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WO2009015561A1 - The use of leonurine and compositions thereof - Google Patents

The use of leonurine and compositions thereof Download PDF

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Publication number
WO2009015561A1
WO2009015561A1 PCT/CN2008/001409 CN2008001409W WO2009015561A1 WO 2009015561 A1 WO2009015561 A1 WO 2009015561A1 CN 2008001409 W CN2008001409 W CN 2008001409W WO 2009015561 A1 WO2009015561 A1 WO 2009015561A1
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WIPO (PCT)
Prior art keywords
acid
motherwort
preparation
compound
pharmaceutically acceptable
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PCT/CN2008/001409
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English (en)
French (fr)
Inventor
Yizhun Zhu
Xinhua Liu
Yichun Zhu
Aijun Hou
Xun Sun
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Fudan University
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Fudan University
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Priority to JP2010518479A priority Critical patent/JP5680412B2/ja
Priority to EP08783598.9A priority patent/EP2184063B1/en
Publication of WO2009015561A1 publication Critical patent/WO2009015561A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to the use of a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament for reducing the leakage rate of lactate dehydrogenase; a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof Use in the preparation of a medicament for preventing and/or treating acute heart-to-heart infarction or heart failure; and a pharmaceutical composition for preventing and/or treating acute myocardial infarction or heart failure.
  • Chinese herbal medicine Motherwort (Herbaceae, Herba Leonuri, Chinese Motherwort), was first included in the ancient books such as "Shen Nong's Herbal Classic” and “Compendium of Materia Medica”. It has the effect of promoting blood circulation and diuresis and diuresis.
  • the Pharmacopoeia of the People's Republic of China (2000 edition) is used for treatment of irregular menstruation, dysmenorrhea, amenorrhea, endless lochia, edema, edema, acute nephritis and edema.
  • motherwort is one of the main active ingredients of traditional Chinese medicine motherwort, its English name is Leonurine; chemical name is: 4-hydroxy-3, 5-dimethoxy, 4-[(aminoiminomethyl)amino] Butyl benzoate, ⁇ Benzoic acid, 4-hydroxy-3, 5-dimethoxy, 4-[(aminoiminomethyl) amino] butyl ester ⁇ ;
  • the molecular formula is: C 14 3 ⁇ 4iN 3 05;
  • the structural formula is:
  • the molecular weight is: 311.33;
  • melting point 238 ° C decomposition at this temperature
  • soluble in pentanol Nitrite
  • the melting point is 229 ⁇ 230°C, the hydrochloride containing a crystal water, melting point 193 ⁇ 194°C, soluble in cold water, hot water dissolved 1% ⁇ 2%;
  • the toxicity of the motherwort is 0. 4 ⁇ 0. 6g /kg; the MLD of the frog subcutaneous injection of the motherwort is 0. 4 ⁇ 0. 6g / kg;
  • the main sources of the ingredients are: Labiatae var. Leonurussibiricus L. leaves; Motherwort L. heterophyllus Sweet, Artemisia argyi L. artemisia, whole grass.
  • the dose has a linear relationship, and the maximum tension is reached above 2 mg/ml.
  • the motherwort has a bidirectional effect on the specimen of spontaneous contraction.
  • the minimum effective amount or the sudden increase in concentration (more than 5 times the original concentration)
  • High concentrations (greater than 20 mg/ml) are inhibited by local anesthetic effects on the uterine sarcolemma.
  • the uterine contraction of leonurus can last for several hours, but it can be recovered after washing.
  • Atropine 2mg/ml does not affect its contraction.
  • Motherwort A also has a significant excitatory effect on rabbit and cat isolated uterus, but has no effect on rabbit uterus.
  • the low-dose motherwort has an enhanced contraction effect on the isolated frog heart, and it is inhibited when used in a large amount. This inhibition may be due to excitability of the vagus nerve endings.
  • the frog vascular perfusion was performed with the motherwort, which showed vasoconstriction.
  • the degree of shrinkage is proportional to the concentration of the test solution used. Injecting the motherwort (2mg/kg) into the vein of the anesthetized cat, that is, seeing a drop in blood pressure, and recovering after a few minutes. This transient blood pressure drop can still be found after the vagus nerve is cut off.
  • the motherwort is injected, and the blood pressure drops, but it is not as good as the former. Therefore, it can be speculated that the blood pressure lowering effect of the motherwort is not in the vagus nerve center, but may be caused by the excitatory effect on the vagus nerve endings. Motherwort has a significant expansion of blood vessels in warm-blooded animals and has anti-adrenalin effects.
  • a small amount of parenteral base can relax the intestines of the rabbit's intestines, increase the amplitude, and the amplitude becomes smaller and the frequency increases.
  • Rabbits were given intravenous neviator lmg / kg, showing a significant increase in urine output.
  • Motherwort has an arrow-like effect on frog neuromuscular specimens. Motherwort can cause rabbit blood to occlude at a higher concentration.
  • Motherwort can be used as an effective active ingredient, which not only has a good effect of reducing the leakage rate of lactate dehydrogenase and preventing or treating myocardial infarction or heart failure. , and it has quick onset, small side effects and high safety.
  • particillin refers to an optional racemate, a pure stereoisomer, especially an enantiomer or diastereomer of leonurus, or The form of the mixture of stereoisomers in the desired proportions; the “probiotics” forms are in the form of their acids or in the form of their salts, or in the form of their solvates, especially hydrates.
  • the term also includes the individual enantiomers which may be present as their salts or in free form, generally in admixture with less than 5%, preferably less than 2%, especially less than 1%, of another enantiomer. Or a mixture of such enantiomers in any proportion, the mixture of enantiomers comprising a racemic mixture comprising substantially equal amounts of the two enantiomers.
  • the amount of the active ingredient used is the weight of the motherwort or a pharmaceutically acceptable salt thereof or a solvate thereof unless otherwise stated.
  • salt Including acid addition salts, such as hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, sulfurous acid, sodium hydrogen sulfite, nitric acid, phosphoric acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, Glutamate, fumaric acid, maleic acid, aspartic acid, citric acid or succinic acid. These acids are mentioned for illustrative purposes only and are not intended to be limiting.
  • pharmaceutically acceptable carrier refers to those materials which are well known in the art for use as fillers or carrier materials in pills, tablets, capsules and the like. These substances are generally approved by health care professionals for this purpose and as an inactive ingredient of the agent. Compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients, 2nd edition, Edited by A. Wade and P. J. Weller; American
  • the present invention provides the following technical solutions:
  • the present invention provides the use of a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament having an effect of reducing the leakage rate of lactate dehydrogenase.
  • the present invention provides a use of a parentergic compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament for the prevention and/or treatment of acute cardiac infarction or heart failure.
  • the motherwort compound is a racemate, a pure stereoisomer, especially an enantiomer or a diastereomer of leonurus, or any desired Proportionally mixed stereoisomer mixture;
  • the solvate of the motherwort compound is a hydrate of motherwort.
  • the virgin base compound is pharmaceutically acceptable
  • the salt is an acid addition salt of the motherwort with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, sulfurous acid, sodium hydrogen sulfite, nitric acid, phosphoric acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, hydrazine. Acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or succinic acid.
  • the pharmaceutical dosage form is selected from the group consisting of: oral preparations, parenteral preparations, topical preparations, inhaled administration preparations, and transdermal preparations.
  • the present invention provides a pharmaceutical composition for preventing and/or treating acute heart; L infarction or heart failure, the pharmaceutical composition comprising: a motherwort compound as an active ingredient or a pharmaceutically acceptable compound thereof a salt or solvate thereof, and one or more pharmaceutically acceptable carriers.
  • the solvate of the motherwort compound is a hydrate of motherwort.
  • the pharmaceutically acceptable salt of the motherwort compound is an acid addition salt of the motherwort and an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, and sub Acid, sodium bisulfite, nitric acid, lithic acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or amber acid.
  • an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, and sub Acid, sodium bisulfite, nitric acid, lithic acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or amber acid.
  • the pharmaceutical composition is: an oral preparation, a parenteral preparation such as an injection, a topical preparation, an inhalation preparation or a transdermal preparation.
  • the pharmaceutical composition is an oral preparation selected from the group consisting of a tablet, a capsule, a granule, a pill, a drop, a juice or a syrup; preferably,
  • the pharmaceutically acceptable carrier is selected from the group consisting of: disintegrants, lubricants, binders, fillers, solvents, perfumes, sweeteners, antioxidants, surfactants, preservatives, flavoring agents, and coloring agents.
  • compositions of the invention may be prepared by methods well known in the art, preferably in the form of a formulation. Such methods include the step of mixing the active component with a carrier which comprises one or more accessory ingredients.
  • auxiliary components include those commonly used in the art, such as fillers, binders, thinners, disintegrants, lubricants, colorants, flavoring agents, and wetting agents.
  • Formulations suitable for oral administration may be prepared as dispersion units, pellets or granules, as solutions or suspensions, such as pills, tablets or capsules containing a predetermined amount of active ingredient. It is also possible to prepare a formulation for rectal administration as a suppository or enemas.
  • suitable formulations include aqueous and non-aqueous sterile injectables (purity of the active compound ⁇ 90%).
  • Such formulations may be presented in unit dosage form or in the form of multi-dose containers such as sealed vials and ampoules, and such formulations may be lyophilized (lyophilized) in a sterile liquid carrier such as water, such as water, before use. Store under.
  • Formulations suitable for nasal inhalation administration include fine dust or mist which can be produced by metered doses of pressurized aerosols, nebulizers or inhalers.
  • Suitable additives and/or carriers in the context of the present invention are all materials known to the skilled person from the prior art for obtaining herbal preparations.
  • the choice of these carriers and their amount depends on whether the drug is administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, orally or locally.
  • Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration, while solutions, suspensions, reconstituted dry preparations and sprays are suitable for parenteral administration. , topical preparation, inhaled administration. It may also be a test for rectal use.
  • the carrier film or patch, optionally in storage form with other agents that promote skin penetration, is an example of a dosage form suitable for transdermal administration.
  • Examples of carriers and additives in oral administration dosage forms are disintegrants, lubricants, binders, fillers, and optionally used include solvents, perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
  • solvents perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
  • waxes and fatty acid esters can be used, and for parenterally administered components, carrier materials, preservatives, suspending agents and the like can be used.
  • the amount of active substance administered to the patient will vary as a function of patient weight, mode of administration, and severity of disease.
  • the compounds according to the invention can be released from the formulation in a delayed manner for oral, rectal or transdermal administration.
  • the corresponding sustained release formulations especially once daily once a day, are particularly suitable for the indication according to the invention.
  • the carrier for oral administration of the present invention may be, for example, water, ethanol, dimethylmethanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, syrup , starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolid Pyrrolidone, paraffin, wax, natural rubber and synthetic rubber, gum arabic, alginate, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearic acid Ester, sodium lauryl sulfate, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene
  • the pharmaceutical and pharmaceutical components according to the present invention can be prepared with the aid of known pharmaceutical preparation techniques, such as advanced means, equipment, methods and procedures.
  • a solid preparation such as a tablet
  • the active ingredient of the drug that is, motherwort or a pharmaceutically acceptable salt thereof or a solvate thereof
  • a pharmaceutical carrier for example, a conventional tablet ingredient , for example, corn flour, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or a pharmaceutically acceptable gum to form a uniformly distributed motherwort or a pharmaceutically acceptable thereof a solid component of a salt or a solvate thereof.
  • Uniform distribution is understood herein to mean that the active ingredient, the parenteral base, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is uniformly distributed throughout the composition, so that it can be readily divided into unit dosage forms having the same activity, such as tablets, pills or Plastic bottles.
  • the solid components are then divided into unit dosage forms.
  • a tablet or pill of a pharmaceutical or pharmaceutical ingredient according to the invention may also be coated or mixed in another component to provide a sustained release dosage form.
  • suitable coating components are a mixture of a polymeric acid and a polymeric acid with materials such as shellac, cetyl alcohol and/or cellulose acetate.
  • compositions of the present invention can be formulated into clinically acceptable dosage forms such as tablets, capsules, granules, oral liquid preparations, subcutaneous administration preparations, suppositories and the like.
  • Oral preparations such as tablets, granules or capsules can be prepared by adding an appropriate amount of the carrier.
  • These dosage forms are prepared according to methods well known to those skilled in the art.
  • the carrier used for the molding process of tablets, granules, capsules, etc. is a commonly used auxiliary agent, such as starch, gelatin, gum arabic, polyethylene glycol, etc., in addition to surfactants, lubricants, disintegrants. , preservatives, flavoring agents, pigments, etc.
  • the above-mentioned motherwort compound of the present invention is subjected to the following in vivo and in vitro experiments, thereby fully verifying the feasibility of the medical use of the present invention:
  • the in vitro experimental study was conducted to examine the effect of leonurus on the amount of LDH leaked out into the culture solution, and the leakage rate of lactate dehydrogenase was measured.
  • Cardiac function and plasma levels of vitamin C and cysteine were detected by ligating the heart failure model of the anterior descending coronary artery.
  • the results showed that the motherwort can reduce ventricular end-systolic pressure, increase the contraction rate, and improve the heart. Function, can increase plasma vitamin C and reduce cysteine content.
  • the experimental results prove that the motherwort can reduce the leakage rate of lactate dehydrogenase, and has a significant effect on preventing and/or treating acute myocardial infarction or heart failure, and can prepare a medicament for preventing acute myocardial infarction or heart failure.
  • Figure 1 is a bar graph showing the lactate (LDH) leakage rate, where the data is expressed as a percentage of the normal group (100%), control indicates no hypoxic group, vehicle indicates hypoxia, losartan Indicated in the losartan group, leonurine in the group treated with leonurus; *: p ⁇ 0.01 compared with the normal group, #: p ⁇ 0.01 compared with the hypoxic group;
  • LDH lactate
  • Figure 2 is a graph showing that motherwort reduces myocardial infarct size, wherein sham indicates a false surgery group, AMI indicates a myocardial infarction group, and Leo 7.5 mg/kg indicates a low dose of motherwort.
  • Leol 5mg/kg means high dose (15mg/kg) of the motherwort; *: Compared with the myocardial infarction group? ⁇ 0.05;
  • Figure 3 is a bar graph showing that natal care reduces the LDH in plasma of rats with myocardial infarction, in which sham is a sham operation group, AMI is a myocardial infarction group, and Leo 7.5 mg.kg- 1 is a low dose of motherwort.
  • Leo mgJcg- 1 was treated with high dose of motherwort (15 mg.kg); *: compared with myocardial infarction group; ⁇ 0.05, #: compared with sham operation group; ⁇ 0.05.
  • Figure 4 is a bar graph showing that motherwort reduces CK in plasma of rats with myocardial infarction, wherein sham represents a sham operation group, AMI represents a myocardial infarction group, and Leo 7.5 mg.kg 4 represents a low dose of motherwort with mg-kg- 1 In the treatment group, Leol 5 mg.kg 4 was treated with high dose of motherwort (mg.kg- 1 ); *: ⁇ ⁇ 0.05 compared with myocardial infarction group, #: and ⁇ - compared with surgery group ⁇ ⁇ 0.05.
  • Figure 5 is a bar graph showing that tryptophan reduces the expression of Bax and increases the mRNA level of Bcl-2, wherein sham represents a sham operation group, AMI represents a myocardial infarction group, and Leo 7.5 mg.kg _1 represents a low dose of motherwort.
  • LeolSmg g was expressed in the high-dose (15 mg.kg _1 ) group of the motherwort; *: compared with the myocardial infarction group; ? ⁇ 0.05, #: compared with the sham-operated group ⁇ 0.05.
  • Figure 6 is a bar graph showing the expression of motherwort minus Bax and increasing the protein level of Bcl-2, wherein sham indicates sham operation group, AMI indicates myocardial infarction group, and Leo 7.5 mg.kg- 1 indicates low dose of motherwort.
  • Leo rngJig- 1 showed a high dose (15 mg.kg -1 ) in the treatment group; *: compared with the myocardial infarction group ⁇ 0.05, #: and ⁇ compared with the surgery group ⁇ 0.05.
  • Example 1 In vitro experiment to examine the effect of leonurus on the leakage rate of lactate dehydrogenase
  • this example used losartan as a positive control drug, and the concentration of the motherwort used was 1 (T 6 mol/L, the experimental data were analyzed by one-way ANOVA, ⁇ 0.01, and the results showed that cell death can be Leading to the leakage of lactase, the amount of leakage of LDH into the culture solution was analyzed by the test, and the results showed that the motherwort could significantly reduce the leakage of lactate dehydrogenase.
  • this embodiment uses the mature heart of the ligature of the anterior descending coronary artery in the field.
  • the infarction model was administered by intraperitoneal injection.
  • the infarct size was detected by TTC staining.
  • the experimental data were analyzed by one-way analysis of variance. Results: ⁇ 0.05, indicating that the motherwort could significantly reduce the myocardial infarct size.
  • Myocardial infarction can cause the release of myocardial enzymes LDH and CK into the plasma, which can significantly reduce the levels of LDH and CK in plasma and reduce the degree of myocardial damage, one-way analysis of variance, ⁇ ⁇ 0.05.
  • Bax is a pro-apoptotic gene
  • Bcl-2 is an anti-apoptotic gene.
  • the motherwort can significantly reduce the expression of Bax mR A and protein levels, and significantly increase the expression of Bcl-2 mRNA and protein.
  • Example 3 Heart failure model test of leonurus
  • a heart failure model in which the anterior descending coronary artery is ligated in the field is used, and the cardiac function is detected by intra-arterial and ventricular intubation.
  • the results show that the motherwort can reduce the end of ventricular systole. Pressure, increase the rate of contraction, and improve heart function.
  • the content of vitamin C and cysteine in plasma was measured by capillary electrophoresis. The results showed that motherwort could increase plasma vitamin C and decrease cysteine content by one-way variance analysis, p ⁇ 0.05.
  • Table 1 shows the results of cardiac function in heart failure models, showing that motherwort improves cardiac function in rats with myocardial infarction, where *: compared with heart failure group p ⁇ 0.05, #: compared with sham operation group ⁇ 0.05.
  • Table 2 shows the results of the test of parentergic to increase vitamin C and cysteine in plasma, where *: compared with heart failure group ⁇ 0.05, **: compared with heart failure group /? ⁇ 0.01, #: ⁇ - Compared to the surgery group? ⁇ 0.05.
  • vitamin c Ascorbic acid (vitamin c), 26.02 ⁇ 3.95**

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Description

益母草碱的用途及其组合物 技术领域
本发明属于医药技术领域。 本发明涉及益母草碱化合物或其药学上可 接受的盐或其溶剂化物在制备具有减少乳酸脱氢酶漏出率作用的药物中的 应用； 益母草碱化合物或其药学上可接受的盐或其溶剂化物在制备用于预 防和 /或治疗急性心月几梗死或心力衰竭的药物中的应用； 以及一种用于预防 和 /或治疗急性心肌梗死或心力衰竭的的药物组合物。 皆景技术
中草药益母草 (唇形科植物, Herba Leonuri, Chinese Motherwort )， 最早收载于《神农本草经》、 《本草纲目》等古籍中， 有活血调经、 利尿 消肿的功效。 中华人民共和国药典（2000年版） 中用于月经不调、 痛经、 经闭、 恶露不尽、 水肿尿少、 急性肾炎水肿等治疗。
已经知道益母草碱是传统中药益母草的主要活性成分之一， 其英文名 称为 Leonurine; 化学名称为： 4-羟基 -3 , 5-二甲氧基， 4-【 （氨基亚氨基 甲基）氨基】丁基苯甲酸酯， {Benzoic acid, 4-hydroxy-3 , 5-dimethoxy, 4- 【 ( aminoiminomethyl ) amino】 butyl ester}; 分子式为： C14¾iN305; 结 构式为：
Figure imgf000003_0001
分子量为： 311.33;
其物理性质为： 熔点 238°C (该温度下分解） ， 溶于戊醇。 亚硝酸盐 溶点 229~230°C, 含一结晶水的盐酸盐， 熔点 193~ 194°C, 溶于冷水， 热 水溶解 1% ~2%；
毒性为： 益母草碱毒性较小； 大鼠腹腔注射益母草碱， 每次 2mg, 连 续 4天， 无明显不良反应； 蛙皮下注射益母草碱的 MLD为 0. 4~0. 6g /kg;
成分来源主要为： 唇形科植物细叶益母草 LeonurussibiricusL.叶； 益 母草 L.heterophyllus Sweet、 艾蒿益母草 L. artemisia, 全草。
益母草碱已知的药理作用包括：
1. 对子宫的作用益母草碱对兔、猫、 犬、豚鼠等多种动物的子宫均呈 兴奋作用。 对动情前期或卵巢切除后肌注雌二醇 50mg的大鼠离体子宫， 益母草碱均可使其振幅增加。 益母草碱的作用与剂量相关， 浓度为 0. 2~
1. Omg/ml时， 剂量一张力呈线性关系， 至 2mg/ml以上时达最大张力。 有时可见益母草碱对自发性收缩的标本呈双向性作用， 用最低有效量或突 然增加浓度 (超过原浓度 5倍）时， 在引起兴奋之前可有 10― 20min的 短暂抑制。 高浓度（大于 20mg/ml) 因对子宫肌膜的局部麻醉作用而呈 抑制作用。 益母草碱的子宫收缩作用可持续几小时， 但冲洗后可恢复。 阿 托品 2mg/ml不影响其收缩作用。益母草碱甲对兔和猫离体子宫也有明显 兴奋作用 , 而对兔在位子宫无作用。
2.对循环系统的作用小剂量益母草碱对离体蛙心有增强收缩作用，使 用大量时反呈抑制现象。 这种抑制现象可能由于迷走神经末梢兴奋所致。 用益母草碱进行蛙血管灌流， 呈血管收缩现象。 其收缩程度与所用试液浓 度呈正比例。 用益母草碱（2mg/ kg)注射于麻醉猫的静脉， 即见血压下 降， 数分钟后恢复， 这种短暂性的血压下降现象， 在两侧迷走神经切断后 也仍能发现， 若先使用阿托品， 然后注射益母草碱， 血压下降即恢复， 但 不如前者显著， 故可推测益母草碱的降低血压作用不在迷走神经中枢， 而 可能对迷走神经末梢兴奋作用所致。 益母草碱对温血动物的血管呈明显的 扩长现象， 有抗肾上腺素的作用。
3.对呼吸中枢的作用麻醉猫静注益母草碱后，呼吸频率及振幅均呈显 著增加， 但在大剂量时， 呼吸则由兴奋转入抑制， 且变为微弱而不规则。 在切断两侧迷走神经后， 仍有呼吸兴奋作用， 故认为本品可能对呼吸中枢 有直接兴奋作用。
4. 其他作用小量益母草碱能使兔离体肠管紧张性弛緩， 振幅扩大， 多 量则振幅变小， 而频率增加。 兔静注益母草碱 lmg / kg, 可见尿量显著增 加。 益母草碱对蛙神经肌肉标本呈箭毒样作用。 益母草碱在较高浓度时能 使兔血悬¾ ^生溶血作用。
有文献报道， 益母草碱能通过抑制外钙内流和内钙释放而显著的抑制 血管平滑肌收缩。 然而， 迄今未见有关益母草碱能够减少乳酸脱氢酶漏出 率或是能够预防或治疗心肌梗死或心衰的报道。 发明内容
本发明人经过多年研究 , 发现并经过大量的动物试验和临床试验证 明： 益母草碱可以作为有效的活性成分， 不仅具有良好的减少乳酸脱氢酶 漏出率并且预防或治疗心肌梗死或心衰的作用， 而且起效快，毒副作用小， 安全性高。
为有助于理解本发明， 下面定义了一些术语。 本文定义的术语具有本 发明相关领域的普通技术人员通常理解的含义。
除非另外说明 , 本文所用的术语 "益母草碱，，是指益母草碱的任选的外 消旋体、 单纯立体异构体， 尤其是对映异构体或非对映异构体， 或以任意 所需比例混合的立体异构体混合物的形式； 所述"益母草碱"形式是以它们 的酸的形式或以它们的盐的形式， 或以它们的溶剂化物， 尤其是水合物的 形式存在。 该术语还包括各个对映体， 可以将它们作为其盐或以游离形式 存在， 一般是以与低于 5 %、 优选低于 2 %、 特别是低于 1% 的另一对映 体混合使用或是按照任意比例的这类对映体的混合物使用， 所述的对映体 的混合物包括含有基本上等量的两种对映体的外消旋混合物。
除非另外说明 , 活性成分的用量指的是益母草碱或其药学上可接受的 盐或其溶剂化物的重量。
除非另外说明， 本文所用的术语 "药学上可接受的盐 "可被理解成由具 有生理学上-尤其在作为药物施加至人类和 /或哺乳动物时可接受的盐。盐 包括酸加成的盐， 所述的酸例如有盐酸、 硫酸、 硫酸氢钠、 亚硫酸、 亚硫 酸氢钠、 硝酸、 磷酸、 醋酸、 乳酸、 甲磺酸、 乳糖酸、 枸橼酸、 草酸、 谷 氨酸、 富马酸、 马来酸、 天冬氨酸、 柠檬酸或琥珀酸。 所提及的这些酸仅 作为说明的目的而不用来起限定作用。
除非另外说明， 本文所用的术语"可药用载体"指的是那些本领域中公 知用作丸剂、 片剂、 胶嚢剂等中的填充剂或载体物质的物质。 这些物质通 常被保健专家认可用于这一目的且作为药剂的非活性成分. 有关可药用载 体和赋形剂的汇编可以在《药物赋形剂手册》 （ Handbook of Pharmaceutical excipients, 第 2版, 由 A . Wade和 P . J . Weller编辑； American
Pharmaceutical Association 出版, Washington and The Pharmaceutical Press , London , 1994 )等工具书中找到。
本发明的一个目的在于， 提供益母草碱化合物或其药学上可接受的盐 或其溶剂化物在减少乳酸脱氢酶漏出率的新医药用途。 本发明的另一个目 的在于， 提供益母草碱化合物或其药学上可接受的盐或其溶剂化物在制备 用于预防和 /或治疗急性心肌梗死或心力衰竭的药物中的应用。本发明的另 一个目的在于，提供一种用于预防和 /或治疗急性心肌梗死或心力衰竭的的 药物组合物。
针对上述发明目的， 本发明提供以下技术方案：
一方面， 本发明提供益母草碱化合物或其药学上可接受的盐或其溶剂 化物在制备具有减少乳酸脱氢酶漏出率作用的药物中的应用。
另一方面， 本发明提供益母草碱化合物或其药学上可接受的盐或其溶 剂化物在制备用于预防和 /或治疗急性心几梗死或心力衰竭的药物中的应 用。
优选地， 在本发明的应用中， 所述益母草碱化合物为益母草碱的外消 旋体、 单纯立体异构体， 尤其是对映异构体或非对映异构体， 或以任意所 需比例混合的立体异构体混合物；
优选地， 在本发明的应用中， 所述益母草碱化合物的溶剂化物是益母 草碱的水合物。
优选地， 在本发明的应用中， 所述益母草碱化合物的药学上可接受的 盐是益母草碱与选自如下的酸形成的酸加成盐： 盐酸、 硫酸、 硫酸氢钠、 亚硫酸、 亚硫酸氢钠、 硝酸、 磷酸、 醋酸、 乳酸、 甲磺酸、 乳糖酸、 枸橼 酸、 草酸、 谷氨酸、 富马酸、 马来酸、 天冬氨酸、 柠檬酸或琥珀酸。
优选地， 在本发明的应用中， 所述药物的剂型选自： 口服制剂、 肠胃 外给药制剂、 局部给药制剂、 吸入式给药制剂和透皮制剂。
又一方面，本发明 ^是供一种预防和 /或治疗急性心 ; L梗死或心力衰竭的 药物组合物， 所述药物组合物包含： 作为活性组分的益母草减化合物或其 药学上可接受的盐或其溶剂化物， 以及一种或多种药学上可接受的载体。
优选地， 在本发明的药物组合物中， 所述益母草碱化合物的溶剂化物 是益母草碱的水合物。
进一步优选地， 在本发明的药物组合物中， 所述益母草碱化合物的药 学上可接受的盐是益母草碱与选自如下的酸形成的酸加成盐： 盐酸、硫酸、 硫酸氢钠、 亚 酸、 亚硫酸氢钠、 硝酸、 碑酸、 醋酸、 乳酸、 甲磺酸、 乳 糖酸、 枸橼酸、 草酸、 谷氨酸、 富马酸、 马来酸、 天冬氨酸、 柠檬酸或琥 珀酸。
优选地， 在本发明的药物组合物中， 所述药物组合物为: 口服制剂、 肠胃外给药制剂如注射剂、 局部给药制剂、 吸入式给药制剂或透皮制剂。
进一步优选地 , 在本发明的药物组合物中， 所述药物组合物为选自如 下的口服制剂： 片剂、 胶嚢剂、 颗粒剂、 丸剂、 滴剂、 果汁或糖浆剂； 优 选地， 所述药学上可接受的载体选自： 崩解剂、 润滑剂、 粘合剂、 填充剂、 溶剂、 香料、 甜味剂、 抗氧化剂、 表面活性剂、 防腐剂、 矫味剂和色素。
可以采用本领域所公知的方法来制备本发明的组合物， 优选为制剂形 式。 这类方法包括将活性组分与构成一种或多种辅助组分的载体混合的步 骤。 这类辅助組分包括那些本领域中常用的组分， 诸如填充剂、 粘合剂、 稀锋剂、 崩解剂、 润滑剂、 着色剂、 调味剂和湿润剂。
可以将适合于口服给药的制剂制成诸知含有预定量活性组分的丸剂、 片剂或胶嚢这样的分散单位、 制成粉剂或颗粒剂、 制成溶液或混悬液。 还 可以将直肠给药用制剂制成栓剂或灌肠剂。 就非肠道给药而言， 合适的制剂包括含水和非水性无菌注射剂 （活性 化合物的纯度≥90% )。 可以将这类制剂制成单位剂量或例如密封小瓶和安 瓿这样多剂量容器的形式且可以将这类制剂在仅需要在使用前添加例如水 这样的无菌液体载体的冷冻干燥（冻干）条件下储存。
适合于经鼻部吸入给药的制剂包括可以通过计量剂量的加压气雾剂、 喷雾器或吸入器产生的细粉尘或雾。
为了制备例如片剂这样的剂量单位， 所关注的是常用添加剂的应用 , 诸如填充剂、 着色剂、 聚合粘合剂等。 一般来说， 可以使用不会干扰活性 化合物的功能的任意可药用添加剂。
本发明内容中合适的添加剂和 /或载体是技术人员从以往技术中已知 的所有用来获得草本制剂的物质。 这些载体的选择和它们的用量依赖于药 物是否口服地、 静脉地、 腹腔地、 皮内地、 肌肉地、 鼻内地、 口腔地或局 部地给药。 以药片、 咀嚼片、 包衣片、 胶嚢、 颗粒、 滴剂、 果汁或糖浆形 式的制剂适合于口 艮给药， 而溶液、 悬浮液、 易复水的干燥制剂和喷剂适 合于肠胃外、 局部给药制剂、 吸入式给药。 还可能是供直肠使用的检剂。 载体膜片或贴片， 可任选地与其它促进皮肤渗透的试剂一起以溶解的形式 贮存使用， 是适合于透皮给药的剂型的范例。
口服给药剂型中的载体和添加剂的实例是崩解剂、 润滑剂、 粘合剂、 填充剂， 可选择性使用的包括溶剂、 香料、 甜味剂， 尤其是载体物质、 稀 释液、 染料、 抗氧化剂等等。 其中， 对于栓剂而言， 可使用蜡和脂肪酸酯， 对于非肠道给药的组分可使用载体物质、 防腐剂、 助悬剂等等。 给病人使 用的活性物质的量随着由病人体重， 给药方式和病重程度组成的函数关系 而变化。 按本发明的化合物能以一种迟緩的方式从制剂剂型中释放， 供口 服， 直肠或透皮给药。 相应的持续释放式制剂， 尤其是每天只需服用一次 的"一日一次，，式剂型尤其适合于按本发明的适应症。
本发明的口服给药剂型的载体可以是， 例如： 水、 乙醇、二甲基甲醇， 丙三醇、 乙二醇、 丙二醇、 聚乙二醇、 聚丙二醇、 葡萄糖、 果糖、 乳糖、 蔗糖、 糖浆、 淀粉、 改性淀粉、 明胶、 山梨醇、 肌醇、 甘露醇、 微晶纤维 素、 甲基纤维素、 羧甲基纤维素、 醋酸纤维素、 虫胶、 鲸蜡醇、 聚乙烯吡 咯烷酮、 石蜡、 蜡、 天然橡胶与合成橡胶、 阿拉伯树胶、 藻酸盐、 右旋糖 苷、 饱和脂肪酸与不饱和脂肪酸、 硬脂酸、 硬脂酸镁、 硬脂酸锌、 甘油硬 脂酸酯、 月桂醇硫酸钠、 食用油、 芝麻油、 椰子油、 花生油、 大豆油、 卵 磷脂、 乳酸钠、 聚氧乙烯和丙烯脂肪酸酯、 山梨糖醇醉脂肪酸酯、 山梨酸、 苯甲酸、 柠檬酸、 抗坏血酸、 丹宁酸、 氯化钠、 氯化钾、 氯化镁、 氯化钙、 氧化镁、 氧化锌、 二氧化硅、 氧化钛、 二氧化钛、 硫酸镁、 硫酸锌、 硫酸 钙、 碳酸钟、 磷酸 4弓、 磷酸二钙、 澳化钾、 碘化钾、 滑石粉、 高岭土、 胶 质、 交聚维酮、 琼脂和皂土。
根据本发明的药物和药物组分可以使用已知的先进的手段、 设备、 方 法和工序等所述的药物制剂技术的帮助下制备的。 例如， 对固体制剂如片 剂而言， 可以将药物的活性成分， 也就是益母草碱或其药学上可接受的盐 或其溶剂化物， 与药物载体一起颗粒化， 举例来说， 常规的药片成分， 例 如玉米面粉、 乳糖、 蔗糖、 山梨醇、 滑石粉、 硬脂酸镁、 磷酸二钙或药物 学上可接受的胶质， 以形成一种含有均匀分布的益母草碱或其药学上可接 受的盐或其溶剂化物的固体组分。
均匀分布在这里可理解成活性成分益母草碱或其药学上可接受的盐或 其溶剂化物在整个组分中均一分布， 从而可以很容易地被分成具有同样活 性的单位剂型， 如药片、 药丸或胶嚢。 然后固体组分被分成单位剂型。 按 本发明的药物或药物组分的片剂或丸剂也可以被包衣或混合在另一组分中 以提供一种緩释剂型。 其中， 合适的包衣组分是， 聚合酸以及聚合酸与例 如虫胶， 鲸蜡醇和 /或醋酸纤维素等材料的混合物。
可以将本发明的药物組合物制成临床可接受的剂型， 如片剂， 胶嚢， 颗粒剂， 口服液体制剂， 皮下给药制剂， 栓剂等。 加入适量的载体， 可制 成片剂、 颗粒剂或胶嚢剂等口服制剂。 这些剂型是按照本领域的技术人员 所熟知方法制备的。 用于制造片剂、 颗粒剂、 胶嚢剂等成型工艺的载体是 常用的助剂， 例如淀粉、 明胶、 阿拉伯胶、 聚乙二醇等， 此外还有表面活 性剂、 润滑剂、 崩解剂、 防腐剂、 矫味剂、 色素等。
本发明 上述益母草碱化合物进行了下述体内、 体外实验， 从而充 分验证了本发明医药用途的可实施性： 通过体外实验研究， 检测益母草碱对 LDH漏出到培养液中的量的影 响， 检测乳酸脱氢酶漏出率。
通过结扎冠状动脉前降支的心梗模型研究 , '检测益母草碱对梗死面积 的影响； 对心肌酶肌酸激酶（CK )和乳酸脱氢酶（LDH )的影响； 对凋亡 基因 Bax和 Bcl-2 mRNA和蛋白水平的影响， 检测结果显示， 益母草碱降 低梗死面积，减轻心肌酶 LDH和 CK在血浆中的水平；增加 Bcl-2和降低 Bax mRNA和蛋白水平的表达；
通过结扎冠状动脉前降支的心衰模型，检测心脏功能和血浆中维生素 c 和半胱氨酸的含量， 检测结果显示， 所述的益母草碱能降低心室收缩末期 压， 提高收缩速率， 改善心功能， 能增加血浆中维生素 C和降低半胱氨酸 的含量。
实验结果证明， 所述的益母草碱能够减少乳酸脱氢酶漏出率， 对于预 防和 /或治疗急性心肌梗死或心力衰竭具有明显作用，可制备防治急性心肌 梗死或心力衰竭的药物。 附图的简要说明
以下， 结合附图来评细说明本发明的实施例， 其中：
图 1为显示乳 氢酶（ LDH )漏出率 (relative LDH release)的柱形图， 其中，数据用正常组（ 100% )的百分数表示， control表示未缺氧组， vehicle 表示缺氧组， losartan表示用氯沙坦治疗组， leonurine表示用益母草碱治 疗组； *: 和正常组相比 p < 0.01 , #: 和缺氧组相比 p < 0.01;
图 2为显示益母草碱降低心肌梗死面积的图表， 其中， sham表示假手 术组， AMI表示心肌梗死组， Leo7.5mg/kg表示用益母草碱低剂量
( 7.5mg/kg )治疗组， Leol5mg/kg表示用益母草碱高剂量（15mg/kg )治 疗组； *: 和心肌梗死组相比？< 0.05;
图 3为显示益母草碱降低心梗大鼠血浆的 LDH的柱形图，其中， sham 表示假手术組， AMI表示心肌梗死组， Leo7.5mg.kg-1表示用益母草碱低剂 量
Figure imgf000010_0001
治疗组， Leo mgJcg-1表示用益母草碱高剂量（ 15mg.kg ) 治疗组； *: 和心肌梗死组相比；? < 0.05, #: 和假手术組相比；？ < 0.05。 图 4为显示益母草碱降低心梗大鼠血浆的 CK的柱形图， 其中， sham 表示假手术组， AMI表示心肌梗死组， Leo7.5mg.kg4表示用益母草碱低剂 量 mg-kg-1治疗组， Leol5mg.kg4表示用益母草碱高剂量（ mg.kg-1 ) 治疗组； *: 和心肌梗死组相比 ρ < 0.05, #: 和^ -手术組相比 ρ < 0.05。
图 5为显示益母草碱降低 Bax和增加 Bcl-2的 mRNA水平的表达的柱 形图， 其中， sham表示假手术组， AMI表示心肌梗死组， Leo7.5mg.kg_1 表示用益母草碱低剂量 ^mg g-1治疗组， LeolSmg g 表示用益母草碱高 剂量（15mg.kg_1 )治疗组； *: 和心肌梗死组相比； ? < 0.05, #: 和假手术 組相比 < 0.05。
图 6 为显示益母草减降低 Bax和增加 Bcl-2的蛋白水平的表达的柱形 图， 其中， sham表示假手术组， AMI表示心肌梗死组， Leo7.5mg.kg-1表 示用益母草碱低剂量 y^mg g-1治疗组， Leo rngJig-1表示用益母草碱高剂 量（15mg.kg-1 )治疗组； *: 和心肌梗死组相比 < 0.05, #: 和^■手术组 相比 ρ < 0.05。 实施发明的最佳方式
下面结合具体实施例， 进一步阐述本发明。 但这些实施例仅限于说明 本发明而不用于限制本发明的范围。 下列实施例中未注明具体实验条件的 实验方法， 通常按照常规条件， 或按照厂商所建议的条件。 实施例 1 ： 检测益母草碱对于乳酸脱氢酶的漏出率影响的体外实验
如图 1所示， 本实施例使用氯沙坦做阳性对照药， 选用的益母草碱的 浓度为 l(T6mol/L， 实验数据进行单因素方差分析， < 0.01， 结果显示， 细 胞死亡可导致乳 氢酶的漏出， 通过检测分析 LDH漏出到培养液中的 量， 结果显示，益母草碱能明显减少乳酸脱氢酶的漏出。单因素方差分析， p < COL 实施例 2 ： 益母草碱的心梗模型试验
如图 2-6所示， 本实施例采用本领域成熟的结扎冠状动脉前降支的心 梗模型， 用腹腔注射给药的方法， 用 TTC染色的方法检测梗死面积， 实验 数据单因素方差分析， 结果： < 0.05, 表明益母草碱能明显减低心肌梗死 面积。
心肌梗死可导致心肌酶 LDH和 CK释放到血浆中， 所述的益每草碱 能明显减少血浆中 LDH和 CK的水平，减轻心肌损伤的程度，单因素方差 分析， ρ < 0.05。
Bax是促凋亡基因， Bcl-2是抗凋亡基因， 所述的益母草碱能明显降低 Bax mR A和蛋白水平的表达，明显升高 Bcl-2 mRNA和蛋白水平的表达。
实验结果表明，所述的益母草碱对急性心肌梗塞具有明显的治疗改善 作用， 可制备防治急性心肌梗塞的药物。 实施例 3 ： 益母草碱的心衰模型试验
本实施例采用本领域成熟的结扎冠状动脉前降支的心衰模型，采用腹腔 灌胃给药的方法， 用动脉和心室插管的方法， 检测心功能， 结果表明益母 草碱能降低心室收缩末期压， 提高收缩速率， 改善心功能。 单因素方差分 析， p < 0.05。
用毛细血管电泳方法检测血浆中维生素 C和半胱氨酸的含量。 结果表 明益母草碱能增加血浆中维生素 c和降低半胱氨酸的含量， 单因素方差分 析， p < 0.05。
表 1是心衰模型心功能的检测结果，显示益母草碱提高心梗大鼠的心功 能， 其中， *: 和心衰组相比 p < 0.05, #: 和假手术组相比 < 0.05。
表 1. 心衰模型心功能的检测结果
心衰模型（HF ) + 心衰模型 ( HF ) +益母草 假手术組
生理盐水組 碱組
Figure imgf000012_0001
441±29
HR,次 /分钟 410d=22 408±78
427±78
143.77±26.82
LVSP, mmHg 186.73±36.71 113.15±12.9'
126.37±2.28
LVEDP, mmHg 3.88±1.54 15.54±1.36# 11.53±1.83* 13±5.96 4205±412.71 dP/dt, mmHg/s 6139.47±635.55 3047.26±322.71#
4095±433.45*
-4368.83±662.12'
-dP/dt, mmHg/s -5571.52±626.56 -2599.37±587.44
-3276.62±283.77
下面的表 2显示益母草碱提高血浆中维生素 C和降低半胱氨酸含量 的实验结果，其中， *: 和心衰组相比 < 0.05， **:和心衰组相比 /? < 0.01 , #: 和^ -手术组相比？ < 0.05。
表 2.益母草碱提高血浆中维生素 C和降低半胱氨酸含量
心衰模型
( HF ) +生
假手术组 理盐水組 益母草碱組
15 mg/kg (n = 4) 30 mg/kg
Figure imgf000013_0001
羊胱氨酸， μηιοΐ/ΐ 29.8±2.29 55±14.31# 35.29±9.73
抗坏血酸 (维生素 c )， 26.02±3.95**
μιηοΐ/ΐ 11.63±1.66 8.42±2.93 39.79±4.33**

Claims

权 利 要 求
1、 益母草碱化合物或其药学上可接受的盐或其溶剂化物在制备具有减少 乳酸脱氢酶漏出率作用的药物中的应用。
2、 益母草碱化合物或其药学上可接受的盐或其溶剂化物在制备用于预防 和 /或治疗急性心肌梗死或心力衰竭的药物中的应用。
3、权利要求 2的应用，其中所述益母草碱化合物为益母草碱的外消旋体、 单純立体异构体， 尤其是对映异构体或非对映异构体， 或以任意所需 比例混合的立体异构体混合物。
4、权利要求 1-3任一项的应用， 其中所述益母草碱化合物的溶剂化物是 益母草碱的水合物。
5、权利要求 1-3任一项的应用， 其中所述益母草碱化合物的药学上可接 受的盐是益母草碱与选自如下的酸形成的酸加成盐： 盐酸、 硫酸、 硫 酸氢钠、 亚硫酸、 亚硫酸氢钠、 硝酸、 磷酸、 醋酸、 乳酸、 甲磺酸、 乳糖酸、 枸橼酸、 草酸、 谷氨酸、 富马酸、 马来酸、 天冬氨酸、 柠檬 酸或琥珀酸。
6、 权利要求 1-5任一项的应用， 其中所述药物的剂型选自： 口服制剂、 肠胃外给药制剂、 局部给药制剂、 吸入式给药制剂和透皮制剂。
7、 一种用于预防和 /或治疗急性心月几梗死或心力衰竭的药物组合 物， 所述药物组合物包含： 作为活性组分的益母草碱化合物 或其药学上可接受的盐或其溶剂化物， 以及一种或多种药学 上可接受的载体。
8、 权利要求 7 的药物组合物， 其中所述益母草碱化合物的溶剂化物是 益母草碱的水合物。
9、权利要求 7的药物组合物，其中所述益母草碱化合物的药学上可接受 的盐是益母草碱与选自如下的酸形成的酸加成盐： 盐酸、 硫酸、 硫酸 氢钠、 亚硫酸、 亚硫酸氢钠、 硝酸、 磷酸、 醋酸、 乳酸、 甲磺酸、 乳 糖酸、 枸橼酸、 草酸、 谷氨酸、 富马酸、 马来酸、 天冬氨酸、 柠檬酸 或琥珀酸。
10、 权利要求 7-9任一项的药物组合物， 其中所迷药物组合物为： 口服制 剂、 肠胃外给药制剂如注射剂、 局部给药制剂、 吸入式给药制剂或透 皮制剂。
、权利要求 10的组合物，其中所述药物组合物为选自如下的口服制剂： 片剂、 胶嚢剂、 颗粒剂、 丸剂、 滴剂、 果汁或糖浆剂； 优选地， 所述 药学上可接受的载体选自： 崩解剂、 润滑剂、 粘合剂、 填充剂、 溶剂、 香料、 甜味剂、 抗氧化剂、 表面活性剂、 防腐剂、 矫味剂和色素。
PCT/CN2008/001409 2007-08-02 2008-08-01 The use of leonurine and compositions thereof Ceased WO2009015561A1 (en)

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