CH3),3.70(s,3H,O-CH3),3.35(m,1H,H-22),3.03(dd,1H,J＝4.46,17.16Hz,-CH2-),2.84(dd,1H,J＝4.58,17.16Hz,-CH2-),2.68(m,1H,-CH-),2.34(m,1H,-CH-),1.14(d,3H,J＝6.86Hz,27-CH3),1.04(s,3H,19-CH3),0.99(d,3H,J＝6.64Hz,21-CH3),0.80(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):213.3,176.3,171.6,171.3,89.7,83.2,65.2,56.7,52.8,52.0,48.2,44.2,42.3,41.2,41.0,40.9,39.8,37.6,37.2,37.0,36.1,35.3,35.0,32.1,30.9,30.5,26.5,26.0,22.7,20.8,18.8,17.6,16.6.ESI-HRMS:m/z 596.3559[M+Na]+(Calcd for C33H51NO7Na,596.3558).
实施例97：(22R,25S)-3β-苄氧基-32-苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-1)的合成
A.J的制备：将中间体g(1g，1.9mmol)溶于5mL二氯甲烷中，加入炔丙胺(0.2g，3.8mmol)，室温搅拌5min，再加入TBTU(0.74g，2.3mmol)和二异丙基乙胺(0.5g，3.8mmol)，室温搅拌至反应完全。一次用水(20mL)、饱和食盐水(20mL)萃取，分出有机层，干燥过滤浓缩得淡黄色固体，经硅胶柱色谱纯化得白色固体J(0.96g，90.0％)。
O.ZL-1-1的合成：将中间体J(0.5g，0.89mmol)和苄基叠氮化合物(1.7mmol)溶于二氯甲烷和水(5mL:5mL)混合溶液中，加入五水硫酸铜(0.45g，1.7mmol)和维生素C钠(0.71g，0.36mmol)，室温搅拌至反应完全。依次用水(5mL)、饱和食盐水(5mL)萃取，分出有机层，干燥过滤浓缩得固体，经硅胶柱色谱纯化得目标产物ZL-1-1(0.56g，90.6％)。1H NMR(400MHz,CDCl3,δ):7.47(s,1H,H-31),7.30-7.44(m,8H,Ar-H),7.24-7.26(m,2H,Ar-H),6.40(t,J＝5.30Hz,1H,H-28),5.49(br.s,2H,H-29),4.47(m,4H,Ar-CH2),4.24(td,J＝7.7&5.5Hz,1H,H-16),3.70(br.s,1H,H-3),3.27(m,1H,H-22),1.10(d,J＝6.9Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.74(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.5,139.5,134.5,129.1,128.8,128.3,128.3,128.3,128.1,128.1,127.3,127.3,127.3,127.2,122.2,89.6,83.3,73.8,69.5,65.2,56.9,54.2,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.8,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:693.4740[M+H]+(Calcd for C44H61N4O3,693.4738).
实施例98：(22R,25S)-3β-苄氧基-32-对氟苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-2)的合成
制备步骤同实施例97，仅将反应试剂更换为对氟苄基叠氮化合物，得白色固体ZL-1-2(0.63g，89.2％)。1H NMR(400MHz,CDCl3,δ):7.47(s,1H,H-31),7.30-7.35(m,4H,Ar-H),7.22-7.26(m,3H,H-4′,H-2″,6″),7.02-7.07(m,4H,Ar-H,H-3″,5″),6.41(t,J＝5.30Hz,1H,H-28),5.45(br.s,2H,H-29),4.47(m,4H,Ar-CH2),4.24(td,J＝5.5,7.7Hz,1H,H-16),3.69(br.s,1H,H-3),3.27(m,1H,H-22),1.10(d,J＝6.8Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.73(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.5,161.6,139.5,130.0,129.9,129.5,128.8,128.3,128.3,127.3,127.3,127.2,122.2,116.2,116.0,89.6,83.3,73.8,69.5,65.2,56.9,53.4,45.8,41.1,41.0,40.1,39.9,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.7,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:711.4643[M+H]+(Calcd for C44H60FN4O3,711.4644).
实施例99：(22R,25S)-3β-苄氧基-5β-32-对氯苄基-1H-1,2,3-三氮唑-呋甾烷(ZL-1-3)的合成
制备步骤同实施例97，仅将反应试剂更换为对氯苄基叠氮化合物，得白色固体ZL-1-3(0.62g，84.8％)。1H NMR(400MHz,CDCl3,δ):7.55(s,1H,H-31),7.33(m,6H,Ar-H,H-2″,6″),7.23-7.27(m,1H,H-4′),7.18(d,2H,J＝8.3Hz,H-3″,5″),6.37(s,1H,H-28),5.46(br.s,2H,H-29),4.50(d,J＝12.2Hz,2H,Ar-CH2),4.46(d,J＝12.2Hz,2H,Ar-CH2),4.24(td,J＝7.7,5.5Hz,1H,H-16),3.69(br.s,1H,H-3),3.27(m,1H,H-22),1.10(d,J＝6.7Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.73(s,3H,18-CH3).13CNMR(100MHz,CDCl3,δ):176.5,139.5,134.8,133.1,129.4,129.4,129.3,129.3,128.3,128.3,127.3,127.3,127.2,122.2,89.6,83.3,73.8,69.5,65.2,56.9,53.5,45.8,41.1,41.0,40.1,39.9,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.7,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:727.4384[M+H]+(Calcd forC44H60ClN4O3,727.4348).
实施例100：(22R,25S)-3β-苄氧基-32-对溴苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-4)的合成
制备步骤同实施例97，仅将反应试剂更换为对溴苄基叠氮化合物，得白色固体ZL-1-4(0.73g，94.8％)。1H NMR(400MHz,CDCl3,δ):7.49(s,1H,H-31),7.48(d,1H,J＝8.3Hz,H-2″,6″),7.30-7.35(m,4H,Ar-H),7.23-7.27(m,1H,Ar-H),7.12(d,1H,J＝8.3Hz,H-3″,5″),6.38(s,1H,H-28),5.44(br.s,2H,H-29),4.47(m,4H,Ar-CH2),4.24(td,J＝7.7,5.5Hz,1H,H-16),3.69(br.s,1H,H-3),3.26(m,1H,H-22),1.10(d,J＝6.9Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.73(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.5,139.5,139.5,133.6,132.3,132.3,129.6,129.6,128.3,128.3,127.3,127.3,127.2,122.9,122.9,89.6,83.3,73.8,69.5,65.2,56.9,53.5,45.8,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.8,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:773.3938[M+H]+(Calcd for C44H62BrN4O3,773.4000).
实施例101:(22R,25S)-3β-苄氧基-32-对甲基苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-5)的合成
制备步骤同实施例97，仅将反应试剂更换为对甲基苄基叠氮化合物，得白色固体ZL-1-5(0.59g，83.2％)。1H NMR(400MHz,CDCl3,δ):7.43(s,1H,H-31),7.30-7.35(m,4H,Ar-H),7.25-7.27(m,1H,H-4′),7.15(s,4H,H-2′,6′,H-3′,5′),6.39(t,J＝5.30,1H,H-28),5.43(br.s,2H,H-29),4.46(m,4H,Ar-CH2),4.24(td,J＝7.7,5.5Hz,1H,H-16),3.70(br.s,1H,H-3),3.27(m,1H,H-22),2.34(s,3H,38-CH3),1.10(d,J＝6.9Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.74(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.4,139.5,138.7,131.5,129.8,129.8,128.3,128.3,128.1,128.1,127.3,127.3,127.2,122.0,89.6,83.3,73.8,69.5,65.3,56.9,54.0,45.8,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.8,30.6,30.5,26.7,26.5,24.7,23.9,21.2,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:707.4895[M+H]+(Calcd for C45H63N4O3,707.4895).
实施例102：(22R,25S)-3β-苄氧基-32-对甲氧基苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-6)的合成
制备步骤同实施例97，仅将反应试剂更换为对甲氧基苄基叠氮化合物，得白色固体ZL-1-6(0.64g，85.5％)。1H NMR(400MHz,CDCl3,δ):7.42(s,1H,H-31),7.30-7.35(m,4H,Ar-H),7.24-7.27(m,1H,H-4′),7.21(d,1H,J＝8.6Hz,H-2″,6″),6.88(d,1H,J＝8.6Hz,H-3″,5″),6.37(t,J＝5.30,1H,H-28),5.41(br.s,2H,H-29),4.46(m,4H,Ar-CH2),4.24(td,J＝5.5,7.7Hz,1H,H-16),3.79(br.s,1H,38-CH3),3.69(br.s,1H,H-3),3.26(m,1H,H-22),1.10(d,J＝6.9Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.91(d,J＝6.6Hz,3H,27-CH3),0.74(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.4,159.9,139.5,129.7,129.7,129.5,128.3,128.3,127.3,127.3,127.2,126.5,121.9,114.5,114.5,89.6,83.3,73.8,69.5,65.3,56.9,55.3,53.8,41.1,41.0,40.1,40.0,37.4,37.0,35.5,35.1,34.8,32.2,30.9,30.8,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z:745.4687[M+H]+(Calcd for C45H62N4NaO4,745.4663).
实施例103:(22R,25S)-3β-苄氧基-32-对硝基苄基-1H-1,2,3-三氮唑-5β-呋甾烷(ZL-1-7)的合成
制备步骤同实施例97，仅将反应试剂更换为对硝基苄基叠氮化合物，得白色固体ZL-1-7(0.62g，82.2％)。1H NMR(400MHz,CDCl3,δ):7.57(s,1H,H-31),8.22(d,1H,J＝8.6Hz,H-2″,6″),7.38(d,1H,J＝8.6Hz,H-3″,5″),7.30-7.35(m,4H,Ar-H),7.23-7.27(m,1H,H-4′),6.36(t,1H,J＝5.30,H-28),5.60(br.s,2H,H-29),4.50(d,J＝12.2Hz,2H,Ar-CH2),4.46(d,J＝12.2Hz,2H,Ar-CH2),4.25(td,J＝7.7,5.3Hz,1H,H-16),3.70(br.s,1H,H-3),3.27(m,1H,H-22),1.10(d,J＝6.9Hz,3H,21-CH3),0.96(s,3H,19-CH3),0.92(d,J＝6.7Hz,3H,27-CH3),0.73(s,3H,18-CH3).13C NMR(100MHz,CDCl3,δ):176.6,148.1,146.0,141.6,139.5,128.6,128.6,128.3,128.3,127.3,127.3,127.2,124.3,124.3,122.8,89.7,83.4,73.8,69.5,65.2,56.9,53.1,41.1,41.0,40.1,39.9,37.5,37.0,35.5,35.1,34.8,32.2,30.9,30.7,30.6,30.5,26.7,26.5,24.7,23.9,20.7,18.8,17.5,16.6.ESI-HRMS:m/z:760.4429[M+H]+(Calcd for C44H59N5NaO5,760.4408).
实施例104:(22R,25S)-3β-羟基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZM-1-1)的合成
A.a、b、g的制备同实施例56。
B.ZH-1-12的制备同实施例67。
C.ZM-1-1的制备：在三颈瓶中加入ZH-1-12(0.59g,1.00mmol)，10％Pt/C，无水乙醇、二氯甲烷或者二者的混合溶剂10ml，氢气下回流搅拌至反应完全。放冷，过滤浓缩得白色固体ZM-1-1(0.29g，56.0％)。1H NMR(400MHz,CDCl3,δ):6.16(d,1H,-NH-),4.59(m,1H,J＝7.21Hz,-CH-),4.28(dt,1H,J＝5.36,7.69Hz,H-16),4.10(br.s,1H,H-3),3.74(s,3H,O-CH3),3.30(m,1H,H-22),2.32(m,1H,-CH-),1.39(d,3H,J＝7.24Hz,2″-CH3),1.15(d,3H,J＝6.96Hz,27-CH3),0.97(d,3H,J＝6.64Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.9,173.7,89.7,83.3,67.1,65.3,56.9,52.4,47.8,41.2,41.0,39.9,39.9,37.5,36.5,35.4,35.3,33.6,32.2,30.9,30.5,30.0,27.8,26.6,26.5,23.9,20.7,18.8,18.5,17.6,16.6.ESI-HRMS:m/z 540.3663[M+Na]+(Calcd forC31H51NO5Na,540.3659).
实施例105：(22R,25S)-3β-羟基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZM-1-2)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-13，得到白色固体ZM-1-2(0.33g，58.4％)。1H NMR(400MHz,CDCl3,δ):6.04(d,1H,-NH-),4.62(dt,1H,J＝5.05,8.59Hz,-CH-),4.28(dt,1H,J＝5.40,7.69Hz,H-16),4.10(br.s,1H,H-3),3.72(s,3H,O-CH3),3.33(m,1H,H-22),2.34(m,1H,-CH-),1.15(d,3H,J＝6.99Hz,27-CH3),0.97(d,3H,J＝6.43Hz,21-CH3),0.97(s,3H,19-CH3),0.94(d,6H,J＝6.05Hz,3″-CH3,4″-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,173.7,89.8,83.3,67.0,65.2,56.9,52.2,50.4,41.6,41.1,41.0,39.9,39.9,37.4,36.5,35.4,35.2,33.5,32.1,31.0,30.4,30.0,27.8,26.6,26.5,24.9,23.9,22.8,21.9,20.7,18.8,17.8,16.6.ESI-HRMS:m/z 582.4119[M+Na]+(Calcd for C34H57NO5Na,582.4129).
实施例106：(22R,25S)-3β-羟基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZM-1-3)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-14，得到白色固体ZM-1-3(0.32g，57.8％)。1H NMR(400MHz,CDCl3,δ):6.16(d,1H,-NH-),4.62(dd,1H,J＝4.99,8.56Hz,-CH-),4.28(dt,1H,J＝5.38,7.74Hz,H-16),4.10(br.s,1H,H-3),3.73(s,3H,O-CH3),3.35(m,1H,H-22),2.37(m,1H,-CH-),1.15(d,3H,J＝6.86Hz,27-CH3),0.97(d,3H,J＝6.28Hz,21-CH3),0.97(s,3H,19-CH3),0.92(t,3H,J＝7.45Hz,2″-CH3),0.90(d,3H,J＝6.87Hz,4″-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,172.7,89.8,83.3,67.0,65.2,56.9,56.1,52.0,41.2,41.2,39.9,39.9,37.9,37.4,36.5,35.4,35.3,33.6,32.2,31.0,30.4,30.0,27.8,26.6,26.5,25.2,23.9,20.7,18.8,17.9,16.6,15.5,11.6.ESI-HRMS:m/z 582.4127[M+Na]+(Calcd for C34H57NO5Na,582.4129).
实施例107:(22R,25S)-3β-羟基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷(ZM-1-4)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-15，得到白色固体ZM-1-4(0.33g，65.3％)。1H NMR(400MHz,CDCl3,δ):6.14(t,1H,-NH-),4.28(dt,1H,J＝5.31,7.77Hz,H-16),4.11(br.s,1H,H-3),4.04(d,2H,J＝5.20Hz,-CH2-),3.76(s,3H,O-CH3),3.33(m,1H,H-22),2.36(m,1H,-CH-),1.16(d,3H,J＝6.93Hz,27-CH3),0.97(d,3H,J＝6.72Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.6,170.6,89.7,83.3,67.1,65.3,56.9,52.3,41.2,41.1,41.0,39.9,39.9,37.4,36.5,35.4,35.3,33.6,32.2,30.9,30.5,30.0,27.8,26.6,26.5,23.9,20.7,18.8,17.6,16.6.ESI-HRMS:m/z 526.3498[M+Na]+(Calcd for C30H49NO5Na,526.3505).
实施例108：(22R,25S)-3β-羟基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZM-1-5)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-16，得到白色固体ZM-1-5(0.32g，57.9％)。1H NMR(400MHz,CDCl3,δ):6.14(d,1H,-NH-),4.56(dd,1H,J＝4.93,J＝8.77Hz,-CH-),4.28(dt,1H,J＝5.34,7.81Hz,H-16),4.10(br.s,1H,H-3),3.73(s,3H,O-CH3),3.34(m,1H,H-22),2.38(m,1H,-CH-),2.16(m,1H,-CH-),1.16(d,3H,J＝7.12Hz,27-CH3),0.97(d,3H,J＝6.48Hz,21-CH3),0.97(s,3H,19-CH3),0.94(d,3H,J＝6.84Hz,2″-CH3),0.90(d,3H,J＝6.84Hz,-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.4,172.7,89.8,83.3,67.0,65.2,56.9,56.7,52.0,41.2,41.2,39.9,39.9,37.4,36.5,35.4,35.3,33.6,32.2,31.2,31.0,30.4,30.0,27.8,26.6,26.5,23.9,20.7,19.0,18.8,18.0,17.8,16.6.ESI-HRMS:m/z568.3975[M+Na]+(Calcd for C33H55NO5Na,568.3972).
实施例109:(22R,25S)-3β-羟基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷(ZM-1-6)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-17，得到白色固体ZM-1-6(0.35g，64.2％)。1H NMR(400MHz,CDCl3,δ):4.48(dd,1H,J＝4.13,8.57Hz,-CH-),4.28(dt,1H,J＝5.37,7.63Hz,H-16),4.10(br.s,1H,H-3),3.71(s,3H,O-CH3),3.55(m,1H,H-3),3.34(m,1H,H-22),2.64(m,1H,-CH-),1.11(d,3H,J＝6.68Hz,27-CH3),0.99(d,3H,J＝6.88Hz,21-CH3),0.97(s,3H,19-CH3),0.78(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.5,172.9,89.7,83.3,67.1,65.4,58.8,56.9,52.1,46.9,41.2,39.9,39.9,37.5,37.4,36.5,35.4,35.3,33.5,32.2,30.5,30.3,30.0,29.1,27.8,26.6,26.5,24.9,23.9,20.7,18.9,17.0,16.6.ESI-HRMS:m/z 544.3996[M+H]+(Calcd for C33H54NO5,544.3997).
实施例110：(22R,25S)-3β-羟基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZM-1-7)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-18，得到白色固体ZM-1-7(0.35g，59.4％)。1H NMR(400MHz,CDCl3,δ):7.26(m,2H,H-3',5'),7.26(m,1H,H-4'),7.09(d,2H,H-2',6'),6.03(d,1H,-NH-),4.88(m,1H,-CH-),4.26(dt,1H,J＝5.45,7.56Hz,H-16),4.10(br.s,1H,H-3),3.72(s,3H,O-CH3),3.31(m,1H,H-22),3.16(dd,1H,J＝5.70,13.79,Ar-CH2),3.07(dd,1H,J＝5.70,13.79Hz,Ar-CH2),2.26(m,1H,-CH-),1.09(d,3H,J＝6.33Hz,27-CH3),0.97(s,3H,19-CH3),0.94(d,3H,J＝6.72Hz,21-CH3),0.75(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.9,172.2,136.0,129.3,129.3,128.5,128.5,127.1,89.7,83.3,67.1,65.3,56.9,52.8,52.2,41.1,41.0,39.9,39.9,37.9,37.4,36.5,35.4,35.3,33.6,32.2,30.8,30.4,30.0,27.8,26.6,26.5,23.9,20.7,18.8,17.7,16.6.ESI-HRMS:m/z 616.3967[M+Na]+(Calcd for C37H55NO5Na,616.3972).
实施例111：(22R,25S)-3β-羟基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZM-1-8)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-19，得到白色固体ZM-1-8(0.33g，56.7％)。1H NMR(400MHz,CDCl3,δ):6.33(d,1H,-NH-),4.70(dt,1H,J＝5.22,J＝7.44Hz,-CH-),4.28(dt,1H,J＝5.32,7.75Hz,H-16),4.10(br.s,1H,H-3),3.75(s,3H,O-CH3),3.34(m,1H,H-22),2.51(t,2H,-CH2-),2.36(m,1H,-CH-),2.10(s,3H,-CH3),1.16(d,3H,J＝6.94Hz,27-CH3),0.97(d,3H,J＝6.52Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.5,172.7,89.9,83.5,67.2,65.3,57.0,52.6,51.4,41.3,41.2,40.0,40.0,37.5,36.6,35.5,35.4,33.7,32.3,31.8,31.0,30.6,30.1,30.1,27.9,26.7,26.6,24.0,20.8,18.9,17.9,16.7,15.6.ESI-HRMS:m/z 600.3694[M+Na]+(Calcd for C33H55NO5NaS,600.3693).
实施例112：(22R,25S)-3β-羟基-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZM-1-9)的合成
制备步骤同实施例104，仅将步骤C中反应原料更换为ZH-1-20，得到白色固体ZM-1-9(0.32g，55.8％)。1H NMR(400MHz,CDCl3,δ):6.57(d,1H,-NH-),4.87(m,1H,-CH-),4.28(dt,1H,J＝5.29,7.78Hz,H-16),4.10(br.s,1H,H-3),3.75(s,3H,O-CH3),3.70(s,3H,O-CH3),3.34(m,1H,H-22),3.03(dd,1H,J＝4.36,17.11Hz,-CH2-),2.83(dd,1H,J＝4.52,17.11Hz,-CH2-),2.33(m,1H,-CH-),1.14(d,3H,J＝6.73Hz,27-CH3),0.97(d,3H,J＝6.36Hz,21-CH3),0.97(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.2,171.6,171.3,89.7,83.3,67.1,65.3,56.9,52.7,52.0,48.2,41.2,41.0,39.9,39.9,37.5,36.5,36.2,35.4,35.3,33.6,32.2,30.9,30.5,30.0,27.8,26.6,26.5,23.9,20.7,18.9,17.6,16.6.ESI-HRMS:m/z 598.3721[M+Na]+(Calcd for C33H53NO7Na,598.3714).
实施例113：(22R,25S)-3β-甲氧基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZN-1-1)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为丙氨酸甲酯盐酸盐，得到白色固体ZN-1-1(0.34g，64.7％)。1H NMR(400MHz,CDCl3,δ):6.26(d,1H,J＝7.38Hz,-NH-),4.50(m,1H,J＝7.22Hz,-CH-),4.21(dt,1H,J＝5.34,7.54Hz,H-16),3.66(s,3H,O-CH3),3.42(br.s,1H,H-3),3.26(m,1H,H-22),3.21(s,3H,O-CH3),2.25(m,1H,-CH-),1.92(m,1H,-CH-),1.31(d,3H,J＝7.29Hz,2″-CH3),1.07(d,3H,J＝6.84Hz,27-CH3),0.91(d,3H,J＝6.70Hz,21-CH3),0.88(s,3H,19-CH3),0.70(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.0,172.6,88.7,82.3,75.0,64.3,55.9,54.5,51.3,46.7,40.1,39.9,39.0,38.9,36.4,35.9,34.5,34.0,31.1,29.9,29.5,29.4,29.3,25.7,25.5,23.2,22.8,19.7,17.8,17.3,16.6,15.6.ESI-HRMS:m/z 554.3831[M+Na]+(Calcdfor C31H51NO5Na,554.3816).
实施例114：(22R,25S)-3β-甲氧基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZN-1-2)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为亮氨酸甲酯盐酸盐，得到白色固体ZN-1-2(0.39g，67.4％)。1H NMR(400MHz,CDCl3,δ):6.04(d,1H,J＝7.41Hz,-NH-),4.62(dt,1H,J＝4.26,J＝8.33Hz,-CH-),4.28(dt,1H,J＝5.18,7.61Hz,H-16),3.72(s,3H,O-CH3),3.49(br.s,1H,H-3),3.34(m,1H,H-22),3.28(s,3H,O-CH3),2.34(m,1H,-CH-),1.99(m,1H,-CH-),1.15(d,3H,J＝6.79Hz,27-CH3),0.96(d,3H,J＝7.37Hz,21-CH3),0.94(s,3H,19-CH3),0.94(d,6H,J＝6.04Hz,3″-CH3,4″-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,173.7,89.8,83.3,76.0,65.2,56.9,55.6,52.2,50.4,41.6,41.1,41.0,40.1,40.0,37.3,36.9,35.5,35.1,32.1,31.0,30.4,30.3,30.3,26.7,26.5,24.9,24.2,23.8,22.8,21.9,20.7,18.7,17.8,16.6.ESI-HRMS:m/z 596.4271[M+Na]+(Calcd for C34H57NO5Na,596.4285).
实施例115：(22R,25S)-3β-甲氧基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷(ZN-1-3)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为异亮氨酸甲酯盐酸盐，得到白色固体ZN-1-3(0.34g，59.8％)。1H NMR(400MHz,CDCl3,δ):6.16(d,1H,J＝8.54Hz,-NH-),4.52(dd,1H,J＝4.99,8.46Hz,-CH-),4.21(dt,1H,J＝5.37,7.62Hz,H-16),3.65(s,3H,O-CH3),3.42(br.s,1H,H-3),3.28(m,1H,H-22),3.21(s,3H,O-CH3),2.31(m,1H,-CH-),1.92(m,1H,-CH-),1.08(d,3H,J＝6.81Hz,27-CH3),0.89(d,3H,J＝6.64Hz,21-CH3),0.88(s,3H,19-CH3),0.85(t,3H,J＝7.45Hz,4″-CH3),0.83(d,3H,J＝6.97Hz,2″-CH3),0.70(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.3,171.6,88.7,82.3,75.0,64.2,55.9,55.1,54.5,51.0,40.1,40.1,39.0,38.9,36.8,36.3,35.9,34.5,34.0,31.1,30.0,29.4,29.3,29.3,25.7,25.5,24.2,23.2,22.8,19.7,17.8,16.9,15.6,14.5,10.6.ESI-HRMS:m/z596.4280[M+Na]+(Calcd for C34H57NO5Na,596.4285).
实施例116：(22R,25S)-3β-甲氧基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷(ZN-1-4)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为甘氨酸甲酯盐酸盐，得到白色固体ZN-1-4(0.33g，63.5％)。1H NMR(400MHz,CDCl3,δ):6.29(t,1H,J＝5.13Hz,-NH-),4.21(dt,1H,J＝5.40,7.69Hz,H-16),3.95(d,2H,J＝5.33Hz,-CH2-),3.67(s,3H,O-CH3),3.42(br.s,1H,H-3),3.26(m,1H,H-22),3.21(s,3H,O-CH3),2.30(m,1H,-CH-),1.92(m,1H,-CH-),1.08(d,3H,J＝6.80Hz,27-CH3),0.90(d,3H,J＝6.58Hz,21-CH3),0.88(s,3H,19-CH3),0.70(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.7,169.5,88.7,82.3,75.0,64.3,55.9,54.5,51.2,40.1,40.1,39.9,39.0,38.9,36.4,35.9,34.5,34.0,31.2,29.9,29.5,29.4,29.3,25.7,25.5,23.2,22.8,19.7,17.8,16.6,15.6.ESI-HRMS:m/z540.3656[M+Na]+(Calcd for C30H49NO5Na,540.3659).
实施例117：(22R,25S)-3β-甲氧基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZN-1-5)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为缬氨酸甲酯盐酸盐，得到白色固体ZN-1-5(0.38g，67.9％)。1H NMR(400MHz,CDCl3,δ):6.15(d,1H,J＝8.68Hz,-NH-),4.48(dd,1H,J＝4.97,J＝8.53Hz,-CH-),4.21(dt,1H,J＝5.55,7.31Hz,H-16),3.66(s,3H,O-CH3),3.42(br.s,1H,H-3),3.28(m,1H,H-22),3.21(s,3H,O-CH3),2.32(m,1H,-CH-),2.08(m,1H,-CH-),1.92(m,1H,-CH-),1.09(d,3H,J＝7.09Hz,27-CH3),0.89(d,3H,J＝6.90Hz,21-CH3),0.88(s,3H,19-CH3),0.86(d,3H,J＝6.90Hz,2″-CH3),0.83(d,3H,J＝6.90Hz,-CH3),0.70(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.4,171.6,88.7,82.3,75.0,64.2,55.9,55.7,54.5,51.0,40.1,40.1,39.0,38.9,36.3,35.9,34.5,34.0,31.1,30.2,30.0,29.4,29.3,29.3,25.7,25.5,23.2,22.8,19.7,18.0,17.8,17.0,16.8,15.5.ESI-HRMS:m/z 582.4121[M+Na]+(Calcd forC33H55NO5Na,582.4129).
实施例118：(22R,25S)-3β-甲氧基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷(ZN-1-6)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为脯氨酸甲酯盐酸盐，得到白色固体ZN-1-6(0.36g，64.3％)。1H NMR(400MHz,CDCl3,δ):4.48(dd,1H,J＝4.09,8.49Hz,-CH-),4.27(dt,1H,J＝5.26,7.89Hz,H-16),3.70(s,3H,O-CH3),3.55(m,1H,H-3),3.49(br.s,1H,H-3),3.34(m,1H,H-22),3.28(s,3H,O-CH3),2.64(m,1H,-CH-),1.10(d,3H,J＝6.79Hz,27-CH3),0.98(d,3H,J＝6.70Hz,21-CH3),0.94(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.5,172.9,89.7,83.3,76.0,65.4,58.7,57.0,55.6,52.1,46.9,41.2,40.1,40.0,37.5,37.4,36.9,35.5,35.1,32.2,30.4,30.4,30.3,30.3,29.1,26.7,26.5,24.9,24.2,23.8,20.7,18.9,17.0,16.6.ESI-HRMS:m/z 558.4140[M+H]+(Calcd for C33H54NO5,558.4153).
实施例119：(22R,25S)-3β-甲氧基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZN-1-7)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为苯丙氨酸甲酯盐酸盐，得到白色固体ZN-1-7(0.36g，59.5％)。1H NMR(400MHz,CDCl3,δ):7.26(m,2H,H-3',5'),7.26(m,1H,H-4'),7.09(d,2H,H-2',6'),6.03(d,1H,J＝7.63Hz,-NH-),4.88(m,1H,-CH-),4.26(dt,1H,J＝5.31,7.74Hz,H-16),3.72(s,3H,O-CH3),3.49(br.s,1H,H-3),3.31(m,1H,H-22),3.15(dd,1H,J＝5.88,J＝13.91,Ar-CH2),3.07(dd,1H,J＝5.88,J＝13.91,Ar-CH2),2.27(m,1H,-CH-),1.97(m,1H,-CH-),1.09(d,3H,J＝6.79Hz,27-CH3),0.95(d,3H,J＝6.72Hz,21-CH3),0.94(s,3H,19-CH3),0.75(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.0,172.2,135.9,129.3,129.3,128.5,128.5,127.1,89.6,83.3,76.0,65.3,56.9,55.6,52.8,52.3,41.1,41.0,40.1,40.0,37.9,37.4,36.9,35.5,35.1,32.2,30.8,30.4,30.4,30.3,26.7,26.5,24.2,23.8,20.7,18.8,17.7,16.6.ESI-HRMS:m/z 630.4130[M+Na]+(Calcd for C37H55NO5Na,630.4129).
实施例120：(22R,25S)-3β-甲氧基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷(ZN-1-8)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为蛋氨酸甲酯盐酸盐，得到白色固体ZN-1-8(0.41g，68.9％)。1H NMR(400MHz,CDCl3,δ):6.33(d,1H,J＝7.85Hz,-NH-),4.70(dt,1H,J＝5.26,7.39Hz,-CH-),4.28(dt,1H,J＝5.44,7.49Hz,H-16),3.75(s,3H,O-CH3),3.49(br.s,1H,H-3),3.34(m,1H,H-22),3.28(s,3H,O-CH3),2.51(m,2H,-CH2-),2.36(m,1H,-CH-),2.16(m,1H,-CH-),2.10(s,3H,-CH3),1.98(m,2H,-CH2-),1.15(d,3H,J＝6.83Hz,27-CH3),0.97(d,3H,J＝6.67Hz,21-CH3),0.95(s,3H,19-CH3),0.77(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):176.3,172.6,89.7,83.3,76.0,65.2,56.9,55.6,52.4,51.3,41.1,41.0,40.1,40.0,37.4,36.9,35.5,35.1,32.2,31.7,30.9,30.4,30.4,30.3,30.0,26.7,26.5,24.2,23.8,20.7,18.8,17.8,16.6,15.5.ESI-HRMS:m/z 614.3847[M+Na]+(Calcd for C33H55NO5NaS,614.3850).
实施例121：(22R,25S)-3β-甲氧基-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷(ZN-1-9)的合成
制备步骤同实施例56，仅将步骤A中反应试剂更换为硫酸二甲酯，步骤C中反应试剂更换为天冬氨酸甲酯盐酸盐，得到白色固体ZN-1-9(0.38g，65.0％)。1H NMR(400MHz,CDCl3,δ):6.56(d,1H,J＝8.10Hz,-NH-),4.80(m,1H,-CH-),4.21(dt,1H,J＝5.29,7.60Hz,H-16),3.68(s,3H,O-CH3),3.62(s,3H,O-CH3),3.42(br.s,1H,H-3),3.26(m,1H,H-22),3.21(s,3H,O-CH3),2.94(dd,1H,J＝4.72,17.07Hz,-CH2-),2.76(dd,1H,J＝4.66,17.07Hz,-CH2-),2.27(m,1H,-CH-),1.92(m,1H,-CH-),1.06(d,3H,J＝6.85Hz,27-CH3),0.91(d,3H,J＝6.85Hz,21-CH3),0.88(s,3H,19-CH3),0.70(s,3H,18-CH3).13C NMR(400MHz,CDCl3,δ):175.2,170.6,170.3,88.6,82.3,75.0,64.3,55.9,54.5,51.7,51.0,47.2,40.1,39.9,39.0,38.9,36.5,35.9,35.1,34.5,34.0,31.1,29.8,29.4,29.4,29.3,25.7,25.5,23.2,22.8,19.7,17.8,16.6,15.6.ESI-HRMS:m/z 612.3862[M+Na]+(Calcd for C33H53NO7Na,612.3871).
实施例122：菝葜皂苷元衍生物马来酸盐的制备
将5g菝葜皂苷元衍生物、100mL甲醇、2.6g顺丁烯二酸(马来酸)加入反应瓶中，升温至回流，搅拌反应30min，蒸除约80mL甲醇，剩余溶液冷冻静置析晶，过滤得马来酸司普替林粗品，将粗品加入乙醇加热溶解，趁热过滤，滤液冷冻静置，析晶，抽滤，真空干燥后得终产品菝葜皂苷元衍生物马来酸盐。
实施例123：菝葜皂苷元及其衍生物体外抑制β淀粉样蛋白聚集活性评价
1、实验材料
β淀粉样蛋白(Aβ1-40,Sigma公司)，六氟异丙醇(HFIP,Sigma公司)，硫磺素T(Th-T,Sigma公司)，姜黄素(Curcumin,Sigma公司)，磷酸二氢钾(KH2PO4)，氢氧化钠(NaOH)，DMSO。
2、实验仪器
恒温孵育箱，Varoskan Flash酶标仪，Dragonmed手动可调式移液器，Costar 96孔透明平底板，涡旋混匀器
3、实验方法
3.1Aβ的预处理
将预先保存于-80℃冰箱中的Aβ取出，以1mg/mL的浓度溶于HFIP中。室温下静置30min待其二级结构完全去除后，真空冷冻干燥去除HFIP，并置于-20℃冰箱中保存。
3.2磷酸缓冲液(PBS,pH＝7.4,0.1M)制备
缓冲液的制备(PBS,buffer)：pH＝7.4，浓度为0.1mol/mL。参照中华人民共和国药典2010年版第二部附录，取磷酸二氢钾1.36g，加0.l mol/L氢氧化钠溶液79mL，用水稀释至200mL，用精密pH酸度计进行校正，即得。
3.3Aβ反应试液的制备
取预处理后的Aβ冻干粉，用pH＝7.4的0.1mol/mL PBS将其配制成50μmol/L的Aβ试液，-20℃冻存备用。
3.4显色剂配置
精密称取Th-T粉末，用pH＝7.4的0.1mol/mL PBS，配制成为10μmol/L的Th-T试液，现用现配。
3.5化合物溶液的配制
用pH＝7.4的0.1mol/mL PBS和DMSO，将待测样品分别配置浓度为10-3，10-4，10-5，10-6和10-7mol/L，DMSO的最终体积分数不大于0.001。
3.6测定方法
组别设置：
3.6.1空白对照组：PBS 60μL,Aβ10μL,PBS+DMSO 10μL
3.6.2样品抑制组：PBS 60μL,Aβ10μL,药物10μL
3.6.3空白本底组：PBS 60μL,PBS 10μL,PBS+DMSO 10μL
3.6.4样品本底组：PBS 60μL,PBS 10μL,药物10μL
于96孔板分别加入上述各组溶液，置于恒温孵育箱中37℃孵育24h，然后向各组中加入80μL Th-T溶液，置于恒温孵育箱中37℃孵育5min，用酶标仪于λex＝450nm，λem＝485nm处测定各组荧光值。每组重复3次。
3.7结果分析：
以Aβ单独孵育后用Th-T测定的485nm处荧光值作为对照：为了避免化合物本身具有的荧光对结果的干扰，以扣除单独受试化合物用Th-T测定的荧光值作为本底。抑制率的计算公式如下：
4、各样品(c＝50-6mol/L)对Aβ1-40的抑制率(％)如下表所示：
实施例124：菝葜皂苷元衍生物乙酰胆碱酯酶抑制活性
1实验材料
磷酸氢二钠；磷酸二氢钾；氢氧化钠；浓盐酸；三氯化铁；盐酸羟胺；乙酰胆碱；他克林；考马斯亮蓝；牛血清白蛋白；实验动物：Wistar大鼠，雌性，体重260g左右。
2试验方法
2.1溶液的配置
他克林和待筛选的药物的浓度为10-6mol/L，DMSO的体积分数为0.001。
2.2乙酰胆碱酯酶的制备
Wistar大鼠(约260g，雌性)断头处死后，在冰上迅速取出大脑，用干净的滤纸吸去大脑组织表面的水分和血液，精密称重，加入4℃PBS溶液为脑重的10倍，冰上匀浆。离心机温度设置为0～4℃，以3000r/min的转速离心20min，取上清。
2.3考马斯亮蓝测定蛋白总量
2.3.1标准曲线的绘制
配制浓度为0，0.1，0.2，0.3，0.4，0.5，0.6mg/ml的标准蛋白，取100ul加入到5ml事先配制好的考马斯亮蓝溶液中，混匀，使用酶标仪检测其在595nm波长下的吸光度值。
2.3.2样品总蛋白含量的测定
把酶液稀释5倍，与上部同样的操作检测稀释后酶液的蛋白浓度。
2.3.3酶反应液的制备
根据上述酶液总蛋白含量，将酶反应液的蛋白浓度定量为0.52mg/ml。
2.3.4AChE抑制剂的检测
2.3.4.1在反应体系中含有0.007mol/l乙酰胆碱(20μl)，浓度10-6mol/L的药物(10μl)和乙酰胆碱酶溶液(20μl)，反应终体积为50μl。
2.3.4.2组别的设置
2.3.4.3 37℃孵育50min后加入70μl的盐酸羟氨与氢氧化钠的混合液(1mol/l盐酸羟氨与3.5mol/l氢氧化钠提前20min，等容混合)，振荡1min。
2.3.4.4加入40μl 1:2盐酸溶液，振荡1min。
2.3.4.5加入10％FeCl3 40μl，振荡充分反应。
2.3.4.6 530nm波长处测吸光度。
2.3.4.7计算公式
全酶活性T全酶＝(A空白2－A空白1)－(A对照2－A对照1)，
加药后酶的活性T酶＝(A空白2－A空白1)－(A样－A对照1)
酶的抑制率＝(T全酶－T酶)/T全酶×100％
3试验结果
3.1总蛋白含量测定结果
标准曲线如图1所示：
经测定酶液中总蛋白含量为2.33mg/ml，将其稀释4.5倍后至总蛋白含量为0.52mg/ml
3.2各样品的酶的抑制率(％)
经测定，各样品(c＝1.0-6mol/L)的酶的抑制率值(％)如下表所示：
实施例125：菝葜皂苷元及其衍生物对β-amyloid protein 40的抑制作用
1材料与方法
1.1实验细胞：大鼠PC12细胞。
1.2药物和化学试剂：
菝葜皂苷元及其衍生物，由沈阳药科大学提供，其纯度大于98％；β-amyloidprotein 40购于北京博奥森生物技术有限公司；DMEM高糖培养基、双抗、胰酶购于购于美国Sigma公司。
1.3实验仪器：
水套CO2培养箱；生物安全柜；Leica倒置相差显微镜；BD流式细胞仪；BIO-RAD酶标仪。
1.4实验方法
1.4.1Aβ40的老化：
将10mg的Aβ溶解于4715.6μL的灭菌水中，配制成2mmol/L的母液，分装，在37℃孵育96h后，零下20℃保存待用。同时孵育不含Aβ40的灭菌水96h，作为阴性对照组。
1.4.2药物配制：
取菝葜皂苷元及其衍生物100mg，加2ml的灭菌水混匀使其溶解，配制成50g/L的母液并分装。工作液浓度分别为0.05，0.5，5，15，20mg/L。MTT液用PBS配制，使用浓度为6g/L。
1.4.3细胞培养：
将PC12细胞接种于培养瓶中，培养在含12％胎牛血清，200U/ml青霉素和200μg/ml链霉素的DMEM培养基内，37℃，10％CO2培养箱中培养，采用对数生长期的细胞进行实验。
1.4.4Aβ40的损伤模型构建及其活力测定：
对数生长期的PC12细胞，以2.5×105/ml的浓度接种于96孔细胞培养板，培养24h后加入不同终浓度为5、10、20、40μmol/L的Aβ40，每组5复孔；并设立相应的阴性对照组，即加入与10μmol/L Aβ42相同量的孵育4天的灭菌水，12、36、72h后，倒置荧光显微镜观察细胞的形态变化。每孔加入10μl MTT继续孵育8h，弃去培养基并加入DMSO250μL，37℃振荡15min，酶标仪测定490nm的吸光度值(OD490)，计算抑制率。
1.4.5MTT法测菝葜皂苷元及其衍生物的抑制作用：
对数生长期的PC12细胞，以2.5×105/mL的浓度接种于96孔细胞培养板，培养24h后加入不同浓度的菝葜皂苷元及其衍生物，每组5复孔，再加入10μmol/L的Aβ40，36h后倒置相差显微镜下观察其形态变化。MTT法和抑制率的计算方法同上。
2结果
2.1Aβ40刺激后细胞形态观察：
倒置相差显微镜观察，正常组细胞密集，连接紧密，周围有光圈，有立体感。在Aβ40作用下，细胞突触变短，贴壁性差，胞间连接较松，碎片较多，胞质较暗淡，部分发生皱缩，胞浆中有较多颗粒。Aβ40浓度越大时间越长细胞的状态越差48小时的细胞数目明显太多，细胞圆润性变差。
2.2不同浓度的菝葜皂苷元及其衍生物对Aβ40诱导PC12细胞的影响：
倒置显微镜下观察，在菝葜皂苷元衍生物的影响下，细胞突触相对模型组变长，在低浓度时变化不大，在中间浓度时观察到细胞碎片变少，细胞光圈变明显，在高浓度时细胞碎片反而增多，变圆细胞的数目增多。用不同浓度的菝葜皂苷元衍生物保护，从0.15mg/L开始和模型组有了显著性差异，在0.4mg/L浓度时其抑制率达到最小，与模型组和菝葜皂苷元组有显著性差异(P<0.01)，在10mg/L浓度时抑制率大于模型组和菝葜皂苷元组。故在后期实验中就采用0.4mg/L浓度的菝葜皂苷元及其衍生物。
2.3菝葜皂苷元及其衍生物对Aβ40诱导的PC12细胞凋亡影响：
荧光显微镜下观察正常细胞，虽然细胞铺板密度较大，但染色的很少。模型组和菝葜皂苷元组出现明显的凋亡的特点，即细胞核和膜同时染色，而且胞核浓染或颗粒状荧光团块比较多。治疗组主要较多出现早期凋亡的特点，即细胞膜被染成了绿色，而细胞核染色的数目较模型组少，晚期凋亡的特点相对较少。表明菝葜皂苷元衍生物较模型组和菝葜皂苷元组明显抑制Aβ40诱导的PC12细胞凋亡。
实施例126：菝葜皂苷元及其衍生物行为学活性实验
1.实验动物
APP转基因小鼠,清洁级，由扬州大学比较医学中心提供，动物质量合格证号：SCXK(苏)2007-0001。体重：18-22g，性别：雌雄各半，各组动物数:10只/组
2.药物与试剂
名称：ZA-3-6(Ⅰ)、ZB-3-1(Ⅱ)、ZC-3-5(Ⅲ)、ZD-3-7(Ⅳ)、ZE-3-8(Ⅴ)、ZF-3-6(Ⅵ)、ZG-1-8(Ⅶ)、ZH-1-1(Ⅷ)、ZH-1-12(Ⅸ)、ZI-1-6(Ⅹ)、ZL-1-3(Ⅺ)，溶剂：0.5％CMC-Na；配制方法：给药前用水0.5％CMC-Na分别配制成1.67mg/mL和3.33mg/mL溶液。阳性对照药：石杉碱甲片(huperzine A tablets，0.05mg)，上海复旦复华药业有限公司批号：091101。
3.主要试剂与仪器
3.1药品与试剂：
石杉碱甲片：上海复旦复华药业有限公司批号：091101；氢溴酸东莨菪碱注射液(scopolamine hydrobromide inJection，1ml:0.3mg)，上海禾丰制药，批号：090303。
3.2主要仪器：
Morris水迷宫：上海吉量软件科技有限公司；Sartorius分析天平：北京多利斯天平有限公司；TLS-2000A型电子秤：常熟双杰测试仪器厂。
4.试验主要步骤
小鼠按体重随机分为5组：正常对照组，阴性对照组，石杉碱甲组，化合物分为中剂量组和高剂量组，每组10只，雌雄各半。连续灌胃给药7天，并腹腔注射东莨菪碱(0.8mg/kg，0.2ml/10g)，正常对照组动物腹腔注射等容积的生理盐水。水迷宫试验为期5天，前4天为定位航行试验，第5天为空间搜索试验。水迷宫试验期间继续每天灌胃给药，并予试验开始前10-15min腹腔注射东莨菪碱。
4.1定位航行试验：
将水迷宫平台置于第4象限，放入25℃左右水至没过平台5mm。分别从1、2、3、4四个象限(4个入水点)将小鼠面向池壁放入水中，使其自由游泳90s，90s内小鼠找到平台并上台停留10s后将其从平台上取下休息，计算机监测并记录动物从入水开始寻找至爬上平台的路线、所需的时间(潜伏期)及游泳速度等。若90s内动物未找到平台，则将小鼠引到平台，并停留30s，这时潜伏期记为90s。
4.2空间搜索试验：
试验第5天撤除平台，任选一象限将各组小鼠依次从该象限面向池壁放入水中，使其自由游泳90s，记录小鼠在第4象限停留的时间占总时间的百分比以及跨越原平台所在位置的次数。数据采集和处理均由图像自动监视和处理系统完成。
5.统计学处理
所有数据均用均值±标准差表示。采用SPSS11.5软件进行分析,数据比较采用单因素方差分析。P﹤0.05表示有显著性差异，P﹤0.01表示有极显著性差异。
6.剂量设置
化合物Ⅰ低组(Ⅰa组)：5mg/kg；化合物Ⅰ中组(Ⅰb组)：10mg/kg；
化合物Ⅰ高组(Ⅰc组)：50mg/kg
化合物Ⅱ低组(Ⅱa组)：5mg/kg；化合物Ⅱ中组(Ⅱb组)：10mg/kg；
化合物Ⅱ高组(Ⅱc组)：50mg/kg
化合物Ⅲ低组(Ⅲa组)：5mg/kg；化合物Ⅲ中组(Ⅲb组)：10mg/kg；
化合物Ⅲ高组(Ⅲc组)：50mg/kg
化合物Ⅳ低组(Ⅳa组)：5mg/kg；化合物Ⅳ中组(Ⅳb组)：10mg/kg；
化合物Ⅳ高组(Ⅳc组)：50mg/kg
化合物Ⅴ低组(Ⅴa组)：5mg/kg；化合物Ⅴ中组(Ⅴb组)：10mg/kg；
化合物Ⅴ高组(Ⅴc组)：50mg/kg
化合物Ⅵ低组(Ⅵa组)：5mg/kg；化合物Ⅵ中组(Ⅵb组)：10mg/kg；
化合物Ⅵ高组(Ⅵc组)：50mg/kg
化合物Ⅶ低组(Ⅶa组)：5mg/kg，化合物Ⅶ中组(Ⅶb组)：10mg/kg；
化合物Ⅶ高组(Ⅶc组)：50mg/kg
化合物Ⅸ低组(Ⅸa组)：5mg/kg；化合物Ⅸ中组(Ⅸb组)：10mg/kg
化合物Ⅸ高组(Ⅸc组)：50mg/kg
化合物Ⅹ低组(Ⅹa组)：5mg/kg；化合物Ⅹ中组(Ⅹb组)：10mg/kg
化合物Ⅹ高组(Ⅹc组)：50mg/kg
化合物Ⅺ低组(Ⅺa组)：5mg/kg；化合物Ⅺ中组(Ⅺb组)：10mg/kg
化合物Ⅺ高组(Ⅺc组)：50mg/kg
阳性对照药：石杉碱甲0.08mg/kg
给药容量为0.3ml/10g
7.给药方法
灌胃给药
8.试验对照
正常对照组：给予与阳性对照等体积的0.5％CMC-Na溶液
阴性对照组：给予与阳性对照等体积的0.5％CMC-Na溶液
阳性对照组：给予石杉碱甲溶液(2.67×10-3mg/ml)，0.3ml/10g
9.试验结果
定位航行试验结果显示,与阴性对照组相比，正常对照组、阳性对照组、化合物ZA-3-6(Ⅰ)和ZB-3-1(Ⅱ)组小鼠第3天和第4天潜伏期与阴性对照组有显著或极显著差异(P<0.05,P<0.01)，结果见表1。空间搜索试验显示,与阴性对照组相比，正常对照组、阳性对照组、化合物ZA-3-6(Ⅰ)和ZB-3-1(Ⅱ)组小鼠在第4象限停留时间占总时间的百分比与阴性对照组有显著差异(P<0.05)结果见表2。
表1化合物Ⅰ和Ⅱ对东莨菪碱致小鼠记忆获得障碍的影响(n＝9-10)
*P<0.05,**P<0.01，与阴性对照组相比较；##P<0.01,与阳性对照组相比较
表2化合物Ⅰ和Ⅱ对东莨菪碱致小鼠记忆获得障碍的影响(n＝9-10)
*P<0.05与阴性对照组相比较
10.实验结论：
10.1小鼠东莨菪碱模型水迷宫实验
化合物Ⅱ的高、中剂量组具有提高东莨菪碱模型小鼠学习记忆能力的作用。表现在缩短潜伏期作用、增加经过平台次数、延长平台停留时间、增加平台停留距离、延长有效区停留时间、等方面，后面应进一步将此剂量范围在大鼠身上进行验证并探讨机制。
化合物Ⅰ的高剂量组具有一定的提高东莨菪碱模型小鼠学习记忆能力的作用。
10.2小鼠跳台实验(记忆获得)
化合物Ⅱ高、中、低剂量均有对抗东莨菪碱造成小鼠记忆获得障碍的作用。表现在记忆潜伏期明显延长、记忆错误次数明显降低，药效现良好的剂量依赖关系，高剂量作用强度优于石杉碱甲片。
化合物Ⅱ高、中剂量有对抗东莨菪碱造成的记忆获得障碍的作用。表现在潜伏期延长、错误次数降低，低剂量没有明显的对抗作用，高、中剂量之间药效呈现剂量依赖关系，高剂量作用强度优于石杉碱甲片。
化合物Ⅱ高、中、低剂量均有对抗东莨菪碱造成的记忆获得障碍的作用。表现在潜伏期延长、错误次数降低，但三个剂量药效强度没有剂量依赖关系，作用强度不如石杉碱甲片。而化合物Ⅰ高、中、低剂量对东莨菪碱造成的记忆获得障碍无明显对抗作用。
10.3小鼠跳台实验(记忆再现)
化合物Ⅱ高剂量有明显对抗乙醇造成小鼠记忆再现障碍的作用，尤其对降低错误次数表现更突出，效果优于石杉碱甲片。化合物Ⅰ高、中、低剂量对乙醇造成的记忆再现障碍无明显对抗作用。
实施例127：菝葜皂苷元及其衍生物急毒实验
化合物ZA-3-6(Ⅰ)和ZB-3-1(Ⅱ)经口服给药，观察菝契皂苷元衍生物对清醒小白鼠精神，神经系统及自主活动；对麻醉犬血压、心率、呼吸，心电的影响。试验结果表明：小鼠以40.0mg/Kg，80.0mg/Kg，160.0mg/Kg灌胃给药对受试小白鼠精神，神经系统，自主活动均无明显影响。以7.0mg/Kg、14.0mg/Kg、28.0mg/Kg。经胃管给药后，在给药后3小时观察各给药组受试动物血压、呼吸、心率、心电与给药前比较及各给药组与对照组比较。
化合物Ⅰ和Ⅱ给小鼠急毒实验均未发生死亡，做不出LD50，其最大给药量(MLD)为20mg·kg-1·d-1和4mg·kg-1·d-1；化合物Ⅰ在给药后5天内会有小鼠食少、体重减轻、怠动等毒性表现，第6天起逐渐缓解。
化合物Ⅰ具有明显的药效且低毒，但量效关系显示，后续需要剂量区间摸索和大鼠药效验证，化合物Ⅱ虽有一定药效，但有迟发毒性，后续开发会有一系列工作待做。
实施例128：菝葜皂苷元及其衍生物活性的分子对接实验评价
应用的主要实验软件有：Discovery Studio 3.0、MVD等。
实验目标蛋白为：β-淀粉样蛋白，乙酰胆碱酯酶。
分子对接的实验过程：
Aβ三维晶体结构的获取与格式转换
从蛋白质数据库中获得Aβ(PDB；entry code：1IYT)，AChE(PDB；entry code：4BDT)晶体结构(图2)。使用Discovery Studio 3.0软件中的蛋白准备程序“ProteinPreparation”对蛋白进行预处理，分配键级、加氢、删除多余的水分子及不必要的离子和辅因子等，检查氨基酸结构和构型，分配氢键作用、产生质子化状态并优化氢键网络，最后对蛋白氢原子进行能量最小化。根据文献资料，选择Aβ的Aβ28-42氨基酸片段为活性位点。
待筛选化合物的预处理：将设计的小分子化合物，用Discovery Studio 3.0软件中小分子准备程序“Protein Ligands”对化合物进行预处理，再对化合物进行加氢。
分子对接
对处理好的小分子化合物与Aβ受体和AChE受体，利用MVD软件中分子对接程序“Docking wizard”进行分子对接运算，设计对接各项参数，最后点击start运行作业，等待作业完成。对接完成后，查看配体-受体间的氢键相互作用和Pi-Pi相互作用，并查看配体分子每个pose相应的“MolDock score”值，对接结果如下表所示。
菝葜皂苷元衍生物与靶蛋白对接结果如图3所示，打分值显示菝葜皂苷元衍生物对接结果良好，与修饰前的菝葜皂苷元比较具有明显提高。
药理结果表明菝契皂苷元衍生物对AchE具有一定的抑制作用，能够很强地抑制Aβ蛋白聚集，明显改善APP转基因痴呆模型小鼠的病理学特征，这可能是其主要的作用机制，对神经系统退行性疾病具有良好的治疗效果。
实施例129：菝葜皂苷元衍生物胶囊剂的制备
菝葜皂苷元衍生物20g，制成1000粒
菝葜皂苷元衍生物20g过80目筛加15％的淀粉浆制成软材后，过14目尼龙筛制粒，于65℃干燥至含水量在3％以下，填入空胶囊中，即得。
实施例130：菝葜皂苷元衍生物颗粒剂的制备
菝葜皂苷元衍生物30g加适量70％乙醇溶解，搅匀，静止12h，过滤，滤液减压回收乙醇，浓缩汁膏状，加入6倍量的糖粉，混合均匀，加入70％的乙醇少许，制成软材，过14目尼龙筛制粒，湿颗粒于65℃干燥，干颗粒过14目筛整粒，再过4号筛(65目)筛去细粉，分装，密封，包装即得。
Claims (10)
1.如下结构所示的菝葜皂苷元衍生物及其药学上可接受的盐：
R1为H、取代或未取代的苄基，所述取代基为卤素、C1-C4烷基、C1-C4烷氧基；R2为OH、卤素、-NH2、-NR’R”、取代或未取代的5-12元含氮杂环或含氮芳杂环(其中氮原子位置为1位、1,3位、1,4位，所述取代基为卤素、C1-C4烷基、C1-C4烷氧基)、含氮生物碱及其盐、R取代的氨基酸酯及其相应的氨基酸，所述的R为H、C1-C4烷基(其中烷基链中氢原子可以由苯基、甲硫基、甲氧甲酰基所取代)，R’、R”为CnH2n+1，n＝1、2、3、4；
R3为C1-C4烷基；
R4为C1-C4烷基、取代或未取代的苄基，所述取代基为：卤素、C1-C4烷基、C1-C4烷氧基。
2.权利要求1的菝葜皂苷元衍生物及其药学上可接受的盐，其特征在于：R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基。
3.权利要求1或2的菝葜皂苷元衍生物及其药学上可接受的盐，其特征在于：
R2为OH、卤素、-NH2、-NR’R”、 含氮生物碱及其盐、及其相应的氨基酸；
R为H、-CH3、 。
4.权利要求1-3中任何一项所述的菝葜皂苷元衍生物及其药学上可接受的盐，其特征在于：
式Ⅰ中，当3位为α或β构型时，R1为苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R2为-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅱ中，R2为-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅲ中，R2为-NH2、-NR’R”、 含氮生物碱及其盐；
式Ⅳ中，当3位为α或β构型时，R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R2为-NH2、-NR’R”、 含氮生物碱及其盐和(R为H、-CH3、 )和及其相应的氨基酸；
式Ⅴ中，当3位为α或β构型时，R1为H、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R3为甲基、乙基；
式Ⅵ中，R2为-NH2、NR’R”、 含氮生物碱及其盐和(R为H、-CH3、 )和及其相应的氨基酸；
式Ⅶ中，当3位为α或β构型时，R1为苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基时，R4为甲基、乙基、苄基、对氟苄基、对氯苄基、对溴苄基、对甲基苄基、对甲氧基苄基；
R’、R”为CnH2n+1，n＝1、2、3、4。
5.如下的菝葜皂苷元衍生物及其药学上可接受的盐，选自：
(22R,25S)-3β-苄氧基-26-哌啶基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二正丙氨基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二正丁氨基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-吡咯基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(N-甲基哌嗪基)-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-吗啉基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-二甲氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-二正丙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-二正丁氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-吡咯基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-吡啶基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷；
(22R,25S)-3β-(4’-氟苄氧基)-26-吗啡啉基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-二甲氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-二正丙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-二正丁氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-吡咯基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-哌啶基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷；
(22R,25S)-3β-(4’-溴苄氧基)-26-吗啉基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二甲氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二正丙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二正丁氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-吡咯基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-哌啶基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基哌嗪基)-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-吗啉基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二甲氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二正丙氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-二正丁氨基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吡咯基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吡啶基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3β-(4’-甲氧基苄氧基)-26-吗啉基-5β-呋甾烷；
(22R,25S)-3-氧代-26-二甲氨基-5β-呋甾烷；
(22R,25S)-3-氧代-26-二乙氨基-5β-呋甾烷；
(22R,25S)-3-氧代-26-吡咯基-5β-呋甾烷；
(22R,25S)-3-氧代-26-吡啶基-5β-呋甾烷；
(22R,25S)-3-氧代-26-哌嗪基-5β-呋甾烷；
(22R,25S)-3-氧代-26-(N-甲基哌嗪基)-5β-呋甾烷；
(22R,25S)-3-氧代-26-吗啉基-5β-呋甾烷；
(22R,25S)-3-氧代-26-咪唑基-5β-呋甾烷；
(22R,25S)-3-氧代-26-(苯并咪唑基)-5β-呋甾烷；
(22R,25S)-26-二乙氨基-3-氧代-4-烯-呋甾烷；
(22R,25S)-26-哌啶基-3-氧代-4-烯-呋甾烷；
(22R,25S)-26-苯并咪唑基-3-氧代-4-烯-呋甾烷；
(22R,25S)-3β-苄氧基-26-二甲氨基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二乙胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二正丙胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-二正丁胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-吡咯基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-吡啶基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-哌嗪基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(N-甲基哌嗪基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-吗啡基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-[N-(4-甲基苯基)]-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(N-甲基苯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(1,2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二甲氨基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二乙胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二丙胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-二丁胺基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-吡咯基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-吡啶基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-哌嗪基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基哌嗪基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-吗啡基-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-[N-(4-甲基苯基)]-26-氧代-5β-呋甾烷；
(22R,25S)-3β-(4’-甲基苄氧基)-26-(N-甲基苯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-26-(5-乙基-1,3,4-恶二唑-2-基)-5β-呋甾烷；
(22R,25S)-3氧代-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3氧代-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对氟苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对氯苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对溴苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对甲基苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对甲氧基苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-苄氧基-32-对硝基苄基-1H-1,2,3-三氮唑-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-羟基-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(3-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(2-甲基-1-甲氧甲酰基-丁胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(1-甲氧甲酰基-甲胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(2-甲基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(2-甲氧甲酰基-吡咯基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(2-苯基-1-甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(3-甲硫基-1-甲氧甲酰基-丙胺基)-26-氧代-5β-呋甾烷；
(22R,25S)-3β-甲氧基-26-(1，2-二甲氧甲酰基-乙胺基)-26-氧代-5β-呋甾烷。
6.一种制备权利要求1所述的菝契皂苷元衍生物的方法，其特征在于，包括以下步骤：
(1)
(2)
(3)
(4)
7.一种药物组合物，包含权利要求1-5中任何一项所述的菝葜皂苷元衍生物及其药学上可接受的盐作为活性成分。
8.一种药物制剂，包含权利要求1-5中任何一项所述的菝葜皂苷元衍生物及其药效学上可接受的盐或权利要求7所述的药物组合物。
9.权利要求1-5中任何一项所述的菝葜皂苷元衍生物及其药效学上可接受的盐或权利要求7所述的药物组合物或权利要求8所述的药物制剂在制备治疗神经系统退行性病变药物中的应用。
10.权利要求1-5中任何一项所述的菝葜皂苷元衍生物及其药效学上可接受的盐或权利要求7所述的药物组合物或权利要求8所述的药物制剂在制备治疗阿尔兹海默病、帕金森病药物中的应用。
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|---|---|---|---|---|
| CN1452630A (zh) * | 2000-01-06 | 2003-10-29 | 菲特法姆股份有限公司 | 取代的皂苷配基及它们的用途 |
| CN101223185A (zh) * | 2005-05-17 | 2008-07-16 | 萨托里医药公司 | 用于治疗神经变性障碍的化合物 |
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