WO2015165382A1 - 灵芝酸a在抗抑郁症中的用途 - Google Patents

灵芝酸a在抗抑郁症中的用途 Download PDF

Info

Publication number
WO2015165382A1
WO2015165382A1 PCT/CN2015/077691 CN2015077691W WO2015165382A1 WO 2015165382 A1 WO2015165382 A1 WO 2015165382A1 CN 2015077691 W CN2015077691 W CN 2015077691W WO 2015165382 A1 WO2015165382 A1 WO 2015165382A1
Authority
WO
WIPO (PCT)
Prior art keywords
ganoderic acid
acid
antidepressant
ganoderma lucidum
derivative
Prior art date
Application number
PCT/CN2015/077691
Other languages
English (en)
French (fr)
Inventor
杜若甫
Original Assignee
北京冠瑞金生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京冠瑞金生物科技有限公司 filed Critical 北京冠瑞金生物科技有限公司
Publication of WO2015165382A1 publication Critical patent/WO2015165382A1/zh

Links

Images

Classifications

    • 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

Definitions

  • the invention relates to the field of pharmacy, in particular to the use of ganoderic acid A in antidepressant.
  • Depression has become a common and frequently-occurring disease in modern society, and its incidence is still rising. The condition is characterized by low mood, decreased interest, slow thinking, and reduced speech and movement. Severe depression has the idea of being sick or suicidal. The pain caused by such diseases to patients and their families, as well as the loss to society, is unmatched by many other diseases. According to a report published by the World Health Organization (WHO), affective disorders have now become the fourth largest disease in the world, with 340 million people worldwide suffering from depression. The current incidence of depression in China is about 4%. At least 26 million people in China suffer from depression, and the total economic burden of depression in China is 62.2 billion yuan.
  • WHO World Health Organization
  • the main drugs used are serotonin reuptake inhibitors, etc.
  • the use of these drugs is slow in action, narrow in action spectrum, and has a large side effect, and is easy to relapse after stopping the drug.
  • the field of antidepressant treatment is in urgent need of quick onset, small side effects, and more effective treatment.
  • Current antidepressants and their weaknesses Current antidepressants can be broadly classified into three categories: monoamine oxidase inhibitors, tricyclic antidepressants, and heterocyclic antidepressants.
  • the existing antidepressant drugs are far from satisfying the needs of patients.
  • the main disadvantages are mainly slow onset, narrow antidepressant spectrum, large side effects and easy recurrence.
  • the development of new drugs with rapid onset of action, extensive antidepressant spectrum, and less toxic side effects is a very urgent need in this field and will bring huge economic returns.
  • Ganoderma lucidum (Curtis: Fr.) P. Karst]. In the fungal classification, it belongs to the Eumycota Basidiomycotina, and the Polyporaceae Ganodermatoideae Ganoderma. There are 44 species of Ganoderma in China (including 21 species of Ganoderma lucidum and 23 species of Ganoderma lucidum). In the 2005 edition of the Chinese Pharmacopoeia, two of them are the legal sources of Ganoderma lucidum: Ganoderma lucidum (Leyss.ex Fr.) Karst. and Ganoderma Ganoderma Sinense is also known as Ganoderma lucidum. Ganoderma lucidum is a fruiting body of the plant Ganoderma lucidum.
  • Ganoderma lucidum triterpenoids The main active ingredient in Ganoderma lucidum is Ganoderma lucidum triterpenoids.
  • Ganoderma acid belongs to the triterpenoids of Ganoderma lucidum. The most studied is Japan, followed by China. So far, a comprehensive report has revealed that there are about 106 triterpenoids isolated from the fruit body and spore powder of G. lucidum.
  • Ganoderic acid A Ganoderic lucidie acid A
  • Ganoderma acid A is a Ganoderma lucidum triterpenoid.
  • citric acid A has many English synonyms: such as GANODERIC ACID A (P); AIDS070759; AIDS-070759Aids070759 (25R)-7 ⁇ , 15 ⁇ -Dihydroxy-3, 11, 23-trioxo-5 ⁇ -lanost-8 -en-26-oic acid;(7beta,15alpha,25R)-7,15-Dihydroxy-3,11,23-trioxo-lanost-8-en-26-oic acid;Lanost-8-en-26-oic Acid,7,15-dihydroxy-3,11,23-trioxo-,(7.beta.,15.alpha.,25R)-(25R)-7 ⁇ ,15 ⁇ -Dihydroxy-3,11,23-trioxo-5 ⁇ -lanost-8-en-26-oicaci.
  • GANODERIC ACID A P
  • AIDS070759 AIDS-070759Aids070759 (25R)-7 ⁇ , 15 ⁇ -Dihydroxy
  • Ganoderma lucidum A, B, C, and D from the bioactive components extracted from the fruiting body of Hongzhi can significantly inhibit the histamine release of mast cells induced by Concanavalin A.
  • Wang Mingyu and others obtained five triterpenoid components from the fruit body of G. chinensis.
  • Ganoderma lucidum A had better protection against three liver injury model mice caused by carbon tetrachloride, galactosamine and BCG+ lipopolysaccharide. Liver function can significantly reduce serum ALT and liver TG content in model animals, and reduce liver damage in animals to varying degrees.
  • Ganoderma glycerol triol and Ganolucidie acid A can significantly inhibit the activity of HIV-1 type protease (HIV) type HIV-1 virus.
  • HIV HIV-1 type protease
  • Wu et al. isolated six triterpenoids from the ethanol extract of Ganoderma lucidum fruiting body.
  • ganoderic lucidenic acid A and ganoderic acid E on hepatoma cells Hep G2 and Hep G2.2.15 And tumor cell P-338 has a significant cytotoxic effect. It can be seen from the above analysis that natural ganoderic acid has its unique advantages, and ganoderic acid A may be a very effective component in anti-tumorization.
  • Ganoderma lucidum A also treats cardiovascular diseases, such as lowering blood lipids, treating digestive diseases, such as hepatitis gastritis and duodenitis, protecting liver and kidney, clearing away heat and detoxification; and treating respiratory diseases such as asthma and bronchitis , bronchial asthma, etc.
  • Ganoderma lucidum A is beneficial to human health and can effectively prevent retinal oxidation and photoreceptor cell damage, as well as protect the central nervous system, especially the brain, so as to effectively treat ischemia.
  • Central nervous system damage such as reperfusion injury, spinal cord injury, Parkinson's syndrome, Alzheimer syndrome. Therefore, in the study of the classification of Ganoderma lucidum, it is quite reasonable to use the high and low levels of Ganoderma lucidum as the basis for distinguishing the quality of Ganoderma lucidum.
  • the present invention provides ganoderma lucidum A as an antidepressant drug and an antidepressant drug prepared therefrom.
  • the drug has the advantages of significant antidepressant effect, quick effect, and small side effects.
  • the technical scheme is as follows:
  • ganoderic acid A for preparing an antidepressant medicine, characterized in that the medicinal active ingredient of the antidepressant medicine is a derivative of ganoderic acid A or ganoderic acid A, and the derivative refers to ganoderic acid A and A pharmaceutically acceptable salt, ester or saccharified synthetic hydrazine.
  • ganoderic acid A for preparing an antidepressant medicine, characterized in that the pharmaceutically active ingredient of the antidepressant medicine comprises a derivative of ganoderic acid A or ganoderic acid A, and the derivative refers to ganoderic acid A and A pharmaceutically acceptable salt, ester or saccharified synthetic hydrazine.
  • the antidepressant drug refers to a drug for preventing or treating depression.
  • the dosage form of the antidepressant drug is a tablet, a capsule, a solution, a suspension, an injection or a drip.
  • An antidepressant medicine characterized in that the pharmaceutically active ingredient is a derivative of ganoderic acid or ganoderic acid A, and the derivative of ganoderic acid A refers to ganoderic acid A and a pharmaceutically acceptable salt or ester or The sugar made by sugar.
  • the antidepressant refers to prevention or treatment of depression.
  • the dosage form is a tablet, a capsule, a solution, a suspension, an injection or a drip.
  • the medicament further comprises a pharmaceutically acceptable auxiliary ingredient.
  • the drug further includes a pharmaceutical ingredient which has a positive effect on the treatment of depression when used in combination with Ganoderma lucidum A or a derivative thereof, or an ingredient which improves the stability of Ganoderma lucidum A.
  • a method for antidepressant characterized in that a therapeutically effective dose of a medicament is provided to a subject on time, and the medicinal component of the medicament comprises a derivative of ganoderic acid A or ganoderic acid A, and the derivative refers to a ganoderma lucidum Acid A is a pharmaceutically acceptable salt, ester or saccharified synthetic hydrazine.
  • the agent for providing a therapeutically effective dose on time refers to 0.5 mg to 1000 mg of Ganoderma lucidum A/kg body weight per day, which is administered orally, by instillation or injection; the subject is a mammal, and the mammal includes a human.
  • the dose is 0.5 mg to 1000 mg of Ganoderma lucidum A/1 kg per day.
  • ganoderic acid A has a significant antidepressant effect on mammals. Experimental studies have found that in mammalian mice, ganoderic acid A has a rapid and strong antidepressant effect in a short period of time (24 hours), and the antidepressant effect can continue to occur. People with depression generally complain of inflammatory pain symptoms such as headache, stomach pain, back pain and so on. Ganoderma lucidum can also improve the patient's inflammatory symptoms while resisting depression. Many patients with cancer diseases are treated with chemotherapy and radiotherapy, and they have depression. Ganoderma lucidum A can simultaneously play an anti-tumor and anti-depression effect.
  • the small molecule compound Ganoderma lucidum A can comprehensively improve various symptoms of patients with depression, including depressive symptoms, pain, inflammation and the like. Its antidepressant effect is significant, fast, and long lasting in animal models. The antidepressant drugs currently used are very slow and usually take several weeks. There is an urgent need in the industry to develop fast-acting antidepressants.
  • Ganoderic acid A Ganoderic lucidie acid A
  • Its structural diagram is shown in Figure 1. It is one of the triterpenoids isolated from the Ganoderma lucidum karst of the genus Ganoderma lucidum. It can be taken by humans for a long time. Its toxic side effects have not been seen so far. It is reported that there are no shortcomings such as calming, inducing epilepsy and ataxia of conventional antidepressants during the trial.
  • Ganoderma acid A can also be extracted from cultured red algae and yeast. It has the potential to be a fast, efficient, non-toxic anti-depressant new drug with strong industrial applicability and great commercial value.
  • the drug screening test used in the invention is: forced swimming and tail suspension test of mice, and is a commonly used two animal behavior despair depression model test, which can better ensure the reliability of the screening result.
  • the mouse forced swimming test has been used in screening tests for many antidepressants. Moreover, most antidepressants with clinical therapeutic effects have also been shown to be effective in reducing immobility time in forced swimming trials.
  • immobility means that "the animal stops struggling in the water, or is floating, only revealing the nostrils to keep breathing, only small limb movements to keep the head floating on the water.” Give the drug to be screened before testing. Because animals swim under compulsive conditions, animals cannot escape from harsh environments, causing animals to behave exclusively. This model method is simple and reliable, and has been widely used in the screening and evaluation of antidepressants.
  • the mouse tail suspension test is that the mouse is no longer struggling in the sling state, showing a unique quiet state, and the antidepressant can significantly shorten the duration of the immobile state.
  • the tail of the mouse was fixed with medical tape and suspended. Do not twist the tail of the mouse. Recording time is not moving. The immobile indicator is: "All animals except the breathing are not moving.”
  • the tail suspension test is sensitive to various antidepressants and avoids the interference of temperature and animal motor dysfunction in swimming tests. Therefore, when screening antidepressants with some mouse species, it can effectively verify and supplement the forced swimming experiment. result.
  • the use of the ganoderma acid A provided by the present invention as an antidepressant drug is not limited to the use of the ganoderic acid of the structural formula shown in FIG. 1 in the preparation of an antidepressant, and the ganoderma lucidum A is prepared as a salt or an ester of the ganoderic acid A or
  • the enthalpy formed with sugar is a routine experimental skill possessed by those skilled in the art, and the salt, ester of ganoderic acid A or its saccharide formed by the saccharide and ganoderic acid A have similar pharmacodynamic effects, which can be reasonable for those skilled in the art. It is anticipated that the present invention therefore also claims the use of a salt, an ester of ganoderic acid A or a saccharide thereof with a sugar to prepare an antidepressant drug.
  • ganoderma lucidum A provided by the invention for preparing an antidepressant medicine
  • the antidepressant medicine prepared by the invention can be added to an auxiliary component which does not affect the drug efficacy, such as a carrier and a type, based on the common sense of a person skilled in the pharmaceutical field. Agents, etc. Since the drug is effective by oral administration, injection, subcutaneous embedding, etc., the dosage form can be varied.
  • the antidepressant medicine provided by the present invention may also be a pharmaceutical ingredient which is mixed with other ganoderic acid or a derivative thereof to have a positive effect on the treatment of depression.
  • the antidepressant medicine provided by the present invention includes two stages of prevention and treatment.
  • the present invention also claims the use of ganoderic acid A in the treatment of antidepressant, and the dose range for achieving antidepressant treatment in an animal model test is from 0.5 mg to 1000 mg/1 kg per day.
  • the abscissa from left to right: Ganoderma acid A control, Ganoderma acid A low, Ganoderma lucidum A high, imipramine control group, imipramine.
  • the abscissa from left to right: Ganoderma acid A control, Ganoderma acid A low, Ganoderma lucidum A high, imipramine control group, imipramine;
  • Animal CD1 mouse male, weighing 25-35 grams, provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., license number: SCXK (Beijing) 2011-0011.
  • SCXK Beijing 2011-0011.
  • the animals are kept in cages and the water is free.
  • the feed is provided by the Experimental Animal Center of the Institute of Genetics of the Chinese Academy of Sciences, and the normal feed for the rats can be used.
  • Ganoderma Acid A was purchased from Shanghai Fusheng Industrial Co., Ltd., 10 mg package.
  • the positive control, Imipramine hydrochloride was a product of Sigma, product number I7379, batch number O56K1380.
  • mice Male CD1 mice were conditioned for one week and divided into 5 groups, eight in each group, respectively: Ganoderma lucidum A control group: normal saline plus 1.0% ethanol, injected at 0.3 ml/30 g body weight; Ganoderma lucidum A dose Group: 5mg/kg body weight, lucidum acid A dissolved in normal saline plus 1.0% ethanol; high dose of lucidum acid A: 12.5mg/kg body weight, lucidum acid A dissolved in normal saline plus 1.0% ethanol; imipramine positive control group : 15 mg / kg body weight, imipramine physiological saline dissolved; imipramine control group: normal saline, according to 0.3ml / 30g body weight injection.
  • the drug was administered intraperitoneally at a design dose at 10 am.
  • the drug was administered at 10 am the next day, and the tail suspension experiment was started 90 minutes after the injection.
  • mice tail suspension experiment the mouse tail was adhered to a horizontal crossbar 2 cm from the tip of the tail with a medical tape, and the animal was placed upside down, and the head was about 15 cm from the table top. Observe for 6 minutes and accumulate the immobility time within 4 minutes after recording.
  • the immobile indicator is: "All animals except the breathing do not move.”
  • the immobility time of Ganoderma lucidum A dose at 12.5 mg/kg was reduced from 86.15 ⁇ 8.36s to 48.33 ⁇ 8.89 (P ⁇ 0.05), which was shortened by 43.9%.
  • the low dose of Ganoderma lucidum A showed a decreasing trend, but it has not been significantly reduced.
  • the animal is a male mouse of CD1, and is provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., license number: SCXK (Beijing) 2011-0011. Animals were housed in cages one week before the experiment, with a light-dark cycle of 12 h/12 h and a room temperature of 20-22 °C. The feed was provided by the Experimental Animal Center of the Institute of Genetics, Chinese Academy of Sciences.
  • Experimental drug Ganoderma lucidum A, Imipramine hydrochloride as in Example 1; Test apparatus: glass cylinder (20 cm high, diameter 14 cm); mouse open box (diameter 30 cm, height 20 cm, bottom 16 aliquots) ); thermometer; JUNSO multi-function timer.
  • Drug preparation was the same as in Example 1 tail suspension experiment.
  • mice CD1 mice, aged 7 weeks, weighing 25-35 grams, started the experiment one week after the adaptation to the environment. Animals were randomly divided into 5 groups of eight animals each. Intraperitoneal injection was started every day at 10 am. The injection volume is 0.3 ml / 30 g.
  • Ganoderma acid A blank control group: daily intraperitoneal injection of normal saline plus 1.0% ethanol, the injection volume is 0.3 ml / 30 g;
  • Ganoderma acid A group different amounts of ganoderic acid A were dissolved in physiological saline plus 1.0% ethanol,
  • imipramine was dissolved in physiological saline, and the injection volume was 15 mg/kg.
  • Imipramine blank control group only saline was injected, the injection volume was 0.3 ml / 30 g.
  • the above test group was intraperitoneally injected once a day for three days, and the forced swimming test was started 90 minutes after the third day of injection.
  • Forced swimming test Each group of CD1 mice was placed vertically in a plexiglass cylinder (40 cm x 14 cm diameter) with a water depth of 15 cm and a water temperature of 23 °C.
  • Each of the drug-administered groups and the control group was videotaped for 6 minutes, and the mice in each group were compared for the immobilization time in the last 4 minutes.

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)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

灵芝药效活性成分在制备抗抑郁症药物中的用途和包含灵芝药效活性成分的抗抑郁药物，其中药效活性成分为灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接受的盐、酯或糖化合成的甙。

Description

灵芝酸A在抗抑郁症中的用途 技术领域
本发明涉及制药领域，特别涉及灵芝酸A在抗抑郁症中的用途。
背景技术
抑郁症已成为现代社会的常见病和多发病，其发病率还在不断升高。病症以情绪低落、兴趣减退、思维迟缓、以及言语与动作减少为特征，重症抑郁有厌世或***的念头。这类疾病对患者及其家属造成的痛苦，以及对社会造成的损失，是许多其他疾病所无法比拟的。根据世界卫生组织(WHO)发表的报告，情感障碍目前已成为世界第四大疾患，全球的抑郁症患者已达3.4亿人。目前抑郁症在中国发病率大约为4％。中国至少有2600万人患有抑郁症，抑郁症在中国造成的总经济负担达到622亿元人民币。美国估计有1700万人患有抑郁症,300万人患躁郁症，每年治疗情感障碍的费用高达440亿美元(冠心病为430亿美元)。在过去对情感障碍研究的40年中，特别引人注目的是其发病率和死亡率高，据报道***率高达10％以上，中国每年有25万人***。
目前主要使用的药物是五羟色胺再摄取抑制剂等,使用这类药物起效慢,作用谱窄，副作用大，停药后易复发。目前，抗抑郁治疗领域急需起效快，副作用小，更为有效的治疗药物。
目前的抗抑郁药物及其弱点：当前的抗抑郁药大致可分为三类：即单胺氧化酶抑制剂、三环类抗抑郁剂及杂环类抗抑郁剂。现有的抗抑郁药物远远不能满足病人的需求，其不足之处大主要集中表现为起效慢、抗抑郁谱窄、副作用大、易复发等。开发起效快、抗抑郁谱广泛、毒副作用较小的新药，在这个领域是非常迫切的需要，将带来巨大的经济回报。
灵芝[Ganoderma lucidum(Curtis:Fr.)P.Karst].在真菌分类上属于真菌门(Eumycota)担子菌纲(Basidiomycotina)，多孔菌科(Polyporaceae)灵芝亚科(Ganodermatoideae)灵芝属(Ganoderma)。灵芝属在我国有44种(包括灵芝组21种，紫芝组23种)，2005年版中国药典将其中两种作为灵芝的法定来源:即赤芝Ganoderma lucidum(Leyss.ex Fr.)Karst.和紫芝Ganoderma sinense并被誉为灵芝正品。灵芝是植物灵芝的子实体，古称“瑞草”，俗称“神仙草”，日本人称其为“万年茸”。在灵芝中主要有效成分为灵芝三萜类化合物。灵芝酸属于灵芝三萜类化合物，研究最多的是日本，其次是中国。到目前为止，综合各种报道，从赤芝子实体和孢子粉中分离到的三萜类化合物约有106种。
自从1982年Kubora.T等人首次从灵芝的子实体中分离得到灵芝酸A(ganoderie aeidA)和灵芝酸B(ganoderie aeidB)"以来。对于灵芝酸国内外普遍开展了研究。
灵芝酸A(Ganoderic acid A)，赤灵芝酸A(Ganoderic lucidie acid A)，其分子式为C30H42O7，分子量为514.65，其化学结构如图1所示，灵芝酸A是灵芝三萜中的一种，芝酸A有许多英文的同义词：如GANODERIC ACID A(P)；AIDS070759；AIDS-070759Aids070759(25R)-7β,15α-Dihydroxy-3,11,23-trioxo-5α-lanost-8-en-26-oic acid；(7beta,15alpha,25R)-7,15-Dihydroxy-3,11,23-trioxo-lanost-8-en-26-oic acid；Lanost-8-en-26-oic acid,7,15-dihydroxy-3,11,23-trioxo-,(7.beta.,15.alpha.,25R)-(25R)-7β,15α-Dihydroxy-3,11,23-trioxo-5α-lanost-8-en-26-oicaci。陈国良等(1995)在国内首次在综述中提及灵芝酸的研究进展，其中也特别提到灵芝酸A的保健作用，日本学者在专利中报道了灵芝酸的制备方法以及液体培养的菌丝体中灵芝酸的制备方法；王芳生等从灵芝的二氯甲烷溶解部分分离得到灵芝酸DM。1999年,李平作等研究了发酵液中灵芝酸的分离与纯化。从红芝的子实体甲醇提取的生物活性组分中分离出三萜化合物灵芝酸A、B、C、D能明显抑制伴刀豆球蛋白A等诱导的肥大细胞的组胺释放。王明宇等从赤芝子实体中得到5个三萜组分,其中的灵芝酸A对四氯化碳、氨基半乳糖昔和卡介苗+脂多糖所致的3种肝损伤模型小鼠有较好的保肝作用,可明显降低模型动物的血清ALT和肝脏TG含量，并不同程度减轻动物肝损伤。灵芝酮三醇和赤灵芝酸A(Ganolucidie acid A)均能够显著抑制HIV一1型蛋白酶的活性，(艾滋病病毒)HIV－1型病毒的特性。Min等从灵芝孢子中分离出Canoderi cacid，Canoderic acid与灵芝酮二醇(Ganoder manondiol)灵芝酮三醇和赤灵芝酸A这些成分均能显著抑制HIV－1型蛋白酶的活性。Wu等从灵芝子实体乙醇提取液分离出六种三萜类化合物，药理学实验表明，赤芝酸A(ganoderic lucidenic acid)A和灵芝酸(ganoderic acid)E对肝癌细胞Hep G2和Hep G2.2.15及肿瘤细胞P-338具有显著的细胞毒性作用。从上述分析可以看出,天然灵芝酸有其独特的优势，灵芝酸A在抗肿瘤化方面可能是一个十分有效的成分。灵芝酸A还有治疗心血管疾病，如降低血脂,治疗消化***疾病，又如肝炎胃炎和十二指肠炎、保护肝脏和肾、清热解毒；又能治疗呼吸***疾病，如缓解哮喘、支气管炎、支气管哮喘等。还能治疗神经***疾病，如健忘，失眠，紧张，呼吸难衰老，养颜。目前研究和实践表明，灵芝酸A对人类的健康很有益处，能有效地防止视网膜的氧化和感光细胞的损伤，以及对中枢神经***尤其是对大脑起到保护作用，从而有效治疗缺血-再灌注损伤、脊髓损伤、帕金森综合征、Alzheimer综合征等中枢神经***损伤。因此，在区分灵芝种类研究中，多将灵芝酸含量高低作为区分灵芝质量优劣的依据，这是很有道理的。
目前在全世界有超过30多项关于灵芝酸A用途的专利，见附表，但在现有文献或发明专利中尚未见有学者关于化合物灵芝酸A用于治疗抑郁症的报道。
发明内容
本发明提供灵芝酸A作为抗抑郁症药物及用它制备而得的抗抑郁症药物。这种药物具有抗抑郁效果显著、见效快、副作用小等优点，技术方案如下：
灵芝酸A在制备抗抑郁症药物中的用途，其特征在于，所述抗抑郁症药物的药效活性成分为灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
灵芝酸A在制备抗抑郁症药物中的用途，其特征在于，所述抗抑郁症药物的药效活性成分包括灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
所述抗抑郁症药物是指预防或治疗抑郁症的药物。
所述抗抑郁症药物的剂型为片剂、胶囊、溶液、悬浮液、注射液或滴注液。
一种抗抑郁症的药物，其特征在于：其药效活性成分为灵芝酸或灵芝酸A的衍生物，所述灵芝酸A的衍生物指灵芝酸A与药学上可接收的盐、酯或糖所成的甙。
所述抗抑郁症是指预防或治疗抑郁症。
其剂型为片剂、胶囊、溶液、悬浮液、注射液或滴注液。
所述药物，还包括制药学上可接受的辅助成分。
所述药物，还包括有与灵芝酸A或其衍生物配合使用时对治疗抑郁症有积极作用的药物成分，或使灵芝酸A稳定性提高的成分。
一种抗抑郁症的方法，其特征在于：向受试者按时提供治疗有效剂量的药剂，所述药剂的药效成分包括灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
上述方法，所述按时提供治疗有效剂量的药剂指每天0.5mg～1000mg灵芝酸A/kg体重，给药方式为口服、滴注或注射；给药对象为哺乳动物，所述哺乳动物包括人。
所述给药剂量为每天0.5mg-1000mg灵芝酸A/1kg。
本发明发明人发现灵芝酸A对哺乳动物具有显著的抗抑郁效果。经实验研究发现，在哺乳动物小鼠实验中，灵芝酸A在短时间内(24小时)就迅速具有了明显的且较强的抗抑郁症效果，且抗抑郁效果可以持续产生。抑郁症患者普遍主诉有炎性疼痛症状，如头痛，胃痛，背痛等等。灵芝酸在抗抑郁的同时，还能改善病人的炎性症状。许多肿瘤疾病患者经化疗、放疗治疗后，并发抑郁症，灵芝酸A可同时起到抗肿瘤和抗抑郁的作用。因此小分子化合物灵芝酸A能够综合性地改善抑郁症病人的各种症状，包括精神抑郁症状、疼痛、炎症等等。它的抗抑郁效果在动物模型中显著、快速、并且持久。目前使用的抗抑郁药物见效很慢，一般需要几个星期。业界急需发展快速见效的抗抑郁药物。
灵芝酸A(Ganoderic acid A)，赤灵芝酸A(Ganoderic lucidie acid A)，其分子式为C30H42O7，分子量为514.65。它的结构图如图1所示，是从真菌多孔菌科灵芝属的赤芝(Ganoderma lucidum karst)中分离出的三萜化合物中的一种，能长期被人类服用，它的毒副作用至今未见报道，在试验过程未见常规抗抑郁药物的镇定、诱发癫痫、共济失调等缺点。灵芝酸A也可以从培养的红藻菌和酵母中提取。其具有成为快速的、高效的、无毒副作用的抗抑郁新药的潜力，具有很强的工业实用性和巨大的商业价值。
本发明采用的药物筛选试验为：小鼠强迫游泳和悬尾试验，是常用的两种动物行为绝望抑郁症模型试验，能较好保证筛选结果的可靠性。
小鼠强迫游泳试验已用于很多抗抑郁药物的筛选试验。而且大多数有临床治疗作用的抗抑郁药也被证实在强迫游泳试验中能有效地减少不动时间。所谓不动是指“动物在水中停止挣扎，或呈漂浮状态，仅露出鼻孔保持呼吸，仅有细小的肢体运动，以保持头部浮在水面”。在测试前给拟筛选的药物。由于动物在强迫状态下游泳使动物不能逃出恶劣环境，导致动物行为绝望。此种模型方法简便，可靠，已广泛用于抗抑郁药剂的筛选和评价。
小鼠悬尾试验是小鼠在悬尾状态下不再挣扎，呈现特有的安静不动状态，抗抑郁药可明显缩短不动状态的持续时间。测试时，将小鼠尾部用医用胶带固定、倒悬。勿使小鼠尾部扭曲折叠。计录不动时间。不动指标为：“动物除呼吸外所有肢体均不动”。悬尾试验对各种抗抑郁药均很敏感，而且避免了游泳试验中温度和动物运动功能障碍的干扰,因而在用一些鼠种筛选抗抑郁药物时,可以有效地验证和补充强迫游泳实验的结果。
本发明提供的灵芝酸A作为抗抑郁症药物的用途，不限于如图1所示结构式的灵芝酸在制备抗抑郁症中的用途，将灵芝酸A制备成灵芝酸A的盐、酯或其与糖所成的甙是本领域技术人员所具备的常规实验技能，灵芝酸A的盐、酯或其与糖所成的甙与灵芝酸A具有相似的药效作用是本领域技术人员可以合理预料的，因此本发明还请求保护灵芝酸A的盐、酯或其与糖所成的甙在制备抗抑郁症药物中的用途。
本发明提供的灵芝酸A制备抗抑郁症药物的用途，所制备而得的抗抑郁症药物，可以基于制药领域的技术人员的常识而加入不影响药物药效的辅助成分，如载体、赋型剂等。由于该药物通过口服、注射、皮下包埋等方式均可见效，因此，剂型可以是多样的。
本发明提供的抗抑郁症药物还可以是混合有其它与灵芝酸或其衍生物配合使用对治疗抑郁症有积极作用的药物成分。
由于灵芝酸A稳定性较差，本领域技术人员可以加入稳定剂，只要不影响灵芝酸A药效的发挥，所得的抗抑郁症药物均在本发明要求保护的范围内。
本发明所提供的抗抑郁症药物，所述抗抑郁症包括预防和治疗两个阶段。
在专利法允许的范围内，本发明还要求保护灵芝酸A在抗抑郁症治疗中的用途，在动物模型试验中达到抗抑郁治疗效果的剂量范围是每天0.5mg-1000mg/1kg。
附图说明
图1.灵芝酸A的化学结构式，
图2.灵芝酸A对小鼠悬尾实验的影响，
竖坐标：悬尾实验小鼠不动时间(％对照)，
横坐标：从左到有依次为：灵芝酸A对照，灵芝酸A低，灵芝酸A高，丙咪嗪对照组，丙咪嗪。
结果：CD1雄性小鼠经不同剂量的灵芝酸A的腹腔注射二十四小时后，高剂量组(12.5毫克/公斤)在小鼠悬尾实验中显示出显著的抗抑郁的效果。(每组动物12-15,*t检验p<0.05)
图3灵芝酸A对小鼠强迫游泳实验的影响，
竖坐标：强迫游泳实验小鼠不动时间(％对照)，
横坐标：从左到有依次为：灵芝酸A对照，灵芝酸A低，灵芝酸A高，丙咪嗪对照组，丙咪嗪；
结果：CD1雄性小鼠经不同剂量的灵芝酸A的腹腔注射三天后，在小鼠强迫游泳实验中显示出抗抑郁的效果。这个抗抑郁效果可以和传统抗抑郁药物丙咪嗪相媲美。(每组动物N＝12-15,*t检验p<0.05)。
具体实施方案
以下实施方案仅用于详细说明和证明本发明所发现的灵芝酸A在抗抑郁症中的新用途，而不用来限制本发明。
实施例1：灵芝酸A对动物抑郁模型悬尾实验的影响
动物CD1种小鼠，雄性，重量25-35克，由北京维通利华实验动物技术有限公司提供，许可证号:SCXK(京)2011-0011。动物分笼饲养，食水自由，饲料由中国科学院遗传研究所实验动物中心提供，实验鼠食用的普通饲料均可。
试验药品：
灵芝酸A购自上海抚生实业有限公司，10毫克包装。
灵芝酸A母液：灵芝酸A溶于少量纯乙醇得20ug/ul，注射前再稀释。
阳性对照盐酸丙米嗪(Imipramine hydrochloride)为Sigma公司产品，货号I7379，批号O56K1380。
实验器材：杆，胶布，Sumsung Intelli-200m数码摄像机(韩国三星公司)，JUNSO多功能计时器。
实验步骤：雄性CD1小鼠经适应性饲养一周，分成5组，每组八只，分别为：灵芝酸A对照组：生理盐水加1.0％乙醇，按0.3ml/30g体重注射；灵芝酸A剂量组：5mg/kg体重，灵芝酸A溶于生理盐水加1.0％乙醇；灵芝酸A高剂量组：12.5mg/kg体重，灵芝酸A溶于生理盐水加1.0％乙醇；丙咪嗪阳性对照组：15mg/kg体重，丙咪嗪生理盐水溶解；丙咪嗪对照组：生理盐水，按0.3ml/30g体重注射。
上午10时按设计剂量腹腔注射给药。第二天上午10时给药,注射九十分钟后开始悬尾实验。
小鼠悬尾实验时，用医用胶布将小鼠尾在距尾尖2厘米处粘在一根水平横杆上，使动物成倒挂状态，其头部离桌面约15厘米。观察6分钟，记录后4分钟内的累计不动时间。
不动指标为：“动物除呼吸外所有肢体均不动。”
统计方法：实验结果用均值±SE表示,两个样本平均数比较用t检验。
结果见图二。灵芝酸A的高剂量组与空白对照组相比,在24小时后就能明显缩短小鼠悬尾不动时间。其中低剂量组尚未起效，显示出了一个剂量反应。结果表明高剂量的灵芝酸A在很短的时间内即可起效。可以对抗小鼠因强迫悬尾造成的抑郁症状。
与空白对照组比较,灵芝酸A剂量为12.5毫克/公斤时的不动时间与空白对照组相比由86.15±8.36s降低为48.33±8.89(P<0.05)，缩短了43.9％。低剂量的灵芝酸A显示出一个降低的趋势，但尚未明显减低。
实施例2小鼠强迫游泳实验
动物为CD1种小鼠雄性，由北京维通利华实验动物技术有限公司提供，许可证号:SCXK(京)2011-0011。实验前一周将动物分笼饲养,明暗周期12h/12h,室温20～22℃,自由饮食。饲料由中国科学院遗传研究所实验动物中心提供。
实验药物：灵芝酸A，盐酸丙米嗪(Imipramine hydrochloride)同实实施例1；试验仪器：玻璃圆筒(高20cm,直径14cm)；小鼠开阔箱(直径30cm,高20cm,底部16等分)；温度计；JUNSO多功能计时器。
药物准备同实施例1悬尾实验。
灵芝酸A母液：灵芝酸A溶于乙醇得20ug/ul悬浮液，分装并保存-80℃冰箱,注射前再用乙醇和生理盐水稀释。
实验步骤：动物药物注射：CD1小鼠,年龄7周，重量25-35克，适应环境一周后开始实验。动物随机分组，共有5组，每组八只动物。每天上午10点开始腹腔注射。注射量为0.3毫升/30克。
灵芝酸A空白对照组：每天腹腔注射生理盐水加1.0％乙醇,注射量为0.3毫升/30克；
灵芝酸A组：给予不同量的灵芝酸A溶于生理盐水加1.0％乙醇，
低剂量灵芝酸A：5mg/kg
高剂量灵芝酸A：12.5mg/kg。
传统抗抑郁药丙咪嗪阳性对照组，丙咪嗪溶于生理盐水，注射量按15mg/kg。
丙咪嗪空白对照组：只注射生理盐水，注射量为0.3毫升/30克。
上述试验组，每天腹腔注射一次，注射三天,第三天注射九十分钟后开始强迫游泳实验。强迫游泳实验：将各组CD1鼠单个垂直地放入有机玻璃圆筒中(40cm×14cm直径),水深15cm,水温23℃。各给药组和对照组录像6分钟,比较各组小鼠在后4分钟内累计不动时间。
不动时间判定:小鼠漂浮在水面，不努力爬出圆筒，仅做一些必须保持其头部在水面的动作。
统计分析方法：分析人按照统一标准分析结果。实验结果用均值±SE表示,两个样本平均数比较用t检验。
结果表明灵芝酸A具有较强的抗抑郁作用。与空白对照组比较，灵芝酸A高剂量组和低剂量组小鼠强迫游泳4分钟内的不动时间显著缩短,灵芝酸A剂量为5毫克/克或12.5毫克/克时的不动时间与空白对照组相比,由99.42±8.89s分别降低为45.10±8.35秒(P<0.05)和59.89±8.81秒(P<0.05),分别缩短了54.63％和39.76％。结果见图3。和传统抗抑郁药丙咪嗪相比，高剂量和低剂量的灵芝酸A的均有可比的且较强的抗抑郁作用。
参考文献
1.陈若芸,于德泉.灵芝三萜化学成分研究进展口.药学学报,1990,25(12):940-953.
2.Kubota T,Asaka Y,Miura l,et al.Struetures of ganoderie A and B,two new lanostane type bitter tritepenes from Ganderma lucidum(Fr.)Karst{J].Helv Chim Acta,1982,65(2):611-619.
3.大阪药品研究所,有用成分ガノデンリ酸类を多量に含む灵び芝粉碎物及びでの製法[p]:日本:昭61-194032,1986-05-2-194032,1986，05-28.
4.日束雷工株式会社,ガノデンリ酸类"製造方法[P]日本:特開平4304890,1992，10-28.
5.陈国良,陈晓清.灵芝有效成分研究综述.中国食用菌,1995,14(4):7-9.
6.王芳生,蔡辉,杨峻山等.赤芝子实体中灵芝酸类成分的研究工.药学学报,1997, 32(6):447-450.
7.李平作,章克昌.灵芝发酵菌丝体中灵芝酸的分离纯化及生物活性检测.天然产物与研究,1999,11(4):67-70
8.曾祥丽,包海鹰.灵芝三萜类成分与药理学研究进展.菌物研究,2004,2(l):68-77.
9.马礼金,姚汝华.灵芝的药用及食用研究.食品与发酵工业,1998,24(l):62-66.
10.王明宇,刘强,车庆明等.灵芝三萜类化合物对3种小鼠肝损伤模型的影响.药学学报,2000,35(5):326-329。
11.Byung-sun MIN,Jiang-Jing GAO,Norio NAKAMURA,et al.Triterpenes From the Spores of Ganoderma lucidum and Their Cytotoxicity against Meth-A and L LC Tumor Cells[J].Chem Pharm Bull,2000,48(7)：1026-1033.
12.周昌艳,唐庆九,杨众等.灵芝中有效成分灵芝酸的抑制肿瘤作用研究.菌物学报,2004,23(2):275-279。
13.王帮武,杨新林,张利刚等.灵芝酸性组分的提取分离及抑菌活性研究.北京理工大学学报,2002,22(1):125-128.
14.黄书铭,杨新林,王帮武等.灵芝醇溶酸性组分的抗肿瘤作用.天然产物研究与开发,2004,16(2):146-148。
15.ヒ-エィチエス株式会社,血管新生阻害剂[P]日本:特開，2004-196761,2004-07-15.
16.日本大学,發癌予防剂[p]日本:特開，2005-35898,2005-02-10.
17.日本大学,發癌予防剂[P].日本:特開，2006-22017,2006-01-26.
18.NishitobaT,SatoH,sakamuras,etal.AgrBiolChem,1985,49:1793.
19.Kohda H,Tokumoto W,Sakamoto K,et al.The biologieally aetive Constituents of Ganoderma Lucidum(Fr.)Karst histaminerelease-in hibitory triter Pene[J].Chem Pharm Bull,1985,33:1367-1374.
20.Morigiwa A,Kitabatake K,FujimotoY,et al.Chem Pharm Bull,2956,34:3025-3028.
Komoda Y,Shimizu M,SonodaY,et al.Ganoderic aeid and its derivatives as cholesterol synthesis inhibitors[J].Chem Pharm Bull,1989,37(2):531-533.

Claims (10)

  1. 灵芝在制备抗抑郁药症药物中的用途，其特征在于，所述药效成分为灵芝全草为原料进行物理加工而得的产物。
  2. 灵芝酸A在制备抗抑郁症药物中的用途，其特征在于，所述抗抑郁症药物的药效活性成分为灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
  3. 灵芝酸A在制备抗抑郁症药物中的用途，其特征在于，所述抗抑郁症药物的药效活性成分包括灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
  4. 根据权利要求2或3所述的用途，所述抗抑郁症药物的剂型为片剂、胶囊、溶液、悬浮液、注射液或滴注液。
  5. 一种抗抑郁症的药物，其特征在于：其药效活性成分为灵芝酸或灵芝酸A的衍生物，所述灵芝酸A的衍生物指灵芝酸A与药学上可接收的盐、酯或糖所成的甙。
  6. 根据权利要求5所述的药物，所述抗抑郁症是指预防或治疗抑郁症。
  7. 根据权利要求5或6所述的药物，其剂型为片剂、胶囊、溶液、悬浮液、注射液或滴注液。
  8. 根据权利要求4所述的药物，还包括制药学上可接受的辅助成分。
  9. 根据权利要求4所述的药物，还包括有与灵芝酸A或其衍生物配合使用时对治疗抑郁症有积极作用的药物成分，或使灵芝酸A稳定性提高的成分。
  10. 一种抗抑郁症的方法，其特征在于：向受试者按时提供治疗有效剂量的药剂，所述药剂的药效成分包括灵芝酸A或灵芝酸A的衍生物，所述衍生物是指灵芝酸A与药学上可接收的盐、酯或糖化合成的甙。
PCT/CN2015/077691 2014-04-30 2015-04-28 灵芝酸a在抗抑郁症中的用途 WO2015165382A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410183394 2014-04-30
CN201410183394.9 2014-04-30
CN201410197934.9A CN105012356B (zh) 2014-04-30 2014-05-12 灵芝酸a在抗抑郁症中的用途
CN201410197934.9 2014-05-12

Publications (1)

Publication Number Publication Date
WO2015165382A1 true WO2015165382A1 (zh) 2015-11-05

Family

ID=54358176

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/077691 WO2015165382A1 (zh) 2014-04-30 2015-04-28 灵芝酸a在抗抑郁症中的用途

Country Status (2)

Country Link
CN (1) CN105012356B (zh)
WO (1) WO2015165382A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111304091A (zh) * 2019-11-28 2020-06-19 昆明理工大学 一种提高灵芝细胞培养中灵芝酸含量的方法
CN112263584B (zh) * 2020-10-30 2021-09-07 广东省微生物研究所（广东省微生物分析检测中心） 灵芝酸a及其衍生物或灵芝总三萜在制备治疗眼部疾病药物中的应用
CN112618552B (zh) * 2020-12-30 2021-11-23 首都医科大学 灵芝酸a或灵芝酸a的衍生物在制备治疗自闭症药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101077357A (zh) * 2006-05-25 2007-11-28 北京大学 灵芝提取物在制备治疗和改善抑郁症状及各种原因引起的睡眠障碍的药物及保健品中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101574499A (zh) * 2009-06-05 2009-11-11 李振爽 安神宁心胶囊
CN102846756A (zh) * 2012-09-10 2013-01-02 李承平 一组莲子安神补脾片

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101077357A (zh) * 2006-05-25 2007-11-28 北京大学 灵芝提取物在制备治疗和改善抑郁症状及各种原因引起的睡眠障碍的药物及保健品中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIU, CHAO ET AL.: "Chemical Constituents from Fruiting Bodies of Ganoderma Tsugae (II", CHINESE TRADITIONAL AND HERBAL DRUGS, vol. 38, no. 1, 30 November 2007 (2007-11-30) *
ZHANG, YONGHE ET AL.: "Ganoderma lucidum: The ''An-Shen'' Agent", THE 2011 INTERNATIONAL MEETING ON GANODERMA RESEARCH, 31 December 2011 (2011-12-31) *

Also Published As

Publication number Publication date
CN105012356B (zh) 2018-10-16
CN105012356A (zh) 2015-11-04

Similar Documents

Publication Publication Date Title
TWI527586B (zh) 牛樟芝萃取物用於製備調節Ｔｈ１７細胞之藥物的用途
WO2010021247A1 (ja) セロトニントランスポーター阻害活性を有する医薬品又は飲食品
WO2018113027A1 (zh) 白果内酯作为增效剂在制备防治脑神经损伤性疾病药物的应用
WO2015165382A1 (zh) 灵芝酸a在抗抑郁症中的用途
Jang et al. Immune-modulating activity of extract prepared from mycelial culture of Chinese caterpillar mushroom, Ophiocordyceps sinensis (Ascomycetes)
CN114209739A (zh) 一种白头翁提取物在制备治疗抗抑郁药物上的应用
WO2016099055A2 (ko) 상심자 및 복령피 혼합 추출물을 함유하는 퇴행성 신경질환의 예방, 개선 또는 치료용 조성물
RU2334524C2 (ru) Применение производных эфиров янтарной кислоты для лечения деменции
Lin et al. Immunomodulatory effects of the stout camphor medicinal mushroom, Taiwanofungus camphoratus (Agaricomycetes)-based health food product in mice
CN107693530A (zh) 橙皮苷和/或柚皮苷在制备改善认知功能障碍药物中的应用
CN109419787B (zh) 一种松香烷型二萜类化合物的用途
CN102309483B (zh) 小檗碱离子对化合物的抗肿瘤作用用途
WO2023207054A1 (zh) 一种灵芝孢子油在制备延长肿瘤患者生存期药物的应用
Jang et al. In vitro stimulation of NK cells and lymphocytes using an extract prepared from mycelial culture of Ophiocordyceps sinensis
KR20150035276A (ko) 라파마이신 및 미콜페놀산을 유효성분으로 포함하는 아토피 피부염 예방 및 치료용 조성물
CN110183522B (zh) 一种具有抗抑郁功能的糖肽及其制备方法与应用
CN1246326C (zh) 化合物菠萝黄酮苷及用途
US9629866B2 (en) Use of cordycepin in manufacture of medicaments for anti-depression
KR20170003293A (ko) 모과 추출물을 포함하는 뇌신경질환 예방 또는 치료용 의약 조성물
US20150079157A1 (en) Composition comprising purine derivatives or salt thereof for preventing or treating atopic dermatitis
Sharma et al. Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents
CN103860578A (zh) 香菇多糖作为抗抑郁症药物的用途
US20240197799A1 (en) Ganoderma lucidum spore oil and use thereof in preparation of anti-cancer-related fatigue medicaments
US20130261147A1 (en) Composition for preventing or treating dementia
WO2019041778A1 (zh) 麝香酮在制备治疗神经免疫性疾病药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15785488

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15785488

Country of ref document: EP

Kind code of ref document: A1