WO2022183493A1 - Application of polyphenol compound - Google Patents
Application of polyphenol compound Download PDFInfo
- Publication number
- WO2022183493A1 WO2022183493A1 PCT/CN2021/079344 CN2021079344W WO2022183493A1 WO 2022183493 A1 WO2022183493 A1 WO 2022183493A1 CN 2021079344 W CN2021079344 W CN 2021079344W WO 2022183493 A1 WO2022183493 A1 WO 2022183493A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- solvate
- acceptable salt
- procyanidin
- cerebral ischemia
- Prior art date
Links
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
Definitions
- Procyanidin B 3 (Procyanidin B 3 , CAS: 23567-23-9) is a compound extracted from grape seeds with the following structural formula:
- the present invention provides the following technical solutions.
- the drug is preferably an anti-pyrostatic agent
- the pyroptosis is pyroptosis caused by cerebral ischemia.
- the cerebral ischemic disease may be conventional in the art, such as transient ischemic attack (TIA), ischemic stroke (cerebral infarction), moyamoya disease, chronic cerebral insufficiency, etc., but not limited thereto.
- TIA transient ischemic attack
- ischemic stroke Cerebral infarction
- moyamoya disease chronic cerebral insufficiency, etc., but not limited thereto.
- ischemic stroke also known as cerebral infarction
- cerebral infarction refers to the ischemic necrosis or ischemic necrosis of limited brain tissue caused by cerebral blood supply disorder, ischemia and hypoxia. soften.
- cerebral infarction refers to the ischemic necrosis or ischemic necrosis of limited brain tissue caused by cerebral blood supply disorder, ischemia and hypoxia. soften.
- cerebral infarction refers to the ischemic necrosis or ischemic necrosis of limited brain tissue caused by cerebral blood supply disorder, ischemia and hypoxia. soften.
- the common clinical types of cerebral infarction are: atherothrombotic cerebral infarction, cerebral embolism, and lacunar cerebral infarction.
- the third technical solution of the present invention is: a solvate comprising the procyanidin B 3 described in one or two of the above technical solutions, a pharmaceutically acceptable salt thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof drug, or a pharmaceutical composition of its crystalline form.
- the pharmaceutical composition may further comprise other drugs for preventing and treating cerebral ischemia-related diseases.
- the fourth technical solution of the present invention is: procyanidin B 3 , its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt, or its crystal form are prepared for preventing and treating cerebral ischemia
- the CAS number of procyanidin B 3 is 23567-23-9.
- the fifth technical solution of the present invention is: a method for treating and/or preventing cerebral ischemia-related diseases, comprising administering procyanidin B 3 , a pharmaceutically acceptable salt thereof, and a solvate thereof to a subject in need thereof , a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, the CAS number of the procyanidin B 3 is 23567-23-9.
- pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by a subject.
- subject is preferably a mammal, more preferably a human.
- pharmaceutically acceptable salts refers to salts of compounds of the present invention, and pharmaceuticals, pharmaceutical compositions containing them, prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
- a relatively acidic functional group is contained in the compounds of the present invention and the drugs and pharmaceutical compositions containing them, the compounds of the present invention can be mixed with such drugs by using a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
- the base addition salt is obtained by contacting the neutral form.
- Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine salts.
- a drug of the present invention contains relatively basic functional groups
- acid addition can be obtained by contacting the neutral form of such drug with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
- a pharmaceutically acceptable acid include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
- Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
- the “multiple” in the term “one or more” can mean 2, 3, 4, 5, 6, 7, 8, 9 or more.
- the compounds of the present invention, medicines or pharmaceutical compositions containing them can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa , eyes, lungs and respiratory tract, skin, vagina, rectum, etc.
- the dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
- Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
- the medicament or pharmaceutical composition of the present invention can be made into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
- “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate , various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, anhydrous stearate, cellulose, anhydrous carbonate, acrylic acid polymer or methacrylic acid polymer, gel, water, polyethylene glycol, Propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ sesame oil or polyethoxy hydrogenated EZ sesame oil, sesame oil, corn oil, peanut oil, etc.
- treatment refers to therapeutic therapy.
- treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
- solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
- the solvent includes, but is not limited to, water, ethanol, and the like.
- Figure 2 shows the expression of apoptosis-related proteins in OGD/R-injured HT22 hippocampal neurons detected by Western blot and Immunofluorescence methods.
- MT-8 could inhibit the post-ischemia Inflammatory and apoptotic responses induced, inhibition of pyroptosis, and promotion of linker protein recovery.
- the cerebral ischemia model was established by OGD/R-induced hippocampal neurons in HT22 mice to explore the effect of MT-8 on neuronal cells after cerebral ischemia.
- Immunofluorescence results showed that it could significantly reduce inflammatory response and pyroptosis, and up-regulate the expression of anti-apoptotic indicators; at the same time, Western blot results showed that it could significantly inhibit neuronal inflammatory and apoptotic responses, and inhibit cell pyroptosis. It is proved that the compound has a protective effect on cerebral ischemic diseases.
Abstract
Disclosed is the application of a polyphenol compound, in particular the application thereof in the preparation of drugs for the prevention and treatment of cerebral ischaemia. The polyphenol compound particularly relates to proanthocyanidin B 3. In vitro experiments show that the polyphenol compound proanthocyanidin B3 can inhibit the pyroptosis and apoptosis response and cellular inflammation of HT22 hippocampal neurons treated with OGD/R; in vivo experiments show that the compound can reduce the apoptosis, apoptotic response, and cellular inflammation caused by cerebral ischaemia, and can reduce the area of infarction caused by cerebral ischaemia, improve neurological function scores, and improve cerebral blood flow.
Description
本发明属于生物医药领域，具体涉及一种多酚类化合物的应用，特别是其在制备防治脑缺血相关疾病的药物中的应用。The invention belongs to the field of biomedicine, and in particular relates to the application of a polyphenolic compound, in particular to its application in the preparation of a medicine for preventing and treating cerebral ischemia-related diseases.
脑缺血是指脑的血液供应不足，难以满足脑组织代谢需要，从而产生的一系列症状。临床可表现为头晕、头痛、肢体麻木或短暂的意识丧失，严重者会造成脑功能不可逆的损伤甚至死亡。和脑缺血相关的疾病有短暂性脑缺血发作(TIA)、缺血性脑卒中(脑梗死)、烟雾病、慢性脑供血不足等。脑缺血是威胁人类健康的三大疾病之一，具有患病率高、复发率高、致残率高、死亡率高的特点。缺血性脑卒中占脑卒中的60％～80％，然而临床上尚缺乏有效治疗缺血性脑卒中的药物，因此对于脑缺血的研究至关重要。脑缺血后缺血区域会水肿，分泌大量炎性因子；由于神经元细胞最为敏感，故梗死中心及其周围区域神经元细胞大量死亡。因此如何保护神经元，减少神经元的死亡也是研究脑缺血后神经修复的一大重点。Cerebral ischemia refers to a series of symptoms caused by insufficient blood supply to the brain, making it difficult to meet the metabolic needs of brain tissue. Clinical manifestations may be dizziness, headache, limb numbness or transient loss of consciousness, and in severe cases, it may cause irreversible damage to brain function or even death. Diseases related to cerebral ischemia include transient ischemic attack (TIA), ischemic stroke (cerebral infarction), moyamoya disease, and chronic cerebral insufficiency. Cerebral ischemia is one of the three major diseases that threaten human health. It has the characteristics of high prevalence, high recurrence rate, high disability rate and high mortality rate. Ischemic stroke accounts for 60% to 80% of strokes. However, there is still no effective drug for ischemic stroke in clinical practice, so it is very important for the study of cerebral ischemia. After cerebral ischemia, the ischemic area will swell and secrete a large number of inflammatory factors; because neuronal cells are the most sensitive, a large number of neuronal cells in the infarct center and its surrounding areas die. Therefore, how to protect neurons and reduce neuronal death is also a major focus of research on neural repair after cerebral ischemia.
尽管现有技术中有脑保护剂，如依达拉奉。然而该药物效果并不突出，且有诸多严重的不良反应，例如急性肾功能衰竭、肝功能异常、血小板减少等等。因此，亟需其他能够有效治疗脑缺血的药物。Although there are cerebral protective agents such as edaravone in the prior art. However, the effect of the drug is not outstanding, and there are many serious adverse reactions, such as acute renal failure, abnormal liver function, thrombocytopenia and so on. Therefore, other drugs that can effectively treat cerebral ischemia are urgently needed.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是针对现有技术中缺乏有效防治缺血性脑卒中药物的缺陷，提供一种多酚类化合物的应用，特别是其在制备防治脑缺血的药物中的应用。所述多酚类化合物特别涉及原花青素B
3。
The technical problem to be solved by the present invention is to provide the application of a polyphenolic compound, especially its application in the preparation of a medicine for preventing and treating cerebral ischemia, aiming at the defect of lack of effective drugs for preventing and treating ischemic stroke in the prior art. The polyphenolic compound is particularly concerned with procyanidin B 3 .
原花青素B
3(Procyanidin B
3,CAS:23567-23-9)是从葡萄籽中提取的一 种化合物，结构式如下：
Procyanidin B 3 (Procyanidin B 3 , CAS: 23567-23-9) is a compound extracted from grape seeds with the following structural formula:
目前，在脑缺血中，原花青素B
3的作用还没有任何相关报道。本发明意外发现原花青素B
3(MT-8)在脑缺血方面的药理作用和用途，尤其是在防治脑缺血相关疾病的应用。
At present, there is no relevant report on the role of procyanidin B3 in cerebral ischemia. The present invention unexpectedly discovered the pharmacological action and application of procyanidin B 3 (MT-8) in cerebral ischemia, especially the application in preventing and treating cerebral ischemia-related diseases.
为解决上述问题，本发明提供以下技术方案。To solve the above problems, the present invention provides the following technical solutions.
本发明的技术方案之一为：原花青素B
3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型；其用于治疗和/或预防脑缺血相关疾病，所述原花青素B
3的CAS号为23567-23-9。
One of the technical solutions of the present invention is: procyanidin B 3 , its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, or its crystal form; its use in treatment and/or For the prevention of cerebral ischemia-related diseases, the CAS number of procyanidin B 3 is 23567-23-9.
本发明的技术方案之二为：原花青素B
3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型；其用于制备用于治疗和/或预防脑缺血相关疾病的药物，所述原花青素B
3的CAS号为23567-23-9。
The second technical solution of the present invention is: procyanidin B 3 , its pharmaceutically acceptable salt, its solvate, its solvate of its pharmaceutically acceptable salt, or its crystal form; it is used for preparation for treatment And/or a drug for preventing cerebral ischemia-related diseases, the CAS number of procyanidin B 3 is 23567-23-9.
其中，所述药物优选抗凋亡剂，所述凋亡为脑缺血引起的细胞凋亡。Wherein, the drug is preferably an anti-apoptotic agent, and the apoptosis is cell apoptosis caused by cerebral ischemia.
或者，所述药物优选抗焦亡剂，所述焦亡为脑缺血引起的焦亡。Alternatively, the drug is preferably an anti-pyrostatic agent, and the pyroptosis is pyroptosis caused by cerebral ischemia.
或者，所述药物优选抗细胞炎症药物，所述细胞炎症为脑缺血引起的细胞炎症。Alternatively, the drug is preferably an anti-cellular inflammatory drug, and the cellular inflammation is cellular inflammation caused by cerebral ischemia.
所述的脑缺血疾病可为本领域中常规，例如短暂性脑缺血发作(TIA)、缺血性脑卒中(脑梗死)、烟雾病、慢性脑供血不足等，但不限于此。The cerebral ischemic disease may be conventional in the art, such as transient ischemic attack (TIA), ischemic stroke (cerebral infarction), moyamoya disease, chronic cerebral insufficiency, etc., but not limited thereto.
缺血性脑血管病中比较常见的就是缺血性脑卒中(也叫脑梗死)，是指因脑部血液供应障碍，缺血、缺氧所导致的局限性脑组织的缺血性坏死或软 化。脑梗死的临床常见类型有：动脉粥样硬化性血栓性脑梗死、脑栓塞、腔隙性脑梗死。The most common ischemic cerebrovascular disease is ischemic stroke (also known as cerebral infarction), which refers to the ischemic necrosis or ischemic necrosis of limited brain tissue caused by cerebral blood supply disorder, ischemia and hypoxia. soften. The common clinical types of cerebral infarction are: atherothrombotic cerebral infarction, cerebral embolism, and lacunar cerebral infarction.
本发明的技术方案之三为：一种包含如上技术方案之一或者之二所述的原花青素B
3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型的药物组合物。
The third technical solution of the present invention is: a solvate comprising the procyanidin B 3 described in one or two of the above technical solutions, a pharmaceutically acceptable salt thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof drug, or a pharmaceutical composition of its crystalline form.
较佳地，所述的药物组合物包含药学上可接受的载体、赋形剂和/或溶剂。Preferably, the pharmaceutical composition comprises pharmaceutically acceptable carriers, excipients and/or solvents.
所述的药物组合物较佳地还可以包含其他用于防治脑缺血相关疾病的药物。Preferably, the pharmaceutical composition may further comprise other drugs for preventing and treating cerebral ischemia-related diseases.
本发明的技术方案之四为：原花青素B
3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型在制备用于防治脑缺血相关疾病的药物中的应用，所述原花青素B
3的CAS号为23567-23-9。
The fourth technical solution of the present invention is: procyanidin B 3 , its pharmaceutically acceptable salt, its solvate, the solvate of its pharmaceutically acceptable salt, or its crystal form are prepared for preventing and treating cerebral ischemia For use in medicines for related diseases, the CAS number of procyanidin B 3 is 23567-23-9.
对于以上技术方案中药物和脑缺血相关疾病的进一步优选限定同以上技术方案之一和二。The further preferred definitions for drugs and cerebral ischemia-related diseases in the above technical solutions are the same as those of the above technical solutions one and two.
本发明的技术方案之五为：一种治疗和/或预防脑缺血相关疾病的方法，其包括向有需要的受试者施用原花青素B
3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，所述原花青素B
3的CAS号为23567-23-9。
The fifth technical solution of the present invention is: a method for treating and/or preventing cerebral ischemia-related diseases, comprising administering procyanidin B 3 , a pharmaceutically acceptable salt thereof, and a solvate thereof to a subject in need thereof , a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof, the CAS number of the procyanidin B 3 is 23567-23-9.
对于以上技术方案中药物和脑缺血相关疾病的进一步优选限定同以上技术方案之一和二。The further preferred definitions for drugs and cerebral ischemia-related diseases in the above technical solutions are the same as those of the above technical solutions one and two.
术语解释Terminology Explanation
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于受试者使用。所述的“受试者”优选哺乳动物，更优选为人类。The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by a subject. The "subject" is preferably a mammal, more preferably a human.
术语“药学上可接受的盐”是指本发明的化合物及包含其的药物、药物组合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物及包含其的药物、药物组合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类药物的 中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的药物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类药物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的药物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention, and pharmaceuticals, pharmaceutical compositions containing them, prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When a relatively acidic functional group is contained in the compounds of the present invention and the drugs and pharmaceutical compositions containing them, the compounds of the present invention can be mixed with such drugs by using a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. The base addition salt is obtained by contacting the neutral form. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine salts. When a drug of the present invention contains relatively basic functional groups, acid addition can be obtained by contacting the neutral form of such drug with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the medicaments of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
术语“一种或多种”中的“多种”可以是指2种、3种、4种、5种、6种、7种、8种、9种或者更多种。The "multiple" in the term "one or more" can mean 2, 3, 4, 5, 6, 7, 8, 9 or more.
本发明的化合物、含其的药物或药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，例如口服、外敷、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。The compounds of the present invention, medicines or pharmaceutical compositions containing them can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa , eyes, lungs and respiratory tract, skin, vagina, rectum, etc.
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾 片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。The dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
本发明的药物或药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。The medicament or pharmaceutical composition of the present invention can be made into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。"Pharmaceutical composition" refers to mixing one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier, . The purpose of a pharmaceutical composition is to facilitate the process of administration to an animal.
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镇、纤维素、碳酸镇、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、EZ麻油或氢化EZ麻油或多乙氧基氢化EZ麻油、芝麻油、玉米油、花生油等。"Pharmaceutically acceptable carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate , various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, anhydrous stearate, cellulose, anhydrous carbonate, acrylic acid polymer or methacrylic acid polymer, gel, water, polyethylene glycol, Propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ sesame oil or polyethoxy hydrogenated EZ sesame oil, sesame oil, corn oil, peanut oil, etc.
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。In the aforementioned pharmaceutical composition, in addition to a pharmaceutically acceptable carrier, it may also include adjuvants commonly used in pharmacy (agents), such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, conditioning agents. Colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, carbohydrates, vitamins, minerals, trace elements, sweeteners, pigments, flavors or their combinations, etc.
术语“防治”指预防未病、治疗疾病的方法。The term "prevention and treatment" refers to a method of preventing disease, treating disease.
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。 所述的溶剂包括但不限于：水、乙醇等。The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, ethanol, and the like.
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物与相对无毒的、药学上可接受的酸或碱、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。"Pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt", as described above, refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or bases, substances formed in combination with stoichiometric or non-stoichiometric amounts of solvents. Said "solvates of pharmaceutically acceptable salts" include, but are not limited to, hydrochloric acid monohydrates of the compounds of the present invention.
术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”可以以晶型或无定型的形式存在。术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" can exist in crystalline or amorphous forms. The term "crystal form" means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
本发明中，所述“包括、包含或含有”可以是指除了包括后面所列举的成分，还存在其他成分；也可以是指“由……组成”，即只包括后面所列举的成分而不存在其他成分。In the present invention, the "comprising, comprising or containing" may mean that there are other components in addition to the components listed below; it may also mean "consisting of", that is, only the components listed below are included without Other ingredients are present.
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of conforming to common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：The positive progressive effect of the present invention is:
本发明的体内外实验表明，原花青素B
3(MT-8)对于脑梗死体积的降低以及血流恢复的促进显著优于已知药物依达拉奉(EDA)，其他体内外实验也能够达到与EDA相当的水平。具体地，体外实验显示：多酚类化合物原花青素B
3能够抑制OGD/R处理的HT22海马神经元细胞的焦亡、凋亡反应以及其细胞炎症；体内实验显示：能够降低脑缺血引起的细胞凋亡、凋亡反应以及细胞炎症，并能够降低脑缺血引起梗死面积，改善神经功能评分，提高脑血流。因此，其有可能成为有效防治脑缺血疾病的药物。
The in vitro and in vivo experiments of the present invention show that procyanidin B 3 (MT-8) is significantly better than the known drug Edaravone (EDA) in reducing the volume of cerebral infarction and promoting blood flow recovery, and other in vitro and in vivo experiments can also achieve the same EDA quite level. Specifically, in vitro experiments showed that the polyphenolic compound procyanidin B 3 could inhibit the pyroptosis, apoptosis response and cellular inflammation of HT22 hippocampal neurons treated with OGD/R; Apoptosis, apoptosis response and cellular inflammation, and can reduce the infarct size caused by cerebral ischemia, improve neurological function scores, and increase cerebral blood flow. Therefore, it may become an effective drug for preventing and treating cerebral ischemia.
图1是Western blot方法和Immunofluorescence方法检测OGD/R损伤的HT22海马神经元细胞的炎症及焦亡相关反应的表达。Figure 1 shows the expression of inflammation and pyroptosis-related responses in OGD/R-injured HT22 hippocampal neurons detected by Western blot and Immunofluorescence.
图2是Western blot方法和Immunofluorescence方法检测OGD/R损伤的HT22海马神经元细胞的凋亡相关蛋白表达。Figure 2 shows the expression of apoptosis-related proteins in OGD/R-injured HT22 hippocampal neurons detected by Western blot and Immunofluorescence methods.
图3是诱导小鼠脑缺血模型，MT-8可改善脑缺血小鼠行为学症状，减少脑梗死体积，促进脑血流的恢复，促进神经元的存活。Figure 3 is a model of induced cerebral ischemia in mice. MT-8 can improve the behavioral symptoms of cerebral ischemia mice, reduce the volume of cerebral infarction, promote the recovery of cerebral blood flow, and promote the survival of neurons.
Sham：假手术组；MCAO：线栓制备的脑缺血组；MT-8：40mg/kg/day；依达拉奉(EDA)：50mg/kg/day。
**p<0.01；
***p<0.001。
Sham: sham-operated group; MCAO: suture-prepared cerebral ischemia group; MT-8: 40 mg/kg/day; Edaravone (EDA): 50 mg/kg/day. ** p<0.01; *** p<0.001.
图4是诱导小鼠脑缺血模型，MT-8明显减轻MCAO引起的凋亡。Figure 4 is a model of induced cerebral ischemia in mice, and MT-8 significantly reduced the apoptosis caused by MCAO.
图5是诱导小鼠脑缺血模型，MT-8明显减轻MCAO引起的炎症、焦亡，修复血脑屏障。Figure 5 is a model of induced cerebral ischemia in mice. MT-8 significantly reduced inflammation and pyroptosis caused by MCAO, and repaired the blood-brain barrier.
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
实施例1 MT-8对体外OGD/R(氧糖剥夺再灌注)损伤的HT22海马神经元细胞的保护作用Example 1 Protective effect of MT-8 on HT22 hippocampal neurons injured by OGD/R (oxygen-glucose deprivation-reperfusion) in vitro
分组：将HT22海马神经元细胞(购自赛默飞)随机分成5组，即：1)Control组；2)OGD/R组；3)MT-8(5μM)组；4)MT-8(10μM)组；5)MT-8(20μM)组。对于第3)～5)组，MT-8提前4h给予(浓度分别为5μM、10μM、20μM)，对细胞刺激4h后，缺氧缺糖2h，再复氧24h，制备体外脑缺血模型。对于第2)组，缺氧缺糖2h之后再复氧24h。收集蛋白，用Western blot法检测p53、cleaved-PARP1、cleaved-Caspase3、cleaved-Caspase9、Bax、iNOS、COX-2、VCAM-1、Capase-1(p20)、IL-1β、IL-18、GSDMD蛋白表达； 细胞相应处理后爬片，用免疫荧光染色检测Bcl-2、iNOS、IL-1β等表达。结果显示，MT-8能显著降低炎症、凋亡和焦亡蛋白表达，抑制细胞炎症、焦亡反应和凋亡反应，促进链接蛋白表达(图1、图2)。Grouping: HT22 hippocampal neurons (purchased from Thermo Fisher Scientific) were randomly divided into 5 groups, namely: 1) Control group; 2) OGD/R group; 3) MT-8 (5 μM) group; 4) MT-8 ( 10 μM) group; 5) MT-8 (20 μM) group. For groups 3) to 5), MT-8 was administered 4 hours in advance (concentrations of 5 μM, 10 μM, and 20 μM, respectively), after 4 hours of cell stimulation, hypoxia and glucose deficiency for 2 hours, and then reoxygenation for 24 hours to prepare an in vitro model of cerebral ischemia. For group 2), hypoxia and glucose deficiency for 2 h were followed by reoxygenation for 24 h. Collect proteins and detect p53, cleaved-PARP1, cleaved-Caspase3, cleaved-Caspase9, Bax, iNOS, COX-2, VCAM-1, Capase-1(p20), IL-1β, IL-18, GSDMD by Western blot Protein expression; After corresponding treatment of cells, the slides were climbed, and the expressions of Bcl-2, iNOS, IL-1β, etc. were detected by immunofluorescence staining. The results showed that MT-8 could significantly reduce inflammation, apoptosis and pyroptosis protein expression, inhibit cellular inflammation, pyroptosis response and apoptotic response, and promote linker protein expression (Figure 1, Figure 2).
实验结果证明，所述的MT-8对OGD/R诱导的体外脑缺血模型有显著的保护作用，可制备抗脑缺血相关疾病的药物。The experimental results prove that the MT-8 has a significant protective effect on the OGD/R-induced cerebral ischemia model in vitro, and can be used to prepare drugs against cerebral ischemia-related diseases.
实施例2 MT-8对体内小鼠脑缺血模型的治疗作用Example 2 Therapeutic effect of MT-8 on in vivo mouse cerebral ischemia model
分组：体重21-24g雄性C57小鼠(小鼠购自于上海B&K公司，饲养于复旦大学药学院动物实验中心，SPF级)1％戊巴比妥钠腹腔注射麻醉后仰卧固定，开颈部正中皮肤，切口长约2cm。钝性分离皮下组织，暴露左侧颈总动脉(CCA)，向上依次分离暴露颈外动脉(ECA)与颈内动脉(ICA)，分别在颈总动脉，颈外动脉远心端挂线，活结结扎颈总动脉，死结结扎颈外动脉，然后在颈内动脉远心端挂线，用拉钩拉住。再在颈外动脉近心端挂线，打活结。然后在颈外动脉与颈内动脉“Y形”分叉处，用显微剪在偏颈外动脉处剪一小口，将线栓从切口处导入颈外动脉，顺势插入颈总动脉，然后拉紧结扎口，剪断一侧颈外动脉，在轻微牵拉颈外动脉残端，使得颈外动脉与颈内动脉在一条直线上，调整线栓角度，与颈前正中呈45°角水平向外的夹角。待线栓插入颈内动脉，移去颈内动脉的挂线，轻柔的将线栓导入颅内，遇阻力即停止，然后固定结扎线栓。剪去多余线栓，仅留1mm左右长的残端。移去颈总动脉的挂线，观察有无出血情况后，缝合切口。待梗塞1.5h后，打开切口，拔出线栓至颈外动脉与颈总动脉分支处。缝合皮肤，碘伏消毒后放置在笼中，全程注意保温，术后提供充足的水和食物。假手术组除不插线栓，其他操作与模型组相同。MT-8以ddH
2O溶解，将小鼠随机分为假手术组(Sham,ig.n＝10)，模型组(MCAO，溶剂对照，ig.n＝10)，模型+MT-8组(40mg/kg/day,ip.n＝10)，模型+阳性药依达拉奉对照组(EDA,50mg/kg/day,ig.n＝10)。预给药7天后，造模。造模24小时后，行为学评价；TTC检测脑梗死体积；多普勒超声技术检测小鼠颅内脑血流状态分布；取材脑组织， 4％多聚甲醛固定，包埋做石蜡切片，染色HE。收集脑组织，裂解蛋白，用Western blot法检测p53、cleaved-PARP1、cleaved-Caspase 3、cleaved-Caspase 9、Bax、Bcl-2、iNOS、COX-2、VCAM-1、ZO-1、Claudin-1、p20、IL-18、GSDMD蛋白表达。结果显示，MT-8能够改善脑缺血小鼠行为学症状、减少脑梗死体积且促进脑血流的恢复(图3)，促进神经元的存活，抑制炎症和凋亡、抑制细胞焦亡，促进链接蛋白表达(图4、图5)。
Grouping: Male C57 mice weighing 21-24g (the mice were purchased from Shanghai B&K Company, and were raised in the Animal Experiment Center of the School of Pharmacy, Fudan University, SPF grade) after intraperitoneal injection of 1% pentobarbital sodium was anesthetized and fixed in a supine position, and the neck was opened. In the middle of the skin, the incision is about 2cm long. The subcutaneous tissue was bluntly dissected, the left common carotid artery (CCA) was exposed, and the external carotid artery (ECA) and the internal carotid artery (ICA) were separated and exposed upward in turn. The common carotid artery was ligated, the external carotid artery was ligated with a dead ligation, and then a thread was hung on the distal end of the internal carotid artery and pulled with a retractor. Then hang a thread at the proximal end of the external carotid artery and tie a slip knot. Then, at the "Y-shaped" bifurcation of the external carotid artery and the internal carotid artery, use microscissors to cut a small incision at the partial external carotid artery, introduce the suture from the incision into the external carotid artery, and insert it into the common carotid artery. Tighten the ligature, cut one external carotid artery, slightly pull the stump of the external carotid artery so that the external carotid artery and the internal carotid artery are in a straight line, and adjust the angle of the suture to form a 45° angle with the anterior midline of the neck. angle. After the suture is inserted into the internal carotid artery, remove the hanging thread from the internal carotid artery, gently introduce the suture into the brain, stop when it encounters resistance, and then fix the ligature. Cut off the excess thread tie, leaving only the stump about 1mm long. The suture of the common carotid artery was removed, and the incision was sutured after observing whether there was bleeding. After 1.5 hours of infarction, the incision was opened, and the suture was pulled out to the branch of the external carotid artery and the common carotid artery. The skin was sutured, sterilized with iodophor, and placed in a cage. The whole process was kept warm, and sufficient water and food were provided after surgery. In the sham operation group, other operations were the same as those in the model group, except that the suture was not inserted. MT-8 was dissolved in ddH 2 O, and the mice were randomly divided into sham operation group (Sham, ig.n=10), model group (MCAO, solvent control, ig.n=10), model+MT-8 group ( 40mg/kg/day, ip.n=10), model + positive drug edaravone control group (EDA, 50mg/kg/day, ig.n=10). After 7 days of pre-dosing, the model was established. 24 hours after modeling, behavioral evaluation; cerebral infarction volume was detected by TTC; intracranial cerebral blood flow distribution of mice was detected by Doppler ultrasound; brain tissue was collected, fixed with 4% paraformaldehyde, embedded in paraffin section, and stained HE. Brain tissue was collected, protein was split, and Western blot was used to detect p53, cleaved-PARP1, cleaved-Caspase 3, cleaved-Caspase 9, Bax, Bcl-2, iNOS, COX-2, VCAM-1, ZO-1, Claudin- 1. Expression of p20, IL-18, GSDMD protein. The results show that MT-8 can improve the behavioral symptoms of cerebral ischemia mice, reduce the volume of cerebral infarction and promote the recovery of cerebral blood flow (Figure 3), promote the survival of neurons, inhibit inflammation and apoptosis, and inhibit cell pyroptosis. Promotes link protein expression (Fig. 4, Fig. 5).
实验结果证明，所述的MT-8对线栓法制备的体内脑缺血模型有显著的保护作用。The experimental results show that the MT-8 has a significant protective effect on the in vivo cerebral ischemia model prepared by the suture method.
综上：本发明采用C57小鼠线栓法制备脑缺血损伤模型，Bederson评分检测小鼠脑缺血后行为学损伤，结果表明MT-8可改善脑缺血小鼠行为学症状；TTC法检测小鼠脑缺血后脑梗死体积，结果表明MT-8可减少脑梗死体积；多普勒超声技术检测小鼠颅内脑血流状态分布，结果表明MT-8可促进脑血流的恢复；HE染色结果显示MT-8可促进神经元的存活，Western blot法检测小鼠脑缺血后炎症和凋亡相关蛋白、焦亡通路及链接蛋白的表达，结果显示MT-8可抑制缺血后引起的炎症和凋亡反应、抑制细胞焦亡，促进链接蛋白恢复。此外，体外通过OGD/R诱导的HT22小鼠海马神经元细胞来建立脑缺血模型，探索MT-8对脑缺血后神经元细胞的作用。免疫荧光结果显示其能显著降低炎症反应和细胞焦亡，上调抗凋亡指标的表达；同时，Western blot结果显示其能显著抑制神经元的炎症和凋亡反应、抑制细胞焦亡。证明所述化合物对脑缺血疾病有保护作用。To sum up: the present invention adopts C57 mouse suture method to prepare cerebral ischemia injury model, Bederson score detects behavioral injury after cerebral ischemia in mice, and the results show that MT-8 can improve the behavioral symptoms of cerebral ischemia mice; TTC method Measure the volume of cerebral infarction after cerebral ischemia in mice, the results show that MT-8 can reduce the volume of cerebral infarction; Doppler ultrasound technology detects the distribution of intracranial cerebral blood flow in mice, the results show that MT-8 can promote the recovery of cerebral blood flow; The results of HE staining showed that MT-8 could promote the survival of neurons. Western blot was used to detect the expressions of inflammation and apoptosis-related proteins, pyroptosis pathways and link proteins after cerebral ischemia in mice. The results showed that MT-8 could inhibit the post-ischemia Inflammatory and apoptotic responses induced, inhibition of pyroptosis, and promotion of linker protein recovery. In addition, the cerebral ischemia model was established by OGD/R-induced hippocampal neurons in HT22 mice to explore the effect of MT-8 on neuronal cells after cerebral ischemia. Immunofluorescence results showed that it could significantly reduce inflammatory response and pyroptosis, and up-regulate the expression of anti-apoptotic indicators; at the same time, Western blot results showed that it could significantly inhibit neuronal inflammatory and apoptotic responses, and inhibit cell pyroptosis. It is proved that the compound has a protective effect on cerebral ischemic diseases.
此外，在降低脑梗死体积、促进脑血流恢复两者指标中甚至优于现有药物EDA，其他体内外实验与EDA相当。In addition, it is even better than the existing drug EDA in reducing the volume of cerebral infarction and promoting the recovery of cerebral blood flow, and other in vitro and in vivo experiments are comparable to EDA.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.
Claims (10)
- 原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型；其用于治疗和/或预防脑缺血相关疾病，所述原花青素B 3的CAS号为23567-23-9。 Procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof; its use in the treatment and/or prevention of cerebral ischemia-related diseases, said The CAS number of procyanidin B 3 is 23567-23-9.
- 如权利要求1所述的原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其特征在于，所述的缺血相关疾病包括：短暂性脑缺血发作、缺血性脑卒中、烟雾病和慢性脑供血不足。 The procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof according to claim 1, wherein the ischemia Associated diseases include: transient ischemic attack, ischemic stroke, moyamoya disease and chronic cerebral insufficiency.
- 原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型；其用于制备治疗和/或预防脑缺血相关疾病的药物，所述原花青素B 3的CAS号为23567-23-9。 Procyanidin B 3 , its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, or its crystalline form; its use in the preparation of a medicament for treating and/or preventing cerebral ischemia-related diseases , the CAS number of the procyanidin B 3 is 23567-23-9.
- 如权利要求3所述的原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，其特征在于，所述的缺血相关疾病包括：短暂性脑缺血发作、缺血性脑卒中、烟雾病和慢性脑供血不足； The procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystalline form thereof according to claim 3, wherein the ischemia Related diseases include: transient ischemic attack, ischemic stroke, moyamoya disease and chronic cerebral insufficiency;或者，所述药物为抗凋亡剂，所述凋亡为脑缺血引起的细胞凋亡；Alternatively, the drug is an anti-apoptotic agent, and the apoptosis is cell apoptosis caused by cerebral ischemia;或者，所述药物为抗焦亡剂，所述焦亡为脑缺血引起的焦亡；Or, the drug is an anti-pyrostatic agent, and the pyroptosis is pyroptosis caused by cerebral ischemia;或者，所述药物为抗细胞炎症药物，所述细胞炎症为脑缺血引起的细胞炎症。Alternatively, the drug is an anti-cellular inflammatory drug, and the cellular inflammation is cellular inflammation caused by cerebral ischemia.
- 一种包含如权利要求1～4任一项所述的原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型的药物组合物。 A medicine comprising the procyanidin B 3 according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof combination.
- 原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型在制备用于防治脑缺血相关疾病的药物中的应用，所述原花青素B 3的CAS号为23567-23-9；较佳地： Use of procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in the preparation of a medicament for preventing and treating cerebral ischemia-related diseases, the The CAS number of the procyanidin B 3 is 23567-23-9; preferably:所述药物为抗凋亡剂，所述凋亡为脑缺血引起的细胞凋亡；The drug is an anti-apoptotic agent, and the apoptosis is cell apoptosis caused by cerebral ischemia;或者，所述药物为抗焦亡剂，所述焦亡为脑缺血引起的焦亡；Or, the drug is an anti-pyrostatic agent, and the pyroptosis is pyroptosis caused by cerebral ischemia;或者，所述药物为抗细胞炎症药物，所述细胞炎症为脑缺血引起的细胞炎症。Alternatively, the drug is an anti-cellular inflammatory drug, and the cellular inflammation is cellular inflammation caused by cerebral ischemia.
- 如权利要求6所述的应用，其特征在于，所述脑缺血相关疾病包括：短暂性脑缺血发作、缺血性脑卒中、烟雾病和慢性脑供血不足。The use according to claim 6, wherein the cerebral ischemia-related diseases include transient ischemic attack, ischemic stroke, moyamoya disease and chronic cerebral insufficiency.
- 如权利要求6或7所述的应用，其特征在于，所述原花青素B 3为所述药物的唯一活性成分。 The use according to claim 6 or 7, wherein the procyanidin B 3 is the only active ingredient of the medicine.
- 一种治疗和/或预防脑缺血相关疾病的方法，其包括向有需要的受试者施用原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型，所述原花青素B 3的CAS号为23567-23-9； A method of treating and/or preventing cerebral ischemia-related diseases, comprising administering procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable salt thereof to a subject in need thereof A solvate or a crystalline form thereof, the CAS number of the procyanidin B 3 is 23567-23-9;较佳地，所述脑缺血相关疾病包括：短暂性脑缺血发作、缺血性脑卒中、烟雾病和慢性脑供血不足。Preferably, the cerebral ischemia-related diseases include transient ischemic attack, ischemic stroke, moyamoya disease and chronic cerebral insufficiency.
- 原花青素B 3、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或其晶型在防治脑缺血相关疾病中的应用，所述原花青素B 3的CAS号为23567-23-9； Use of procyanidin B 3 , a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in preventing and treating cerebral ischemia-related diseases, the procyanidin B 3 The CAS number is 23567-23-9;较佳地，所述脑缺血相关疾病包括：短暂性脑缺血发作、缺血性脑卒中、烟雾病和慢性脑供血不足。Preferably, the cerebral ischemia-related diseases include transient ischemic attack, ischemic stroke, moyamoya disease and chronic cerebral insufficiency.
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| CN101530410A (en) * | 2009-04-10 | 2009-09-16 | 浙江萧山医院 | Application of oligomeric proantho cyanidins in preparing products resisting vascular dementia |
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