CN108299541B - 海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与抗炎应用 - Google Patents
海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与抗炎应用 Download PDFInfo
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Abstract
本发明公开了海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与抗炎应用。其化学结构如结构式I的酯类衍生物、结构式Ⅱ的酰胺类衍生物、结构式Ⅲ五元环脱水衍生物或结构式Ⅳ的八元环脱水酰胺类衍生物，或其药学上可接受的盐或立体异构体或其前药分子：
R0：为X取代的碳原子数为1‑10的烷烃、烯烃、炔烃、环烷烃或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或者COOCH3；R1、R2：为X取代的碳原子数为1‑10的烷烃、烯烃、炔烃、环烷烃、N/O/S杂环或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或者COOCH3。本发明通过将Asperterpinol B结构修饰，得到一系列具有很好的抗炎活性化合物，为临床治疗选择提供了新的抗炎药物。
Description
技术领域
本发明涉及药物化学领域，具体地说，涉及海洋微生物来源的二倍半萜Asperterpinol B衍生物的制备和其衍生物在抗炎药物方面的应用。
背景技术
炎症，是免疫的基本防御机制，是对有害刺激、感染或者组织损伤引起的适 应性反应。然而，炎症本身可能会导致组织损伤并导致许多疾病或者是癌症(R. Medzhitov etal.,2008；R.Medzhitov et al.,2010)。因此，一般认为控制炎症反应 是有益的(例如，在预防感染方面)，但是如果失调(例如，引起脓毒性的)会成为 有害休克。
炎症与一氧化氮有着密切关系。一氧化氮(Nitric oxide，NO)是一种重要 的细胞内和细胞间的高度活性信号分子，在心血管、神经和神经生理及病理生理 机制的调节免疫系统中扮演重要角色。它可以调节血管系统中的血管张力，是免 疫系统中重要的宿主防御效应物；另一方面，它是一个自由基(NO.)，在病理 过程中是细胞毒素，特别是在炎症过程中(Alderton et al.,2001；Bogdan,2001； Dawn and Bolli,2002；Moncada and Higgs,1991)。胞内L-精氨酸(L-arginine)经一 氧化氮合成酶(NOS)催化分解为L-瓜氨酸和NO自由基。机体中NOS可分为结 构型NOS(cNOS)和诱导型NOS(iNOS)两大类，而cNOS又可分为神经元型一氧 化氮合成酶(nNOS)，存在于神经元细胞；和内皮型一氧化氮合成酶(eNOS)，存在于内皮细胞。cNOS催化产生固定量的NO，主要维持机体的正常生理活动， 包括血管扩张、平滑肌松弛及抑制血小板凝集等作用；当致炎因子如LPS刺激 巨噬细胞会产生iNOS，iNOS诱导产生大量的N0(Lanas et al.,2008；Mackenzie et al.,2008)，造成血管过度舒张和细胞损伤，导致炎症反应及相关病变，如败血性 休克、中风、DNA损伤、基因突变或细胞癌变等(Kanwar et al.,2009)，因此对 iNOS酶的抑制可能有利于炎症性疾病的治疗(Bogdanet al.,2001；Kroncke et al., 1998)。
目前，临床上使用的抗炎药物主要是非甾体类抗炎药。非甾体类抗炎药，在 世界范围内普遍使用处方药和非处方制剂。这些药物在用于治疗短期常见的疼痛 疾病，如头痛、月经疼痛，还有用于长期治疗慢性炎性疾病，如风湿性关节炎(Y.C. Lee et al,.2012；C.Pereira-Leite et al.,2017)。这种非甾类药物治疗方法很普遍，但 是存在的缺点就是出现广泛的不良反应。非甾体类抗炎药(NSAIDs)长期治疗会 诱导GI毒性包括胃食管反流、出血、穿孔和阻塞，严重增加了血管和胃肠道的 风险，同时心脏衰竭的风险也会翻一倍(Y.C.Lee et al.,2012；C.Pereira-Leite et al., 2017)。因此，在发明阿司匹林100多年后，仍然需要一个安全、无毒副作用的 抗炎药物非常重要。
海洋特殊生态环境中的生物，其代谢产物丰富新颖，是具有新药开发潜力 的新领域，拓展新药的重要资源。人们从海洋生物中提取出的海洋天然产物代谢 物如萜类、甾醇类、多糖、生物碱、脂肪酸和蛋白质，这些海洋天产物具有良好 的生物活性包括抗菌、抗真菌、抗原生生物、抗结核、抗病毒、抗炎、酶抑制剂 等药理活性(Alejandro et al.,2013)，对开发高效安全抗炎药物提供重要资源。人们 发现萜类具有良好的抗炎活性，如来自无脊椎海鸡冠(俗称珊瑚虫)的elisabethin H(Shi,Y.P et al.,2009)、durumhemiketalolideC(Cheng,S.Y et al.,2009)、L. crassum diterpenes(Wanzola et el.,2010)，来自海绵的tedanol(Costantino et al.,2009) 和coscinolactams(De Marino et al.,2009)，来自海鞘的rossinones A&B(Appleton et al.,2009)，这些萜类化合物具有很强的抗炎活性IC50值达10uM以内。
本专利的Asperterpinol B是一种结构稀有的的5/8/6/6的四环骨架，从红树林内生真菌曲霉菌085242中分离出来的二倍半萜(Ze’en et al.,2013)。因此本发明对 其进行结构修饰，得到一系列具有很好的抗炎活性化合物，为临床治疗选择提供 了新的可能选择。
发明内容
本发明的目的之一是提供一类对炎症具有良好治疗效果的二倍半萜Asperterpinol B衍生物或其药学上可接受的盐或立体异构体及其前药分子。
实现上述目的的技术方案如下：
通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱 水形成的二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构 体或其前药分子，具有式I，Ⅱ，Ⅲ或Ⅳ的结构。
通过与酸酐类化合物构成酯键的二倍半萜Asperterpinol B的衍生物中，酸酐 化合物优选地，酸酐化学结构可不同，包括，但不局限于，乙酸酐、丙酸酐、丁 酸酐、异丁酸酐、正己酸酐、丁二酸酐、戊二酸酐、一氯二氟乙酸酐；通过与胺 类化合物构成酰胺键的二倍半萜Asperterpinol B的衍生物中，胺类化学结构可不 同，包括，但不局限于，正丙胺，环己胺，呋喃甲胺，苯乙胺，噻吩甲按，环己 烯乙胺，噻吩乙胺，对溴苯胺，庚胺，呋喃乙胺，4-(2-氨乙基)吗啉，二烯丙氨， 四氢吡咯烷，o-苄基羟胺，四氢异喹啉，N-(3-氨丙基)-吗啡啉，吗啡，1-三氟甲 基环戊氨，对甲氧基苯胺，环丙氨，环戊胺，萘胺，3-溴-吡啶-2-氨，3-溴-1-氢吡唑-4-氨。
本发明的另一目的是提供二倍半萜Asperterpinol B衍生物的合成方法。
实现上述目的技术方案如下：
通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱 水形成的二倍半萜Asperterpinol B的衍生物。
1)二倍半萜Asperterpinol B与酰卤、羧酸、酸酐反应成具有式I结构的酯类衍生物。
2)结构式为
的二倍半萜Asperterpinol B衍生物与胺类化合物反应生成具有结构式Ⅱ的酰胺类衍生物。
3)二倍半萜Asperterpinol B在三氟化硼乙醚作用下五元环脱水生成具有式Ⅲ的衍 生物。
4)结构为
的二倍半萜Asperterpinol B先与无水二氯亚砜反应生成中间体酰氯
再与胺类化合物反应生成具有式Ⅳ的 衍生物。
所述胺类化合物为伯胺或仲胺。
本发明的另一目的是提供一种治疗炎症的药用化合物。
实现上述目的技术方案如下：
一种治疗炎症的药用衍生物，其药学活性成份通过与酸酐反应形成酯键或与 胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜Asperterpinol B的 衍生物或者其药学上可接受的盐或立体异构体或其前药分子。
本发明的另一目的是提供上述二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体或其前药分子的应用。
实现上述目的技术方案如下：
上述通过通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或 八元环脱水形成的二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或 立体异构体或其前药分子在制备抗炎药物中的应用。
本发明通过将二倍半萜Asperterpinol B进行衍生化，得到新的化学实体，得 到的新化合物具有很好的治疗炎症的效果，为临床治疗选择提供了新的药物。
具体实施方式
通过以下实施例对本发明具体实施方法进行描述，但该实施例并非用于限制 本发明的保护范围。
实施例1
AsB-1:(2aS,6aS,6bS,12S,12aS,13R,13aS,Z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3, 4,5,6,6a,6b,7,8,12,12a,13,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]nap hthalen-13-ol的合成
实验步骤：
称取AsB(38.7mg，0.103mmol，1eq)于50ml的圆底烧瓶，加入2ml二氯 甲烷溶解，1ml注射器滴加三氟化硼乙醚(质量分数为46.5％-49.5％)(50ul， 0.135mmol，1.3eq)于溶液中，室温搅拌反应半小时，半小时反应完加三乙胺停 止反应，调节PH至中性，加饱和食盐水15ml及二氯甲烷(3×20ml)萃取，分 离得有机相，加无水硫酸镁干燥，减压蒸馏得粗产品，石油醚乙酸乙酯体系 (V:V＝1：10)柱层析得白色固体38.5mg，产率为95％。
白色固体,产率为95％,m.p.122.5-124.7℃.1H NMR(500MHz,CDCl3)δ5.60 (d,J＝11.3Hz,1H),5.15–4.68(m,1H),3.94(d,J＝5.8Hz,1H),3.16(s,1H),2.66 (dd,J＝18.5,5.5Hz,1H),2.41(dd,J＝11.1,9.8Hz,1H),2.26–2.17(m,1H),1.90 (dd,J＝13.9,10.4Hz,1H),1.85–1.76(m,2H),1.64(s,3H),1.42(ddd,J＝11.4,9.6, 3.7Hz,3H),1.34–1.21(m,4H),1.19–1.10(m,2H),1.08–1.02(m,2H),0.97(t,J ＝10.3Hz,1H),0.91(s,3H),0.89(s,3H),0.87(d,J＝5.4Hz,3H),0.83(s,3H),0.64 (d,J＝7.2Hz,3H).
EIMS:calcd for C25H40O:356.Found:356.
实施例2
AsB-S1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl acetate的合成
实验步骤：
称取AsB(42.3mg，0.11mmol，1eq)于50ml两口圆底烧瓶，加2ml无水吡啶 溶解，加入酸酐(1.1mmol，10eq)，置于90℃油浴锅冷凝回流反应，TLC跟踪 反应直至反应完全。冷却至室温加2M HCl溶液停反应，调节溶液PH至2，搅拌 15min，加饱和食盐水15ml和EA(3×15ml)萃取得有机相，无水硫酸镁干燥，减 压蒸馏得粗产品，石油醚乙酸乙酯体系(V:V＝1:2)柱层析得纯白色固体。
白色固体,产率为67.6％,m.p.58.2-60.8℃.1H NMR(500MHz,CDCl3)δ 4.73(d,J＝6.5Hz,1H),4.57(d,J＝10.7Hz,1H),2.99(d,J＝2.1Hz,1H),2.79(dd, J＝17.7,6.6Hz,1H),2.61(t,J＝14.7Hz,1H),2.29–2.17(m,2H),2.03(s,3H), 1.68(ddd,J＝10.2,9.7,5.8Hz,2H),1.63(s,3H),1.60(dd,J＝13.1,6.0Hz,1H), 1.53(td,J＝11.4,3.8Hz,1H),1.40(td,J＝13.5,3.8Hz,2H),1.35–1.25(m,6H), 1.21–1.10(m,3H),1.09(s,3H),0.91(s,3H),0.90–0.84(m,6H),0.78(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C27H44O3Na:439.31827.Found:439.31755.
实施例3
AsB-S2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl butyrate的合成
实验步骤：同实施例2
白色固体,产率为72.04％,m.p.51.7-54.7℃.1H NMR(500MHz,CDCl3)δ4.75 (d,J＝6.5Hz,1H),4.57(d,J＝10.7Hz,1H),3.01(d,J＝1.8Hz,1H),2.78(dd,J＝ 17.8,6.5Hz,1H),2.62(t,J＝14.8Hz,1H),2.22(ddd,J＝18.3,14.3,7.0Hz,4H), 1.73–1.65(m,3H),1.64(d,J＝0.5Hz,1H),1.63(s,3H),1.62–1.49(m,2H),1.43 –1.36(m,2H),1.35–1.24(m,6H),1.19–1.09(m,3H),1.08(s,3H),0.97–0.92(m, 3H),0.91(s,3H),0.88(d,J＝6.8Hz,6H),0.77(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C29H48O3Na:467.34957.Found:467.3492.
实施例4
AsB-S3:4-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,1 3a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclop enta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-4-oxobutanoic acid的合成
实验步骤：同实施例2
白色固体，产率为81％；m.p.130.1-131.7℃；1H NMR(400MHz,CDCl3)δ4.77 (d,J＝6.5Hz,1H),4.55(d,J＝10.8Hz,1H),2.99(s,1H),2.77(dd,J＝17.7,6.5Hz, 1H),2.63(ddd,J＝26.4,11.6,7.3Hz,5H),2.21(dd,J＝20.9,13.6Hz,2H),1.67(d, J＝8.4Hz,2H),1.63(s,3H),1.61–1.46(m,2H),1.46–1.20(m,8H),1.14(dd,J＝ 17.8,14.0Hz,3H),1.07(s,3H),0.90(s,3H),0.88–0.82(m,6H),0.77(s,3H)；13C NMR(100MHz,CDCl3)δ:177.17,171.80,132.70,127.20,77.32,77.00,76.68, 47.66,43.00,42.00,40.20,38.56,38.47,37.49,36.69,36.25,33.98,33.80,33.41, 31.44,29.39,29.04,29.00,25.95,25.62,23.43,17.47,15.91,12.37；
HRMS(ESI)for[M-H]-:calcd for C29H45O5：473.32615.Found:473.32678.
实施例5
AsB-S4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl propionate的合成
实验步骤：同实施例2
白色固体,产率为78.08％,m.p.108.8-109.4℃.1H NMR(400MHz,CDCl3)δ 4.74(d,J＝6.4Hz,1H),4.56(d,J＝10.7Hz,1H),2.99(s,1H),2.78(dd,J＝17.8, 6.5Hz,1H),2.61(t,J＝14.6Hz,1H),2.29(q,J＝7.6Hz,2H),2.25–2.14(m,2H), 1.73–1.64(m,2H),1.62(s,3H),1.61–1.47(m,3H),1.42–1.22(m,8H),1.18– 1.15(m,1H),1.15–1.11(m,3H),1.10(s,1H),1.07(s,3H),0.89(s,3H),0.89–0.83 (m,6H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C28H46O3Na:453.33392.Found:453.33326.
实施例6
AsB-S5:5-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12, 13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclo penta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-5-oxopentanoic acid的合成
实验步骤：同实施例2
白色固体，产率为86.69％；m.p.66.1-76.9℃；1H NMR(400MHz,CDCl3)δ4.74 (d,J＝6.4Hz,1H),4.56(d,J＝10.7Hz,1H),2.98(s,1H),2.78(dd,J＝18.0,6.6Hz, 1H),2.60(t,J＝14.9Hz,1H),2.42(t,J＝7.2Hz,2H),2.36(td,J＝7.3,2.4Hz,2H), 2.25–2.15(m,2H),1.99–1.90(m,2H),1.67(d,J＝8.3Hz,1H),1.63(s,3H),1.61 –1.47(m,2H),1.43–1.24(m,10H),1.18–1.08(m,3H),1.07(s,3H),0.90(s,3H), 0.87(d,J＝4.6Hz,5H),0.76(s,3H)；
HRMS(ESI)for[M-H]-:calcd for C30H47O5:487.3418.Found:487.34256
实施例7
AsB-S6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl hexanoate的合成
实验步骤：同实施例2
白色固体,产率为86.54％,m.p.74.8-75.9℃.1H NMR(400MHz,CDCl3)δ4.74 (d,J＝6.4Hz,1H),4.57(d,J＝10.7Hz,1H),3.00(s,1H),2.78(dd,J＝17.8,6.5Hz, 1H),2.61(t,J＝14.7Hz,1H),2.30–2.24(m,2H),2.24–2.14(m,2H),1.74–1.64 (m,3H),1.63(s,3H),1.62–1.48(m,4H),1.45–1.21(m,12H),1.20–1.09(m,3H), 1.08(s,3H),0.90(s,3H),0.87(t,J＝9.8Hz,8H),0.77(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C31H52O3Na:495.38087.Found:495.38027.
实施例8
AsB-S9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl isobutyrate的合成
实验步骤:同实施例2
白色固体,产率为84.18％,m.p.104.6-106.1℃.1H NMR(400MHz,CDCl3)δ 4.72(d,J＝6.4Hz,1H),4.58(d,J＝10.7Hz,1H),3.02(s,1H),2.77(dd,J＝18.0, 6.4Hz,1H),2.62(t,J＝14.9Hz,1H),2.49(dq,J＝14.0,7.0Hz,1H),2.25–2.13(m, 2H),1.73–1.65(m,2H),1.63(s,3H),1.61–1.45(m,3H),1.44–1.22(m,9H),1.15 (d,J＝1.4Hz,3H),1.13(t,J＝2.1Hz,3H),1.11–1.09(m,1H),1.08(s,3H),0.90(s, 3H),0.89–0.83(m,6H),0.75(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C29H48O3Na:467.34957.Found:467.34877.
实施例9
AsB-S10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a -hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 2-chloro-2,2-difluoroacetate的合成
实验步骤：同实施例2
白色固体,产率为89％,m.p.124.8-125.4℃.1H NMR(400MHz,CDCl3)δ6.28 (d,J＝11.1Hz,1H),4.95(d,J＝6.1Hz,1H),3.34(d,J＝10.5Hz,1H),2.87(dd,J＝ 18.4,6.0Hz,1H),2.74(t,J＝13.6Hz,1H),2.40(d,J＝18.4Hz,1H),2.35–2.25(m, 1H),1.88–1.71(m,3H),1.69(s,3H),1.66–1.58(m,1H),1.44–1.08(m,11H), 1.02(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.68(d,J＝6.9Hz,3H).
实施例10
AsB-n1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate的合成
实验步骤：
称取AsB-COOH(67.4mg,0.142mmol,1eq)于20ml的螺纹口样品瓶，2ml无水 二氯甲烷溶解化合物，再称取EDC(57.2mg,0.298mmol,2eq)，HoBt (75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再加胺(0.3mmol,2eq) 加进去反应4h-12h，TLC跟踪反应。反应完后，室温减压旋蒸除去二氯甲烷，0.5M HCl和EA(V:V＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再转移 至125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液 (2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的 PH，PH呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸 乙酯石油醚体系柱层析得纯化合物。
白色固体,产率为60.9％,m.p.66.0-66.5℃.1H NMR(500MHz,CDCl3)δ5.68 (s,1H),4.75(d,J＝6.5Hz,1H),4.57(dd,J＝21.7,8.8Hz,1H),3.19(td,J＝13.6, 6.5Hz,2H),2.98(s,1H),2.78(dd,J＝17.8,6.5Hz,1H),2.70–2.54(m,3H),2.45(t, J＝6.8Hz,2H),2.31–2.14(m,2H),1.72–1.65(m,2H),1.63(s,3H),1.54(ddt,J＝ 29.1,14.5,7.2Hz,5H),1.39(td,J＝13.8,3.6Hz,2H),1.29(ddd,J＝14.0,11.9,3.1 Hz,6H),1.15(ddd,J＝23.4,12.7,7.5Hz,3H),1.08(s,3H),0.92(d,J＝7.4Hz,2H), 0.91(s,3H),0.87(dd,J＝11.8,8.4Hz,6H),0.78(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C32H53O4NNa:538.38668.Found:538.38560.
实施例11
AsB-n2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclohexylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率40.5％,m.p.69.1-69.7℃.1H NMR(500MHz,CDCl3)δ5.53(d, J＝6.9Hz,1H),4.75(d,J＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),3.82–3.66(m, 1H),2.98(s,1H),2.76(dt,J＝25.5,12.8Hz,1H),2.67–2.55(m,3H),2.42(t,J＝ 6.8Hz,2H),2.25–2.16(m,2H),1.93–1.84(m,2H),1.73–1.64(m,4H),1.62(s, 3H),1.54(ddd,J＝22.7,11.5,7.8Hz,3H),1.43–1.23(m,10H),1.21–1.09(m,6H), 1.08(s,3H),0.90(s,3H),0.86(dd,J＝10.9,7.1Hz,6H),0.77(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H57O4NNa:578.41798；Found:578.41690
实施例12
AsB-n3:(2aS,6aS,6bS,9Z,11R,12R,12aZ,13aS)-2a,5,5,9,12,13a-hexamethyl-2,2 a,3,4,5,6,6a,6b,7,8,10,11,12,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]n aphthalen-11-yl 4-oxo-4-(propylamino)butanoate的合成
实验步骤：
称取AsB-COOH(45.4mg，0.096mmol，1eq)于50ml圆底烧瓶中，2ml无 水二氯甲烷溶解，冰浴下加入二氯亚砜(42ul，0.58mmol，6eq)，冰浴下反应 6h。待原料完全转化，35℃减压蒸馏二氯甲烷及SOCl2。继续加无水二氯甲烷， 冰浴下加正丙胺(26ul，0.316mmol，3.3eq)及TEA，室温搅拌反应。TLC跟踪 反应完后，加2M HCl溶液调至PH至中性，加二氯甲烷及饱和食盐水萃取的得 有机相，加无水硫酸钠干燥，35℃减压蒸馏得粗产品，甲醇二氯甲烷体系 (V:V＝1:200)柱层析得纯化合物。
白色固体,产率为56.3％；m.p.49.9-52.0℃；1H NMR(400MHz,CDCl3)δ5.72 (s,1H),5.59(d,J＝11.3Hz,1H),4.97–4.89(m,1H),4.81(d,J＝6.0Hz,1H),3.20 (dd,J＝13.5,6.6Hz,2H),3.00(s,1H),2.75–2.63(m,3H),2.45(t,J＝6.9Hz,2H), 2.33(dd,J＝24.3,14.8Hz,2H),1.97–1.82(m,2H),1.75(td,J＝13.4,4.1Hz,1H), 1.59(d,J＝13.9Hz,3H),1.52(dt,J＝14.5,7.4Hz,2H),1.47–1.36(m,3H),1.34– 1.10(m,5H),1.08–1.01(m,2H),0.93(t,J＝8.3Hz,2H),0.89(dd,J＝8.7,4.3Hz, 7H),0.86(s,3H),0.82(s,3H),0.68(d,J＝7.2Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C32H51O3NNa:520.37612；Found:520.37544
实施例13
AsB-n4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((furan-2-ylmethyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率90.2％,m.p.76.1-78.0℃.1H NMR(400MHz,CDCl3)δ7.33(d, J＝1.3Hz,1H),6.35–6.26(m,1H),6.21(d,J＝3.2Hz,1H),6.01(s,1H),4.74(d,J ＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),4.46–4.36(m,2H),2.96(s,1H),2.76(dd,J ＝17.8,6.5Hz,1H),2.64(t,J＝6.8Hz,2H),2.58(d,J＝14.1Hz,1H),2.48(t,J＝6.8 Hz,2H),2.25–2.14(m,2H),1.66(dd,J＝16.7,8.4Hz,3H),1.62(s,3H),1.60– 1.45(m,3H),1.42–1.33(m,2H),1.31–1.22(m,5H),1.13(dd,J＝21.4,8.7Hz, 3H),1.07(s,3H),0.91(d,J＝11.7Hz,3H),0.86(t,J＝3.4Hz,5H),0.76(s,3H). HRMS(ESI)for[M+Na]+:calcd for C34H51O5NNa:576.36594；Found:576.36511.
实施例14
AsB-n5:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(phenethylamino)butanoate的合成
实验步骤：同实施例10
白色固体，产率为77％,m.p.60.1-62.1℃.1H NMR(400MHz,CDCl3)δ7.31(t, J＝7.3Hz,2H),7.25–7.12(m,3H),5.64(s,1H),4.73(d,J＝6.5Hz,1H),4.54(d,J ＝10.7Hz,1H),3.51(d,J＝5.9Hz,2H),2.97(s,1H),2.85–2.72(m,3H),2.68– 2.53(m,3H),2.41(t,J＝6.7Hz,2H),2.21(dd,J＝15.2,8.9Hz,2H),1.73–1.63(m, 2H),1.62(s,3H),1.60–1.47(m,3H),1.38(dd,J＝18.4,8.0Hz,2H),1.33–1.22(m, 6H),1.14(dd,J＝21.6,9.1Hz,3H),1.07(s,3H),0.90(s,3H),0.87(t,J＝3.4Hz, 5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C37H55O4NNa:600.40233；Found: 600.40134
实施例15
AsB-n6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-((thiophen-2-ylmethyl)amino)butanoate 的合成
实验步骤：同实施例10
白色固体，产率85.13％,m.p.58.1-59.0℃.1H NMR(400MHz,CDCl3)δ7.20 (dd,J＝4.9,1.1Hz,1H),6.94(dd,J＝8.4,3.5Hz,2H),6.05(s,1H),4.74(d,J＝6.4 Hz,1H),4.59(d,J＝5.6Hz,2H),4.54(d,J＝10.7Hz,1H),2.96(s,1H),2.76(dd,J ＝17.8,6.5Hz,1H),2.68–2.53(m,3H),2.48(t,J＝6.8Hz,2H),2.25–2.15(m,2H), 1.67(dd,J＝15.1,6.8Hz,2H),1.62(s,3H),1.57(dd,J＝13.0,6.1Hz,1H),1.50(dd, J＝10.8,7.8Hz,2H),1.38(dd,J＝20.9,9.2Hz,2H),1.26(dd,J＝17.3,10.2Hz,6H), 1.13(dd,J＝21.1,8.5Hz,3H),1.07(s,3H),0.89(s,3H),0.86(t,J＝3.4Hz,5H), 0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C34H51O4NNaS:592.3431；Found:592.34214
实施例16
AsB-n7:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(cyclohex-1-en-1-yl)ethyl)amino)-4-oxobut anoate的合成
实验步骤：同实施例10
白色固体，产率为83.69％,m.p.100.3-102.8℃.1H NMR(400MHz,CDCl3)δ 5.61(s,1H),5.45(s,1H),4.74(d,J＝6.5Hz,1H),4.53(d,J＝10.8Hz,1H),3.30(dd, J＝12.5,6.5Hz,2H),2.97(s,1H),2.77(dd,J＝17.7,6.5Hz,1H),2.64–2.54(m, 3H),2.43(t,J＝6.9Hz,2H),2.26–2.16(m,2H),2.10(t,J＝6.7Hz,2H),1.99(s, 2H),1.90(s,2H),1.72–1.63(m,3H),1.61(s,3H),1.60–1.46(m,5H),1.39(dd,J＝ 22.3,10.2Hz,3H),1.26(dd,J＝19.1,10.1Hz,6H),1.18–1.08(m,3H),1.07(s,3H), 0.89(s,3H),0.86(t,J＝3.4Hz,5H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C37H59O4NNa:604.43363；Found:604.43275
实施例17
AsB-n8:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-((2-(thiophen-2-yl)ethyl)amino) butanoate的合成
实验步骤：同实施例10
淡粉色固体，产率79.3％,m.p.70.3-72.2℃.1H NMR(400MHz,CDCl3)δ7.15 (d,J＝5.1Hz,1H),6.94(dd,J＝5.0,3.5Hz,1H),6.83(d,J＝3.3Hz,1H),5.85(s, 1H),4.73(d,J＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),3.56–3.47(m,2H),3.02(t, J＝6.7Hz,2H),2.97(s,1H),2.77(dd,J＝17.8,6.5Hz,1H),2.69–2.53(m,3H), 2.43(t,J＝6.8Hz,2H),2.27–2.14(m,2H),1.67(dd,J＝16.4,8.1Hz,3H),1.62(s, 3H),1.61–1.44(m,3H),1.43–1.21(m,7H),1.21–1.08(m,3H),1.05(d,J＝19.9 Hz,3H),0.96–0.89(m,3H),0.87(t,J＝3.4Hz,5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H53O4NNaS:606.35875；Found: 606.35734
实施例18
AsB-n9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-bromophenyl)amino)-4-oxobutanoate的合 成
实验步骤：同实施例10
白色固体，产率为75.69％,m.p.194.6-195.9℃.1H NMR(400MHz,CDCl3)δ 7.89(s,1H),7.39(s,4H),4.76(d,J＝6.4Hz,1H),4.54(d,J＝10.7Hz,1H),2.97(s, 1H),2.83–2.67(m,3H),2.67–2.53(m,3H),2.27–2.16(m,2H),1.72–1.64(m, 2H),1.62(s,3H),1.60–1.44(m,3H),1.43–1.19(m,8H),1.13(dd,J＝20.4,8.2Hz, 3H),1.07(s,3H),0.89(s,3H),0.87(t,J＝3.4Hz,5H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C35H50O4NBrNa:650.28154；Found:650.28136.
实施例19
AsB-n10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(heptylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色油状物，产率为70.69％，m.p.1H NMR(400MHz,CDCl3)δ5.71(s,1H), 4.73(d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),3.21(dd,J＝13.0,6.6Hz,2H), 2.96(s,1H),2.76(dd,J＝17.9,6.6Hz,1H),2.66–2.53(m,3H),2.43(t,J＝6.7Hz, 2H),2.27–2.14(m,2H),1.66(dd,J＝17.3,8.6Hz,4H),1.61(s,3H),1.59–1.42(m, 4H),1.42–1.18(m,15H),1.18–1.08(m,3H),1.06(s,3H),0.89(s,3H),0.85(d,J＝ 3.4Hz,8H),0.73(d,J＝22.3Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H61O4NNa:594.44928；Found:594.44892
实施例20
AsB-n11:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(furan-2-yl)ethyl)amino)-4-oxobutanoat e的合成
实验步骤：同实施例10
白色固体，产率为79.75％,m.p.56.4-58.4℃.1H NMR(400MHz,CDCl3)δ 7.32(s,1H),6.29(s,1H),6.07(s,1H),5.85(s,1H),4.73(d,J＝6.4Hz,1H),4.54(d, J＝10.4Hz,1H),3.52(d,J＝5.9Hz,2H),2.97(s,1H),2.90–2.70(m,3H),2.70– 2.51(m,3H),2.44(t,J＝6.4Hz,2H),2.22(d,J＝17.6Hz,2H),1.65(s,4H),1.62(s, 3H),1.60–1.46(m,2H),1.38(t,J＝13.7Hz,2H),1.29(d,J＝13.3Hz,5H),1.18– 1.10(m,2H),1.07(s,3H),0.90(s,3H),0.89–0.79(m,6H),0.76(s,3H)；
HRMS(ESI)for[M+Na]+:calcd for C35H53O5NNa:590.38159；Found:590.38071
实施例21
AsB-n12:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-morpholinoethyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体,产率为51.77％,m.p.64.0-66.2℃.1H NMR(400MHz,CDCl3)δ6.21 (s,1H),4.71(d,J＝6.4Hz,1H),4.51(d,J＝7.3Hz,1H),3.76–3.60(m,4H),3.32 (dd,J＝11.1,5.5Hz,2H),2.94(s,1H),2.74(dd,J＝17.8,6.6Hz,1H),2.63–2.52 (m,3H),2.50–2.32(m,8H),2.18(dd,J＝19.5,12.4Hz,3H),1.70–1.61(m,2H), 1.59(s,3H),1.57–1.53(m,1H),1.52–1.44(m,1H),1.34(d,J＝13.8Hz,2H),1.26 (d,J＝14.8Hz,5H),1.15–1.06(m,3H),1.04(s,3H),0.87(s,3H),0.86–0.79(m, 6H),0.74(s,3H)
HRMS(ESI)for[M+H]+:calcd for C35H59O5N2:587.44185；Found:587.44143.
实施例22
AsB-n13:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(diallylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为71.68％,m.p.66.9-68.9℃.1H NMR(400MHz,CDCl3)δ5.75(dddd,J＝22.1,16.4,10.9,5.4Hz,2H),5.25–5.06(m,4H),4.74(d,J＝6.5Hz,1H), 4.52(d,J＝10.8Hz,1H),3.96(t,J＝7.7Hz,2H),3.89(d,J＝4.8Hz,2H),2.99(s, 1H),2.76(dd,J＝17.7,6.6Hz,1H),2.60(d,J＝9.4Hz,4H),2.20(dd,J＝19.7,12.7 Hz,2H),1.73–1.62(m,3H),1.61(s,3H),1.58(d,J＝6.0Hz,1H),1.51(td,J＝11.4, 3.6Hz,1H),1.43–1.21(m,8H),1.13(dd,J＝21.6,8.8Hz,3H),1.06(s,3H),0.89(s, 3H),0.88–0.82(m,6H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H55O4NNa:576.40233；Found:576.40181.
实施例23
AsB-n14:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(pyrrolidin-1-yl)butanoate的合成
实验步骤：同实施例10
白色固体，产率为64.65％,m.p.148.2-148.9℃.1H NMR(400MHz,CDCl3)δ 4.73(d,J＝6.6Hz,1H),4.51(d,J＝10.8Hz,1H),3.51–3.33(m,4H),2.98(s,1H), 2.75(dd,J＝17.8,6.6Hz,1H),2.64–2.58(m,2H),2.55(d,J＝5.9Hz,2H),2.27– 2.17(m,2H),1.98–1.90(m,2H),1.87–1.79(m,2H),1.66(dd,J＝14.6,7.8Hz, 3H),1.60(s,3H),1.59–1.44(m,2H),1.37(t,J＝13.2Hz,2H),1.25(t,J＝13.7Hz, 5H),1.16–1.08(m,2H),1.06(s,3H),0.88(s,3H),0.87–0.81(m,6H),0.72(d,J＝ 20.8Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C33H53O4NNa:550.38668；Found:550.38594
实施例24
AsB-n15:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((benzyloxy)amino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为71.2％,m.p.69.8-71.5℃.1H NMR(400MHz,CDCl3)δ8.59 (s,1H),7.45–7.30(m,5H),4.88(s,2H),4.71(d,J＝5.2Hz,1H),4.53(d,J＝10.7 Hz,1H),2.95(s,1H),2.76(dd,J＝17.8,6.4Hz,1H),2.58(t,J＝10.3Hz,3H),2.36 –2.13(m,4H),1.72–1.64(m,2H),1.61(s,3H),1.59–1.54(m,1H),1.50(dd,J＝ 15.3,7.3Hz,1H),1.42–1.32(m,2H),1.31–1.20(m,6H),1.17–1.07(m,3H),1.06 (s,3H),0.89(s,3H),0.88–0.82(m,6H),0.75(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H53O5NNa:602.38159；Found: 602.38068.
实施例25
AsB-n16:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobut anoate的合成
实验步骤：同实施例10
白色固体，产率为68.9％,m.p.66.5-67.4℃.1H NMR(500MHz,CDCl3)δ7.24 –7.04(m,4H),4.76(d,J＝6.6Hz,1H),4.71(s,1H),4.64(s,1H),4.54(d,J＝10.7 Hz,1H),3.81(t,J＝5.9Hz,1H),3.70(t,J＝6.0Hz,1H),3.01(s,1H),2.91(t,J＝5.8 Hz,1H),2.84(t,J＝5.8Hz,1H),2.78(dd,J＝17.7,6.6Hz,1H),2.75–2.68(m,2H), 2.68–2.63(m,2H),2.61(t,J＝12.0Hz,1H),2.24(dd,J＝14.8,8.8Hz,2H),1.77– 1.64(m,4H),1.62(s,3H),1.57(d,J＝7.3Hz,1H),1.56–1.48(m,1H),1.42–1.33 (m,2H),1.32–1.25(m,4H),1.25–1.22(m,1H),1.13(dd,J＝11.5,4.9Hz,2H), 1.08(s,3H),0.90(s,3H),0.87(dd,J＝8.7,5.1Hz,6H),0.76(d,J＝5.0Hz,3H).
HRMS(ESI)for[M+Na]+:calcd for C38H55O4NNa:612.40233；Found:612.40165.
实施例26
AsB-n17:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 7-morpholino-4-oxoheptanoate的合成
实验步骤：同实施例10
白色固体，产率为71.95％,m.p.68.6-70.9℃.1H NMR(500MHz,CDCl3)δ6.90 (s,1H),4.72(d,J＝6.5Hz,1H),4.52(d,J＝10.4Hz,1H),3.81–3.71(m,4H),3.37 –3.28(m,2H),2.96(s,1H),2.75(dd,J＝17.7,6.6Hz,1H),2.61(t,J＝6.8Hz,2H), 2.58–2.45(m,6H),2.42(t,J＝6.8Hz,2H),2.25–2.17(m,2H),1.75–1.63(m,4H), 1.61(s,3H),1.59–1.55(m,1H),1.50(td,J＝11.4,3.6Hz,1H),1.42–1.33(m,2H), 1.29(d,J＝4.0Hz,1H),1.26(d,J＝3.3Hz,3H),1.25–1.20(m,2H),1.18–1.08(m, 3H),1.06(s,3H),0.88(d,J＝8.0Hz,3H),0.85(d,J＝6.6Hz,5H),0.76(s,3H)
实施例27
AsB-n18:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-morpholino-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为82.9％,m.p.63.8-65.8℃.1H NMR(500MHz,CDCl3)δ4.75 (d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),3.69–3.43(m,8H),2.99(s,1H),2.77 (dd,J＝17.7,6.6Hz,1H),2.64–2.59(m,4H),2.28–2.17(m,2H),1.73–1.63(m, 4H),1.62(s,3H),1.59(d,J＝5.1Hz,1H),1.51(td,J＝11.4,3.7Hz,1H),1.38(dd,J ＝21.3,8.7Hz,2H),1.32–1.21(m,6H),1.18–1.08(m,3H),1.07(s,3H),0.90(s, 3H),0.86(d,J＝4.8Hz,6H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C33H53O5NNa:566.38159；Found:566.38068.
实施例28
AsB-n19:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a -hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(2-(trifluoromethyl)pyrrolidin-1-yl) butanoate的合成
实验步骤：同实施例10
白色固体，产率为62.75％,m.p162.3-163.4℃.1H NMR(500MHz,CDCl3)δ 4.92–4.64(m,2H),4.53(t,J＝11.0Hz,1H),3.80–3.43(m,2H),2.99(s,1H),2.86 –2.65(m,3H),2.65–2.49(m,3H),2.22(dd,J＝17.8,10.5Hz,2H),2.16(s,1H), 2.15–2.09(m,1H),2.00(dt,J＝19.6,9.5Hz,2H),1.72–1.63(m,3H),1.62(s,3H), 1.61–1.56(m,1H),1.55–1.48(m,1H),1.42–1.33(m,2H),1.32–1.28(m,2H), 1.26(s,2H),1.23(dd,J＝8.5,5.5Hz,1H),1.18–1.08(m,3H),1.07(s,3H),0.90(s, 3H),0.86(d,J＝6.9Hz,6H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C34H52O4NF3Na:618.37406；Found: 618.37329.
实施例29
AsB-n20:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-methoxyphenyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率为75.57％,m.p.90.5-92.5℃.1H NMR(400MHz,CDCl3)δ7.58 (s,1H),7.38(d,J＝8.8Hz,2H),6.83(d,J＝8.8Hz,2H),4.76(d,J＝6.4Hz,1H), 4.53(d,J＝10.7Hz,1H),3.77(s,3H),2.97(s,1H),2.77(dd,J＝17.9,6.5Hz,1H), 2.70(t,J＝6.4Hz,2H),2.60(dd,J＝18.0,11.2Hz,3H),2.21(t,J＝12.6Hz,2H), 1.74–1.62(m,3H),1.61(s,3H),1.60–1.51(m,2H),1.49(d,J＝11.1Hz,1H),1.42 –1.22(m,7H),1.19–1.08(m,3H),1.06(s,3H),0.88(s,3H),0.87(d,J＝6.4Hz, 5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H53O5NNa:602.38159；Found:602.38147.
实施例30
AsB-n21:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopropylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为78％,m.p.138.4-141.7℃.
HRMS(ESI)for[M+Na]+:calcd for C32H51O4NNa:536.37103；Found: 536.37073.
实施例31
AsB-n22:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopentylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为80.5％,m.p.73.7-75.1℃.1H NMR(600MHz,CDCl3)δ5.65 (d,J＝6.6Hz,1H),4.74(d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),4.21–4.13(m, 1H),2.97(s,1H),2.76(dd,J＝17.8,6.6Hz,1H),2.67–2.54(m,3H),2.41(t,J＝6.9 Hz,2H),2.28–2.13(m,2H),1.96(td,J＝12.8,6.9Hz,2H),1.79–1.63(m,5H), 1.61(s,3H),1.57(ddd,J＝11.3,7.5,3.6Hz,2H),1.50(td,J＝11.5,3.5Hz,1H), 1.41–1.32(m,4H),1.31–1.23(m,6H),1.17–1.09(m,3H),1.07(s,3H),0.92– 0.88(m,3H),0.86(dd,J＝13.6,9.4Hz,6H),0.77(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C34H55O4NNa:564.40233；Found:564.40198.
实施例32
AsB-n23:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(naphthalen-1-ylamino)-4-oxobutanoate的合 成
实验步骤：同实施例10
淡粉色固体，产率为42.12％,m.p.86.1-90.1℃.1H NMR(600MHz,CDCl3)δ 8.09(s,1H),7.94(dd,J＝15.7,7.8Hz,2H),7.86(d,J＝7.9Hz,1H),7.69(d,J＝8.0 Hz,1H),7.50(ddd,J＝26.5,15.2,7.3Hz,3H),4.82(d,J＝6.2Hz,1H),4.54(d,J＝ 10.6Hz,1H),2.98(s,1H),2.81(s,4H),2.60(t,J＝14.7Hz,1H),2.24(dd,J＝20.4, 12.9Hz,2H),1.70–1.63(m,2H),1.61(s,3H),1.59–1.47(m,3H),1.41–1.31(m, 2H),1.31–1.19(m,9H),1.15–1.07(m,3H),1.06(s,3H),0.92–0.87(m,6H),0.86 (s,3H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C39H53O4NNa:622.38668；Found: 622.38612.
实施例33
AsB-n24:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-((3-bromopyridin-2-yl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率为55％,m.p.57.2-59.2℃.1H NMR(600MHz,CDCl3)δ8.34(d, J＝3.9Hz,1H),8.03(s,1H),7.86(dd,J＝7.9,1.4Hz,1H),6.99–6.88(m,1H),4.77 (d,J＝6.4Hz,1H),4.54(d,J＝10.7Hz,1H),3.11–2.94(m,3H),2.78(dd,J＝17.7, 6.6Hz,1H),2.75–2.70(m,2H),2.60(t,J＝14.4Hz,1H),2.28–2.19(m,2H),1.70 –1.64(m,2H),1.62(s,3H),1.57(dd,J＝13.5,4.6Hz,1H),1.51(td,J＝11.6,3.9Hz, 1H),1.40–1.31(m,2H),1.30–1.27(m,2H),1.23(ddd,J＝16.1,7.0,4.4Hz,5H), 1.16–1.08(m,3H),1.07(s,3H),0.89(s,3H),0.89–0.85(m,6H),0.74(s,3H)
HRMS(ESI)for[M+H]+:calcd for C34H50O4N2Br:629.29485；Found:629.29474.
实施例34
AsB-n25:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((4-bromo-1H-pyrazol-3-yl)amino)-4-oxob utanoate的合成
实验步骤：
称取AsB-COOH(67.4mg,0.142mmol,1eq)于50ml圆底烧瓶，2ml无水1,2-二氯 乙烷溶解化合物，再称取EDC(57.2mg,0.298mmol,2eq)，HoBt (75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再胺(0.3mmol,2eq) 80℃冷凝回流反应12h，TLC跟踪反应。反应完后，冷凝室温减压旋蒸除去溶剂， 0.5M HCl和EA(V:V＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再 转移至125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液 (2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的 PH，PH呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸 乙酯石油醚体系柱层析得纯化合物。
白色固体，产率为60.5％.1H NMR(600MHz,CDCl3)δ8.06(s,1H),4.76(d,J ＝6.5Hz,1H),4.55(d,J＝10.7Hz,1H),4.16(dd,J＝31.0,26.6Hz,1H),3.29–3.19 (m,2H),2.97(d,J＝2.2Hz,1H),2.83–2.74(m,1H),2.70(t,J＝6.7Hz,2H),2.60(t, J＝14.7Hz,1H),2.21(dt,J＝17.1,14.3Hz,2H),1.71–1.64(m,2H),1.62(s,3H), 1.61–1.55(m,1H),1.51(td,J＝11.7,3.7Hz,1H),1.41–1.34(m,2H),1.32–1.24 (m,6H),1.17–1.08(m,3H),1.07(s,3H),0.89(d,J＝8.3Hz,3H),0.87(t,J＝3.5 Hz,6H),0.74(s,3H)；
HRMS(ESI)for[M+Na]+:calcd for C32H48O4N3BrNa:640.27204；Found:640.27167.
下面为本发明化合物抗炎活性测定结果
实验材料：RAW 264.7细胞，96孔板，LPS，酶标仪，MTT溶液，
试验方法：
1.化合物对NO生成量的影响
取对数生长期的RAW 264.7细胞，按1×105个/孔将其接种于96孔板，100 μL/孔。放入培养箱中培养24h使细胞贴壁并进入对数生长期，更换新的完全培 养基，加入LPS(终浓度1μg/mL)和样品溶液或吲哚美辛溶液，每个浓度设3 孔重复。阳性对照组只加LPS不加药物，阴性对照组只加细胞和完全培养基， 空白孔只加完全培养基。培养箱培养24h后，取细胞培养上清液50μL加入新 的96孔板，再分别加入一氧化氮检测试剂I与一氧化氮检测试剂Ⅱ各50μL。 用酶标仪测定540nm处的吸光度(OD)。
2.化合物对细胞活力的影响
取对数生长期的RAW 264.7细胞，按1×105个/孔将其接种于96孔板，100μL/ 孔。放入培养箱中培养24h使细胞贴壁并进入对数生长期，更换新的完全培养基， 加入LPS(终浓度1μg/mL)和样品溶液或吲哚美辛溶液，每个浓度设3孔重复。 阳性对照组只加LPS不加药物，阴性对照组只加细胞和完全培养基，空白孔只 加完全培养基。培养箱培养24h后，每孔加入1mg/mL的MTT溶液50μL，培 养箱继续培养4h，吸去培养基和MTT，再向各孔中加入150μL的DMSO，震 荡混匀，用酶标仪测定490nm处的吸光度值(OD)。药物对细胞生长的抑制作用以存活率表示，存活率越高表明药物毒性越低。
下表为部分化合物的生物活性数据：
表2化合物的抗炎活性结果(IC50μM)
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (3)
1.二倍半萜Asperterpinol B衍生物，其化学结构选自以下：
AsB-1: (2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z) -2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,12,12a,13,13a -14氢-13H-环戊并【4，5】环辛并【1，2-a】萘-9，10-二烯-13-醇；
AsB-S9: 异丁酸((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4，5】环辛并【1，2-a】萘-9-烯-11-醇酯；
AsB-n3: 丁酸(2aS,6aS,6bS,9Z,11R,12R,12aZ,13aS)-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,13a-14氢-1H-环戊并【4，5】环辛并【1，2-a】萘-9，12a-二烯-11-醇酯；
AsB-n4: 4-N-（2-呋喃）甲基胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n11: 4-N-（2-呋喃）乙基胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n12: 4-N-（4-吗啉）乙基胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n14: 4-（1-吡咯）酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n17: 4-N-（3-（4-吗啉）丙基）胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n18: 4-（4-吗啉）酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n21: 4-（环丙基）胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯；
AsB-n24: 4-N-（2-（3-溴吡啶））胺酰基-丁酸(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-羟基-2a,5,5,9,12,13a-六甲基-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-16氢-13H-环戊并【4,5】环辛并【1,2-a】萘-9-烯-11-醇酯。
2.一种药用组合物，其药学活性成份包括有权利要求1所述二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体。
3.权利要求1所述的二倍半萜Asperterpinol B衍生物或者其药学上可接受的盐或立体异构体在制备抗炎症药物中的应用。
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