CN116869993A - 3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用 - Google Patents
3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用 Download PDFInfo
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- CN116869993A CN116869993A CN202310741490.XA CN202310741490A CN116869993A CN 116869993 A CN116869993 A CN 116869993A CN 202310741490 A CN202310741490 A CN 202310741490A CN 116869993 A CN116869993 A CN 116869993A
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- andrographolide
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- compound
- chloroform
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 49
- 229940124599 anti-inflammatory drug Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- -1 methoxy, methyl Chemical group 0.000 claims abstract description 7
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
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- 238000000034 method Methods 0.000 claims description 8
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- 238000005481 NMR spectroscopy Methods 0.000 description 66
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
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- 229910052757 nitrogen Inorganic materials 0.000 description 10
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Abstract
本发明属于药物学合成领域，具体为3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用。所述通式(X)如以下所示：
Description
技术领域
本发明属于药物学合成领域，具体为3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用。
背景技术
穿心莲内酯(Andrographolide)又名穿心莲乙素，是传统中药穿心莲中发挥药效的主要活性物质，现代药理学研究表明穿心莲内酯具有抗肿瘤、抗病毒、抗菌消炎、免疫调节和保肝利胆等多种药理活性。
在临床上穿心莲内酯多用于治疗上呼吸道感染，在炎症的治疗方面有着举足轻重的地位。近年来，国内外的研究学者掀起了对穿心莲内酯进行结构修饰的热潮，在抗炎活性方面进行了广泛的研究。
由于穿心莲内酯结构在体内不稳定，存在代谢软点，其化学结构中3位、14位和19位羟基，在体内易发生代谢氧化反应，形成羧基，从而降低其药效活性和作用时间。同时，穿心莲内酯存在水溶性差的问题，直接影响其在体内的吸收，降低生物利用度。
发明内容
本发明的目的在于为解决穿心莲内酯体内不稳定和溶解度差的问题，提供一种3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用。为了进一步提高药效活性和作用时间，本发明设计将3位,19位羟基部分或全部替换成胺基，一方面增强化合物的代谢稳定性，提高药效活性和作用时间；另一方面，引入胺基，增大了化合物的极性，使化合物的水溶性增加，同时，也可以与HCl反应，结合形成盐酸盐，从而进一步增加化合物的水溶性，提高生物利用度。
为了实现以上发明的目的，本申请的技术方案为：
一类含有通式(X)的3位、19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；所述通式(X)如以下所示：
所述通式(X)中，
R选自取代或未取代的5-6元芳香杂环基或苯基，所述取代基选自卤素、三氟甲基、甲氧基、甲基、中的一个或多个。
一类含有通式(Y)的3位、19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；所述通式(Y)如以下所示：
所述通式(Y)中，
R选自取代或未取代的5-6元芳香杂环基或苯基，所述取代基选自卤素、三氟甲基、甲氧基、甲基、中的一个或多个。
一类含有通式(Z)的3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用，所述通式(Z)如以下所示：
所述通式(Z)中，
R选自取代或未取代的苯基或者C2-C3的脂肪链，所述取代基选自卤素、甲基。
一类含有通式(W)的3位、19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用，所述通式(W)如以下所示：
所述通式(W)中，
R为未取代的苯环或叔丁氧基。
本申请还提供一种3位、19位含胺基的穿心莲内酯衍生物的全新的结构式：(6aR,7R,10aS,10bR)-6a,10b-dimethyl-8-methylene-7-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)dodecahydrobenzo[f]quinazolin-3(2H)-one(化合物6)的结构式如下：
进一步的，所述的3位、19位含胺基的穿心莲内酯衍生物代谢稳定，可提高药效活性和作用时间。
进一步的，所述的3位、19位含胺基的穿心莲内酯衍生物极性好，水溶性增加。
进一步的，所述的3位、19位含胺基的穿心莲内酯衍生物可与HCl反应结合形成盐酸盐，增加化合物的水溶性，提高生物利用度。
进一步的，所述药物含有如通式(X)、通式(Y)、通式(Z)、通式(W)中的3位、19位含胺基的穿心莲内酯衍生物，和/或还含有其它药学上可接受的成分。
更进一步的，所述药物的剂型为胶囊剂、片剂、口服制剂、微囊制剂或栓剂。
更进一步的，所述药物给药方式为口服给药。
与现有技术相比，本发明具有以下有益效果：
(一)本发明提供一种全新结构的3位、19位含胺基的穿心莲内酯衍生物在抗炎中的应用，NO、TNF-α、IL-1β表现出较好的抑制率，且IC50值更好，具有良好的抗炎活性前景，化合物4d有望开发成为新的抗炎的先导化合物。
(二)本发明将穿心莲内酯衍生物的3位,19位羟基部分或全部替换成胺基，一方面增强化合物的代谢稳定性，提高药效活性和作用时间；另一方面，引入胺基，增大了化合物的极性，使化合物的水溶性增加，同时，也可以与HCl反应，结合形成盐酸盐，从而进一步增加化合物的水溶性，提高生物利用度。
具体实施方式
下面结合实施例对本发明作进一步阐述，但这些实施例绝不是对本发明的任何限制。所有实施例中，终产品纯化由四川轻化工大学本课题组高效液相色谱仪LC-3000制备纯化。液相柱为Extend-C18，0.5um.30*100mm。1H-NMR用四川轻化工大学的Bruker AvanceIII 600MHz核磁共振仪测定，化学位移以δ(ppm)表示；质谱用昆明植物研究所的AB SciexTriple TOF 5600质谱仪测定。
穿心莲内酯购买于陕西冠晨生物科技有限公司，三氧化二铝、吡啶、乙酸钠、Dess-Martin、盐酸羟胺、氰基硼氢化钠、钛酸四异丙酯、三光气、胺类化合物、酰氯类化合物购买于上海泰坦科技股份有限公司。
本发明提供穿心莲内酯衍生物在抗炎方面的新进展。
本发明中，所采用的抗炎活性试验方法，是本领域技术研发人员所熟知且公认的方法。
本发明中，所采用的小鼠单核巨噬细胞RAW264.7购自中国科学院细胞库，DMEM培养基和胎牛血清购自BI公司。LPS购自Sigma公司。
穿心莲内酯衍生物，四川轻化工大学(Sichuan University of Science&Engineering)提供。
FBS(胎牛血清)，购自BI。
高糖DMEM培养基，购自Hyclone。
RPMI-1640培养基，购自Hyclone。
下面结合实施例对本发明提供的具体实施方式作详细说明。
目标化合物的合成
实施例1：19位含胺基的穿心莲内酯衍生物的合成
步骤1：化合物2的制备
将化合物1(5g，14.2mmol)、Al2O3(1.4g)和30mL吡啶加入到100mL单口烧瓶中，氮气保护下，将体系升温至115℃回流12h。反应完毕后，减压旋蒸抽干大量吡啶，用二氯甲烷溶解，过滤除去不溶性杂质，再用0.1mol/L稀盐酸洗涤，二氯甲烷萃取3次，合并有机相，随后依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经柱层析(PE/EA＝6:5)得白色固体4.2g，产率90％。分子量ESI-MS(m/z):333[M+H]+。1H NMR(600MHz,CDCl3)δ7.12(s,1H),6.79(dd,J＝15.6,10.2Hz,1H),6.04(d,J＝15.6Hz,1H),4.75(s,2H),4.71(s,1H),4.45(s,1H),4.14(d,J＝10.8Hz,1H),3.39(d,J＝7.8Hz,1H),3.26(d,J＝10.8Hz,2H),2.38(d,J＝13.8Hz,1H),2.24(d,J＝10.2Hz,1H),1.97(t,J＝10.8Hz,1H),1.77–1.62(m,3H),1.43(d,J＝13.6Hz,1H),1.27(d,J＝9.6Hz,1H),1.18(s,3H),1.13(d,J＝12.6Hz,1H),1.06(t,J＝14.4Hz,1H),0.74(s,3H).13C NMR(150MHz,CDCl3)δ172.38,148.11,143.02,136.00,129.25,121.09,109.17,80.79,69.68,64.20,61.67,54.68,42.94,38.58,38.26,36.58,28.09,22.98,22.68,15.92.
步骤2：化合物3的制备
将化合物2(4g，12.0mmol)、无水二氯甲烷(40mL)和戴斯马丁高碘烷(10.2g，24.1mmol)依次加入到100mL单口烧瓶中，在氮气保护下，室温反应2h。反应完毕后，加入30mL二氯甲烷稀释体系，过滤除去不溶性杂质，用等体积饱和NaHCO3洗涤有机相，二氯甲烷萃取3次，合并有机相，随后用无水硫酸钠干燥，过滤，减压浓缩，残余物采用柱层析纯化(PE/EA＝2：1)得淡黄色固体3.55g，产率90％。分子量ESI-MS(m/z):329[M+H]+。1H NMR(600MHz,CDCl3)δ9.63(s,1H),7.21(s,1H),6.83(dd,J＝15.6,10.2Hz,1H),6.09(d,J＝15.6Hz,1H),4.80(s,1H),4.76(s,2H),4.56(s,1H),2.58–2.45(m,2H),2.37(d,J＝10.2Hz,2H),2.03(td,J＝13.2,4.2Hz,1H),1.94(d,J＝12.6Hz,1H),1.84–1.74(m,2H),1.73–1.68(m,1H),1.47–1.39(m,1H),1.20(s,3H),0.94(s,3H).13C NMR(150MHz,CDCl3)δ208.61,201.52,172.24,146.70,144.32,134.45,128.60,122.00,110.41,69.77,63.51,59.63,56.47,39.12,38.93,36.89,36.12,23.96,16.86,13.99.
步骤3：化合物4a-4n的制备
在氮气保护下，将化合物3(200mg，0.61mmol)、无水二氯甲烷(10mL)、对应的伯胺(1.22mmol)、钛酸四异丙酯(173mg，0.61mmol)依次加入到50mL的圆底烧瓶中，室温下搅拌1h，然后再向反应瓶中加入甲醇(3mL)、氰基硼氢化钠(190mg，3.05mmol)和催化量的冰乙酸，在室温下继续搅拌反应4h。反应完毕后，加水(1ml)淬灭反应，此时反应体系中出现大量白色浑浊物，用硅藻土过滤掉反应，将滤液减压浓缩旋干，向残留物中加入饱和碳酸氢钠溶液洗涤，二氯甲烷萃取3次，然后无水硫酸钠干燥有机相，减压浓缩旋干，残余物用硅胶柱层析纯化得到对应的产物4a-4n。
化合物4a，淡黄色油状物，产率55％。分子量ESI-MS(m/z):456[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.30–7.27(m,2H),7.20(d,J＝8.4Hz,2H),7.16(t,J＝1.8Hz,1H),6.89(dd,J＝15.6,10.2Hz,1H),6.10(d,J＝15.6Hz,1H),4.80(d,J＝1.8Hz,2H),4.77–4.73(m,1H),4.55–4.46(m,1H),3.71(d,J＝13.2Hz,1H),3.64(d,J＝13.2Hz,1H),3.29(dd,J＝11.4,3.6Hz,1H),3.00(d,J＝12.0Hz,1H),2.64(d,J＝12.6Hz,1H),2.42(ddd,J＝13.2,4.2,2.4Hz,1H),2.29(d,J＝10.2Hz,1H),2.03(td,J＝12.6,12.0,4.8Hz,1H),1.80–1.66(m,2H),1.52–1.42(m,2H),1.36(qd,J＝13.2,4.2Hz,1H),1.23(s,3H),1.11(ddd,J＝28.2,13.2,2.4Hz,2H),0.77(s,3H).13C NMR(150MHz,Chloroform-d)δ172.28,148.17,143.12,137.31,135.87,133.15,129.68,129.18,128.68,121.16,109.00,80.40,69.63,61.91,55.46,53.87,50.86,41.13,38.74,38.41,36.57,28.67,23.29,23.06,15.90.
化合物4b，淡黄色油状物，产率58％。分子量ESI-MS(m/z):452[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.20(d,J＝8.4Hz,2H),7.16(t,J＝1.8Hz,1H),6.90(dd,J＝16.2,10.8Hz,1H),6.88–6.84(m,2H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.79–4.75(m,1H),4.56–4.50(m,1H),3.80(s,3H),3.72(d,J＝12.6Hz,1H),3.64(d,J＝12.6Hz,1H),3.31(dd,J＝12.0,3.6Hz,1H),3.04(d,J＝12.0Hz,1H),2.66(d,J＝12.6Hz,1H),2.43(ddd,J＝13.2,4.2,2.4Hz,1H),2.29(d,J＝10.2Hz,1H),2.03(td,J＝13.2,4.8Hz,1H),1.73(td,J＝12.6,11.4,3.0Hz,2H),1.45(dt,J＝13.2,4.2Hz,2H),1.36(qd,J＝13.2,4.2Hz,1H),1.23(s,3H),1.10(ddd,J＝31.8,13.2,2.8Hz,2H),0.77(s,3H).13C NMR(150MHz,Chloroform-d)δ172.28,159.06,148.16,143.12,135.89,130.11,129.76,129.19,121.17,113.96,109.00,80.34,69.62,61.90,55.40,55.30,53.72,50.49,40.98,38.71,38.35,36.55,28.55,23.26,23.12,15.87.
化合物4c，淡黄色油状物，产率56％。分子量ESI-MS(m/z):440[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.26–7.22(m,2H),7.16(t,J＝1.8Hz,1H),7.06–6.97(m,2H),6.90(dd,J＝15.6,10.1Hz,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.79–4.73(m,1H),4.57–4.49(m,1H),3.74(d,J＝12.6Hz,1H),3.65(d,J＝12.6Hz,1H),3.31(dd,J＝12.0,3.6Hz,1H),3.02(d,J＝12.0Hz,1H),2.66(d,J＝12.0Hz,1H),2.43(ddd,J＝13.8,4.2,2.4Hz,1H),2.29(d,J＝10.2Hz,1H),2.03(dt,J＝13.2,6.6Hz,1H),1.74(ddq,J＝15.6,10.8,3.0Hz,2H),1.45(ddd,J＝12.0,7.2,3.6Hz,2H),1.37(dd,J＝12.6,4.2Hz,1H),1.24(s,3H),1.18–1.08(m,2H),0.78(s,3H).13C NMR(151MHz,Chloroform-d)δ171.23,161.94,160.31,147.11,142.04,134.84,133.26,129.02,128.17,120.13,114.45,114.31,107.98,79.35,68.58,60.88,54.40,52.71,49.67,40.04,37.69,37.35,35.53,27.59,22.24,22.04,14.85.
化合物4d，淡黄色油状物，产率56％。分子量ESI-MS(m/z):458[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.16(s,1H),6.93–6.87(m,2H),6.81(d,J＝6.0Hz,1H),6.70(dt,J＝6.6,2.4Hz,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.78–4.75(m,1H),4.55–4.50(m,1H),3.78(s,1H),3.75–3.64(m,2H),3.32(dd,J＝12.0,3.0Hz,1H),3.01(d,J＝12.0Hz,1H),2.66(d,J＝10.8Hz,1H),2.43(ddd,J＝13.2,4.2,2.4Hz,1H),2.30(d,J＝10.2Hz,1H),2.07–2.00(m,1H),1.82–1.77(m,1H),1.75–1.70(m,1H),1.54(td,J＝12.6,12.0,3.0Hz,1H),1.47(dt,J＝13.8,3.6Hz,1H),1.36(dd,J＝12.6,4.2Hz,1H),1.25(s,3H),1.12(ddd,J＝30.6,13.2,3.0Hz,2H),0.78(s,3H).13C NMR(150MHz,Chloroform-d)δ172.27,163.95,163.22,148.10,143.10,135.85,129.20,121.19,110.96,110.65,109.05,102.83,102.45,80.39,69.61,61.91,55.48,53.92,51.05,41.23,38.74,38.42,36.56,28.61,23.29,23.03,15.91.
化合物4e，淡黄色油状物，产率56％。分子量ESI-MS(m/z):490[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.59(dd,J＝8.4,3.6Hz,2H),7.40(d,J＝7.8Hz,2H),7.16(t,J＝1.8Hz,1H),6.90(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.78–4.74(m,1H),4.55–4.51(m,1H),3.81(d,J＝13.2Hz,1H),3.75(d,J＝13.2Hz,1H),3.31(dd,J＝11.4,3.6Hz,1H),3.04(d,J＝12.0Hz,1H),2.69(d,J＝12.6Hz,1H),2.44(ddd,J＝13.2,4.2,2.4Hz,1H),2.30(d,J＝10.2Hz,1H),2.04(td,J＝13.2,4.8Hz,1H),1.77(dq,J＝13.8,4.2Hz,1H),1.75–1.70(m,1H),1.54–1.44(m,2H),1.37(qd,J＝13.2,4.2Hz,1H),1.25(s,3H),1.12(ddd,J＝31.2,13.2,3.0Hz,2H),0.78(s,3H).13C NMR(150MHz,Chloroform-d)δ172.27,148.12,143.10,142.89,135.84,129.19,128.52,128.29,125.51,125.48,121.18,109.04,80.40,69.61,61.91,55.48,54.15,51.09,41.21,38.74,38.41,36.56,28.65,23.29,23.03,15.89.
化合物4f，淡黄色油状物，产率56％。分子量ESI-MS(m/z):440[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.31–7.28(m,1H),7.16(t,J＝1.8Hz,1H),7.06(d,J＝7.8Hz,1H),7.00–6.94(m,2H),6.90(dd,J＝15.6,10.1Hz,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.79–4.73(m,1H),4.53(s,1H),3.74(d,J＝13.2Hz,1H),3.69(d,J＝13.2Hz,1H),3.31(dd,J＝11.4,3.0Hz,1H),3.02(d,J＝12.0Hz,1H),2.66(d,J＝12.0Hz,1H),2.43(ddd,J＝13.8,4.2,2.4Hz,1H),2.30(d,J＝10.2Hz,1H),2.04(td,J＝13.2,4.8Hz,1H),1.80–1.75(m,1H),1.72(ddd,J＝10.8,5.4,2.4Hz,1H),1.53–1.49(m,1H),1.46(dt,J＝13.2,2.4Hz,1H),1.37(qd,J＝13.2,4.2Hz,1H),1.25(s,3H),1.13(td,J＝15.0,13.8,3.0Hz,2H),0.78(s,3H).13C NMR(150MHz,Chloroform-d)δ172.26,163.72,162.09,148.18,143.07,135.91,130.08,129.21,123.85,121.16,115.19,114.37,108.99,80.41,69.61,61.94,55.49,54.12,50.96,41.17,38.75,38.44,36.58,28.66,23.30,23.06,15.90.
化合物4g，淡黄色油状物，产率54％。分子量ESI-MS(m/z):428[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.22(dd,J＝4.8,1.2Hz,1H),7.16(s,1H),6.95(dd,J＝4.8,3.6Hz,1H),6.93(s,1H),6.92–6.87(m,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.78–4.74(m,1H),4.56–4.50(m,1H),3.96(d,J＝13.8Hz,1H),3.89(d,J＝13.8Hz,1H),3.31(dd,J＝12.0,3.0Hz,1H),3.06(d,J＝12.0Hz,1H),2.69–2.65(m,1H),2.43(ddd,J＝13.8,4.2,2.4Hz,1H),2.30(d,J＝10.2Hz,1H),2.04(td,J＝13.2,4.8Hz,1H),1.77(dq,J＝13.2,3.6Hz,1H),1.74–1.68(m,1H),1.54(qd,J＝13.8,3.6Hz,1H),1.47(dt,J＝13.8,3.6Hz,1H),1.37(qd,J＝13.2,4.2Hz,1H),1.24(s,3H),1.12(ddd,J＝27.0,13.2,3.0Hz,2H),0.80(s,3H).13C NMR(150MHz,Chloroform-d)δ172.27,148.22,143.10,142.01,135.93,129.19,126.77,125.73,124.92,121.15,108.96,80.44,69.61,61.95,55.51,50.65,48.75,41.16,38.76,38.48,36.58,28.65,23.29,23.06,15.91.
化合物4h，淡黄色油状物，产率50％。分子量ESI-MS(m/z):423[M+H]+。1H NMR(600MHz,Chloroform-d)δ8.60–8.52(m,2H),7.22(d,J＝6.0Hz,2H),7.16(t,J＝1.8Hz,1H),6.95–6.82(m,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.78–4.74(m,1H),4.56–4.47(m,1H),3.80(d,J＝13.8Hz,1H),3.71(d,J＝13.8Hz,1H),3.33(dd,J＝12.0,3.6Hz,1H),3.02(d,J＝12.0Hz,1H),2.68(d,J＝12.0Hz,1H),2.44(ddd,J＝13.8,4.2,2.4Hz,1H),2.30(d,J＝10.2Hz,1H),2.04(td,J＝13.8,5.4Hz,1H),1.79(dq,J＝12.0,4.8,4.2Hz,1H),1.75–1.70(m,1H),1.53–1.44(m,2H),1.36(dd,J＝12.6,4.2Hz,1H),1.27(s,3H),1.16(dd,J＝12.6,2.4Hz,1H),1.10(dd,J＝18.0,3.6Hz,1H),0.77(s,3H).13C NMR(150MHz,Chloroform-d)δ172.24,149.97,148.05,147.78,143.06,135.81,129.21,123.08,121.20,109.10,69.60,61.89,55.47,53.43,51.16,41.27,38.73,38.39,36.55,28.62,23.29,23.02,15.91.
化合物4i，淡黄色油状物，产率46％。分子量ESI-MS(m/z):456[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.32(s,1H),7.26(d,J＝7.8Hz,1H),7.23(dd,J＝6.6,1.7Hz,1H),7.19(d,J＝7.2Hz,1H),7.16(t,J＝1.8Hz,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.77(d,J＝1.8Hz,1H),4.53(d,J＝1.8Hz,1H),3.92(t,J＝3.0Hz,1H),3.86(s,1H),3.75(d,J＝10.8Hz,1H),3.51(d,J＝10.8Hz,1H),2.49–2.42(m,2H),2.08(td,J＝13.2,4.8Hz,1H),1.89–1.85(m,3H),1.72–1.68(m,2H),1.63–1.53(m,2H),1.40(qd,J＝13.2,4.4Hz,1H),1.22(dt,J＝13.8,3.6Hz,1H),1.11(s,3H),0.84(s,3H).13C NMR(150MHz,Chloroform-d)δ172.39,148.70,143.06,136.16,129.86,129.26,127.32,127.07,125.29,121.15,108.78,70.49,69.65,65.97,61.79,48.63,45.83,43.07,38.73,36.87,32.94,25.65,23.08,22.00,15.82.
化合物4m，淡黄色油状物，产率66％。分子量ESI-MS(m/z):436[M+H]+。1H NMR(600MHz,Chloroform-d)δ7.22(t,J＝7.8Hz,1H),7.16(s,1H),7.12–7.04(m,3H),6.90(dd,J＝15.6,10.2Hz,1H),6.11(d,J＝15.6Hz,1H),4.81(d,J＝1.8Hz,2H),4.79–4.73(m,1H),4.57–4.50(m,1H),3.75–3.62(m,2H),3.32(dd,J＝11.4,3.6Hz,1H),3.05(d,J＝12.0Hz,1H),2.74–2.62(m,1H),2.43(ddd,J＝13.8,4.2,2.4Hz,1H),2.34(s,3H),2.29(d,J＝10.2Hz,1H),2.04(td,J＝13.2,4.8Hz,1H),1.81–1.68(m,2H),1.51–1.42(m,2H),1.36(td,J＝12.6,4.2Hz,1H),1.24(s,3H),1.16–1.10(m,2H),0.78(s,3H).13C NMR(150MHz,Chloroform-d)δ172.27,148.20,143.10,138.21,138.26,135.93,129.24,129.20,128.49,128.29,125.49,121.16,108.99,80.38,69.62,61.94,55.44,54.47,50.82,41.04,38.74,38.41,36.58,28.58,23.28,23.14,21.38,15.85.
步骤4：化合物5a-5n的制备
在氮气保护下，将相应的底物化合物4a-4n(100mg)、吡啶和10mL二氯甲烷(重蒸)加入到25mL单口瓶中。将体系降温至0℃，缓慢滴加乙酰氯的二氯甲烷溶液2mL，滴加完后，将体系升温至室温搅拌反应2h。反应完全后，加入二氯甲烷(5mL)稀释反应体系，然后依次用0.1mol/L的稀盐酸洗涤，饱和碳酸氢钠溶液洗涤，饱和食盐水溶液洗，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化得到对应的产物5a-5n。。
化合物5a，无色油状物，产率66％。分子量ESI-MS(m/z):562[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.35(d,J＝8.4Hz,2H),7.16(s,1H),7.06(d,J＝8.4Hz,2H),6.92(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.87–4.81(m,1H),4.80(s,2H),4.59(d,J＝17.4Hz,1H),4.55–4.51(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.2Hz,1H),2.12(s,3H),2.04(s,3H),1.94–1.83(m,2H),1.66(dq,J＝11.4,3.6Hz,1H),1.56(d,J＝13.2Hz,1H),1.48(dt,J＝13.8,3.0Hz,1H),1.33(dd,J＝11.4,4.2Hz,1H),1.25(td,J＝13.2,13.2,3.6Hz,1H),0.98(s,3H),0.82(s,3H).13C NMR(150MHz,Chloroform-d)δ172.35,172.22,169.92,148.01,143.19,135.95,135.66,133.23,129.29,129.17,127.08,121.26,108.93,81.65,69.60,61.53,55.90,52.09,45.68,43.66,38.99,38.35,36.46,24.12,23.30,22.28,22.07,21.64,15.45.
化合物5b，无色油状物，产率68％。分子量ESI-MS(m/z):558[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.08(s,1H),6.97(d,J＝8.4Hz,2H),6.88–6.80(m,3H),6.04(d,J＝15.6Hz,1H),4.73(s,2H),4.71(d,J＝10.8Hz,1H),4.49(d,J＝16.8Hz,1H),4.46–4.43(m,2H),3.74(s,3H),2.44(dt,J＝13.2,3.0Hz,1H),2.26(d,J＝10.2Hz,1H),2.06(s,3H),2.00(s,3H),1.86–1.79(m,2H),1.62–1.55(m,1H),1.41(dt,J＝13.8,3.6Hz,1H),1.24(ddd,J＝18.0,9.0,4.2Hz,2H),1.21–1.13(m,2H),0.91(s,3H),0.74(s,3H).13C NMR(150MHz,Chloroform-d)δ172.39,172.22,170.06,158.90,148.11,143.19,135.73,129.25,129.17,127.00,121.22,114.44,108.83,81.68,69.60,61.55,55.94,55.34,52.04,45.40,43.65,39.01,38.40,36.49,24.13,23.31,22.13,21.64,15.45.
化合物5c，无色油状物，产率60％。分子量ESI-MS(m/z):546[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.16(t,J＝1.9Hz,1H),7.13–7.00(m,4H),6.92(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.83(d,J＝17.4Hz,1H),4.81–4.79(m,3H),4.62–4.56(m,1H),4.55–4.51(m,2H),2.52(dt,J＝13.2,3.6Hz,1H),2.34(d,J＝10.2Hz,1H),2.13(s,3H),2.09(s,1H),2.05(s,3H),1.94–1.84(m,2H),1.76(s,2H),1.67(dq,J＝12.6,3.6Hz,2H),1.48(dt,J＝13.8,3.6Hz,2H),1.33(dd,J＝11.4,3.6Hz,2H),1.25(dd,J＝26.4,3.6Hz,4H),0.99(s,3H),0.87(dd,J＝14.4,7.2Hz,2H),0.82(s,3H).13C NMR(150MHz,Chloroform-d)δ172.32,172.21,169.96,162.87,161.24,148.03,143.18,135.69,129.18,127.35,127.30,121.25,116.12,115.97,108.92,81.67,69.60,61.55,55.91,52.01,45.57,43.67,39.00,38.37,36.47,24.13,23.30,22.28,22.09,21.63,15.45.
化合物5d，无色油状物，产率70％。分子量ESI-MS(m/z):564[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.17(s,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.75(tt,J＝9.0,2.4Hz,1H),6.65(d,J＝5.4Hz,2H),6.12(d,J＝15.6Hz,1H),4.88(d,J＝18.0Hz,1H),4.84–4.82(m,1H),4.81(s,2H),4.59(d,J＝17.4Hz,1H),4.56–4.51(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.35(d,J＝10.2Hz,1H),2.13(s,3H),2.04(s,3H),1.90(d,J＝19.6Hz,3H),1.68(dd,J＝13.2,3.6Hz,1H),1.61–1.46(m,3H),1.45–1.37(m,1H),1.37–1.32(m,1H),0.97(s,3H),0.84(s,3H).13C NMR(150MHz,Chloroform-d)δ172.22,169.82,164.51,162.82,147.95,143.22,141.97,135.60,129.16,121.28,108.97,108.65,108.48,103.02,81.63,69.61,61.50,55.88,52.17,45.87,43.66,38.98,38.33,36.44,24.12,23.29,22.26,21.99,21.63,15.47.
化合物5e，无色油状物，产率76％。分子量ESI-MS(m/z):596[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.65(d,J＝8.4Hz,2H),7.24(d,J＝7.8Hz,2H),7.16(s,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.96(d,J＝18.0Hz,1H),4.81(d,J＝7.2Hz,3H),4.67(d,J＝18.0Hz,1H),4.55–4.51(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.2Hz,1H),2.13(s,3H),2.03(s,3H),1.94–1.87(m,2H),1.79–1.71(m,1H),1.67(dq,J＝12.6,3.6Hz,1H),1.58–1.52(m,1H),1.49(dt,J＝13.2,3.0Hz,1H),1.37–1.32(m,1H),1.29–1.22(m,2H),1.00(s,3H),0.83(s,3H).13C NMR(150MHz,Chloroform-d)δ172.34,172.21,169.85,147.96,143.19,141.71,135.64,129.18,126.17,126.14,125.94,121.28,108.98,81.65,69.59,61.52,55.90,52.39,45.91,43.67,38.99,38.33,36.45,24.13,23.31,22.29,22.04,21.63,15.45.
化合物5f，无色油状物，产率70％。分子量ESI-MS(m/z):546[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.35(td,J＝7.8,6.0Hz,1H),7.16(t,J＝1.8Hz,1H),6.99(td,J＝8.4,2.2Hz,1H),6.95–6.89(m,2H),6.83(d,J＝9.6Hz,1H),6.12(d,J＝15.6Hz,1H),4.88(d,J＝17.4Hz,1H),4.84–4.78(m,3H),4.61(d,J＝17.4Hz,1H),4.55–4.50(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.2Hz,1H),2.13(s,3H),2.04(s,3H),1.95–1.87(m,2H),1.71–1.63(m,1H),1.61–1.52(m,1H),1.49(dt,J＝13.8,3.4Hz,1H),1.33(dd,J＝9.0,6.0Hz,1H),1.25(td,J＝13.8,3.8Hz,2H),0.99(s,3H),0.83(s,3H).13C NMR(150MHz,Chloroform-d)δ172.39,172.22,169.94,164.18,162.54,148.02,143.20,140.31,135.67,130.75,129.17,121.25,114.36,112.69,108.92,81.66,69.60,61.53,55.90,52.30,45.83,43.66,39.00,38.36,36.46,24.12,23.30,22.28,22.05,21.63,15.45.
化合物5g，无色油状物，产率62％。分子量ESI-MS(m/z):534[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.26(dd,J＝4.8,1.2Hz,1H),7.16(s,1H),7.00(dd,J＝4.8,3.6Hz,1H),6.96–6.91(m,1H),6.90(d,J＝3.6Hz,1H),6.12(d,J＝15.6Hz,1H),4.96(d,J＝16.8Hz,1H),4.81(t,J＝9.6Hz,4H),4.73(d,J＝16.8Hz,1H),4.59–4.49(m,2H),2.52(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.2Hz,1H),2.19(s,3H),2.13(s,3H),1.95–1.84(m,2H),1.71(dq,J＝12.6,3.6Hz,1H),1.66–1.54(m,2H),1.50(dt,J＝13.8,3.6Hz,1H),1.43(t,J＝3.6Hz,1H),1.33(dd,J＝10.2,4.8Hz,1H),1.31–1.22(m,4H),0.96(s,3H),0.88(q,J＝6.0,4.8Hz,2H),0.83(s,3H).13C NMR(151MHz,Chloroform-d)δ172.22,171.79,170.04,148.07,143.19,140.51,135.74,129.18,127.13,125.02,124.92,121.23,108.87,81.69,69.60,61.55,55.96,47.76,44.52,43.47,39.01,38.39,36.46,29.71,24.18,23.28,22.13,21.64,15.42.
化合物5i，无色油状物，产率66％。分子量ESI-MS(m/z):562[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.32(t,J＝7.8Hz,1H),7.29(d,J＝4.8Hz,1H),7.16(s,1H),7.11(s,1H),7.00(d,J＝7.2Hz,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.86(d,J＝17.4Hz,1H),4.81(d,J＝7.8Hz,3H),4.59(d,J＝17.4Hz,1H),4.55–4.50(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.0Hz,1H),2.13(s,3H),2.04(s,3H),1.95–1.87(m,2H),1.78–1.71(m,1H),1.67(dt,J＝13.2,3.6Hz,1H),1.61–1.53(m,1H),1.49(dt,J＝13.8,3.6Hz,1H),1.33(dd,J＝9.0,6.4Hz,1H),1.28–1.21(m,2H),0.98(s,3H),0.84(s,3H).13C NMR(150MHz,Chloroform-d)δ172.34,172.21,169.93,148.02,143.17,139.71,135.68,135.14,130.45,129.19,127.71,125.90,123.72,121.26,108.93,81.67,69.60,55.91,52.25,45.85,43.68,39.00,38.37,36.46,29.71,24.13,23.31,22.29,22.09,21.65,15.47.
化合物5m，无色油状物，产率66％。分子量ESI-MS(m/z):542[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.25(d,J＝7.8Hz,1H),7.16(s,1H),7.10(d,J＝7.8Hz,1H),6.96–6.89(m,3H),6.12(d,J＝15.6Hz,1H),4.84(d,J＝17.4Hz,1H),4.80(dd,J＝4.8,1.6Hz,3H),4.58(d,J＝17.4Hz,1H),4.56–4.51(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.36(s,3H),2.34(d,J＝9.6Hz,1H),2.14(s,3H),2.05(s,3H),1.95–1.87(m,2H),1.66(dt,J＝11.4,3.6Hz,1H),1.63–1.54(m,1H),1.48(dt,J＝13.8,3.6Hz,1H),1.33(dd,J＝10.8,4.2Hz,1H),1.25(td,J＝13.8,12.6,3.6Hz,3H),0.99(s,3H),0.83(s,3H).13C NMR(150MHz,Chloroform-d)δ172.60,172.22,170.07,148.12,143.17,138.88,137.44,135.76,129.19,128.97,128.14,126.25,122.75,121.22,108.85,81.70,69.60,61.56,55.94,52.68,45.87,43.69,39.03,38.41,36.50,29.71,24.12,23.33,22.34,22.13,21.64,15.45.
化合物5n，无色油状物，产率66％。分子量ESI-MS(m/z):606[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.43(d,J＝8.4Hz,1H),7.27–7.23(m,2H),7.16(t,J＝1.8Hz,1H),7.04(d,J＝7.8Hz,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.86(d,J＝17.4Hz,1H),4.81(d,J＝7.2Hz,3H),4.59(d,J＝17.4Hz,1H),4.55–4.51(m,2H),2.53(dt,J＝13.2,3.0Hz,1H),2.34(d,J＝10.2Hz,1H),2.13(s,3H),2.04(s,3H),1.93–1.87(m,2H),1.70–1.64(m,1H),1.58–1.53(m,1H),1.49(dt,J＝13.8,3.6Hz,1H),1.33(dd,J＝9.0,6.0Hz,1H),1.31–1.21(m,4H),0.98(s,3H),0.84(s,3H).13C NMR(150MHz,Chloroform-d)δ172.35,172.22,169.94,148.01,143.19,139.95,135.68,130.74,130.65,129.18,128.84,124.17,123.32,121.26,108.93,81.67,69.61,61.53,55.91,52.19,45.86,43.68,39.00,38.36,36.46,29.71,24.13,23.31,22.10,21.66,15.47.
实施例2：3,19位含亚胺基团的穿心莲内酯衍生物的合成
步骤1：化合物4的制备
将化合物3(200mg，0.61mmol)、CH3COONa(100mg，1.22mmol)、NH2OH·HCl(170mg，2.44mmol)、无水乙醇(8mL)依次加入到25mL烧瓶中，在氮气保护下室温反应12h。反应完毕后，减压旋蒸抽干乙醇，然后用二氯甲烷溶解，等体积的蒸馏水洗涤，二氯甲烷萃取3次，合并有机相，随后用无水硫酸钠干燥，过滤，减压浓缩，残余物采用柱层析纯化(PE/EA＝1：2)得白色固体192mg，产率88％。分子量ESI-MS(m/z):359[M+H]+。
1H NMR(600MHz,CDCl3)δ7.48(s,1H),7.19(s,1H),6.91(dd,J＝15.6,10.2Hz,1H),6.12(d,J＝15.6Hz,1H),4.85(s,1H),4.82(s,2H),4.60(s,1H),3.31(d,J＝14.4Hz,1H),2.51(s,1H),2.38(d,J＝10.2Hz,1H),2.07(td,J＝14.4,4.8Hz,2H),1.92–1.87(m,1H),1.70–1.65(m,1H),1.57(dt,J＝20.4,8.4Hz,2H),1.33(s,3H),1.29–1.25(m,1H),0.94(s,3H).13C NMR(150MHz,CDCl3)δ172.32,162.20,154.28,147.37,143.42,135.39,129.10,121.54,109.92,69.69,60.40,55.93,46.14,39.19,38.90,36.16,23.61,22.58,18.78,13.97.
步骤2：化合物6a-6g的制备
将化合物4(0.1g,0.28mmol)、二氯甲烷(5mL)和吡啶(0.18mL,2.23mmol)依次加入到50mL单口瓶中。将体系降温至0℃，在氮气保护下，缓慢滴加对应酰氯(1.18mmol)的二氯甲烷溶液3mL，滴加完全后，将体系升温至室温搅拌反应4h。反应完全后，加入适量二氯甲烷稀释反应体系，然后依次用0.1moL/L的稀盐酸洗，饱和碳酸氢钠溶液洗，饱和食盐水溶液洗，无水硫酸钠干燥有机相，过滤，减压旋蒸浓缩，残余物经硅胶柱层析纯化得到对应的产物6a-6g。
化合物6a:无色油状物，产率40％。分子量ESI-MS(m/z):589[M+Na]+。1H NMR(600MHz,Chloroform-d)δ8.10–8.02(m,4H),7.98(s,1H),7.63–7.56(m,2H),7.46(t,J＝7.7Hz,4H),7.19–7.17(m,1H),6.93(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),3.41(dt,J＝14.4,4.2Hz,1H),2.68(td,J＝14.4,5.4Hz,1H),2.56(dt,J＝13.8,3.0Hz,1H),2.43(d,J＝10.2Hz,1H),2.14(td,J＝13.2,5.4Hz,1H),2.06–2.00(m,1H),1.80(td,J＝11.4,10.2,3.6Hz,2H),1.66(s,3H),1.46–1.36(m,2H),1.29–1.25(m,1H),1.02(s,3H).13C NMR(150MHz,Chloroform-d)δ172.16,170.32,164.03,163.76,162.49,146.81,143.63,141.81,134.96,133.42,133.28,133.23,131.86,130.19,129.68,129.23,129.01,128.55,128.52,128.01,121.84,110.31,94.63,69.66,60.24,56.85,48.00,39.35,35.98,23.67,22.07,14.21.
化合物6b:无色油状物，产率48％。分子量ESI-MS(m/z):625[M+Na]+。1H NMR(600MHz,Chloroform-d)δ8.08(dddd,J＝16.8,9.0,5.4,3.0Hz,4H),7.96(s,1H),7.22-7.07(m,5H),6.93(dd,J＝15.6,10.2Hz,1H),6.14(dd,J＝15.6,4.8Hz,1H),4.87(s,1H),4.82(s,2H),4.63(s,1H),3.37(dt,J＝14.4,3.6Hz,1H),2.67(td,J＝14.4,5.4Hz,1H),2.56(d,J＝13.8Hz,1H),2.43(d,J＝10.2Hz,1H),2.15(td,J＝13.2,4.2Hz,1H),2.07-1.95(m,1H),1.85-1.71(m,2H),1.65(s,3H),1.45-1.36(m,1H),1.27(d,J＝18.0Hz,2H),1.01(s,3H).13C NMR(150MHz,Chloroform-d)δ172.16,170.32,163.06,162.81,162.55,146.73,143.66,134.90,132.82,132.76,132.31,132.25,132.18,129.00,125.42,124.68,121.87,115.88,115.83,115.73,115.68,115.58,110.37,69.67,60.21,56.77,47.99,39.42,39.32,35.95,23.67,22.07,21.87,14.18.
化合物6c:无色油状物，产率52％。分子量ESI-MS(m/z):617[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.94(s,1H),7.90(ddd,J＝24.0,8.0,1.2Hz,2H),7.43(tt,J＝7.4,1.8Hz,2H),7.27(dt,J＝7.4,4.2Hz,5H),7.18(t,J＝1.8Hz,1H),6.93(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),4.89-4.85(m,1H),4.81(d,J＝1.6Hz,2H),4.65-4.61(m,1H),3.37(dt,J＝14.4,4.2Hz,1H),2.65(s,4H),2.60(s,3H),2.56(ddd,J＝13.2,3.6,1.8Hz,1H),2.42(d,J＝10.2Hz,1H),2.14(td,J＝13.2,4.2Hz,1H),2.03(ddd,J＝9.6,4.8,2.4Hz,1H),1.83-1.75(m,2H),1.65(s,3H),1.44-1.36(m,1H),1.30-1.23(m,1H),1.01(s,3H).13C NMR(150MHz,Chloroform-d)δ172.15,169.83,164.86,164.52,162.15,146.87,143.61,140.60,134.99,132.38,132.19,131.81,131.78,130.33,130.27,129.00,128.53,127.85,125.73,121.82,110.29,69.65,60.24,56.88,47.99,39.54,39.36,35.99,23.64,22.00,21.65,21.57,14.18.
化合物6d:无色油状物，产率58％。分子量ESI-MS(m/z):645[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.67(s,1H),7.28(q,J＝6.6,6.0Hz,4H),7.20(td,J＝10.8,9.0,7.2Hz,7H),6.90(dd,J＝15.6,10.2Hz,1H),6.13(d,J＝15.6Hz,1H),4.86(s,1H),4.82(s,2H),4.61(d,J＝1.8Hz,1H),3.09(dt,J＝14.4,3.6Hz,1H),2.99(dt,J＝18.6,7.8Hz,4H),2.76(td,J＝7.8,2.4Hz,2H),2.67(q,J＝7.8Hz,2H),2.56–2.48(m,1H),2.39–2.29(m,2H),2.09(td,J＝13.2,4.2Hz,1H),1.96–1.89(m,1H),1.65(dt,J＝13.2,4.2Hz,2H),1.54(td,J＝12.6,4.2Hz,1H),1.48(s,3H),1.29–1.18(m,2H),0.89(s,3H).13C NMR(150MHz,Chloroform-d)δ172.18,170.84,170.19,169.11,161.47,146.80,143.67,140.35,140.13,134.92,129.00,128.56,128.55,128.40,128.37,128.29,126.41,126.32,121.82,110.30,69.69,60.19,56.60,47.56,39.28,39.18,35.94,34.76,34.38,30.83,30.75,23.57,21.96,21.37,14.11.
化合物6e:无色油状物，产率52％。分子量ESI-MS(m/z):465[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.76(s,1H),7.20(s,1H),6.91(dd,J＝15.6,10.2Hz,1H),6.13(d,J＝15.6Hz,1H),4.86(s,1H),4.83(s,2H),4.62(s,1H),3.24(dt,J＝15.0,3.6Hz,1H),2.54(ddd,J＝13.2,3.6,2.4Hz,1H),2.44–2.34(m,2H),2.19(s,3H),2.13(s,3H),1.99–1.92(m,1H),1.78–1.67(m,3H),1.59(td,J＝12.8,4.2Hz,1H),1.50(s,3H),1.35–1.25(m,2H),0.93(s,3H).13C NMR(150MHz,Chloroform-d)δ172.16,169.22,168.64,168.43,161.09,146.75,143.68,134.86,128.97,121.84,110.32,69.67,60.20,56.61,47.47,39.25,39.18,35.93,23.57,21.98,21.32,19.94,19.58,14.11.
化合物6f:无色油状物，产率49％。分子量ESI-MS(m/z):561[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.78(s,1H),7.20(s,1H),6.91(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),4.87(s,1H),4.83(s,2H),4.62(s,1H),3.82(td,J＝6.6,3.0Hz,2H),3.78(t,J＝6.6Hz,1H),3.23(ddd,J＝15.0,7.2,3.6Hz,1H),3.01–2.93(m,2H),2.87(td,J＝6.6,1.2Hz,1H),2.60–2.50(m,1H),2.43–2.37(m,1H),2.12(td,J＝13.2,4.8Hz,1H),2.01–1.91(m,1H),1.76–1.69(m,3H),1.62–1.56(m,1H),1.51(s,3H),1.32(td,J＝14.4,4.8Hz,1H),0.93(s,3H).13C NMR(150MHz,Chloroform-d)δ172.15,169.49,168.44,161.90,146.64,143.77,134.74,128.94,121.93,110.43,69.67,60.12,56.58,47.65,39.17,38.71,38.49,36.52,36.07,35.90,23.56,21.93,21.50,14.09.
化合物6g:无色油状物，产率52％。分子量ESI-MS(m/z):745[M+Na]+。1H NMR(600MHz,Chloroform-d)δ7.98(dd,J＝7.2,1.8Hz,1H),7.94(s,1H),7.80(dd,J＝7.8,1.8Hz,1H),7.74(dd,J＝7.8,1.8Hz,1H),7.72–7.61(m,2H),7.42–7.35(m,4H),7.19(s,1H),6.92(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),4.87(s,1H),4.82(s,2H),4.62(s,1H),3.39(dt,J＝14.4,3.6Hz,1H),2.65–2.51(m,2H),2.42(d,J＝10.2Hz,1H),2.14(td,J＝12.0,11.4,3.6Hz,1H),2.05–1.98(m,1H),1.82–1.73(m,2H),1.62(s,3H),1.43–1.33(m,2H),1.31–1.23(m,2H),1.00(s,3H).13C NMR(150MHz,Chloroform-d)δ172.22,170.33,164.02,163.59,162.61,146.78,143.75,134.87,134.77,134.20,133.35,132.85,132.72,132.30,131.71,131.41,131.10,128.96,127.29,121.87,121.55,121.46,110.37,69.70,60.14,56.80,47.99,39.43,39.31,35.94,23.60,22.10,21.88,14.20.
实施例3：3,19位含胺基的穿心莲内酯衍生物的合成
步骤1：化合物5的合成
将化合物4(500mg，1.40mmol)、AcONH4(1.62g，21.3mmol)，甲醇(40mL)，加入到100mL烧瓶中，在氮气保护下加入氰基硼氢化钠(1.76g，28.0mmol)。将体系降温至0℃，缓慢滴加TiCl3溶液冰浴反应40min后，升温至室温反应过夜。反应完毕后，减压旋蒸抽干甲醇，残余物采用柱层析纯化(二氯甲烷：甲醇＝15：1)得淡黄色油状物。
步骤2：化合物6的合成
将三光气(215mg，0.73mmol)和二氯甲烷(5mL)加入25mL单口烧瓶中，氮气保护下，搅拌溶解。将体系降温至-70℃，缓慢滴加化合物5(200mg，0.61mmol)和吡啶(0.3mL，3.6mmol)的二氯甲烷混合溶液5mL，滴加完全，升温至室温反应3h。反应完毕后，加入饱和氯化铵溶液，搅拌几分钟淬灭反应，随后加入二氯甲烷(20mL)稀释反应体系，分离出有机相，随后用0.1mol/L HCl溶液洗涤，饱和碳酸氢钠溶液洗涤，蒸馏水洗涤，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物用柱层析纯化(二氯甲烷：甲醇＝35:1)，得淡黄色油状物40mg，产率18％。分子量ESI-MS(m/z):379[M+Na]+,1H NMR(600MHz,CDCl3)δ7.18(t,J＝1.8Hz,1H),6.90(dd,J＝15.6,10.2Hz,1H),6.14(d,J＝15.6Hz,1H),4.83(d,J＝1.8Hz,2H),4.82–4.79(m,1H),4.60–4.53(m,1H),3.58(d,J＝12.0Hz,1H),2.84(dt,J＝11.4,4.2Hz,1H),2.74–2.64(m,1H),2.54–2.46(m,1H),2.37(d,J＝10.2Hz,1H),2.13(dd,J＝16.2,9.6Hz,1H),1.85–1.79(m,1H),1.64–1.60(m,1H),1.51(dt,J＝13.8,3.6Hz,1H),1.41–1.33(m,2H),1.24(s,3H),1.10(td,J＝13.8,3.6Hz,1H),0.91(s,3H).13C NMR(150MHz,CDCl3)δ172.26,155.90,147.66,143.15,135.49,129.20,121.43,109.63,69.65,61.81,59.00,53.72,43.18,38.57,37.37,36.27,35.09,29.29,25.77,22.82,16.22.
步骤3：化合物6s的合成
将化合物4(500mg，1.40mmol)、AcONH4(1.62g，21.3mmol)，40mL甲醇，加入到100mL烧瓶中，在氮气保护下加入氰基硼氢化钠(1.76g，28.0mmol)。将体系降温至0℃，缓慢滴加TiCl3溶液冰浴反应40min后，升温至室温反应12h。监测反应完全后，用稀盐酸调PH至4，静置4小时，随后加入三乙胺调至PH约为8，加入二碳酸二叔丁酯(1.1g)，室温搅拌反应6h。反应完毕后，减压旋蒸抽干甲醇，残余物用二氯甲烷溶解，等体积的蒸馏水洗涤，二氯甲烷萃取3次，合并有机相，随后用无水硫酸钠干燥，过滤，减压浓缩，残余物采用柱层析纯化(PE/EA＝4：1)得淡黄色油状物50mg，产率20％。分子量ESI-MS(m/z):553[M+Na]+,1H NMR(600MHz,CDCl3)δ7.16(s,1H),6.91(dd,J＝15.6,10.2Hz,1H),6.10(d,J＝15.6Hz,1H),5.71(d,J＝9.6Hz,1H),4.80(s,2H),4.77(s,1H),4.66(dd,J＝8.4,4.2Hz,1H),4.53(s,1H),3.63(dd,J＝14.4,9.6Hz,1H),3.29(d,J＝9.6Hz,1H),2.76(d,J＝14.4Hz,1H),2.44(d,J＝13.8Hz,1H),2.32(d,J＝10.2Hz,1H),2.07(d,J＝4.8Hz,1H),1.80–1.66(m,3H),1.60(dd,J＝13.7,3.4Hz,1H),1.45(s,10H),1.39(s,9H),1.32(s,1H),1.27(s,1H),1.00(s,3H),0.82(s,3H).
步骤4：化合物6m的合成
将化合物5(200mg，0.61mmol)、10mL二氯甲烷和吡啶(300uL，3.63mmol)加入到50mL单口烧瓶中，氮气保护下，搅拌溶解。将体系降温至0℃，缓慢滴加苯甲酰氯(300uL，2.42mmol)的二氯甲烷溶液5mL，滴加完毕，将体系升至室温反应2h。反应完毕后，加入二氯甲烷稀释反应体系，然后依次用0.1mol/L稀盐酸洗涤，碳酸氢钠饱和溶液洗涤，蒸馏水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物采用柱层析纯化(PE/EA＝2：1)得淡黄色油状物55mg，产率25％。分子量ESI-MS(m/z):561[M+Na]+,1H NMR(600MHz,CDCl3)δ7.98(dd,J＝8.4,1.2Hz,2H),7.88–7.78(m,2H),7.56–7.48(m,1H),7.43–7.31(m,5H),7.13–7.11(m,1H),6.86(dd,J＝15.6,10.2Hz,1H),6.08(d,J＝15.6Hz,1H),4.83–4.76(m,1H),4.75(d,J＝1.8Hz,2H),4.57–4.52(m,1H),3.83(dd,J＝13.8,7.8Hz,1H),3.51(dd,J＝13.8,3.6Hz,1H),3.09–2.99(m,1H),2.54–2.48(m,1H),2.37(d,J＝10.2Hz,1H),2.33(ddd,J＝16.2,13.8,5.4Hz,1H),2.07(td,J＝12.6,11.4,3.6Hz,1H),1.96–1.90(m,1H),1.70–1.61(m,4H),1.36(s,3H),1.31(dd,J＝13.8,4.8Hz,1H),1.01(s,3H).13C NMR(150MHz,CDCl3)δ175.37,172.19,167.72,164.35,147.17,143.39,135.24,134.24,133.42,131.36,129.59,129.12,128.84,128.61,128.45,127.27,121.73,110.11,69.66,61.11,55.11,46.24,42.71,38.74,37.19,36.30,23.56,22.46,20.81,15.45.
实施例4：穿心莲内酯衍生物的抗炎活性实验
药理学实验采用小鼠单核巨噬细胞白血病细胞RAW 264.7为实验细胞株，采用CCK-8法(Cell Counting Kit-8)，对所合成的穿心莲内酯衍生物进行体外抗炎活性进行测定。
具体方法如下：培养小鼠单核巨噬细胞白血病细胞RAW 264.7，细胞贴壁生长，待细胞生长至对数期，吹打细胞至细胞从培养瓶中脱落(一般5-10min)，然后将细胞转移至离心管中，以2000r/min离心3min，弃去上层清液，收集底部细胞。随后，加入10％ FBS的DMEM培养液调节细胞浓度，然后接种细胞至96孔板中，每孔加入100μL细胞悬浮液,使每孔细胞数大约为1×104个，37℃，5％CO2条件下培养8-12h至细胞贴壁，加入药物前，更换细胞培养液,将不同浓度梯度的药物加入96孔板中(每孔100μL)。实验组设置药品的浓度梯度分别为50，100，150，200，250μg/mL(用DMSO配制母液的终浓度为20mg/mL,并用10％ FBS的DMEM培养液进行稀释),每组4个复孔，同时对照组加入等体积的细胞培养液。96孔板在细胞培养箱中培养24h，随后每孔中加入10μl CCK-8溶液继续在细胞培养箱中孵育1-4h后，小心取出96孔板，在450nm处测定吸光度值(A值)。细胞活力(％)＝[A(加药)-A(空白)]/[A(0加药)-A(空白)]*100。A(加药)：具有细胞、CCK-8溶液和药物溶液的孔的OD值，A(0加药)：具有细胞、CCK-8溶液而没有药物溶液的孔的OD值，A(空白)：没有细胞的孔的OD值。实验结果见表1。
表1穿心莲内酯衍生物的NO抑制率
续表1
筛选出NO抑制率较高的化合物4d、6测试对其他炎症因子的抑制效果。结果见表2。
表2
结果与结论：所测定的27个穿心莲内酯衍生物中，其中的化合物4d对NO、TNF-α、IL-1β表现出较好的抑制率，且IC50值更好，具有良好的抗炎活性前景，化合物4d有望开发成为新的抗炎的先导化合物。化合物6对TNF-α、IL-1β两个炎因子的抑制率均高于穿心莲内酯和脱水穿心莲内酯，但其IC50值也更高，其活性不如化合物4d。此研究为穿心莲内酯衍生物在抗炎方面的研究也提供了一定思路。
以上所述是本发明的优选实施方式，需要指出的是，对于本发明所涵盖技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干补充和改善，但这些补充和改善也应视为本发明的保护范围。
Claims (10)
1.一类含有通式(X)的3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；其特征在于：所述通式(X)如以下所示：
所述通式(X)中，
R选自取代或未取代的5-6元芳香杂环基或苯基，所述取代基选自卤素、三氟甲基、甲氧基、甲基、中的一个或多个。
2.一类含有通式(Y)的3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；其特征在于：所述通式(Y)如以下所示：
所述通式(Y)中，
R选自取代或未取代的5-6元芳香杂环基或苯基，所述取代基选自卤素、三氟甲基、甲氧基、甲基、中的一个或多个。
3.一类含有通式(Z)的3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；其特征在于：所述通式(Z)如以下所示：
所述通式(Z)中，
R选自取代或未取代的苯基或者C2-C3的脂肪链，所述取代基选自卤素、甲基。
4.一类含有通式(W)的3,19位含胺基的穿心莲内酯衍生物在制备抗炎药物中的应用；其特征在于：所述通式(W)如以下所示：
所述通式(W)中，
R为未取代的苯环或叔丁氧基。
5.如权利要求1-4所述的应用，其特征在于，所述的3,19位含胺基的穿心莲内酯衍生物代谢稳定，可提高药效活性和作用时间。
6.如权利要求1-4所述的应用，其特征在于，所述的3,19位含胺基的穿心莲内酯衍生物极性好，水溶性增加。
7.如权利要求1-4所述的应用，其特征在于，所述的3,19位含胺基的穿心莲内酯衍生物可与HCl反应结合形成盐酸盐，增加化合物的水溶性，提高生物利用度。
8.如权利要求1-4中任一所述的应用，其特征在于，所述药物含有通式(X)、通式(Y)、通式(Z)或通式(W)中的3,19位含胺基的穿心莲内酯衍生物，和/或还含有其它药学上可接受的成分。
9.如权利要求1-4所述的应用，其特征在于，所述药物的剂型为胶囊剂、片剂、口服制剂、微囊制剂或栓剂。
10.如权利要求1-4所述的应用，其特征在于，所述药物给药方式为口服给药。
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