CN111303058B - 续随子醇衍生物及其制备方法和用途 - Google Patents

续随子醇衍生物及其制备方法和用途 Download PDF

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CN111303058B
CN111303058B CN202010174639.7A CN202010174639A CN111303058B CN 111303058 B CN111303058 B CN 111303058B CN 202010174639 A CN202010174639 A CN 202010174639A CN 111303058 B CN111303058 B CN 111303058B
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陈丽霞
李华
王望
吴艳丽
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Shenyang Pharmaceutical University
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Abstract

本发明属于医药技术领域，涉及续随子醇衍生物及其制备方法和用途,具体涉及一种新的具有抗炎症活性的化合物、其消旋体或旋光异构体，或其药学上可接受的盐和溶剂化物，以及含有该化合物的药物组合物。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。所述的化合物、及其异构体或其药学上可接受的盐如通式(I)、(II)或(III)所示，其中R1、R2如权利要求书和说明书所述。

Description

续随子醇衍生物及其制备方法和用途
技术领域
本发明属于医药技术领域，涉及续随子醇衍生物及其制备方法和用途,具体涉及一种新的具有抗炎症活性的化合物、其消旋体或旋光异构体，或其药学上可接受的盐和溶剂化物，以及含有该化合物的药物组合物。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。
根据本课题组的前期研究，发现千金子中的大戟因子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。于是我们以大戟因子L3为原料制得续随子醇(Lathyrol)，再进行衍生，以得到抗炎活性更好的化合物。
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，该化合物可用于制备治疗/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)、(II)或(III)所示的化合物、其异构体或其药学上可接受的盐：
Figure BDA0002410368960000021
其中，R1为C1-C6烷基、C2-C6烯基、5-10元芳基或杂芳基，所述烷基、烯基、芳基或杂芳基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、C1-C6烷氧基苯基、羧基、C1-C6磺酸基、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；
R2为苯氧基、C1-C6烷氧基、C1-C6酯基或C1-C6酰胺基，所述C1-C6烷氧基、C1-C6酯基或C1-C6酰胺基可以连接一个或多个取代基，所述取代基为C1-C6烷基、苯基或5-10元杂环基；所述的苯氧基、C1-C6烷基、苯基或5-10元杂环基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、羰基、羧基、胺基、C1-C4酯基和C1-C4酰胺基；所述的杂环基含有1-3个N、O或S的杂原子；
进一步地，本发明优选如下结构的通式(I)所示的化合物、其异构体或其药学上可接受的盐：
其中，R1为C1-C6烷基、C2-C6烯基、5-6元芳基或杂芳基，所述烷基、烯基、芳基或杂芳基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、C1-C4烷氧基苯基、羧基、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；
R2为苯氧基、C1-C6烷氧基、C1-C6酯基、C1-C6酰胺基，所述C1-C6烷氧基、C1-C6酯基或C1-C6酰胺基可以连接一个或多个取代基，所述取代基为C1-C6烷基、苯基或5-10元杂环基；所述的苯氧基、C1-C6烷基、苯基或5-10元杂环基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、羰基、羧基、胺基、C1-C4酯基和C1-C4酰胺基；所述的杂环基含有1-3个N、O或S的杂原子；
进一步地，本发明优选如下结构的通式(I)所示的化合物、其异构体或其药学上可接受的盐：
R1为C1-C6烷基、C2-C6烯基、苯基、
Figure BDA0002410368960000031
所述芳基或杂芳基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、C1-C4烷氧基苯基、羧基、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；
优选地，R1为C1-C6烷基、C2-C6烯基、苯基、
Figure BDA0002410368960000032
所述芳基或杂芳基可以被一个或多个取代基取代，所述取代基为羟基、C1-C6烷基、卤素、硝基、C1-C4烷氧基苯基、羧基、胺基、苯基、
Figure BDA0002410368960000033
R2为C1-C6烷氧基、苯氧基、C1-C6酯基、C1-C6酰胺基，所述C1-C6烷氧基、C1-C6酯基和C1-C6酰胺基可以连接一个或多个取代基，所述取代基为苯基、C1-C6烷基、
Figure BDA0002410368960000034
所述的苯氧基上可以连接一个或多个取代基，所述取代基为C1-C6酯基、C1-C6酰胺基、羰基、羧基、苯基、
Figure BDA0002410368960000035
所述烷氧基和酰胺基可以与取代基形成环状结构，如
Figure BDA0002410368960000036
优选地，R2为以下结构：
Figure BDA0002410368960000041
本发明的部分化合物结构如下：
Figure BDA0002410368960000042
Figure BDA0002410368960000051
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：
Figure BDA0002410368960000061
合成路线
以大戟因子L3(1)为原料，首先用氢氧化钾的甲醇溶液进行水解，得到续随子醇(中间体2)；续随子醇在不同的条件下进行酰化和酯化，得到通式(I)或(II)的化合物。
中间体2与氯乙酸发生酯化后，得到中间体3；中间体3与叠氮化钠发生取代反应，用叠氮基取代氯原子，得到中间体4；然后用具有活泼氢的化合物与溴丙炔发生取代反应得到一系列的中间体5，再与中间体4发生click反应，得到通式(III)的化合物。
本发明所述的药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐，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；无机酸包括，盐酸、氢溴酸、硝酸、硫酸、磷酸；有机碱包括葡甲胺、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。
本发明还提供了一种药物组合物，是以上式(I)的化合物或其药学上可接受的盐作为活性成分。本发明的化合物或其药学上可接受的盐可与药学上可接受的稀释剂、辅助剂和/或载体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、耐药性更好，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为不同浓度下的化合物15的RAW264.7细胞的存活率。
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：本发明化合物的制备
Figure BDA0002410368960000071
的制备：
将在5％氢氧化钾/甲醇溶液(100mL)中的大戟因子L3(5g，9.6mmol)在室温搅拌6小时。完成后，减压除去溶剂，并将残余物用二氯甲烷萃取，用盐水洗涤，用无水硫酸钠干燥，过滤，蒸发并通过柱色谱纯化，得到中间体2(续随子醇)，为白色固体(82％收率)。ESI-MS m/z 335.2[M+H]+(Calcd.for C20H31O4,335.2)；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).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.
用3mL二氯甲烷溶解乙酸(0.23mmol)和EDCI(44mg,0.23mmol),20分钟后，加入续随子醇(40mg,0.15mmol)，DMAP(催化量)和DIPEA(49μL,0.3mmol)。室温反应8-10个小时。反应结束后，反应液用20％柠檬酸溶液洗一次，饱和食盐水洗一次。开放硅胶柱色谱纯化，即可得到最终产物，白色固体，收率95％。HR-MS(ESI)m/z:399.2138[M+Na]+(Calcd.forC22H32NaO5,399.2142)；1H NMR(400MHz,CDCl3)δ6.92(brs,1H),5.79(d,J＝10.2Hz,1H),4.86(d,J＝6.0Hz,2H),4.28(s,1H),4.13–4.02(m,1H),2.99(dt,J＝16.9,8.4Hz,1H),2.94(t,J＝5.2Hz,1H),2.43(dd,J＝10.1,2.8Hz,1H),2.15(ddd,J＝10.3,6.8,3.3Hz,2H),2.06(s,3H),1.88(ddd,J＝9.7,7.2,4.0Hz,2H),1.78(s,3H),1.63(q,J＝10.1Hz,2H),1.56–1.45(m,1H),1.40(dd,J＝11.5,8.6Hz,1H),1.18(d,J＝6.2Hz,3H),1.14–1.10(m,6H).13CNMR(100MHz,CDCl3)δ201.78,171.41,148.89,144.00,135.13,114.19,88.16,78.53,71.26,53.68,49.02,37.35,36.03,28.76,28.08,25.56,21.15,16.02,14.36,13.15.
实施例2
Figure BDA0002410368960000091
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率93％。HR-MS(ESI)m/z:413.2300[M+Na]+(Calcd.for C23H34NaO5,413.2298)；1H NMR(400MHz,CDCl3)δ6.85(brs,1H),5.79(d,J＝10.0Hz,1H),4.87(d,J＝5.5Hz,2H),4.30(s,1H),4.13–4.00(m,1H),2.98(d,J＝5.2Hz,2H),2.44(dd,J＝9.9,2.8Hz,1H),2.38–2.28(m,2H),2.16(ddd,J＝13.7,6.7,3.4Hz,2H),1.88(ddd,J＝13.2,8.5,3.8Hz,2H),1.79(s,3H),1.70–1.58(m,2H),1.56–1.45(m,1H),1.40(dd,J＝11.4,8.6Hz,1H),1.19–1.16(m,3H),1.16–1.10(m,9H).13C NMR(100MHz,CDCl3)δ201.79,174.88,148.58,144.10,135.20,114.04,88.30,78.41,70.85,53.69,48.95,37.38,35.99,28.75,28.02,27.76,25.51,21.23,15.99,14.36,13.16,9.13.
实施例3
Figure BDA0002410368960000092
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率75％。HR-MS(ESI)m/z:461.2305[M+Na]+(Calcd.for C27H34NaO5,461.2298)；1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.3Hz,2H),7.59(dd,J＝12.7,5.3Hz,1H),7.47(d,J＝7.8Hz,2H),6.08(d,J＝10.0Hz,1H),4.97(d,J＝8.8Hz,2H),4.18(t,J＝3.0Hz,1H),3.07(s,1H),2.60(dd,J＝10.0,2.6Hz,1H),2.37–2.08(m,2H),2.01–1.86(m,2H),1.82(s,3H),1.73–1.55(m,2H),1.44(dd,J＝11.4,8.6Hz,1H),1.27–1.18(m,4H),1.15(s,3H),1.11(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ201.58,171.79,166.98,149.27,144.08,135.19,133.68,133.31,130.16,129.84,128.43,114.40,88.50,78.64,71.55,54.03,49.02,37.45,36.17,28.79,28.21,25.64,21.36,16.07,14.10,13.17.
实施例4
Figure BDA0002410368960000101
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率76％。HR-MS(ESI)m/z:487.2463[M+Na]+(Calcd.for C29H36NaO5,487.2455)；1H NMR(400MHz,CDCl3)δ7.70(d,J＝16.0Hz,1H),7.50(dd,J＝6.8,2.9Hz,2H),7.41–7.31(m,3H),6.42(d,J＝16.0Hz,1H),5.94(d,J＝10.4Hz,1H),4.93(s,1H),4.89(s,1H),4.36(s,1H),4.12(dd,J＝7.1,3.4Hz,1H),3.19(s,1H),3.14–3.03(m,1H),2.51(dd,J＝10.4,2.6Hz,1H),2.30–2.09(m,2H),2.01–1.86(m,2H),1.77(s,3H),1.64(ddd,J＝20.9,12.7,7.1Hz,3H),1.47–1.37(m,1H),1.19(d,J＝5.0Hz,4H),1.15(d,J＝5.8Hz,3H),1.13–1.08(m,3H).13C NMR(100MHz,CDCl3)δ206.55,167.75,146.23,144.11,135.12,134.08,130.60,128.91,128.20,117.41,114.52,88.68,78.82,70.91,54.34,49.43,37.27,36.24,29.03,28.82,28.33,25.70,16.13,14.10,13.01.
实施例5
Figure BDA0002410368960000102
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率80％。HR-MS(ESI)m/z:489.2631[M+Na]+(Calcd.for C29H38NaO5,489.2611)；1H NMR(400MHz,CDCl3)δ7.32–7.16(m,5H),7.01(brs,1H),5.81(d,J＝10.4Hz,1H),5.29(s,1H),4.86(s,1H),4.80(s,1H),4.17(s,1H),3.73(s,1H),2.98(ddd,J＝15.5,13.4,10.4Hz,3H),2.67(t,J＝7.4Hz,2H),2.42–2.27(m,2H),2.12–1.97(m,2H),1.93–1.80(m,2H),1.74(s,3H),1.67–1.49(m,3H),1.39(dd,J＝11.5,8.6Hz,1H),1.20–1.15(m,4H),1.14(s,3H),1.03(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ201.57,173.18,149.90,144.08,140.28,134.99,128.47,128.42,126.41,114.34,88.50,78.80,70.65,53.40,49.23,37.23,36.18,35.82,30.80,28.81,28.30,25.67,21.24,16.11,14.30,12.97.
实施例6
Figure BDA0002410368960000111
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率63％。HR-MS(ESI)m/z:506.2152[M+Na]+(Calcd.for C27H33NaO7,506.2149)；1H NMR(400MHz,CDCl3)δ8.29–8.23(m,2H),8.22–8.17(m,2H),6.73(brs,1H),6.08(d,J＝9.6Hz,1H),5.29(s,1H),5.02(s,1H),4.95(s,1H),4.30(s,1H),4.19–4.10(m,1H),2.99(dd,J＝14.3,10.2Hz,1H),2.72(d,J＝6.8Hz,1H),2.61(dd,J＝9.5,3.0Hz,1H),2.32–2.13(m,2H),1.96–1.83(m,5H),1.69–1.53(m,3H),1.44(dd,J＝11.3,8.7Hz,1H),1.27–1.19(m,5H),1.15(s,3H),1.12(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ202.20,164.08,150.60,143.65,135.43,135.27,130.85,123.57,114.52,87.24,78.32,67.27,53.40,48.37,37.67,35.82,28.72,27.88,25.46,21.05,15.92,14.34,13.41.
实施例7
Figure BDA0002410368960000121
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率67％。HR-MS(ESI)m/z:495.1907[M+Na]+(Calcd.for C27H33ClNaO5,495.1909)；1H NMR(400MHz,CDCl3)δ7.85(t,J＝1.7Hz,1H),7.78(d,J＝7.8Hz,1H),7.42–7.36(m,1H),7.24(t,J＝7.9Hz,1H),6.82(d,J＝23.6Hz,1H),5.95(d,J＝10.1Hz,1H),4.84(s,1H),4.81(s,1H),4.24(d,J＝7.1Hz,1H),4.01(s,1H),2.90(s,1H),2.78(d,J＝5.0Hz,1H),2.46(dd,J＝10.1,2.7Hz,1H),2.16–1.98(m,2H),1.85–1.73(m,2H),1.70(s,3H),1.52(dd,J＝14.6,10.2Hz,2H),1.30(dt,J＝16.9,8.5Hz,1H),1.10–1.05(m,4H),1.02(s,3H),0.97(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ201.82,165.60,144.01,135.32,134.77,133.43,131.85,129.99,129.92,128.17,114.76,88.53,78.80,77.55,77.23,76.91,72.16,53.83,49.04,37.69,36.25,28.97,28.35,25.80,21.31,16.23,14.55,13.41.
实施例8
Figure BDA0002410368960000122
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率58％。HR-MS(ESI)m/z:504.2716[M+Na]+(Calcd.for C29H39NNaO5,504.2720)；1H NMR(400MHz,CDCl3)δ7.88(d,J＝9.0Hz,2H),6.62(d,J＝9.0Hz,2H),5.99(d,J＝10.5Hz,1H),4.94(s,1H),4.88(s,1H),4.48(s,1H),4.12(d,J＝2.8Hz,1H),3.78–3.56(m,1H),3.17(d,J＝19.4Hz,1H),3.03(s,6H),2.53(dd,J＝10.4,2.3Hz,1H),2.24(dt,J＝15.6,7.7Hz,1H),2.19–2.09(m,1H),2.05–1.85(m,2H),1.75(s,3H),1.72–1.61(m,3H),1.43(dd,J＝11.6,8.5Hz,1H),1.19(s,4H),1.17–1.13(m,4H),1.09(d,J＝6.8Hz,3H).13CNMR(100MHz,CDCl3)δ201.53,167.36,153.70,144.51,135.12,131.78,114.22,110.70,88.49,78.96,70.64,55.01,49.55,40.02,37.12,36.37,28.86,28.46,25.73,21.51,16.21,14.44,12.90.
实施例9
Figure BDA0002410368960000131
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率62％。HR-MS(ESI)m/z:475.2474[M+Na]+(Calcd.for C28H36NaO5,475.2455)；1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.2Hz,2H),7.22(d,J＝8.0Hz,2H),6.04(d,J＝10.1Hz,1H),5.28(s,1H),4.94(s,2H),4.38(s,1H),4.14(d,J＝3.0Hz,1H),3.17(s,2H),2.56(dd,J＝10.1,2.7Hz,1H),2.39(s,3H),2.31–2.20(m,1H),2.20–2.11(m,1H),2.00–1.86(m,2H),1.80(s,3H),1.65(dt,J＝30.8,15.4Hz,3H),1.48–1.39(m,1H),1.20(s,3H),1.15(s,3H),1.09(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ202.03,167.11,144.18,135.19,129.91,129.54,129.17,126.91,114.33,88.76,78.69,71.55,53.39,49.19,37.37,36.17,29.67,28.81,28.23,25.62,21.67,21.35,16.10,14.37,13.09.
实施例10：
Figure BDA0002410368960000132
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率57％。HR-MS(ESI)m/z:462.2244[M+Na]+(Calcd.for C26H33NNaO5,462.2251)；1H NMR(400MHz,CDCl3)δ9.16(dd,J＝2.1,0.7Hz,1H),8.70(dd,J＝4.9,1.7Hz,1H),8.26(dt,J＝8.0,1.9Hz,1H),7.34(ddd,J＝8.0,4.9,0.7Hz,1H),6.93(d,J＝41.2Hz,1H),6.14(d,J＝10.1Hz,1H),5.28(s,1H),4.96(d,J＝16.0Hz,2H),4.40(s,1H),4.16(s,1H),3.17(s,1H),3.03(s,1H),2.61(dd,J＝10.1,3.0Hz,1H),2.31–2.13(m,2H),1.97–1.87(m,2H),1.83(s,3H),1.75(s,1H),1.65(dd,J＝14.6,10.2Hz,2H),1.44(dd,J＝11.4,8.6Hz,1H),1.26–1.17(m,5H),1.15(s,3H),1.12–1.09(m,3H).13C NMR(100MHz,CDCl3)δ201.78,165.20,153.36,150.87,146.65,143.80,137.29,135.11,126.01,123.35,114.61,88.06,78.55,72.55,53.40,48.74,37.60,36.01,28.77,28.14,25.59,21.04,16.02,14.37,13.25.
实施例11：
Figure BDA0002410368960000141
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率58％。HR-MS(ESI)m/z:451.2101[M+Na]+(Calcd.for C25H32NaO6,451.2091)；1H NMR(400MHz,CDCl3)δ7.57(d,J＝0.8Hz,1H),7.19(d,J＝3.5Hz,1H),6.96(brs,1H),6.49(dd,J＝3.5,1.7Hz,1H),6.01(d,J＝9.9Hz,1H),5.28(s,1H),4.94(d,J＝3.3Hz,2H),4.31(s,1H),4.21–4.14(m,1H),3.04(s,1H),2.93(d,J＝4.9Hz,1H),2.56(dd,J＝9.9,2.8Hz,1H),2.33–2.22(m,1H),2.17(ddd,J＝13.5,6.7,3.4Hz,1H),1.91(ddd,J＝11.5,9.7,5.8Hz,2H),1.81(s,3H),1.70–1.53(m,3H),1.42(dd,J＝11.4,8.6Hz,1H),1.23–1.16(m,4H),1.14(s,3H),1.11(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ201.90,158.72,146.66,144.31,143.80,135.23,118.69,114.55,111.96,105.14,88.22,78.50,71.30,53.39,48.89,37.46,36.04,28.78,28.09,25.55,21.28,16.02,14.32,13.16.
实施例12：
Figure BDA0002410368960000151
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率35％。HR-MS(ESI)m/z:537.2634[M+Na]+(Calcd.for C33H38NaO5,537.2611)；1H NMR(400MHz,CDCl3)δ8.14–8.07(m,2H),7.67–7.63(m,2H),7.62–7.57(m,2H),7.49–7.43(m,2H),7.39(ddd,J＝7.3,3.7,1.2Hz,1H),7.05(brs,1H),6.09(d,J＝10.0Hz,1H),5.29(s,1H),4.97(s,2H),4.38(s,1H),4.18(dd,J＝7.5,3.3Hz,1H),3.10(d,J＝13.4Hz,2H),2.60(dd,J＝10.0,2.7Hz,1H),2.33–2.24(m,1H),2.19(dd,J＝6.8,3.4Hz,1H),2.04–1.88(m,2H),1.82(s,3H),1.72–1.57(m,3H),1.45(dd,J＝11.5,8.6Hz,1H),1.27–1.18(m,5H),1.16(s,3H),1.11(d,J＝5.3Hz,3H).13C NMR(100MHz,CDCl3)δ201.78,165.20,146.15,144.13,139.87,135.21,130.38,128.94,128.41,128.23,127.26,127.16,114.41,88.06,78.55,72.55,53.40,49.09,37.44,36.15,28.81,28.21,25.62,21.38,16.09,14.39,13.14.
实施例13：
Figure BDA0002410368960000152
的制备：
具体操作及配比参考化合物1的制备。
白色固体，收率40％。HR-MS(ESI)m/z:514.2575[M+Na]+(Calcd.for C30H37NNaO5,514.2564)；1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.59(d,J＝7.8Hz,1H),7.34(d,J＝8.1Hz,1H),7.18(dd,J＝11.1,3.9Hz,1H),7.11(t,J＝7.4Hz,2H),5.87(d,J＝10.2Hz,1H),5.28(s,1H),4.87(s,1H),4.79(s,1H),4.12(s,1H),3.77(s,2H),3.62(s,1H),2.97(d,J＝11.9Hz,1H),2.36(dd,J＝10.1,2.7Hz,1H),2.16(dd,J＝16.3,9.8Hz,2H),1.89(dqd,J＝11.0,6.8,3.6Hz,3H),1.73(s,4H),1.63–1.46(m,2H),1.44–1.35(m,1H),1.21–1.08(m,7H),0.86(d,J＝8.7Hz,3H).13C NMR(100MHz,CDCl3)δ201.37,172.08,149.90,144.31,136.05,134.94,126.92,123.37,122.32,119.68,118.57,114.25,111.41,108.09,88.75,78.75,70.52,53.80,49.00,37.22,36.20,31.87,28.82,28.32,25.67,21.36,16.09,14.06,12.97.
实施例14
Figure BDA0002410368960000161
的制备：
在氮气保护下，向0℃的续随子醇(120mg，0.36mmol)和苯甲酰氯(1.44mmol)的无水DCM(4mL)溶液中滴加TEA(181μL，1.47mmol)。然后撤去冰浴，反应10个小时。反应结束后，将有机层分别用饱和碳酸氢钠溶液和盐水洗涤1次，用无水硫酸钠干燥，过滤，蒸发，并通过柱色谱纯化，得到化合物14。
白色固体，收率38％。HR-MS(ESI)m/z:565.2583[M+Na]+(Calcd.for C34H38NaO6,565.2561)；1H NMR(400MHz,CDCl3)δ7.90(d,J＝7.6Hz,2H),7.78(d,J＝7.5Hz,2H),7.49(dt,J＝19.8,7.4Hz,2H),7.39(t,J＝7.7Hz,2H),7.30(t,J＝7.7Hz,2H),6.60(brs,1H),6.14(d,J＝9.7Hz,1H),5.89(t,J＝3.6Hz,1H),5.08(s,1H),4.92(s,1H),3.00(s,1H),2.90(dd,J＝9.8,3.6Hz,1H),2.51–2.37(m,1H),2.21(dd,J＝10.9,6.7Hz,1H),1.94(s,3H),1.87(ddd,J＝10.0,6.2,2.8Hz,2H),1.76(dd,J＝14.3,11.2Hz,1H),1.55(s,1H),1.45(dd,J＝11.4,8.7Hz,1H),1.29–1.18(m,5H),1.15(s,3H),1.00(d,J＝6.7Hz,3H).13C NMR(100MHz,CDCl3)δ201.55,165.68,165.42,144.04,134.84,133.58,132.81,132.70,130.13,130.02,129.93,129.60,129.51,128.43,128.28,128.04,114.10,79.46,52.15,49.24,37.62,36.01,28.77,27.98,25.54,20.52,16.00,14.50,13.34.
实施例15
Figure BDA0002410368960000171
的制备：
具体操作及配比参考化合物14的制备。
白色固体，收率30％。HR-MS(ESI)m/z:617.2894[M+Na]+(Calcd.for C38H42NaO6,617.2874)；1H NMR(400MHz,CDCl3)δ7.62(d,J＝16.0Hz,1H),7.55(d,J＝16.0Hz,1H),7.29(dd,J＝9.4,4.0Hz,3H),7.24–7.18(m,5H),7.14–7.07(m,2H),6.33(d,J＝16.0Hz,1H),6.20(d,J＝16.0Hz,1H),6.01(d,J＝9.4Hz,1H),5.41(dd,J＝8.1,3.5Hz,1H),5.38(s,1H),5.20(s,1H),4.50(s,1H),4.09(dd,J＝6.0,3.3Hz,1H),3.75(s,1H),3.09(dd,J＝14.2,10.1Hz,1H),2.59(dd,J＝9.3,2.3Hz,1H),2.20(ddd,J＝10.0,6.6,3.3Hz,1H),2.14–1.98(m,2H),1.74(dd,J＝14.3,10.3Hz,1H),1.60(s,2H),1.51(dd,J＝11.4,8.5Hz,1H),1.43–1.31(m,2H),1.26(d,J＝11.9Hz,1H),1.22(s,3H),1.17(d,J＝7.0Hz,3H),1.13(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ201.79,167.89,165.80,146.62,145.25,141.93,136.36,133.93,133.68,130.55,130.18,128.73,128.61,128.13,127.89,117.73,117.29,89.30,78.30,68.71,55.65,50.07,37.26,32.02,29.79,28.55,27.77,24.81,16.11,14.39,12.82.
实施例16
Figure BDA0002410368960000181
的制备：
用3mL二氯甲烷溶解氯乙酸(0.23mmol)和EDCI(44mg,0.23mmol),20分钟后，加入续随子醇(40mg,0.15mmol)，DMAP(催化量)和DIPEA(49μL,0.3mmol)。室温反应8-10个小时。反应结束后，反应液用20％柠檬酸溶液洗一次，饱和食盐水洗一次。用无水硫酸钠干燥，过滤，蒸干，即可得到中间体3的粗品，白色固体，无需进一步纯化即可进行下一步。
在中间体3(50mg,1.23mmol,1.0eq)的DMF(1.5mL)溶液中室温条件下加入叠氮化钠(96mg,1.48mmol,1.2eq)，反应体系加热至60℃后反应8个小时。待体系冷却至室温后加入乙酸乙酯，合并有机层后水洗几次除去DMF，无水硫酸钠干燥，过滤，蒸干，得到中间体4的粗品，无需进一步纯化即可进行下一步。
在乙酰水杨酸(400mg,2.65mmol,1.0eq)的DMF(4mL)溶液中加入无水碳酸钾(549mg,3.98mmol,1.5eq)，反应体系搅拌30分钟后滴加溴丙炔(274μL，3.18mmol,1.2eq)。反应体系60℃条件下搅拌10小时。待反应完全后，加入乙酸乙酯，合并的有机层用水洗多次后，用饱和食盐水洗涤一次，无水硫酸钠干燥，减压蒸干，柱色谱纯化，即可得到中间体5。1HNMR(400MHz,CDCl3)δ8.17(dd,J＝7.9,1.6Hz,1H),7.70(td,J＝8.0,1.7Hz,1H),7.44(td,J＝7.8,1.1Hz,1H),7.23(dd,J＝8.1,0.9Hz,1H),4.99(d,J＝2.5Hz,2H),2.64(t,J＝2.5Hz,1H),2.49(s,3H).
在中间体4(50mg,0.12mmol,1.0eq)和中间体5(27mg,0.14mmol,1.2eq)的THF(1mL)和水(0.3mL)的混合体系中加入铜粉(23mg,0.36mmol,3.0eq)和无水硫酸铜(19mg,0.12mmol,1.0eq)。反应体系在室温条件下过夜反应。待反应结束后，过滤除去固体，滤液减压蒸干后经柱层析分离得到目标化合物。
白色固体，收率40％。HR-MS(ESI)m/z:658.2742[M+Na]+(Calcd.for C34H41N3NaO9,658.2735)；1H NMR(400MHz,CDCl3)δ8.04–7.92(m,2H),7.79(s,1H),7.60–7.46(m,2H),7.30–7.26(m,1H),7.06(d,J＝8.1Hz,1H),5.99(d,J＝10.3Hz,1H),5.46–5.37(m,3H),5.22–5.16(m,1H),5.13(t,J＝4.0Hz,2H),4.89(d,J＝6.9Hz,1H),4.84(s,1H),4.00(s,1H),2.97(dd,J＝14.2,10.0Hz,1H),2.45(dd,J＝10.3,3.2Hz,1H),2.26(d,J＝5.2Hz,3H),2.12–2.00(m,2H),1.93–1.81(m,3H),1.59–1.47(m,3H),1.40–1.32(m,2H),1.12(d,J＝8.5Hz,7H),1.04(t,J＝6.0Hz,3H).13C NMR(101MHz,CDCl3)δ170.48,166.20,164.86,151.17,151.08,147.07,135.36,134.72,132.47,132.41,126.59,126.12,124.30,124.24,123.33,115.59,112.23,79.21,58.57,51.87,51.45,49.01,38.09,37.51,36.40,29.28,29.06,28.76,26.14,21.51,16.51,14.82,13.63.
实施例17
Figure BDA0002410368960000191
的制备：
具体操作及配比参考化合物16的制备。
橙色固体，收率42％。HR-MS(ESI)m/z:625.2653[M+Na]+(Calcd.for C33H38N4NaO7,625.2633)；1H NMR(400MHz,CDCl3)δ7.82(d,J＝6.9Hz,1H),7.54(t,J＝7.4Hz,3H),7.31–7.18(m,1H),7.08(t,J＝7.5Hz,1H),5.96(d,J＝10.1Hz,1H),5.50(d,J＝3.6Hz,1H),5.27(d,J＝5.9Hz,2H),5.17(d,J＝4.3Hz,1H),5.12(s,2H),5.00(d,J＝4.2Hz,1H),4.98(s,2H),4.86(s,2H),4.80(s,1H),4.00(d,J＝3.6Hz,1H),2.97(dd,J＝14.2,10.1Hz,1H),2.41(dd,J＝10.1,3.0Hz,1H),2.29–2.09(m,4H),1.91–1.79(m,5H),1.54(dd,J＝14.5,10.3Hz,2H),1.40–1.32(m,2H),1.11(d,J＝4.7Hz,7H),1.04(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ183.26,165.54,158.19,150.34,150.31,142.20,138.84,135.04,125.54,125.04,124.26,117.69,115.23,111.65,111.56,98.59,86.75,78.85,76.91,67.57,60.60,53.64,51.14,48.68,37.83,37.11,36.09,28.95,28.71,28.43,25.81,21.06,16.19,14.36,13.32.
实施例18
Figure BDA0002410368960000201
的制备：
具体操作及配比参考化合物16的制备。
白色固体，收率45％。HR-MS(ESI)m/z:629.2942[M+Na]+(Calcd.for C33H42N4NaO7,629.2946)；1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.33–7.22(m,2H),6.82(d,J＝8.6Hz,2H),6.01(t,J＝9.7Hz,1H),5.18(d,J＝7.2Hz,1H),5.15–5.04(m,4H),4.87(s,1H),4.13(s,1H),3.95(s,1H),3.02(d,J＝7.8Hz,1H),2.44–2.30(m,2H),1.95–1.80(m,3H),1.62–1.48(m,2H),1.41–1.27(m,2H),1.09(dd,J＝14.3,4.8Hz,7H),1.04(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ
162.83,155.00,134.92,131.68,131.52,124.84,122.83,122.32,115.20,111.85,78.97,72.52,61.99,56.62,53.33,51.08,49.05,37.82,36.75,35.38,31.66,29.02,28.75,26.00,24.28,16.30,14.61,13.14.
实施例19
Figure BDA0002410368960000202
的制备：
具体操作及配比参考化合物16的制备。
白色固体，收率38％。HR-MS(ESI)m/z:653.2944[M+Na]+(Calcd.for C35H42N4NaO7,653.2946)；1H NMR(400MHz,CDCl3)δ7.52(dd,J＝7.7,4.2Hz,1H),7.40(s,1H),7.30(d,J＝8.1Hz,1H),7.14(t,J＝7.5Hz,1H),7.10–7.03(m,2H),6.01(t,J＝12.4Hz,1H),5.21(d,J＝9.3Hz,2H),5.06(dd,J＝22.1,11.5Hz,1H),4.98(d,J＝7.3Hz,1H),4.88(s,1H),4.84(s,1H),4.01(s,1H),3.75(d,J＝3.2Hz,2H),3.05–2.93(m,1H),2.45(dd,J＝10.2,3.2Hz,1H),2.21–2.12(m,2H),1.87(d,J＝4.4Hz,3H),1.62–1.50(m,3H),1.39(dt,J＝17.2,6.1Hz,1H),1.13(d,J＝7.8Hz,6H),1.10–1.05(m,4H).13C NMR(101MHz,CDCl3)δ206.06,172.10,165.81,146.81,143.46,136.22,135.02,127.27,125.64,123.52,122.32,119.79,118.95,115.28,111.48,107.99,78.67,60.55,57.93,53.26,51.32,50.93,48.59,46.94,37.80,37.19,36.15,31.35,28.95,28.75,28.46,25.89,24.59,16.19,15.74,14.56.
实施例20
Figure BDA0002410368960000211
的制备：
具体操作及配比参考化合物16的制备。
白色固体，收率43％。HR-MS(ESI)m/z:702.3144[M+Na]+(Calcd.for C40H45N3NaO7,702.3150)；1H NMR(400MHz,CDCl3)δ7.53–7.46(m,2H),7.42(dd,J＝15.9,2.8Hz,2H),7.35(ddd,J＝11.6,5.4,2.6Hz,4H),7.27–7.21(m,5H),7.03–6.91(m,3H),5.84(d,J＝10.2Hz,1H),5.16(t,J＝10.9Hz,3H),4.84(s,1H),4.78–4.68(m,4H),3.84(d,J＝12.0Hz,1H),2.87(dd,J＝14.1,9.9Hz,1H),2.49(dd,J＝14.8,9.5Hz,1H),2.33–2.25(m,1H),2.09–1.98(m,3H),1.75(dd,J＝10.7,9.6Hz,4H),1.44(dt,J＝14.6,8.6Hz,3H),1.26(ddd,J＝21.8,13.8,8.4Hz,2H),1.01(d,J＝6.2Hz,6H),0.95–0.92(m,3H).13C NMR(101MHz,CDCl3)δ206.62,193.24,166.16,157.21,144.70,143.83,143.62,135.44,133.67,131.08,130.87,129.95,129.47,128.94,127.88,125.20,124.99,122.05,121.88,115.59,113.57,88.42,79.16,68.95,63.33,60.92,53.76,51.36,38.14,37.54,36.43,29.28,29.09,28.78,26.12,24.82,21.55,16.50,14.84,13.64.
实施例21
Figure BDA0002410368960000221
的制备：
具体操作及配比参考化合物16的制备。
白色固体，收率35％。HR-MS(ESI)m/z:642.3145[M+Na]+(Calcd.for C35H45N3NaO7,642.3150)；1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.56(d,J＝16.1Hz,1H),7.42–7.32(m,2H),7.29–7.18(m,3H),6.29(d,J＝16.0,1H),5.88(d,J＝10.2Hz,1H),5.25–5.19(m,2H),5.03(s,1H),4.77(t,J＝9.7Hz,2H),3.91(s,1H),2.94–2.78(m,1H),2.34(dd,J＝10.3,2.9Hz,1H),2.12–1.93(m,2H),1.82–1.69(m,3H),1.44(dt,J＝14.9,9.3Hz,2H),1.30–1.21(m,1H),1.00(d,J＝11.5Hz,6H),0.97(s,3H).13C NMR(101MHz,CDCl3)δ166.93,165.89,145.90,143.57,143.43,135.05,134.31,130.72,129.12,128.45,128.34,125.94,125.73,117.49,115.31,111.95,88.05,78.86,61.14,57.69,52.85,51.16,48.68,37.82,36.10,35.33,28.95,28.42,25.84,20.96,16.18,14.56,13.39.
实施例22
Figure BDA0002410368960000231
的制备：
具体操作及配比参考化合物16的制备。
橙色固体，收率22％。HR-MS(ESI)m/z:704.1896[M+Na]+(Calcd.forC34H39N3NaO6S3,704.1893)；1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.60(d,J＝8.9Hz,2H),7.37(s,1H),7.06(d,J＝8.9Hz,2H),5.96(d,J＝10.0Hz,2H),5.27(d,J＝7.1Hz,2H),5.15(d,J＝9.1Hz,2H),4.88(d,J＝9.4Hz,3H),3.02–2.87(m,2H),2.47(d,J＝8.2Hz,2H),2.28–2.21(m,2H),1.91(s,3H),1.77–1.70(m,2H),1.39(dd,J＝11.5,8.6Hz,2H),1.12(d,J＝3.9Hz,7H),1.10(d,J＝1.7Hz,4H).13C NMR(101MHz,CDCl3)δ166.93,165.89,145.90,143.57,143.43,135.05,134.31,130.72,129.12,128.45,128.34,125.94,125.73,117.49,115.31,111.95,88.05,78.86,61.14,57.69,52.85,51.16,48.68,37.82,36.10,35.33,28.95,28.42,25.84,21.26,15.75,14.17,13.62.
实施例23
Figure BDA0002410368960000232
的制备：
具体操作及配比参考化合物16的制备。
白色固体，收率46％。HR-MS(ESI)m/z:716.2938[M+Na]+(Calcd.for C40H43N3NaO8,716.2942)；1H NMR(400MHz,CDCl3)δ8.26(dd,J＝8.0,1.5Hz,1H),8.06–7.98(m,2H),7.97(s,1H),7.67(ddd,J＝8.6,7.1,1.7Hz,1H),7.54–7.37(m,6H),6.08(d,J＝10.7Hz,1H),5.56(t,J＝3.5Hz,1H),5.26–5.18(m,3H),5.13(s,2H),5.05(t,J＝7.5Hz,1H),4.88(s,1H),4.83(s,1H),4.56(s,1H),4.16(d,J＝3.9Hz,1H),2.66(dd,J＝14.6,9.4Hz,1H),2.39(ddd,J＝21.4,7.4,3.5Hz,2H),2.22(dt,J＝21.9,17.1Hz,2H),1.85(s,4H),1.65–1.50(m,3H),1.41–1.27(m,2H),1.08(d,J＝3.9Hz,6H),1.03(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)δ204.88,175.37,165.61,156.76,156.76,155.54,147.07,147.07,139.96,133.87,131.04,130.85,128.93,128.69,126.03,125.09,124.25,118.27,111.92,86.99,79.75,68.46,65.58,60.61,53.50,51.55,47.17,37.33,35.34,28.79,26.44,24.47,21.30,21.26,15.75,14.17,13.62.
实施例24
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
Figure BDA0002410368960000241
Figure BDA0002410368960000251
从表中可以发现，化合物15具有最好的抑制活性。
实施例25
本发明产物化合物15在RAW264.7细胞中抗炎作用与机制研究
(1)CCK8法检测化合物15对细胞存活率的影响
对数生长期的RAW264.7细胞以5000个/孔接种于96孔板中培养12小时。换不同浓度的化合物15(100、50、25、12.5、6.25和3.125μmol/L)处理细胞。以加入相应体积的DMSO的细胞孔作为空白对照。24小时后弃掉培养基，每孔均加入100μL的含10％CCK8的培养基，培养20分钟后，酶标仪检测450nm处各孔的OD值计算实验组细胞存活率(以空白对照组细胞存活率为100％)。结果图1所示：
由图1可知，化合物15对RAW264.7细胞的存活率没有显著影响。
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.如下的化合物或其药学上可接受的盐：
Figure 890149DEST_PATH_IMAGE001
。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述的药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐。
3.权利要求1所述的化合物的制备方法，其特征在于，
以大戟因子L3为原料，首先用氢氧化钾的甲醇溶液进行水解，得中间体2；中间体2与氯乙酸发生酯化后，得到中间体3；中间体3与叠氮化钠发生取代反应，用叠氮基取代氯原子，得到中间体4；然后用乙酰水杨酸与溴丙炔发生取代反应得到中间体5，再与中间体4发生click反应，即得权利要求1所述的化合物；
Figure 277137DEST_PATH_IMAGE002
Figure 739342DEST_PATH_IMAGE003
Figure 962513DEST_PATH_IMAGE004
Figure 168366DEST_PATH_IMAGE005
。
4.一种药物组合物，包含权利要求1或2所述的化合物或其药学上可接受的盐和一种或多种药用载体和/或稀释剂。
5.一种药物制剂，包含权利要求1或2所述的化合物或其药学上可接受的盐或权利要求4所述的药物组合物。
6.权利要求1或2所述的化合物或其药学上可接受的盐或权利要求4所述的药物组合物或权利要求5所述的药物制剂在制备治疗和/或预防炎症疾病的药物中的应用。
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