CN108840899B - 一种五环三萜类化合物及其衍生物和应用 - Google Patents
一种五环三萜类化合物及其衍生物和应用 Download PDFInfo
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- CN108840899B CN108840899B CN201810829415.8A CN201810829415A CN108840899B CN 108840899 B CN108840899 B CN 108840899B CN 201810829415 A CN201810829415 A CN 201810829415A CN 108840899 B CN108840899 B CN 108840899B
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Abstract
本发明提供一种五环三萜类化合物及其衍生物，该五环三萜类化合物及其衍生物不仅具有显著的拟神经生长因子活性，而且是能够通过血脑屏障的小分子化合物。因此，以本发明提供的五环三萜类化合物及其衍生物添加药学上可接受的载体，可制备预防、治疗老年痴呆症(特别是阿尔茨海默病)等神经退行性疾病的药物。或者以五环三萜类化合物及其衍生物作为活性成分，添加食品上可接受的载体，制备预防、治疗老年痴呆症等神经退行性疾病的食品。本发明提供的五环三萜类化合物及其衍生物还可以在制备预防及治疗神经退行性疾病或者改善认知、学习记忆能力的食品和药品中获得应用。结构通式如式(Ⅰ)所示：
Description
技术领域
本发明属于化学制药领域，涉及五环三萜类化合物，具体涉及一种五环三萜类化合物及其衍生物和应用。
背景技术
随着社会快速发展以及人类生活水平和医疗卫生保健的巨大改善，人类寿命延长，老龄化进程逐步加快，人口日趋老龄化已经是一个全球性问题。
国家统计局发布的第六次全国人口普查主要数据显示，截至2010年11月1日，我国总人口为13.4亿人。其中60岁以上人口达到1.78亿，占全国总人口的13.26％，比2000年上升2.93％；65岁以上人口达到1.19亿，占全国总人口的8.87％，比2000年上升1.91％，是全球唯一的老年人口超过一个亿的国家。预计到2035年，我国将成为全球人口老龄化程度最高的国家。
随着老龄化进程的加快，老年性痴呆的患病率也明显升高,已成为导致成年人死亡的第四位主要原因,仅次于心脏病、癌症、中风，成为严重威胁老年人健康的顽症。
根据病因，老年痴呆主要分为三大类：1)脑变性疾病引起的痴呆即阿尔茨海默病性痴呆(Alzheimer’s disease,AD)，又叫老年性痴呆；2)脑血管病引起的痴呆即血管性痴呆(Vascular dementia，VD)；3)混合型痴呆。迄今为止，AD的确切病理机制尚不清楚，尚无能够治愈痴呆症或者改变其病程发展的方案，目前所采用的治疗方法主要是尽量减轻疾病过程中所出现的包括精神症状在内的各种症状，延缓痴呆症的进一步发展。因此，研究和开发有效的预防治疗老年性痴呆药物已成为全世界迫切需要解决的医学问题，不仅有重要的科研价值，而且具有潜在的巨大的经济和社会意义。
现阶段治疗AD的药物种类甚多，主要有胆碱能药，其中乙酰胆碱酯酶(Acetylcholinesterase,AChE)抑制剂，主要上市的药物有他克林(tacrine)、酒石酸卡巴拉汀(rivastigmine)、石杉碱甲(huperzine A)、多奈哌齐(donepezil)等；β、γ分泌酶抑制药；脑代谢调节剂，如长春胺、尼莫地平、脑益嗪；影响自由基代谢的药物，如维生素C、维生素E等。然而上述这些药物只能暂时改善认知功能，并不能阻止和延缓神经退行性病变的进展。而且，长期服用疗效逐渐降低，并且有较强的副作用。因此，开发抗脑衰老和预防老年痴呆的新药物，已成为目前研究的焦点。
研究表明，脑的神经细胞死亡和神经系统功能下降是导致认知功能障碍的主要原因。神经生长因子(nerve growth factor，NGF)是人类最早发现的一种对神经的生长、发育、分化和功能保持等方面有重要调控作用的生物活性蛋白，也是最重要的神经营养因子。特别是在神经系统疾病过程中，NGF对神经细胞和神经再生都有重要的保护作用。对神经萎缩、神经变性、外伤修复等神经疾病的治疗有显著效果。研究发现，NGF一定程度可阻止AD进展，其促进神经生长和神经保护作用是长期的研究热点。然而，NGF是一个由100多个氨基酸组成的蛋白；由于分子量大和极性强等原因，不能通过血脑屏障，并且难以大规模制备等诸多因素，局限了它的实际临床应用。目前，除脑内手术直接投药之外还没有找到更好的治疗方法。因此，寻找具有类似NGF活性或能增强NGF活性并且能通过血脑屏障的小分子化合物就成为了研究热点。
发明内容
本发明的目的在于针对现有技术的不足，提供一种五环三萜类化合物及其衍生物，该五环三萜类化合物及其衍生物不仅具有显著的拟神经生长因子活性，而且是能够通过血脑屏障的小分子化合物。
本发明解决上述技术问题的技术方案为：
一种五环三萜类化合物及其衍生物，结构通式如式(Ⅰ)所示：
其中：
R1为咖啡酸、肉桂酸、3-羟基肉桂酸、4-羟基肉桂酸、3,4,5-三羟基肉桂酸、2,5-二羟基肉桂酸、3,4-二羟基苯丙酸、3,4-二羟基苯乙酸、3,4-二羟基苯甲酸、3-硝基-4-羟基肉桂酸、3-氨基-4-羟基肉桂酸、反3-(3-吡啶)丙烯酸、反3-(3-呋喃基)丙烯酸、烟酸、3-糠酸、丁酸、己酸或酚羟基被乙酰基取代咖啡酸；
R2为氢、乙酰基或羟基；
R3为CH2OH、CH2OAc或COOH。
上述的五环三萜类化合物及其衍生物，从结构通式可知在五环三萜类化合物的C-3、C-23和C-28含有羟基、羧酸等取代，
作为优选，所述的式(Ⅰ)中的R1为咖啡酸或者3,4,5-三羟基肉桂酸。
作为优选，所述的式(Ⅰ)中的R2为CH2OH。
作为优选，所述的式(Ⅰ)中的R3为CH2OH。
具体的，所述的五环三萜类化合物及其衍生物可以为：
本发明的另一个目的是提供所述的五环三萜类化合物及其衍生物在制备预防、治疗神经退行性疾病的食品或药品中的应用。本发明的五环三萜类化合物及其衍生物在老年痴呆症的体外筛选模型PC12细胞中具有显著的拟神经生长因子活性，因此，可以以有效剂量的五环三萜类化合物或其衍生物作为活性成分，添加药学上可接受的载体等，制备预防、治疗老年痴呆症(特别是阿尔茨海默病)等神经退行性疾病的药物。或者以有效剂量的五环三萜类化合物及其衍生物作为活性成分，添加食品上可接受的载体，制备预防、治疗老年痴呆症等神经退行性疾病的食品。
本发明的再一个目的是提供所述的五环三萜类化合物及其衍生物在制备改善认知、学习记忆能力的食品或药品中的应用。
所述药学上可接受的载体是指药学上常规的载体，包括淀粉、蔗糖、微晶纤维素等填充剂，淀粉浆、羟丙纤维素、明胶、聚乙二醇等粘合剂，硬脂酸镁、微粉硅胶、聚乙二醇类等湿润剂，聚山梨脂、卵磷脂等吸收促进剂，伯洛沙姆、脂肪酸山梨坦、聚山梨脂等表面活性剂，还可以加入香味剂、甜味剂等其它辅剂。
所述的食品上可接受的载体可参见现有技术。
本发明所述的五环三萜类化合物及其衍生物可以以单位剂量形式给药，给药途径为肠内给药或非肠内给药，包括口服、肌肉注射、皮下注射、静脉注射等。
药物的剂型可以是固体制剂、半固体剂、液体制剂等，包括片剂、丸剂、粉剂、分散片、小药囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂、软胶囊、硬胶囊、无菌注射液、搽剂、栓剂等。
上述各种剂型可采用常规方法进行制备，例如使活性成分五环三萜类化合物或其衍生物与一种或多种载体混合，然后将其制成所需的剂型。
同现有技术相比，本发明的有益效果体现在：
(1)本发明提供了五环三萜类化合物及其衍生物，该五环三萜类化合物及其衍生物具有显著的拟神经生长因子的活性，且活性高；
(2)本发明提供的五环三萜类化合物及其衍生物为小分子化合物，能够通过血脑屏障，具有实际临床应用的前景。
(3)本发明提供的五环三萜类化合物及其衍生物可以在制备预防及治疗神经退行性疾病或者改善认知、学习记忆能力的食品和药品中获得应用。
附图说明
图1为加入化合物Ⅰ-1、Ⅰ-2、Ⅰ-3、Ⅰ-4、Ⅰ-5、Ⅰ-6经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为1,3μM)。
图2为加入化合物Ⅰ-7、Ⅰ-8、Ⅰ-9经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为3μM)。
图3为加入化合物Ⅰ-10、Ⅰ-11、Ⅰ-12、Ⅰ-13、Ⅰ-14、Ⅰ-15、Ⅰ-16、Ⅰ-17经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为1,3μM)。
图4为加入化合物Ⅰ-18、Ⅰ-19、Ⅰ-20、Ⅰ-21经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为3,10μM)。
图5为化合物Ⅰ-1，Ⅰ-5经48小时后，化合物引起PC12细胞神经突起伸长的显微照片a)0.5％DMSO为阴性对照；b)阳性对照NGF的浓度为40ng/mL；c)化合物I-1的浓度为1μM；d)化合物I-5的浓度为1μM。
具体实施方式
以下通过实施例和附图再对本发明的上述内容作进一步的详细说明，但不应将此理解为本发明上述主题的范围仅限于下述的实施例，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
化合物Ⅰ-1：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3,4-dihydroxyphenyl)acrylate
将酚羟基O-TBS保护的咖啡酸(A)(408mg,1mmol)，DCC(413mg,2mmol)和DMAP(122mg,1.0mmol)溶于10mL无水二氯甲烷中，冷致0℃，加入两个伯羟基O-TBS保护的3β,23,28-Triol olean-12-ene(B)(34.3mg,0.05mmol)，反应体系室温搅拌过夜。纯化后，得无色固体C 30mg，收率：56％。化合物结构如下所示：
化合物C(21.5mg,0.02mmol)溶于5mL甲醇中，加入樟脑磺酸(23mg,0.1mmol)。反应体系室温搅拌4小时。水淬灭，乙酸乙酯萃取，有机相饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸浓缩得粗产物，纯化后得无色固体12.4mg，收率：88％。
1H NMR(500MHz,CD3OD):7.53(d,J＝15.8Hz,1H),7.05(d,J＝2.0Hz,1H),6.96(dd,J＝8.0,2.0Hz,1H),6.79(d,J＝8.0Hz,1H),6.26(d,J＝15.8Hz,1H),5.22(t,J＝3.5Hz,1H),4.98(dd,J＝12.5,4.0Hz,1H),3.56(d,J＝11.0Hz,1H),3.38(d,J＝11.0Hz,1H),3.18(d,J＝11.0Hz,1H),3.13(d,J＝11.0Hz,1H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.85(s,3H)。
该化合物的结构式为：
实施例2
化合物Ⅰ-2：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-phenylacrylate；
合成方法同化合物Ⅰ-1，反应投料为：肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.65(d,J＝16.0Hz,1H),7.62(m,2H),7.43(m,3H),6.53(d,J＝16.0Hz,1H),5.23(t,J＝3.5Hz,1H),5.03(dd,J＝11.5.0,6.0Hz,1H),3.56(d,J＝11.0Hz,1H),3.39(d,J＝12.0Hz,1H),3.19(d,J＝11.0Hz,1H),3.14(d,J＝12.0Hz,1H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.87(s,3H).13C NMR(125MHz,CDCl3)167.8,145.8,141.8,134.5,130.3,128.9,128.1,123.4,117.9,75.8,69.8,64.7,49.1,47.9,47.8,43.8,43.4,43.0,41.2,39.2,38.1,37.7,35.3,33.8,33.1,32.3,31.8,26.6,26.6,24.6,24.1,23.5,22.9,18.8,17.3,16.5,13.9.HRMS:m/z[M+Na]+calcd forC39H56O4Na:611.4071,found:611.4063。
该化合物的结构式为：
实施例3
化合物Ⅰ-3：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3-hydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的3-羟基肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.07mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.63(d,J＝16.0Hz,1H),7.23(t,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,1H),7.00(t,J＝2.5Hz,1H),6.85(dd,J＝8.0,2.5Hz,1H),6.47(d,J＝16.0Hz,1H),5.21(t,J＝3.5Hz,1H),5.02(dd,J＝11.0,6.0Hz,1H),3.54(d,J＝11.0Hz,1H),3.38(d,J＝11.5Hz,1H),3.18(d,J＝11.0Hz,1H),3.11(d,J＝11.5Hz,1H),1.13(s,3H),1.02(s,3H),0.99(s,3H),0.88(s,3H),0.87(s,3H),0.86(s,3H).13C NMR(125MHz,CDCl3)168.2,159.5,146.3,145.8,136.1,131.5,123.4,121.9,119.2,118.1,115.5,75.1,69.9,65.2,49.1,47.3,46.9,43.8,43.1,42.5,41.6,39.2,38.3,37.3,35.8,33.3,33.1,32.4,31.8,26.4,26.4,24.6,24.1,24.0,22.7,18.6,17.8,16.5,13.5.HRMS:m/z[M+Na]+calcd forC39H56O5Na:627.4020,found:627.4027。
该化合物的结构式为：
实施例4
化合物Ⅰ-4：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(4-hydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的4-羟基肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.07mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.57(d,J＝16.0Hz,1H),7.41(d,J＝8.5Hz,2H),6.83(d,J＝8.5Hz,2H),6.27(d,J＝16.0Hz,1H),5.16(t,J＝3.5Hz,1H),4.97(dd,J＝11.5,5.0Hz,1H),3.40(d,J＝9.5Hz,1H),3.27(d,J＝10.0Hz,1H),3.16(d,J＝9.5Hz,1H),3.15(d,J＝10.0Hz,1H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)167.9,159.5,145.2,145.8,130.7,126.5,123.4,116.5,115.1,74.8,68.3,64.2,48.8,47.3,47.5,43.2,42.9,42.5,41.0,39.2,37.7,37.5,35.3,33.7,33.1,32.3,31.8,26.6,26.9,24.2,24.5,24.2,22.9,18.6,17.0,16.2,13.4.HRMS:m/z[M+Na]+calcd for C39H56O5Na:627.4020,found:627.4016。
该化合物的结构式为：
实施例5
化合物Ⅰ-5：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3,4,5-trihydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的3,4,5-三羟基肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.12mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.58(d,J＝16.0Hz,1H),6.72(s,2H),6.19(d,J＝16.0Hz,1H),5.21(t,J＝3.5Hz,1H),5.02(dd,J＝11.0,6.0Hz,1H),3.54(d,J＝11.0Hz,1H),3.38(d,J＝11.5Hz,1H),3.18(d,J＝11.0Hz,1H),3.11(d,J＝11.5Hz,1H),1.23(s,3H),1.07(s,3H),1.02(s,3H),0.90(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)167.4,146.1,145.8,145.3,136.4,128.7,124.0,115.4,107.1,76.6,69.9,65.8,49.7,48.3,47.8,43.8,43.6,43.4,41.7,39.2,38.2,37.7,35.7,33.9,33.7,32.3,31.8,26.8,26.6,24.6,24.4,24.2,22.9,18.9,17.6,16.7,13.9.HRMS:m/z[M+Na]+calcd for C39H56O7Na:659.3918,found:659.3926。
该化合物的结构式为：
实施例6
化合物Ⅰ-6：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3,5-dihydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的2,5-二羟基肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3)；7.53(d,J＝15.8Hz,1H),7.09(d,J＝2.0Hz,2H),6.51(d,J＝2.5Hz,1H),6.26(d,J＝15.8Hz,1H),5.17(t,J＝3.5Hz,1H),5.03(dd,J＝11.5,5.0Hz,1H),3.40(d,J＝10.0Hz,1H),3.30(d,J＝10.0Hz,1H),3.16(t,J＝10.0Hz,2H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)167.6,159.5,146.3,145.9,127.3,123.1,118.5,109.6,103.1,75.6,69.5,64.9,49.2,47.9,47.8,43.9,43.5,43.2,41.5,39.2,38.1,37.7,35.4,33.6,33.0,32.3,31.8,26.6,26.4,24.6,24.1,24.0,22.8,18.7,17.5,16.2,13.4.HRMS:m/z[M+Na]+calcd for C39H56O6Na:643.3969,found:643.3973。
该化合物的结构式为：
实施例7
化合物Ⅰ-7：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl 3-(3,4-dihydroxyphenyl)propanoate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的3,4-二羟基苯丙酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):6.72(d,J＝8.0Hz,1H),6.65(d,J＝2.0Hz,1H),6.62(dd,J＝5.0,2.0Hz,1H),5.16(t,J＝3.5Hz,1H),4.87(dd,J＝12.0,5.0Hz,1H),3.39(d,J＝9.5Hz,1H),3.24(d,J＝10.0Hz,1H),3.15(d,J＝9.5Hz,1H),3.08(d,J＝10.0Hz,1H),2.81(t,J＝8.0Hz,2H),2.51(t,J＝8.0Hz,2H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)174.2,146.5,145.7,143.8,133.0,123.0,120.1,116.5,116.0,76.6,69.5,64.6,49.1,47.4,47.6,43.9,43.6,43.3,41.5,39.2,38.1,37.5,37.1,35.3,33.7,33.1,32.3,31.8,31.2,26.4,25.9,24.6,24.1,23.7,22.9,18.6,17.5,16.2,14.1.HRMS:m/z[M+Na]+calcd for C39H58O6Na:645.4126,found:645.4119。
该化合物的结构式为：
实施例8
化合物Ⅰ-8：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl2-(3,4-dihydroxyphenyl)acetate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的3,4-二羟基苯乙酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):6.72(m,3H),5.15(t,J＝3.5Hz,1H),4.84(dd,J＝11.5,5.0Hz,1H),3.38(s,2H),3.41(d,J＝9.5Hz,1H),3.14(d,J＝10.0Hz,1H),3.12(d,J＝9.5Hz,1H),2.88(d,J＝10.0Hz,1H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)173.5,145.8,145.4,144.1,125.0,123.4,121.3,118.4,117.2,77.8,69.8,65.7,49.1,47.8,47.6,43.6,43.2,42.9,41.1,40.6,39.2,38.1,37.5,34.3,33.3,33.1,32.3,31.6,27.6,26.6,24.6,24.3,23.6,22.9,18.7,17.3,16.5,14.1.HRMS:m/z[M+Na]+calcd for C38H56O6Na:631.3969,found:631.3962。
该化合物的结构式为：
实施例9
化合物Ⅰ-9：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl 3,4-dihydroxybenzoate；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的3,4-二羟基苯甲酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.43(dd,J＝8.0,2.0Hz,1H),7.40(d,J＝2.0Hz,1H),6.81(d,J＝8.0Hz,1H),5.21(t,J＝3.5Hz,1H),4.63(dd,J＝11.5,5.0Hz,1H),3.40(d,J＝9.5Hz,1H),3.33(d,J＝9.5Hz,1H),3.16(t,J＝9.5Hz,2H),1.22(s,3H),1.06(s,3H),1.05(s,3H),1.03(s,3H),0.94(s,3H),0.90(s,3H).13C NMR(125MHz,CDCl3)168.5,152.4,146.3,146.0,124.7,123.6,122.5,117.1,115.5,74.8,69.8,64.3,48.6,47.9,47.5,43.8,43.7,43.1,41.6,38.3,37.3,36.2,35.3,33.7,33.1,32.3,31.6,27.6,26.4,24.1,23.5,23.1,22.9,18.6,17.3,16.8,13.5.HRMS:m/z[M+Na]+calcd for C37H54O6Na:617.3813,found:617.3819。
该化合物的结构式为：
实施例10
化合物Ⅰ-10：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3-nitro-4-hydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：3-硝基-4-羟基-肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):8.24(d,J＝2.0Hz,1H),7.98(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝15.8Hz,1H),7.43(d,J＝8.5Hz,1H),6.71(d,J＝15.8Hz,1H),5.21(t,J＝3.5Hz,1H),5.02(dd,J＝11.0,6.0Hz,1H),3.54(d,J＝10.0Hz,1H),3.38(d,J＝10.0Hz,1H),3.18(d,J＝10.0Hz,1H),3.11(d,J＝10.0Hz,1H),1.23(s,3H),1.07(s,3H),1.02(s,3H),0.90(s,6H),0.85(s,3H).13C NMR(125MHz,CDCl3)167.2,157.1,148.3,145.5,137.6,135.5,129.2,125.9,123.4,118.5,117.6,75.6,69.8,64.7,49.1,47.9,47.8,43.8,43.7,43.4,41.5,39.2,38.2,37.7,35.3,33.5,33.1,32.4,31.8,26.9,26.6,24.6,24.4,24.1,22.9,18.8,17.3,15.5,14.3.HRMS:m/z[M+Na]+calcd for C39H55O7NNa:672.3871,found:672.3883。
该化合物的结构式为：
实施例11
化合物Ⅰ-11：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(3-amino-4-hydroxyphenyl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：3-氨基-4-羟基-肉桂酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.50(d,J＝15.5Hz,1H),6.97(d,J＝1.5Hz,1H),6.79(dd,J＝8.0,1.5Hz,1H),6.68(d,J＝8.0Hz,1H),6.21(d,J＝15.5Hz,1H),5.23(t,J＝3.5Hz,1H),5.03(dd,J＝11.0,6.0Hz,1H),3.56(d,J＝10.0Hz,1H),3.39(d,J＝11.5Hz,1H),3.19(d,J＝10.0Hz,1H),3.14(d,J＝11.5Hz,1H),1.25(s,3H),1.09(s,3H),1.04(s,3H),0.92(s,6H),0.87(s,3H).13C NMR(125MHz,CDCl3)167.2,147.2,145.6,141.7,136.1,127.4,123.9,123.6,117.5,117.1,114.4,75.5,69.8,64.4,49.6,47.9,47.1,43.8,43.6,43.4,41.7,38.2,38.0,36.7,35.3,33.7,33.1,32.3,31.8,27.6,26.9,24.6,23.7,23.5,22.9,18.8,17.3,16.9,14.3.HRMS:m/z[M+Na]+calcd for C39H57O5NNa:642.4129,found:642.4116。
该化合物的结构式为：
实施例12
化合物Ⅰ-12：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(pyridine-3-yl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：反3-(3-吡啶)丙烯酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):8.73(d,J＝2.0Hz,1H)8.53(dd,J＝5.0,2.0Hz,1H),8.12(dd,J＝8.0,2.0Hz,1H),7.65(d,J＝16.5Hz,1H),7.48(dd,J＝8.0,5.0Hz,1H),6.64(d,J＝16.5Hz,1H),5.23(t,J＝3.5Hz,1H),5.18(dd,J＝12.0,5.0Hz,1H),3.59(d,J＝11.0Hz,1H),3.34(d,J＝10.0Hz,1H),3.24(d,J＝11.0Hz,1H),3.18(d,J＝10.0Hz,1H),1.20(s,3H),1.05(s,3H),0.99(s,3H),0.91(s,3H),0.90(s,6H).13C NMR(125MHz,CDCl3)167.0,149.9,148.7,146.5,145.7,134.1,129.9,125.5,123.4,120.0,75.8,69.7,64.6,49.1,47.9,47.8,43.8,43.6,43.1,41.8,39.2,38.1,37.5,35.3,33.7,33.1,32.3,31.8,26.8,26.6,24.6,24.1,24.0,22.9,18.8,17.3,16.4,13.8.HRMS:m/z[M+Na]+calcd forC38H55O4NNa:612.4023,found:612.4023。
该化合物的结构式为：
实施例13
化合物Ⅰ-13：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl(2E)-3-(furan-3-yl)acrylate；
合成方法同化合物Ⅰ-1，反应投料为：反3-(3-呋喃基)丙烯酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.47(d,J＝1.5Hz,1H),7.37(d,J＝15.5Hz,1H),6.59(d,J＝3.0Hz,1H),6.46(dd,J＝3.0,1.5Hz,1H),6.29(d,J＝15.5Hz,1H),5.20(t,J＝3.5Hz,1H),4.95(dd,J＝11.5,5.0Hz,1H),3.56(d,J＝10.0Hz,1H),3.26(d,J＝10.0Hz,1H),3.21(d,J＝11.0Hz,1H),3.14(d,J＝11.0Hz,1H),1.18(s,3H),1.03(s,3H),0.95(s,3H),0.89(s,3H),0.87(s,3H),0.77(s,3H).13C NMR(125MHz,CDCl3)166.5,151.3,144.7,144.3,130.6,122.6,116.9,114.5,112.4,74.8,70.0,64.2,47.8,46.6,46.5,42.7,42.0,41.9,40.0,38.3,37.2,36.5,34.3,33.4,32.2,31.2,29.9,25.9,25.7,23.8,23.2,,22.2,18.3,18.1,17.6,16.1,13.3.HRMS:m/z[M+Na]+calcd for C37H54O5Na:601.3863,found:601.3855。
该化合物的结构式为：
实施例14
化合物Ⅰ-14：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl nicotinate；
合成方法同化合物Ⅰ-1，反应投料为：烟酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):9.22(s,1H),8.80(s,1H),8.31(d,J＝8.0Hz,1H),7.43(s,1H),5.23(t,J＝3.5Hz,1H),5.17(dd,J＝12.0,4.5Hz,1H),3.59(d,J＝10.0Hz,1H),3.34(d,J＝10.0Hz,1H),3.24(d,J＝10.0Hz,1H),3.18(d,J＝10.0Hz,1H),1.20(s,3H),1.05(s,3H),0.99(s,3H),0.91(s,3H),0.90(s,6H).13C NMR(125MHz,CDCl3)164.5,152.8,150.4,144.4,137.6,123.9,122.5,120.1,76.2,69.9,64.2,47.8,46.6,46.5,42.6,42.3,42.0,39.9,38.2,37.2,36.5,34.3,33.4,32.2,31.2,31.1,25.9,25.7,23.8,23.2,22.1,18.3,17.9,17.0,16.1,13.6.HRMS:m/z[M+Na]+calcd for C36H53O4NNa:586.3867,found:586.3859。
该化合物的结构式为：
实施例15
化合物Ⅰ-15：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl furan-3-carboxylate；
合成方法同化合物Ⅰ-1，反应投料为：3-糠酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.60(s,1H),7.18(d,J＝3.5Hz,1H),6.52(d,J＝3.5Hz,1H),5.20(t,J＝3.5Hz,1H),5.12(dd,J＝11.5,5.0Hz,1H),3.55(d,J＝10.0Hz,1H),3.41(d,J＝10.0Hz,1H),3.22(d,J＝10.0Hz,1H),3.01(d,J＝10.0Hz,1H),1.18(s,3H),1.03(s,3H),0.95(s,3H),0.89(s,3H),0.87(s,3H),0.77(s,3H).13C NMR(125MHz,CDCl3)162.2,149.3,145.6,143.7,123.5,119.5,111.6,75.6,67.8,63.7,48.1,46.7,46.2,43.8,42.6,42.1,41.3,39.2,38.1,37.7,35.3,33.7,33.1,32.3,31.8,26.8,26.6,24.6,24.1,24.0,22.9,18.8,17.3,15.7,13.6.HRMS:m/z[M+Na]+calcd for C35H52O5Na:575.3707,found:575.3714。
该化合物的结构式为：
实施例16
化合物Ⅰ-16：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl butyrate；
合成方法同化合物Ⅰ-1，反应投料为：丁酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):5.19(t,J＝3.5Hz,1H),4.89(dd,J＝12.0,5.0Hz,1H),3.55(d,J＝9.5Hz,1H),3.38(d,J＝10.0Hz,1H),3.21(d,J＝9.5Hz,1H),2.98(d,J＝10.0Hz,1H),2.31(t,J＝7.5Hz,2H),1.25(s,3H),1.17(s,3H),0.99(s,3H),0.94(t,J＝7.5Hz,3H),0.89(s,3H),0.87(s,3H),0.68(s,3H).13C NMR(125MHz,CDCl3)164.5,144.4,122.5,76.3,69.9,64.2,47.8,46.6,46.5,42.6,42.3,42.0,40.0,38.3,37.2,36.5,34.3,33.4,32.2,31.2,31.1,30.0,26.0,25.9,25.7,23.8,23.2,22.1,18.3,17.9,17.0,16.1,13.6.HRMS:m/z[M+Na]+calcd for C34H56O4Na:551.4071,found:551.4077。
该化合物的结构式为：
实施例17
化合物Ⅰ-17：(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl hexanoate；
合成方法同化合物Ⅰ-1，反应投料为：己酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和化合物B(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.05mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):5.20(t,J＝3.5Hz,1H),4.90(dd,J＝12.0,5.0Hz,1H),3.55(d,J＝9.5Hz,1H),3.38(d,J＝10.0Hz,1H),3.21(d,J＝9.5Hz,1H),2.99(d,J＝10.0Hz,1H),2.31(t,J＝7.5Hz,2H),1.25(s,3H),1.16(s,3H),0.97(s,3H),0.94(t,J＝7.5Hz,3H),0.89(s,3H),0.87(s,3H),0.78(s,3H).13C NMR(125MHz,CDCl3)166.5,144.7,122.6,74.8,70.0,64.2,47.8,46.6,46.5,42.7,42.1,42.0,40.0,38.3,37.2,36.5,34.3,33.4,32.2,32.1,31.2,31.1,29.9,26.1,25.9,25.7,23.8,23.2,22.2,18.3,17.9,17.0,16.1,14.4,13.5.HRMS:m/z[M+Na]+calcd for C36H60O4Na:579.4384,found:579.4389。
该化合物的结构式为：
实施例18
化合物Ⅰ-18：(3S,4R)-23,28-Diacetoxyolean-12-en-3-yl(2E)-3-(3,4-diacetoxyphenyl)acrylate；
25mL圆底烧瓶中用2mL二氯甲烷和2mL吡啶溶解化合物Ⅰ-1(10mg)加入0.5mgDMAP，搅拌，加入100mL乙酸酐，旋干反应液，用水和乙酸乙酯进行溶剂分配，回收酯层，纯化后得到无色化合物(13mg)，收率：96％。
1H NMR(500MHz,CDCl3):7.57(d,J＝16.0Hz,1H),7.39(dd,J＝9.0,2.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.21(d,J＝9.0Hz,1H),6.34(d,J＝16.0Hz,1H),5.21(t,J＝3.0,1H),4.94(dd,J＝12.0,5.0Hz,1H),4.00(dd,J＝25.0,10.0Hz,2H),3.68(dd,J＝12.0,9.0Hz,2H),2.30(s,3H),2.30(s,3H),2.07(s,3H),2.06(s,3H),1.15(s,3H),1.01(s,3H),0.95(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,3H).13C NMR(125MHz,CDCl3)171.4,171.0,168.1,168.0,166.1,143.7,143.4,142.7,142.4,133.3,126.4,123.9,122.7,122.7,119.7,77.2,70.8,65.7,50.9,47.8,47.6,46.1,42.5,41.5,40.7,39.7,37.9,36.6,35.7,34.0,33.2,32.2,31.4,30.9,25.8,25.5,23.5,23.1,22.1,21.1,21.0,20.7,20.6,18.0,16.7,16.0,13.2.HRMS:m/z[M+Na]+calcd for C47H64O10Na:811.4392,found:811.4422。
该化合物的结构式为：
实施例19
化合物Ⅰ-19：(3S,4R)-23,28-Diacetoxyolean-12-en-3-yl(2E)-3-(3,4-dihydroxyphenyl)acrylate；
25mL圆底烧瓶中用2mL重蒸甲醇溶解10mg甲醇钠，加入10mg化合物Ⅰ-18，搅拌反应30min，加入10mL冰醋酸停止反应，旋干反应液，用水和乙酸乙酯进行溶剂分配，回收酯层，纯化后得到无色化合物(8mg)，收率：71％。
1H NMR(500MHz,CDCl3):7.49(d,J＝16.0Hz,1H),7.04(s,1H),6.90(d,J＝9.0Hz,1H),6.82(d,J＝9.0Hz,1H),6.18(d,J＝16.0Hz,1H),5.20(t,J＝3.0,1H),4.93(dd,J＝12.0,5.0Hz,1H),4.08(d,J＝10.0Hz,1H),3.98(d,J＝10.0Hz,1H),3.72(d,J＝10.0Hz,1H),3.69(d,J＝10.0Hz,1H),2.08(s,3H),2.07(s,3H),1.15(s,3H),1.00(s,3H),0.94(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,3H).13C NMR(125MHz,CDCl3)171.8,171.3,167.2,146.6,145.1,144.2,143.6,127.2,122.7,122.3,115.5,115.3,114.2,74.6,70.9,65.9,50.9,47.8,47.6,46.2,42.5,41.6,40.8,39.7,37.9,36.6,35.8,33.9,33.2,32.1,31.4,30.9,25.9,25.5,23.5,23.2,21.1,21.0,18.0,16.7,16.0,14.2,13.3.HRMS:m/z[M+Na]+calcd for C43H60O8Na:727.4180,found:727.4212。
该化合物的结构式为：
实施例20
化合物Ⅰ-20：(3S)-3-(3,4-Dihydroxycinnamoyl)oxyolean-12-en-28-oic acid；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的咖啡酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和伯羟基O-TBS保护的二羟基齐墩果烷(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.55(d,J＝16.0Hz,1H),7.09(d,J＝2.0Hz,1H),7.01(dd,J＝8.0,2.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.26(d,J＝16.0Hz,1H),5.19(t,J＝3.0,1H),4.62(dd,J＝8.0,6.0Hz,1H),3.57(d,J＝11.0Hz,1H),3.24(d,J＝8.0Hz,1H),1.17(s,3H),0.98(s,3H),0.94(s,3H),0.93(s,3H),0.91(s,3H),0.89(s,3H),0.88(s,3H)。
该化合物的结构式为：
实施例21
化合物Ⅰ-21：3O-(3,4-Dihydroxycinnamoyl)erythrodiol；
合成方法同化合物Ⅰ-1，反应投料为：酚羟基O-TBS保护的咖啡酸(1mmol)，DCC(2mmol)，DMAP(1.0mmol)和齐墩果酸(0.05mmol)。得到的产物取0.02mmol溶于5mL甲醇中，加入0.1mmol樟脑磺酸。
1H NMR(500MHz,CDCl3):7.55(d,J＝16.0Hz,1H),7.09(d,J＝2.0Hz,1H),7.01(dd,J＝8.0,2.0Hz,1H),6.87(d,J＝8.0Hz,1H),6.26(d,J＝16.0Hz,1H),5.29(t,J＝3.0,1H),4.64(dd,J＝11.5,5.0Hz,1H),2.83(dd,J＝10.0,4.0Hz,1H),1.15(s,3H),0.97(s,3H),0.96(s,6H),0.93(s,3H),0.91(s,3H),0.77(s,3H)。
该化合物的结构式为：
实施例22性能实验
生物活性鉴定：在老年痴呆动物模型中，研究发现NGF能阻止或减少神经元的退变，一定程度可阻止AD进展，具有促进神经生长和神经保护作用。由于PC12细胞具有神经细胞的一般特征，在NGF的作用下PC12细胞会停止分裂，长出突起，转化成神经元样细胞。因此，能导致PC12细胞转化成神经元样细胞的化合物具有预防及治疗老年性痴呆的应用价值。
实验方法：
(1)PC12细胞的培养：接20×104个PC12细胞于100mm的培养皿中，含10ml DMEM培养基(其中含10％马血清、5％胎牛血清)，两天后更换一次培养基，再过三天继代。先用PBS将细胞洗两次，再加入10ml PBS于培养皿中，在37℃，5％CO2的培养箱内培养10分钟，吹洗，转移到15ml的一次性离心管，离心后血球计数板上计数。24孔细胞培养板每孔先加入1ml含血清的DMEM培养基，细胞计数后，每孔接2×104个细胞，CO2培养箱培养24小时后加样。
(2)活性测试：以0.5％DMSO为阴性对照，NGF 40ng/mL为阳性对照，将化合物Ⅰ-1，Ⅰ-2，Ⅰ-3，Ⅰ-4，Ⅰ-5，Ⅰ-6，Ⅰ-7，Ⅰ-8，Ⅰ-9，Ⅰ-10，Ⅰ-11，Ⅰ-12，Ⅰ-13，Ⅰ-14，Ⅰ-15，Ⅰ-16，Ⅰ-17，Ⅰ-18，Ⅰ-19，Ⅰ-20，Ⅰ-21配置成不同浓度的DMSO溶液。用1ml含0.5％DMSO和样品的DMEM溶液(不含血清)将24孔细胞板的每孔原培养基取代后，放入37℃，5％CO2的培养箱中培养。倒置显微镜下每隔24小时、连续6天观察细胞形态变化，记录细胞分化率NA(神经突起长于胞体直径一倍的细胞数目与视野下总细胞数目的比值)，每个视野下约100个细胞，随机选取3处，并统计作图。
(3)实验结果：
图1为加入化合物Ⅰ-1、Ⅰ-2、Ⅰ-3、Ⅰ-4、Ⅰ-5、Ⅰ-6经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为1,3μM)。
图2为加入化合物Ⅰ-7、Ⅰ-8、Ⅰ-9经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为3μM)。
图3为加入化合物Ⅰ-10、Ⅰ-11、Ⅰ-12、Ⅰ-13、Ⅰ-14、Ⅰ-15、Ⅰ-16、Ⅰ-17经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为1,3μM)。
图4为加入化合物Ⅰ-18、Ⅰ-19、Ⅰ-20、Ⅰ-21经48小时后PC12细胞的神经突起分化率(阴性对照0.5％DMSO，阳性对照为40ng/ml NGF，受试化合物的浓度为3,10μM)。
图5为化合物Ⅰ-1，Ⅰ-5经48小时后，化合物引起PC12细胞神经突起伸长的显微照片a)0.5％DMSO为阴性对照；b)阳性对照NGF的浓度为40ng/mL；c)化合物I-1的浓度为1μM；d)化合物I-5的浓度为1μM。
图1-图4中，纵坐标为神经突起分化率(％)。
结果发现，在1μM、3μM的浓度下，48小时后所测试的本发明的五环三萜类化合物及其衍生物均显示出良好的NGF-mimics(拟神经生长因子)活性，在1μM活性浓度下，化合物I-5的活性最佳(图1)。
Claims (3)
1.一种五环三萜类化合物及其衍生物，其特征在于，结构通式如式（Ⅰ）所示：
具体选自如下化合物：
2.权利要求1所述的一种五环三萜类化合物及其衍生物在制备预防、治疗神经退行性疾病的药品中的应用。
3.根据权利要求2所述的应用，其特征在于，所述药物以五环三萜类化合物及其衍生物作为活性成分与药学上可接受的载体制备获得。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011009032A1 (en) * | 2009-07-16 | 2011-01-20 | Pacific Arrow Limited | Inhibiting the invasion and metastasis of cancer cells |
| CN103288914A (zh) * | 2013-06-16 | 2013-09-11 | 浙江大学 | 中药饿蚂蝗提取物的制备及抗老年性痴呆药物用途 |
| CN104224796A (zh) * | 2013-06-16 | 2014-12-24 | 浙江大学 | 齐墩果烷型三萜类酯衍生物抗神经退行性药物用途 |
| CN104725456A (zh) * | 2013-12-24 | 2015-06-24 | 中国药科大学 | 五环三萜类胆固醇酯转运蛋白抑制剂、其药物组合物及医药用途 |
-
2018
- 2018-07-25 CN CN201810829415.8A patent/CN108840899B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011009032A1 (en) * | 2009-07-16 | 2011-01-20 | Pacific Arrow Limited | Inhibiting the invasion and metastasis of cancer cells |
| CN103288914A (zh) * | 2013-06-16 | 2013-09-11 | 浙江大学 | 中药饿蚂蝗提取物的制备及抗老年性痴呆药物用途 |
| CN104224796A (zh) * | 2013-06-16 | 2014-12-24 | 浙江大学 | 齐墩果烷型三萜类酯衍生物抗神经退行性药物用途 |
| CN104725456A (zh) * | 2013-12-24 | 2015-06-24 | 中国药科大学 | 五环三萜类胆固醇酯转运蛋白抑制剂、其药物组合物及医药用途 |
Non-Patent Citations (2)
| Title |
|---|
| 《Olean-12-en-28-oic acid, 3-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-propen-1-yl]oxy]-, (3β)- (CA INDEX NAME)》;STN;《REGISTRY数据库》;19850810;全文 * |
| 《Olean-12-ene-3,28-diol, 3-[(2E)-3-(3,4-dihydroxyphenyl)-2-propenoate],(3β)- (CA INDEX NAME)》;STN;《REGISTRY数据库》;19880319;全文 * |
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