CN116332767A - 二倍半萜衍生物及其制备方法和抗新型冠状病毒应用 - Google Patents
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Abstract
本发明公开了二倍半萜Asperterpenoid C衍生物、其制备方法和抗新型冠状病毒的应用。本发明通过将天然产物二倍半萜Asperterpenoid C进行修饰改造，制备得到一系列具备良好抑制新型冠状病毒活性的Asperterpenoid C衍生物，为临床治疗选择提供了新的可能选择，为高效低毒地治疗新型冠状病毒感染(COVID‑19)提供候选药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及二倍半萜Asperterpenoid C衍生物及其制备方法，和其衍生物在制备抗新型冠状病毒药物方面的应用。
背景技术
目前全球范围内传播的新型冠状病毒感染(COVID-19)由严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)所引起。轻度新型冠状病毒患者的临床症状包括咳嗽、发热、头痛、呼吸困难，重症病例包括多器官衰竭、急性呼吸窘迫综合征和炎症。此外，新型冠状病毒引起的血管渗漏、凝血异常和过度炎症也是导致这些患者病情迅速恶化甚至死亡的关键。寻找和开发新型高效抗新型冠状病毒药物是当下面临的急切任务。
地球上最大的生态环境是海洋，占到了约占地球总表面积的71％，海洋是一个高压、高盐、低温且黑暗、寡营养的特殊环境，迫使海洋微生物产生了独特的生命机制来适应这种极端条件，从而产生结构独特、丰富多样、生物活性显著的次级代谢产物，是新药来源的重要基础，被认为是天然药物资源的新宝库。
目前已发现大量抗肿瘤、治疗心血管疾病、抗菌、抗病毒等活性的化合物。到2016年底，从海洋生物中发现的新天然产物已超过28000个，其中来源于海洋真菌的新天然产物也已超过3000个。其中有9种上市药物来源于海洋天然产物或其衍生物，还有23种海洋来源的天然产物处于I，II和III期临床实验。表明从海洋中开发新药有巨大的前景。
天然产物Asperterpenoid C是从中国红树林内生真菌Aspergillus sp.16-5C次级代谢产物中提取分离得到的二倍半萜类化合物，根据报道，该二倍半萜类化合物具有抑制结核分枝杆菌酪氨酸磷酸酶活性，可用于制备抗结核药物，该二倍半萜类化合物同时具有抑制乙酰胆碱酯酶的作用，可用于制备治疗老年痴呆的药物，本发明通过对天然产物二倍半萜类化合物Asperterpenoid C进行结构修饰，得到一系列具有抑制新型冠状病毒活性的化合物，为临床治疗选择提供了新的可能选择，为高效低毒地治疗新型冠状病毒感染(COVID-19)提供候选药物。
发明内容
本发明旨在提供具有抑制新型冠状病毒活性的二倍半萜Asperterpenoid C衍生物及其制备方法，以及其在抗新型冠状病毒药物中的应用。本发明提供二倍半萜Asperterpenoid C衍生物，实验证明该系列二倍半萜Asperterpenoid C衍生物对新型冠状病毒(SARS-CoV-2)具有显著的抗新型冠状病毒活性的效果且细胞毒性低，可用于抗新型冠状病毒的防治中，特别是用于制备抗新型冠状病毒的药物。
本发明首要的目的是提供二倍半萜Asperterpenoid C衍生物。
本发明的另一目的是提供所述二倍半萜Asperterpenoid C衍生物的制备方法。
本发明的再一目的是提供所述二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物在制备抗新型冠状病毒药物中的应用。
本发明的再一目的是提供一种抗新型冠状病毒的药物。
实现上述目的的技术方案如下：
本发明天然产物二倍半萜Asperterpenoid C的衍生物包括二倍半萜Asperterpenoid C酯类衍生物、二倍半萜Asperterpenoid C酰胺类衍生物。所述二倍半萜Asperterpenoid C酯类衍生物其化学结构如式Ⅰ所示，所述二倍半萜Asperterpenoid C酰胺类衍生物如式Ⅱ所示：
其中，式Ⅰ的R选自C1-C8直链烷基；C1-C4卤素取代烷基，所述卤素包括：F、Cl、Br；
式Ⅱ的R选自C1-C6直链氨基；连接三元环、五元环、六元环、苯基、卤素取代苯基、甲苯的氨基，所述卤素原子包括：I、Br；连接三元环、五元环、六元环、苯基、卤素取代苯基、甲苯的C1-C3仲胺，所述卤素原子包括：I、Br；连接含有N和/或O的六元杂环的C3仲胺；连接含有S或O的五元杂环的C1-C3仲胺。
作为一种优选的可实施方式，式Ⅰ所示的二倍半萜Asperterpenoid C酯类衍生物的R可以是如下基团：
作为一种优选的可实施方式，式Ⅰ所示的二倍半萜Asperterpenoid C酯类衍生物的结构具体可以为：
本发明的式Ⅰ所示的二倍半萜Asperterpenoid C酯类衍生物通过下述所示合成路线合成得到：
本发明的式Ⅰ所示的二倍半萜Asperterpenoid C酯类衍生物制备方法为：Asperterpenoid C在碱的催化和30-80℃加热回流的条件下与卤代烷烃类化合物反应得到相应的Asperterpenoid C酯类衍生物。所述碱优选自K2CO3、Na2CO3、Cs2CO3、NaH、NaOH中的任意一项。
作为一种优选的可实施方式，式Ⅱ所示的二倍半萜Asperterpenoid C酰胺类衍生物的R可以是如下基团：
作为一种优选的可实施方式，式Ⅱ所示的二倍半萜Asperterpenoid C酰胺类衍生物的结构具体可以为：
本发明式Ⅱ所示的二倍半萜Asperterpenoid C酰胺类衍生物通过如下所示合成路线合成得到：
本发明式Ⅱ所示的Asperterpenoid C酰胺类衍生物的制备方法，包括以下步骤：
S1：Asperterpenoid C先与EDC(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺亚胺)生成加成中间体，HOBT(1-羟基苯丙三唑)再与该中间体反应得到活性中间酯；
S2：活性中间酯与胺类化合物发生酰胺化反应后得到相应的二倍半萜Asperterpenoid C酰胺类衍生物。
本领域技术人员应该理解的是，本发明所述的Asperterpenoid C衍生物的制备方法还可以包括对所得产物进行提纯的步骤，例如，可以采用萃取剂萃取，干燥剂干燥，并通过柱层析等方法除杂。
实验显示，上述二倍半萜Asperterpenoid C衍生物对于新型冠状病毒具有显著的抑制作用，可用于抗新型冠状病毒的防治。
因此，所述二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物在制备抗新型冠状病毒药物中的应用也在本发明的保护范围内。
优选地，所述新型冠状病毒为SARS-CoV-2、B.1.1.7变异株(Alpha)、B.1.351变异株(Beta)、P.1变异株(Gamma)、B.1.617.2变异株(Delta)或B.1.1.529变异株(Omicron)。
所述二倍半萜Asperterpenoid C衍生物药学上可接受的盐为其无机酸盐、无机碱盐或复盐。
所述无机酸盐的酸选自于盐酸、氢碘酸、氢溴酸、硝酸、硼酸、碳酸、硫酸、磷酸、硅酸、乙酸、丙酸、丙二酸、丁酸、乳酸、甲磺酸、乙磺酸、苯磺酸、马来酸、苯甲酸、琥珀酸、苦味酸、酒石酸、柠檬酸、富马酸中任意一种或几种。
所述无机碱盐的碱选自于氢氧化钠、氢氧化钾、氢氧化钡、氢氧化钙、氢氧化铵、氢氧化锂、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三甲胺、三乙胺、吡啶中的任意一种或几种。
所述二倍半萜Asperterpenoid C衍生物前药是指可在体内转变成所述Asperterpenoid C衍生物或其盐的物质。
本发明还进一步提供了一种抗新型冠状病毒的药物，包含所述二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物。
优选地，所述药物还包括药用载体和/或赋形剂，制成不同的剂型。
所述药物剂型包括但不限于散剂、片剂、颗粒剂、胶囊剂、溶液剂、糖浆剂、混悬剂、注射剂、粉针剂、水针剂、气雾剂、软膏剂、滴眼剂或栓剂。
所述药物的给药方式包括但不限于经胃肠道给药、注射给药、呼吸道给药、皮肤给药、粘膜给药或腔道给药。
本发明要求保护的二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物应用于制备抗新型冠状病毒的药物，包括但不限于，使用本发明的化合物、或其药学上可接受的盐、或其立体异构体、或其前药化合物用于预防或治疗新型冠状病毒引发的疾病，减轻新型冠状病毒引发的疾病症状或者缓解新型冠状病毒引发的疾病的发展或发作的药品的用途。
本发明要求保护的二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等。
本发明具有以下有益效果：
本发明通过对天然产物二倍半萜Asperterpenoid C进行结构修饰，得到新的化合物。初步药理学研究结果显示，本发明合成的二倍半萜Asperterpenoid C酯类衍生物的EC50为0.8-25.0μM，二倍半萜Asperterpenoid C酰胺类衍生物的EC50为2.3-20.3μM，可见，本发明合成的新的二倍半萜Asperterpenoid C衍生物具有显著的抗新型冠状病毒(SARS-CoV-2)活性的效果，可用于抗新型冠状病毒的防治中，为研究开发新的抗新型冠状病毒的药物提供了新的选择和途径，具有很好的研究开发、应用前景。
具体实施方式
以下结合具体实施例来进一步说明本发明，实施例给出了代表性新化合物的合成、相关结构鉴定数据及化合物活性数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1化合物1A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入K2CO3(0.12mmol，3eq)在30℃下回流搅拌15～60min，再加入1mL碘代丁烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物1A。
化合物1A的结构式为：
化合物1A的结构理化数据如下：无色油状，产率60％，mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.71(1H,dd,J＝8.6Hz,J＝4.3Hz),0.76(3H,s),0.83(3H,d,J＝6.8Hz),0.86(3H,d,J＝6.9Hz),0.93(3H,t,J＝6.2Hz),0.97(3H,t,J＝7.4Hz),1.01(1H,d,J＝6.7Hz),1.24(2H,m),1.37-1.45(4H,m),1.59(1H,d,J＝13.5Hz),1.68-1.71(2H,m),1.76(1H,m),1.82(1H,m),1.97-2.01(3H,m),2.27-2.37(3H,m),2.60(2H,m),3.51(1H,d,J＝13.6Hz),3.61(1H,s),3.66(1H,d,J＝7.6Hz),3.86-3.88(1H,dd,J＝11.5Hz,J＝3.8Hz),4.17(2H,m).13C
NMR(δC,CDCl3,150MHz):167.9,159.3,127.7,78.3,64.6,61.2,57.0,48.0,47.6,45.9,45.9,44.9,43.1,32.8,32.5,30.8,29.3,29.1,28.3,27.8,26.7,26.2,23.3,21.9,20.9,19.4,17.9,15.8,13.9.FTMS(ESI):m/z calcd for C29H46O4Na
([M+Na]+)481.32883,Found 481.32903。
实施例2化合物2A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入Na2CO3(0.12mmol，3eq)在40℃下回流搅拌15-60min，再加入1mL 1-溴-2-氯乙烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物2A。
化合物2A的结构式为：
化合物2A的结构理化数据如下：无色油状,产率85％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.69(1H,dd,J＝8.6Hz,J＝4.3Hz),0.74(3H,s),0.81(3H,d,J＝6.8Hz),0.84(3H,d,J＝6.9Hz),0.91(3H,s),1.19-1.24(2H,m),1.36(1H,dd,J＝15.2Hz),1.42(1H,t,J＝10.9Hz),1.59(1H,d,J＝13.5Hz),1.67(1H,t,J＝11.2Hz),1.74(1H,m),1.80(1H,m),1.96-2.08(3H,m),2.23-2.27(1H,m),2.30-2.35(2H,m),2.60,(2H,m),3.48(1H,d,J＝13.6Hz),3.56-3.61(2H,s),3.64(1H,d,J＝5.5Hz),3.72(2H,t,J＝5.7Hz),4.40(2H,m).13CNMR(δC,CDCl3,150MHz):167.3,161.1,126.9,78.3,64.2,61.3,57.0,47.9,47.6,45.8,45.8,45.0,43.1,41.7,32.7,32.6,29.4,29.0,28.3,27.8,26.9,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m/z calcd for C27H41O4ClNa([M+Na]+)487.25856,Found487.25888。
实施例3化合物3A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入Cs2CO3(0.12mmol，3eq)在50℃下回流搅拌15-60min，再加入1mL 1，4-二溴丁烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物3A。
化合物3A的结构式为：
化合物3A的结构理化数据如下：无色油状,产率82％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.69(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.81(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),1.18-1.24(3H,m),1.34(1H,dd,J＝15.1Hz),1.42(2H,t,J＝10.9Hz),1.59(1H,d,J＝13.5Hz),1.67(1H,t,J＝11.2Hz),1.73-1.86(4H,m),1.94-2.07(5H,m),2.23-2.34(3H,m),2.57(2H,m),3.44(1H,t,J＝6.6Hz),3.47(1H,d,J＝13.9Hz),3.59(1H,m),3.62(1H,d,J＝5.5Hz),3.78(1H,dd,J＝8.23Hz),4.18(2H,t,J＝6.3Hz).13C
NMR(δC,CDCl3,150MHz):167.7,160.1,127.3,78.3,63.8,61.2,57.0,47.9,47.6,45.9,45.9,44.96,43.1,33.2,32.8,32.6,29.6,29.4,29.1,28.3,27.8,27.4,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m/z calcd forC29H46O4Br([M+H]+)537.25740,Found 537.25766。
实施例4化合物4A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入NaH(0.12mmol，3eq)在60℃下回流搅拌15-60min，再加入1mL1-溴-4，4，4-三氟丁烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物4A。
化合物4A的结构式为：
化合物4A的结构理化数据如下：无色油状,产率61％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.19(1H,m),0.42(1H,t,J＝5.0Hz),0.72(1H,dd,J＝8.6Hz,J＝4.3Hz),0.76(3H,s),0.83(3H,d,J＝6.8Hz),0.86(3H,d,J＝6.9Hz),0.93(3H,s),1.20-1.27(2H,m),1.38(1H,dd,J＝15.2Hz),1.44(1H,t,J＝10.9Hz),1.61(1H,d,J＝13.5Hz),1.69(1H,t,J＝11.2Hz),1.75-1.84(2H,m),1.96-2.01(3H,m),2.03-2.11(2H,m),2.19-2.29(3H,m),2.32-2.36,(2H,m),2.60(2H,m),3.50(1H,d,J＝13.5Hz),3.61(1H,s),3.66(1H,d,J＝5.5Hz),3.74(1H,d,J＝9.0Hz),4.23(2H,m).13CNMR(δC,CDCl3,150MHz):167.5,160.7,127.0(t),78.2,62.9,61.2,57.0,47.9,47.6,45.8,45.8,45.0,43.1,32.7,32.6,31.0(dd),29.8,29.4,29.1,28.2,27.8,26.7,26.2,23.3,21.9,21.7,20.8,17.9,15.8.FTMS(ESI):m/zcalcd forC29H43O4F3Na([M+Na]+)535.30057,Found 535.30099。
实施例5化合物5A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入NaOH(0.12mmol，3eq)在70℃下回流搅拌15-60min，再加入1mL1-溴-3-氟丙烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物5A。
化合物5A的结构式为：
化合物5A的结构理化数据如下：无色油状,产率63％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.71(1H,dd,J＝8.6Hz,J＝4.3Hz),0.76(3H,s),0.83(3H,d,J＝6.8Hz),0.85(3H,d,J＝6.9Hz),0.93(3H,s),1.19-1.24(2H,m),1.36(1H,dd,J＝15.2Hz),1.42(1H,t,J＝11.0Hz),1.59(1H,d,J＝13.5Hz),1.68-1.71(2H,m),1.74-1.84(2H,m),1.94-2.08(4H,m),2.09-2.13(1H,m),2.30-2.40(3H,m),2.5-2.60(2H,m),3.50(1H,d,J＝13.5Hz),3.58-3.61(1H,t,J＝11.5Hz),3.65(1H,d,J＝5.5Hz),3.77(1H,s),4.30(2H,t,J＝6.2Hz),4.50(1H,t,J＝5.9Hz),4.60(1H,t,J＝5.9Hz).13C NMR(δC,CDCl3,150MHz):167.6,160.3,127.2,80.8,78.3(d),61.2,60.7,60.6,57.0,47.9,47.6,45.9,45.0,43.1,32.8,32.6,29.9(t),29.4,29.1,28.3,27.8,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m/z calcd for C28H44O4F([M+H]+)463.32181,Found463.32193。
实施例6化合物6A的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入K2CO3(0.12mmol，3eq)在80℃下回流搅拌15-60min，再加入1mL正溴辛烷在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物6A。
化合物6A的结构式为：
化合物6A的结构理化数据如下：无色油状,产率40％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.15(1H,m),0.38(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.88(3H,t,J＝6.8Hz),0.90(3H,s),1.17-1.24(2H,m),1.24-1.32(9H,m),1.33-1.37(3H,m),1.41(1H,t,J＝11.0Hz),1.56(1H,d,J＝13.7Hz),1.63-1.68(3H,m),1.73-1.81(2H,m),1.93-2.07(3H,m),2.24-2.34(3H,m),2.52-2.62(2H,m),3.48(1H,d,J＝13.6Hz),3.58-3.60(1H,m),3.63(1H,d,J＝5.5Hz),3.84(1H,dd,J＝10.3Hz),4.13(2H,m).13CNMR(δC,CDCl3,150MHz):167.7,159.2,127.5,78.16,64.8,61.0,56.8,47.8,47.4,45.7,45.7,44.8,43.0,32.7,32.4,31.8,29.2,29.2,29.2,29.0,28.6,28.2,27.6,26.5,26.1,26.0,23.2,22.6,21.8,20.7,17.8,15.6,14.1.FTMS(ESI):m/z calcd for C33H55O4([M+H]+)515.40949,Found 515.40969。
实施例7化合物1C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的N-胺丙基吗啉继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物1C。
化合物1C的结构式为：
化合物1C的结构理化数据如下：无色油状,产率60％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.38(1H,t,J＝5.2Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),1.15-1.23(3H,m),1.35(1H,dd,J＝15.1Hz),1.41(1H,t,J＝10.9Hz),1.52(1H,d,J＝13.3Hz),1.66(2H,t,J＝10.2Hz),1.73-1.81(5H,m),1.99-2.07(3H,m),2.24-2.34(3H,m),2.50-2.57(6H,m),3.42(2H,m),3.55(1H,d,J＝13.4Hz),3.61(2H,s),3.63(1H,d,J＝5.5Hz),3.72(3H,m).13C NMR(δC,CDCl3,150MHz):167.1,167.1,128.9,78.3,66.9,60.8,58.5,57.0,54.0,57.0,54.0,48.1,47.6,45.9,45.9,44.9,43.3,39.8,33.7,32.2,29.2,28.3,27.7,26.6,26.2,24.4,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m/z calcd for C32H53O4N2([M+H]+)529.39998,Found 529.39985。
实施例8化合物2C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的2-噻吩甲胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物2C。
化合物2C的结构式为：
化合物2C的结构理化数据如下：无色油状,产率50％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.17(1H,m),0.38(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),1.17-1.23(2H,m),1.35(1H,dd,J＝15.4Hz,J＝5.2Hz),1.41(1H,t,J＝10.9Hz),1.52(2H,d,J＝13.5Hz),1.66(1H,t,J＝11.2Hz),1.72-1.82(2H,m),1.99-2.07(3H,m),
2.21-2.25(1H,m),2.29(1H,d,J＝8.6Hz),2.32-2.36(1H,m),2.40-2.45(1H,m),2.57-2.59(1H,m),3.55(1H,d,J＝13.5Hz),3.61-3.63(2H,m),4.43(1H,s),4.68(2H,m),6.96(1H,m),7.00(1H,m),7.24(1H,dd,J＝5.1Hz,J＝1.2Hz).13C
NMR(δC,CDCl3,150MHz):166.6,155.2,140.8,128.6,127.1,126.4,125.5,78.3,61.0,57.0,48.0,47.6,45.9,45.9,44.9,43.3,38.4,33.3,32.6,29.3,29.2,28.3,27.7,26.5,26.2,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m/z calcd forC30H44O3NS([M+H]+)498.30364,Found 498.30409。
实施例9化合物3C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的2-呋喃乙胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物3C。
化合物3C的结构式为：
化合物3C的结构理化数据如下：无色油状，产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.17(1H,m),0.40(1H,t,J＝5.0Hz),0.70(1H,dd,J＝8.6Hz,J＝4.3Hz),0.75(3H,s),0.82(3H,d,J＝6.8Hz),0.85(3H,d,J＝6.9Hz),0.92(3H,s),1.18-1.25(2H,m),1.36-1.43(2H,m),1.52(1H,d,J＝13.4Hz),1.67(1H,t,J＝13.9Hz),1.75-1.82(2H,m),1.98-2.10(3H,m),2.24-2.27(1H,m),2.29(1H,d,J＝8.5Hz),2.33-2.41(2H,m),2.54-2.60(1H,m),2.90(2H,m),3.53(1H,d,J＝13.5Hz),
3.59-3.66(5H,m),4.60(1H,br),6.10(1H,d,J＝3.1Hz),6.33(1H,dd,J＝3.1Hz,J＝1.9Hz),7.36(1H,d,J＝1.1Hz).13C NMR(δC,CDCl3,150MHz):166.9,154.7,153.4,141.7,128.8,110.5,106.6,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,38.2,33.3,32.5,29.2,29.2,28.3,28.1,27.7,26.5,26.2,23.3,22.1,20.8,17.9,
15.8.FTMS(ESI):m/z calcd for C31H46O4N([M+H]+)496.34214,Found496.34224。
实施例10化合物4C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的环丙胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物4C。
化合物4C的结构式为：
化合物4C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.15(1H,m),0.37(1H,t,J＝5.1Hz),0.50-0.56(2H,m),0.66(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.80(2H,m),0.83(3H,d,J＝6.9Hz),0.90(3H,s),1.15-1.23(2H,m),1.33(1H,dd,J＝15.2Hz,J＝5.2Hz),1.42(1H,t,J＝10.9Hz),1.52(1H,d,J＝13.5Hz),1.66(2H,t,J＝11.2Hz),1.72-1.82(2H,m),1.95-2.07(3H,m),2.23-2.28(2H,m),2.32-2.39(2H,m),
2.52-2.56(1H,m),2.80-2.82(1H,m),3.53(1H,d,J＝13.4Hz),3.61-3.63(2H,m),4.56(1H,br).13C NMR(δC,CDCl3,150MHz):168.5,154.8,128.7,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,33.4,32.5,29.2,29.2,28.3,27.7,26.5,26.2,23.3,22.9,22.1,20.8,17.9,15.8,6.9,6.7.FTMS(ESI):m/z calcd forC28H44O3N([M+H]+)442.33157,Found 442.33145。
实施例11化合物5C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的环戊胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物5C。
化合物5C的结构式为：
化合物5C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.37(1H,t,J＝5.0Hz),0.67(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.90(3H,s),1.15-1.22(2H,m),1.33-1.41(5H,m),1.50(1H,d,J＝13.4Hz),1.58-1.65(4H,m),1.70-1.81(2H,m),1.96-2.01(5H,m),2.24-2.28(2H,m),2.32-2.40(2H,m),
2.55-2.59(1H,m),3.54(1H,d,J＝13.4Hz),3.62(3H,m),4.28(1H,m),4.74(1H,br).13CNMR(δC,CDCl3,150MHz):166.6,154.5,128.8,78.3,60.9,57.0,51.2,48.1,47.6,45.9,45.9,44.8,43.3,33.5,33.4,33.3,32.5,29.2,29.2,28.3,27.7,26.5,26.2,23.9,23.9,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m/z calcd forC30H48O3N([M+H]+)470.36287,Found 470.3627。
实施例12化合物6C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的苯乙胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物6C。
化合物6C的结构式为：
化合物6C的结构理化数据如下：无色油状,产率87％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.15(1H,m),0.37(1H,t,J＝5.0Hz),0.67(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.90(3H,s),1.14-1.23(2H,m),1.35(1H,dd,J＝10.0Hz,J＝5.2Hz),1.41(1H,t,J＝10.9Hz),1.50(1H,d,J＝13.5Hz),1.64(1H,t,J＝11.1Hz),1.71-1.81(4H,m),1.93-2.07(3H,m),2.19(1H,m),2.25-2.35(3H,m),2.40-2.50(1H,m),2.85(2H,t,J＝6.9Hz),3.48(1H,d,J＝13.5Hz),3.55-3.60(3H,m),3.63(1H,d,J＝5.5Hz),4.54(1H,s),7.20(2H,d,J＝7.4Hz),7.24(1H,t,J＝7.3Hz),7.26(1H,s),7.32(1H,t,J＝7.5Hz).13CNMR(δC,CDCl3,150MHz):165.8,153.2,138.0,127.8,127.8,127.8,127.6,127.6,125.5,77.1,59.7,55.83,46.8,46.4,44.8,44.7,43.6,42.1,39.5,34.5,32.1,31.4,28.1,28.0,27.1,26.6,25.3,25.0,22.1,21.0,19.6,16.7,14.6.FTMS(ESI):m/z calcd for C33H48O3N([M+H]+)506.36287,Found 506.36311。
实施例13化合物7C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的2-(1-环己烯基)乙胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物7C。
化合物7C的结构式为：
化合物7C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.37(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.90(3H,s),1.17-1.25(2H,m),1.33-42(3H,m),1.50(1H,d,J＝7.4Hz),1.53-1.58(2H,m),
1.61-1.67(3H,m),1.73-1.82(2H,m),1.93(2H,m),2.00-2.06(4H,m),2.16(2H,m),2.26-2.36(4H,m),2.54-2.57(1H,m),3.32-3.37(1H,m),3.40-3.44(1H,m),3.57(1H,d,J＝13.4Hz),3.60(2H,s),3.63(1H,d,J＝5.5Hz),4.86(1H,br),5.49(1H,s).13CNMR(δC,CDCl3,150MHz):165.2,153.8,138.1,137.9,137.9,130.7,122.3,122.3,87.6,78.2,61.4,57.4,47.8,47.5,46.0,45.9,44.7,43.4,33.7,32.7,29.6,29.2,28.3,27.7,27.1,26.5,26.3,23.3,23.3,22.2,20.7,17.9,15.8.FTMS(ESI):m/z calcd for C33H52O3N([M+H]+)510.39417,Found 510.39469。
实施例14化合物8C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的对甲苯胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物8C。
化合物8C的结构式为：
化合物8C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.70(1H,dd,J＝8.6Hz,J＝4.3Hz),0.74(3H,s),0.81(3H,d,J＝6.8Hz),0.84(3H,d,J＝6.9Hz),0.97(3H,s),1.20-1.28(2H,m),1.35(1H,dd,J＝15.1Hz,J＝5.2Hz),1.44(1H,t,J＝10.9Hz),1.60(1H,d,J＝13.7Hz),1.67(1H,t,J＝10.9Hz),1.72-1.77(1H,m),1.74-1.82(1H,m),2.03-2.09(3H,m),2.18-2.21(1H,m),2.31(3H,s),2.33-2.37(2H,m),2.62-2.72(2H,m),3.51(1H,d,J＝13.7Hz),3.64(1H,d,J＝5.5Hz),3.70(2H,s),4.21(1H,br),7.11(2H,d,J＝8.2Hz),7.45(2H,d,J＝8.3Hz),7.90(1H,s).13C NMR(δC,CDCl3,150MHz):165.1,154.5,135.4,134.2,130.1,129.6,120.5,129.6,120.5,78.3,61.2,57.3,47.9,47.5,46.0,45.9,44.8,43.4,33.7,32.6,29.4,29.2,28.3,27.7,26.5,26.3,23.3,22.2,21.0,20.7,17.8,15.8.FTMS(ESI):m/z calcd forC32H46O3N([M+H]+)492.34722,Found492.34763。
实施例15化合物9C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的苄胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物9C。
化合物9C的结构式为：
化合物9C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.17(1H,m),0.38(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.74(3H,s),0.81(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.92(3H,s),1.17-1.23(2H,m),1.35(1H,dd,J＝15.2Hz,J＝5.2Hz),1.42(1H,m),1.54(1H,d,J＝13.4Hz),1.66(1H,t,J＝10.9Hz),1.72-1.82(2H,m),1.96-2.08(3H,m),2.22-2.26(1H,m),2.30(1H,d,J＝8.8Hz),2.31-2.35(1H,m),2.39-2.43(1H,m),2.57-2.62(1H,m),3.57(1H,d,J＝13.4Hz),3.63(3H,m),4.48-4.55(2H,m),4.58(1H,s),7.28-7.36(5H,
m).13C NMR(δC,CDCl3,150MHz):166.8,155.3,138.2,128.9,128.9,128.6,128.2,128.2,127.8,78.3,61.0,57.0,48.0,47.6,45.9,45.9,44.9,43.8,43.3,33.4,32.6,29.3,29.2,28.3,27.7,26.5,26.2,23.3,22.1,20.8,17.9,15.8.FTMS(ESI):m/z calcd forC32H46O3N([M+H]+)492.34722,Found 492.34763。
实施例16化合物10C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的对溴苯胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物10C。
化合物10C的结构式为：
化合物10C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.42(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.71(3H,s),0.74(3H,d,J＝6.8Hz),0.84(3H,d,J＝6.9Hz),0.97(3H,s),1.22-1.28(2H,m),1.36(1H,dd,J＝15.2Hz,J＝5.2Hz),1.45(1H,t,J＝10.9Hz),
1.61-1.67(2H,m),1.72-1.74(1H,m),1.81-1.82(1H,m),2.05-2.10(2H,m),
2.13-2.15(1H,m),2.34-2.37(2H,m),2.67-2.70(2H,m),3.40(1H,d,J＝13.85Hz),3.64(1H,d,J＝5.5Hz),3.72(2H,t,J＝15.2Hz),4.02(1H,br),7.40(2H,dt,J＝8.8Hz,J＝2.0Hz),7.50(2H,dt,J＝8.8Hz,J＝2.0Hz),8.40(1H,s).13C
NMR(δC,CDCl3,150MHz):165.3,153.6,137.4,132.0,132.0,130.8,122.0,122.0,116.9,78.2,61.3,57.5,47.8,47.5,46.0,45.9,44.7,43.4,33.6,32.7,29.6,29.4,28.3,27.7,26.5,26.4,23.3,22.2,20.7,17.9,15.9.FTMS(ESI):m/z calcd for C31H43O3NBr([M+H]+)556.24208,Found 556.24237。
实施例17化合物11C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的对碘苯胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物11C。
化合物11C的结构式为：
化合物11C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.42(1H,t,J＝5.0Hz),0.70(1H,dd,J＝8.6Hz,J＝4.3Hz),0.74(3H,s),0.81(3H,d,J＝6.8Hz),0.84(3H,d,J＝6.9Hz),0.97(3H,s),1.23-1.28(2H,m),1.34(1H,dd,J＝15.2Hz,J＝5.2Hz),1.45(1H,t,J＝10.9Hz),
1.61-1.68(2H,m),1.72-1.83(2H,m),1.06-2.15(3H,m),2.34-2.37(2H,m),
2.32-2.37(2H,m),2.70(2H,m),3.41(1H,d,J＝13.8Hz),3.65(1H,d,J＝5.5Hz),3.72(2H,t,J＝11.0Hz),3.88(1H,s),7.38(2H,d,J＝8.8Hz),7.69(1H,dt,J＝8.8Hz,J＝2.0Hz).13C NMR(δC,CDCl3,150MHz):165.2,153.8,138.1,137.9,137.9,130.7,122.3,122.3,87.6,78.2,61.4,57.4,47.8,47.5,46.0,45.9,44.7,43.4,33.7,32.7,29.6,29.2,28.3,27.7,27.1,26.5,26.3,23.3,23.3,22.2,20.7,17.9,15.8.FTMS(ESI):m/zcalcd forC31H43O3NI([M+H]+)604.22821,Found 604.22859。
实施例18化合物12C的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的正丙胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到化合物12C。
化合物12C的结构式为：
化合物12C的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.38(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),0.94(3H,t,J＝7.4Hz),1.17-1.23(2H,m),1.32-1.42(3H,m),1.50-1.59(3H,m),1.65-1.68(1H,m),1.73-1.80(2H,m),1.97-2.07(3H,m),2.24-2.28(2H,m),
2.32-2.36(1H,m),2.39-2.43(1H,m),2.56-2.61(1H,m),3.26-3.30(2H,m),3.55(1H,d,J＝13.4Hz),3.61-3.63(2H,m),4.76(1H,t,J＝7.3Hz).13C NMR(δC,CDCl3,150MHz):δ167.0,154.6,128.8,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,41.4,33.4,32.5,29.2,29.2,28.3,27.7,26.5,26.2,23.3,22.9,22.1,20.8,17.9,15.8,
11.6.FTMS(ESI):m/z calcd for C28H46O3N([M+H]+)444.34722,Found444.34746。
对比例1
将二倍半萜Asperterpenoid C设计为本发明的第一个对比案例。
对比例2对比例2化合物的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(0.04mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥纯乙腈溶解，接着加入K2CO3(0.12mmol，3eq)在50℃下回流搅拌15-60min，再加入1mL溴乙酸甲酯在该温度下回流反应4-6h左右，并用氮气保护。TLC监测反应，反应完毕后产物用3M盐酸调节pH为4-5左右，加入饱和食盐水，乙酸乙酯萃取三次(3*5ml)，有机层用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。用二氯甲烷/甲醇＝60:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到对比例2化合物。
对比例2化合物的结构式为：
对比例2化合物的结构理化数据如下：无色油状,产率63％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.18(1H,m),0.41(1H,t,J＝5.0Hz),0.71(1H,dd,J＝8.6Hz,J＝4.3Hz),0.76(3H,s),0.83(3H,d,J＝6.8Hz),0.85(3H,d,J＝6.9Hz),0.94(3H,s),1.20-1.26(2H,m),1.38(1H,dd,J＝15.1Hz),1.44(1H,t,J＝5.8Hz),1.62(1H,d,J＝13.5Hz),1.70(1H,t,J＝11.2Hz),1.74-1.79(1H,m),1.80-1.84(1H,m),1.99-2.02(1H,m),2.05-2.10(2H,m),2.23-2.27(1H,m),2.25-2.28(1H,m),2.36,(2H,m),2.67(2H,m),3.53(1H,t,J＝13.7Hz),3.60(1H,s),3.63(1H,s),3.66(1H,d,J＝5.5Hz),3.80(3H,s),4.64(1H,d,15.9),4.80(1H,d,15.9).13C NMR(δC,CDCl3,150MHz):168.5,166.8,161.6,126.6,78.3,61.3,60.7,57.0,52.5,47.8,47.5,45.8,45.8,45.0,43.0,32.8,32.6,29.4,29.0,28.3,27.8,26.7,26.2,23.3,21.9,20.8,17.9,15.8.FTMS(ESI):m/z calcd for C28H42O6Na([M+Na]+)497.28736,Found 497.28754。
对比例3对比例3化合物的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的吗啡啉继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到对比例3化合物。
对比例3化合物的结构式为：
对比例3化合物的结构理化数据如下：无色油状,产率70％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.19(1H,m),0.37(1H,t,J＝5.0Hz),0.66(1H,dd,J＝8.6Hz,J＝4.3Hz),0.72(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),1.01(3H,s),1.12-1.23(2H,m),1.33-1.41(2H,m),1.50(1H,d,J＝13.6Hz),1.64(1H,t,J＝11.2Hz),1.71-1.81(2H,m),1.99-2.07(2H,m),2.12-2.17(2H,m),2.23(1H,d,J＝9Hz),
2.24-2.28(1H,m),2.32-2.37(1H,m),2.67(1H,d,J＝13.7Hz),2.73(1H,m),3.30(1H,m),3.37(1H,m),3.45(1H,m),3.52-3.58(2H,m),3.62(1H,d,J＝5.5Hz),3.66(1H,m),3.70-3.76(3H,m),3.90(1H,d,J＝13.5Hz),4.06(1H,s).13C
NMR(δC,CDCl3,150MHz):169.9,147.4,132.3,78.2,67.3,67.0,60.6,54.3,47.5,47.4,47.2,46.0,45.9,44.3,42.7,42.1,34.5,32.4,29.23,29.2,28.2,28.0,27.6,26.7,23.2,22.4,21.2,17.7,15.6.FTMS(ESI):m/z calcd forC29H46O4N([M+H]+)472.34214,Found 472.34255。
对比例4对比例4化合物的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的N-(2-氨基乙基)吗啉继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到对比例4化合物。
对比例4化合物的结构式为：
对比例4化合物的结构理化数据如下：无色油状,产率58％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.38(1H,t,J＝5.0Hz),0.68(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),1.15-1.23(2H,m),1.35(1H,dd,J＝15.1Hz),1.41(1H,t,J＝10.9Hz),1.52(1H,d,J＝11.3Hz),1.66(1H,t,J＝11.2Hz),1.73-1.81(3H,m),1.99-2.07(3H,m),2.26-2.36(3H,m),2.42-2.49(4H,m),2.54-2.62(3H,m),3.43(2H,m),3.56(1H,d,J＝13.4Hz),3.61(2H,s),3.63(1H,d,J＝5.5Hz),3.72(4H,m).13C NMR(δC,CDCl3,150MHz):166.8,154.8,128.5,78.2,67.0,60.7,56.9,56.7,53.2,53.2,53.2,47.9,47.4,45.8,45.8,44.7,43.2,35.4,33.2,32.34,29.1,29.1,28.1,27.6,26.4,26.1,23.2,22.0,20.7,17.8,15.6.FTMS(ESI):m/z calcd forC31H51O4N2([M+H]+)515.38433,Found 515.38481。
对比例5对比例5化合物的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的1-(2-氨乙基)哌啶继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到对比例5化合物。
对比例5化合物的结构式为：
对比例5化合物的结构理化数据如下：无色油状,产率88％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.14(1H,m),0.38(1H,t,J＝5.0Hz),0.66(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.83(3H,d,J＝6.9Hz),0.91(3H,s),1.15-1.23(3H,m),1.29-1.36(5H,m),1.40(2H,m),1.53(2H,d,J＝13.6Hz),
1.71-1.79(5H,m),1.99-2.07(4H,m),2.21-2.26(2H,m),2.34(1H,m),2.58(1H,m),2.80(1H,m),3.10(2H,m),3.42(1H,d,J＝13.5Hz),3.63-3.68(5H,m),3.82(1H,s).13CNMR(δC,CDCl3,150MHz):129.5,78.4,60.8,57.1,57.1,54.8,48.0,47.6,46.0,45.9,44.8,43.4,33.3,32.6,29.9,29.9,29.9,29.3,29.2,29.1,28.3,27.7,26.5,26.4,23.3,22.2,20.8,17.9,15.8.FTMS(ESI):m/z calcd forC32H53O3N2([M+H]+)513.40507,Found513.40532。
对比例6对比例6化合物的合成方法、结构式及其结构理化数据
合成方法：称取样品Asteipenoid C(10mg，0.027mmol，1eq)于25ml圆底烧瓶中，加入2ml超干燥DCM溶解，接着加入EDC(10.35mg，0.052mmol，2eq)和HOBT(14.6mg，0.108mmol，4eq)在0℃或者室温下反应2-3h，TLC跟踪，反应完全后再加入1eq的正庚胺继续反应3-4h左右。TLC监测反应，反应完毕后旋去二氯甲烷，产品用乙酸乙酯或二氯甲烷溶解，水洗三次(3*5ml)，除去副产物，有机相用无水硫酸镁干燥、过滤、减压蒸馏得到粗产品。再用二氯甲烷/甲醇＝100:1(V/V)为洗脱剂通过硅胶柱层析纯化处理，得到对比例6化合物。
对比例6化合物的结构式为：
对比例6化合物的结构理化数据如下：无色油状,产率43％,mp：>300℃.1HNMR(δH,CDCl3,600MHz)：0.16(1H,m),0.38(1H,t,J＝5.0Hz),0.67(1H,dd,J＝8.6Hz,J＝4.3Hz),0.73(3H,s),0.80(3H,d,J＝6.8Hz),0.84(3H,d,J＝6.9Hz),0.90(3H,t,J＝6.9Hz),0.91(3H,s),1.15-1.23(2H,m),1.25-1.29(8H,m),1.33-1.42(2H,m),1.49-1.54(3H,m),1.65(1H,t,J＝11.0Hz),1.73-1.80(2H,m),1.97-2.07(3H,m),2.32-2.42(2H,m),2.24-2.28(2H,m),2.56-2.60(1H,m),3.30(2H,m),3.55(1H,d,J＝13.4Hz),3.60-3.63(3H,m),4.75(1H,m).13C NMR(δC,CDCl3,150MHz):166.9,154.7,128.7,78.3,60.9,57.0,48.0,47.6,45.9,45.9,44.8,43.3,39.7,33.4,32.5,31.9,29.8,29.2,29.1,28.3,27.7,27.1,26.5,26.0,23.3,22.7,22.1,20.8,17.9,15.8,14.2.FTMS(ESI):m/z calcd for C32H54O3N([M+H]+)500.40982,Found 500.41023。
应用例1：Asperterpenoid C衍生物在细胞水平上的抗新型冠状病毒活性检测(抗病毒半数有效剂量，50％ Effective Concentration，EC50)
测试病毒株：新型冠状病毒株SARS-CoV-2(BA.2GDPCC 2.00299)
细胞系：hACE2-293T(高表达人源血管紧张素转化酶2的293T细胞系)
检测方法：
RT-qPCR法进行测试。Asperterpenoid C衍生物梯度剂量(0，1.563，3.125，6.25，12.5，25μM或0，5，10，20，40，80μM)提前1h加入到hACE2-293T细胞上清中，病毒感染1h后，换含对应浓度药物的无病毒培养基维持48h。收集细胞上清，用QIAGEN公司病毒核酸提取试剂盒(QIAGEN，#74104)提取病毒RNA，操作方法按试剂盒的说明书进行；再用新型冠状病毒2019-nCoV核酸检测试剂盒(荧光PCR法)(广州达安基因股份有限公司，DA0932)，按照试剂盒提供的实验操作方法及参数设置进行检测和结果分析，qPCR检测病毒感染后化合物不同剂量组与溶剂组(DMSO)Ct值，再用以下公式计算出新型冠状病毒RNA水平抑制率。
对应给药组抑制率(％)＝2^(溶剂对照组Ct值-给药组Ct值)×100％，用EXCEL2013的Forecast公式计算，当抑制率等于50％时，对应Asperterpenoid C衍生物的浓度，作为EC50。三次重复实验取平均值。
应用例2：Asperterpenoid C衍生物细胞毒半数细胞活性抑制剂量检测(50％Cytotoxic Concentration，CC50)
MTT法进行测试。按8000～10000个/孔细胞使用96孔板进行铺板，铺板后放置37℃、5％CO2孵箱中进行培养，12h后Asperterpenoid C衍生物梯度剂量(0，1.563，3.125，6.25，12.5，25μM或0，5，10，20，40，80μM)加入到hACE2-293T细胞上清中，维持48h后加入噻唑蓝(MTT)25μL孵育4h，吸出培养基，加入160μL DMSO检测490nm吸光度值与DMSO溶剂对照组进行比较，计算抑制率(％)＝(1-给药组490nm吸光度值/溶剂对照组490nm吸光度值)100％，用EXCEL2013的Forecast公式计算，当抑制率等于50％时，对应Asperterpenoid C衍生物的浓度，作为CC50。三次重复实验取平均值。
表1是本发明Asperterpenoid C衍生物1A～6A以及相关对比例的抗新型冠状病毒活性结果。
表1Asperterpenoid C衍生物1A～6A以及相关对比例的抗新型冠状病毒活性
a Selectivity Index，即选择指数(SI)，计算方法为SI＝CC50/EC50。
b NS是指在小于该化合物对应的CC50范围以内未检测出抗新型冠状病毒活性。
从表1结果可以看出，化合物1A-6A具有很好的抑制新型冠状病毒活性的作用，尤其是化合物4A抑制新型冠状病毒活性的效果最为显著，其EC50为0.8μM，其选择指数(SI)也最大，为19.1，非常具备开发抗新型冠状病毒药物的潜力。而Asperterpenoid C经过初步的试验，该化合物并未显示出抑制新型冠状病毒活性的作用。
表2是本发明化合物1C～12C以及相关对比例的抗新型冠状病毒活性结果。
表2Asperterpenoid C衍生物1C～12C以及相关对比例的抗新型冠状病毒活性
a Selectivity Index，即选择指数(SI)，计算方法为SI＝CC50/EC50
b NS是指在小于该化合物对应的CC50范围以内未检测出抗新型冠状病毒活性。
从表2结果可以看出，化合物1C-12C具有很好的抑制新型冠状病毒活性的作用，尤其是化合物10C抑制新型冠状病毒活性的效果最为显著，其EC50为2.3μM，其选择指数(SI)也较大，为4.0；化合物6C的选择指数(SI)也较大，为4.4。而Asperterpenoid C经过初步的试验结果，该化合物并未显示出抑制新型冠状病毒活性的作用。
从上述结果可知，本发明保护的Asperterpenoid C衍生物具有很好的抑制新型冠状病毒活性作用，且在有效抗病毒剂量下对于宿主细胞具有较好的安全性，可制备成为高效低毒的抗新型冠状病毒药物进行应用，对于新型冠状病毒的防治具有重要意义。
显然，本发明的上述实施例仅仅是为了清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (10)
1.二倍半萜Asperterpenoid C衍生物，其特征在于，其化学结构如式Ⅰ的酯类衍生物、式Ⅱ的酰胺类衍生物：
其中，式Ⅰ的R选自C1-C8直链烷基；C1-C4卤素取代烷基，所述卤素包括：F、Cl、Br；
式Ⅱ的R选自C1-C6直链氨基；连接三元环、五元环、六元环、苯基、卤素取代苯基、甲苯的氨基，所述卤素原子包括：I、Br；连接三元环、五元环、六元环、苯基、卤素取代苯基、甲苯的C1-C3仲胺，所述卤素原子包括：I、Br；连接含有N和/或O的六元杂环的C3仲胺；连接含有S或O的五元杂环的C1-C3仲胺。
2.根据权利要求1所述的Asperterpenoid C酯类衍生物，其特征在于，式Ⅰ的R选自如下基团：
3.根据权利要求1所述的Asperterpenoid C酰胺类衍生物，其特征在于，式Ⅱ的R选自如下基团：
4.权利要求1-3任一项所述的二倍半萜Asperterpenoid C衍生物的制备方法，其特征在于，该制备方法为：
(1)所述Asperterpenoid C酯类衍生物制备方法为：Asperterpenoid C在碱的催化和加热回流的条件下与卤代烷烃类化合物反应得到式Ⅰ结构的Asperterpenoid C酯类衍生物；
(2)所述Asperterpenoid C酰胺类衍生物制备方法为：Asperterpenoid C与EDC、HOBT反应得到活性酯后，活性酯与胺类化合物反应得到式Ⅱ结构的Asperterpenoid C酰胺类衍生物。
5.权利要求1所述二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物在制备抗新型冠状病毒药物中的应用。
6.根据权利要求5所述应用，其特征在于，所述新型冠状病毒为SARS-CoV-2、B.1.1.7变异株(Alpha)、B.1.351变异株(Beta)、P.1变异株(Gamma)、B.1.617.2变异株(Delta)或B.1.1.529变异株(Omicron)。
7.根据权利要求5所述应用，其特征在于，所述二倍半萜Asperterpenoid C衍生物药学上可接受的盐为其无机酸盐、无机碱盐或复盐。
8.根据权利要求5所述应用，其特征在于，所述二倍半萜Asperterpenoid C衍生物前药是指可在体内转变成所述Asperterpenoid C衍生物或其盐的物质。
9.一种抗新型冠状病毒的药物，其特征在于，包含权利要求1所述二倍半萜Asperterpenoid C衍生物、或其药学上可接受的盐、或其立体异构体、或其前药化合物。
10.根据权利要求9所述药物，其特征在于，还包括药用载体和/或赋形剂，制成不同的剂型。
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