CN115043849B - 环内酯骨架拼接茚二酮双螺环类化合物及其制备方法及应用 - Google Patents

环内酯骨架拼接茚二酮双螺环类化合物及其制备方法及应用 Download PDF

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CN115043849B
CN115043849B CN202210558788.2A CN202210558788A CN115043849B CN 115043849 B CN115043849 B CN 115043849B CN 202210558788 A CN202210558788 A CN 202210558788A CN 115043849 B CN115043849 B CN 115043849B
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彭礼军
刘雄利
潘博文
石洋
刘雄伟
张磊
田又平
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Abstract

本发明公开了一种环内酯骨架拼接茚二酮双螺环类化合物，本发明以各种取代的环内酯烯烃1、茚三酮2与脯氨酸或硫代脯氨酸3，在有机溶剂中，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4，该类化合物包含潜在生物活性环内酯骨架和茚二酮骨架，可以为生物活性筛选提供化合物源，且该类骨架化合物对人白血病细胞(K562)和人非小细胞肺癌肺癌(A549)具有肿瘤生长抑制活性作用，对药物的筛选和制药行业具有重要的应用价值。

Description

环内酯骨架拼接茚二酮双螺环类化合物及其制备方法及应用
技术领域
本发明涉及化学技术和药学技术领域，尤其是一种环内酯骨架拼接茚二酮双螺环类化合物及其制备方法及应用。
背景技术
根据药物设计的活性骨架拼接原理，把两个或多个具有生物活性骨架拼接成一个潜在生物活性的多骨架分子在有机化学和医药化学中是极其重要的研究领域。(1)环内酯骨架化合物也具有较强的生物活性，例如小白菊内酯、去氢木香内酯、木香内酯、郁金香素A、等。这些化合物在解除病痛、经济发展中起着重要作用。(2)茚二酮骨架在天然产物中占有重要的地位，由于其明显的生物活性以及独特的结构，吸引了许多化学工作者及医药化学团队的广泛关注。鉴于环内酯骨架和茚二酮骨架具有潜在的生物活性。因此，把环内酯骨架拼接到茚二酮骨架上，合成一系列新的潜在多活性官能团的环内酯骨架拼接茚二酮双螺环类化合物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。
发明内容
本发明的目的是：提供一种环内酯骨架拼接茚二酮双螺环类化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的：一种环内酯骨架拼接茚二酮双螺环类化合物，该化合物具有如下通式(Ⅰ)的结构：
式中，n为1或2；X为亚甲基或硫；R1为各种取代基的苯环或氢；
具体为如下结构式之一:
环内酯骨架拼接茚二酮双螺环类化合物的制备方法，将各种取代的环内酯烯烃1、茚三酮2与脯氨酸或硫代脯氨酸3，在有机溶剂中，加温条件下，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4。
合成路线举例如下：
其中合成路线中的化合物，其取代基满足式中，n为1或2；X为亚甲基或硫；R1为各种取代基的苯环或氢。
反应机理举例如下：
所述的有机溶剂为甲醇、甲苯、乙醇或乙腈。
将各种取代的环内酯烯烃1、茚三酮2与脯氨酸或硫代脯氨酸3，在有机溶剂中，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4，反应温度60℃-90℃,反应时间为3-10小时。
环内酯骨架拼接茚二酮双螺环类化合物作为新型冠状病毒3CL水解酶抑制剂的药物应用。
通过采用上述技术方案，各种取代的环内酯烯烃1、茚三酮2与脯氨酸或硫代脯氨酸3，在有机溶剂中，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4，该类化合物包含潜在生物活性环内酯骨架和茚二酮骨架(例如化合物4da为小白菊内酯骨架拼接茚二酮双螺环类衍生物；4ea和4eb为去氢木香内酯骨架拼接茚二酮双螺环类衍生物)，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该骨架化合物可以作为新型冠状病毒3CL水解酶潜在抑制剂。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明
图1为本发明的实施例的化合物4be,4cb和4ea单晶图；
图2为本发明所合成的化合物的设计思路及其创造性图。
具体实施方式
本发明的实施例：在反应管中依次加入环内酯烯烃1a(0.20mmol)，茚三酮2(0.30mmol)，脯氨酸(0.5mmol)和2.5mL甲苯溶液，在80℃中搅拌反应5h，TLC检测至基本反应完全，经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝7:1)纯化得化合物4aa，淡黄色固体,熔点：237.9-238.6℃；产率87％,>20:1dr。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.88-2.04(m,3H),2.16-2.29(m,2H),2.57-2.63(m,1H),2.76-2.80(m,1H),2.83-2.90(m,1H),3.18-3.24(m,1H),3.64-3.70(m,1H),4.25(d,J＝10.0Hz,1H),4.30-4.36(m,1H),7.20-7.25(m,5H),7.75-7.79(m,1H),7.82-7.88(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:23.8,28.3,28.9,45.3,53.0,63.6,64.4,65.3,77.5,121.5,121.8,126.4,127.0,127.3,133.3,134.4,135.7,138.4,139.6,173.1,198.4,198.9；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO4[M+Na]+:410.1363；Found:410.1366。
化合物4ab至4gb的制备方法同化合物4aa，投料比与化合物4aa相同，可得到化合物4ab至4gb，反应产率见表1和表2，但需强调的是本发明的化合物不限于表1和表2所表示的内容。
表1为一种环内酯骨架拼接茚二酮双螺环类化合物的化学结构
表2为一种环内酯骨架拼接茚二酮双螺环类化合物的化学结构
本实施例制备化合物4ab:淡黄色固体,熔点：240.1-241.0℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.88-2.03(m,3H),2.16-2.23(m,2H),2.57-2.63(m,1H),2.76-2.81(m,1H),2.85-2.92(m,1H),3.31-3.37(m,1H),3.66-3.72(m,1H),4.21-4.29(m,2H),6.93-6.97(m,2H),7.17-7.20(m,2H),7.76-7.80(m,1H),7.83-7.89(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.2,29.8,30.5,46.9,53.8,65.1,66.1,67.2,79.0,115.8(d,JCF＝21.3Hz),123.1,123.5,130.2(d,JCF＝8.1Hz),130.6,136.2,137.3,140.0,141.1,162.9(d,JCF＝245.2Hz),174.6,199.8,200.4；HRMS(ESI-TOF)m/z:Calcd.for C24H20FNNaO4[M+Na]+:428.1269；Found:428.1264。
本实施例制备化合物4ac:淡黄色固体,熔点：235.7-236.4℃；产率86％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.87-2.03(m,3H),2.15-2.21(m,2H),2.57-2.63(m,1H),2.76-2.80(m,1H),2.86-2.92(m,1H),3.35-3.41(m,1H),3.66-3.72(m,1H),4.20-4.28(m,2H),7.14(d,J＝7.6Hz,2H),7.20-7.24(m,2H),7.76-7.80(m,1H),7.83-7.88(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.2,29.8,30.5,46.9,53.8,65.0,66.1,67.0,79.0,123.1,123.5,129.1,130.0,133.5,134.0,136.2,137.3,140.0,141.0,174.5,199.8,200.3；HRMS(ESI-TOF)m/z:Calcd.for C24H20ClNNaO4[M+Na]+:444.0973；Found:444.0976。
本实施例制备化合物4ad:淡黄色固体,熔点：235.9-236.6℃；产率89％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.87-2.03(m,3H),2.13-2.20(m,2H),2.56-2.63(m,1H),2.75-2.80(m,1H),2.85-2.92(m,1H),3.36-3.42(m,1H),3.66-3.72(m,1H),4.19-4.28(m,2H),7.08(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.76-7.80(m,1H),7.83-7.88(m,2H),7.94(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.2,28.8,29.5,45.9,52.8,63.9,65.1,65.9,77.9,121.1,122.1,122.5,129.3,131.0,132.9,135.2,136.4,139.0,140.0,173.4,198.8,199.2；HRMS(ESI-TOF)m/z:Calcd.forC24H20BrNNaO4[M+Na]+:488.0468；Found:488.0471。
本实施例制备化合物4ae:淡黄色固体,熔点：245.1-245.7℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.88-2.03(m,3H),2.15-2.29(m,5H),2.56-2.62(m,1H),2.75-2.87(m,2H),3.19-3.24(m,1H),3.64-3.70(m,1H),4.20(d,J＝10.0Hz,1H),4.27-4.33(m,1H),7.04-7.17(m,4H),7.74-7.78(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.0,25.4,29.9,30.5,46.9,54.3,65.2,66.1,66.9,79.2,123.1,123.4,128.5,129.6,131.7,136.0,137.2,137.8,140.0,141.3,174.7,200.0,200.5；HRMS(ESI-TOF)m/z:Calcd.for C25H23NNaO4[M+Na]+:424.1519；Found:424.1516。
本实施例制备化合物4ba:淡黄色固体,熔点：250.7-251.0℃；产率83％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.22-2.30(m,1H),2.83-2.90(m,1H),2.95-2.99(m,1H),3.18-3.28(m,2H),3.54(d,J＝7.6Hz,1H),3.63-3.69(m,1H),3.92(d,J＝7.6Hz,1H),4.31(d,J＝8.8Hz,1H),4.55-4.61(m,1H),7.21-7.27(m,5H),7.77-7.81(m,1H),7.84-7.88(m,2H),7.96(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:23.7,34.2,49.0,51.8,63.7,64.2,68.9,77.4,121.4,121.8,126.6,126.9,127.3,132.3,134.5,135.7,138.3,139.6,172.3,196.5,197.6；HRMS(ESI-TOF)m/z:Calcd.forC23H19NNaO4S[M+Na]+:428.0927；Found:428.0923。
本实施例制备化合物4bb:淡黄色固体,熔点：242.4-244.4℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.17-2.25(m,1H),2.85-2.98(m,2H),3.22-3.26(m,1H),3.32-3.38(m,1H),3.54(d,J＝7.6Hz,1H),3.65-3.71(m,1H),3.92(d,J＝7.6Hz,1H),4.30(d,J＝8.8Hz,1H),4.48-4.54(m,1H),6.95-6.70(m,2H),7.19-7.22(m,2H),7.78-7.82(m,1H),7.83-7.89(m,2H),7.95-7.97(m,1H)；13C NMR(CDCl3,100MHz)δ:23.9,34.5,49.3,51.4,63.9,64.6,69.5,77.6,114.6(d,JCF＝21.2Hz),121.8,122.2,128.3,128.4,128.9(d,JCF＝8.0Hz),134.9,136.1,138.6,139.8,161.2(d,JCF＝247.2Hz),172.5,196.7,197.8；HRMS(ESI-TOF)m/z:Calcd.for C23H18FNNaO4S[M+Na]+:446.0833；Found:446.0835。
本实施例制备化合物4bc:淡黄色固体,熔点：236.2-237.0℃；产率88％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.15-2.22(m,1H),2.86-2.98(m,2H),3.22-3.26(m,1H),3.37-3.42(m,1H),3.54(d,J＝7.6Hz,1H),3.65-3.72(m,1H),3.92(d,J＝7.6Hz,1H),4.29(d,J＝8.8Hz,1H),4.48-4.54(m,1H),7.16(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),7.79-7.82(m,1H),7.86-7.89(m,2H),7.96(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.3,34.9,49.7,51.8,64.3,65.1,69.8,78.0,122.2,122.6,128.3,129.0,131.6,133.4,135.4,136.6,139.0,140.2,172.8,197.1,198.2；HRMS(ESI-TOF)m/z:Calcd.for C23H18ClNNaO4S[M+Na]+:462.0537；Found:462.0537。
本实施例制备化合物4bd:淡黄色固体,熔点：237.4-238.1℃；产率76％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45-2.51(m,1H),2.79-2.87(m,1H),2.90-2.94(m,1H),2.98-3.04(m,1H),3.33-3.37(m,1H),3.57(d,J＝8.0Hz,1H),3.68-3.73(m,1H),3.94(d,J＝7.6Hz,1H),4.51-4.56(m,1H),5.05(d,J＝8.4Hz,1H),7.18-7.26(m,2H),7.35-7.38(m,1H),7.54-7.57(m,1H),7.76-7.80(m,1H),7.84-7.89(m,2H),8.01(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.0,35.2,48.8,50.0,62.8,65.0,71.9,78.1,122.4,122.5,125.9,128.5,128.6,129.8,131.2,135.0,136.4,139.2,141.2,172.6,197.5,198.5；HRMS(ESI-TOF)m/z:Calcd.for C23H18ClNNaO4S[M+Na]+:462.0537；Found:462.0539。
本实施例制备化合物4be:淡黄色固体,熔点：230.2-231.0℃；产率83％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.14-2.22(m,1H),2.86-2.98(m,2H),3.21-3.26(m,1H),3.38-3.43(m,1H),3.54(d,J＝7.6Hz,1H),3.65-3.72(m,1H),3.92(d,J＝7.6Hz,1H),4.27(d,J＝8.2Hz,1H),4.47-4.53(m,1H),7.10(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),7.79-7.82(m,1H),7.86-7.89(m,2H),7.95-7.97(m,1H)；13CNMR(CDCl3,100MHz)δ:25.3,35.9,50.8,52.9,65.3,66.1,70.7,79.1,122.6,123.3,123.7,130.4,132.3,133.2,136.5,137.6,140.0,141.2,173.9,198.1,199.2；HRMS(ESI-TOF)m/z:Calcd.for C23H18BrNNaO4S[M+Na]+:506.0032；Found:506.0028。
本实施例制备化合物4bf:淡黄色固体,熔点：240.7-241.5℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.17-2.25(m,1H),2.89-2.99(m,2H),3.22-3.27(m,1H),3.42-3.47(m,1H),3.53(d,J＝7.6Hz,1H),3.66-3.72(m,1H),3.92(d,J＝7.6Hz,1H),4.28(d,J＝9.2Hz,1H),4.47-4.53(m,1H),7.14-7.20(m,2H),7.38-7.40(m,2H),7.79-7.83(m,1H),7.86-7.89(m,2H),7.96(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.4,34.9,49.7,51.9,64.3,65.1,69.8,78.0,122.2,122.6,126.7,129.6,130.6,135.4,135.5,136.5,139.0,140.2,172.7,197.0,198.1；HRMS(ESI-TOF)m/z:Calcd.for C23H18BrNNaO4S[M+Na]+:506.0032；Found:506.0032。
本实施例制备化合物4bg:淡黄色固体,熔点：235.8-236.2℃；产率79％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.47-2.53(m,1H),2.77-2.84(m,1H),2.90-2.94(m,1H),3.02-3.08(m,1H),3.34-3.39(m,1H),3.58(d,J＝7.6Hz,1H),3.67-3.72(m,1H),3.93(d,J＝7.6Hz,1H),4.45-4.51(m,1H),5.09(d,J＝7.6Hz,1H),7.10-7.14(m,1H),7.27-7.31(m,1H),7.55-7.58(m,2H),7.77-7.80(m,1H),7.84-7.89(m,2H),8.01(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.1,35.1,50.0,51.1,62.8,64.9,72.7,78.1,122.4,122.6,125.7,126.5,128.7,128.8,133.1,133.3,135.0,136.4,139.2,141.2,172.6,197.5,198.3；HRMS(ESI-TOF)m/z:Calcd.for C23H18BrNNaO4S[M+Na]+:506.0032；Found:506.0027。
本实施例制备化合物4bh:淡黄色固体,熔点：238.5-239.3℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.23(s,3H),2.26-2.30(m,1H),2.80-2.87(m,1H),2.94-2.98(m,1H),3.19-3.27(m,2H),3.52-3.55(m,1H),3.63-3.69(m,1H),3.91-3.93(m,1H),4.27(d,J＝8.8Hz,1H),4.52-4.57(m,1H),7.06-7.12(m,4H),7.77-7.80(m,1H),7.84-7.87(m,2H),7.95-7.97(m,1H)；13C NMR(CDCl3,100MHz)δ:20.0,24.5,35.0,49.8,52.4,64.5,65.1,69.8,78.2,122.2,122.5,127.5,128.8,129.9,135.2,136.5,137.2,139.0,140.4,173.1,197.3,198.4；HRMS(ESI-TOF)m/z:Calcd.forC24H21NNaO4S[M+Na]+:442.1083；Found:442.1085。
本实施例制备化合物4bi:淡黄色固体,熔点：237.8-237.9℃；产率80％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.26-2.32(m,1H),2.82-2.89(m,1H),2.95-2.98(m,1H),3.22-3.27(m,2H),3.53(d,J＝7.6Hz,1H),3.63-3.70(m,1H),3.92(d,J＝7.6Hz,1H),4.26(d,J＝8.8Hz,1H),4.53-4.59(m,1H),7.02-7.06(m,3H),7.14(d,J＝7.6Hz,1H),7.77-7.81(m,1H),7.84-7.88(m,2H),7.96(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.5,24.6,35.0,49.8,52.6,64.5,65.1,69.8,78.2,122.2,122.5,124.6,127.9,128.1,128.6,133.0,135.2,136.4,137.8,139.0,140.4,173.1,197.3,198.4；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO4S[M+Na]+:442.1083；Found:442.1087。
本实施例制备化合物4bj:淡黄色固体,熔点：245.7-246.5℃；产率79％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.30(s,3H),2.58-2.65(m,1H),2.82-2.88(m,1H),2.90-2.94(m,1H),3.11-3.17(m,1H),3.26-3.31(m,1H),3.55(d,J＝7.6Hz,1H),3.66-3.72(m,1H),3.95(d,J＝7.6Hz,1H),4.45-4.51(m,1H),4.77(d,J＝8.8Hz,1H),7.12-7.15(m,3H),7.41-7.43(m,1H),7.77-7.80(m,1H),7.84-7.89(m,2H),7.98(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.9,25.5,35.4,48.3,50.1,63.4,65.3,72.7,78.6,122.3,122.5,124.9,127.0,127.2,130.7,131.2,135.1,136.4,137.8,139.2,140.8,173.5,197.5,198.7；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO4S[M+Na]+:442.1083；Found:442.1089。
本实施例制备化合物4bk:淡黄色固体,熔点：234.3-234.6℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.22(s,3H),2.25(s,3H),2.57-2.64(m,1H),2.80-2.85(m,1H),2.89-2.93(m,1H),3.12-3.18(m,1H),3.24-3.29(m,1H),3.54(d,J＝8.0Hz,1H),3.66-3.72(m,1H),3.95(d,J＝8.0Hz,1H),4.43-4.49(m,1H),4.72(d,J＝8.4Hz,1H),6.95(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,1H),7.76-7.79(m,1H),7.83-7.88(m,2H),7.97(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.8,21.0,26.5,36.4,49.2,51.2,64.5,66.3,73.6,79.7,123.3,123.5,126.7,128.1,129.1,132.4,136.1,137.3,137.8,138.6,140.2,141.9,174.6,198.6,199.7；HRMS(ESI-TOF)m/z:Calcd.forC25H23NNaO4S[M+Na]+:456.1240；Found:456.1245。
本实施例制备化合物4bl:淡黄色固体,熔点：237.6-238.9℃；产率78％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.23-2.31(m,1H),2.80-2.87(m,1H),2.94-2.98(m,1H),3.22-3.27(m,2H),3.54(d,J＝7.6Hz,1H),3.65-3.69(m,1H),3.71(s,3H),3.92(d,J＝7.6Hz,1H),4.25(d,J＝8.2Hz,1H),4.49-4.54(m,1H),6.80(d,J＝8.8Hz,2H),7.14(d,J＝8.8Hz,2H),7.77-7.81(m,1H),7.84-7.88(m,2H),7.95-7.97(m,1H)；13C NMR(CDCl3,100MHz)δ:24.5,35.0,49.8,52.1,54.3,64.5,65.1,70.0,78.2,113.4,122.2,122.5,124.7,128.7,135.2,136.4,139.0,140.4,158.6,173.2,197.3,198.4；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO5S[M+Na]+:458.1033；Found:458.1029。
本实施例制备化合物4bm:淡黄色固体,熔点：232.7-232.9℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.29-2.33(m,1H),2.74-2.80(m,2H),2.95-2.98(m,1H),3.28-3.33(m,1H),3.53(d,J＝7.6Hz,1H),3.63(s,3H),3.68-3.71(m,1H),3.95(d,J＝7.6Hz,1H),4.70-4.75(m,2H),6.78(d,J＝8.0Hz,1H),6.88-6.92(m,1H),7.22-7.26(m,1H),7.39(d,J＝7.2Hz,1H),7.74-7.77(m,1H),7.83-7.87(m,1H),8.00(d,J＝7.6Hz,1H)；13CNMR(CDCl3,100MHz)δ:25.1,34.3,46.3,49.0,52.8,62.2,64.2,68.6,77.1,108.6,118.6,120.9,121.2,121.4,126.4,127.5,133.7,135.2,138.2,140.7,156.4,169.2,172.1,197.1,198.3；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO5S[M+Na]+:458.1033；Found:458.1036。
本实施例制备化合物4ca:淡黄色固体,熔点：248.6-248.9℃；产率80％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.20-1.22(m,1H),1.28-1.35(m,1H),1.87-1.95(m,1H),2.84-2.91(m,1H),2.92-2.96(m,1H),3.26-3.31(m,1H),3.32-3.38(m,1H),3.53(d,J＝7.2Hz,1H),3.77-3.82(m,1H),3.91(d,J＝6.8Hz,1H),4.43(d,J＝9.2Hz,1H),4.53-4.59(m,1H),7.20-7.30(m,5H),7.73-7.77(m,1H),7.83-7.88(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.8,23.2,35.7,50.2,56.4,67.0,69.3,69.9,81.3,123.0,123.6,128.2,128.6,129.0,134.7,135.6,137.3,140.2,142.6,169.4,198.1,199.1；HRMS(ESI-TOF)m/z:Calcd.for C24H21NNaO4S[M+Na]+:442.1083；Found:442.1086。
本实施例制备化合物4cb:淡黄色固体,熔点：242.5-243.8℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.22-1.24(m,1H),1.31-1.38(m,1H),1.82-1.90(m,1H),2.84-2.94(m,2H),3.24-3.29(m,1H),3.38-3.44(m,1H),3.52(d,J＝7.2Hz,1H),3.79-3.84(m,1H),3.90(d,J＝7.2Hz,1H),4.41(d,J＝9.2Hz,1H),4.46-4.52(m,1H),6.96-7.00(m,2H),7.18-7.22(m,2H),7.74-7.78(m,1H),7.83-7.88(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.7,21.1,33.5,48.1,53.6,64.8,67.5,67.9,79.1,113.8(d,JCF＝21.2Hz),121.0,121.5,128.2(d,JCF＝7.3Hz),133.6,135.3,138.2,140.4,160.4(d,JCF＝246.2Hz),167.2,195.9,197.0；HRMS(ESI-TOF)m/z:Calcd.for C24H20FNNaO4S[M+Na]+:460.0989；Found:460.0995。
本实施例制备化合物4cc:淡黄色固体,熔点：249.6-250.5℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.22-1.26(m,1H),1.33-1.39(m,1H),1.83-1.90(m,1H),2.85-2.96(m,2H),3.25-3.30(m,1H),3.42-3.47(m,1H),3.52(d,J＝6.8Hz,1H),3.81-3.84(m,1H),3.90(d,J＝6.8Hz,1H),4.42-4.50(m,2H),6.93-7.00(m,3H),7.22-7.28(m,1H),7.74-7.78(m,1H),7.83-7.88(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.7,22.3,34.5,49.1,54.7,65.7,68.3,69.0,80.1,114.0,114.2,114.5,114.7,122.0,122.6,123.4,123.5,129.5,129.6,134.7,136.3,139.2,141.4,160.6,163.1,168.1,196.8,198.0；HRMS(ESI-TOF)m/z:Calcd.for C24H20FNNaO4S[M+Na]+:460.0989；Found:460.0989。
本实施例制备化合物4cd:淡黄色固体,熔点：237.9-238.1℃；产率75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.22-1.24(m,1H),1.30-1.35(m,1H),1.88-1.92(m,1H),2.26(s,3H),2.82-2.88(m,1H),2.91-2.95(m,1H),3.24-3.29(m,1H),3.34-3.40(m,1H),3.52(d,J＝7.2Hz,1H),3.77-3.81(m,1H),3.90(d,J＝7.2Hz,1H),4.40(d,J＝9.2Hz,1H),4.50-4.55(m,1H),7.06-7.11(m,4H),7.73-7.76(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.8,23.2,35.7,50.2,56.2,67.0,69.4,69.9,81.3,123.0,123.5,128.5,129.7,131.5,135.5,137.2,138.0,140.2,142.6,169.5,198.1,199.1；HRMS(ESI-TOF)m/z:Calcd.for C25H23NNaO4S[M+Na]+:456.1240；Found:456.1241。
本实施例制备化合物4ce:淡黄色固体,熔点：248.1-249.2℃；产率80％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.21-1.26(m,1H),1.31-1.35(m,1H),1.89-1.96(m,1H),2.26(s,3H),2.83-2.89(m,1H),2.92-2.96(m,1H),3.25-3.30(m,1H),3.34-3.39(m,1H),3.52(d,J＝7.2Hz,1H),3.79-3.81(m,1H),3.91(d,J＝7.2Hz,1H),4.39(d,J＝9.2Hz,1H),4.51-4.57(m,1H),7.01-7.05(m,3H),7.14-7.19(m,1H),7.73-7.77(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.5,20.8,22.2,34.7,49.2,55.4,66.0,68.4,68.9,80.3,122.0,122.5,124.6,127.8,127.9,128.4,133.5,134.5,136.2,137.7,139.2,141.6,168.4,197.1,198.1；HRMS(ESI-TOF)m/z:Calcd.for C25H23NNaO4S[M+Na]+:456.1240；Found:456.1243。
本实施例制备化合物4cf:淡黄色固体,熔点：234.4-235.9℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.24-1.28(m,1H),1.31-1.36(m,1H),1.90-1.97(m,1H),2.16(s,6H),2.82-2.88(m,1H),2.91-2.95(m,1H),3.24-3.29(m,1H),3.35-3.41(m,1H),3.52(d,J＝6.8Hz,1H),3.77-3.82(m,1H),3.90(d,J＝6.8Hz,1H),4.36(d,J＝9.2Hz,1H),4.49-4.55(m,1H),6.94(d,J＝8.4Hz,2H),7.02(d,J＝7.6Hz,1H),7.72-7.76(m,1H),7.82-7.87(m,2H),7.95(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.4,18.9,20.8,22.2,34.7,49.2,55.2,66.0,68.4,68.9,80.3,122.0,122.5,124.9,128.9,129.1,130.9,134.5,135.6,136.2,139.2,141.6,168.5,197.2,198.1；HRMS(ESI-TOF)m/z:Calcd.for C26H25NNaO4S[M+Na]+:470.1397；Found:470.1395。
本实施例制备化合物4cg:淡黄色固体,熔点：236.1-236.7℃；产率75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.13-1.19(m,3H),1.20-1.24(m,1H),1.28-1.34(m,1H),1.89-1.93(m,1H),2.53-2.59(m,2H),2.82-2.88(m,1H),2.92-2.96(m,1H),3.24-3.29(m,1H),3.32-3.38(m,1H),3.52(d,J＝7.2Hz,1H),3.78-3.80(m,1H),3.90(d,J＝7.2Hz,1H),4.40(d,J＝9.2Hz,1H),4.51-4.57(m,1H),7.09-7.14(m,4H),7.72-7.76(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.4,20.8,22.2,27.4,34.7,49.2,55.2,66.0,68.4,68.9,80.3,122.0,122.5,127.1,127.4,127.5,129.4,130.7,134.5,136.2,139.2,141.6,143.2,168.5,197.1,198.1；HRMS(ESI-TOF)m/z:Calcd.for C26H25NNaO4S[M+Na]+:470.1397；Found:470.1395。
本实施例制备化合物4ch:淡黄色固体,熔点：240.8-241.5℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.15(s,3H),1.17(s,3H),1.22-1.24(m,1H),1.30-1.34(m,1H),1.88-1.95(m,1H),2.80-2.87(m,2H),2.92-2.96(m,1H),3.25-3.30(m,1H),3.32-3.37(m,1H),3.52(d,J＝6.8Hz,1H),3.78-3.81(m,1H),3.91(d,J＝7.2Hz,1H),4.40(d,J＝9.2Hz,1H),4.51-4.57(m,1H),7.13(s,4H),7.72-7.76(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.8,22.2,22.9,32.7,34.7,49.2,55.2,66.0,68.4,68.9,80.3,122.0,122.5,126.0,127.5,130.8,134.5,136.2,139.2,141.6,147.9,168.5,197.1,198.1；HRMS(ESI-TOF)m/z:Calcd.forC27H27NNaO4S[M+Na]+:484.1553；Found:484.1549。
本实施例制备化合物4ci:淡黄色固体,熔点：246.2-246.7℃；产率75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.18-1.23(m,10H),1.30-1.38(m,1H),1.88-1.97(m,1H),2.84-2.87(m,1H),2.92-2.96(m,1H),3.24-3.26(m,2H),3.52(d,J＝6.8Hz,1H),3.78-3.81(m,1H),3.90(d,J＝6.8Hz,1H),4.40(d,J＝9.2Hz,1H),4.51-4.57(m,1H),7.13(d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),7.73-7.76(m,1H),7.82-7.87(m,2H),7.95(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.8,22.2,30.2,33.5,34.7,49.2,55.1,66.0,68.4,68.9,80.3,122.0,122.5,124.8,127.2,130.4,134.5,136.2,139.2,141.6,150.2,168.5,197.1,198.1；HRMS(ESI-TOF)m/z:Calcd.forC28H29NNaO4S[M+Na]+:498.1710；Found:498.1714。
本实施例制备化合物4da:淡黄色固体,熔点：243.7-244.5℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.02-1.10(m,1H),1.22(s,3H),1.59-1.64(m,4H),1.87-2.13(m,6H),2.25-2.47(m,6H),2.55(d,J＝8.8Hz,1H),2.71-2.76(m,1H),3.06-3.11(m,1H),3.73-3.77(m,1H),3.82-3.85(m,1H),5.13(d,J＝10.0Hz,1H),7.73-7.77(m,1H),7.80-7.84(m,1H),7.88(d,J＝8.0Hz,1H),7.94(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:12.1,15.0,19.0,22.3,28.1,30.8,33.8,34.8,44.3,49.6,58.3,59.9,63.8,64.1,64.7,77.1,78.2,121.1,123.2,133.0,133.3,135.0,138.5,140.5,169.1,171.8,198.8,198.9；HRMS(ESI-TOF)m/z:Calcd.for C28H31NNaO5[M+Na]+:484.2089；Found:484.2084。
本实施例制备化合物4ea:淡黄色固体,熔点：240.3-241.1℃；产率79％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.42-1.46(m,1H),1.69-1.75(m,1H),1.83-1.92(m,4H),2.05-2.13(m,2H),2.27-2.51(m,7H),2.58-2.62(m,1H),2.69-2.73(m,1H),2.78-2.86(m,2H),3.77-3.82(m,2H),4.71(s,1H),4.83(s,1H),4.91(d,J＝12.8Hz,1H),7.71-7.75(m,1H),7.79-7.83(m,1H),7.87(d,J＝7.6Hz,1H),7.94(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.8,18.6,26.4,27.8,29.8,30.1,34.6,44.0,44.5,48.0,49.0,57.9,63.4,76.6,79.9,107.6,109.0,120.6,120.8,132.9,134.5,138.1,140.1,148.3,148.6,168.7,172.1,198.7,198.8；HRMS(ESI-TOF)m/z:Calcd.for C28H30NO4[M+H]+:444.2169；Found:444.2175。
本实施例制备化合物4eb:淡黄色固体,熔点：241.1-241.9℃；产率78％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.34-1.44(m,1H),1.68-1.75(m,1H),1.84-1.93(m,1H),2.02-2.09(m,1H),2.27-2.51(m,6H),2.59-2.63(m,1H),2.79-2.88(m,2H),2.95-2.98(m,1H),3.27-3.32(m,1H),3.41-3.43(m,1H),3.77-3.82(m,1H),3.91-3.94(m,1H),4.01-4.09(m,1H),4.73(s,1H),4.85(s,1H),4.91(d,J＝5.6Hz,2H),7.73-7.77(m,1H),7.81-7.89(m,2H),7.95-7.97(m,1H)；13C NMR(CDCl3,100MHz)δ:27.6,28.7,31.2,33.3,35.7,37.1,46.0,49.4,49.9,50.3,64.3,67.7,77.9,81.3,109.2,110.7,122.3,122.4,134.5,136.1,139.5,141.9,149.5,149.8,173.0,197.7,199.1；HRMS(ESI-TOF)m/z:Calcd.for C27H27NNaO4S[M+Na]+:484.1548；Found:484.1542。
本实施例制备化合物4fa:淡黄色固体,熔点：248.3-249.1℃；产率73％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.33(s,3H),1.59(s,3H),1.63-1.66(m,1H),1.84-1.88(m,1H),2.09-2.23(m,5H),2.28-2.33(m,1H),2.44-2.49(m,1H),2.52-2.57(m,1H),2.95-3.03(m,2H),3.30-3.35(m,1H),3.43(d,J＝8.0Hz,1H),3.96(d,J＝8.0Hz,1H),4.10-4.14(m,1H),4.40(d,J＝10.0Hz,1H),4.51-4.56(m,1H),4.77(d,J＝10.4Hz,1H),7.73-7.77(m,1H),7.81-7.84(m,1H),7.89(d,J＝7.6Hz,1H),7.96(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:16.3,17.3,23.4,26.2,34.4,38.4,39.6,40.3,50.9,53.9,66.3,68.9,79.3,123.4,126.6,126.8,135.5,137.1,137.8,140.5,140.7,143.1,174.4,198.7,199.8；HRMS(ESI-TOF)m/z:Calcd.for C27H29NNaO4S[M+Na]+:486.1710；Found:486.1713。
本实施例制备化合物4ga:淡黄色固体,熔点：249.6-250.1℃；产率80％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.93-2.06(m,4H),2.11-2.22(m,2H),2.48-2.57(m,2H),2.69-2.73(m,1H),2.93-3.00(m,1H),3.90-4.01(m,2H),4.10-4.16(m,1H),7.74-7.78(m,1H),7.80-7.91(m,3H)；13C NMR(CDCl3,100MHz)δ:30.2,31.3,31.6,40.1,46.6,60.7,64.9,66.0,77.7,123.1,123.2,135.9,137.1,140.2,141.3,174.9,200.3,200.5；HRMS(ESI-TOF)m/z:Calcd.for C18H17NNaO4[M+Na]+:334.1050；Found:334.1048。
本实施例制备化合物4gb:淡黄色固体,熔点：252.7-253.3℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.87-2.06(m,4H),2.11-2.22(m,2H),2.48-2.57(m,2H),2.69-2.73(m,1H),2.93-3.00(m,1H),3.90-4.01(m,2H),4.10-4.16(m,1H),7.74-7.78(m,1H),7.80-7.91(m,3H)；13C NMR(CDCl3,100MHz)δ:31.8,37.1,39.1,50.7,60.8,65.9,68.2,77.8,123.2,123.4,136.1,137.3,140.2,141.7,174.3,198.4,199.8；HRMS(ESI-TOF)m/z:Calcd.for C17H15NNaO4S[M+Na]+:352.0614；Found:352.0611。
本发明的式(1)化合物具有重要的生物活性，体外对K562(人白血病细胞)和A549(人非小细胞肺癌肺癌)的细胞毒性试验表明：此类式(1)所示结构的环内酯骨架拼接茚二酮双螺环类化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人白血病细胞(K562)和人非小细胞肺癌肺癌(A549)表示的细胞毒性。
药理实施例1：化合物4da,4ea和4ga对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的化合物4da,4ea和4ga的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后，每孔加入10μL MTT(5mg/mL)的磷酸盐缓冲液，再继续在37℃培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan)，用酶标仪在490nm波长测定OD值。其中化合物4da,4ea和4ga对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物4da对K562肿瘤细胞的IC50为18.81μmol/L；化合物4ea对K562肿瘤细胞的IC50为27.17μmol/L；化合物4ga对K562肿瘤细胞的IC50为54.7μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为22.7μmol/L。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的环内酯骨架拼接茚二酮双螺环类化合物对K562细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物，值得继续深入研究下去。
药理实施例2：化合物4da,4ea和4ga对A549细胞的细胞毒性
A549(人非小细胞肺癌肺癌)用DMEM培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔4000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物4da对A549肿瘤细胞的IC50为41.23μmol/L；化合物4ea对A549肿瘤细胞的IC50为38.71μmol/L；化合物4ga对A549肿瘤细胞的IC50为72.9μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为23.2μmol/L。
实验结论：A549细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的环内酯骨架拼接茚二酮双螺环类化合物对A549细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物。

Claims (5)

1.一种环内酯骨架拼接茚二酮双螺环类化合物，其特征在于：该化合物具有如下结构式之一：
2.一种如权利要求1所述的环内酯骨架拼接茚二酮双螺环类化合物的制备方法，其特征在于：将环内酯烯烃1、茚三酮2与脯氨酸3，在有机溶剂中，加温条件下，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4；
其中n为1，X为亚甲基，R1为H。
3.根据权利要求2所述的环内酯骨架拼接茚二酮双螺环类化合物的制备方法，其特征在于：所述的有机溶剂为甲醇、甲苯、乙醇或乙腈。
4.根据权利要求2所述的环内酯骨架拼接茚二酮双螺环类化合物的制备方法，其特征在于：将环内酯烯烃1、茚三酮2与脯氨酸3，在有机溶剂中，进行Michael加成环化反应，获得环内酯骨架拼接茚二酮双螺环类化合物4，反应温度60℃-90℃,反应时间为3-10小时。
5.一种如权利要求1所述的环内酯骨架拼接茚二酮双螺环类化合物在制备防治肿瘤疾病药物中的应用。
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