CN1304723A - 含二氢呋喃环结构的丹参酮类化合物用于治疗肝性脑病的药物 - Google Patents
含二氢呋喃环结构的丹参酮类化合物用于治疗肝性脑病的药物 Download PDFInfo
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Abstract
本发明涉及含二氢呋喃环结构的丹参酮类化合物隐丹参酮及二氢丹参酮Ⅰ在制备用于治疗肝性脑病等疾病的药物中的应用。实验证明,该类化合物可用于降低体内有毒的含N代谢产物,如血液中过高浓度的血氨、苯乙胺等,从而可用于治疗如肝性脑病等疾病。所说的含二氢呋喃环结构的丹参酮类化合物的化学结构式如式Ⅰ所示,式中R如说明书所定义。
Description
本发明涉及一类含二氢呋喃环结构的丹参酮类化合物在制备治疗因血液中氨和苯乙胺浓度过高而引起的脑昏迷等疾病的药物中的应用。
肝性脑病(Hepatic encephalopathy,HE)，是一种以代射紊乱为基础的中枢神经系统功能失调的综合病症，其主要临床表现是意识障碍、行为失常和昏迷(药理学，李玉玲主编，人民卫生出版社，2000年，p340-350)。
肝性脑病的发病机制主要有两种原因。一是由于肝功能失常引起血氨升高，高浓度血氨能透过血脑屏障。氨对脑毒性主要表现为对脑的能量代谢的影响，使高能磷酸化合物、某些辅酶及α-酮戊二酸的浓度降低。一般情况下，肝脏能将大部分体内代谢产生的对人体有毒的物质氨合成尿素，经肾排出。肝细胞受损时，清除氨的功能减退，血氨因此增高。另外，当碱中毒时，体内离子型铵转变成分子氨，也能使氨浓度升高，引起肝性脑病。二是伪神经递质的作用。肠道中一些氨基酸如苯丙氨酸等经脱羧酶作用形成苯乙胺，正常情况下它们可在肝内被分解而清除，肝功能失常时，血液中苯乙胺浓度增高，并通过血脑屏障进入脑组织，在神经细胞内经酶作用转变成苯乙醇胺，它们在结构上与正常神经递质如去甲肾上腺素等非常相似但生理效应远比正常递质弱，导致神经功能失常。
去除血液中高浓度的氨和苯乙胺等能有效改善肝昏迷症状。目前用于治疗因血氨增高的肝性脑病的药物有乳果糖、阿波莫斯(Hepa-Merz)及谷氨酸钠等[药物，王汝龙，原正平主编，化学工业出版社，第三版(1999)]，但均有其局限性，如其用量大，降血氨时需体内酶的参与，且不适用于糖尿病患者及肾功能衰竭者，效果也不理想。
丹参是唇形科植物丹参(Salvia miltiorrhiza Bunge)的干燥根及根茎，性苦、微寒，归心、肝经。作为传统中药，在临床方药中被广泛应用，主要用于祛瘀止痛，活血通经，清心除烦。近年来的研究发现它的主要生理活性可以大致归纳为如下几个方面。
1．促进肝细胞DNA的合成，对肝损伤具保护作用以及对肝细胞再生具有促进作用；有减轻肺纤维化及抗结核作用。
2．抑制溃疡，有保持胃粘膜屏障完整性增强其防御机能的作用。
3．改善诱导性肾功能衰竭，大鼠尿毒症症状。明显降低尿素氮、肌肝、甲基胍、胍基丁二酸的血清浓度，能促进肾功能恢复。
4．扩张冠状动脉，增加冠脉流量，防治心肌梗塞。抗氧自由基，活血化瘀。抑制血小板，促进纤溶活性。
5．镇痛，对中枢神经系统的抑制。抗炎，抑菌。抗肿瘤。
本发明的目的是开发含二氢呋喃环结构的丹参酮类化合物的新的医药用途，即用于制备治疗肝性脑病的药物。
本发明所说的含二氢呋喃环结构的丹参酮类化合物的结构如式Ⅰ所示，式Ⅰ中的R基团为-CH2CH2CH2C(CH3)2-或-CHCHCHC(CH3)-。
我们的研究表明，含二氢呋喃环结构的丹参酮类化合物隐丹参酮〔R基团为-CH2CH2CH2C(CH3)2-〕及二氢丹参酮Ⅰ(R基团为-CHCHCHC(CH3)-)能与氨和苯乙胺等反应形成新的丹参酮类衍生物，揭示这类化合物对治疗肝性脑病具有独特的作用。其反应式如下所示，式中R如式Ⅰ所定义：
本发明所说的含二氢呋喃环结构的丹参酮类化合物可从丹参中提取、分离和纯化。
本发明通过进行体外实验和动物药理实验，确定含二氢呋喃环结构的丹参酮类化合物隐丹参酮及二氢丹参酮Ⅰ能降低水溶液或缓冲溶液中氨和苯乙胺等的浓度；能有效降低小鼠血氨浓度，显示可成为治疗肝性脑病的有效药物。
本发明的实验说明，含二氢呋喃环结构的丹参酮类化合物隐丹参酮及二氢丹参酮Ⅰ能与氨、苯乙胺等作用形成丹参酮类衍生物，有效降低体内有毒的含氮代谢产物，如血液中过高浓度的血氨和苯乙胺等，从而治疗肝性脑病。因此，二氢丹参酮类化合物隐丹参酮及二氢丹参酮Ⅰ可用于制备治疗肝性脑病的药物。由于丹参酮对肝肾功能具有良好的促进恢复作用，因而以本发明涉及的二氢丹参酮类化合物为主的药物制剂不仅能有效降低血氨和苯乙胺等而改善肝性脑病症状，还能促进肝功能的有效恢复，从而可能对肝性脑病起到理想的治疗作用。
以下通过实施例对本发明做进一步说明。
实施例一：丹参中二氢丹参酮Ⅰ的提取、分离及纯化
干燥丹参1kg，用95％乙醇抽提3次，每次24小时，抽提液减压浓缩至500mL，然后加入500mL水，用1000mL三氯甲烷分四次萃取，萃取液减压浓缩，柱层析分离，硅胶为100-200目，洗脱液为含1％-20％的乙酸乙酯的石油醚/乙酸乙酯混合溶液，进行梯度洗脱。可得二氢丹参酮Ⅰ约0.55g。
实施例二：丹参中隐丹参酮的提取、分离及纯化
干燥丹参1kg，用95％乙醇抽提3次，每次24小时，抽提液减压浓缩至500mL，然后加入500mL水，用1000mL三氯甲烷分四次萃取，萃取液减压浓缩，柱层析分离，硅胶为100-200目，洗脱液为含10％-50％的乙酸乙酯的石油醚/乙酸乙酯混合溶液，进行梯度洗脱。可得隐丹参酮约1.20g。
施例三：二氢丹参酮Ⅰ体外与氨的作用
试管中，加入0.5mmol的氨及30mL水，再加入溶于1.0mL乙醇中0.5mmol的二氢丹参酮Ⅰ，在37±5℃振荡2～8小时，用TLC进行监测，柱层析分离，可得二氢丹参酮Ⅰ与氨的作用产物1-Amino-2-(1’-hydroxy-2’-propyl)-8-methyl-phenanthrene-3,4-dione和3-Amino-2-(1’-hydroxy-2’-propyl)-8-methyl-phenanthrene-1,4-dione，产物结构已经13C-1HNMR、MS及元素分析等数据证明，表明二氢丹参酮Ⅰ能在体外与氨发生反应而降低其浓度。
实施例四：二氢丹参酮Ⅰ体外与苯乙胺的作用
试管中，加入0.5mmol的苯乙胺及30mL水，再加入溶于1.0mL乙醇中0.5mmol的二氢丹参酮Ⅰ，在37±5℃振荡2～8小时，用TLC进行监测，可得二氢丹参酮Ⅰ与苯乙胺的作用产物2-Benzyl-4,9-dimethyl-4,5-dihydro-1,6-dioxa-3-aza-dicyclopenta[a,c]phenanthrene和2-(1’-hydroxy-2’-propyl)-8-methyl-3-phenethylamino-4-phenethylimino-4H-phenanthren-1-one，产物结构已经13C-1HNMR、MS及元素分析等数据证明，表明二氢丹参酮Ⅰ能在体外与苯乙胺发生反应而降低其浓度
实施例五：隐丹参酮体外与氨的作用
试管中，加入0.5mmol的氨及30mL水，再分别加入溶于1.0mL乙醇中0.5mmol的隐丹参酮，在37±5℃振荡0.5～3小时，用TLC进行监测，可得隐丹参酮与氨的作用产物1-Amino-2-(1’-hydroxy-2’-propyl)-8,8-dimethyl-5,6,7,8-tetrahydro-phenanthrene-3,4-dione和3-Amino-2-(1’-hydroxy-2’-propyl)-8,8-dimethyl-5,6,7,8-tetrahydro-phenanthrene-1,4-dione，产物结构已经13C-1HNMR、MS及元素分析等数据证明，表明隐丹参酮能在体外与氨发生反应而降低其浓度。
实施例六：隐丹参酮体外与苯乙胺的作用
试管中，加入0.5mmol的苯乙胺及30mL水，再加入溶于1.0mL乙醇中0.5mmoi的隐丹参酮，在37±5℃振荡0.5～3小时，用TLC监测，可得隐丹参酮与苯乙胺的作用产物2-Benzyl-4,9,9-trimethyl-4,5,9,10,11,12-hexahydro-1,6-dioxa-3-aza-dicyclopenta[a,c]phenanthrene和2-(1’-hydroxy-2’-propyl)-8,8-dimethyl-3-phenethylamino-4-phenethylimino-5,6,7,8-tetrahydro-4H-phenanthren-l-one，产物结构已经13C-1HNMR、MS及元素分析等数据证明，表明隐丹参酮能在体外与苯乙胺发生反应而降低其浓度。
实施例七：丹参酮ⅡA(含呋喃环结构的丹参酮类化合物)体外与氨的作用
按实施例三的条件，以丹参酮ⅡA取代二氢丹参酮Ⅰ,TLC监测，在48小时内未见明显反应。表明丹参酮ⅡA与氨在此条件下无相互作用。
实施例八：丹参酮ⅡA体外与苯乙胺的作用
按实施例四的条件，以丹参酮ⅡA取代二氢丹参酮Ⅰ,TLC监测，在48小时内未见明显反应。表明丹参酮ⅡA与苯乙胺在此条件下无相互作用。
实施例九：二氢丹参酮Ⅰ降血氨的动物实验(注射)
实验用动物为成年雄性小鼠45只，体重为270-320g，分空白对照组，醋酸胺组、二氢丹参酮Ⅰ/醋酸胺组、丹参酮ⅡA/醋酸胺组及谷氨酸钠/醋酸胺五组。分别由腹腔注射剂量为10mmol/kg醋酸胺的生理盐水溶液，其中空白对照组注射生理盐水。30分钟后分别由腹腔注射生理盐水、生理盐水、二氢丹参酮Ⅰ的生理盐水溶液(含少量表面活性剂，剂量为10mmol/kg)、丹参酮ⅡA的生理盐水溶液(含少量表面活性剂，剂量为10mmol/kg)、谷氨酸钠的生理盐水溶液(剂量为10mmol/kg)，1h后抽取血液样本，立即封存于-5℃的冰盐水中，并在-5℃下离心，取清液，用酶法进行分析。其结果如下(括号内为实验动物数)：
| 组别 | 空白对照 | 醋酸胺 | 二氢丹参酮Ⅰ/醋酸胺 | 丹参酮ⅡA/醋酸胺 | 谷氨酸钠/醋酸胺 |
| 血氨浓度(μmol/L) | 45±9(5) | 135±12(10) | 71±7(10) | 130±11(10) | 98±8(10) |
实施例十：隐丹参酮降血氨的动物实验(注射)
实施例九的实验条件下，以隐丹参酮/醋酸胺组取代二氢丹参酮Ⅰ/醋酸胺组，腹腔注射剂量为10mmol/kg醋酸胺的生理盐水溶液(其中空白对照组注射生理盐水)，30分钟后，分别由腹腔注射生理盐水、生理盐水、隐丹参酮的生理盐水溶液(含少量表面活性剂，剂量为10mmol/kg)、丹参酮ⅡA的生理盐水溶液(含少量表面活性剂，剂量为10mmol/kg)及谷氨酸钠的生理盐水溶液(剂量为10mmol/kg)，1h后抽取血液样本，立即封存于-5℃的冰盐水中，并在-5℃下离心，取清液，用酶法进行分析。其结果如下(括号内为实验动物数)：
| 组别 | 空白对照 | 醋酸胺 | 隐丹参酮/醋酸胺 | 丹参酮ⅡA/醋酸胺 | 谷氨酸钠/醋酸胺 |
| 血氨浓度(μmol/L) | 45±9(5) | 135±12(10) | 65±4(10) | 130±11(10) | 98±8(10) |
实施例十一：二氢丹参酮Ⅰ降血氨的动物实验(喂食)
实验用动物为成年雄性小鼠45只，体重为240-285g,分空白对照组，醋酸胺组、二氢丹参酮Ⅰ/醋酸胺组、丹参酮ⅡA/醋酸胺及谷氨酸钠/醋酸胺五组。除空白组外，均喂食剂量为40mmol/kg/d的醋酸胺，其中二氢丹参酮Ⅰ/醋酸胺组、丹参酮ⅡA/醋酸胺及谷氨酸钠/醋酸胺组同时分别喂食剂量为40mmol/kg/d的二氢丹参酮Ⅰ、丹参酮ⅡA和谷氨酸钠，连续喂食3天后再分别抽取血液样本，立即封存于-5℃的冰盐水中，并在-5℃下离心，取清液，用酶法进行分析。其结果如下(括号内为实验动物数)：
| 组别 | 空白孹照 | 醋酸胺 | 二氢丹参酮Ⅰ/醋酸胺 | 丹参酮ⅡA/醋酸胺 | 谷氨酸钠/醋酸胺 |
| 血氨浓度(μmol/L) | 55±8(5) | 125±l0(10) | 102±9(10) | 128±12(10) | 110±8(10) |
实施例十二：隐丹参酮降血氨的动物实验(喂食)
实施例十一的实验条件下，以隐丹参酮/醋酸胺组取代二氢丹参酮Ⅰ/醋酸胺组，除空白组外，均喂食剂量为40mmol/kg/d的醋酸胺，其中隐丹参酮/醋酸胺组、丹参酮ⅡA/醋酸胺及谷氨酸钠/醋酸胺组同时分别喂食剂量为40mmol/kg/d的隐丹参酮、丹参酮ⅡA和谷氨酸钠，连续喂食3天后再分别抽取血液样本，立即封存于-5℃的冰盐水中，并在-5℃下离心，取清液，用酶法进行分析。其结果如下(括号内为实验动物数)：
| 组别 | 空白对照 | 醋酸胺 | 隐丹参酮/醋酸胺 | 丹参酮ⅡA/醋酸胺 | 谷氨酸钠/醋酸胺 |
| 血氨浓度(μmol/L) | 55±8(5) | 125±10(10) | 92±6(10) | 128±12(10) | 110±8(10) |
上述实例证明，具有二氢呋喃环结构的丹参酮类化合物能在生理条件下与氨或苯乙胺作用，从而达到清除血液中氨和苯乙胺的目的。具有其他结构特征的丹参酮类化合物如丹参酮ⅡA等，则无此功能。由于二氢丹参酮Ⅰ和隐丹参酮清除血氨和苯乙胺反应不需要酶的参与，因此其清除血氨和苯乙胺的功能适应性更广，而且更有效。显示二氢丹参酮Ⅰ和隐丹参酮可用于制备治疗由于肝功能不正常而导致的血液中氨和苯乙胺浓度增高引起的脑昏迷疾病。
Claims (1)
1、式Ⅰ所示的含二氢呋喃环结构的丹参酮类化合物用于制备治疗肝性脑病的药物，式Ⅰ中的R基团为-CH2CH2CH2C(CH3)2-或-CHCHCHC(CH3)-。
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| CNB018197604A CN1210025C (zh) | 2001-01-16 | 2001-05-24 | 用于治疗高血氨症及肝性脑病的含二氢呋喃环结构的丹参酮类化合物 |
| US10/399,468 US20040024056A1 (en) | 2001-01-16 | 2001-05-24 | Dihydrofuran cyclic tanshinones used in treating hyperammonemia and hepatic encephalopathy |
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| PCT/CN2001/000861 WO2002055070A1 (fr) | 2001-01-16 | 2001-05-24 | Tanshinones cycliques de dihydrofuranne utilisees pour le traitement de l'hyperammoniemie et de l'encephalopathie hepatique |
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| CN1277840A (zh) * | 2000-07-11 | 2000-12-27 | 上海维来现代科技发展有限公司 | 丹参酮固体分散物及其制备方法 |
| US20020077352A1 (en) * | 2000-08-03 | 2002-06-20 | Sucher Nikolaus J. | N-methyl-D-aspartate receptor antagonists |
| CN1286083A (zh) * | 2000-08-08 | 2001-03-07 | 上海维来现代科技发展有限公司 | 丹参酮微粉制剂及其微波辅助共研磨制备方法 |
-
2001
- 2001-01-16 CN CN01107460A patent/CN1304723A/zh active Pending
- 2001-05-24 CN CNB018197604A patent/CN1210025C/zh not_active Expired - Fee Related
- 2001-05-24 JP JP2002555804A patent/JP2004517134A/ja active Pending
- 2001-05-24 US US10/399,468 patent/US20040024056A1/en not_active Abandoned
- 2001-05-24 WO PCT/CN2001/000861 patent/WO2002055070A1/zh not_active Application Discontinuation
- 2001-05-24 EP EP01940097A patent/EP1352653A1/en not_active Withdrawn
- 2001-10-23 US US10/399,957 patent/US20040039050A1/en not_active Abandoned
- 2001-10-23 CN CNB018197590A patent/CN1210024C/zh not_active Expired - Fee Related
- 2001-10-23 WO PCT/CN2001/001497 patent/WO2002060435A1/zh not_active Application Discontinuation
- 2001-10-23 EP EP01273578A patent/EP1364648A4/en not_active Withdrawn
- 2001-10-23 JP JP2002560627A patent/JP4377130B2/ja not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084884A1 (en) * | 2003-03-24 | 2004-10-07 | The Chinese University Of Hong Kong | Use of tanshinone derivates as cholinesterase inhibitors in treating related diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004517134A (ja) | 2004-06-10 |
| EP1352653A1 (en) | 2003-10-15 |
| EP1364648A4 (en) | 2004-10-13 |
| CN1477957A (zh) | 2004-02-25 |
| CN1210024C (zh) | 2005-07-13 |
| JP2004517939A (ja) | 2004-06-17 |
| WO2002060435A1 (fr) | 2002-08-08 |
| JP4377130B2 (ja) | 2009-12-02 |
| EP1364648A1 (en) | 2003-11-26 |
| CN1477956A (zh) | 2004-02-25 |
| WO2002060435A8 (fr) | 2004-05-21 |
| WO2002055070A1 (fr) | 2002-07-18 |
| US20040024056A1 (en) | 2004-02-05 |
| CN1210025C (zh) | 2005-07-13 |
| US20040039050A1 (en) | 2004-02-26 |
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