CN113234053A - 裂环羽扇豆烷衍生物及在制备ask1抑制剂中的应用 - Google Patents

裂环羽扇豆烷衍生物及在制备ask1抑制剂中的应用 Download PDF

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CN113234053A
CN113234053A CN202110611140.2A CN202110611140A CN113234053A CN 113234053 A CN113234053 A CN 113234053A CN 202110611140 A CN202110611140 A CN 202110611140A CN 113234053 A CN113234053 A CN 113234053A
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lupane
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赵岩
王豪豪
王旭
滕虹伯
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Abstract

本发明涉及一种裂环羽扇豆烷衍生物及在制备ASK1抑制剂中的应用，属于药物领域。该裂环羽扇豆烷衍生物如式I所示，是一类具有预防和治疗ASK1介导的相关疾病的化合物。本发明的优势在于：运用半合成的方式得到了一系列ASK1受体拮抗剂，可用于预防、治疗或缓解ASK1介导的相关疾病的裂环羽扇豆烷衍生物，通过药理实验验证了其ASK1受体拮抗剂样作用，可以通过进一步的实验将此类化合物开发为应用于预防、治疗或缓解ASK1介导的相关疾病的药物。

Description

裂环羽扇豆烷衍生物及在制备ASK1抑制剂中的应用
技术领域
本发明属于药物领域，尤其涉及裂环羽扇豆烷衍生物、其光学异构体或其药学上可接受的盐，并涉及其在制备预防和治疗ASK1介导的相关疾病药物中的应用。
背景技术
凋亡信号调节激酶1(ASK1,Apoptosis signal-regulating kinase 1)是一种广泛表达的顶端有丝分裂原激活激酶激酶激酶(MAP3K)，被各种病理刺激激活，包括缺血及缺血再灌注损伤、神经退行性疾病、糖尿病、心脑血管系统疾病、炎症性疾病、移植排斥、自身免疫性疾病、癌症、代谢障碍性疾病等(Ichijo H,等人,Sci,1997,275:90-94；Guo X,等人,Adv Biol Regul,2017,66:63-71；Nakagawa H,等人,Hepatology,2011,54(1):185-95.)。ASK1蛋白激酶级联通路主要通过响应氧化应激激活钙超载、内质网应激、感染以及受体介导的炎症信号，脂多糖和肿瘤坏死因子等也可诱导ASK1信号转导(Shiizaki S,等人,AdvBiol Regul,2013,53(1):135-144.)。由于ASK1在细胞凋亡信号传导过程中的重要作用，其中内源性和外源性刺激都能使ASK1异常活化，并且激活后的ASK1参与多种疾病的过程。因此，使用ASK1抑制剂进行预防性治疗在疾病的发生发展过程中起着重要的作用。
羽扇豆烷型(lupane type)三萜及其皂苷主要分布于豆科、五加科、葫芦科、石竹科、伞形科、桦木科、木犀科、卫矛科等植物中。现代药理研究表明，该类化合物具有抗炎、抗肿瘤、抗病毒、抗氧化、抗菌、提高免疫力(AMIRI S,等人,Biotechnol Adv,2020,38:107409；Bian X,等人,RSC Adv,7(66):41640-41650；CHANIAD P,等人,Adv PharmacolSci,2019:11；BELLAMPALLI S S,等人,Pain,2019,160(1):117-135；程晓华,等人,中草药,2007,38(5):792-795.)等作用，对脂多糖诱导的肝炎、肺炎等亦具有很好的保护作用。近年来，越来越多结构复杂、新颖的羽扇豆烷型三萜被发现。骨架上不同位置的取代、环裂解、降碳、重排等类型的新三萜化合物及多个糖连接的复杂三萜皂苷的发现及活性研究，已经成为天然产物研究的热点。尤其是20世纪80年代以来，随着提取分离技术的不断进步和波谱技术的快速发展，羽扇豆烷型三萜化合物的结构研究取得了突飞猛进的发展，1991-2010年二十年间共发现新羽扇豆烷型三萜化合物200余个，其中糖苷类化合物50余个。
发明内容
本发明提供一种裂环羽扇豆烷衍生物及在制备ASK1抑制剂中的应用，合成了一系列裂环羽扇豆烷衍生物，并提供了这些化合物及组合物在制备预防或治疗ASK1介导的相关疾病的药物中的用途。
本发明采取的技术方案是：
通式Ⅰ所示裂环羽扇豆烷衍生物及其光学异构体或其药学上可接受的盐或溶剂化物：
Figure BDA0003091307060000021
其中R选自：
Figure BDA0003091307060000022
Figure BDA0003091307060000023
本发明的技术方案中，以所述通式Ⅰ中所列化合物及R为羟基或糖基化合物为原料，经系列化学反应得到通式II所示裂环羽扇豆烷衍生物：
Figure BDA0003091307060000024
其中Ra选自：
Figure BDA0003091307060000025
本发明的技术方案中，以所述通式Ⅰ中所列化合物及R为羟基或糖基化合物为原料，经系列化学反应得到通式III所示裂环羽扇豆烷衍生物：
Figure BDA0003091307060000031
其中Ra选自：
Figure BDA0003091307060000032
本发明的技术方案中，以所述通式Ⅰ中所列化合物及R为羟基或糖基化合物为原料，经系列化学反应得到通式Ⅳ所示裂环羽扇豆烷衍生物：
Figure BDA0003091307060000033
其中Ra选自：
Figure BDA0003091307060000034
Rb选自C1-C9烷基。
本发明的技术方案中，以上述通式I-IV中所述化合物的光学异构体或其药学上可接受的盐或溶剂化物。
本发明还提供了一种药物组合物，其含有上述裂环羽扇豆烷衍生物及其光学异构体或其药学上可接受的盐或溶剂化物和药学上可接受的载体和赋形剂。
所述“载体”包括药学领域常用的蛋白、叶酸、抗体、纳米材料等。术语“赋形剂”，指在药物制剂中除主药以外的附加物，也可称为辅料，如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
本发明药物可以制成片剂、粉剂、颗粒剂、胶囊、口服液及注射剂等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明还提供了所述衍生物及其光学异构体或其药学上可接受的盐或溶剂化物及组合物在制备预防或治疗ASK1介导的相关疾病的药物中的用途。其中所述的ASK1介导的相关疾病包括：缺血及缺血再灌注损伤、炎症疾病、移植排斥、自身免疫性疾病、心脑血管疾病、糖尿病、呼吸系统疾病、急性慢性肝脏疾病、代谢障碍、癌症、胃肠疾病以及阿尔茨海默病和帕金森病等神经退行性疾病等。
本发明所述的衍生物、及其光学异构体或其药学上可接受的盐或者溶剂化物可以单独给药，组合物给药以及多种药物联合给药。
本发明所涉及的裂环羽扇豆烷衍生物是目前羽扇豆烷型三萜类化合物中的一种特殊的3,4-裂环3,11-环合羽扇豆烷型三萜类衍生物。在此结构基础上，运用化学手段进行结构修饰和改造，形成了一类具有预防和治疗ASK1介导的相关疾病的裂环羽扇豆烷衍生物。
与现有技术相比，本发明的优势在于：运用半合成的方式得到了一系列ASK1受体拮抗剂，可用于预防、治疗或缓解ASK1介导的相关疾病的裂环羽扇豆烷衍生物。通过药理实验验证了其ASK1受体拮抗剂样作用，可以通过进一步的实验将此类化合物开发为应用于预防、治疗或缓解ASK1介导的相关疾病的药物。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
本发明所包括的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面所列举的具体实施方式、结合其他化学合成方法所形成的实施方式以及本领域技术人员所熟知的同等替换方式。其中优选的实施方式包括但不限于本发明的实施方式。
衍生物的合成：
本发明使用的溶剂及其合成药品可经市售所得，所用的缩写具有如下各自的定义：HOBT，1-羟基苯并三唑；EDC，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DMAP，4-二甲氨基吡啶；DMF，N,N-二甲基甲酰胺；DCM，二氯甲烷；MeOH，甲醇；EtOH，乙醇；PrOH，丙醇；PeOH，戊醇；NoOH，壬醇；TEA，三乙胺；NaOH，氢氧化钠；HCl，盐酸；TBHP，叔丁基过氧化氢；MOPS：3-(N-吗啡啉)丙磺酸；EGTA：乙二醇双(2-氨基乙基醚)四乙酸；EDTA：乙二胺四乙酸；DTT：二硫苏糖醇；BSA：牛血清白蛋白；MBP：髓磷脂碱性蛋白；DMSO：二甲基亚砜；r.t.，室温；O/N，过夜；reflux，回流；stir，搅拌。
实施例1：化合物C-1(Chiisanogenin)的制备
Figure BDA0003091307060000051
将Chiisanoside(1910.2mg，2.0mmol)溶于10％氢氧化钠甲醇中，加热回流4h，加入盐酸中和反应液使pH＝6-7，减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得白色固体(Chiisanogenin,C-1)363.51mg，收率为75％。C30H44O5.MS：[M]+484.31969.1H NMR(300MHz,Chloroform-d)δ5.23(ddt,J＝8.7,5.9,2.7Hz,1H),4.83(tt,J＝1.7,0.9Hz,1H),4.79(dddt,J＝7.3,2.7,1.8,0.9Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.16–4.08(m,1H),3.88(d,J＝6.4Hz,1H),3.44(dddq,J＝7.9,6.2,4.8,1.6Hz,1H),2.67(dd,J＝12.5,7.9Hz,1H),2.55(dd,J＝12.5,8.6Hz,1H),2.13–1.92(m,3H),1.89(ddd,J＝11.9,4.5,3.3Hz,1H),1.81–1.43(m,20H),1.39(dd,J＝8.5,6.5Hz,1H),1.08(s,3H),1.02(s,3H),1.01(s,3H)。
实施例2：通式I化合物C-1-1的合成
Figure BDA0003091307060000052
将化合物C-1(484.68mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，投入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-1-1)280.6mg，收率为43.81％。C38H61N3O5.MS：[M]+639.45568.1H NMR(300MHz,Chloroform-d)δ8.31(t,J＝5.6Hz,1H),5.27–5.19(m,1H),4.84(tq,J＝1.7,0.8Hz,1H),4.79(dtt,J＝7.4,1.9,0.9Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.18–4.10(m,1H),3.88(d,J＝6.4Hz,1H),3.48–3.30(m,4H),2.84(dddt,J＝8.4,6.8,5.0,1.6Hz,1H),2.74(t,J＝5.9Hz,2H),2.67(dd,J＝12.5,7.9Hz,1H),2.55(dd,J＝12.5,8.6Hz,1H),2.28(s,3H),2.26(s,3H),2.09(ddd,J＝11.9,8.1,5.3Hz,1H),2.03(dddd,J＝7.0,5.7,3.9,1.7Hz,1H),1.93–1.81(m,2H),1.85–1.62(m,17H),1.65–1.43(m,7H),1.29(t,J＝8.0Hz,3H),1.06(s,2H),1.01(s,3H),0.99(s,3H)。
实施例3：通式I化合物C-1-2、C-1-3、C-1-4和C-1-5的合成
Figure BDA0003091307060000061
将化合物C-1(484.68mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环丙胺(285.45μL，5mmol)反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-1-2)378.42mg，收率为72.25％。C33H49NO4.MS：[M]+523.36046.1H NMR(300MHz,Chloroform-d)δ5.61(d,J＝7.0Hz,1H),5.26–5.16(m,1H),4.85(tt,J＝1.8,0.9Hz,1H),4.79(dddt,J＝7.5,2.3,1.8,0.9Hz,2H),4.73(tq,J＝1.7,0.8Hz,1H),4.16–4.08(m,1H),3.88(d,J＝6.4Hz,1H),2.84(dtt,J＝8.6,5.0,1.6Hz,1H),2.76–2.63(m,2H),2.55(dd,J＝12.5,8.6Hz,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.83–1.66(m,12H),1.69–1.60(m,2H),1.63–1.58(m,1H),1.58(dd,J＝4.9,1.0Hz,1H),1.58–1.41(m,6H),1.08(s,2H),1.03(s,3H),0.98(s,3H),0.71–0.55(m,4H)。
将环丙胺替换为糠胺(509.88μL，5mmol)、酪胺(685.9mg，5mmol)和Boc-二甘醇胺(435.54μL，2mmol)，其余同上述所示。分别得到淡黄色粉末(C-1-3)402.20mg，收率为71.34％。C35H49NO5.MS：[M]+563.35884.1H NMR(300MHz,Chloroform-d)δ7.26(s,1H),6.31(dd,J＝3.3,1.9Hz),6.20(d,J＝3.3Hz,1H),5.92(t,J＝5.7Hz,1H),4.83(tt,J＝1.7,0.9Hz,1H),4.79(dddt,J＝7.3,2.7,1.8,0.9Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.35(dd,J＝4.8,1.8Hz,2H),4.16–4.08(m,1H),3.88(d,J＝6.4Hz,1H),2.84(dddt,J＝8.5,6.8,5.0,1.6Hz,1H),2.67(dd,J＝12.5,7.9Hz,1H),2.55(dd,J＝12.5,8.6Hz,1H),2.02(ddq,J＝7.0,3.9,2.0Hz,1H),1.93–1.84(m,2H),1.84–1.77(m,1H),1.80–1.73(m,4H),1.76–1.69(m,5H),1.72–1.66(m,2H),1.69–1.62(m,2H),1.64–1.59(m,1H),1.62–1.41(m,8H),1.03(s,3H),0.99(s,3H),0.84(s,3H)。浅棕色粉末(C-1-4)480.42mg，收率为79.56％。C38H53NO5。MS：[M]+603.38128.1H NMR(300MHz,Chloroform-d)δ7.09–7.00(m,2H),6.85–6.76(m,2H),5.57(t,J＝5.5Hz,1H),6.14(s,1H),5.27–5.19(m,1H),4.83(tt,J＝1.7,0.9Hz,1H),4.79(dddt,J＝7.3,2.7,1.8,0.9Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.18–4.10(m,1H),3.88(d,J＝6.4Hz,1H),3.34(dd,J＝4.6,3.7Hz,1H),3.32(dd,J＝4.7,3.6Hz,1H),2.88–2.80(m,1H),2.81(tt,J＝4.6,1.1Hz,2H),2.67(dd,J＝12.5,7.9Hz,1H),2.55(dd,J＝12.5,8.6Hz,1H),2.02(ddq,J＝7.1,3.9,2.0Hz,1H),1.93–1.84(m,2H),1.84–1.41(m,22H),1.08(s,2H),1.00(s,3H),0.83(s,3H)。白色粉末(C-1-5)690.40mg，收率为87.50％。C45H64N4O8.MS：[M]+788.46782.1H NMR(300MHz,Chloroform-d)δ8.08(d,J＝8.4Hz,1H),7.56(t,J＝7.7Hz,1H),7.43(t,J＝7.7Hz,1H),7.34(d,J＝8.3Hz,1H),5.27–5.19(m,1H),4.83(tq,J＝1.7,0.9Hz,1H),4.79(dtt,J＝7.3,1.8,0.9Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.21(t,J＝5.1Hz,2H),4.16–4.08(m,1H),3.88(d,J＝6.4Hz,1H),3.76–3.68(m,4H),3.71–3.62(m,2H),2.84(dtq,J＝8.6,5.0,1.6Hz,1H),2.67(dd,J＝12.5,7.9Hz,1H),2.55(dd,J＝12.5,8.6Hz,1H),2.06–1.99(m,1H),1.93–1.81(m,2H),1.81–1.73(m,6H),1.76(s,3H),1.75–1.68(m,6H),1.73(s,3H),1.71–1.63(m,1H),1.70(s,3H),1.67–1.54(m,6H),1.13(s,3H),0.99(s,3H),0.93(s,3H)。
实施例4：化合物C-2的制备
Figure BDA0003091307060000081
将化合物C-1(484.68mg，1.0mmol)溶于10％氢氧化钠甲醇中，加热回流4h，加入盐酸中和反应液使pH＝6-7，减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得淡黄色固体(C-2)319.41mg，收率为63.54％。将C-1替换成C-1-1/C-1-2/C-1-3/C-1-4/C-1-5同法得到化合物C-2，收率分别为66.93％、65.47％、68.85％、70.11％、60.04％。C30H46O6.MS：[M]+502.32367.1H NMR(300MHz,Chloroform-d)δ4.83(tt,J＝1.7,0.8Hz,1H),4.79–4.73(m,2H),4.71(h,J＝1.4Hz,1H),4.18(ddddd,J＝8.3,5.9,4.6,3.4,2.5Hz,1H),4.06(tdt,J＝8.2,5.9,2.6Hz,1H),3.90(d,J＝5.7Hz,1H),3.44(dddq,J＝7.9,6.2,4.8,1.6Hz,1H),2.50(dd,J＝16.8,8.1Hz,1H),2.42(dd,J＝16.8,8.0Hz,1H),2.30(d,J＝4.8Hz,1H),2.13–2.05(m,2H),1.97(ddd,J＝12.5,8.1,5.3Hz,1H),1.88–1.79(m,1H),1.81–1.76(m,1H),1.79–1.73(m,4H),1.75–1.67(m,5H),1.71–1.61(m,2H),1.61–1.55(m,1H),1.58–1.51(m,2H),1.54–1.47(m,4H),1.50–1.43(m,1H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。
实施例5：通式Ⅱ化合物C-2-1的制备
Figure BDA0003091307060000082
将C-2(502.69mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-2-1)588.17mg，收率为72.33％。C46H80N6O6.MS：[M]+812.60892.1H NMR(300MHz,Chloroform-d)δ8.48(t,J＝5.6Hz,1H),8.31(t,J＝5.6Hz,1H),4.83(td,J＝1.9,0.9Hz,1H),4.78(dtd,J＝5.5,1.8,0.8Hz,2H),4.73(tq,J＝1.7,0.9Hz,1H),4.24–4.14(m,1H),4.14–4.05(m,1H),3.80(d,J＝5.9Hz,1H),3.48–3.41(m,1H),3.44–3.35(m,3H),3.39–3.30(m,4H),2.84(dddq,J＝8.4,5.0,3.2,1.6Hz,1H),2.74(t,J＝5.9Hz,4H),2.63(d,J＝7.6Hz,2H),2.30(d,J＝4.8Hz,1H),2.28(s,12H),2.14–2.05(m,2H),1.89–1.83(m,1H),1.86–1.78(m,2H),1.80(d,J＝2.0Hz,1H),1.81–1.76(m,3H),1.76(dt,J＝1.6,0.9Hz,4H),1.76–1.72(m,4H),1.74–1.68(m,2H),1.72–1.66(m,3H),1.68–1.64(m,0H),1.65(s,0H),1.66–1.60(m,1H),1.63–1.56(m,1H),1.59–1.43(m,5H),1.29(t,J＝8.0Hz,6H),1.18(s,3H),1.06(s,3H),1.01(s,3H)。
实施例6：通式Ⅱ化合物C-2-2的合成
Figure BDA0003091307060000091
将C-2(502.69mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-2-2)601.76mg，收率为81.66％。C42H52N6O6.MS：[M]+736.38803.1H NMR(300MHz,Chloroform-d)δ8.05(dd,J＝7.5,1.2Hz,2H),7.59(dd,J＝8.2,1.7Hz,2H),7.51(ddd,J＝8.4,7.0,1.3Hz,2H),7.45(td,J＝7.5,1.7Hz,2H),4.84(tt,J＝2.0,0.7Hz,1H),4.77(dtd,J＝5.6,1.8,0.9Hz,2H),4.72(tq,J＝1.5,0.9Hz,1H),4.24–4.15(m,1H),4.11(tdt,J＝7.0,6.0,2.6Hz,1H),3.78(d,J＝5.9Hz,1H),2.84(dddq,J＝8.4,5.0,3.2,1.6Hz,1H),2.56(d,J＝6.9Hz,2H),2.30(d,J＝4.8Hz,1H),2.14–2.05(m,2H),1.88–1.81(m,2H),1.81–1.55(m,17H),1.58–1.43(m,5H),1.15(s,3H),1.03(s,3H),0.98(s,3H)。
实施例7：通式Ⅱ化合物C-2-3、C-2-4和C-2-5的合成
Figure BDA0003091307060000092
Figure BDA0003091307060000101
将C-2(502.69mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-2-3)438.48mg，收率为68.84％。C40H64N2O4.MS：[M]+636.48227.1H NMR(300MHz,Chloroform-d)δ6.77(d,J＝7.5Hz,0H),6.51(d,J＝7.3Hz,0H),4.84(tt,J＝2.1,0.9Hz,1H),4.75(dtd,J＝5.5,1.8,0.7Hz,2H),4.75(tq,J＝1.8,0.9Hz,1H),4.24–4.13(m,1H),4.12(tdt,J＝7.5,6.3,2.5Hz,1H),3.96–3.86(m,1H),3.77(d,J＝5.8Hz,1H),2.83(dddq,J＝8.7,5.2,3.1,1.6Hz,1H),2.55(d,J＝7.1Hz,2H),2.31(d,J＝4.5Hz,1H),2.13–2.04(m,2H),1.93–1.35(m,16H),1.88–1.81(m,2H),1.81–1.55(m,17H),1.58–1.43(m,5H),1.18(s,3H),1.13(s,3H),1.06(s,3H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到淡黄色粉末(C-2-4)536.41mg，收率为80.66％。C40H64N2O4.MS：[M]+664.51573.1H NMR(300MHz,Chloroform-d)δ6.56(d,J＝8.2Hz,0H),5.72(d,J＝8.0Hz,0H),4.84(tt,J＝2.5,0.8Hz,1H),4.74(dtd,J＝5.6,1.7,0.8Hz,2H),4.72(tq,J＝1.6,0.6Hz,1H),4.22–4.11(m,1H),4.11(tdt,J＝7.4,6.0,2.3Hz,1H),3.76(d,J＝5.7Hz,1H),3.76–3.65(m,1H),2.85(dddq,J＝8.8,5.4,3.0,1.7Hz,1H),2.55(d,J＝7.6Hz,2H),2.30(d,J＝4.4Hz,1H),2.13–2.06(m,2H),1.94–1.33(m,20H),1.87–1.82(m,2H),1.81–1.56(m,17H),1.55–1.42(m,5H),1.17(s,3H),1.15(s,3H),1.08(s,3H)。黄色粉末(C-2-5)471.49mg，收率为71.34％。C40H56N2O6.MS：[M]+660.40488.1H NMR(300MHz,Chloroform-d)δ7.33(t,J＝1.6Hz,2H),6.78(t,J＝4.8Hz,1H),6.69(t,J＝4.3Hz,1H),6.30–6.24(m,4H),4.84(tt,J＝1.6,0.8Hz,1H),4.79(td,J＝1.9,0.8Hz,1H),4.75(tt,J＝2.1,1.2Hz,1H),4.71(tq,J＝1.8,0.9Hz,1H),4.40(dd,J＝14.7,4.4Hz,1H),4.39–4.28(m,3H),4.24(d,J＝5.5Hz,1H),4.23–4.14(m,1H),3.96–3.87(m,1H),2.85(dddt,J＝8.5,6.6,5.2,1.6Hz,1H),2.49(dd,J＝16.8,7.6Hz,1H),2.42(dd,J＝15.8,7.7Hz,1H),2.32(d,J＝4.8Hz,1H),2.25–2.19(m,1H),1.95–1.57(m,18H),1.58–1.42(m,5H),1.39(dd,J＝8.7,6.5Hz,1H),1.16(s,3H),1.12(s,3H),1.09(s,3H)。
实施例8：化合物C-3的制备
Figure BDA0003091307060000111
将C-2(502.69mg，1.0mmol)溶于热盐酸溶液(6mol/L)中，加热回流4h。加入氢氧化钠溶液中和反应液使pH＝6-7，减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得淡黄色固体(C-3)381.34mg，收率为75.86％。C30H46O6.MS：[M]+502.32845.1H NMR(300MHz,Chloroform-d)δ4.78(tq,J＝1.7,0.8Hz,1H),4.73(tq,J＝1.7,0.9Hz,1H),4.40(tq,J＝5.7,1.6Hz,1H),4.21–4.12(m,1H),3.44(dddq,J＝7.9,6.2,4.8,1.6Hz,1H),2.56(dd,J＝16.9,5.5Hz,1H),2.48(dd,J＝16.9,5.5Hz,1H),2.20(d,J＝4.8Hz,1H),2.09(ddd,J＝12.3,8.0,5.3Hz,1H),2.08–2.01(m,1H),1.97(ddd,J＝12.5,8.1,5.3Hz,1H),1.86(ddd,J＝12.1,5.0,3.5Hz,1H),1.82–1.46(m,18H),1.24(s,3H),1.17(s,3H),1.09(s,3H),1.01(s,3H),0.94(s,3H)。
实施例9：通式Ⅲ化合物C-3-1的合成
Figure BDA0003091307060000112
将C-3(502.69mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到浅黄色粉末(C-3-1)567.03mg，收率为69.73％。C46H80N6O6.MS：[M]+812.60774.1H NMR(300MHz,Chloroform-d)δ8.36(t,J＝5.5Hz,0H),8.31(t,J＝5.6Hz,0H),4.75(tq,J＝1.8,0.9Hz,1H),4.25–4.13(m,1H),3.51–3.40(m,1H),3.43–3.29(m,2H),2.83(tdp,J＝6.5,4.5,1.7Hz,0H),2.78–2.69(m,2H),2.28(s,4H),2.21(d,J＝5.0Hz,0H),2.15–2.02(m,1H),1.90–1.44(m,9H),1.29(t,J＝7.9Hz,2H),1.23(s,3H),1.15(s,3H),1.09(s,3H),1.00(s,3H),0.97(s,3H)。
实施例10：通式Ⅲ化合物C-3-2的合成
Figure BDA0003091307060000121
将C-3(502.69mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-3-2)598.22mg，收率为80.18％。C42H52N6O6.MS：[M]+736.38657.1H NMR(300MHz,Chloroform-d)δ8.05(dd,J＝7.6,1.2Hz,2H),7.59(dd,J＝8.2,1.7Hz,2H),7.50(ddd,J＝8.2,7.1,1.3Hz,2H),7.44(td,J＝7.3,1.7Hz,2H),4.78(h,J＝1.6Hz,1H),4.74(h,J＝1.7Hz,1H),4.28(tq,J＝4.6,1.8Hz,1H),4.21–4.15(m,1H),2.88–2.80(m,1H),2.81(d,J＝4.4Hz,2H),2.22(d,J＝5.1Hz,1H),2.10(ddd,J＝12.1,7.7,5.4Hz,1H),2.05(tdd,J＝5.4,3.0,1.5Hz,1H),1.90–1.81(m,2H),1.81–1.73(m,1H),1.79–1.69(m,6H),1.72–1.46(m,12H),1.21(s,3H),1.11(s,3H),1.06(s,3H),1.01(s,3H),0.96(s,3H)。
实施例11：通式Ⅲ化合物C-3-3、C-3-4和C-3-5的合成
Figure BDA0003091307060000122
将C-3(502.69mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到黄色粉末(C-3-3)426.44mg，收率为66.95％。C42H68N2O4.MS：[M]+636.48834.1H NMR(300MHz,Chloroform-d)δ6.72(d,J＝7.3Hz,1H),6.51(d,J＝7.3Hz,1H),4.80(tq,J＝2.4,1.0Hz,1H),4.73(tq,J＝1.5,0.8Hz,1H),4.22–4.12(m,1H),4.05(tq,J＝5.6,1.4Hz,1H),3.94–3.85(m,2H),2.84(dddt,J＝8.8,6.8,5.2,1.5Hz,1H),2.45(dd,J＝17.2,5.4Hz,1H),2.37(dd,J＝16.6,5.5Hz,1H),2.20(d,J＝4.8Hz,1H),2.05(dddt,J＝6.8,5.6,2.9,1.3Hz,1H),1.93–1.85(m,1H),1.88–1.81(m,2H),1.85–1.80(m,1H),1.83–1.76(m,2H),1.80–1.75(m,1H),1.77–1.63(m,7H),1.67–1.61(m,4H),1.63–1.57(m,1H),1.62–1.47(m,11H),1.52–1.40(m,1H),1.38(dd,J＝8.6,6.4Hz,1H),1.25(s,3H),1.18(s,3H),1.08(s,3H),1.00(s,3H),0.97(s,3H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到淡黄色粉末(C-3-4)506.55mg，收率为76.17％。C40H64N2O4.MS：[M]+664.51466.1H NMR(300MHz,Chloroform-d)δ6.83(d,J＝7.4Hz,1H),6.52(d,J＝7.1Hz,1H),4.81(tq,J＝2.5,0.9Hz,1H),4.73(tq,J＝1.8,0.9Hz,1H),4.22–4.11(m,1H),4.05(tq,J＝5.8,1.3Hz,1H),3.95–3.86(m,2H),2.83(dddt,J＝9.0,6.7,5.2,1.6Hz,1H),2.45(dd,J＝16.2,5.5Hz,1H),2.36(dd,J＝15.9,5.6Hz,1H),2.21(d,J＝4.8Hz,1H),2.06(dddt,J＝6.9,5.7,2.9,1.2Hz,1H),1.94–1.86(m,1H),1.88–1.82(m,2H),1.85–1.80(m,2H),1.83–1.76(m,2H),1.80–1.74(m,1H),1.77–1.63(m,7H),1.67–1.60(m,5H),1.63–1.57(m,1H),1.61–1.44(m,13H),1.53–1.40(m,1H),1.39(dd,J＝8.8,6.5Hz,1H),1.22(s,3H),1.14(s,3H),1.06(s,3H),1.01(s,3H),0.93(s,3H)。黄色粉末(C-3-5)465.64mg，收率为70.44％。C40H56N2O6.MS：[M]+660.40755.1H NMR(300MHz,Chloroform-d)δ7.48(t,J＝4.5Hz,1H),7.33(t,J＝1.6Hz,2H),6.78(t,J＝4.8Hz,1H),6.30–6.24(m,4H),4.78(h,J＝1.6Hz,1H),4.73(h,J＝1.6Hz,1H),4.41(dd,J＝14.7,4.4Hz,1H),4.40–4.31(m,3H),4.21–4.12(m,1H),4.02(ddt,J＝6.6,5.1,1.5Hz,1H),2.84(dddt,J＝8.5,6.9,5.0,1.6Hz,1H),2.51–2.39(m,2H),2.20(d,J＝4.8Hz,1H),2.04(dddt,J＝6.8,5.3,2.9,1.5Hz,1H),1.93–1.82(m,2H),1.85–1.77(m,1H),1.80–1.72(m,4H),1.72–1.47(m,12H),1.50–1.42(m,1H),1.39(dd,J＝8.7,6.5Hz,1H),1.23(s,3H),1.15(s,3H),1.06(s,3H),1.00(s,3H),0.94(s,3H)。
实施例12：化合物C-4、C-5、C-6、C-7和C-8的制备
Figure BDA0003091307060000141
将C-3(502.69mg，1.0mmol)溶于80％MeOH 6％HCl水溶液中，随后加热回流2h，反应结束后取出，减压回收溶剂，干燥后得淡黄色粉末(C-4)277.22mg，收率为53.65％。C31H48O6.MS：[M]+516.34754.1H NMR(300MHz,Chloroform-d)δ4.80(tq,J＝1.7,0.8Hz,1H),4.75(tq,J＝1.7,0.8Hz,1H),4.25–4.12(m,2H),3.66(s,2H),3.44(dddq,J＝7.9,6.2,4.8,1.6Hz,1H),2.69–2.57(m,2H),2.20(d,J＝4.8Hz,1H),2.09(ddd,J＝12.3,8.0,5.3Hz,1H),2.04(dddt,J＝6.8,5.3,3.1,1.5Hz,1H),1.97(ddd,J＝12.4,8.1,5.3Hz,1H),1.86(ddd,J＝12.1,5.0,3.5Hz,1H),1.82–1.46(m,16H),1.23(s,3H),1.16(s,3H),1.08(s,3H),1.01(s,3H),0.96(s,3H)。
将反应式中80％MeOH 6％HCl水溶液换为80％EtOH(或PrOH或PeOH或NoOH)6％HCl水溶液，最后得白色粉末(C-5)336.76mg，收率为63.45％。C32H50O6.MS：[M]+530.35669.1HNMR(300MHz,Chloroform-d)δ4.78(tq,J＝1.6,0.8Hz,1H),4.45-4.25(m,1H),4.00-3.94(m,1H),4.20–4.12(m,2H),3.47(s,1H),3.08(d,J＝11.2Hz,1H)，2.99(td,J＝10.07,4.9Hz,1H),2.81(d,J＝4.7Hz,1H),2.31(d,J＝5.2Hz,2H),1.99(dq,J＝13.5,8.5,8.0Hz,3H),1.67-1.60(m,2H),1.58-1.49(m,2H),1.54-1.42(m,4H),1.40-1.35(m,1H),1.30(s,1H),1.25(s,1H),1.24(s,3H),1.23(s,3H),1.17(s,3H),1.09(s,3H),1.01(s,3H),0.94(s,3H)。白色粉末(C-6)355.57mg，收率为65.27％。C33H52O6.MS：[M]+544.37558.1H NMR(300MHz,Chloroform-d)δ4.81(tq,J＝1.7,0.8Hz,1H),4.74(tq,J＝1.9,0.9Hz,1H),4.21(tt,J＝5.3,1.6Hz,1H),4.21–4.12(m,1H),4.07(td,J＝5.7,2.9Hz,2H),3.44(dddq,J＝7.9,6.2,4.8,1.6Hz,1H),2.62(dd,J＝5.1,0.7Hz,2H),2.20(d,J＝4.8Hz,1H),2.09(ddd,J＝12.3,8.0,5.3Hz,1H),2.04(ddq,J＝6.9,3.8,1.6Hz,1H),1.97(ddd,J＝12.5,8.1,5.3Hz,1H),1.86(ddd,J＝12.1,5.0,3.5Hz,1H),1.82–1.46(m,20H),1.24(s,3H),1.18(s,3H),1.08(s,3H),1.01(s,3H),0.94(s,3H)。黄色粉末(C-7)408.83mg，收率为71.37％。C35H56O6.MS：[M]+572.40698.1H NMR(300MHz,Chloroform-d)δ4.82(tq,J＝2.1,0.9Hz,1H),4.74(tq,J＝1.6,0.8Hz,1H),4.22(tt,J＝5.5,1.5Hz,1H),4.21–4.13(m,1H),4.02(t,J＝5.9Hz,2H),3.46(dddq,J＝8.2,6.4,4.6,1.6Hz,1H),2.64(dd,J＝5.4,0.8Hz,2H),2.21(d,J＝4.5Hz,1H),2.08(ddd,J＝12.5,8.8,5.4Hz,1H),2.04(dddt,J＝7.1,5.4,3.2,1.7Hz,1H),1.98(ddd,J＝13.0,8.2,5.2Hz,1H),1.88(ddd,J＝12.8,5.5,3.6Hz,1H),1.82–1.59(m,11H),1.62–1.46(m,8H),1.42–1.31(m,4H),1.24(s,3H),1.16(s,3H),1.09(s,3H),1.03(s,3H),0.97(s,3H),0.95–0.85(m,3H)。淡黄色粉末(C-8)453.84mg，收率为72.16％。C39H64O6.MS：[M]+628.46332.1H NMR(300MHz,Chloroform-d)δ4.80(tq,J＝2.0,1.1Hz,1H),4.75(h,J＝1.6Hz,1H),4.21(tt,J＝5.8,1.5Hz,1H),4.20–4.11(m,1H),4.03(t,J＝6.5Hz,2H),3.45(dddq,J＝8.3,6.0,4.9,1.6Hz,1H),2.63(dd,J＝5.0,0.9Hz,2H),2.21(d,J＝4.7Hz,1H),2.10(ddd,J＝13.3,8.1,5.5Hz,1H),2.02(ddq,J＝6.2,3.5,1.6Hz,1H),1.96(ddd,J＝13.5,8.2,5.4Hz,1H),1.88(ddd,J＝12.8,5.2,3.5Hz,1H),1.82–1.45(m,19H),1.42–1.30(m,2H),1.35–1.28(m,4H),1.31–1.24(m,6H),1.24(s,3H),1.14(s,3H),1.08(s,3H),1.01(s,3H),0.95(s,3H),0.94–0.85(m,3H)。
实施例13：通式Ⅳ化合物C-4-1的合成
Figure BDA0003091307060000161
将C-4(516.72mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到浅黄色粉末(C-4-1)343.38mg，收率为50.20％。C40H67N3O6.MS：[M]+685.49268.1H NMR(300MHz,Chloroform-d)δ8.31(t,J＝5.6Hz,1H),4.77(h,J＝1.8Hz,1H),4.72(h,J＝1.5Hz,1H),4.25(tt,J＝5.2,1.5Hz,1H),4.21–4.11(m,1H),3.67(s,2H),3.48–3.29(m,4H),2.84(dddt,J＝8.5,6.9,5.2,1.6Hz,1H),2.75(t,J＝6.1Hz,2H),2.69–2.56(m,2H),2.20(d,J＝4.8Hz,1H),2.09(ddd,J＝12.0,8.5,5.4Hz,1H),2.05(dddt,J＝6.8,5.4,3.3,1.4Hz,1H),1.90–1.44(m,23H),1.29(t,J＝7.9Hz,3H),1.23(s,3H),1.15(s,3H),1.06(s,3H),1.00(s,3H),0.96(s,3H)。
实施例14：通式Ⅳ化合物C-4-2的合成
Figure BDA0003091307060000162
将C-4(516.72mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，和HOBT(270.60mg，2.0mmol)，完全溶解后，滴加适量的三乙胺(555.98μL，4mmol)，室温反应过夜。减压回收溶剂，得到白色固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-4-1)471.06mg，收率为74.32％。C36H47N3O6.MS：[M]+633.37693.1H NMR(300MHz,Chloroform-d)δ8.05(dd,J＝7.6,1.4Hz,1H),7.59(dd,J＝8.2,1.8Hz,1H),7.50(ddd,J＝8.3,7.1,1.3Hz,1H),7.44(td,J＝7.2,1.7Hz,1H),4.80(tq,J＝2.1,0.9Hz,1H),4.74(tq,J＝1.9,1.0Hz,1H),4.23–4.11(m,2H),3.65(s,2H),2.83(dtq,J＝8.2,5.5,1.8Hz,1H),2.71–2.56(m,2H),2.20(d,J＝5.1Hz,1H),2.09(ddd,J＝12.7,7.5,5.0Hz,1H),2.02(dddt,J＝7.0,5.1,2.9,1.6Hz,1H),1.91–1.43(m,20H),1.25(s,3H),1.13(s,3H),1.08(s,3H),1.02(s,3H),0.98(s,3H)。
实施例15：通式Ⅳ化合物C-4-3、C-4-4和C-4-5的合成
Figure BDA0003091307060000171
将C-4(516.72mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-4-3)419.47mg，收率为70.16％。C36H57NO5.MS：[M]+583.41490.1H NMR(300MHz,Chloroform-d)δ6.51(d,J＝7.3Hz,1H),4.81(tq,J＝1.9,0.7Hz,1H),4.75(tq,J＝2.3,1.1Hz,1H),4.25–4.13(m,2H),3.91(dq,J＝7.5,3.5Hz,1H),3.64(s,2H),2.85(dddt,J＝8.0,6.5,4.8,1.4Hz,1H),2.68–2.55(m,2H),2.20(d,J＝5.1Hz,1H),2.03(dddd,J＝8.8,5.6,3.2,1.6Hz,1H),1.95–1.74(m,5H),1.73–1.40(m,22H),1.38(dd,J＝8.6,6.4Hz,1H),1.25(s,3H),1.14(s,3H),1.09(s,3H),1.00(s,3H),0.97(s,3H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到淡黄色粉末(C-4-4)462.94mg，收率为77.43％。C37H59NO5.MS：[M]+597.43364.1H NMR(300MHz,Chloroform-d)δ5.72(d,J＝8.1Hz,1H),4.83(tq,J＝2.5,1.2Hz,1H),4.75(tq,J＝2.0,0.9Hz,1H),4.26–4.12(m,2H),3.74(dq,J＝8.3,4.8Hz,1H),3.65(s,2H),2.86(dddt,J＝8.8,7.0,5.2,1.8Hz,1H),2.69–2.55(m,2H),2.21(d,J＝4.9Hz,1H),2.05(dddt,J＝7.0,5.5,3.0,1.6Hz,1H),1.95–1.84(m,1H),1.86–1.81(m,1H),1.79(ddd,J＝12.2,6.5,4.1Hz,1H),1.72(dt,J＝1.8,0.9Hz,3H),1.71–1.63(m,5H),1.68–1.62(m,1H),1.66–1.54(m,8H),1.55–1.40(m,7H),1.43–1.32(m,4H),1.23(s,3H),1.12(s,3H),1.07(s,3H),0.99(s,3H),0.93(s,3H)。淡黄色粉末(C-4-5)594.24mg，收率为75.88％。C36H53NO6.MS：[M]+595.38616.1H NMR(300MHz,Chloroform-d)δ7.33(t,J＝1.5Hz,1H),6.78(t,J＝4.8Hz,1H),6.30–6.24(m,2H),4.84(tq,J＝1.8,1.0Hz,1H),4.75(tq,J＝2.3,0.9Hz,1H),4.35(dd,J＝5.3,2.1Hz,2H),4.21(tt,J＝5.6,1.4Hz,1H),4.21–4.10(m,1H),3.64(s,2H),2.85(dtt,J＝9.0,5.5,1.8Hz,1H),2.69–2.55(m,2H),2.20(d,J＝5.6Hz,1H),2.03(dddt,J＝7.4,5.5,3.0,1.6Hz,1H),1.95–1.77(m,3H),1.75–1.41(m,17H),1.39(dd,J＝8.7,6.5Hz,1H),1.25(s,3H),1.16(s,3H),1.08(s,3H),0.99(s,3H),0.91(s,3H)。
实施例16：通式Ⅳ化合物C-5-1的合成
Figure BDA0003091307060000181
将C-5(530.75mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-5-1)412.48mg，收率为60.13％。C40H67N3O6.MS：[M]+685.98377.1H NMR(300MHz,Chloroform-d)δ8.30(t,J＝5.8Hz,1H),4.82(h,J＝1.9Hz,1H),4.73(h,J＝1.5Hz,1H),4.20(ddt,J＝6.9,5.3,1.8Hz,1H),4.19–4.11(m,2H),4.09(d,J＝6.7Hz,1H),3.46–3.32(m,4H),2.84(dddt,J＝8.9,7.1,5.2,1.7Hz,1H),2.73(t,J＝6.3Hz,2H),2.60(dd,J＝5.5,1.7Hz,2H),2.28(s,5H),2.23(d,J＝5.4Hz,1H),2.10(ddd,J＝12.8,8.8,5.1Hz,1H),2.03(dddt,J＝6.6,5.1,3.0,1.6Hz,1H),1.90–1.44(m,22H),1.29(t,J＝8.0Hz,3H),1.26(s,3H),1.23(s,3H),1.15(s,3H),1.08(s,3H),1.00(s,3H),0.95(s,3H)。
实施例17：通式Ⅳ化合物C-5-2的合成
Figure BDA0003091307060000182
将C-5(530.75mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，和HOBT(270.60mg，2.0mmol)，完全溶解后，滴加适量的三乙胺(555.98μL，4mmol)，室温反应过夜。减压回收溶剂，得到白色固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-5-2)502.48mg，收率为77.56％。C38H53N3O6.MS：[M]+647.38902.1H NMR(300MHz,Chloroform-d)δ8.04(dd,J＝7.8,1.5Hz,1H),7.60(dd,J＝8.0,1.6Hz,1H),7.52(ddd,J＝8.8,7.3,1.4Hz,1H),7.42(td,J＝7.5,1.8Hz,1H),4.81(tq,J＝1.8,0.7Hz,1H),4.72(tq,J＝2.1,1.1Hz,1H),4.20(tt,J＝5.5,1.5Hz,1H),4.20–4.13(m,1H),4.12(d,J＝6.5Hz,1H),4.10(d,J＝7.5Hz,1H),2.83(dtq,J＝8.7,5.3,1.4Hz,1H),2.62(dd,J＝5.8,1.6Hz,2H),2.22(d,J＝4.6Hz,1H),2.10(ddd,J＝12.8,7.8,5.4Hz,1H),2.01(dddt,J＝7.1,5.6,3.0,1.5Hz,1H),1.90–1.42(m,21H),1.27(s,3H),1.24(s,3H),1.16(s,3H),1.09(s,3H),1.00(s,3H),0.96(s,3H).
实施例18：通式Ⅳ化合物C-5-3、C-5-4和C-5-5的合成
Figure BDA0003091307060000191
将C-5(530.75mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-5-3)452.36mg，收率为75.66％。C37H59NO5.MS：[M]+597.43638.1H NMR(300MHz,Chloroform-d)δ6.54(d,J＝7.7Hz,1H),4.84(tq,J＝2.7,1.8Hz,1H),4.74(tq,J＝1.7,0.8Hz,1H),4.23(ddq,J＝6.2,4.9,1.5Hz,1H),4.21–4.13(m,1H),4.12(d,J＝6.9Hz,1H),4.08(d,J＝6.1Hz,1H),3.90(tt,J＝6.0,3.0Hz,1H),2.84(dddt,J＝7.6,6.2,5.0,1.3Hz,1H),2.59(dd,J＝5.5,1.6Hz,2H),2.21(d,J＝4.4Hz,1H),2.05(dddt,J＝6.6,5.3,2.9,1.6Hz,1H),1.95–1.74(m,5H),1.73–1.40(m,21H),1.35(dd,J＝8.8,6.6Hz,1H),1.26(s,3H),1.22(s,3H),1.14(s,3H),1.07(s,3H),0.99(s,3H),0.91(s,3H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到白色粉末(C-5-4)422.46mg，收率为69.04％。C38H61NO5.MS：[M]+611.44476.1H NMR(300MHz,Chloroform-d)δ5.76(d,J＝8.8Hz,1H),4.83(tq,J＝1.8,1.0Hz,1H),4.72(tq,J＝2.5,1.2Hz,1H),4.23(ddq,J＝7.7,5.9,1.8Hz,1H),4.22–4.13(m,1H),4.13(d,J＝6.9Hz,1H),4.11(d,J＝6.1Hz,1H),3.70(dq,J＝8.7,4.3Hz,1H),2.82(dtt,J＝9.0,6.4,1.8Hz,1H),2.64(dd,J＝5.4,1.7Hz,2H),2.20(d,J＝4.6Hz,1H),2.05(dddt,J＝7.8,5.8,3.5,2.1Hz,1H),1.94–1.76(m,3H),1.74–1.31(m,29H),1.28(s,3H),1.25(s,3H),1.16(s,3H),1.08(s,3H),1.02(s,3H),0.95(s,3H)。白色粉末(C-5-5)399.39mg，收率为65.49％。C37H55NO6.MS：[M]+609.39553.1H NMR(300MHz,Chloroform-d)δ7.35(t,J＝1.8Hz,1H),6.77(t,J＝5.5Hz,1H),6.32–6.25(m,2H),4.82(tq,J＝2.6,1.3Hz,1H),4.76(tq,J＝1.8,0.7Hz,1H),4.34(dd,J＝5.6,2.1Hz,2H),4.21(ddq,J＝7.4,5.9,1.8Hz,1H),4.20–4.12(m,1H),4.12(d,J＝6.2Hz,1H),4.11(d,J＝7.6Hz,1H),2.83(dtt,J＝8.8,6.0,1.8Hz,1H),2.61(dd,J＝5.3,1.6Hz,2H),2.20(d,J＝4.5Hz,1H),2.06(dddt,J＝8.7,6.1,3.8,1.8Hz,1H),1.93–1.77(m,3H),1.74–1.60(m,8H),1.64–1.44(m,8H),1.51–1.40(m,1H),1.35(dd,J＝8.9,6.3Hz,1H),1.27(s,3H),1.24(s,3H),1.16(s,3H),1.09(s,3H),1.01(s,3H),0.93(s,3H)。
实施例19：通式Ⅳ化合物C-6-1的合成
Figure BDA0003091307060000201
将C-6(544.77mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-6-1)407.62mg，收率为58.23％。C41H69N3O6.MS：[M]+699.51588.1H NMR(300MHz,Chloroform-d)δ8.35(t,J＝5.7Hz,0H),4.83(dq,J＝26.2,2.1Hz,1H),4.25–4.11(m,1H),4.08(td,J＝6.7,2.8Hz,1H),3.46–3.28(m,2H),2.75(t,J＝6.3Hz,1H),2.64(dd,J＝5.8,1.8Hz,1H),2.27(s,2H),2.15–2.00(m,1H),1.90–1.43(m,9H),1.28(t,J＝7.5Hz,1H),1.23(s,3H),1.14(s,3H),1.07(s,3H),1.00(s,3H),0.95(s,3H),0.97(t,J＝8.0Hz,1H)。
实施例20：通式Ⅳ化合物C-6-2的合成
Figure BDA0003091307060000211
将C-6(530.75mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，和HOBT(270.60mg，2.0mmol)，完全溶解后，滴加适量的三乙胺(555.98μL，4mmol)，室温反应过夜。减压回收溶剂，得到白色固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-6-2)481.72mg，收率为72.78％。C39H55N3O6.MS：[M]+661.40604.1H NMR(300MHz,Chloroform-d)δ8.06(dd,J＝8.6,1.5Hz,1H),7.61(dd,J＝8.1,1.7Hz,1H),7.49(ddd,J＝8.8,7.5,1.6Hz,1H),7.42(td,J＝7.9,1.8Hz,1H),4.80(h,J＝2.3Hz,1H),4.71(h,J＝1.9Hz,1H),4.20(tt,J＝6.3,2.2Hz,1H),4.19–4.11(m,1H),4.06(td,J＝6.2,2.8Hz,2H),2.84(dtt,J＝8.8,5.3,1.8Hz,1H),2.61(dd,J＝5.5,1.7Hz,2H),2.19(d,J＝5.7Hz,1H),2.09(ddd,J＝13.1,8.2,5.6Hz,1H),2.02(dddt,J＝6.8,5.5,3.0,1.6Hz,1H),1.91–1.46(m,22H),1.23(s,3H),1.13(s,3H),1.06(s,3H),1.01(s,3H),0.97(s,3H),0.96(t,J＝8.6Hz,1H)。
实施例21：通式Ⅳ化合物C-6-3、C-6-4和C-6-5的合成
Figure BDA0003091307060000212
将C-6(530.75mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-6-3)458.20mg，收率为74.88％。C38H61NO5.MS：[M]+611.44367.1H NMR(300MHz,Chloroform-d)δ6.54(d,J＝7.5Hz,1H),4.83(tq,J＝1.8,0.9Hz,1H),4.71(tq,J＝2.2,1.0Hz,1H),4.25–4.12(m,2H),4.08(td,J＝5.7,2.8Hz,2H),3.91(tt,J＝6.7,3.4Hz,1H),2.84(dddt,J＝8.6,6.3,4.8,1.7Hz,1H),2.60(dd,J＝5.6,0.8Hz,2H),2.21(d,J＝5.3Hz,1H),2.03(dddt,J＝7.3,5.6,3.2,1.4Hz,1H),1.93–1.72(m,5H),1.75–1.40(m,23H),1.45–1.34(m,1H),1.23(s,3H),1.15(s,3H),1.08(s,3H),1.01(s,3H),0.96(s,3H),0.94(t,J＝9.1Hz,1H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到白色粉末(C-6-4)434.59mg，收率为69.43％。C39H63NO5.MS：[M]+625.46655.1H NMR(300MHz,Chloroform-d)δ5.80(d,J＝8.7Hz,1H),4.81(tq,J＝2.3,1.1Hz,1H),4.75(tq,J＝1.6,0.7Hz,1H),4.21(ddq,J＝6.5,4.8,1.5Hz,1H),4.20–4.12(m,1H),4.12(d,J＝6.4Hz,1H),4.09(d,J＝7.7Hz,1H),3.72(dq,J＝8.6,4.5Hz,1H),2.83(dtt,J＝7.8,5.0,1.8Hz,1H),2.63(dd,J＝5.7,1.6Hz,2H),2.20(d,J＝4.4Hz,1H),2.05(dddt,J＝7.2,5.8,3.0,1.5Hz,1H),1.94–1.74(m,3H),1.74–1.31(m,29H),1.24(s,3H),1.13(s,3H),1.09(s,3H),1.03(s,3H),0.98(s,3H),0.96(t,J＝8.4Hz,1H)。白色粉末(C-6-5)422.49mg，收率为67.72％。C38H57NO6.MS：[M]+623.41753.1H NMR(300MHz,Chloroform-d)δ7.35(t,J＝2.5Hz,1H),6.77(t,J＝4.4Hz,1H),6.31–6.25(m,2H),4.84(h,J＝2.7Hz,1H),4.74(h,J＝1.8Hz,1H),4.34(dd,J＝5.8,2.2Hz,2H),4.23–4.11(m,2H),4.07(td,J＝6.5,2.5Hz,2H),2.82(dddt,J＝7.9,6.4,5.1,1.3Hz,1H),2.61(dd,J＝5.2,1.4Hz,2H),2.22(d,J＝5.3Hz,1H),2.03(dddt,J＝7.2,5.6,3.3,1.5Hz,1H),1.95–1.41(m,23H),1.35(dd,J＝8.5,6.3Hz,1H),1.24(s,3H),1.12(s,3H),1.08(s,3H),1.01(s,3H),0.98(s,3H),0.93(t,J＝8.4Hz,1H)。
实施例22：通式Ⅳ化合物C-7-1的合成
Figure BDA0003091307060000221
将C-7(573.83mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-7-1)445.51mg，收率为61.19％。C43H73N3O6.MS：[M]+727.54228.1H NMR(300MHz,Chloroform-d)δ8.34(t,J＝5.5Hz,1H),4.81(h,J＝2.4Hz,1H),4.72(h,J＝1.8Hz,1H),4.23(ddq,J＝7.2,5.2,1.5Hz,1H),4.20–4.10(m,1H),4.03(t,J＝6.3Hz,2H),3.47–3.30(m,4H),2.85(dddt,J＝8.2,7.1,5.7,1.5Hz,1H),2.74(t,J＝6.3Hz,2H),2.61(dd,J＝5.8,1.1Hz,2H),2.20(d,J＝5.6Hz,1H),2.06(ddd,J＝12.3,9.1,5.8Hz,1H),2.03(dddt,J＝6.7,5.5,3.2,1.6Hz,1H),1.91–1.43(m,23H),1.42–1.33(m,4H),1.28(t,J＝8.6Hz,3H),1.25(s,3H),1.13(s,3H),1.08(s,3H),1.03(s,3H),0.97(s,3H),0.96–0.88(m,3H)。
实施例23：通式Ⅳ化合物C-7-2的合成
Figure BDA0003091307060000231
将C-7(573.83mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，和HOBT(270.60mg，2.0mmol)，完全溶解后，滴加适量的三乙胺(555.98μL，4mmol)，室温反应过夜。减压回收溶剂，得到白色固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-7-2)504.28mg，收率为73.09％。C41H59N3O6.MS：[M]+684.43831.1H NMR(300MHz,Chloroform-d)δ8.08(dd,J＝7.7,1.6Hz,1H),7.61(dd,J＝8.2,1.6Hz,1H),7.48(ddd,J＝8.6,7.3,1.4Hz,1H),7.43(td,J＝7.6,1.4Hz,1H),4.83(h,J＝2.1Hz,1H),4.72(h,J＝1.9Hz,1H),4.22(tt,J＝5.6,1.7Hz,1H),4.21–4.11(m,1H),4.03(t,J＝5.7Hz,2H),2.82(dddq,J＝9.5,6.2,3.6,1.5Hz,1H),2.61(dd,J＝5.3,0.8Hz,2H),2.23(d,J＝4.9Hz,1H),2.10(ddd,J＝12.8,7.6,5.5Hz,1H),2.01(dddt,J＝7.1,5.4,3.0,1.4Hz,1H),1.91–1.43(m,23H),1.42–1.30(m,4H),1.23(s,3H),1.12(s,3H),1.06(s,3H),1.02(s,3H),0.97(s,3H),0.93–0.82(m,3H)。
实施例24：通式Ⅳ化合物C-7-3、C-7-4和C-7-5的合成
Figure BDA0003091307060000232
Figure BDA0003091307060000241
将C-7(573.83mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-7-3)429.61mg，收率为67.13％。C40H65NO5.MS：[M]+639.48424.1H NMR(300MHz,Chloroform-d)δ6.54(d,J＝7.7Hz,1H),4.84(tq,J＝2.7,1.3Hz,1H),4.72(tq,J＝2.2,0.8Hz,1H),4.23–4.11(m,2H),4.04(t,J＝6.5Hz,2H),3.92(tt,J＝6.9,3.6Hz,1H),2.83(dddt,J＝9.5,6.8,5.2,1.8Hz,1H),2.60(dd,J＝5.3,0.8Hz,2H),2.19(d,J＝5.4Hz,1H),2.03(dddt,J＝7.2,5.8,3.2,1.4Hz,1H),1.92–1.83(m,1H),1.87–1.80(m,2H),1.84–1.78(m,1H),1.80–1.73(m,1H),1.74–1.41(m,22H),1.42–1.30(m,5H),1.23(s,3H),1.13(s,3H),1.06(s,3H),1.01(s,3H),0.96(s,3H),0.95–0.87(m,3H).
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到白色粉末(C-7-4)524.37mg，收率为80.18％。C41H67NO5.MS：[M]+653.49956.1H NMR(300MHz,Chloroform-d)δ5.74(d,J＝8.3Hz,1H),4.81(tq,J＝1.9,0.7Hz,1H),4.71(tq,J＝2.4,0.8Hz,1H),4.24–4.10(m,2H),4.00(t,J＝5.7Hz,2H),3.68(dq,J＝8.3,4.2Hz,1H),2.82(dddt,J＝8.6,7.0,5.3,1.7Hz,1H),2.60(dd,J＝5.5,0.9Hz,2H),2.21(d,J＝4.7Hz,1H),2.04(dddt,J＝7.4,5.6,3.0,1.5Hz,1H),1.93–1.81(m,2H),1.79(ddd,J＝12.3,6.9,4.7Hz,1H),1.75–1.31(m,32H),1.36(s,1H),1.24(s,3H),1.13(s,3H),1.05(s,3H),1.00(s,3H),0.94(s,3H),0.92–0.86(m,3H)。白色粉末(C-7-5)494.36mg，收率为75.83％。C40H61NO6.MS：[M]+651.44552.1H NMR(300MHz,Chloroform-d)δ7.34(t,J＝1.8Hz,1H),6.76(t,J＝5.2Hz,1H),6.30–6.22(m,2H),4.83(p,J＝1.9Hz,1H),4.73(h,J＝1.5Hz,1H),4.33(dd,J＝4.9,1.7Hz,2H),4.25–4.10(m,2H),4.01(t,J＝6.8Hz,2H),2.82(dddt,J＝8.7,6.2,5.3,1.7Hz,1H),2.63(dd,J＝5.6,1.5Hz,2H),2.20(d,J＝4.3Hz,1H),2.03(dddt,J＝6.9,5.3,3.0,1.6Hz,1H),1.93–1.75(m,3H),1.74–1.51(m,17H),1.55–1.48(m,1H),1.51–1.41(m,1H),1.42–1.33(m,4H),1.34(d,J＝7.0Hz,1H),1.23(s,3H),1.13(s,3H),1.07(s,3H),1.03(s,3H),0.98(s,3H),0.96–0.84(m,3H)。
实施例25：通式Ⅳ化合物C-8-1的合成
Figure BDA0003091307060000251
将C-8(628.94mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，加入DMAP(122.17mg，1.0mmol)，完全溶解后，滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-8-1)497.88mg，收率为63.49％。C47H81N3O6.MS：[M]+783.60368.1H NMR(300MHz,Chloroform-d)δ8.33(t,J＝6.3Hz,1H),4.83(tq,J＝2.3,0.9Hz,1H),4.73(tq,J＝1.7,0.8Hz,1H),4.21(ddt,J＝5.1,3.7,1.6Hz,1H),4.21–4.12(m,1H),4.03(t,J＝6.2Hz,2H),3.47–3.36(m,1H),3.36(dd,J＝8.3,6.1Hz,1H),3.35–3.33(m,1H),3.34–3.31(m,1H),2.82(dddt,J＝9.4,6.6,5.1,1.8Hz,1H),2.75(t,J＝6.4Hz,2H),2.60(dd,J＝5.8,0.9Hz,2H),2.20(d,J＝4.8Hz,1H),2.08(ddd,J＝12.9,8.8,5.3Hz,1H),2.02(dddt,J＝6.9,5.6,3.2,1.5Hz,1H),1.90–1.80(m,2H),1.83–1.45(m,23H),1.42–1.32(m,2H),1.35–1.26(m,13H),1.24(s,3H),1.15(s,3H),1.07(s,3H),1.02(s,3H),0.98(s,3H),0.95–0.87(m,3H)。
实施例26：通式Ⅳ化合物C-8-2的合成
Figure BDA0003091307060000252
将C-8(573.83mg，1.0mmol)溶于DMF(10mL)中，加入EDCI(766.80mg，4.0mmol)，和HOBT(270.60mg，2.0mmol)，完全溶解后，滴加适量的三乙胺(555.98μL，4mmol)，室温反应过夜。减压回收溶剂，得到白色固体粉末，硅胶柱层析分离，干燥后得到淡黄色粉末(C-8-2)576.62mg，收率为77.29％。C45H67N3O6.MS：[M]+745.49431.1H NMR(300MHz,Chloroform-d)δ8.08(dd,J＝8.1,1.6Hz,1H),7.58(dd,J＝8.7,1.8Hz,1H),7.52(ddd,J＝8.8,7.3,1.4Hz,1H),7.43(td,J＝7.3,1.8Hz,1H),4.84(tq,J＝1.8,0.9Hz,1H),4.73(tq,J＝2.5,0.9Hz,1H),4.20(tt,J＝5.7,1.4Hz,1H),4.22–4.10(m,1H),4.01(t,J＝6.4Hz,2H),2.84(dtt,J＝8.6,5.4,1.7Hz,1H),2.60(dd,J＝5.8,0.9Hz,2H),2.18(d,J＝5.4Hz,1H),2.10(ddd,J＝12.3,7.8,5.2Hz,1H),2.03(dddt,J＝7.3,5.5,3.4,1.2Hz,1H),1.90–1.80(m,2H),1.80–1.61(m,12H),1.65–1.59(m,1H),1.61–1.55(m,2H),1.55(q,J＝2.8,2.1Hz,2H),1.55–1.50(m,3H),1.53–1.46(m,1H),1.42–1.31(m,2H),1.34–1.28(m,1H),1.32–1.23(m,9H),1.24(s,3H),1.12(s,3H),1.07(s,3H),1.01(s,3H),0.95(s,3H),0.93–0.84(m,3H)。
实施例27：通式Ⅳ化合物C-8-3、C-8-4和C-8-5的合成
Figure BDA0003091307060000261
将C-8(573.83mg，1.0mmol)溶于DMF(5mL)中，加入EDCI(766.80mg，4.0mmol)，反应15分钟。取HOBT(270.60mg，2.0mmol)溶于DMF(5mL)，加入环戊胺(425.75μL，5mmol)，反应15分钟。随后合并上述两种DMF溶液，并滴加适量的三乙胺(416.98μL，3mmol)，室温反应过夜。减压回收溶剂，得到固体粉末，硅胶柱层析分离，干燥后得到白色粉末(C-8-3)465.46mg，收率为66.87％。C44H73NO5.MS：[M]+695.54389.1H NMR(300MHz,Chloroform-d)δ6.53(d,J＝7.9Hz,1H),4.85(dqd,J＝26.1,1.7,0.8Hz,1H),4.23–4.11(m,1H),4.02(t,J＝6.2Hz,1H),3.90(dq,J＝6.9,3.4Hz,1H),2.83(dddt,J＝8.6,6.8,5.0,1.5Hz,1H),2.60(dd,J＝5.3,0.8Hz,1H),2.19(d,J＝5.1Hz,1H),2.03(dddt,J＝6.6,5.4,3.2,1.6Hz,1H),1.93–1.73(m,2H),1.72–1.48(m,9H),1.52–1.24(m,6H),1.24(s,3H),1.14(s,3H),1.08(s,3H),1.02(s,3H),0.97(s,3H),0.92–0.86(m,1H)。
将环戊胺替换成环己胺(495.87μL，5mmol)和糠胺(509.88μL，5mmol)，其余同上述所示。分别得到白色粉末(C-8-4)580.36mg，收率为81.73％。C45H75NO5.MS：[M]+709.55773.1H NMR(300MHz,Chloroform-d)δ5.74(d,J＝8.3Hz,0H),4.82(dqd,J＝26.2,1.7,0.9Hz,1H),4.23–4.12(m,1H),4.01(t,J＝6.2Hz,1H),3.72(dt,J＝7.9,4.5Hz,1H),2.82(dtp,J＝8.4,4.8,1.6Hz,1H),2.62(dd,J＝5.6,0.8Hz,2H),2.21(d,J＝5.5Hz,1H),2.04(dddd,J＝8.4,5.3,3.0,1.5Hz,1H),1.93–1.75(m,2H),1.74–1.25(m,34H),1.25(s,3H),1.13(s,3H),1.09(s,3H),1.02(s,3H),0.96(s,3H),0.92–0.83(m,1H)。白色粉末(C-8-5)529.26mg，收率为74.75％。C44H69NO6.MS：[M]+707.50562.1H NMR(300MHz,Chloroform-d)δ7.36(t,J＝1.4Hz,1H),6.75(t,J＝5.2Hz,1H),6.31–6.25(m,2H),4.83(tq,J＝1.8,0.9Hz,1H),4.75(tq,J＝2.1,0.7Hz,1H),4.33(dd,J＝4.7,1.6Hz,2H),4.24–4.13(m,2H),4.02(t,J＝6.2Hz,2H),2.81(dddt,J＝8.7,7.0,5.2,1.6Hz,1H),2.60(dd,J＝5.7,0.9Hz,2H),2.23(d,J＝5.2Hz,1H),2.01(dddt,J＝6.9,5.2,3.1,1.4Hz,1H),1.93–1.75(m,3H),1.74–1.43(m,19H),1.46–1.30(m,4H),1.32–1.27(m,1H),1.31–1.24(m,9H),1.23(s,3H),1.12(s,3H),1.07(s,3H),1.00(s,3H),0.93(s,3H),0.91–0.82(m,3H)。
下边通过生物活性测试来进一步说明本发明的效果。
实施例28：裂环羽扇豆烷衍生物的抗ASK1酶活性试验
实验材料：蛋白-人源ASK1蛋白激酶(购自Sigma公司，货号14-606-M)；底物-[γ32P]ATP(购自PerkinElmer，货号NEG035C001MC)；纤维素试纸(购自英国Whatrnan，货号7001-0004)；其他试剂均为分析纯级产品。
测试方法：ASK1激酶抑制活性测试采用[γ-32P]ATP方法，反应液中加入6μL缓冲液(25mM MOPS(pH＝7.2),2.5mM EGTA,2.5mM EDTA,0.5mM DTT,0.25mg/mL BSA,20mMβ-磷酸甘油)，3μL MBP溶液(5.0μg/μL)，0.3μL ASK1蛋白激酶(激酶催化亚基，0.1μg/μL)，10.25μL水。然后室温下取19μL反应液迅速加入l.5mL EP管中。
待测物溶于DMSO，配成初始浓度为1mM的储备液，随后将1μL待测物溶液加入每个EP管中，用移液管混合均匀，冰上孵育10分钟。
每个样品中含有0.5mCi[γ-32P]ATP，其放射性比度为100μCi/μM。
将含有150μM ATP，30mM MgC12，15mM MOPS，pH＝7.2的ATP溶液加入反应液中，终浓度为100mM，30℃下反应20分钟，加入20μL 0.5M磷酸终止反应，反应液点在铺有纤维素试纸的20mm滤板上，滤板用0.075M磷酸溶液在室温下洗涤三次并干燥。将干燥后的滤板置于Tri-Caxb 2800-TR液体闪烁计数器进行读数。阳性对照用1M DMSO替代待测物储备液。
利用[γ-32P]ATP方法对裂环羽扇豆烷衍生物进行抑制活性实验，结果如表1所示。
表1.裂环羽扇豆烷衍生物对ASK1蛋白激酶的半数抑制浓度
化合物 IC<sub>50</sub>(nM)值 等级 化合物 IC<sub>50</sub>(nM)值 等级
C-1 369.96 C C-5 236.21 C
C-1-1 172.69 B C-5-1 99.94 B
C-1-2 118.98 B C-5-2 5.08 A
C-1-3 74.37 B C-5-3 79.4 B
C-1-4 33.32 B C-5-4 140.08 B
C-1-5 2.02 A C-5-5 88.03 B
C-2 417.01 C C-6 459.82 C
C-2-1 22.79 A C-6-1 42.1 B
C-2-2 373.83 C C-6-2 9.85 A
C-2-3 25.34 B C-6-3 55.9 B
C-2-4 28.03 B C-6-4 99.45 B
C-2-5 38.57 B C-6-5 223.4 C
C-3 448.57 C C-7 366.84 C
C-3-1 13.43 A C-7-1 12.67 A
C-3-2 2.94 A C-7-2 17.25 A
C-3-3 34.76 B C-7-3 197.66 B
C-3-4 101.49 B C-7-4 92.36 B
C-3-5 41.27 B C-7-5 167.72 B
C-4 294.38 C C-8 331.85 C
C-4-1 198.72 B C-8-1 19.48 A
C-4-2 11.98 A C-8-2 18.56 A
C-4-3 53.14 B C-8-3 263.23 C
C-4-4 73.52 B C-8-4 156.55 B
C-4-5 227.8 C C-8-5 254.54 C
注：A≤25nM；25nM＜B≤200nM；C＞200nM
结论：本发明裂环羽扇豆烷衍生物对ASK1蛋白激酶具有显著的抑制作用。
实施例29：药代动力学测试
动物实验：本研究选用24只SD大鼠，雌雄各半(7-8周龄，体重200-220g)。随机分为6组，每组4只。经静脉注射或者灌胃相同剂量(20mg/kg)的药物，以评价受试药物在其体内的药代动力学性质。
大鼠采用标准条件饲养，在12h白天/12h黑夜的条件下，给予维持饲料喂养。受试药物用0.5％羧甲基纤维素钠或者二甲基亚砜配制。将相同剂量的裂环羽扇豆烷衍生物分别静脉注射和灌胃大鼠。给药后0、0.083、0.25、0.5、1、2、3、4、6、8、12、24h尾静脉取血，所得血样4℃，5000rpm离心15min后分离血浆和红细胞，加肝素-20℃冻存。
利用LC-MS/MS检测血浆中各化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
结论：血浆药代动力学结果可知，本发明的各裂环羽扇豆烷衍生物均具有较好的药代动力学性质。
剂型制备
实施例30：片剂制备
试剂：淀粉(药用级，天津市津东天正精细化学试剂厂)；枸橼酸(上海麦克林生化科技有限公司)；硬脂酸镁(上海麦克林生化科技有限公司)。
制备方法：
①10％淀粉浆的制备：将0.25g枸橼酸溶于25mL纯水中，加入2.5g淀粉分散均匀，加热使其糊化，即得10％淀粉浆。
②制粒：取适量所得裂环羽扇豆烷衍生物粉末与淀粉混合均匀，加入适量10％淀粉浆混合并研磨均匀，制软材，过16目筛制粒，在50-60℃下干燥1h。16目筛整粒后加入适量润滑剂硬脂酸镁，用直径10mm为的浅冲头压制成片剂。
结果：所得片剂颜色呈米白色，颜色均匀，薄厚均匀一致，硬度适中。片重和崩解的时间符合要求。
结论：所得裂环羽扇豆烷衍生物所制片剂符合要求，可作为片剂使用。
实施例31：混悬型注射剂制备
试剂：聚乳酸(PLA，上海甄准生物科技有限公司)；聚乳酸羟基乙酸共聚物(PLGA，上海源叶生物科技有限公司)；泊洛沙姆188(西安天正药用辅料有限公司)；二氯甲烷、甲醇、乙腈等(天津天泰化学品有限公司)。
制备方法：
①制备聚合物微粒：称取适量的裂环羽扇豆烷衍生物和载体(PLA/PLGA)置于50mL圆底烧瓶中，加入5mL的二氯甲烷溶解，28℃减压蒸馏除去大部分有机溶剂，再在40℃条件下真空干燥24h直至溶剂全部去除，粉碎，过孔径为150μm的筛网，得到连环羽扇豆烷衍生物聚合物微粒。
②制备裂环羽扇豆烷衍生物混悬注射剂：将2.5g上述产物在持续搅拌条件下分散在250mL含有10g/L的泊洛沙姆188稳定剂的水溶液中，使分散完全。将药物分散液进行研磨至所需粒径，取出得到裂环羽扇豆烷衍生物聚合物微粒混悬液，3 000r·min-1离心1min，并用10mL稳定剂水溶液分散，使制剂浓缩至约为25g/L。
结果：所得混悬注射剂粒径均匀，制剂含水量、表面粒径均符合规定。体外缓释效果较佳，稳定性较好。
结论：所得裂环羽扇豆烷衍生物所制混悬注射剂符合要求，可作为混悬注射剂使用。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (8)

1.一种裂环羽扇豆烷衍生物，其特征在于如通式Ⅰ所示：
Figure FDA0003091307050000011
其中R选自：
Figure FDA0003091307050000012
Figure FDA0003091307050000013
2.以权利要求1所述的裂环羽扇豆烷衍生物为原料，其特征在于，经系列化学反应得到通式Ⅱ所示裂环羽扇豆烷衍生物：
Figure FDA0003091307050000014
其中Ra选自：
Figure FDA0003091307050000015
3.以权利要求1所述的裂环羽扇豆烷衍生物为原料，其特征在于，经系列化学反应得到通式Ⅲ所示裂环羽扇豆烷衍生物：
Figure FDA0003091307050000016
其中Ra选自：
Figure FDA0003091307050000021
4.以权利要求1所述的裂环羽扇豆烷衍生物为原料，其特征在于，经系列化学反应得到通式Ⅳ所示裂环羽扇豆烷衍生物：
Figure FDA0003091307050000022
其中Ra选自：
Figure FDA0003091307050000023
Rb选自C1-C9烷基。
5.权利要求1-4所述化合物的光学异构体或其药学上可接受的盐或溶剂化物。
6.一种药物组合物，其含有如权利要求1-5所述的化合物和药学上可接受的赋形剂和载体。
7.如权利要求1-6所述的化合物及组合物在制备预防或治疗ASK1介导的相关疾病的药物中的应用。
8.如权利要求7所述的应用，其特征在于：所述的ASK1介导的相关疾病包括：缺血及缺血再灌注损伤、炎症疾病、移植排斥、自身免疫性疾病、心脑血管疾病、糖尿病、呼吸系统疾病、急性慢性肝脏疾病、代谢障碍、癌症、胃肠疾病以及神经退行性疾病中的阿尔茨海默病和帕金森病。
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