CN117551161A - 一类五环三萜类化合物在治疗神经退行性疾病中的用途 - Google Patents
一类五环三萜类化合物在治疗神经退行性疾病中的用途 Download PDFInfo
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- CN117551161A CN117551161A CN202311516484.0A CN202311516484A CN117551161A CN 117551161 A CN117551161 A CN 117551161A CN 202311516484 A CN202311516484 A CN 202311516484A CN 117551161 A CN117551161 A CN 117551161A
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- neurodegenerative diseases
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Abstract
本发明公开一类五环三萜类化合物在预防和/或治疗神经退行性疾病方面的功能和用途，该类化合物是由锁阳药材中分离提取得到的，发明人在对该类化合物药理活性评价过程中发现：该类化合物对谷氨酸诱导的神经细胞损伤有显著的保护作用，对氧糖剥夺诱导的神经细胞损伤有显著的保护作用，因此可用于神经退行性疾病，如中风、脑损伤、肌萎缩侧索硬化症、亨廷顿病、帕金森病、阿尔茨海默病的治疗和预防，可以开发成药品。
Description
技术领域
本发明涉及医药技术领域，一类五环三萜类化合物在制备预防和/或治疗神经退行性疾病的药物方面的用途。
背景技术
神经退行性疾病，以特异性神经元的大量丢失为主要特征，是一类进行性发展的致残严重可致死的复杂疾病。可分为急性神经退行性病和慢性神经退行性病，前者主要包括中风(stroke)、脑损伤(brain injury)；后者主要包括肌萎缩侧索硬化症(ALS)、亨廷顿病(HD)、帕金森病(PD)、阿尔茨海默病(AD)等。随着人口老龄化，神经退行性疾病已变成现代社会严重的医学问题。神经退行性疾病致病因素多样，发病机制复杂，因而用于治疗神经退行性疾病的药物种类也较多，其中的神经保护药物，包括抗氧化药物、谷氨酸受体拮抗剂，钙离子拮抗剂、抗炎药物及抗凋亡药物等是一类重要的治疗措施。
中医学认为，肾通于脑，补肾可以防治中枢神经系统疾病。而大量的现代医学研究也提示，补肾是一种非常有前途的治疗神经退行性疾病的手段。
中药锁阳是锁阳科植物锁阳Cynomorium songaricum Rupr.的干燥肉质茎。锁阳具有补肾阳，益精血，润肠通便的功效，用于肾阳不足，精血亏虚，腰膝酸软，阳痿滑精，肠燥便秘。作为常用补益药物，锁阳主要分布于新疆、青海、甘肃、宁夏、内蒙古、陕西等荒漠地带，素有“沙漠人参”之美称。锁阳作为中医中药中的重要补肾阳药物，近年来对锁阳提取物在抗衰老、神经保护以及抗氧化等药理活性方面有了较多的进展，特别是有研究表明：锁阳提取物的乙酸乙酯提取物(郑玲艳、韩瑞兰,2016)可明显改善D-半乳糖致衰老和东莨菪碱致衰老小鼠的学习、记忆以及记忆保持能力。但是锁阳中的活性成分研究十分薄弱，目前尚无锁阳中神经保护活性成分的报道。
发明人在前期对锁阳化学成分研究基础上，发现锁阳中的大部分五环三萜类成分，包括锁阳中独有的丙二酸酯型三萜如化合物16和对羟基桂皮酸酯型三萜如化合物19-23，有显著的神经保护活性，因而在治疗神经退行性疾病方面有很好的应用前景。
发明内容
本发明要解决的技术问题是，提供一类五环三萜类化合物、含有其的药物组合物在制备预防和/或治疗神经退行性疾病的产品中的应用，并进一步提供该类化合物的制备方法。
为解决本发明的技术问题，本发明采用如下技术方案：
本发明第一方面提供了一类来源于锁阳的五环三萜类化合物在制备预防和/或治疗神经退行性疾病产品中的应用，该类化合物结构如下：
本发明第二方面提供含有第一方面所述的五环三萜类化合物的药物组合物在制备预防和/或治疗神经退行性疾病产品中的应用，该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型、复乳和脂质体)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物或含有它的药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物或含有它的药物组合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将本发明化合物或含有它的药物组合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将本发明化合物或含有它的药物组合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物或含有它的药物组合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物或含有它的药物组合物的胶囊剂。
为将本发明化合物或含有它的药物组合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
为将本发明化合物或含有它的药物组合物制成脂质体，可以用磷脂和胆固醇为载体材料。磷脂可以是磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二棕榈酰乙醇胺、二油酰磷脂酰胆碱、二油酰磷脂酰甘油、磷脂酰乙醇胺及鞘磷脂、磷脂酸、磷脂酰肌醇、脂酰丝氨酸和磷脂酰甘油、十八胺。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物或含有它的药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选为0.1-100mg/kg体重，更优选为1-6 0mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或药物组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
上述神经退行性疾病包括但不限于中风、脑损伤、肌萎缩侧索硬化症、亨廷顿病、帕金森病、阿尔茨海默病。
本发明第一方面和第二方面所述的产品包括但不限定于药品。
本发明第三方面是提供第一方面和第二方面所述的五环三萜类化合物的制备方法，包括以下步骤：锁阳药材95％乙醇回流提取，浓缩后浸膏通过有机溶剂萃取、硅胶柱层析、凝胶柱层析、反相硅胶柱层析及制备型HPLC分离纯化，得到上述化合物，经各种谱学手段分析鉴定其结构，为五环三萜类化合物，主要为乌苏烷型和齐墩果烷型。
其中所述的有机溶剂萃取，为本领域内公知的方法。将提取物悬浮于水中，可以用乙酸乙酯、氯仿、二氯甲烷、石油醚以及氯仿-甲醇(1:1)进行萃取；萃取次数为1-3次，优选的，萃取3次。
其中所述的大孔吸附树脂为本领域内公知的非极性、弱极性、中极性、极性和强极性大孔吸附树脂；优选的，使用非极性、弱极性和中极性大孔吸附树脂。
其中所述的大孔吸附树脂按照结构来讲，为本领域内公知的苯乙烯型、苯乙烯二乙烯基苯型、交联聚苯乙烯型、苯乙烯腈型、甲基苯乙烯型、甲基丙烯酸酯型、甲基丙烯酸型、丙烯酸型、丙烯酰胺型、乙烯吡咯烷酮型、亚砜型、苯酚-甲醛型或氧化氮型；优选的，使用苯乙烯型、丙烯酸酯型或甲基丙烯酸酯型大孔吸附树脂。
其中所述的大孔吸附树脂具体的型号包括但并不限于D101，DA201，D301，D3520，D4006，D4020，H103，H107，H30，H60，AB-8，X-5，NKA，Diaion HP-20，Sepabeads SP-700，HP2MGL，HPD100，HPD722，HPD-600，HPD-826,ADS-17，Amberlite XAD-4，XAD-1600等。
大孔吸附树脂洗脱溶剂选用50％～95％的乙醇，洗脱2～4个柱体积；优选的，使用70～95％乙醇进行洗脱。
其中所述的硅胶柱层析，为本领域内公知的方法。将萃取物蒸干后，溶解于氯仿或甲醇中，加入适量硅胶，拌匀干燥后，装到硅胶柱上，选用氯仿-甲醇、氯仿-丙酮、石油醚-丙酮、二氯甲烷-甲醇、二氯甲烷-丙酮等洗脱溶剂系统，进行梯度洗脱；优选的，使用氯仿-甲醇，二氯甲烷-甲醇为洗脱溶剂。
其中所述的凝胶柱层析，可选用Sephdex LH-20，HW-40等型号的凝胶，选用甲醇、氯仿-甲醇(2:1)、石油醚-氯仿-甲醇(5:5:1)为洗脱溶剂。
其中所述的反相硅胶柱层析，通常选用反相C18、C8等填料，以甲醇-水或乙腈-水为流动相；优选的，使用C18为填料，甲醇-水为流动相。
其中所述的制备型HPLC，通常选用反相C18、C8等填料，以甲醇-水或乙腈-水为流动相，可根据需要，在流动相中加入0.1-1％的甲酸、乙酸、三氟乙酸等。
有益技术效果：
1，本发明提供一类五环三萜类化合物在预防或治疗神经退行性疾病方面的新用途。
2，实验证明本发明所述的化合物在药理上具有以下两方面显著活性：一，该类化合物可保护谷氨酸诱导的神经细胞损伤；二，该类化合物可显著保护氧糖剥夺诱导的神经细胞损伤。
3，该类化合物的制备方法成熟，简单易得。
具体实施方式
下面的实施例及药理活性实验用于进一步说明本发明，但这并不意味着对本发明的任何限制。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述实施例中，部分物质的全称或相应的中文名称如下：
UV:紫外-可见光谱
IR:红外光谱
FT-IR:傅里叶变换红外光谱
ODS:碳十八键合硅胶
ESIHRMS:电喷雾高分辨质谱
ESIMS:电喷雾质谱
1H-NMR:核磁共振氢谱
13C-NMR:核磁共振碳谱
下述实施例中所述室温如本领域常规所述，一般指15～25℃。
实施例1.五环三萜类化合物的制备方法
60kg干燥锁阳，粉碎后用提取罐提取，95％乙醇回流提取3次，每次2小时，过滤后收集上清，减压回收乙醇得到粗浸膏8.4kg。锁阳浸膏水分散后分别用氯仿萃取，氯仿部位回收溶剂，得浸膏1.5kg。将氯仿部位与硅胶1:1拌样，上样至硅胶层析柱，采用氯仿-甲醇(1:0→1:1)梯度洗脱，TLC检测三萜成分，收集三萜富集部位。回收溶剂后经硅胶柱层析、ODS反相硅胶柱层析、Sephadex LH-20凝胶柱层析和制备型HPLC，反复纯化得到化合物1(11.5mg)、2(1.95mg)、3(7.3mg)、4(3.42mg)、5(7mg)、6(2.6mg)、7(5.1mg)、8(5g)、9(1.2mg)、10(2.5mg)、11(5.51mg)、12(4.1mg)、13(3.3mg)、14(3.0mg)、15(2.9mg)、16(13.8mg)、18(4mg)、19(14.1mg)、20(3.41mg)、21(3.06mg)、22(30.8mg)、23(8.1mg)，经各种波谱学手段分析鉴定其结构，为五环三萜类化合物。
上述化合物的波谱信息及核磁信号归属如下：
化合物1：白色粉末，+33.1(c 0.07,CH3CN).UV(CH3CN)λmaxnm(logε):191(3.95),228(3.86).CD(c 0.07,CH3CN)Δε209-3.72,Δε235 9.88,Δε343-1.95.IRνmax 3453,2951,1699,1662cm-1.(-)-ESIHRMS m/z 467.3159[M-H]-(calcd 467.3167for C30H43O4-).1H-NMR和13C-NMR数据见表1和表2.
化合物2：白色粉末，-183.7(c 0.02,CH3CN).CD(c 0.02,CH3CN)Δε215-2.00.IRνmax3276,2959,1693cm-1.(-)-ESIHRMS m/z 455.3506[M-H]-(calcd 455.3531forC30H47O3-).1H-NMR和13C-NMR数据见表1和表2.
化合物3：白色粉末，+28.5(c 0.1,CH3CN).CD(c 0.1,CH3CN)Δε222-1.39.IRνmax2925,1735,1690cm-1.(-)-ESIHRMS m/z 555.3682[M-H]-(calcd 555.3691forC34H51O6 -).1H-NMR(500MHz,CDCl3)δ3.75(3H,s,H-4'),3.38(2H,s,H-2').13C-NMR(125MHz,CDCl3)δ167.2(C-3'),166.3(C-1'),52.5(C-4'),41.8(C-2').其他1H-NMR和13C-NMR数据见表1和表2.
化合物4：白色粉末，+27.8(c 0.07,CH3CN).CD(c 0.07,CH3CN)Δε221-1.22.IRνmax3230,2924,1757,1730,1692cm-1.(-)-ESIHRMS m/z 556.3699[M-H]-(calcd555.3691for C34H51O6-).1H-NMR(500MHz,CDCl3)δ3.68(3H,s,H-4'),3.31(2H,s,H-2').13C-NMR(125MHz,CDCl3)δ166.2(C-3'),165.2(C-1'),51.4(C-4'),40.6(C-2').其他1H-NMR和13C-NMR数据见表1和表2.
表1化合物1～4的1H-NMR数据(δin ppm)
#偶合常数从HMQC谱中读取
测定于a500MHz in CDCl3 or b600 MHz in Pyridine-d5.
表2 1～4的13C-NMR数据(δin ppm)
测定于a125 MHz in CDCl3 or b150 MHz in Pyridine-d5.
化合物5：白色粉末，(-)-ESIMS m/z 467[M-H]-.1H-NMR(500MHz,CDCl3)δ7.02(1H,d,J＝10.1Hz,H-1),5.81(1H,d,J＝10.1Hz,H-2),5.42(1H,t,J＝3.7Hz,H-12),4.20(1H,dd,J＝11.5,5.1Hz,H-15),2.82(1H,dd,J＝13.7,4.0Hz,H-18),1.17(3H,s,H-27),1.16(3H,s,H-23),1.14(3H,s,H-26),1.07(3H,s,H-24),0.94(3H,s,H-25),0.92(3H,s,H-30),0.90(3H,s,H-29)；13C-NMR(125MHz,CDCl3)δ205.3(C-3),183.0(C-28),158.8(C-1),144.7(C-13),125.4(C-2),124.0(C-12),68.2(C-15),53.2(C-5),47.8(C-14),46.0(C-17),45.1(C-19),44.6(C-4),41.9(C-18),41.8(C-9),41.5(C-8),39.6(C-10),35.9(C-7),33.6(C-16),33.2(C-21),33.1(C-29),32.2(C-22),30.8(C-20),27.9(C-23),23.7(C-11),23.6(C-30),21.7(C-24),20.0(C-27),19.2(C-6),18.8(C-25),18.2(C-26).
化合物6:白色粉末，(-)-ESIMS m/z 513[M-H]-.1H-NMR(500MHz,CDCl3)δ5.27(1H,t,J＝3.7Hz,H-12),4.65(1H,d,J＝3.3Hz,H-3),4.12(1H,dd,J＝6.6,3.3Hz,H-2),2.19(1H,d,J＝11.4Hz,H-18),2.15(3H,s,H-2'),1.30(3H,s,H-25),1.08(3H,s,H-23),1.07(3H,s,H-27),0.95(3H,d,J＝6.4Hz,H-30),0.88(3H,s,H-24),0.86(3H,d,J＝6.4Hz,H-29),0.81(3H,s,H-26)；13C-NMR(125MHz,CDCl3)δ181.7(C-28),170.5(C-1'),138.0(C-13),125.8(C-12),80.8(C-3),69.4(C-2),55.4(C-5),52.6(C-18),48.0(C-9),47.9(C-17),43.6(C-1),42.1(C-14),39.6(C-8),39.0(C-20),39.0(C-19),38.8(C-22),37.5(C-4),36.7(C-10),36.7(C-7),30.6(C-21),29.3(C-24),27.9(C-15),24.1(C-16),23.6(C-11),23.4(C-6),21.2(C-30),21.2(C-2'),18.1(C-27),18.0(C-23),17.1(C-29),17.0(C-26),16.5(C-25).
化合物7：白色粉末，(+)-ESIMS m/z 465[M+Na]+.1H-NMR(500MHz,CDCl3)δ5.14(1H,t,J＝3.5Hz,H-12),3.53(1H,d,J＝10.8Hz,H-27),3.22(1H,dd,J＝11.0,4.6Hz,H-3),3.20(1H,d,J＝10.8Hz,H-27),1.10(3H,s,H-28),1.00(3H,s,H-23),0.99(3H,s,H-24),0.95(3H,s,H-26),0.94(3H,d,J＝6.3Hz,H-29),0.81(3H,d,J＝5.8Hz,H-30),0.79(3H,s,H-25)；13C-NMR(150MHz,CDCl3)δ138.7(C-13),125.0(C-12),79.0(C-3),69.9(C-27),55.2(C-5),54.0(C-18),47.7(C-9),42.1(C-14),40.0(C-8),39.4(C-19),39.4(C-20),38.8(C-1),38.8(C-17),38.1(C-4),36.9(C-10),35.2(C-22),32.8(C-7),30.6(C-21),28.1(C-12),27.3(C-2),26.0(C-16),23.4(C-11),23.3(C-12),23.3(C-28),21.3(C-29),18.3(C-6),17.4(C-30),16.8(C-24),15.7(C-26),15.6(C-25).
化合物8：白色粉末，(-)-ESIMS m/z 455[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ5.51(1H,t,J＝3.3Hz,H-12),3.47(1H,dd,J＝11.2,4.5Hz,H-3),2.65(1H,d,J＝11.3Hz,H-18),1.26(3H,s,H-23),1.25(3H,s,H-27),1.07(3H,s,H-26),1.04(3H,s,H-24),1.02(3H,d,J＝6.2Hz,H-29),0.97(3H,d,J＝5.9Hz,H-30),0.91(3H,s,H-25)；13C-NMR(125MHz,Pyridine-d5)δ179.62(C-28),138.98(C-13),125.4(C-12),77.9(C-3),55.5(C-5),53.3(C-18),49.4(C-17),47.8(C-9),42.2(C-14),39.7(C-8),39.2(C-19),39.1(C-20),39.1(C-1),38.8(C-4),37.2(C-22),37.0(C-10),33.3(C-7),30.8(C-21),28.5(C-23),28.4(C-15),27.8(C-2),24.6(C-16),23.6(C-27),23.4(C-11),21.1(C-30),18.5(C-6),17.2(C-29),17.2(C-26),16.3(C-24),15.4(C-25).
化合物9：白色粉末，(-)-ESIMS m/z 453[M-H]-.1H-NMR(600MHz,Pyridine-d5)δ6.70(1H,dd,J＝10.5,2.8Hz,H-11),5.81(1H,d,J＝10.5Hz,H-12),3.51(1H,dd,J＝11.2,4.6Hz,H-3),1.27(3H,s,H-23),1.12(3H,s,H-26),1.12(3H,s,H-25),1.05(3H,s,H-27),1.00(3H,s,H-29),0.95(3H,s,H-24),0.93(3H,s,H-30)；13C-NMR(150MHz,Pyridine-d5)δ178.92(C-28),136.58(C-13),133.8(C-18,overlapped with solvent)127.0(C-12),126.0(C-11),78.1(C-3),55.3(C-5),54.9(C-9),48.7(C-17),42.5(C-14),41.1(C-8),41.0(C-19),39.6(C-4),38.5(C-1),37.5(C-21),37.1(C-10),36.3(C-22),33.3(C-15),32.1(C-7),32.8(C-20),32.4(C-29),28.5(C-23),28.1(C-2),25.7(C-16),24.4(C-30),20.1(C-27),18.8(C-6),18.4(C-25),17.1(C-26),16.1(C-24).
化合物10：白色粉末，(-)-ESIMS m/z 453[M-H]-.1H-NMR(500MHz,CDCl3)δ5.28(1H,t,J＝3.3Hz,H-12),3.22(1H,dd,J＝11.3,4.3Hz,H-3),2.82(1H,dd,J＝13.7,4.0Hz,H-18),1.13(3H,s,H-27),0.99(3H,s,H-23),0.93(3H,s,H-26),0.91(3H,s,H-24),0.90(3H,s,H-30),0.77(3H,s,H-29),0.75(3H,s,H-25)；13C-NMR(125MHz,CDCl3)δ182.8(C-28),143.6(C-13),122.6(C-12),79.0(C-3),55.2(C-5),47.6(C-9),46.5(C-17),45.9(C-19),41.6(C-14),41.0(C-18),39.3(C-8),38.7(C-4),38.4(C-1),37.1(C-10),33.8(C-21),33.0(C-7),32.6(C-29),32.4(C-22),30.7(C-20),28.1(C-23),27.7(C-15),27.2(C-2),25.9(C-27),23.6(C-11),23.4(C-16),23.0(C-30),18.3(C-6),17.1(C-26),15.5(C-24),15.3(C-25).
化合物11：白色粉末，(-)-ESIMS m/z 453[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ5.49(1H,brs,H-21),3.50(1H,t,J＝8.0Hz,H-3),1.75(3H,s,H-30),1.26(3H,s,H-24),1.14(3H,d,J＝6.0Hz,H-29),1.09(3H,s,H-26),1.06(3H,s,H-27),1.05(3H,s,H-23),0.89(3H,s,H-25)；13C-NMR(150MHz,Pyridine-d5)δ178.5(C-28),143.5(C-20),118.3(C-21),78.5(C-3),56.3(C-5),51.42(C-9),50.0(C-18),49.7(C-17),42.7(C-14),41.6(C-8),39.9(C-13),39.8(C-1),39.7(C-4),38.8(C-22),38.2(C-19),37.8(C-10),35.1(C-7),34.0(C-12),30.0(C-16),29.0(C-24),28.7(C-15),28.3(C-2),24.1(C-29),22.6(C-30),22.3(C-11),19.1(C-6),17.0(C-25),16.8(C-23),16.7(C-26),15.4(C-27).
化合物12：白色粉末，(-)-ESIMS m/z 455.5[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ3.51(1H,dd,J＝10.2,5.8Hz,H-3),1.28(s,3H,H-23),1.28(s,3H,H-27),1.19(s,3H,H-26),1.05(s,3H,H-24),0.98(s,3H,H-25),0.93(s,3H,H-29),0.88(s,3H,H-30)；13C-NMR(150MHz,Pyridine-d5)δ179.4(C-28),138.3(C-13),129.7(C-18),78.5(C-3),56.3(C-5),51.6(C-9),50.0(C-17),45.2(C-14),42.2(C-8),42.0(C-19),39.9(C-4),39.7(C-1),38.1(C-21),37.8(C-10),36.9(C-12),35.9(C-7),34.1(C-16),33.3(C-20),32.7(C-30),29.2(C-11),28.7(C-23),28.2(C-15),26.00(C-2),24.8(C-29),22.5(C-22),21.7(C-27),19.2(C-6),18.6(C-26),17.1(C-24),16.9(C-25).
化合物13：白色粉末，(-)-ESIMS m/z 507[M+Cl]-.1H-NMR(500MHz,CDCl3)δ5.36(1H,t,J＝3.2Hz,H-12),3.22(1H,dd,J＝11.2,4.4Hz,H-3),2.60(1H,s,H-18),1.26(3H,s,H-27),1.21(3H,s,H-29),0.99(3H,s,H-23),0.95(3H,d,J＝6.7Hz,H-30),0.91(3H,s,H-25),0.79(3H,s,H-24),0.69(3H,s,H-26).；13C-NMR(125MHz,CDCl3)δ178.5(C-28),138.2(C-13),129.4(C-12),79.2(C-3),73.3(C-19),55.3(C-5),53.4(C-18),51.7(C-17),48.0(C-9),47.4(C-20),41.3(C-14),40.1(C-8),38.9(C-4),38.6(C-1),37.6(C-22),37.1(C-10),32.9(C-7),28.4(C-15),28.3(C-23),27.6(C-2),27.4(C-21),26.2(C-29),25.7(C-16),24.7(C-27),23.8(C-11),18.6(C-6),16.8(C-26),16.3(C-24),15.7(C-30),15.4(C-25).
化合物14：白色粉末，(+)-ESIMS m/z 429[M+H]+.1H-NMR(600MHz,CDCl3)δ5.31(1H,t,J＝3.7Hz,H-12),3.22(1H,dd,J＝11.5,4.4Hz,H-3),2.23(1H,dd,J＝13.3,3.7Hz,H-18),1.14(3H,s,H-27),1.00(3H,s,H-23),0.96(3H,s,H-28),0.95(3H,s,H-26),0.93(3H,s,H-29),0.90(3H,s,H-24),0.79(3H,s,H-25)；13C-NMR(150MHz,CDCl3)δ143.2(C-13),124.4(C-12),79.0(C-3),72.2(C-17),55.2(C-5),48.8(C-18),48.3(C-19),47.6(C-9),41.5(C-14),39.6(C-8),38.8(C-1),38.5(C-4),37.1(C-10),36.8(C-22),36.5(C-21),32.8(C-28),32.8(C-7),31.0(C-20),28.1(C-23),27.3(C-16),27.2(C-15),25.5(C-27),25.5(C-29),24.0(C-11),23.6(C-2),18.4(C-6),17.1(C-26),15.6(C-24),15.3(C-25).
化合物15：白色粉末，(+)-ESIMS m/z 443[M+H]+.1H-NMR(500MHz,Pyridine-d5)δ5.25(2H,t,J＝3.3Hz,H-12),3.95(1H,d,J＝10.5Hz,H-28),3.51(1H,d,J＝10.5Hz,H-28),3.49(1H,dd,J＝10.8,5.4Hz,H-3),1.28(3H,s,H-27),1.25(3H,s,H-25),1.08(3H,s,H-23),1.05(3H,s,H-26),0.99(3H,m,H-30),0.97(3H,s,H-29),0.96(3H,s,H-24)；13C-NMR(150MHz,Pyridine-d5)δ140.0(C-13),125.4(C-12),78.5(C-3),69.5(C-18),56.1(C-5),55.0(C-18),48.5(C-9),42.8(C-14),40.7(C-8),40.3(C-20),40.2(C-19),39.8(C-1),39.6(C-4),39.1(C-10),37.5(C-17),36.6(C-7),33.7(C-21),31.6(C-15),29.2(C-22),28.6(C-2),27.0(C-23),24.2(C-11),24.1(C-16),24.0(C-27),22.0(C-30),19.2(C-6),18.2(C-29),17.4(C-26),17.0(C-25),16.3(C-24).
化合物16：无色针晶(甲醇)，(-)-ESIMS m/z 541[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ5.48(1H,t,J＝3.4Hz,H-12),4.85(1H,dd,J＝11.6,4.3Hz,H-3),3.82(2H,s,H-2'),2.64(1H,d,J＝11.3Hz,H-18),1.23(3H,s,H-27),1.06(3H,s,H-25),1.02(3H,s,H-23),1.02(3H,d,J＝6.2Hz,H-30),0.97(3H,d,J＝6.2Hz,H-29),0.93(3H,s,H-26),0.82(3H,s,H-24)；13C-NMR(125MHz,Pyridine-d5)δ179.9(C-28),170.3(C-3'),167.9(C-1'),139.3(C-13),125.4(C-12),81.6(C-3),55.6(C-5),53.6(C-18),48.1(C-17),47.8(C-9),42.5(C-14),39.9(C-2'),39.9(C-8),39.5(C-19),39.4(C-20),38.3(C-1),38.1(C-4),37.5(C-22),37.0(C-10),33.4(C-7),31.1(C-21),28.7(C-23),28.7(C-15),28.2(C-2),24.9(C-16),23.9(C-27),23.6(C-11),21.4(C-30),18.5(C-6),17.5(C-29),17.4(C-26),17.0(C-24),15.5(C-25).
化合物18：白色粉末，(-)-ESIMS m/z 507[M+Cl]-.1H-NMR(500MHz,Pyridine-d5)δ5.49(1H,t,J＝3.5,H-12),4.12(1H,td,J＝10.5,4.3Hz,H-2),3.42(1H,d,J＝10.5Hz,H-3),2.65(1H,d,J＝11.3Hz,H-18),1.30(3H,s,H-27),1.23(3H,s,H-25),1.10(3H,s,H-23),1.07(3H,s,H-26),1.00(3H,s,H-24),1.00(3H,d,J＝5.9Hz,H-30),0.97(3H,d,J＝6.2Hz,H-29)；13C-NMR(150MHz,Pyridine-d5)δ180.3(C-28),139.7(C-13),125.9(C-12),84.2(C-3),69.0(C-2),56.3(C-5),53.9(C-18),48.5(C-17),48.4(C-1),48.4(C-9),42.9(C-14),40.4(C-8),40.2(C-4),39.8(C-19),39.8(C-20),38.8(C-10),37.8(C-22),33.9(C-7),31.4(C-21),29.8(C-23),29.0(C-15),25.3(C-16),24.3(C-11),24.1(C-27),21.8(C-30),19.2(C-6),18.1(C-29),17.9(C-26),17.9(C-24),17.4(C-25).
化合物19：白色粉末，(-)-ESIMS m/z 617[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ8.01(1H,d,J＝15.9Hz,H-7'),7.57(2H,d,J＝8.5Hz,H-2',6'),7.16(2H,d,J＝8.5Hz,H-3',5'),6.62(1H,d,J＝15.9Hz,H-8'),5.64(1H,td,J＝10.9,4.4Hz,H-2),5.48(1H,t,J＝3.3Hz,H-12),2.66(1H,d,J＝11.2Hz,H-18),1.32(3H,s,H-27),1.26(3H,s,H-23),1.13(3H,s,H-24),1.09(3H,s,H-26),1.04(3H,s,H-25),1.03(3H,d,J＝6.3Hz,H-29),0.97(3H,d,J＝6.2Hz,H-30).13C-NMR(125MHz,Pyridine-d5)δ180.1(C-28),167.5(C-9'),161.4(C-4'),144.71(C-7'),139.4(C-13),130.6(C-2',6'),126.2(C-1'),125.4(C-12),116.9(C-3',5'),116.00(C-7'),79.9(C-3),73.4(C-2),55.6(C-5),53.6(C-18),48.1(C-17),48.0(C-9),44.9(C-1),42.6(C-14),40.5(C-8),40.0(C-19),39.5(C-4),39.4(C-20),38.6(C-10),37.5(C-22),33.5(C-7),31.2(C-21),29.3(C-15),28.7(C-23),25.0(C-16),23.9(C-27),23.7(C-11),21.5(C-30),18.8(C-6),17.7(C-24),17.5(C-25),17.4(C-26),16.8(C-29).
化合物20：白色粉末，(-)-ESIMS m/z 617[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ7.99(1H,d,J＝15.9Hz,H＝7'),7.55(2H,d,J＝8.6Hz,H-2',6'),7.17(2H,d,J＝8.6Hz,H-3',5'),6.58(1H,d,J＝15.9Hz,H-8'),5.67(1H,td,J＝10.5,4.5Hz,H-2),5.53(1H,t,J＝3.8Hz,H-12),3.66(1H,d,J＝10.5Hz,H-3),3.34(1H,dd,J＝14.0,4.5Hz,H-18),1.34(3H,s,H-27),1.33(3H,s,H-25),1.15(3H,s,H-23),1.11(3H,s,H-30),1.03(3H,s,H-29),1.01(3H,s,H-24),0.96(3H,s,H-26)；13C-NMR(150MHz,Pyridine-d5)δ180.0(C-28),167.2(C-9'),161.1(C-4'),144.7(C-7'),144.4(C-13),130.3(C-2',6'),125.9(C-1'),122.1(C-12),116.6(C-3',5'),115.8(C-8'),79.6(C-3),73.1(C-2),55.4(C-5),47.8(C-9),46.2(C-17,19),44.4(C-1),42.0(C-8),41.7(C-18),40.2(C-4),39.6(C-14),38.4(C-10),34.0(C-21),33.0(C-7),33.3(C-22),32.9(C-29),30.7(C-20),29.0(C-23),28.1(C-15),26.0(C-27),23.7(C-11),23.5(C-16,30),18.6(C-6),17.4(C-26),17.2(C-24),16.4(C-25).
化合物21：白色粉末，(-)-ESIMS m/z 617[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ8.02(1H,d,J＝15.9Hz,H-7'),7.57(2H,overlapped with solvent),7.18(2H,d,J＝8.6Hz,H-3',5'),6.71(1H,d,J＝15.9Hz,H-8'),5.48(1H,t,J＝3.2Hz,H-12),5.27(1H,d,J＝10.5Hz,H-3),4.31(1H,td,J＝10.5,4.4Hz,H-2),3.32(1H,dd,J＝13.5,3.4Hz,H-18),1.28(3H,s,H-27),1.07(3H,s,H-25),1.05(3H,s,H-26),1.02(3H,s,H-30),1.02(3H,s,H-29),1.01(3H,s,H-23),0.97(3H,s,H-24)；13C-NMR(150MHz,Pyridine-d5)δ180.3(C-28),168.0(C-9'),161.4(C-4'),145.0(C-6'),145.0(C-13),130.6(C-2',6'),126.3(C-1'),122.3(C-12),116.8(C-3',5'),116.1(C-8'),85.1(C-3),66.4(C-2),55.5(C-5),48.4(C-9),48.1(C-19),46.7(C-1),46.5(C-17),42.2(C-14),42.0(C-18),39.9(C-8),39.8(C-4),38.4(C-10),34.3(C-21),33.3(C-7),33.2(C-29),33.0(C-22),31.0(C-20),29.0(C-23),28.3(C-15),26.2(C-27),23.9(C-16),23.8(C-11),23.7(C-30),18.7(C-6),18.3(C-26),17.4(C-24),16.8(C-25).
化合物22：白色粉末，(-)-ESIMS m/z 617[M-H]-.1H-NMR(600MHz,pyridine-d5)δ8.02(1H,d,J＝15.9Hz,H-7'),7.57(2H,overlapped with solvent),7.16(2H,d,J＝8.6Hz,H-3',5'),6.69(1H,d,J＝15.9Hz,H-2'),5.48(1H,t,J＝3.4Hz,H-12),5.28(1H,d,J＝10.5Hz,H-3),4.31(1H,td,J＝10.5,4.5Hz,H-2),2.65(1H,d,J＝11.3Hz,H-18),1.24(3H,s,H-27),1.08(3H,s,H-23),1.06(3H,s,H-24),1.05(3H,s,H-26),1.01(3H,s,H-25),1.00(3H,d,J＝6.3Hz,H-29),0.97(3H,d,J＝6.3Hz,H-30)；13C-NMR(150MHz,Pyridine-d5)δ179.9(C-28),167.9(C-9'),161.3(C-4'),144.8(C-7'),139.4(C-13),130.6(C-2',6'),126.3(C-1'),125.4(C-12),116.8(C-3',5'),116.1(C-8'),85.1(C-3),66.4(C-2),55.6(C-5),53.5(C-18),48.6(C-9),48.1(C-17),48.0(C-1),42.6(C-14),40.0(C-8),39.8(C-4),39.5(C-19),39.4(C-20),38.3(C-10),37.5(C-22),33.4(C-7),31.1(C-21),29.1(C-23),28.7(C-15),24.9(C-16),24.0(C-27),23.7(C-11),21.4(C-30),18.7(C-6),18.3(C-24),17.5(C-26),17.4(C-29),16.9(C-25).
化合物23：白色粉末，(-)-ESIMS m/z 617[M-H]-.1H-NMR(500MHz,Pyridine-d5)δ8.16(1H,d,J＝8.6Hz,H-3',5'),7.16(1H,d,J＝8.6Hz,H-2',6'),6.94(1H,d,J＝12.9Hz,H-3”),6.10(1H,d,J＝12.9Hz,H-2”),5.47(1H,t,J＝3.2Hz,H-12),5.22(1H,d,J＝9.8Hz,H-3),4.27(1H,m,H-2),2.65(1H,d,J＝11.2Hz,H-18),1.20(3H,s,H-27),1.06(3H,s,H-23),1.04(3H,s,H-24),0.99(3H,s,H-29),0.99(3H,s,H-26),0.98(3H,s,H-25),0.97(3H,s,H-30).13C-NMR(150MHz,Pyridine-d5)δ167.7(C-1'),161.0(C-7'),144.1(C-3'),139.9(C-13),134.3(C-5',9'),127.2(C-4'),125.9(C-12),117.6(C-2'),116.4(C-6',8'),85.5(C-3),66.8(C-2),56.1(C-5),54.1(C-18),49.2(C-9),48.6(C-17),48.5(C-1),43.1(C-14),40.53(C-4),40.2(C-8),40.0(C-19),38.8(C-20),38.0(C-10),33.8(C-7),31.6(C-22),30.5(C-21),29.6(C-23),29.2(C-15),25.4(C-16),24.5(C-11),24.2(C-27),21.9(C-30),19.2(C-6),18.7(C-24),18.1(C-29),18.0(C-26),17.4(C-25).
药理实验五环三萜类化合物的神经保护活性实验
实验例1.谷氨酸诱导SK-N-SH神经母瘤细胞损伤模型
实验方法：将SK-N-SH细胞常规培养，然后使用阳性工具药多奈哌齐(3μmol/L)/送筛化合物(10μmol/L)分别与SK-N-SH细胞共孵育4小时。然后利用谷氨酸损伤SK-N-SH细胞，建立谷氨酸损伤模型，损伤4小时后，MTT法检测细胞存活率。
实验结果：由表3可知：在从锁阳分离得到的化合物中，12个五环三萜类化合物对谷氨酸诱导的神经细胞损伤有显著的神经保护活性
实验例2.连二亚硫酸钠诱导SK-N-SH神经母瘤细胞氧糖剥夺模型
实验方法：将SK-N-SH细胞常规培养，然后使用阳性工具药多奈哌齐(3μmol/L)/PHPB(10μmol/L)/送筛化合物(10μmol/L)分别与SK-N-SH细胞共孵育4小时。然后利用连二亚硫酸钠损伤SK-N-SH细胞，建立氧糖剥夺模型，损伤24小时后，MTT法检测细胞存活率。
实验结果：由表3可知：在从锁阳分离得到的化合物中，12个五环三萜类化合物对氧糖剥夺损伤的神经细胞有显著的保护活性。
表3锁阳分离化合物的神经保护活性(10μmol/ml)
**P<0.01vs Control；#P<0.05vs Model,##P<0.01vs Model,###P<0.001vs Model
参考文献：
郑玲艳,韩瑞兰,2016.锁阳益智作用的活性部位及机理研究.vol.硕士.内蒙古医科大学,呼和浩特,p.47。
Claims (8)
1.如下所示的五环三萜类化合物及其药学上可接受的盐,
2.如下所示的五环三萜类化合物及其药学上可接受的盐在制备预防和/或治疗神经退行性疾病的药物中的应用，
3.权利要求1中五环三萜类化合物及其药学上可接受的盐在制备预防和/或治疗神经退行性疾病的药物中的应用。
4.一种药物组合物，其特征在于，所述的药物组合物中含有有效剂量如权利要求1所述的五环三萜类化合物及其药学上可接受的盐和药学上可接受的载体。
5.一种药物组合物在制备预防和/或治疗神经退行性疾病的药物中的应用，其特征在于，所述的药物组合物含有有效剂量如权利要求2所述的五环三萜类化合物和药学上可接受的载体。
6.根据权利要求5的应用，其特征在于：所述药物组合物的剂型选自片剂、胶囊剂、丸剂、颗粒剂、口服液、注射液和混悬剂。
7.根据权利要求2或3的应用，所述神经退行性疾病包括中风、脑损伤、肌萎缩侧索硬化症、亨廷顿病、帕金森病或阿尔茨海默病。
8.制备权利要求1和权利要求2所述的五环三萜类化合物的制备方法包括如下步骤：锁阳药材95％乙醇回流提取，浓缩后浸膏通过有机溶剂萃取、大孔吸附树脂、硅胶柱层析、凝胶柱层析、反相硅胶柱层析及制备型HPLC分离纯化，得到目标化合物。
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