CN103641688B - 脉络宁二氢蒽及其制备方法和用途 - Google Patents
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- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
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- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
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Abstract
本发明涉及医药技术领域,提供了一种具有治疗心血管疾病的二氢蒽类新化合物——脉络宁二氢蒽,化学名:2,3,6,7-四羟基-9,10-二甲基-9,10-二氢蒽(2,3,6,7-tetrahydroxy-9,10-dimethyl-9,10-dihydroanthracene),结构式如下:
Description
一、技术领域:
本发明涉及医药技术领域,是一种具有治疗心血管疾病的新化合物——脉络宁二氢蒽,化学名:2,3,6,7-四羟基-9,10-二甲基-9,10-二氢蒽(2,3,6,7-tetrahydroxy-9,10-dimethyl-9,10-dihydroanthracene)的制备方法和在医药领域中的治疗心血管疾病的用途。具体涉及从脉络宁注射液中提取分离得到的一种新化合物,该化合物具有对DPPH自由基、·OH自由基和O2 -·自由基的清除作用,研究结果发现脉络宁二氢蒽具有很好的抗炎活性,在1μM脉络宁二氢蒽剂量组抑制率分别达到68.43%、64.24%和61.19%,可用于制备治疗心血管疾病的药物。
二、技术背景:
中药复方制剂脉络宁注射液是在著名医方“四妙勇安汤”临床应用的基础上研究开发出来的、具有自立知识产权的,并于1985年正式批准生产的中药复方静脉注射剂,由中药石斛、玄参、牛膝、金银花、山银花经科学提取精制而成。具有活血化淤、行气止痛、养阴通络和补益肝肾的功效,主要用于治疗缺血性中风急性期、血栓闭塞性脉管炎、下肢深静脉血栓形成、动脉硬化性闭塞症、脑梗塞、心绞痛、心肌梗死、血液循环障碍及其后遗症等疾病,总有效率可达94.5%,与同类药品比较具有见效快、疗效高、疗程短、价格低廉、副作用少、安全性高等优点。
越来越多的科学研究证实自由基是人体疾病和衰老的直接制造者,人寿命的长短与自由基的产生及人体内抗氧化剂的浓度有着密切的关联,许多报道指出,增加抗氧化剂的摄入量可有效降低癌症及冠心病高发人群的发病率。然而研究发现,合成的抗氧化剂对人体具有潜在的威胁,因此,研究开发广谱、高效、安全的天然抗氧化剂已成为当今研究的热点之一。
三、发明内容:
本发明提供一种具有显著抑制自由基的新化合物——脉络宁二氢蒽的制备方法和在医药领域中治疗心血管疾病的用途。
本发明公开了该化合物的结构式(见摘要附图)
分子式为:C16H16O4,不饱和度为9。分子量:272。
命名为:脉络宁二氢蒽,化学名:2,3,6,7-四羟基-9,10-二甲基-9,10-二氢蒽(2,3,6,7-tetrahydroxy-9,10-dimethyl-9,10-dihydroanthracene)。
本发明中上述化合物的制备方法如下:
其特征在于以脉络宁注射液为原料,经反复通过硅胶或球形硅胶、Sephadex LH-20(Sep.)凝胶柱层析、反相材料ODS中的一种或几种柱层析和重结晶等手段分离纯化得到该化合物。
本发明的新化合物及其衍生物与医学上可接受的药用辅料组成药物制剂用于治疗心血管疾病。可制备的剂型有:片剂、胶囊剂、颗粒剂和注射剂。
四、附图说明:
以下图可作为附件材料上报。
图1、化合物的1H-NMR谱 图2、化合物的13C-NMR谱
图3、化合物的DEPT谱 图4、化合物的1H-1H COSY的谱
图5、化合物的HSQC谱 图6、化合物的HMBC谱
图7、化合物的ROESY谱 图8、化合物的ESI-MS谱
五、具体实施方式:
结合具体实施方式对本发明作进一步说明,但本发明的内容并不仅仅限于所列举的实施方式。
实施例1.从脉络宁注射液中分离和鉴定该新化合物
开启脉络宁注射液700支约7000mL,经Sephadex LH-20柱(7.5×120em),50%乙醇洗脱,共收集10个流份,流份1、2色素重,流份7、8分别反复经硅胶柱、Sephadex LH-20柱、反相柱层析从脉络宁注射液中得到该单体化合物,通过理化性质、波谱方法鉴定为脉络宁二氢蒽,经文献检索该化合物是新化合物。
该化合物结构经核磁共振谱鉴定如下:
无色针状结晶,易溶于甲醇、丙酮等有机溶剂。用TLC法显示在254nm紫外灯光下有暗斑,喷浓硫酸-香草醛显色剂并加热后显鲜红色。ESI-MS(m/z):273([M+H]+)得出其分子量为272。化合物的碳、氢谱信号较少,结合分子量推测该化合物为结构对称的化合物,算出化合物分子式为C16H16O4,不饱和度为9。
1H-NMR谱(300MHz,DMSO-d6)中的δ8.59(2H,s)为苯环上酚羟基氢质子信号;化学位移为6.60(2H,s)是苯环上的氢质子信号,而且为单峰,所以可以推出两个H原子位于苯环的对位;δ3.66(1H,q,JA=7.1Hz)的氢原子说明化合物中含有连接甲基的叔碳原子,而且从COSY谱中的δ3.66和δ1.31(3H,d,J=7.1Hz)相关可以进一步证实。
13C-NMR(300MHz)谱的δ143.4、δ131.7、δ114.4为苯环碳原子化学位移,δ38.7和δ29.0是侧链碳原子,结合DEPT谱可以看出化合物中没有亚甲基,δ29.0(q)为甲基碳原子,δ114.4(d)和δ38.7(d)是叔碳原子信号;δ143.4(s)、δ131.7(s)是季碳原子信号。
HSQC谱可以得出δ8.59的氢原子和δ114.4的碳原子相连,δ3.66的氢原子和δ38.7的碳原子相连,δ1.31的氢原子和δ29.0的碳原子相连。
从HMBC谱可以看出:δ6.60的氢与δ38.7、131.7和143.4的碳原子均有相关信号,说明连有甲基的叔碳原子与苯环直接相连。ROESY谱图显示的苯环氢原子和叔碳氢原子、甲基氢原子、羟基氢原子均有相关。
综合以上信息,考虑到化合物为对称结构,推断化合物的结构(见摘要附图)。将化合物结构输入Science Finder进行检索,发现这是一个新化合物。化学名:2,3,6,7-四羟基-9,10-二甲基-9,10-二氢蒽(2,3,6,7-tetrahydroxy-9,10-dimethyl-9,10-dihydroanthracene)。将其中文名命名为:脉络宁二氢蒽(mailuoning dihydroanthracene)。
该化合物的1H-NMR(300MHz),13C-NMR(75MHz)的信号全归属及相互间相关关系
实施例2.
清除DPPH自由基实验
取脉络宁二氢蒽,DMSO溶解,配制成10mg/ml的母液。DPPH用无水乙醇配制成0.16mmol/L,置于棕色瓶中备用。在96孔板中,每孔分别加入100μl0.16mmol/L的DPPH溶液,2μl样品溶液,98μl蒸馏水,反应体系200μl。加样后室温振荡15min,将96孔板放入酶标仪中在517nm波长处检测样品吸光度(Ai);取20μl DMSO代替样品溶液测得空白吸光度(A0);以100μl无水乙醇代替DPPH溶液测得样品本底吸光度(Aj);每个浓度做4个平行,取其平均值。以Vc作阳性对照,按如下公式计算清除率。
对羟自由基(.OH)的清除作用
向干净的96孔板中分别加入质量浓度为10mg/mL的脉络宁二氢蒽2μL,用蒸馏水补齐至50μL,然后每孔依次加入6mmol/L的FeSO4溶液50μL,6mmol/L的H20250μL,摇匀,静置10min后,再向其中加入6mmol/L的水杨酸溶液50μL,混匀。在37℃条件下反应30min后将96孔板放入酶标仪中于510nm波长处测吸光值(Ai);用DMSO代替体系中的样品,测得空白吸光值(Ao);用蒸馏水代替体系中的水杨酸,测得样品本底吸光值(Aj)。每个检测做4个重复,取其平均值。以Vc作阳性对照,按下面公式计算清除率:
对超氧阴离子自由基(O2·)的清除作用
向干净的96孔板中分别加入质量浓度为10mg/mL的各提取物2μL,然后依次加入0.05mol/L Tris-HCl缓冲溶液(pH8.2)50μL,用蒸馏水补齐至190μL,摇匀,置于25℃水浴中预热20min后,再分别加入10μL用10mM HCl配成的25mM焦性没食子酸,混匀后于25℃水溶液中反应5min,于299nm处测吸光值(Ai);用DMSO代替体系中的样品,测得空白吸光值(Ao);用10mM HCl代替体系中的焦性没食子酸,测得样品本底吸光值(Aj)。每个检测做4个重复,取其平均值。以Vc作阳性对照,清除率计算公式为:
对DPPH自由基的清除作用
DPPH是一种稳定的自由基,在有机溶剂中呈紫色,在517nh波长处有较大吸收,当加入抗氧化剂时,一部分自由基被清除掉,使该波长下吸收强度减弱,可借此来评价某物质的抗氧化活性。
对羟基自由基(.OH)的清除作用
参照Fenton反应的方法建立反应体系模型,利用H2O2与Fe2+混合产生.OH,但由于.OH具有很高的反应活性,存活时间短,若在体系中加入水杨酸,就能有效地捕捉.OH,并产生有色产物。该产物在510nm波长处有强吸收,若在反应体系中加入具有清除.OH功能的被测物,便会与水杨酸竞争.OH,而使有色产物生成量减少,采用固定反应时间法,在相同体积的反应体系加入一系列不同浓度的小麦麸皮总黄酮提取液,并以蒸馏水为参比,与试剂空白液比较,通过在510nm波长处测量各浓度下的吸光度A,便能检测被测物对.OH的清除作用。
对超氧阴离子自由基(O2 -.)的清除作用
在碱性条件下邻苯三酚发生自氧化反应生成O2 -.和中间体,该中间产物在299nm波长处有一特征吸收峰,当加入O2 -.清除剂时,O2 -.的生成受到抑制,邻苯三酚自氧化过程受阻,溶液在299nm波长处吸收减弱。因此,通过测定某物质对邻苯三酚自氧化的抑制作用,即可表征其对超氧阴离子自由基的清除作用。
表1 脉络宁二氢蒽对DPPH、.OH、和O2 -.自由基的清除作用(%)
4结论
人体内的自由基过量产生是人体细胞衰老凋亡和癌变的重要原因,研究发现酚类物质可作为抗氧化药物对心血管起保护作用。本发明探讨了脉络宁二氢蒽对DPPH自由基、·OH自由基和O2 -·自由基的清除作用,研究结果发现脉络宁二氢蒽具有很好的抗炎活性,在1μM脉络宁二氢蒽剂量组抑制率分别达到68.43%、64.24%和61.19%,可用于制备治疗心血管疾病的药物。
Claims (6)
1.一种二氢蒽类化合物,其特征在于该化合物的化学结构式为:
2.权利要求1所述脉络宁二氢蒽的制备方法,其特征在于以金陵药业股份有限公司生产的脉络宁注射液为原料,通过多次硅胶柱层析,经石油醚-乙酸乙酯-丙酮溶剂系统或者氯仿-甲醇溶剂系统分离,再经Sephadex LH-20柱层析或ODS反相柱层析,经甲醇、乙醇或者甲醇-水、乙醇-水不同比例的溶液洗脱而得。
3.权利要求2所述的制备方法,其特征在于所述的柱层析用担体选自硅胶、凝胶、反相硅胶中的一种或几种。
4.权利要求1所述的脉络宁二氢蒽与医学上可接受的药用辅料组成的药物制剂。
5.权利要求4所述的药物制剂,其特征在于制剂剂型为片剂、胶囊剂、颗粒剂或注射剂。
6.权利要求1所述的脉络宁二氢蒽在制备治疗心脑血管疾病药物方面的用途。
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