CN108997451A - 野八角新倍半萜及其制备方法、应用和药物组合物 - Google Patents
野八角新倍半萜及其制备方法、应用和药物组合物 Download PDFInfo
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- CN108997451A CN108997451A CN201810808497.8A CN201810808497A CN108997451A CN 108997451 A CN108997451 A CN 108997451A CN 201810808497 A CN201810808497 A CN 201810808497A CN 108997451 A CN108997451 A CN 108997451A
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Abstract
本发明公开了从野八角中提取的一种具有式Ⅰ所示结构的新倍半萜，及其制备方法，以及含有新倍半萜的药物组合物，和在神经保护药物中的应用:特别是脑卒中。药理实验表明本发明化合物体现了神经保护活性，即在H2O2损伤原代神经元模型和谷氨酸诱导原代神经元毒性模型中均具有良好的神经保护活性。式Ⅰ。
Description
技术领域
本发明涉及化合物提取分离领域，特别涉及野八角新倍半萜及其制备方法、应用和药物组合物。
背景技术
野八角（IliiciumsimonsiiMaxim）为八角属（Illicium L.）植物，产于我国贵州西北部至西南部、四川和云南以及印度、缅甸。叶、果实入药，味辛，性热；有镇呕、行气止痛、生肌接骨、灭虱杀虫之效，可治胃寒作呕、膀胱疝气、胸前胀痛、疥疮等功效。
脑卒中（cerebral apoplexy）是导致全球人类致残的首要病因，全球第二大死因。在一些国家和城市，卒中甚至已经超过心血管病，成为第一位死因。根据中国生物技术发展中心抽样调查的数据显示，中国城乡脑血管病的年发病率平均为200/10万，患病率为400~700/10万，全国每年新发脑血管病病例250 万，死亡率为130/10万，是我国人口总死亡第二位原因，在北京已经超过心血管疾病和肿瘤，成为第一位死亡原因。全国每年用于治疗脑血管病的费用达100亿元以上，加上间接经济损失超过200亿元。由此可见，脑血管病已经成为严重影响我国民生的重要公共卫生问题。2010年世界卒中日发布的主题是“六分之一”，即全世界每6个人中有1人可能在一生中罹患卒中；每6s就有1人死于卒中；而每6min就有1人因卒中而永久致残。脑卒中是当今世界重大疾病之一。来源于中草药的有效成分是抗脑卒中新药的研究热点。
发明内容
野八角乙醇提取物具有神经保护作用，从有效部位中分离得到1个新倍半萜，药效学评价显示其具有很好的神经保护的作用。
本发明解决的技术问题在于提供了一个野八角新倍半萜；
本发明解决的另一技术问题在于提供了一个野八角新倍半萜的制备方法；
本发明解决的又一技术问题在于提供一种药物组合物，其含有一个野八角新倍半萜；
本发明解决的技术问题在于提供一种药物组合物，其含有一个野八角新倍半萜作为神经保护药物的应用。
本发明是通过以下技术方案实现的: 野八角新倍半萜具有式Ⅰ所示结构
式Ⅰ。
如式Ⅰ所示化合物的制备方法，其中，每制备式Ⅰ化合物5mg包括以下步骤：a.干燥的野八角果实10.50 kg，粉碎，用95% EtOH 80 L浸泡2 h后，加热回流提取3次，每次2小时，提取液减压浓缩，得到261.2 g浸膏；
b.将浸膏溶解于甲醇中，吸附于500 g硅藻土，干燥，装入索氏提取器，依次用石油醚、乙酸乙酯和甲醇索氏回流提取；
c.各提取液分别减压浓缩得石油醚部位44.2 g，乙酸乙酯部位75.0 g和甲醇部位133.6 g；
d.取甲醇洗脱部位用水溶解，吸附于10倍量的大孔吸附树脂24 h。分别用纯水，50%乙醇:水，95%乙醇:水，得到50 %乙醇:水洗脱部位40 g，将该部位用二氯甲烷-甲醇,二氯甲烷:甲醇= 50:1；25:1；10:1；5:1；2:1；1:1；0:100,梯度洗脱分离得到流份Fr1-Fr8；
e.对7 g ,Fr 6 通过中压柱色谱法,10–60 % 的甲醇梯度洗脱,分为35个流份每500mL为1份，通过制备液相从Fr.2-1得到一个新倍半萜类化合物15 mg。
式Ⅰ化合物在制备预防或治疗脑血管疾病药物中的应用；所述脑血管疾病药物为神经保护药物；所述脑血管疾病为脑卒中、痴呆、神经炎症、重金属中毒、神经毒剂中毒；所述脑卒中为缺血性脑卒中或出血性脑卒中。
一种药物组合物，其中，含有式Ⅰ所示的化合物以及药效学上可接受的载体。
根据本发明的思路，对野八角新倍半萜进行了神经保护相关的药理实验。氧化应激是导致神经元凋亡丢失的重要原因，是缺血性脑卒中的特征。引起氧化应激的原因有很多种，如脑缺血，神经炎症，兴奋性递质释放重摄取机制障碍，重金属暴露，神经毒性剂暴露等，表现为细胞内自由基增加，引起脂质过氧化，线粒体功能障碍继而激活凋亡通路等。谷氨酸，H2O2虽然引发神经元凋亡丢失的机制不一，但都是近年来许多国内外学者倡导的神经元损伤模型的诱发剂。研究认为，脑内兴奋性递质谷氨酸过量通常引起神经元膜上NMDA受体过度激活，从而导致神经元发生氧化应激并丢失，而H2O2是一种过氧化物，以其诱导神经细胞氧化应激损伤模型为基础，揭示了临床有效的药物作用机制，可作为体外筛选抗氧化药物的一种可靠的药理细胞模型，其发生机制，病理生理改变与脑卒中患者脑内表现具有相似性。应用谷氨酸，H2O2制作神经元损伤模型条件要求低，技术易于掌握，可靠性强，重复性好，因此在本研究中，H2O2损伤原代神经元模型、谷氨酸诱导原代神经元凋亡模型2个体外模型作为评价手段。
发明人发现新倍半萜在体外谷氨酸，H2O2诱发的大鼠大脑皮层神经元死亡的试验中均显示出优良的神经保护作用。
阳性对照药物为依达拉奉（edaravone），依达拉奉是以自由基清除为主要作用机制的神经保护药物，能有效抑制因脑缺血导致的脑细胞、血管内皮细胞、神经细胞的氧化应激损伤。
对H2O2诱发大鼠大脑皮层神经元凋亡的保护作用体外研究中，将本发明化合物与依达拉奉（300μM）用神经元培养基稀释，和大鼠大脑皮层神经元温孵24小时后，MTT法测定细胞存活率，同时进行正常对照组和阳性对照组试验。实验结果表明，正常对照组加入H2O2后570 nm处吸光度值（OD570）明显降低，阳性对照组和本发明化合物OD570明显回升，与依达拉奉（edaravone）的细胞存活率相当，新化合物组的细胞存活率与依达拉奉组相当。
对谷氨酸诱发大鼠大脑皮层神经元凋亡的保护作用体外研究中，将本发明化合物与谷氨酸（20 mM）用完全培养基稀释，和大鼠大脑皮层神经元温孵24小时后，MTT法测定细胞存活率，同时进行正常对照组和阳性对照组试验。实验结果表明，正常对照组加入谷氨酸后570 nm处吸光度值（OD570）明显降低，阳性对照组和本发明化合物OD570明显回升，与依达拉奉（edaravone）的细胞存活率相当，新化合物组的细胞存活率与依达拉奉组相当。
因此本发明的有益效果:化合物可用于制备预防和/ 或治疗脑血管疾病的药物。优选的神经退行性疾病选自脑卒中、痴呆、神经炎症、重金属中毒、神经毒剂中毒。优选的脑卒中选缺血性脑卒中和出血性脑卒中。
附图说明
图1 野八角果实的提取流程图。
具体实施方式
下面的实施例及药理活性实验进一步说明本发明，但并不意味着对本发明的任何限制。
提取分离实验（见附图1）
干燥的野八角果实10.50 kg，粉碎，用95% EtOH 80 L浸泡2 h后，加热回流提取3次，每次2小时，提取液减压浓缩，得到261.2 g浸膏。将浸膏溶解于甲醇中，吸附于500 g硅藻土，干燥，装入索氏提取器，依次用石油醚、乙酸乙酯和甲醇索氏回流提取。各提取液分别减压浓缩得石油醚部位44.2 g，乙酸乙酯部位75.0 g和甲醇部位133.6 g。取甲醇洗脱部位用水溶解，吸附于10倍量的大孔吸附树脂（24 h）。分别用纯水，50%乙醇:水，95%乙醇:水。得到50%乙醇:水洗脱部位40 g，将该部位用二氯甲烷-甲醇（二氯甲烷:甲醇= 50:1；25:1；10:1；5:1；2:1；1:1；0:100）梯度洗脱分离得到流份Fr1-Fr8。对Fr 6 (7 g) 通过中压柱色谱法（10–60 % 的甲醇梯度洗脱）分为35个流份（500 ml为1份），通过制备液相从Fr.2-1得到一个新倍半萜类化合物（15 mg）。
新倍半萜的理化、波谱数据如下:
白色粉末; [α]20 D +15.7 (c 0.61 MeOH); IR光谱给出羟基 (3397 cm-1)，羰基(1717cm-1)等官能团的振动吸收; ESIMS m/z429 [M + H]+, 451 [M + Na]+; HRESIMS m/ z451.1935 [M+ H]+ (calcd for C21H33O9, 431.1939)。见下表
表 11H and 13C NMR data of compound 1 in CD3OD
药理实验
试验材料1、受试药：本发明单体化合物。2、阳性对照药：依达拉奉，由中国食品药品检定研究院提供。HPLC检测纯度>98%。3、细胞：出生当天大鼠大脑皮层神经元。4、培养基：DMEM，FBS，美国Gibco公司生产；ES，美国Hyclone公司生产。5、H2O2由和谷氨酸由北京化工厂提供。
本发明还涉及以本发明化合物作为活性成分的药物组合物。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%。
本发明的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、鼻腔、口腔粘膜、皮肤、腹膜、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 型和复乳)、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。
本发明的化合物可以制成普通制剂、也可以是缓释制剂、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，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、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的胶囊剂。
为将本发明化合物制成注射剂，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。
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1-60mg/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。
实施例1：本发明化合物对大鼠大脑皮层神经元存活状态的影响以及在H2O2诱发的神经元凋亡模型中的保护作用。
化合物对神经元存活状态的影响研究中，将原代培养大鼠皮层神经元 (DIV-9)分为对照组和给药组 (10 μM)，n=6；在化合物对H2O2诱发神经元凋亡模型的保护作用研究中，将原代培养大鼠皮层神经元 (DIV-7)分为对照组，H2O2 (300μM)造模组，H2O2 (300μM)+依达拉奉 (100 μM)给药组，H2O2 (300μM)+化合物 (10μM)给药组，n=6。给药后，细胞置于细胞孵箱中继续培养24小时，MTT法 (570nm)测定细胞存活率。以对照组吸光度为标准，计算各组吸光度与对照组的比值。
实施例2：化合物在谷氨酸诱发的大鼠皮层神经元凋亡模型中的保护作用
将原代培养大鼠皮层神经元 (DIV-9)分为对照组，谷氨酸 (20 mM)造模组，谷氨酸(20 mM)+依达拉奉 (100 μM)给药组，谷氨酸 (20 mM)+化合物 (10 μM)给药组，n=6，于细胞孵箱中继续培养24小时后，MTT法测定细胞存活率。以对照组吸光度为标准，计算各组吸光度与对照组的比值。
表2化合物对大鼠皮层神经元存活状态的影响
表3新化合物在H2O2和谷氨酸诱导的原代神经元细胞损伤模型中的神经保护作用
注：* p<0.05 vs mod，** p<0.01 vs mod，*** p<0.001vs mod，## P ＜ 0.01vscontrol.
实验结果表明：对已经鉴定的化合物进了初步的细胞模型筛选，化合物1体现了神经保护活性，即在谷氨酸损伤原代神经元模型中具有良好的神经保护活性，其活性与阳性药依达拉奉相当。
Claims (7)
1.野八角新倍半萜，其特征在于具有式Ⅰ所示结构
式Ⅰ。
2.如权利要求1所示化合物的制备方法，其特征在于：每制备式Ⅰ化合物，15 mg包括以下步骤：
a.干燥的野八角果实10.50 kg，粉碎，用95% EtOH 80 L浸泡2 h后，加热回流提取3次，每次2小时，提取液减压浓缩，得到261.2 g浸膏；
b.将浸膏溶解于甲醇中，吸附于500 g硅藻土，干燥，装入索氏提取器，依次用石油醚、乙酸乙酯和甲醇索氏回流提取；
c.各提取液分别减压浓缩得石油醚部位44.2 g，乙酸乙酯部位75.0 g和甲醇部位133.6 g；
d.取甲醇洗脱部位用水溶解，吸附于10倍量的大孔吸附树脂24 h；
分别用纯水，50%乙醇:水，95%乙醇:水，得到50 %乙醇:水洗脱部位40 g，将该部位用二氯甲烷-甲醇,二氯甲烷:甲醇= 50:1；25:1；10:1；5:1；2:1；1:1；0:100,梯度洗脱分离得到流份Fr1-Fr8；
e.对7 g ,Fr 6 通过中压柱色谱法,10–60 % 的甲醇梯度洗脱,分为35个流份每500mL为1份，通过制备液相从Fr.2-1得到一个新倍半萜类化合物15 mg。
3.如权利要求1所述的化合物在制备预防或治疗脑血管疾病药物中的应用。
4.根据权利要求3 所述的应用，其特征为所述脑血管疾病药物为神经保护药物。
5.根据权利要求3 所述的应用，其特征为所述脑血管疾病为脑卒中、痴呆、神经炎症、重金属中毒、神经毒剂中毒。
6.根据权利要求5 所述的应用，其特征为所述脑卒中为缺血性脑卒中或出血性脑卒中。
7.一种药物组合物，其特征在于：含有权利要求1中所示的化合物以及药效学上可接受的载体。
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| WO2011050481A1 (en) * | 2009-10-30 | 2011-05-05 | National Research Council Of Canada | New eremophilane sesquiterpene lactones from senecio jacobaea |
| CN103508988A (zh) * | 2012-06-27 | 2014-01-15 | 南开大学 | 1个新的蜂斗菜内酯(bakkenolide)型的倍半萜的制备及其应用 |
| CN106554349A (zh) * | 2016-11-22 | 2017-04-05 | 华北理工大学 | 野八角新异戊烯基取代c6‑c3类化合物及其制备方法、应用和其药物组合物 |
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| WO2011050481A1 (en) * | 2009-10-30 | 2011-05-05 | National Research Council Of Canada | New eremophilane sesquiterpene lactones from senecio jacobaea |
| CN103508988A (zh) * | 2012-06-27 | 2014-01-15 | 南开大学 | 1个新的蜂斗菜内酯(bakkenolide)型的倍半萜的制备及其应用 |
| CN106554349A (zh) * | 2016-11-22 | 2017-04-05 | 华北理工大学 | 野八角新异戊烯基取代c6‑c3类化合物及其制备方法、应用和其药物组合物 |
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