CN104434927A - 丙二酸双环戊烷并多氢菲酯b在制备降血压药物中的应用 - Google Patents
丙二酸双环戊烷并多氢菲酯b在制备降血压药物中的应用 Download PDFInfo
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- CN104434927A CN104434927A CN201410772143.4A CN201410772143A CN104434927A CN 104434927 A CN104434927 A CN 104434927A CN 201410772143 A CN201410772143 A CN 201410772143A CN 104434927 A CN104434927 A CN 104434927A
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- Prior art keywords
- malonate
- bicyclopentanoperhydrophenanthrene
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- ace
- dimethyl
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了丙二酸双(3S,10R,13R)-10,13-二甲基-17-((2R,E)-5,6-二甲基庚-3-烯-2-基)-2,3,4,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-3-酯（简称丙二酸双环戊烷并多氢菲酯B）的ACE抑制活性及其在制备降血压药物中的应用。属于中药有效成分的药物新用途。
Description
技术领域
本发明公开了丙二酸双环戊烷并多氢菲酯B的ACE抑制活性及其在制备降血压药物中的应用。属于中药有效成分的药物新用途。
背景技术
西洋参Panax quinquefolius是五加科人参属多年生草木植物，别名花旗参、洋参、西洋人参、American ginseng，原产于加拿大的大魁北克与美国的威斯康辛州，中国北京怀柔与长白山等地也有种植。加拿大产的叫西洋参，美国参产的叫花旗参，服用方法分为煮、炖、蒸食、切片含化、研成细粉冲服等。
树舌Ganoderma applanatum (Pers. Ex Wallr) Pat.，又称平盖树舌、赤色老母菌(《中国药用真菌》)、扁木树舌、扁芝(江苏)、扁蕈、白斑腐菌、皂角菌(四川)。子实体大型或特大型。无柄或几乎无柄。菌盖半圆形，扁半球形或扁平，表面灰色，渐变褐色，有同心环纹棱，有时有瘤，皮壳胶角质，边缘较薄。菌肉浅栗色，菌孔圆形。生于杨、桦、柳、栎等阔叶树的枯立木、倒木和伐桩上，是重要的木腐菌之一，会导致木材木质部形成白色腐朽，可药用。在中国和日本民间作为抗癌药物。还可以治闻风湿性肺结核，有止痛、清热、化积、止血、化痰之功效。主要活性成分包括多糖、甾体化合物、三萜、脂类、氨基酸、多肽、蛋白质类、生物碱类、酚类、内酯、香豆素类和苷类以及微量元素等。
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。原发性高血压的发病因素主要有两大类，一类是内因，如遗传；另一类是外因，如精神紧张、食盐过多、吸烟、肥胖、酗酒、缺乏运动等。长期高血压可影响到心、脑、肾等器官的功能，最终导致这些器官功能的衰竭。高血压属多发病，上世纪80年代，中国高血压发病率为7.7%；到了本世纪初，迅速上升到18.8%；而近10年，高血压的患病率增长了31%。目前，我国高血压病人估计已超过2亿，而且这一趋势仍会继续延续，短时期内不太可能出现逆转。如果再不加以控制，在今后的15年中将增长50%。降压药物种类主要包括利尿药、β受体阻滞剂、钙通道阻滞剂、血管紧张素转换酶抑制剂、血管紧张素II受体阻滞剂。这些药物具有一定的副作用，如心脏抑制、代谢异常、肾脏损害等。且具有我国自主知识产权的降血压药物较少。
课题组在西洋参加工产品研究与开发过程中，发现西洋参与树舌共同加工处理（高温高压）后的产物具有较强的血管紧张素转化酶（ACE）抑制作用，进一步进行活性成分追踪，分离得到了丙二酸双(3S,10R,13R)-10,13-二甲基-17-((2R,E)-5,6-二甲基庚-3-烯-2-基)-2,3,4,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-3-酯[bis((3S,10R,13R)-17-((2R,E)-5,6-dimethylhept-3-en-2-yl)-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl) malonate]，简称丙二酸双环戊烷并多氢菲酯B，经测定该化合物对ACE的半数抑制率（IC50）达到31μg/mL。进一步分析丙二酸双环戊烷并多氢菲酯B的来源，该化合物在西洋参、树舌、西洋参高温高压处理产物、树舌高温高压处理产物中均未被检出，说明该化合物是西洋参、树舌组方并在高温高压处理后产生的。丙二酸双环戊烷并多氢菲酯B有望成为新的降血压药物。
发明内容
本发明提供了丙二酸双(3S,10R,13R)-10,13-二甲基-17-((2R,E)-5,6-二甲基庚-3-烯-2-基)-2,3,4,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-3-酯（简称丙二酸双环戊烷并多氢菲酯B）在制备降血压药物中的用途。丙二酸双环戊烷并多氢菲酯B的化学结构如下式：
当本发明用于制备治疗高血压的药物时，其口服或胃肠外给药，均是安全的。在口服情况下，其可以任何常规形式给药，如散剂、粒剂、片剂、胶囊剂、丸剂、溶液剂、悬浮液、糖浆、口腔含片、舌下含片等；当该药物肠胃外给药时，可采取任何常规形式，例如静脉内注射剂、软膏剂、栓剂、和吸入剂等。
本发明制备治疗高血压的的药物是由有效成分单体或有效成分与固体或液体的赋形剂一起构成的，这里使用的固体或液体的赋形剂在本领域是众所周知的，下面举几个具体例子，散剂是内服的粉末剂，它的赋形剂有乳糖、淀粉、浆糊精、碳酸钙、合成或天然硫酸铝、氧化镁、硬脂酸镁，碳酸氢钠、干燥酵母等；溶液剂的赋形剂有水、甘油、1，2-丙二醇、单糖浆、乙醇、乙二醇、聚乙二醇、山梨糖醇等；软膏剂的赋形剂可以使用脂油，含水羊毛脂、凡士林、甘油、蜂腊、木腊、液体石腊、树脂、高级腊等组合成的疏水剂或亲水剂。
本发明的有益效果在于，丙二酸双环戊烷并多氢菲酯B可用于制备降血压药物，具有疗效显著的特点，其对ACE抑制的IC50可达31μg/mL。下述的实验证实了丙二酸双环戊烷并多氢菲酯B的这一生物活性。
具体实施方式
实施例：
取树舌200g，粉碎，加水2L，高温高压处理4h，过滤，得树舌浸出液；另取生晒参1000g，粉碎，以上述树舌浸出液浸润后，高温高压蒸制4h，取出，干燥，即得西洋参树舌高温高压处理产物；所得的西洋参树舌高温高压处理产物，以氯仿浸提3次，每次5L，合并氯仿提取液，蒸干，得氯仿提取物；所得的氯仿提取物，以硅胶为吸附剂进行柱层析，以石油醚-二氯甲烷（20：1~1：1）进行梯度洗脱，收集丙二酸双环戊烷并多氢菲酯B部分洗脱液，回收溶剂，得丙二酸双环戊烷并多氢菲酯B粗品，再进行硅胶柱层析，以石油醚-丙酮（10：1）为洗脱剂洗脱，收集丙二酸双环戊烷并多氢菲酯B部分洗脱液，回收溶剂，以石油醚-丙酮重结晶，得丙二酸双环戊烷并多氢菲酯B。
1.结构鉴定：
MS：质谱测定其分子离子峰为860.4，结合IR、1H NMR、13C NMR确定其分子式为C59H88O4。
IR光谱：3083 cm-1为双键碳氢伸缩振动峰（υCH），2986-2872 cm-1为饱和烷烃碳氢键的伸缩振动峰（υCH），证明饱和烷烃基团的存在；1726 cm-1为羰基的伸缩振动峰（υC=O），说明该化合物中存在羰基；1699 cm-1为υC=C，说明碳碳双键的存在；1380 cm-1、1370 cm-1为甲基的变形振动峰（δ CH3）。
1H NMR (300 MHz, CDCl3) δppm：5.572 (d, 1H, J=5.7Hz)、5.381 (d, 1H, J=5.7Hz)、5.210 (dd, 1H, J=4.2,7.2Hz)、5.190 (dd, 1H, J=4.2,7.2Hz)为甾体母核6、7、3’、4’位烯氢信号，4.746 (m, 1H)为甾体母核3位连氧碳上氢信号，2.036 (s, 2H)为丙二酸基团中的两个次甲基氢信号，1.041 (d, 3H, J=6.6Hz)、0.945 (s, 3H)、0.921 (d, 3H, J=6.9Hz)、0.842 (d, 3H, J=6.9Hz)、0.827 (d, 3H, J=6.9Hz)、0.620 (s, 3H)为甾体母核及17位侧链上6个甲基氢信号，2.531~0.534为甾体母核及17位侧链其它饱和碳上氢信号，以上数据说明甾体结构和丙二酸基团的存在。
13C NMR (75 MHz, CDCl3) δppm：碳谱数据共给出59个碳信号，具体如下。170.46为羰基碳信号，42.73为丙二酸次甲基信号，共同构成了丙二酸基团；138.45、120.12、116.22、141.42、135.48、131.89为甾体母核C5、C6、C7、C8、C3’、C4’不饱和碳信号，72.72为甾体母核3位连氧碳信号，55.62、54.44、45.95、42.73（×2）、40.36、38.94、37.83、37.01、36.57、33.01、28.21、28.03、21.91、21.03、20.94、19.88、19.57、17.53、16.08、11.98为甾体母核及17位侧链其它饱和碳信号。
结合1H NMR、13C NMR及IR光谱进一步综合分析确定该化合物为丙二酸双(3S,10R,13R)-10,13-二甲基-17-((2R,E)-5,6-二甲基庚-3-烯-2-基)-2,3,4,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-3-酯[bis((3S,10R,13R)-17-((2R,E)-5,6-dimethylhept-3-en-2-yl)-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl) malonate]，简称丙二酸双环戊烷并多氢菲酯B，该化合物的具体NMR信号归属如下：
1H NMR (300 MHz, CDCl3) δppm：5.572 (d, 1H, J=5.7Hz, 6-H)、5.381 (d, 1H, J=5.7Hz, 7-H)、5.210 (dd, 1H, J=4.2,7.2Hz, 3’-H)、5.190 (dd, 1H, J=4.2,7.2Hz, 4’-H)、4.746 (m, 1H, 3-H)、2.036 (s, 2H, 2’’-H)、1.041 (d, 3H, J=6.6Hz, 2’-CH3)、0.945 (s, 3H, 10-CH3)、0.921 (d, 3H, J=6.9Hz, 5’-CH3)、0.842 (d, 3H, J=6.9Hz, 6’-CH3)、0.827 (d, 3H, J=6.9Hz, 7’-H)、0.620 (s, 3H, 13-CH3)、2.531~0.534为甾体母核及17位侧链其它饱和碳上氢信号。
13C NMR (75 MHz, CDCl3) δppm：170.46 (C=O)、141.42 (C8)、138.45 (C5)、135.48 (C3’)、131.89 (C4’)、120.12 (C6)、116.22 (C7)、72.72 (C3)、55.62 (C17)、54.44 (C14)、45.95 (C9)、42.73 (C13,5’,2’’)、40.36 (C2’)、38.94 (C12)、37.83 (C1)、37.01 (C4)、36.57 (C10)、33.01 (C6’)、28.21 (C2)、28.03 (C16)、21.91 (C15)、21.03 (C11)、20.94 (C7’)、19.88 (6’-CH3)、19.57 (C1’)、17.53 (5’-CH3)、16.08 (10-CH3)、11.98 (13-CH3)。
2.ACEI抑制活性实验
肾素-血管紧张素-醛固酮系统（RAS)在高血压发生、发展中起重要作用，其中血管紧张素Ⅱ是主要的效应肽。ACEI抑制血管紧张素Ⅰ转换为血管紧张素Ⅱ，不灭活缓激肽，产生降压效应。本实验采用体外ACE抑制活性实验评价了丙二酸双环戊烷并多氢菲酯B及同时分离得到的、与化合物结构类似的、一已知化合物ergosterol的降血压活性。具体实验方法和结果如下。
2.1 ACE 的制备
将新鲜的猪肺用遇冷的0.9%NaCL溶液冲洗干净，洗去气管、脂肪，切成小块，去一定量的猪肺组织，用遇冷的含PH 8.3、0.1 mol/L 硼酸盐缓冲液5倍体积进行匀浆，将匀浆液置于冰箱中浸提5小时。4℃下离心（8000rmp）离心15 min，得粗提液（上清液）。冷冻干燥待用。
2.2 供试品溶液的制备
取10mg样品（丙二酸双环戊烷并多氢菲酯B或ergosterol）配制成5个不同浓度的提取物溶液。按下表顺序加入溶液，37℃保温5 min后，加入5 μL ACE溶液启动反应，37℃保温30 min后加入1 mol/L HCl溶液300 μL终止反应，10 000 r/min离心 10 min，吸取上清作为供试品溶液。
HHL 溶液：取适量的HHL，加入硼酸盐缓冲液配制成浓度为 5 mmol/L 的 HHL 溶液。
2.3 马尿酸含量测定
色谱条件：LC 3000-C18色谱柱（4.6 mm×250 mm，5 μm）（大连江申分离科学技术公司），流动相甲醇：三氟乙酸水（0.01%），流动相梯度为（0 min，60％B；3 min，60％B；3.01 min，100％B；6 min，100％B；6.01 min，60％B；8 min，60％B），检测波长 228 nm，流速1.0 mL/min，柱温 25℃，进样量20 μL。
马尿酸对照液：取马尿酸适量，加入硼酸盐缓冲液配制成浓度为0.1 mmol/L的马尿酸对照品溶液。
分别精密吸取供试品溶液及马尿酸对照品溶液注入高效液相色谱仪，记录色谱图，通过外标一点法计算马尿酸的含量。
2.4 ACE 抑制率的计算
计算公式如下：R=(A-B)/A×100%
式中， A 和 B 分别为空白对照组和试验组马尿酸的峰面积。
对ACE抑制活性用IC50 值表示，IC50 值采用SPSS软件计算获得。
2.5 ACE 抑制活性结果与结论
采用以上的实验获得了丙二酸双环戊烷并多氢菲酯B及ergosterol对ACE抑制活性的IC50值。丙二酸双环戊烷并多氢菲酯B对ACE的IC50=31μg/mL，而ergosterol对ACE的IC50=892μg/mL。实验结果表明丙二酸双环戊烷并多氢菲酯B具有较强的ACE抑制活性，其对ACE的抑制作用是已知化合物ergosterol的近30倍。该丙二酸双环戊烷并多氢菲酯B将有望成为新的降血压药物。
Claims (1)
1.丙二酸双(3S,10R,13R)-10,13-二甲基-17-((2R,E)-5,6-二甲基庚-3-烯-2-基)-2,3,4,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-3-酯在制备降血压药物中的应用。
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| WO2011078323A1 (ja) * | 2009-12-25 | 2011-06-30 | 花王株式会社 | 活性酸素産生抑制剤及び血圧低下剤 |
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