WO2002055070A1 - Tanshinones cycliques de dihydrofuranne utilisees pour le traitement de l'hyperammoniemie et de l'encephalopathie hepatique - Google Patents

Tanshinones cycliques de dihydrofuranne utilisees pour le traitement de l'hyperammoniemie et de l'encephalopathie hepatique Download PDF

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WO2002055070A1
WO2002055070A1 PCT/CN2001/000861 CN0100861W WO02055070A1 WO 2002055070 A1 WO2002055070 A1 WO 2002055070A1 CN 0100861 W CN0100861 W CN 0100861W WO 02055070 A1 WO02055070 A1 WO 02055070A1
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hepatic encephalopathy
hyperammonemia
caused
cirrhosis
formula
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PCT/CN2001/000861
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English (en)
French (fr)
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Lianquan Gu
Xianzhang Bu
Lin Ma
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Zhongshan University
Guangzhou Medtech Zhongda Biotechnology Company, Ltd.
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Priority to US10/399,468 priority Critical patent/US20040024056A1/en
Priority to EP01940097A priority patent/EP1352653A1/en
Priority to JP2002555804A priority patent/JP2004517134A/ja
Publication of WO2002055070A1 publication Critical patent/WO2002055070A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to a tanshinone compound containing a dihydrofuran ring structure, in particular a cryptotanshinone
  • Hyperammonemia is one of the important symptoms of chronic hepatitis and cirrhosis.
  • intestinal ammonia production When the human liver is functioning normally, most of the ammonia produced by the intestines or kidneys can be detoxified by the urea through the ornithine cycle in the liver.
  • liver function In patients with chronic hepatitis and cirrhosis, liver function is abnormal, and the liver's ability to eliminate ammonia poisoning is weakened, so the amount of ammonia penetration into the blood also increases.
  • gastrointestinal congestion caused a significant increase in intestinal ammonia production.
  • renal function is also impaired in patients with chronic hepatitis and cirrhosis, and ammonia production is also significantly increased. Therefore, patients with chronic hepatitis and cirrhosis are often accompanied by symptoms of hyperammonemia.
  • Ammonia is a kind of alkaline toxic substance, which has toxic effects on many important organs of the human body, especially the most harmful to brain tissues.
  • Long-term hyperammonemia is an important cause of chronic liver disease and liver cirrhosis patients' aggravation and deterioration, leading to hepatic encephalopathy and subclinical hepatic encephalopathy.
  • Hepatic encephalopathy is a comprehensive disorder of the central nervous system dysfunction based on metabolic disorders. Its main clinical manifestations are disorders of consciousness, behavioral disorders and coma, edited by Li Yulin, People's Medical Publishing House , 2000, p340-350). There are two main reasons for the pathogenesis of hepatic encephalopathy. First, high blood ammonia is caused by liver dysfunction, and high concentrations of blood ammonia enter the brain tissue through the blood-brain barrier. The toxicity of ammonia to brain tissue is mainly manifested by the effect on the energy metabolism of brain cells, which reduces the concentration of high-energy phosphate compounds, some coenzymes and ⁇ -ketoglutarate.
  • the liver can convert most of the ammonia produced in the body into urea, which is excreted by the kidneys.
  • the ability to scavenge ammonia decreases and blood ammonia levels increase accordingly.
  • the ionic ammonium in the body changes to molecular ammonia, which can also increase the blood ammonia concentration and cause hepatic encephalopathy.
  • the second is the role of pseudo neurotransmitters use.
  • Phenylethanolamine as a pseudo-neurotransmitter, is similar in structure to normal neurotransmitters such as norepinephrine, but its physiological effects are much weaker than normal neurotransmitters. Competition between phenethanolamine and normal neurotransmitters leads to neurological dysfunction.
  • Subclinical Hepatic encephalopathy refers to a class of hepatic encephalopathy with intellectual, neurological, or mental impairments detected in patients with abnormal liver function. Symptoms of patients with subclinical hepatic encephalopathy are decreased intelligence, poor manipulative ability, and unresponsive nerves. The pathogenesis of subclinical hepatic encephalopathy is similar to that of hepatic encephalopathy. It is mainly caused by abnormal liver function in patients with chronic hepatitis and cirrhosis. The more severe the damage to liver function, the higher the incidence of subclinical hepatic encephalopathy and the more likely it is to deteriorate into hepatic encephalopathy. According to statistics, more than 50% of patients with liver cirrhosis have symptoms of subclinical hepatic encephalopathy [Li Yuyuan et al., Chinese Journal of Internal Medicine, 2000, 39 (9), 625] o
  • the drugs currently used to treat hyperammonemia, hepatic encephalopathy, and subclinical hepatic encephalopathy include lactulose, sodium glutamate, and arginine [Qin Wangrulong, Chief Editor of Zhengping Ping, Chemical Industry Press, Third Edition ( (1999), 655-665], but they all have their limitations. For example, if the dosage is large, the enzymes in the body are needed to lower blood ammonia, and it is not suitable for patients with diabetes and renal failure. The effect is not ideal.
  • Salvia miltiorrhiza is the dry roots and rhizomes of salvia miltiorrhiza Bunge, which is bitter, slightly cold, attentive to heart and liver meridian.
  • As a traditional Chinese medicine it is widely used in clinical prescriptions. It is mainly used for removing stasis and pain, promoting blood circulation, clearing the heart and removing annoyance.
  • salvia miltiorrhiza and its extracts mainly have the following pharmacological activities.
  • the object of the present invention is to find and develop salvia miltiorrhiza extracts, especially new medical uses of tanshinone compounds containing a dihydrofuran ring structure.
  • the present inventors have found through research that tanshinone compounds containing dihydrofuran ring structure extracted from Danshen are used to prevent and treat hyperammonemia caused by chronic hepatitis and cirrhosis, including hepatic properties caused by hyperammonemia. Encephalopathy and subclinical hepatic encephalopathy have good results. Summary of invention
  • the present invention provides a tanshinone compound containing a dihydrofuran ring structure represented by the following formula (I) or a pharmaceutical composition containing any of them, for use in the manufacture and prevention of chronic hepatitis and cirrhosis-related Ammonia, including drugs for hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonemia:
  • R 2 is H or C r C 3 alkyl.
  • the compound represented by the formula (1) is selected from the group consisting of -CH 2 CH 2 CH 2 C (CH 3 ) 2- , -CHCHCHC (CH 3 )-, -CH 2 CH 2 CHC ( C3 ⁇ 4) -, or -CH 2 CH 2 CH 2 C ( CH 2) -; is methyl.
  • the compound represented by formula (1) is selected from cryptotanshinone (1,6,6-trimethyl-1,2,6,7,8,9-hexahydrophenanthrene [1, 2-b] furan-10,11-dione), or dihydrotanshinone I (1,6-dimethyl-1,2-dihydrophenanthrene [1,2-b] furan-10,11-dione ).
  • the present invention also provides a pharmaceutical combination for preventing and treating hyperammonemia caused by chronic hepatitis and cirrhosis, including hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonemia. Thing.
  • This pharmaceutical composition contains a compound represented by the above formula (I), and any pharmaceutically acceptable diluent or carrier.
  • the invention also provides a method for preparing a pharmaceutical composition for the prevention and treatment of hyperammonemia caused by chronic hepatitis and cirrhosis, including hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonemia. This involves formulating the compound of formula (I) above with any pharmaceutically acceptable diluent or carrier.
  • the present invention also provides a method for preventing and treating hyperammonemia caused by chronic hepatitis and cirrhosis, including a method of hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonemia, the method comprising using an effective amount of the above formula
  • the compound represented by (I) or a pharmaceutical composition containing any of them treats a patient.
  • the compound represented by the above formula (I) or a pharmaceutical composition thereof can be prepared by a method known in the art and administered orally, parenterally (for example, intravenously, intramuscularly, subcutaneously, etc.) or topically. Administration (eg, sublingual, urethral, rectal, etc.).
  • Oral preparations include tablets, chews, capsules, pills, suspensions, emulsions, solutions and the like.
  • Parenteral preparations include injections, and topical preparations include creams, ointments, patches, suppositories, sprays, and the like. Detailed description of the invention
  • tanshinone compounds containing a dihydrofuran ring structure such as Cryptotanshinone and Dihydrotanshinone I
  • ammonia methylamine, ethylamine, and phenethylamine under mild conditions.
  • the following reactions form new tanshinone derivatives, suggesting that these compounds are unique for the prevention and treatment of hyperammonemia caused by chronic hepatitis and cirrhosis, and hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonium Therapeutic effect.
  • the reaction formula is shown below, where the neutralization is as defined above:
  • the tanshinone compound containing a dihydrofuran ring structure used in the present invention can be separated from the traditional Chinese medicine danshen by a solvent extraction method; it can also be obtained by a chemical synthesis method. Due to the abundant resources of Salvia miltiorrhiza, considering the cost and other factors, the compounds of the present invention are generally obtained by extraction.
  • the present invention determines tanshinone compounds containing dihydrofuran ring structures, such as cryptotanshinone and dihydrotanshinone I, etc., which can interact with ammonia, methylamine, ethylamine, and phenethylamine to form tanshinone under mild conditions.
  • Class derivatives It is suggested that these compounds may be used to reduce nitrogenous and toxic metabolites in the human body, such as high concentrations of ammonia and phenethylamine in the blood.
  • the invention determines the tanshinone compounds containing a dihydrofuran ring structure, such as cryptotanshinone and dihydrotanshinone I, through an animal model experiment of hyperammonia, which can effectively reduce the blood ammonia concentration of hyperammonium model rats and shorten the risk of hyperaemia.
  • Ammonia-induced liver coma time and reduced mortality. It has been shown to be an effective drug for the prevention and treatment of hyperammonemia caused by chronic hepatitis and cirrhosis, and hepatic encephalopathy and subclinical hepatic encephalopathy caused by hyperammonemia.
  • tanshinone compounds containing a dihydrofuran ring structure such as cryptotanshinone and dihydrotanshinone I, are determined through toxicological experiments in rats, which are non-toxic side effects and can be used safely.
  • a pharmaceutical preparation mainly composed of dihydrotanshinone compounds of the main active ingredient of salvia miltiorrhiza according to the present invention can not only be improved by effectively reducing blood ammonia and phenethylamine concentrations
  • the symptoms of chronic hepatitis, cirrhosis, hepatic encephalopathy, and subclinical hepatic encephalopathy may also promote the effective recovery of liver function, thereby providing an ideal treatment for chronic hepatitis, cirrhosis, hepatic encephalopathy, and subclinical hepatic encephalopathy. effect.
  • the present invention is further described below through examples.
  • Tanshinone ⁇ (Tanshinone llA, a tanshinone compound containing a furan ring structure) in vitro and ammonia:
  • Example 8 tanshinone IIA was substituted for dihydrotanshinone I, and TLC monitoring showed no obvious response within 48 hours. It shows that Tanshinone IIA and ammonia have no interaction under these conditions.
  • Example 8
  • Example 9 tanshinone IIA was substituted for dihydrotanshinone I, and TLC monitoring showed no obvious response within 48 hours. It shows that Tanshinone IIA has no interaction with phenethylamine under these conditions.
  • the experimental animals were 50 healthy male SD rats, weighing 250-300g. They were randomly divided into 5 groups, namely normal control group, test control group (amine acetate group), sodium glutamate / amine acetate group, dihydrotanshinone 1 / amine acetate group, and tanshinone IIA / amine acetate group. Except for the normal control group, physiological saline, sodium glutamate injection (dose 410 mg / kg), and dihydrotanshinone I physiological saline solution (containing a small amount of surfactant, dose 10 mg / kg) were intraperitoneally injected.
  • a physiological saline solution of Tanshinone ⁇ (containing a small amount of surfactant at a dose of 10 mg / kg) ; 45 minutes after administration, except for the normal control group, the other groups were injected intraperitoneally with 5.5 mmol / kg vinegar Acid amines; four consecutive days. On the fourth day, 30 minutes after the injection of the amine acetate solution, the rats in each group were immediately taken off the blood and taken for anticoagulation with EDTA-Na, and the blood ammonia concentration was measured by conventional methods. The results are shown in Table 1.
  • the doses of sodium glutamate in this example and the following examples are determined with reference to the actual clinical doses of the drug.
  • the blood ammonia concentration measurement method in this example and the following examples adopts the enzyme-UV method, the instrument used is fflTACffl-7170 automatic analyzer, and the kit used is AMMONIA. Table 1
  • the experimental animals were 40 healthy male SD rats, weighing 250-300g. Randomly divided into 4 groups, namely normal control group, test control group (amine acetate group), sodium glutamate / amine acetate group, cryptotanshinone / amine acetate group. Except for the normal control group, physiological saline, sodium glutamate injection (a dose of 410 mg / kg), and a physiological saline solution of cryptotanshinone (containing a small amount of a surfactant at a dose of 10 mg / kg) were injected from the abdominal cavity; After 45 minutes of drug administration, except for the normal control group, the other groups were injected intraperitoneally with 5.5 mmol / kg amine acetate; for four consecutive days.
  • Example 9 According to the experimental conditions of Example 9, the difference was that sodium glutamate injection was changed to oral glutamic acid tablets (dose 200 mg / kg), dihydrotanshinone I injection was changed to oral (dose 100 mg / kg), and tanshinone ⁇ The injection was changed to oral (dose 100 mg / kg).
  • the rats in each group were immediately taken off the blood and the blood ammonia concentration was measured. The results are shown in Table 5 below.
  • Tanshinone IIA oral group 865 ⁇ 4 According to the same experimental conditions, on the fourth day, 90 minutes after the injection of the acetic acid solution, the rats in each group were immediately taken out of the eye and blood was collected to determine the blood ammonia concentration. The results are shown in Table 6 below. Table 6
  • Example 10 According to the experimental conditions of Example 10, the difference was that sodium glutamate injection was changed to oral glutamic acid tablets (dose 200 mg / kg), and cryptotanshinone injection was changed to oral (dose 100 mg / kg). On the fourth day, 30 minutes after the injection of the acetic acid solution, the rats of each group were immediately taken out of the eye and blood was collected to determine the blood ammonia concentration. The results are shown in Table 7.
  • the experimental animals were 40 healthy male SD rats, weighing 250-300g. Randomly divided into 4 groups, namely normal control group, test control group (amine acetate group), sodium glutamate / amine acetate group, cryptotanshinone / amine acetate group.
  • physiological saline, sodium glutamate injection (dose 410 mg / kg), and cryptotanshinone physiological saline solution (containing a small amount of surfactant, the dose is 10 mg / kg) were intraperitoneally injected; 45 minutes after the medicine, intraperitoneal injection of a solution containing 0.1% carbon tetrachloride peanut oil (injection dose of 10 mg / kg); for four consecutive days. On the fourth day, 45 minutes after the injection and injection of the carbon tetrachloride peanut oil solution, rats in each group (including the normal control group) were intraperitoneally injected with an 8.5 mmol / kg amine acetate solution. The time (latency time), the time from coma to waking (coma time) and mortality were recorded from the beginning of each group of rats until the rats became comatose. The results are shown in Table 9 below.
  • Acute toxicity test in mice The experimental animals were healthy male mice. Tested by gavage. At the dose of 1.5 g / kg, no symptoms of poisoning and death were found in the test mice. Tests show that cryptotanshinone LD 5 o »1.5 g / kg.
  • mice 30-day toxicity test The experimental animals were healthy male mice. The experiment was performed by gavage, and the dose was 200 mg / kg day for 30 consecutive days. The test showed that there were no deaths, no significant abnormal changes or toxic reactions in the growth and development, hematopoietic function, and biochemical indicators of the rats; no pathological changes were found in the anatomy and tissue microscopy of important organs.
  • the tanshinone compound having a dihydrofuran ring structure represented by formula (I) of the present invention can interact with ammonia or phenethylamine under physiological conditions to achieve the purpose of removing ammonia or phenethylamine.
  • a toxicological test using cryptotanshinone, a tanshinone compound having a dihydrofuran ring structure represented by formula (1) of the present invention shows that it is safe to be used as a drug at a normal dose.
  • the compound of the present invention can obtain glutamine with only a small dose. Acids are the same or more effective. Especially in the case of impaired liver function, the therapeutic effect of the compound of the present invention is more significant than glutamic acid.
  • the reaction to remove blood ammonia and phenethylamine does not require enzymes, so its function to remove blood ammonia and phenethylamine has nothing to do with normal liver function.
  • the commonly used glutamate requires the participation of enzymes in the body to reduce blood ammonia, so it often fails to function when liver function is abnormal.
  • the compounds of the invention are therefore more versatile and more effective.
  • the tanshinone compound having a dihydrofuran ring structure represented by formula (1) of the present invention is used to prepare and prevent and treat hyperammonemia caused by chronic hepatitis and cirrhosis and hepatic encephalopathy caused by hyperammonium. And subclinical hepatic encephalopathy and other effective drugs.

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Description

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 发明领域
本发明涉及含二氢呋喃环结构的丹参酮类化合物，特别是隐丹参酮
(Cryptotanshinone) 及二氢丹参酮 I (Dihydrotanshinone I)在制备预 防和治疗由慢性肝炎和肝硬化产生的高血氯 （血液中氨和苯乙胺等浓 度过高）症及因高血氨引起的肝性脑病（HE)和亚临床肝性脑病（SHE) 等疾病的药物的用途。 发明背景
高血氨症是慢性肝炎和肝硬化的重要症状之一。 人体内的氨主要 来源于两个方面， 即肠道产氨和肾脏产氨。 人体的肝脏功能正常时， 大部分由肠道或肾脏产生的氨都可以通过肝脏内的鸟氨酸循环合成尿 素而解毒。 慢性肝炎和肝硬化患者的肝功能不正常， 肝脏清除氨毒的 功能减弱， 则氨渗透进入血液的量也增加。 特别是肝硬化患者， 由于 门体静脉分流形成和门静脉回流受阻， 消化道淤血， 使肠道产氨大量 增加。 同时， 慢性肝炎和肝硬化患者的肾功能也受损， 产氨量也明显 增加。 因此， 慢性肝炎和肝硬化患者常常伴随有高血氨症状。 氨是一 类碱性有毒物质， 对人体多种重要器官有毒害作用， 尤其对脑组织毒 害最大。 长期高血氨症状， 是导致慢性肝炎和肝硬化患者病情加重和 恶化， 引发肝性脑病和亚临床肝性脑病的重要原因。
肝性脑病 (Hepatic encephalopathy, HE), 是一种以代谢紊乱为基础 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 病理学， 李玉林主编， 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 常引起高血氨， 高浓度血氨透过血脑屏障进入脑组织。 氨对脑组织的 毒性主要表现为对脑细胞能量代谢的影响， 使高能磷酸化合物、 某些 辅酶及 α -酮戊二酸的浓度降低。 正常情况下， 肝脏能将大部分体内代 谢产生的氨转化成尿素， 经肾排出。 肝脏功能受损时， 清除氨的功能 减退， 血氨浓度因此增高。 另外， 当碱中毒时， 体内离子型铵转变成 分子氨， 也能使血氨浓度升高， 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 情况下它们可在肝脏内被分解而清除， 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。 苯乙醇胺作为一种伪神经递质， 在结构上与正常神经递 质如去甲肾上腺素等相似， 但生理效应远比正常递质弱。 苯乙醇胺与 正常神经递质的竞争导致脑神经功能失常。
亚临床肝性脑病 (Subclinical Hepatic encephalopathy, SHE), 是指 肝功能不正常患者检出的智力、 神经或精神缺陷的一类肝性脑病。 亚 临床肝性脑病患者的症状是智力下降， 操作能力低下， 神经反应迟钝。 亚临床肝性脑病的发病机制与肝性脑病相似， 主要是由于慢性肝炎和 肝硬化患者肝功能异常引起血氨和苯乙胺等浓度升高引起的。 肝功能 损伤越严重， 亚临床肝性脑病的发病率越高， 也越容易恶化成肝性脑 病。据统计，肝硬化患者中，有 50%以上具有亚临床肝性脑病的症状 [李 瑜元等， 中华内科杂志, 2000年， 39(9)， 625] o
去除血液中高浓度的氨和苯乙胺等能有效改善肝性脑病和亚临床 肝性脑病的症状。 目前用于治疗高血氨症及肝性脑病和亚临床肝性脑 病的药物有乳果糖、谷氨酸钠和精氨酸等 [ 欽王汝龙， 原正平主编， 化学工业出版社， 第三版（1999)， 655-665] , 但均有其局限性， 如用 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 mUtiorrhiza 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， 清心除烦等。 近年来， 研究发现丹参 及其提取物主要具有以下几个方面的药理活性。
1.促进肝细胞 DNA的合成， 对肝损伤具有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， 具有 保持胃粘膜屏障完整性，增强防御机能作用； 3.改善诱导性肾功能衰竭， 减轻大鼠尿毒症症状； 明显降低尿素氮、 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， 对中枢神经系统有抑制作用及抗炎， 抑菌， 抗肿瘤等。 但是到目前为止， 还没有关于用丹参的提取物， 尤其是含二氢呋 喃环结构的丹参酮类化合物来预防和治疗由慢性肝炎和肝硬化引起的 高血氨症及因高血氨引起的肝性脑病和亚临床肝性脑病等疾病的报 导。
本发明的目的是寻找并开发丹参提取物， 尤其是含二氢呋喃环结 构的丹参酮类化合物的医药新用途。
本发明人经研究发现， 从丹参中提取的含二氢呋喃环结构的丹参 酮类化合物在用于预防和治疗慢性肝炎和肝硬化引起的高血氨症， 包 括由高血氨症引起的肝性脑病和亚临床肝性脑病时具有良好的效果。 发明概要
本发明提供一种使用以下式 (I)所示的含二氢呋喃环结构的丹参酮 类化合物或含有它们中间任何一种的药学组合物制造用于预防和治疗 慢性肝炎和肝硬化引起的高血氨症， 包括由高血氨症引起的肝性脑病 和亚临床肝性脑病的药物：
Figure imgf000004_0001
其中， 选自 -CH2CH2CH2C(CH3)2-、 - CHCHCHC(CH3)-、
-CH2CH2CHC(CH3)-、 或 -CH2C¾CH2C(CH2)-; R2为 H或 CrC3烷基。
在一种优选实施方案中， 上述式 (1)所示化合物中的 选自 -CH2CH2CH2C(CH3)2-、 -CHCHCHC(CH3)-、 -CH2CH2CHC(C¾)-、 或 -CH2CH2CH2C(CH2)-; 是甲基。
在另一种优选实施方案中， 其中 -C¾CH2CH2C(C¾)2 -， 或 -CHCHCHC(CH3)-; R2为甲基
在另一种优选实施方案中， 其中式 (1)所示化合物选自隐丹参酮 ( 1,6,6-三甲基 -1,2,6,7,8，9-六氢菲 [1,2-b]呋喃 -10,11-二酮） ，或二氢丹参 酮 I ( 1，6-二甲基 -1,2-二氢菲 [1,2-b]呋喃 -10,11-二酮）。
本发明还提供一种用于预防和治疗慢性肝炎和肝硬化引起的高血 氨症， 包括由高血氨症引起的肝性脑病和亚临床肝性脑病的药学组合 物。 该药学组合物含有上述式 (I)所示化合物， 以及任意的药学上可接 受的稀释剂或载体。
本发明还提供一种制备用于预防和治疗慢性肝炎和肝硬化引起的 高血氨症， 包括由高血氨症引起的肝性脑病和亚临床肝性脑病的药学 组合物的方法， 该方法包括将上述式 (I)所示化合物与任意的药学上可 接受的稀释剂或载体一起配制。
本发明还提供一种预防和治疗慢性肝炎和肝硬化引起的高血氨 症， 包括由高血氨症引起的肝性脑病和亚临床肝性脑病的方法， 该方 法包括用有效量的上述式 (I)所示的化合物或含有它们中任一种的药学 组合物对患者进行治疗。
根据本发明， 上述式 (I)所示化合物或其药学组合物可以按本领域 公知的方法制备并通过口服给药、 非肠道给药 （例如静脉注射、 肌肉 注射、 皮下注射等）或局部途径 （例如舌下、 尿道、 直肠等） 给药。 口服制剂包括片剂、 口嚼剂、 胶囊、 丸剂,悬浮剂、 乳剂、 溶液等。 非 肠道制剂包括注射剂， 局部给药制剂包括霜剂,软膏剂,贴剂,栓剂，喷雾 剂等。 发明的详细说明
本发明人的研究结果表明，含二氢呋喃环结构的丹参酮类化合物， 例如 隐丹参酮 （ Cryptotanshinone ) 以及二氢丹参酮 I (Dihydrotanshinone ) 能与氨、 甲胺、 乙胺和苯乙胺等在温和条件下 反应形成新的丹参酮类衍生物， 提示这类化合物对预防和治疗由慢性 肝炎和肝硬化引起的高血氨症及因高血氨引起的肝性脑病和亚临床肝 性脑病等疾病具有独特的治疗作用。 其反应式如下所示，式中 和 如上述所定义：
Figure imgf000006_0001
在本发明中使用的含二氢呋喃环结构的丹参酮类化合物， 可以用 溶剂提取的方法从中药丹参中分离得到； 也可以通过化学合成方法得 到。 由于丹参资源丰富， 考虑到成本等因素， 一般采用提取法获得本 发明的化合物。
本发明通过化学反应实验， 确定含二氢呋喃环结构的丹参酮类化 合物， 如隐丹参酮及二氢丹参酮 I等， 在温和条件下能与氨、 甲胺、 乙 胺和苯乙胺等作用形成丹参酮类衍生物。 提示这类化合物有可能用于 降低人体内的含氮有毒代谢产物， 如血液中高浓度的氨和苯乙胺等。
本发明通过高血氨动物模型实验， 确定含二氢呋喃环结构的丹参 酮类化合物，如隐丹参酮及二氢丹参酮 I等，能有效降低高血氨模型大 鼠的血氨浓度和缩短因高血氨引起的肝昏迷时间和降低死亡率。 显示 可成为预防和治疗由慢性肝炎和肝硬化引起的高血氨症及因高血氨引 起的肝性脑病和亚临床肝性脑病等疾病的有效药物。
本发明通过大鼠毒理实验， 确定含二氢呋喃环结构的丹参酮类化 合物，如隐丹参酮及二氢丹参酮 I等， 是一类无毒副作用，可以安全使 用的药物。
由于中药丹参对肝肾功能具有良好的促进恢复作用， 因而以本发 明涉及的丹参主要有效成分的二氢丹参酮类化合物为主的药物制剂， 不仅能通过有效降低血氨和苯乙胺浓度而改善慢性肝炎、 肝硬化、 肝 性脑病和亚临床肝性脑病症状， 还有可能促进肝功能的有效恢复， 从 而对慢性肝炎、 肝硬化、 肝性脑病和亚临床肝性脑病等起到理想的治 疗作用。 以下通过实施例对本发明作进一步说明。 实施例 1
二氢丹参酮 I的提取、 分离及纯化：
干燥丹参 1 kg， 用 1500 mL 95%乙醇分 3次抽提， 每次 24小时， 抽提液减压浓缩至 500 mL， 然后加入 500 mL水， 用 1000 mL三氯甲 烷分四次萃取， 萃取液减压浓縮， 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 0.12g。 实施例 2
丹参中隐丹参酮的提取、 分离及纯化：
干燥丹参 l kg， 用 1500 mL 95%乙醇分 3次抽提， 每次 24小时， 抽提液减压浓缩至 500 mL, 然后加入 500 mL水， 用 1000 mL三氯甲 垸分四次萃取， 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 0.35g。 实施例 3
二氢丹参酮 I体外与氨的作用：
试管中加入 0.5 mmol的氨及 30 mL水，再加入溶于 1.0 mL乙醇的 0.5 mmol二氢丹参酮 I， 在 37±5。C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-氨基 -2-(1'-羟基 -2'- 丙基) -8-甲基-菲 -3，4-二酮 (l-amino-2-(l '-hydroxy-2'-propyl)-8-methyl -phenanthrene-3,4-dione)和 3-氨基 -2-(Γ-羟基 -2'-丙基) -8-甲基-菲 -1,4-二 |sl(3-amino-2-( -hydroxy-2'-propyl)-8-methyl-phenanthrene
-l,4-dione)。 产物结构已经 "C^H MR^ 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 4
二氢丹参酮 I体外与苯乙胺的作用： 试管中加入 0.5 mmol的苯乙胺及 30 mL水， 再加入溶于 1.0 mL 乙醇的 0.5 mmol二氢丹参酮 I， 在 37±5。C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与苯乙胺的作用产物 2-苄基 -4，9-二甲基 -4,5-二氢 -1，6-二氧 -3-偶氮-二环戊 [a,c]菲
(2-benzyl-4,9-dimethyl
-4,5-dihydro- 1 ,6-dioxa-3-azo-dicyclopenta [a,c] phenanthrene)禾口 2-(1'-轻 基 -2'-丙基) -8-甲基 -3-苯乙胺基 -4-苯乙胺基 -4H-菲 -1-酮
(2-(1' -hydroxy-2， -propyl)-8-methyl-3 -phenethylamino-4
-phenethylimino-4H-phenanthren- 1 -one) 0 产物结构已经 C^HNMR^
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 5
隐丹参酮体外与氨的作用：
试管中加入 0.5 mmol的氨及 30 mL水， 再分别加入溶于 1.0 mL 乙醇的 0.5 mmol隐丹参酮， 在 37±5°C振荡 0.5-3小时， 用 TLC进行 监测， 柱层析分离， 可得隐丹参酮与氨的作用产物 1-氨基 -2-(1'羟基 -2'- 丙基）
-8，8-二甲基 -5，6，7，8-四氢菲 -3,4-二酮 (l-amino-2-(l，-hydroxy-
2'-propyl)-8,8-dimethyl-5,657,8-tetrahydro-phenanthrene-
3,4-dione和 3-氨基 -2-(Γ-羟基 -2'-丙基) -8，8-二甲基 -5,6,7,8-四氢菲 -1,4- 二酮 (3-amino-2-(l，-hydroxy-2，-propyl)-8，8-dimethyl-5，6，7，8
-tetrahydro-phenanthrene- 1 ,4-dione) 0产物结构已经
Figure imgf000008_0001
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 6
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 l.OmL乙 醇的 0.5mmol隐丹参酮， 在 37±5。C振荡 0.5-3小时， 用 TLC监测， 柱层析分离， 可得隐丹参酮与苯乙胺的作用产物 2-苄基 -4,9，9-三甲基 -4,5,9,10,11, 12-六氢 -1,6-二氧 -3-偶氮-二环戊 [a,c]菲 (2-benzyl
-4,9,9-trimethyl-4,5,9, 10,11,12-hexahydro- 1 ,6-dioxa-3 -azo
-dicyclopenta[a,c]phenanthre)和 2-(Γ羟基 -2'-丙基) -8,8-二甲基 -3-苯乙胺 基 -4-苯乙胺基 -5，6,7,8-四氢 -4Η-菲小酮 (2-(l，-hydroxy-2，
-propyl)-8,8-dimethyl-3-phenethylamino-4-phenethylimino-5,657,8-tetrahy dro-4H-phenanthren-l-one)。 产物结构已经 "C^HNMIU 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 7
丹参酮 ΠΑ (Tanshinone llA,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 3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 ΠΑ与氨在此条件下无相互作 用。 实施例 8
丹参酮 ΠΑ体外与苯乙胺的作用：
按实施例 4的条件， 以丹参酮 ΠΑ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 9
二氢丹参酮 I和丹参酮 ΠΑ降血氨实验 （注射） ：
实验用动物为健康雄性 SD系大鼠 50只， 体重为 250-300g。 随机 分成 5组， 即分正常对照组， 试验对照组（醋酸胺组)、谷氨酸钠 /醋酸 胺组、 二氢丹参酮 1/醋酸胺组和丹参酮 ΠΑ/醋酸胺组。 除正常对照组 外， 分别由腹腔注射生理盐水，谷氨酸钠注射液（剂量为 410 mg/kg)， 二氢丹参酮 I 的生理盐水溶液（含少量表面活性剂，剂量为 10 mg/kg)， 丹参酮 ΠΑ的生理盐水溶液（含少量表面活性剂， 剂量为 10 mg/kg); 给药 45 min后， 除正常对照组外， 其余各组腹腔注射 5.5 mmol/kg醋 酸胺；连续四天。第四天在注射醋酸胺溶液后 30 min,各组大鼠立即摘 眼取血，用 EDTA-Na抗凝，应用常规方法测定血氨浓度。结果见表 1。 本实施例以及以下的实施例中的谷氨酸钠的剂量是参照该药物的临床 实际剂量而确定的。 本实施例以及以下的实施例中的血氨浓度测定方 法采用酶 -UV法， 使用仪器为 fflTACffl-7170 自动分析仪， 使用的试 剂盒为 AMMONIA。 表 1
Figure imgf000010_0001
按同样实验条件， 第四天在注射醋酸胺溶液后 90 min,各组大鼠立 即摘眼取血， 测定血氨浓度。 所得结果见表 2。
表 2
Figure imgf000010_0002
实施例 10
隐丹参酮降血氨的实验 （注射） ：
实验用动物为健康雄性 SD系大鼠 40只， 体重为 250-300g。 随机 分成 4组， 即分正常对照组， 试验对照组（醋酸胺组）、谷氨酸钠 /醋酸 胺组、隐丹参酮 /醋酸胺组。 除正常对照组外， 分别由腹腔注射生理盐 水，谷氨酸钠注射液 (剂量为 410 mg/kg)，隐丹参酮的生理盐水溶液 (含 少量表面活性剂， 剂量为 lO mg/kg); 给药 45 min后， 除正常对照组 外， 其余各组腹腔注射 5.5 mmol/kg醋酸胺； 连续四天。第四天在注射 醋酸胺溶液后 30 min，各组大鼠立即摘眼取血， 用 EDTA-Na抗凝， 定血氨浓度。 其结果见下表 3。 表 3
Figure imgf000011_0001
按同样实验条件，第四天在注射醋酸胺溶液后 90 min,各组大鼠立 即摘眼取血， 测定血氨浓度。 其结果见下表 4。 表 4
Figure imgf000011_0002
实施例 11
二氢丹参酮 I和丹参酮 ΠΑ降血氨实验 （口服） ：
按实施例 9实验条件，不同的是谷氨酸钠注射改为口服谷氨酸片 (剂 量为 200 mg/kg),二氢丹参酮 I注射改为口服（剂量为 100 mg/kg)，丹 参酮 ΠΑ注射改为口服 （剂量为 100 mg/kg) 第四天在注射醋酸胺溶 液后 30 min,各组大鼠立即摘眼取血，测定血氨浓度。其结果见下表 5。 组别 血氨浓度（P mol/L) 降低率(％) 正常对照组 115 ― 试验对照组 885 ― 谷氨酸口服组 510 49 二氢丹参酮 I口服组 550 44
丹参酮 IIA口服组 865 <4 按同样实验条件， 第四天在注射醋酸胺溶液后 90 min, 各组大鼠立 即摘眼取血， 测定血氨浓度。 其结果见下表 6。 表 6
Figure imgf000012_0001
实施例 12
隐丹参酮降血氨的实验 （口服） ：
按实施例 10实验条件， 不同的是谷氨酸钠注射改为口服谷氨酸片 (剂量为 200 mg/kg)， 隐丹参酮注射改为口服 （剂量为 100 mg/kg)。 第四天在注射醋酸胺溶液后 30 min,各组大鼠立即摘眼取血，测定血氨 浓度。 其结果见小表 7。
表 7
Figure imgf000012_0002
按同样实验条件，第四天在注射醋酸胺溶液后 90 min,各组大鼠立 即摘眼取血， 测定血氨浓度。 其结果见下表 8。 表 8
组别 血氨浓度（μ πιοΙ/L) 降低率(％) 正常对照组 115
试验对照组 285 ―
谷氨酸钠口服组 130 91 隐丹参酮口服组 120 97 隐丹参酮对急性肝硬化大鼠高血氨至昏迷及死亡的影响 （注射） ： 实验用动物为健康雄性 SD系大鼠 40只， 体重为 250-300g。 随机 分成 4组， 即分正常对照组， 试验对照组（醋酸胺组)、谷氨酸钠 /醋酸 胺组、 隐丹参酮 /醋酸胺组。 除正常对照组外， 分别由腹腔注射生理盐 水,谷氨酸钠注射液（剂量为 410 mg/kg),隐丹参酮的生理盐水溶液（含 少量表面活性剂， 剂量为 10 mg/kg); 给药 45 min后腹腔注射含 0.1% 四氯化碳花生油溶液（注射剂量为 10 mg/kg); 连续四天。 第四天在注 射给药和注射四氯化碳花生油溶液 45 min后， 各组大鼠 （包括正常对 照组）腹腔注射 8.5 mmol/kg醋酸胺溶液。记录各组大鼠从注射醋酸胺 开始至大鼠进入昏迷状态的时间（潜伏时间）， 从昏迷状态至苏醒的时 间 (昏迷时间)及死亡率。 其结果见下表 9。
表 9
Figure imgf000013_0001
实施例 14
隐丹参酮对急性肝硬化大鼠高血氨至昏迷及死亡的影响 （口服） ： 按实施例 13实验条件， 不同的是谷氨酸钠注射改为口服谷氨酸片 (剂量为 200 mg/kg), 隐丹参酮注射改为口服 （剂量为 100 mg/kg) o 第四天在注射给药和注射四氯化碳花生油溶液 45 min后，各组大鼠 (包 括正常对照组）腹腔注射 8.5 mmol/kg醋酸胺溶液。记录各组大鼠从注 射醋酸胺开始至大鼠进入昏迷状态的时间（潜伏时间）， 从昏迷状态至 苏醒的时间 (昏迷时间)及死亡率。 其结果见下表 10。 表 10
Figure imgf000014_0001
实施例 15
隐丹参酮毒理试验：
小鼠急性毒性试验： 实验用动物为健康雄性小鼠。 采用灌胃方法 试验。给药量至 1.5 g/kg时仍未发现供试小鼠有中毒症状和死亡。试验 表明， 隐丹参酮 LD5o » 1.5 g / kg。
小鼠 30天毒性试验： 实验用动物为健康雄性小鼠。 采用灌胃方法 试验， 给药量为 200 mg/kg day, 连续 30天。试验表明， 受试大鼠无死 亡， 生长发育、 造血功能、 生化指标等， 均无明显的异常变化或毒性 反应； 重要脏器的解剖检査和组织镜检未发现病理变化。
上述实施例表明：
(1)本发明的式 (I)所示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， 达到清除氨或苯乙胺的目的。
(2)高血氨动物模型实验说明本发明的式 (1)所示具有二氢呋喃环结 构的丹参酮类化合物具有优良的降低血氨浓度功能。 具有其他结构特 征的丹参酮类化合物如丹参酮 ΠΑ等， 则无此功能。
(3)急性肝硬化大鼠高血氨模型实验说明本发明的式 (1)所示具有二 氢呋喃结构的丹参酮类化合物能够有效延长因高血氨引起的肝昏迷潜 伏期， 缩短肝昏迷时间和有效降低死亡率。
(4)使用本发明的式 (1)所示具有二氢呋喃环结构的丹参酮类化合物 -隐丹参酮的毒理试验表明，在正常剂量下，其作为药物应用是安全的。
(5)与现有的临床常用的治疗高血氨及肝性脑病和亚临床肝性脑病 的典型药物谷氨酸相比， 本发明的化合物只要使用较小的剂量， 即可 获得与谷氨酸相同或者更有效的结果。特别是在肝功能受损的情况下， 本发明的化合物的治疗效果比谷氨酸更加显著。
由于本发明的上述式 (I)所示具有二氢呋喃环结构的丹参酮类化合 物清除血氨和苯乙胺的反应不需要酶的参与， 因此其清除血氨和苯乙 胺的功能与肝功能正常与否无关。 而常用的谷氨酸在降低血氨时需要 体内酶的参与， 故在肝功能不正常时， 往往不能发挥作用。 因而本发 明的化合物的适应性更广， 而且更有效。 因此， 本发明的式 (1)所示具 有二氢呋喃环结构的丹参酮类化合物是用于制备预防和治疗由慢性肝 炎和肝硬化引起的高血氨症及因高血氨引起的肝性脑病和亚临床肝性 脑病等疾病的有效药物。

Claims

权利要求
1 . 使用式 (I)所示含有二氢呋喃环结构的丹参酮类化合物或含有它 们中间任何一种的药学组合物制造用于预防和治疗慢性肝炎和肝硬化
Figure imgf000016_0001
引起的高血氨症， 包括由高血氨症引起的肝性脑病和亚临床肝性脑病 的药物： 其中， 是-0¾0¾( ¾(：(( ¾)2-、 - CHCHCHC(CH3)-、
-CH2C¾CHC(CH3)-、 或 -CH2CH2CH2C(CH2)-; R2为 H或 CrC3烷基。
2.根据权利要求 1所述的用途，其中 选自 -CH2CH2CH2C(CH3)2-、 -CHCHCHC(CH3)-、 -CH2CH2CHC(CH3)-、 或 -CH2CH2CH2C(CH2)-； R2 是甲基。
3.根据权利要求 1所述的用途，其中 选自- CH2CH2CH2C(CH3)2-， 或 -CHCHCHC CH3)-; R2是甲基。
4. 根据权利要求 1所述的用途， 其中式 (1)所示化合物选自隐丹参 酮 (Cryptotanshinone)或二氢丹参酮 I(Dihydrotanshinone 1)。
5. 一种用于预防和治疗慢性肝炎和肝硬化引起的高血氨症， 包括 由高血氨症引起的肝性脑病和亚临床肝性脑病的药学组合物， 其中含 有根据权利要求 1至 4中任一项的式 (I)所示化合物， 以及任意的药学 上可接受的稀释剂或载体。
6. 一种制备用于预防和治疗慢性肝炎和肝硬化引起的高血氨症， 包括由高血氨症引起的肝性脑病和亚临床肝性脑病的药学组合物的方 法， 其中包括将权利要求 1至 4中任一项的式 (I)所示化合物与任意的 药学上可接受的稀释剂或载体一起配制。
7. 一种预防和治疗慢性肝炎和肝硬化引起的高血氨症， 包括由高 血氨症引起的肝性脑病和亚临床肝性脑病的方法， 其中包括用有效量 的根据权利要求 1至 4中任一项所述的式 (I)所示的化合物或含有它们 中任一种的药学组合物对患者进行治疗。
8. 根据权利要求 1至 4任一项所述的用途， 其中所述药物是以注 射剂、 片剂、 丸剂、 胶囊剂、 溶液、 悬浮剂、 乳剂、 霜剂、 软膏、 喷 雾剂、 口嚼剂、 栓剂、 贴剂形式使用。
9. 根据权利要求 1至 4中任一项所述的用途， 其中所述药物的给 药途径包括口服、 舌下、 经皮、 静脉、 肌肉、 皮下或直肠。
PCT/CN2001/000861 2001-01-16 2001-05-24 Tanshinones cycliques de dihydrofuranne utilisees pour le traitement de l'hyperammoniemie et de l'encephalopathie hepatique WO2002055070A1 (fr)

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JP2002555804A JP2004517134A (ja) 2001-01-16 2001-05-24 高アンモニア血症および肝性脳症を治療するためのジヒドロフラン環状タンシノン類

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