CN115703748B - 千金二萜烷噻唑衍生物及其制备方法和用途 - Google Patents
千金二萜烷噻唑衍生物及其制备方法和用途 Download PDFInfo
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- CN115703748B CN115703748B CN202110929980.3A CN202110929980A CN115703748B CN 115703748 B CN115703748 B CN 115703748B CN 202110929980 A CN202110929980 A CN 202110929980A CN 115703748 B CN115703748 B CN 115703748B
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- thiazole derivative
- stephania
- diterpene
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Abstract
一种千金二萜烷噻唑衍生物及其制备方法和用途，属于医药技术领域，涉及一种通式(I)或通式(II)千金二萜烷噻唑衍生物,其药学上可接受的盐和溶剂化物，以及含有该千金二萜烷噻唑衍生物的药物组合物。还涉及该化合物的制备方法以及在制备治疗和/或预防炎症药物中的应用。其中，通式(I)或通式(II)中的R如权利要求书和说明书所述。
Description
技术领域
本发明属于医药技术领域，涉及一种千金二萜烷噻唑衍生物及其制备方法和用途，具体涉及一种新的千金二萜烷噻唑衍生物、其药学上可接受的盐和溶剂化物，以及含有该千金二萜烷噻唑衍生物的药物组合物。还涉及该化合物的制备方法以及在制备治疗和/或预防炎症药物中的应用。
背景技术
炎症是人体组织受到诸如病原菌、刺激物等的损伤时，维管组织产生的一系列复杂的生理应激反应。无论是急性还是慢性炎症，对人体都会造成不同程度的损伤。如果炎症得不到及时的治疗，它会发展成为一些严重的疾病，如：类风湿性关节炎、肠炎类疾病、银屑病、慢性哮喘等。所以，对炎症的治疗是人们一直关注的问题，新型抗炎药物的开发更是重中之重。
近年来,随着人们对炎症机制认识的不断深入及分子生物学技术的广泛应用，抗炎药物的研究已从“器官-组织”水平逐渐发展到细胞、分子水平，逐渐呈现出涉及药物品种更多、范围更广、水平比以往更高的局面。凡能消除炎症的药物统称为抗炎类药物，它能够阻断炎症介质的产生或释放，抑制炎性反应。尽管已经开发了多种类型的抗炎药物，如甾体类、非甾体类抗炎药、糖皮质激素、生物制剂类药物等等，但是，对于药物研发工作者来讲，仍然需要不断开发高效低毒的抗炎药物来治疗急性和慢性炎症，减轻炎症带来的疼痛等其它症状。
千金子为大戟科(Euphorbiaceae)大戟属(Euphorbia)植物续随子(Euphorbialathyris L.)的干燥成熟种子。原产于欧洲中南部和俄罗斯南部，后引入我国，现广泛分布于全国各地。千金子是我国的传统中药材之一，始载于《蜀本草》，原名续随子。现代药理学研究表明，千金子具有致泻、抗肿瘤、抗肿瘤多药耐药、美白淡斑和镇痛抗炎等作用。近年来，国内外学者陆续报道了千金子中新的二萜类化学成分及其相应的药理学活性研究，研究结果表明千金子中的二萜类成分结构新颖丰富，具有潜在的药理学研究价值。
根据前期研究(Chem.Biodiversity 2020,17,e1900531；J.Nat.Prod.2019,82,756–764)，发现千金子中的千金二萜烷型化合物大戟因子L1和大戟因子L3具有明显的抗炎活性，并且对正常细胞基本没有毒性。这表明大戟因子L1和大戟因子L3是一种潜在的新型抗炎药物，值得进行进一步的研究与开发。
发明内容
本发明的目的是寻找并开发具有良好抗炎活性的化合物，具体提供了一种千金二萜烷噻唑衍生物及其制备方法和用途，其以大戟因子L1和L3为原料制得环氧续随子醇和续随子醇，再进行衍生，以得到抗炎活性更好的千金二萜烷噻唑衍生物以及含有该千金二萜烷噻唑衍生物的药物组合物，并且研究发现，这些药物可用于制备治疗/或预防炎症疾病的药物。
本发明的具体技术方案如下：
本发明提供了一种通式(I)或通式(II)所示的千金二萜烷噻唑衍生物、或其药学上可接受的盐和溶剂化物：
其中，R为烃基、5-10元芳环或5-10元杂芳环，所述芳环或杂芳环可以被一个或多个取代基取代，所述取代基为氢、羟基、C1-C6各种烃基、卤素、硝基、C1-C4烷氧基苯基、羧基、磺酸基、各种酰基、胺基、5-10元芳基或杂芳基；所述的杂芳基含有1-3个N、O或S的杂原子；烃基为烷基、烯基、炔基中的一种；
本发明的部分化合物结构如下：
本发明进一步提供了上述部分化合物的制备方法，但不仅限于下述制备方法：
合成路线图
硫脲和3-溴丙酮酸乙酯在加热条件下环合成噻唑环得到中间体1，再与各种不同的酰氯发生酰化反应得到中间体2，在碱性条件下水解得到中间体3，最后分别与续随子醇和环氧续随子醇发生酯化反应得到终产物。其中续随子醇和环氧续随子醇分别由大戟因子L3和大戟因子L1在碱性条件下水解得到。
本发明所述的千金二萜烷噻唑衍生物的药学上可接受的盐为千金二萜烷噻唑衍生物和盐类的混合物，其中盐类为有机酸盐、无机酸盐、有机碱盐或无机碱盐中的一种，其中，有机酸包括乙酸、甲磺酸、柠檬酸、富马酸、马来酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、甲磺酸、丙二酸、硫辛酸中的一种或几种；无机酸包括，盐酸、氢溴酸、硝酸、硫酸、磷酸中的一种或几种；有机碱包括葡甲胺和/或氨基葡萄糖；无机碱包括碱金属，如钠、钾、钡、钙、镁、锌的碱性化合物。
本发明的一种千金二萜烷噻唑衍生物，其抗炎性相比于原化合物大戟因子L3和大戟因子L1，以及续随子醇和环氧续随子醇有显著提高，其中活性最好的化合物对RAW264.7细胞生成NO的抑制活性是阳性对照地塞米松的5倍。
本发明还提供了一种药物组合物，是以上式(I)和(II)的千金二萜烷噻唑衍生物或其药学上可接受的盐作为活性成分。
本发明的一种药物组合物，具体的为千金二萜烷噻唑衍生物或其药学上可接受的盐可与药学上可接受的稀释剂、辅助剂、载体中的一种或几种混合，制成临床上需要的药用组合物。
当本发明的药物组合物应用于临床时，可将其配制成若干种剂型，如：口服制剂(如片剂，胶囊剂，锭剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(如软膏或溶液)。用于本发明的药物组合物的载体是药学领域可得到的常见载体，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。
本发明的千金二萜烷噻唑衍生物或所述的药用组合物用于制备治疗和/或预防炎症药物中的应用。
本发明的化合物与最接近的现有技术相比，具有以下优点：
(1)首次提供了一种新的抗炎化合物、其异构体或其药学上可接受的盐，其抗炎活性更强，值得在临床推广使用。
(2)本发明进一步对部分化合物进行了对巨噬细胞NO生成的影响实验，实验结果表明本发明化合物对供试巨噬细胞NO生成有良好的抑制作用，部分化合物活性强于阳性对照药氢化可的松，且对细胞未显示明显毒性，表现出良好的治疗指数，结果见表1。
(3)本发明上述化合物的制备工艺简单，药品纯度高、收率高、质量稳定，易于进行大规模生产。
附图说明
图1为化合物1的1H-NMR光谱图；
图2为化合物1的13C-NMR光谱图；
图3为化合物2的1H-NMR光谱图；
图4为化合物2的13C-NMR光谱图。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容做进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1
本实施例为化合物1的制备，化合物1的结构式为：
的制备：
续随子醇的合成：将大戟因子L3(5g，9.6mmol)在KOH的质量分数为5％的氢氧化钾/甲醇溶液(100mL)中在室温搅拌6小时。完成后，减压除去溶剂，并将残余物用乙酸乙酯溶解，分别用饱和食盐水和饱和碳酸钾溶液洗涤3次，水相用乙酸乙酯洗一次。有机相干燥，旋干，开放硅胶柱色谱纯化，即可得到续随子醇，为白色固体(82％收率)。对其进行检测，核磁共振氢谱分析如下：1H NMR(400MHz,CDCl3)δ5.98(dd,J＝10.5,1.1Hz,1H),5.04(t,J＝1.4Hz,1H),4.90(s,1H),4.46(s,1H),4.38(s,1H),4.30(q,J＝3.4Hz,1H),3.41(d,J＝3.6Hz,1H),3.32(d,J＝3.8Hz,1H),2.73(dd,J＝14.8,9.8Hz,1H),2.46(dd,J＝14.1,7.9Hz,1H),2.20(t,J＝3.5Hz,1H),2.10(ddd,J＝10.1,6.7,3.2Hz,1H),1.91(d,J＝1.2Hz,3H),1.82–1.56(m,4H),1.33(dd,J＝10.5,8.3Hz,1H),1.14(d,J＝6.9Hz,3H),1.12(s,3H),1.10(s,3H).核磁共振碳谱分析如下：13C NMR(100MHz,CDCl3)δ206.69,147.80,139.93,136.99,110.93,87.84,76.59,69.55,53.16,46.82,38.04,34.83,33.62,28.57,26.00,23.97,23.17,15.46,13.87,13.61.
中间体1的合成：取3-溴丙酮酸乙酯用乙醇溶解，加硫脲(1当量)，于氮气保护下回流反应2小时，结束后，旋出乙醇，用乙酸乙酯稀释，饱和食盐水洗有机相3次；有机相干燥，旋干，得到黄色固体，产率83％。对中间体1进行核磁共振氢谱检测，其分析为：1H NMR(600MHz,DMSO)δ7.43(s,1H),7.13(s,2H),4.24–4.10(q,2H),1.22(t,3H).
中间体2的合成：用四氢呋喃溶解中间体1，依次加入乙酰氯、4-二甲氨基吡啶(DMAP)和三乙胺，按摩尔比，中间体1：乙酰氯：4-二甲氨基吡啶：三乙胺＝1:1.5:0.1:1.8；室温过夜反应。结束后，旋出四氢呋喃，用乙酸乙酯稀释反应体系，用饱和氯化铵溶液洗3次，有机相干燥旋干后重结晶，得到白色固体，产率93-95％
中间体3的合成：用四氢呋喃溶解中间体2，加入等体积的氢氧化锂水溶液(1当量)，室温反应3小时结束。调pH为2-3，用乙酸乙酯萃取4次，有机相干燥，浓缩，重结晶得白色固体，产率90％。
终产物的合成：用3mL二氯甲烷溶解中间体3(0.23mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,44mg,0.23mmol),20分钟后，加入续随子醇(40mg,0.15mmol)和DMAP(催化量)。室温反应8-10个小时。反应结束后，反应液用30mL乙酸乙酯稀释后，用饱和氯化铵溶液洗三次，水相用5mL乙酸乙酯洗一次。有机相干燥，旋干，开放硅胶柱色谱纯化，即可得到最终产物，白色固体，收率60％。对最终产物进行核磁共振氢谱分析，其氢谱图见图1，氢谱分析为：1H NMR(400MHz,DMSO)δ12.49(s,1H),7.97(s,1H),6.19(d,J＝10.4Hz,1H),5.54(s,1H),4.91(s,1H),4.69(s,1H),4.12(s,1H),4.09–4.04(m,1H),3.17(d,J＝5.2Hz,1H),3.07–2.89(m,1H),2.41(dd,J＝10.5,3.0Hz,1H),2.22(dd,J＝13.4,6.2Hz,1H),2.13(s,3H),1.99(s,4H),1.77(dd,J＝25.4,11.5Hz,1H),1.59(s,3H),1.48(ddd,J＝16.5,12.7,9.8Hz,2H),1.25–1.18(m,1H),1.15(d,J＝9.5Hz,6H),0.95–0.92(m,3H).核磁共振碳谱(图2)分析如下：13C NMR(101MHz,DMSO)δ200.59,169.43,161.04,158.36,145.63,141.81,134.10,131.99,129.13,122.80,114.70,89.36,78.80,65.49,60.22,54.09,48.92,37.94,36.06,30.46,29.00,28.75,25.58,22.84,21.85,21.22,19.11,16.71,15.06,14.55,14.01,12.91。
实施例2
本实施例为化合物2的制备，化合物2的结构式为：
的制备：
具体操作及配比同实施例1。
环氧续随子醇的合成：将在KOH的质量百分含量为5％氢氧化钾/甲醇溶液(100mL)中的大戟因子L1(5g，9.6mmol)在室温搅拌6小时。完成后，减压除去溶剂，并将残余物用乙酸乙酯溶解，分别用饱和食盐水和饱和碳酸钾溶液洗涤3次，水相用乙酸乙酯洗一次。有机相干燥，旋干，即可得到环氧续随子醇粗产物，为白色固体(82％收率)。对产物核磁共振氢谱分析如下：1H NMR(400MHz,CDCl3)δ6.66(d,J＝10.7Hz,1H),4.40(s,1H),4.28(dd,J＝6.3,3.1Hz,1H),3.81(s,1H),3.31(s,1H),3.01(dd,J＝14.4,9.6Hz,1H),2.68(d,J＝3.8Hz,1H),2.62(d,J＝4.1Hz,1H),2.56(d,J＝7.3Hz,1H),2.24(dd,J＝14.0,6.4Hz,1H),2.12–2.02(m,1H),2.00–1.87(m,4H),1.82(s,1H),1.74–1.68(m,1H),1.44(dd,J＝11.0,8.5Hz,1H),1.30(dd,J＝15.7,10.2Hz,1H),1.17(d,J＝3.0Hz,6H),1.14(d,J＝6.8Hz,3H),1.07(ddd,J＝12.1,8.5,3.3Hz,1H).13C NMR(101MHz,CDCl3)δ202.98,144.37,136.38,88.42,78.89,66.67,60.77,54.31,53.43,48.23,37.66,34.70,32.15,28.76,27.46,25.09,19.71,15.86,13.90,13.09.
最终产品为白色固体，收率56％。其核磁共振氢谱(图3)如下：1H NMR(600MHz,DMSO)δ12.51(s,1H),8.00(s,1H),7.61(d,J＝11.7Hz,1H),6.31(d,J＝9.3Hz,1H),5.56(s,1H),4.02(s,2H),2.97(dd,J＝12.9,9.3Hz,1H),2.15(s,4H),2.10–1.92(m,2H),1.76(s,5H),1.54–1.41(m,2H),1.18(d,J＝12.8Hz,8H),0.89(d,J＝6.5Hz,5H).核磁共振碳谱(图4)分析如下：13C NMR(101MHz,DMSO)δ200.83,169.47,161.12,158.39,149.91,141.67,135.17,123.05,88.83,78.93,67.23,59.31,54.48,52.15,48.38,38.18,35.37,33.82,29.42,29.00,25.93,22.86,20.37,16.74,14.77,12.80。
实施例3
本实施例为化合物3的制备，化合物3的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率75％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(400MHz,DMSO)δ12.45(s,1H),8.00(s,1H),7.61(d,J＝11.7Hz,1H),6.32(d,J＝9.4Hz,1H),5.54(s,1H),4.01(dd,J＝16.8,11.9Hz,2H),2.97(dd,J＝13.3,9.2Hz,1H),2.48–2.42(m,1H),2.14(s,1H),2.10–2.02(m,1H),2.01–1.90(m,1H),1.87–1.70(m,9H),1.67–1.54(m,3H),1.44(dt,J＝22.9,9.2Hz,5H),1.31–1.11(m,11H),0.90(dd,J＝14.1,6.9Hz,4H).核磁共振碳谱分析如下：13C NMR(101MHz,DMSO)δ175.24,161.07,158.47,145.64,141.84,129.12,122.84,114.71,89.39,78.82,65.49,54.05,48.92,43.81,37.93,36.06,29.12,29.01,28.75,25.70,25.57,25.46,21.88,16.72,15.06,12.92。
实施例4
本实施例为化合物4的制备，化合物4的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率76％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(400MHz,DMSO)δ12.45(s,1H),8.00(s,1H),7.61(d,J＝11.7Hz,1H),6.32(d,J＝9.4Hz,1H),5.54(s,1H),4.01(dd,J＝16.8,11.9Hz,2H),2.97(dd,J＝13.3,9.2Hz,1H),2.48–2.42(m,1H),2.14(s,1H),2.10–2.02(m,1H),2.01–1.90(m,1H),1.87–1.70(m,9H),1.67–1.54(m,3H),1.44(dt,J＝22.9,9.2Hz,5H),1.31–1.11(m,11H),0.90(dd,J＝14.1,6.9Hz,4H).核磁共振碳谱分析如下：13C NMR(101MHz,DMSO)δ200.79,175.27,161.17,158.49,149.93,141.70,135.16,123.08,88.85,78.94,67.22,59.31,54.49,52.15,48.39,43.81,38.18,35.38,33.83,29.45,29.15,29.01,25.92,25.71,25.47,20.38,16.74,14.77,12.80。
实施例5
本实施例为化合物5的制备，化合物5的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率80％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(400MHz,DMSO)δ13.01(s,1H),8.15–8.10(m,2H),8.08(s,1H),7.65(s,1H),7.56(d,J＝7.8Hz,2H),6.24(d,J＝10.5Hz,1H),5.54(s,1H),4.93(s,1H),4.71(s,1H),4.15(s,1H),4.10(dt,J＝6.8,3.2Hz,1H),3.05–2.90(m,1H),2.44(dd,J＝10.6,3.0Hz,1H),2.24(dd,J＝13.5,6.2Hz,1H),1.91(s,3H),1.79(dd,J＝24.5,10.7Hz,1H),1.59(s,3H),1.48(ddd,J＝15.0,12.6,7.1Hz,2H),1.25–1.19(m,1H),1.17(s,3H),1.14(s,3H),0.94(d,J＝6.8Hz,3H).核磁共振碳谱分析如下：13CNMR(101MHz,DMSO)δ200.72,162.34,150.86,145.89,135.73,134.08,133.28,131.93,131.21,130.93,128.33,128.19,114.29,111.12,89.27,78.75,66.47,54.34,49.02,47.14,38.08,36.07,29.01,28.76,26.81,25.56,21.86,16.73,15.64,15.07,12.91.
实施例6
本实施例为化合物6的制备，化合物6的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率63％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(400MHz,DMSO)δ13.10(s,1H),8.24–8.10(m,4H),7.70(s,2H),7.61(d,J＝7.8Hz,2H),6.40(d,J＝9.5Hz,1H),5.61(s,1H),4.11(d,J＝6.6Hz,1H),4.07–4.02(m,1H),3.01(dt,J＝35.7,17.9Hz,1H),2.23–2.08(m,2H),2.03(s,2H),1.86(d,J＝11.0Hz,2H),1.80(s,3H),1.68–1.45(m,4H),1.22(d,J＝6.8Hz,8H),1.17–1.08(m,2H),0.94(d,J＝6.5Hz,5H).核磁共振碳谱分析如下：13C NMR(101MHz,DMSO)δ200.83,166.04,161.24,159.10,150.11,141.98,135.17,133.31,132.07,129.11,128.71,128.62,123.79,88.90,78.97,67.36,59.35,54.59,52.17,48.46,38.23,35.41,33.86,29.46,29.00,25.97,20.36,16.77,14.80,12.80.
实施例7
本实施例为化合物7的制备，化合物7的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率67％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(600MHz,DMSO)δ12.53(d,J＝110.0Hz,1H),8.01(d,J＝13.2Hz,1H),7.61(d,J＝11.7Hz,1H),6.31(d,J＝9.3Hz,1H),5.95(s,1H),5.55(d,J＝4.9Hz,1H),4.88(d,J＝15.8Hz,1H),4.07–4.00(m,1H),3.97(s,1H),3.17(s,1H),3.03–2.88(m,1H),2.54(s,0H),2.21(s,2H),2.17–1.94(m,4H),1.90(s,2H),1.81(d,J＝10.3Hz,1H),1.75(d,J＝4.0Hz,6H),1.58(dd,J＝11.5,8.5Hz,1H),1.53–1.43(m,2H),1.18(d,J＝13.2Hz,8H),0.95–0.83(m,5H).核磁共振碳谱分析如下：13C NMR(101MHz,DMSO)δ200.84,169.88,164.72,158.58,158.30,156.94,149.95,141.84,139.53,135.17,123.04,116.90,114.83,88.86,78.94,67.22,59.32,54.50,52.15,48.40,44.35,38.18,35.38,33.83,29.44,29.01,27.87,25.93,22.80,20.51,16.75,14.78,12.80.
实施例8
本实施例为化合物8的制备，化合物8的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率58％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(400MHz,DMSO)δ12.81(s,1H),8.04(s,1H),7.76(d,J＝15.8Hz,1H),7.64(dd,J＝7.3,2.0Hz,2H),7.47(dd,J＝4.9,2.2Hz,3H),6.85(d,J＝15.9Hz,1H),6.21(d,J＝10.4Hz,1H),5.54(s,1H),4.92(s,1H),4.71(s,1H),4.16(d,J＝7.0Hz,1H),4.08(dt,J＝13.1,4.7Hz,1H),3.07–2.90(m,1H),2.43(dd,J＝10.5,3.1Hz,1H),2.24(dd,J＝13.1,6.0Hz,1H),2.09–1.86(m,3H),1.85–1.73(m,1H),1.59(s,3H),1.55–1.42(m,2H),1.26–1.19(m,2H),1.16(s,3H),1.14(s,3H),0.94(d,J＝6.7Hz,3H).核磁共振碳谱分析如下：13C NMR(101MHz,DMSO)δ200.59,164.19,161.03,158.48,151.71,145.64,143.33,142.16,134.60,134.11,130.96,129.58,128.53,123.35,119.63,114.73,89.35,78.79,67.90,54.09,48.94,37.96,36.07,35.22,29.01,28.76,25.58,21.87,16.72,15.06,12.92.
实施例9
本实施例为化合物9的制备，化合物9的结构式为：
的制备：
具体操作及配比同实施例1。
合成的千金二萜烷噻唑衍生物为白色固体，收率62％。对本实施例制备的千金二萜烷噻唑衍生物进行核磁共振氢谱分析如下：1H NMR(600 MHz,DMSO)δ7.73(d,J＝3.8 Hz,2H),7.62(s,2H),7.47–7.34(m,4H),6.65(d,J＝16.0 Hz,1H),6.27(d,J＝9.4 Hz,1H),5.54(s,1H),4.02(dd,J＝23.9,8.0 Hz,1H),3.99–3.89(m,1H),2.96(dd,J＝13.3,9.1 Hz,1H),2.13(s,1H),2.06(dd,J＝13.7,5.9 Hz,1H),2.00–1.93(m,1H),1.84–1.78(m,2H),1.76(s,3H),1.58(dd,J＝11.7,8.4 Hz,1H),1.51–1.42(m,2H),1.18(d,J＝15.6 Hz,8H),0.91(d,J＝6.7 Hz,4H).核磁共振碳谱分析如下：13C NMR(101 MHz,DMSO)δ200.86,166.41,149.95,144.58,135.11,134.66,130.81,129.38,128.78,119.22,88.82,78.89,66.62,59.48,54.56,52.05,48.39,38.27,35.38,33.83,29.46,29.02,25.91,20.38,16.72,14.76,12.79。
应用例
本发明部分产物对RAW264.7细胞生成NO的影响研究
将RAW264.7细胞接种在96孔板中，并用不同浓度(0-100μM)的化合物处理3小时，然后与LPS(1μg/mL)一起温育24小时。将具有或不具有LPS的DMSO作为媒介物对照或模型对照处理。使用Griess试剂在540nm下用酶标仪测量培养基中的亚硝酸盐积累。计算化合物处理组的抑制率(％)并测定IC50值以评价NO抑制活性。以地塞米松为阳性对照药。
表1.化合物抑制RAW264.7细胞NO生成IC50值表
从表中可以发现，水解后的续随子醇和环氧续随子醇的抗炎活性弱于对应的大戟因子，经过衍生后的部分化合物的抗炎活性比对应的大戟因子有所提高，化合物4具有最好的抑制活性，其活性强度是阳性对照地塞米松的5倍。
以上具体实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (6)
1.千金二萜烷噻唑衍生物、或其药学上可接受的盐，其特征在于，选自以下结构式中的一种：
2.根据权利要求1所述的千金二萜烷噻唑衍生物、或其药学上可接受的盐，其特征在于，所述盐为有机酸盐、无机酸盐中的一种。
3.一种药物组合物，其特征在于，以权利要求1所述的千金二萜烷噻唑衍生物或其药学上可接受的盐作为活性成分。
4.一种药物组合物，其特征在于，包括权利要求1所述的千金二萜烷噻唑衍生物或其药学上可接受的盐，与药学上可接受的稀释剂、辅助剂、载体中的一种或几种混合，制成临床上需要的药用组合物。
5.权利要求1所述的千金二萜烷噻唑衍生物、或其药学上可接受的盐在制备治疗和/或预防炎症药物中的应用。
6.权利要求3或4所述的药物组合物在制备治疗和/或预防炎症药物中的应用。
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