WO2022204827A1 - Application of halcinonide and derivatives thereof for preparing drug treating and/or preventing cerebrovascular disease - Google Patents

Application of halcinonide and derivatives thereof for preparing drug treating and/or preventing cerebrovascular disease Download PDF

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WO2022204827A1
WO2022204827A1 PCT/CN2021/082818 CN2021082818W WO2022204827A1 WO 2022204827 A1 WO2022204827 A1 WO 2022204827A1 CN 2021082818 W CN2021082818 W CN 2021082818W WO 2022204827 A1 WO2022204827 A1 WO 2022204827A1
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derivatives
androst
dione
group
ene
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PCT/CN2021/082818
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French (fr)
Chinese (zh)
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陈新平
赵文阳
刘菁菁
李响响
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兰州大学
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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 present invention relates to the technical field of medicine, in particular to the application of hacinide and its derivatives in preparing medicines for treating and/or preventing cerebrovascular diseases.
  • Stroke is a common clinical disease and high morbidity. It has the characteristics of high morbidity, high mortality and high disability rate. It is the first cause of death in my country and the second leading cause of death in the world. It seriously affects the quality of life of patients, and hemiplegia often occurs after treatment, which brings huge economic and social burdens. With the aging of the population in my country, the incidence of stroke is also increasing. Stroke is divided into ischemic stroke and hemorrhagic stroke, of which ischemic stroke accounts for 60% to 70% of the total number of strokes. The general term for brain tissue necrosis caused by stenosis or occlusion and insufficient blood supply to the brain. Cerebral ischemia is very dangerous when it occurs.
  • ischemic stroke Even if it passes through the dangerous period, it will leave various sequelae, and severe cases can lead to disability.
  • Re-recovering or opening diseased blood vessels within an effective time window to achieve reperfusion of ischemic brain tissue is an important measure for the treatment of acute ischemic stroke.
  • the most commonly used clinical treatment method is thrombolysis, and the ultimate goal is to open blood vessels and achieve reperfusion of ischemic brain tissue.
  • its disadvantage is that it is limited by the time window of thrombolysis.
  • Drugs for the treatment of ischemic stroke include antifibrillar drugs, anticoagulant drugs, antiplatelet aggregation drugs and neuroprotective drugs.
  • due to their own limitations such as single component and single target, they may lead to side effects such as hemorrhage and cerebral edema. So far, no drug has achieved significant clinical efficacy.
  • Hasinide and its derivatives are a class of hormones produced by the adrenal cortex stimulated by adrenocorticotropic hormone secreted by the anterior pituitary gland.
  • Hasinide has anti-inflammatory, anti-pruritic and vasoconstrictive effects, and is mainly used clinically against Various inflammations and the late stage of inflammation inhibit the proliferation of capillaries and fibroblasts and reduce the sequelae.
  • Patent CN201610366828.8 discloses the application of the pharmaceutical composition of Hasinide in the treatment of hyperthyroidism
  • Patent CN102641277A discloses that the composition of Hasinide can be used for the treatment of gynecological diseases and skin diseases
  • Patent CN106511505A discloses the application of Hasinide The composition can be used to treat gastric ulcers.
  • Hascinide has the effect of treating cerebrovascular diseases, especially has a significant therapeutic effect on stroke. effects of stroke.
  • the present invention provides new uses of hacinide and its derivatives, and specifically provides the use of hacinide and its derivatives for preparing medicines for the treatment and/or prevention of cerebrovascular diseases.
  • Sinide and its derivatives have the general structural formula shown in formula (I):
  • hacinide and its derivatives may be in the form of tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts;
  • R is selected from H or halogen
  • R 5 and R 6 are each independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyacyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl acyl, aromatic acyl, C 6-10 aryl, C 5-6 cycloalkyl, or R 5 and R 6 are connected to form a saturated or unsaturated 5- or 6-membered carbon A cyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl groups in R 5 and R 6 are substituted with 1-3 of the following substituents: hydroxy, halogen.
  • said R 5 and R 6 are independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxyacyl, C 2- 4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl acyl, phenyl acyl, phenyl, C 5-6 cycloalkyl, or R 5 and R 6 are connected to form a saturated or unsaturated 5 or 6 A membered carbocyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl group in R 5 and R 6 may be substituted by 1-3 of the following substituents: hydroxy, halogen.
  • said R 5 and R 6 are respectively selected from H, -OH, -NH 2 , -COH, CH 3 CO-, -CO-CH 2 OH, -OC(O)CH 2 CH 3 , -CH 2 -C ⁇ CH, -(CH 2 ) 5 CH 3 , -(CH 2 ) 4 CF 3 , cyclohexyl-, -CH 2 -(CH 2 ) 3 -CH 2 -, -C(O)-CF 3 , -C(O)-Ph, wherein the alkyl group is substituted with 1-3 of the following substituents: hydroxy, halogen.
  • the hacinide and its derivatives are selected from the following compounds: Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1- methylethylidene)bis(oxy)]-,(11 ⁇ ,16 ⁇ )-; Pregn-4-ene-3,20-dione, 21-hydroxy-;Androst-4-en-3-one,17-(1-oxopropoxy) -,(17 ⁇ )-; Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-; Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-,( 11 ⁇ )-; Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11 ⁇ )-;Pregna-1,4-diene-3,11,20-trione,17, 21-dihydroxy-; Pregna-1,4-diene-3,20-di
  • the compounds are hacinide, prednisone and testosterone propionate.
  • the cerebrovascular disease is stroke, cerebral ischemia and cerebral infarction.
  • the stroke includes hemorrhagic stroke and/or ischemic stroke.
  • the stroke is ischemic stroke.
  • the second object of the present invention is to provide the application of hacinide and its derivatives in the preparation of medicaments for treating and/or preventing cerebral ischemia-reperfusion injury.
  • the third object of the present invention is to provide the application of the composition containing hacinide and its derivatives in the preparation of medicines for treating and/or preventing cerebrovascular diseases.
  • the fourth object of the present invention is to provide the use of hacinide and its derivatives in the preparation of medicaments for treating and/or preventing nerve function damage.
  • the hacinide and its derivatives can be powders, tablets, granules, capsules, solutions, emulsions, suspensions, and injections.
  • the present invention provides new uses of hacinide and its derivatives, and specifically provides the use of hacinide and its derivatives for preparing medicines for treating and/or preventing cerebrovascular diseases.
  • the specific cerebrovascular disease is ischemic stroke.
  • the MCAO animal model of cerebral ischemia-reperfusion injury was used to evaluate the therapeutic effect of hascinide and its derivatives on ischemic stroke.
  • Both nisone and testosterone propionate can significantly improve the neurological deficit score of animals and reduce the area of infarction, which can be used for the treatment of ischemic stroke and have good application prospects in clinical practice.
  • Fig. 1 is a histogram of neurological function scores of rats in each administration group provided by the present invention.
  • SHAM is the sham operation group
  • IR Iron reperfusion, ischemia-reperfusion
  • NBP butylphthalide, butylphthalide
  • Halcinonide is the ha Sined's group. ### p ⁇ 0.001 vs. sham "SHAM”;*p ⁇ 0.05 vs. "IR”
  • Fig. 2 is the TTC staining diagram of each administration group rat of the present invention.
  • Fig. 3 is the evaluation result of cerebral infarction volume of each group of rats provided by the present invention
  • SHAM is the sham operation group
  • IR Iron reperfusion, ischemia-reperfusion
  • NBP butylphthalide, butylphthalide
  • Halcinonide is the ha Sined's group.
  • Fig. 4 is the histogram of neurological function score of each administration group provided by the present invention.
  • SHAM is the sham operation group
  • IR Iron reperfusion, ischemia-reperfusion
  • NBP butylphthalide, butylphthalide
  • Prednisone is the control group.
  • Prednisone group is the testosterone propionate group.
  • Fig. 5 is the evaluation result of cerebral infarction volume of each group of rats provided by the present invention
  • SHAM is the sham operation group
  • IR Iron reperfusion, ischemia-reperfusion
  • NBP butylphthalide, butylphthalide
  • Prednisone is the control group.
  • Prednisone group is the testosterone propionate group.
  • Fig. 6 is the TTC staining diagram of the rats of each administration group of the present invention
  • SHAM is the sham operation group
  • IR Iron reperfusion, ischemia-reperfusion
  • NBP butylphthalide, butylphthalide
  • Prednisone is the control group.
  • Prednisone group is the testosterone propionate group.
  • the compound according to the present invention is selected from the following compounds numbered Co.1 to Co.20;
  • the TTC staining in the present invention refers to 2,3,5-triphenyltetrazolium chloride staining.
  • butylphthalide mainly treats mild and moderate acute ischemic stroke.
  • butylphthalide is used as a positive drug.
  • MCAO refers to Middle Cerebral Artery Occlusion, middle cerebral artery ischemia.
  • Halcinonide Halcinonide, Co.1
  • Prednisone Prednisone, Co.7
  • testosterone propionate Teestosterone Propionate, Co.3
  • 3-month-old SPF male SD rats were selected, with a body weight of 200 ⁇ 20g. Provided by Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences. No drugs were used before the experiment.
  • the experimental animals were acclimatized and raised for a week in an environment with a temperature of 24-26°C and a 12h/12h alternation of daytime regularity.
  • Halcinonide purchased from Shanghai McLean Biochemical Technology Co., Ltd., batch number: C11650940, molecular weight formula is C 24 H 32 ClFO 5 , molecular weight is 454.96
  • NBP Butylphthalide Soft Capsule
  • TTC 2,3,5-Triphenyltetrazolium chloride
  • Carboxymethylcellulose sodium (CMC-Na) was purchased from McLean Company
  • NBP Positive drug group
  • Halcinonide group (Halcinonide, gavage dose of 2 mg/kg/d)
  • the administration time was one week after adaptive feeding. All SD rats were administered 24 hours before modeling, and administered again 24 hours after modeling.
  • the anesthetized rats were immobilized, their skins were prepared, povidone-iodine was sterilized, and surgical instruments were sterilized.
  • a No. 5 thread for ligation was prepared.
  • the common carotid artery and the internal carotid artery were ligated with surgical suture.
  • a 0.32mm suture was inserted into the internal carotid artery through the incision. When the depth of the suture was about 18-20mm, the insertion was stopped and the ligature was fastened. After washing, layered sutures are performed. The suture was removed after 2 hours of ischemia in the animal, the animal would wake up naturally, and the animals were reperfused for 24 hours, and the relevant indicators were detected.
  • the sham operation group was the same as the MCAO model operation group, except that no suture was inserted and no ischemic stroke was caused. 5. Detection indicators
  • the rats that returned to activity were scored according to Zea Longa grade 5, 0: no neurological deficit; 1: unable to fully extend the forepaw on the opposite side of the lesion; 2: spontaneous rotation to the opposite side of the lesion ; 3 points: dumping to the opposite side of the lesion; 4 points: no spontaneous walking and loss of consciousness.
  • the brain tissue was separated and TTC staining was performed.
  • the brain tissue was separated, the olfactory bulb and brain stem were removed, rinsed with normal saline, and then frozen at -20°C for 15 minutes. After that, the brain tissue was serially sliced from the frontal forehead along the coronal plane. Incubate in TTC staining solution at a constant temperature of 37°C for 45 minutes, and turn it every 15 minutes to observe the staining conditions of each group. Bright red is normal brain tissue, and pale white is infarction. Subsequently, the slices were fixed in paraformaldehyde for 12 h, and the cerebral infarct area of the rats in each group was measured by Image Pro Plus 6.0 software, and then the cerebral infarct volume was calculated.
  • the formula is as follows:
  • Cerebral infarction volume (sum of the mean area of the ischemic side - sum of the mean of the contralateral area) ⁇ the thickness of the infarcted brain tissue
  • the present invention uses MCAO cerebral ischemia-reperfusion injury animal model to evaluate the therapeutic effect of hascinide on ischemic stroke, and confirms that hascinide has the effect of treating ischemic stroke.
  • hascinide belongs to the classic hasineide derivative drugs
  • the inventors speculate that other hasineide derivatives other than hascinide also have the effect of treating ischemic stroke.
  • the invention People evaluated the therapeutic effect of prednisone and testosterone propionate on ischemic stroke. The specific experimental process is as follows.
  • Prednisone was purchased from Shanghai McLean Biochemical Technology Co., Ltd., batch number: C11008416, molecular formula was C 21 H 26 O 5 , and molecular weight was 358.43.
  • the hacinide group was replaced by the prednisone group, and the administration method was gavage, and the dose was 20 mg/kg/d.
  • Model preparation and detection indicators are the same as those in Example 1.
  • the cerebral infarction area in the positive drug group was significantly reduced (**p ⁇ 0.01); compared with the model group, the infarct area in the prednisone group was significantly reduced (***p ⁇ 0.001), confirming that prednisone It has the effect of treating ischemic stroke, and the inhibition rate of cerebral infarction in the prednisone group (77.26%) is stronger than that in the positive drug group (53.07%), indicating that prednisone has better curative effect than the positive drug.
  • Testosterone Propionate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: A1910098, molecular formula is C 22 H 32 O 3 , molecular weight is 344.49.
  • the hacinide group was replaced by the testosterone propionate group, and the administration method was gavage at a dose of 20 mg/kg/d.
  • Model preparation and detection indicators are the same as those in Example 1. 2.
  • the cerebral infarct area in the positive drug group was significantly reduced (**p ⁇ 0.01); compared with the model group, the infarct area in the testosterone propionate group was significantly reduced (***p ⁇ 0.001), confirming that propionate Testosterone has the effect of treating ischemic stroke, and the inhibition rate of cerebral infarction in the testosterone propionate group (78.34%) is stronger than that in the positive drug group (53.07%), which proves that testosterone propionate is more effective than the positive drug. good curative effect.
  • the present invention evaluates the therapeutic effect of hacinide, prednisone and testosterone propionate on ischemic stroke by using MCAO cerebral ischemia-reperfusion injury animal model.
  • testosterone propionate has the effect of treating ischemic cerebral apoplexy
  • hacinide and its derivatives also have the effect of treating ischemic cerebral apoplexy, and have broad application prospect in clinical.

Abstract

The present invention relates to the technical field of medicine, and specifically relates to an application of halcinonide and derivatives thereof for preparing a drug treating and/or preventing a cerebrovascular disease. The halcinonide and the derivatives thereof described in the present invention have a structural general formula as represented by formula (I), and a therapeutic effect thereof on ischemic stroke is evaluated by means of an MCAO cerebral ischemia-reperfusion injury animal model. An experiment result shows that halcinonide and the derivatives prednisone and testosterone propionate thereof can significantly improve the neurological deficit score of an animal, and the area of infarction is reduced, same can be used in the treatment of an ischemic stroke, and has good application prospects in clinical practice.

Description

哈西奈德及其衍生物用于制备治疗和/或预防脑血管疾病药物中的应用Application of hacinide and its derivatives in the preparation of medicines for the treatment and/or prevention of cerebrovascular diseases 技术领域technical field
本发明涉及医药技术领域，具体涉及哈西奈德及其衍生物用于制备治疗和/或预防脑血管疾病药物中的应用。The present invention relates to the technical field of medicine, in particular to the application of hacinide and its derivatives in preparing medicines for treating and/or preventing cerebrovascular diseases.
背景技术Background technique
脑卒中(Stroke)是一种临床常见病和高发病，具有发病率高、死亡率高和致残率高的特点，是我国第一位死亡原因，也是全球第二大致死类疾病。严重影响患者生活质量，且治疗后经常发生偏瘫，带来巨大的经济和社会负担。随着我国人口老龄化水平提高，脑卒中的发病率也逐渐升高。脑卒中分为缺血性脑卒中和出血性脑卒中，其中缺血性卒中占脑卒中总数的60％～70％，缺血性脑卒中是指由于脑的供血动脉(颈动脉和椎动脉)狭窄或闭塞、脑供血不足导致的脑组织坏死的总称。脑缺血发生时十分危险，即使度过危险期也会留下各种各样的后遗症，严重者可致残。在有效时间窗内重新恢复或开通病变血管，实现缺血脑组织的再灌注是缺血性脑卒中急性期治疗的重要措施。目前临床上最常用的治疗方法是溶栓治疗，最终目的是开通血管，实现缺血脑组织再灌注。但是其缺点是受溶栓时间窗的限制，对于来不及接受溶栓治疗的患者来说，只能选择药物治疗来降低其神经功能损伤。缺血性脑卒中的治疗药物包括降纤药物、抗凝药物、抗血小板聚集药物和神经保护药物，但由于其单成分、单靶点等自身局限性会导致出血、脑水肿等副作用的产生，目前为止，临床上还没有一种药物取得显著的疗效。Stroke is a common clinical disease and high morbidity. It has the characteristics of high morbidity, high mortality and high disability rate. It is the first cause of death in my country and the second leading cause of death in the world. It seriously affects the quality of life of patients, and hemiplegia often occurs after treatment, which brings huge economic and social burdens. With the aging of the population in my country, the incidence of stroke is also increasing. Stroke is divided into ischemic stroke and hemorrhagic stroke, of which ischemic stroke accounts for 60% to 70% of the total number of strokes. The general term for brain tissue necrosis caused by stenosis or occlusion and insufficient blood supply to the brain. Cerebral ischemia is very dangerous when it occurs. Even if it passes through the dangerous period, it will leave various sequelae, and severe cases can lead to disability. Re-recovering or opening diseased blood vessels within an effective time window to achieve reperfusion of ischemic brain tissue is an important measure for the treatment of acute ischemic stroke. At present, the most commonly used clinical treatment method is thrombolysis, and the ultimate goal is to open blood vessels and achieve reperfusion of ischemic brain tissue. However, its disadvantage is that it is limited by the time window of thrombolysis. For patients who are too late to receive thrombolysis, they can only choose drug therapy to reduce their neurological damage. Drugs for the treatment of ischemic stroke include antifibrillar drugs, anticoagulant drugs, antiplatelet aggregation drugs and neuroprotective drugs. However, due to their own limitations such as single component and single target, they may lead to side effects such as hemorrhage and cerebral edema. So far, no drug has achieved significant clinical efficacy.
哈西奈德及其衍生物是肾上腺皮质受脑垂体前叶分泌的促肾上腺皮质激素刺激所产生的一类激素，哈西奈德具有抗炎、抗瘙痒和血管收缩作用，在临床上主要用于对抗各种炎症以及炎症后期抑制毛细血管和成纤维细胞的增生，减轻后遗症。专利CN201610366828.8公开了哈西奈德的药物组合物在治疗甲状腺功能亢进中的应用；专利CN102641277A公开了哈西奈德的组合物能够被用于治疗妇科疾病和皮肤病；专利CN106511505A公开了哈西奈德组合物能够被用于治疗胃溃疡。但是，目前并没有将哈西奈德应用于脑血管疾病的文献，亦没有任何文献提示本领域技术人员哈西奈德具有治疗脑血管疾病的功能。Hasinide and its derivatives are a class of hormones produced by the adrenal cortex stimulated by adrenocorticotropic hormone secreted by the anterior pituitary gland. Hasinide has anti-inflammatory, anti-pruritic and vasoconstrictive effects, and is mainly used clinically against Various inflammations and the late stage of inflammation inhibit the proliferation of capillaries and fibroblasts and reduce the sequelae. Patent CN201610366828.8 discloses the application of the pharmaceutical composition of Hasinide in the treatment of hyperthyroidism; Patent CN102641277A discloses that the composition of Hasinide can be used for the treatment of gynecological diseases and skin diseases; Patent CN106511505A discloses the application of Hasinide The composition can be used to treat gastric ulcers. However, at present, there is no literature on the application of Hasinide to cerebrovascular diseases, and there is no literature suggesting that Hascinide has the function of treating cerebrovascular diseases for those skilled in the art.
发明人在实验过程中意外的发现，哈西奈德具有治疗脑血管疾病的效果，尤其是对脑卒中具有显著的治疗效果，对哈西奈德的衍生物进行研究，发现其衍生物也具有治疗脑卒中的效果。During the experiment, the inventor unexpectedly found that Hascinide has the effect of treating cerebrovascular diseases, especially has a significant therapeutic effect on stroke. effects of stroke.
发明内容SUMMARY OF THE INVENTION
针对上述技术问题，本发明提供了哈西奈德及其衍生物的新用途，具体提供了哈西奈德及其衍生物用于制备治疗和/或预防脑血管疾病药物中的应用，所述的哈西奈德及其衍生物具有式(Ⅰ)所示的结构通式：In view of the above-mentioned technical problems, the present invention provides new uses of hacinide and its derivatives, and specifically provides the use of hacinide and its derivatives for preparing medicines for the treatment and/or prevention of cerebrovascular diseases. Sinide and its derivatives have the general structural formula shown in formula (I):
Figure PCTCN2021082818-appb-000001
Figure PCTCN2021082818-appb-000001
其中，所述的哈西奈德及其衍生物可为其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐；Wherein, the hacinide and its derivatives may be in the form of tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts;
R 1和R 2分别独立的选自H、-C＝C； R 1 and R 2 are independently selected from H, -C=C;
R 3选自为H或卤素； R is selected from H or halogen;
R 4选自H、-OH或-C＝OH； R4 is selected from H, -OH or -C=OH;
R 5和R 6分别独立的选自H、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧酰基、C 2-6烯基、C 2-6炔基、C 1-6烷基酰基、芳香酰基、C 6-10芳基、C 5-6环烷基，或R 5和R 6连接形成饱和或不饱和的5或6元碳环或杂环基或含烷基取代的碳环或杂环基，其中R 5和R 6中的烷基被1-3个下列的取代基取代：羟基、卤素。 R 5 and R 6 are each independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyacyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl acyl, aromatic acyl, C 6-10 aryl, C 5-6 cycloalkyl, or R 5 and R 6 are connected to form a saturated or unsaturated 5- or 6-membered carbon A cyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl groups in R 5 and R 6 are substituted with 1-3 of the following substituents: hydroxy, halogen.
优选地，所述的R 5和R 6分别独立选自H、-OH、-NH 2、C 1-6烷基、C 1-4烷氧基、C 1-4烷氧酰基、C 2-4烯基、C 2-4炔基、C 1-4烷基酰基、苯基酰基、苯基、C 5-6环烷基，或R 5和R 6连接形成饱和或不饱和的5或6元碳环或杂环基或含烷基取代的碳环或杂环基，其中R 5和R 6中所述烷基可被1-3个下列的取代基取代：羟基、卤素。 Preferably, said R 5 and R 6 are independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxyacyl, C 2- 4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl acyl, phenyl acyl, phenyl, C 5-6 cycloalkyl, or R 5 and R 6 are connected to form a saturated or unsaturated 5 or 6 A membered carbocyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl group in R 5 and R 6 may be substituted by 1-3 of the following substituents: hydroxy, halogen.
优选地，所述的R 5和R 6分别选自H、-OH、-NH 2、-COH、CH 3CO-、-CO-CH 2OH、-O-C(O)CH 2CH 3、-CH 2-C≡CH、-(CH 2) 5CH 3、-(CH 2) 4CF 3、环己基-、-CH 2-(CH 2) 3-CH 2-、-C(O)-CF 3、-C(O)-Ph、其中所述烷基被1-3个下列的取代基取代：羟基、卤素。 Preferably, said R 5 and R 6 are respectively selected from H, -OH, -NH 2 , -COH, CH 3 CO-, -CO-CH 2 OH, -OC(O)CH 2 CH 3 , -CH 2 -C≡CH, -(CH 2 ) 5 CH 3 , -(CH 2 ) 4 CF 3 , cyclohexyl-, -CH 2 -(CH 2 ) 3 -CH 2 -, -C(O)-CF 3 , -C(O)-Ph, wherein the alkyl group is substituted with 1-3 of the following substituents: hydroxy, halogen.
优选地，所述的哈西奈德及其衍生物选自以下化合物：Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Pregn-4-ene-3,20-dione, 21-hydroxy-；Androst-4-en-3-one,17-(1-oxopropoxy)-,(17β)-；Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-；Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-,(11β)-；Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-；Pregna-1,4-diene-3,11,20-trione,17,21-dihydroxy-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α)-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Androst-4-en-3-one；Androst-4-en-3-one,17-methylene-；Androst-4-ene-3,17-dione；Androst-4-ene-3,16-dione；Androst-4-en-3-one,17-hydroxy-,(17α)-；Androst-4-ene-3,11-dione；Androst-4-en-3-one,17β-amino-；Androst-4-en-3-one,17-chloro-,(17α)-；Androst-4-ene-3,11,16-trione；Pregn-4-en-20-yn-3-one,(17α)-。Preferably, the hacinide and its derivatives are selected from the following compounds: Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1- methylethylidene)bis(oxy)]-,(11β,16α)-; Pregn-4-ene-3,20-dione, 21-hydroxy-;Androst-4-en-3-one,17-(1-oxopropoxy) -,(17β)-; Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-; Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-,( 11β)-; Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-;Pregna-1,4-diene-3,11,20-trione,17, 21-dihydroxy-; Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α)-;Pregna-1,4-diene -3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-; Pregna-1,4-diene-3,20-dione,9-fluoro-11,21 -dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-;Androst-4-en-3-one;Androst-4-en-3-one,17-methylene -;Androst-4-ene-3,17-dione;Androst-4-ene-3,16-dione;Androst-4-en-3-one,17-hydroxy-,(17α)-;Androst-4- ene-3,11-dione;Androst-4-en-3-one,17β-amino-;Androst-4-en-3-one,17-chloro-,(17α)-;Androst-4-ene-3 ,11,16-trione; Pregn-4-en-20-yn-3-one,(17α)-.
优选地，所述的化合物为哈西奈德、***和丙酸***。Preferably, the compounds are hacinide, prednisone and testosterone propionate.
优选地，所述的脑血管疾病为脑卒中、脑缺血、脑梗塞。Preferably, the cerebrovascular disease is stroke, cerebral ischemia and cerebral infarction.
优选地，所述的脑卒中包括出血性脑卒中和/缺血性脑卒中。Preferably, the stroke includes hemorrhagic stroke and/or ischemic stroke.
优选地，所述的脑卒中为缺血性脑卒中。Preferably, the stroke is ischemic stroke.
本发明的第二目的是提供哈西奈德及其衍生物用于制备治疗和/或预防脑缺血再灌注损伤药物中的应用。The second object of the present invention is to provide the application of hacinide and its derivatives in the preparation of medicaments for treating and/or preventing cerebral ischemia-reperfusion injury.
本发明的第三目的是提供含有哈西奈德及其衍生物的组合物在制备治疗和/或预防脑血管疾病药物中的应用。The third object of the present invention is to provide the application of the composition containing hacinide and its derivatives in the preparation of medicines for treating and/or preventing cerebrovascular diseases.
本发明的第四目的是提供哈西奈德及其衍生物用于制备治疗和/或预防神经功能损伤药物中的应用。The fourth object of the present invention is to provide the use of hacinide and its derivatives in the preparation of medicaments for treating and/or preventing nerve function damage.
优选地，所述的哈西奈德及其衍生物可以为散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂。Preferably, the hacinide and its derivatives can be powders, tablets, granules, capsules, solutions, emulsions, suspensions, and injections.
本发明的有益效果是：本发明提供了哈西奈德及其衍生物的新用途，具体提供了哈西奈德及其衍生物用于制备治疗和/或预防脑血管疾病药物中的应用，所述的脑血管疾病具体为缺血性脑卒中，通过MCAO脑缺血再灌注损伤动物模型，评价哈西奈德及其衍生物对缺血性脑卒中的治疗效果，实验结果显示，哈西奈德、***和丙酸***均能显著改善动物神经功能缺损评分，降低梗死灶的面积，可以用于治疗缺血性脑卒中，在临床中具有良好的应用前景。The beneficial effects of the present invention are as follows: the present invention provides new uses of hacinide and its derivatives, and specifically provides the use of hacinide and its derivatives for preparing medicines for treating and/or preventing cerebrovascular diseases. The specific cerebrovascular disease is ischemic stroke. The MCAO animal model of cerebral ischemia-reperfusion injury was used to evaluate the therapeutic effect of hascinide and its derivatives on ischemic stroke. Both nisone and testosterone propionate can significantly improve the neurological deficit score of animals and reduce the area of infarction, which can be used for the treatment of ischemic stroke and have good application prospects in clinical practice.
附图说明Description of drawings
图1为本发明提供的各给药组大鼠神经功能评分柱状图；Fig. 1 is a histogram of neurological function scores of rats in each administration group provided by the present invention;
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注 模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物组，“Halcinonide”为哈西奈德组。与假手术组“SHAM”相比， ###p<0.001；与“IR”相比，*p<0.05 Among them, "SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug group, and "Halcinonide" is the ha Sined's group. ### p<0.001 vs. sham "SHAM";*p<0.05 vs. "IR"
图2为本发明的各给药组大鼠的TTC染色图；Fig. 2 is the TTC staining diagram of each administration group rat of the present invention;
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物组，“Halcinonide”为哈西奈德组。图3为本发明提供的各组大鼠脑梗死体积评价结果"SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug group, "Halcinonide" is the ha Sined's group. Fig. 3 is the evaluation result of cerebral infarction volume of each group of rats provided by the present invention
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物组，“Halcinonide”为哈西奈德组。"SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug group, "Halcinonide" is the ha Sined's group.
与假手术“SHAM”相比， ###p<0.001，与“IR”相比，**p<0.01和***p<0.001 ### p<0.001 vs. sham "SHAM", **p<0.01 and ***p<0.001 vs. "IR"
图4为本发明提供的各给药组大鼠神经功能评分柱状图；Fig. 4 is the histogram of neurological function score of each administration group provided by the present invention;
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物对照组，“Prednisone”为***组，“Testosterone Propionate”为丙酸***组。Among them, "SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug control group, and "Prednisone" is the control group. Prednisone group, "Testosterone Propionate" is the testosterone propionate group.
与假手术组“SHAM”相比，###p<0.001；与“IR”相比，*p<0.05和**p<0.01###p<0.001 vs. sham "SHAM"; *p<0.05 and **p<0.01 vs. "IR"
图5为本发明提供的各组大鼠脑梗死体积评价结果Fig. 5 is the evaluation result of cerebral infarction volume of each group of rats provided by the present invention
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物对照组，“Prednisone”为***组，“Testosterone Propionate”为丙酸***组。Among them, "SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug control group, and "Prednisone" is the control group. Prednisone group, "Testosterone Propionate" is the testosterone propionate group.
与假手术“SHAM”相比，###p<0.001，与“IR”相比，**p<0.01和***p<0.001###p<0.001 vs. sham "SHAM", **p<0.01 and ***p<0.001 vs. "IR"
图6为本发明的各给药组大鼠的TTC染色图Fig. 6 is the TTC staining diagram of the rats of each administration group of the present invention
其中“SHAM”为假手术组，“IR”(Ischemia reperfusion，缺血再灌注)为缺血再灌注模型对照组，“NBP”(Butylphthalide，丁苯酞)为阳性药物对照组，“Prednisone”为***组，“Testosterone Propionate”为丙酸***组。Among them, "SHAM" is the sham operation group, "IR" (Ischemia reperfusion, ischemia-reperfusion) is the ischemia-reperfusion model control group, "NBP" (Butylphthalide, butylphthalide) is the positive drug control group, and "Prednisone" is the control group. Prednisone group, "Testosterone Propionate" is the testosterone propionate group.
具体实施方式Detailed ways
下面将结合本发明实例中的附图，对本发明实例中的技术方案进行清楚完整的描述，很 显然，所描述的实施例仅仅是本发明一部分的实施例，而不是全部的实施例，同时保护哈西奈德及其衍生物在所有脑血管疾病中的治疗效果，包括不同剂型、剂量等。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动力前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions in the examples of the present invention will be clearly and completely described below with reference to the accompanying drawings. The therapeutic effect of hacinide and its derivatives in all cerebrovascular diseases, including different dosage forms, doses, etc. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative labors fall within the protection scope of the present invention.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本文发明主题做任何限制。在本申请中，必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其他形式，例如“包含”、“含”和“含有”并非限制性。It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not intended to limit the subject matter herein. In this application, it must be noted that the singular forms used in this specification and the claims include the plural forms of referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" and "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.
根据本发明所述的化合物，其为选自下列编号为Co.1至Co.20的化合物；The compound according to the present invention is selected from the following compounds numbered Co.1 to Co.20;
Figure PCTCN2021082818-appb-000002
Figure PCTCN2021082818-appb-000002
Figure PCTCN2021082818-appb-000003
Figure PCTCN2021082818-appb-000003
Figure PCTCN2021082818-appb-000004
Figure PCTCN2021082818-appb-000004
Co.1：Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Co.1: Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α) -;
Co.2：Pregn-4-ene-3,20-dione,21-hydroxy-；Co.2: Pregn-4-ene-3,20-dione,21-hydroxy-;
Co.3：Androst-4-en-3-one,17-(1-oxopropoxy)-,(17β)-；Co.3: Androst-4-en-3-one, 17-(1-oxopropoxy)-, (17β)-;
Co.4：Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-；Co.4: Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-;
Co.5：Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-,(11β)-；Co.5: Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-,(11β)-;
Co.6：Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-；Co.6: Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-;
Co.7：Pregna-1,4-diene-3,11,20-trione,17,21-dihydroxy-；Co.7: Pregna-1,4-diene-3,11,20-trione,17,21-dihydroxy-;
Co.8：Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α)-；Co.8: Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α)-;
Co.9：Pregna-1,4-diene-3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-；Co.9: Pregna-1,4-diene-3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-;
Co.10：Pregna-1,4-diene-3,20-dione,9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Co.10: Pregna-1,4-diene-3,20-dione,9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α) -;
Co.11：Androst-4-en-3-one；Co.11: Androst-4-en-3-one;
Co.12：Androst-4-en-3-one,17-methylene-；Co.12: Androst-4-en-3-one, 17-methylene-;
Co.13：Androst-4-ene-3,17-dione；Co.13: Androst-4-ene-3,17-dione;
Co.14：Androst-4-ene-3,16-dione；Co.14: Androst-4-ene-3,16-dione;
Co.15：Androst-4-en-3-one,17-hydroxy-,(17α)-；Co.15: Androst-4-en-3-one, 17-hydroxy-, (17α)-;
Co.16：Androst-4-ene-3,11-dione；Co.16: Androst-4-ene-3,11-dione;
Co.17：Androst-4-en-3-one,17β-amino-；Co.17: Androst-4-en-3-one, 17β-amino-;
Co.18：Androst-4-en-3-one,17-chloro-,(17α)-；Co.18: Androst-4-en-3-one, 17-chloro-, (17α)-;
Co.19：Androst-4-ene-3,11,16-trione；Co.19: Androst-4-ene-3,11,16-trione;
Co.20：Pregn-4-en-20-yn-3-one,(17α)-；Co.20: Pregn-4-en-20-yn-3-one, (17α)-;
或其药学可接受的盐、溶剂合物例如水合物、脂、前药。or pharmaceutically acceptable salts, solvates such as hydrates, lipids, prodrugs thereof.
本发明所述的TTC染色是指2，3，5-氯化三苯基四氮唑染色。The TTC staining in the present invention refers to 2,3,5-triphenyltetrazolium chloride staining.
本发明以下实施例中，丁苯酞主要治疗轻、中度急性缺血性脑卒中。本发明实施例将丁 苯酞作为阳性药使用。In the following embodiments of the present invention, butylphthalide mainly treats mild and moderate acute ischemic stroke. In the embodiment of the present invention, butylphthalide is used as a positive drug.
本发明以下实施例中，MCAO是指Middle Cerebral Artery Occlusion，大脑中动脉缺血。In the following embodiments of the present invention, MCAO refers to Middle Cerebral Artery Occlusion, middle cerebral artery ischemia.
发明人用哈西奈德(Halcinonide，Co.1)、***(Prednisone，Co.7)与丙酸***(Testosterone Propionate，Co.3)小分子化合物，在不同饲喂条件下，对SD(Sprague-Dawley)大鼠进行神经功能评分、脑梗死体积测量，证实了哈西奈德及其衍生物具有治疗缺血性脑卒中的作用。The inventor used Halcinonide (Halcinonide, Co.1), prednisone (Prednisone, Co.7) and testosterone propionate (Testosterone Propionate, Co.3) small molecule compounds, under different feeding conditions, to SD The neurological function score and cerebral infarction volume measurement in Sprague-Dawley rats confirmed that hacinide and its derivatives have the effect of treating ischemic stroke.
实施例一、哈西奈德治疗缺血性脑卒中的效果研究Example 1. Study on the effect of hacinide on ischemic stroke
1.实验动物1. Experimental animals
选用3月龄SPF级雄性SD大鼠，体重均为200±20g。由中国农业科学院兰州兽医研究所提供。实验前未用过任何药物。实验动物于温度为24～26℃，12h/12h的白昼规律交替的环境中适应饲养一周，给予动物饮食并自由饮水，然后分组进行实验。3-month-old SPF male SD rats were selected, with a body weight of 200±20g. Provided by Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences. No drugs were used before the experiment. The experimental animals were acclimatized and raised for a week in an environment with a temperature of 24-26°C and a 12h/12h alternation of daytime regularity.
2.药物及试剂2. Drugs and reagents
哈西奈德(Halcinonide)，购自上海麦克林生化科技有限公司，批号：C11650940，分子量式为C 24H 32ClFO 5，分子量为454.96 Halcinonide, purchased from Shanghai McLean Biochemical Technology Co., Ltd., batch number: C11650940, molecular weight formula is C 24 H 32 ClFO 5 , molecular weight is 454.96
丁苯酞软胶囊(Butylphthalide，NBP)，购自石药集团恩必普药业有限公司；Butylphthalide Soft Capsule (NBP), purchased from NBP Pharmaceutical Co., Ltd. of Shijiazhuang Pharmaceutical Group;
2，3，5-氯化三苯基四氮唑(TTC)，购自Sigma公司。2,3,5-Triphenyltetrazolium chloride (TTC) was purchased from Sigma Company.
羧甲基纤维素钠(Carboxymethylcellulose sodium，CMC-Na)购自麦克林公司Carboxymethylcellulose sodium (CMC-Na) was purchased from McLean Company
3.实验分组和灌胃给药剂量3. Experimental grouping and intragastric administration dose
将雄性3月龄SD大鼠随机分为4组，每组9只，分组和给药剂量如下：Male 3-month-old SD rats were randomly divided into 4 groups with 9 rats in each group. The groups and doses were as follows:
假手术组(SHAM，灌胃给予等体积0.5％CMC-Na)；Sham operation group (SHAM, given equal volume of 0.5% CMC-Na by gavage);
模型对照组(IR，灌胃给予等体积0.5％CMC-Na)；Model control group (IR, given the same volume of 0.5% CMC-Na by gavage);
阳性药组(NBP，灌胃给予丁苯酞，20mg/kg/d)；Positive drug group (NBP, intragastric administration of butylphthalide, 20 mg/kg/d);
哈西奈德组(Halcinonide，灌胃剂量为2mg/kg/d)Halcinonide group (Halcinonide, gavage dose of 2 mg/kg/d)
给药时间为适应性饲养一周后，所有的SD大鼠在造模前24h给药，造模结束后再次给药24h。The administration time was one week after adaptive feeding. All SD rats were administered 24 hours before modeling, and administered again 24 hours after modeling.
4.缺血性脑卒中模型组的制备4. Preparation of ischemic stroke model group
将麻醉后的大鼠固定，备皮，碘伏消毒，并消毒手术器械，预备好结扎用的5号线，沿颈部正中偏右行纵向切口约1.5cm。小心分离右侧颈动脉和迷走神经后，用手术缝合线将颈总动脉与颈内动脉结扎，颈总动脉结扎位置在分岔口10mm处，之后在离颈总动脉分叉处5mm处切口，将直径为0.32mm的线栓经切口***颈内动脉，线栓深度约为18-20mm时，停止插线，系紧结扎线。清洗后，进行分层缝合。在动物缺血2h后去除线栓，动物会自然苏醒， 再灌注24h，进行相关指标检测。The anesthetized rats were immobilized, their skins were prepared, povidone-iodine was sterilized, and surgical instruments were sterilized. A No. 5 thread for ligation was prepared. After careful separation of the right carotid artery and vagus nerve, the common carotid artery and the internal carotid artery were ligated with surgical suture. A 0.32mm suture was inserted into the internal carotid artery through the incision. When the depth of the suture was about 18-20mm, the insertion was stopped and the ligature was fastened. After washing, layered sutures are performed. The suture was removed after 2 hours of ischemia in the animal, the animal would wake up naturally, and the animals were reperfused for 24 hours, and the relevant indicators were detected.
假手术组与MCAO模型操作组相同，只是不需要***线栓，亦不会造成缺血性脑卒中。5.检测指标The sham operation group was the same as the MCAO model operation group, except that no suture was inserted and no ischemic stroke was caused. 5. Detection indicators
(1)神经功能缺损评分(1) Neurological deficit score
给药处理24h后，按照Zea Longa 5级对恢复活动的大鼠进行评分，0分：无神经功能缺损；1分：病灶对侧前爪不能完全伸展；2分：向病灶对侧自发性旋转；3分：向病灶对侧倾倒；4分：无自发性行走且出现意识丧失，评分完成后，分离脑组织，进行TTC染色。After 24 hours of drug treatment, the rats that returned to activity were scored according to Zea Longa grade 5, 0: no neurological deficit; 1: unable to fully extend the forepaw on the opposite side of the lesion; 2: spontaneous rotation to the opposite side of the lesion ; 3 points: dumping to the opposite side of the lesion; 4 points: no spontaneous walking and loss of consciousness. After scoring, the brain tissue was separated and TTC staining was performed.
(2)TTC染色(2) TTC staining
分离脑组织，去除嗅球和脑干，生理盐水冲洗后放入-20℃冷冻15min,之后将脑组织从前脑额部沿冠状面向后进行连续切片，切片厚度约为2mm，然后迅速放入1.5％TTC染色液中37℃恒温避光孵育45min，每15min翻一次，观察各组染色情况，鲜红色则为正常脑组织，苍白色即为梗死灶。随后把切片放入多聚甲醛中固定12h，用Image Pro Plus 6.0软件测量各组大鼠脑梗死面积，然后计算脑梗死体积。公式如下：The brain tissue was separated, the olfactory bulb and brain stem were removed, rinsed with normal saline, and then frozen at -20°C for 15 minutes. After that, the brain tissue was serially sliced from the frontal forehead along the coronal plane. Incubate in TTC staining solution at a constant temperature of 37°C for 45 minutes, and turn it every 15 minutes to observe the staining conditions of each group. Bright red is normal brain tissue, and pale white is infarction. Subsequently, the slices were fixed in paraformaldehyde for 12 h, and the cerebral infarct area of the rats in each group was measured by Image Pro Plus 6.0 software, and then the cerebral infarct volume was calculated. The formula is as follows:
脑梗死体积＝(缺血侧面积均值总和-对侧面积均值总和)×梗死脑组织厚度Cerebral infarction volume = (sum of the mean area of the ischemic side - sum of the mean of the contralateral area) × the thickness of the infarcted brain tissue
6.实验结果6. Experimental results
(1)神经功能缺损评分评价(1) Evaluation of neurological deficit score
SD大鼠给药1天，MCAO模型缺血2h后，再次进行药物治疗，再灌注24h后，各组大鼠神经功能行为学评分见附图1。如图1所示，与假手术组相比，模型组神经功能评分显著升高( ###p<0.001)，表明模型构建成功，哈西奈德组与模型组相比，神经功能行为学评分降低(*p<0.05)，表明哈西奈德具有治疗缺血性脑卒中的作用。 SD rats were administered for 1 day. After 2 hours of ischemia in the MCAO model, drug treatment was performed again. After 24 hours of reperfusion, the neurobehavioral scores of the rats in each group were shown in Figure 1. As shown in Figure 1, compared with the sham operation group, the neurological function score of the model group was significantly increased ( ### p<0.001), indicating that the model was successfully constructed. decreased (*p<0.05), indicating that hacinide has the effect of treating ischemic stroke.
(2)TTC染色和脑梗死体积评价(2) TTC staining and cerebral infarction volume evaluation
TTC染色结果和脑梗死体积结果见图2和图3，假手术组脑组织未缺血区为均匀的红色，未见缺血白色梗死灶，而模型组缺血侧可见大区域的白色梗死灶，表明模型构建成功。与模型组相比，阳性药组的脑梗死区域显著减少(***p<0.001)；与模型组相比，哈西奈德组梗死区域显著减少(**p<0.01)，表明哈西奈德具有治疗缺血性脑卒中的作用。The results of TTC staining and cerebral infarction volume are shown in Figures 2 and 3. The non-ischemic area of the brain tissue in the sham-operated group was uniformly red, and no ischemic white infarction was found, while the model group showed a large area of white infarction on the ischemic side. , indicating that the model was successfully constructed. Compared with the model group, the cerebral infarction area in the positive drug group was significantly reduced (***p<0.001); compared with the model group, the infarct area in the Hasinide group was significantly reduced (**p<0.01), indicating that the Hasinide group Has the effect of treating ischemic stroke.
7.实验结论7. Experimental conclusion
综上所述，本发明通过采用MCAO脑缺血再灌注损伤动物模型评价哈西奈德对缺血性脑卒中治疗效果，证实哈西奈德具有治疗缺血性脑卒中的作用。To sum up, the present invention uses MCAO cerebral ischemia-reperfusion injury animal model to evaluate the therapeutic effect of hascinide on ischemic stroke, and confirms that hascinide has the effect of treating ischemic stroke.
由于哈西奈德属于经典的哈西奈德衍生物药物，因此，发明人推测，除了哈西奈德之外的其他哈西奈德衍生物也具有治疗缺血性脑卒中的效果，为了验证上述推测，发明人评价了***和丙酸***对缺血性脑卒中的治疗效果，具体实验过程如下。Since hascinide belongs to the classic hasineide derivative drugs, the inventors speculate that other hasineide derivatives other than hascinide also have the effect of treating ischemic stroke. In order to verify the above speculation, the invention People evaluated the therapeutic effect of prednisone and testosterone propionate on ischemic stroke. The specific experimental process is as follows.
实施例二、***治疗缺血性脑卒中的效果研究Example 2. Study on the effect of prednisone on ischemic stroke
1.具体实施方法同实施例一。1. The specific implementation method is the same as that in Example 1.
***(Prednisone)购自购自上海麦克林生化科技有限公司，批号：C11008416，分子式为C 21H 26O 5，分子量为358.43。实验分组参见实施例一，将哈西奈德组替换为***组，给药方式为灌胃，剂量为20mg/kg/d。模型制备与检测指标同实施例一。 Prednisone was purchased from Shanghai McLean Biochemical Technology Co., Ltd., batch number: C11008416, molecular formula was C 21 H 26 O 5 , and molecular weight was 358.43. For the experimental grouping, see Example 1. The hacinide group was replaced by the prednisone group, and the administration method was gavage, and the dose was 20 mg/kg/d. Model preparation and detection indicators are the same as those in Example 1.
2.实验结果2. Experimental results
(1)神经功能缺损评分评价(1) Evaluation of neurological deficit score
SD大鼠给药1天，MCAO模型缺血2h后，再次进行药物治疗，再灌注24h后，各组大鼠神经功能行为学评分见附图4。如图4所示，与假手术组相比，模型组神经功能评分显著升高( ###p<0.001)，表明模型构建成功，***组与模型组相比，神经功能行为学评分降低(*p<0.05)，表明***具有治疗缺血性脑卒中的作用。 SD rats were administered for 1 day. After 2 hours of ischemia in the MCAO model, drug treatment was performed again. After 24 hours of reperfusion, the neurobehavioral scores of the rats in each group were shown in Figure 4. As shown in Figure 4, compared with the sham operation group, the neurological function score of the model group was significantly increased ( ### p<0.001), indicating that the model was successfully constructed. Compared with the model group, the neurological behavioral score of the prednisone group decreased (*p<0.05), indicating that prednisone has the effect of treating ischemic stroke.
(2)TTC染色和脑梗死体积评价(2) TTC staining and cerebral infarction volume evaluation
TTC染色结果和脑梗死体积结果见图5和图6，由图6可知，假手术组脑组织未缺血区为均匀的红色，未见缺血白色梗死灶，而模型组缺血测可见大区域的白色梗死灶，表明模型构建成功。与模型组相比，阳性药组的脑梗死区域显著减少(**p<0.01)；与模型组相比，***组梗死区域显著减少(***p<0.001)，证实***具有治疗缺血性脑卒中的作用，且***组脑梗死抑制率(77.26％)强于阳性药组脑梗死抑制率(53.07％)，说明***比阳性药具更好疗效。The results of TTC staining and cerebral infarction volume are shown in Figure 5 and Figure 6. It can be seen from Figure 6 that the non-ischemic area of the brain tissue in the sham operation group was uniform red, and no ischemic white infarction was found, while the model group showed large ischemia in the ischemia test. The white infarct in the area indicates that the model was successfully constructed. Compared with the model group, the cerebral infarction area in the positive drug group was significantly reduced (**p<0.01); compared with the model group, the infarct area in the prednisone group was significantly reduced (***p<0.001), confirming that prednisone It has the effect of treating ischemic stroke, and the inhibition rate of cerebral infarction in the prednisone group (77.26%) is stronger than that in the positive drug group (53.07%), indicating that prednisone has better curative effect than the positive drug.
实施例三、丙酸***治疗缺血性脑卒中的效果研究Example 3. Study on the effect of testosterone propionate in the treatment of ischemic stroke
1.具体实施方法参见实施例一。1. For the specific implementation method, see Example 1.
丙酸***(Testosterone Propionate)购自购自上海阿拉丁生化科技股份有限公司，批号：A1910098，分子式为C 22H 32O 3，分子量为344.49。实验分组参见实施例一，将哈西奈德组替换为丙酸***组，给药方式为灌胃，剂量为20mg/kg/d。模型制备与检测指标同实施例一。2.实验结果 Testosterone Propionate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: A1910098, molecular formula is C 22 H 32 O 3 , molecular weight is 344.49. For the experimental grouping, see Example 1. The hacinide group was replaced by the testosterone propionate group, and the administration method was gavage at a dose of 20 mg/kg/d. Model preparation and detection indicators are the same as those in Example 1. 2. Experimental results
(1)神经功能缺损评分评价(1) Evaluation of neurological deficit score
SD大鼠给药1天，MCAO模型缺血2h后，再次进行药物治疗，再灌注24h后，各组大鼠神经功能行为学评分见附图4。如图4所示，与假手术组相比，模型组神经功能评分显著升高( ###p<0.001)，表明模型构建成功，丙酸***组与模型组相比，神经功能行为学评分降低(**p<0.01)，表明丙酸***具有治疗缺血性脑卒中的作用。 SD rats were administered for 1 day. After 2 hours of ischemia in the MCAO model, drug treatment was performed again. After 24 hours of reperfusion, the neurobehavioral scores of the rats in each group were shown in Figure 4. As shown in Figure 4, compared with the sham-operated group, the neurological function score of the model group was significantly increased ( ### p<0.001), indicating that the model was successfully constructed. The score decreased (**p<0.01), indicating that testosterone propionate has the effect of treating ischemic stroke.
(2)TTC染色和脑梗死体积评价(2) TTC staining and cerebral infarction volume evaluation
TTC染色结果和脑梗死体积结果见图5和图6，假手术组脑组织未缺血区为均匀的红色，未见缺血白色梗死灶，而模型组缺血测可见大区域的白色梗死灶，表明模型构建成功。与模型组相比，阳性药组的脑梗死区域显著减少(**p<0.01)；与模型组相比，丙酸***组梗死区域显著减少(***p<0.001)，证实丙酸***具有治疗缺血性脑卒中的作用，且丙酸***组脑梗死抑制率(78.34％)强于阳性药组脑梗死抑制率(53.07％)，证明丙酸***比阳性药具更好疗效。The results of TTC staining and cerebral infarction volume are shown in Figures 5 and 6. The non-ischemic area of the brain tissue in the sham-operated group was uniformly red, and no ischemic white infarction was found, while the model group waschemia showed a large area of white infarction. , indicating that the model was successfully constructed. Compared with the model group, the cerebral infarct area in the positive drug group was significantly reduced (**p<0.01); compared with the model group, the infarct area in the testosterone propionate group was significantly reduced (***p<0.001), confirming that propionate Testosterone has the effect of treating ischemic stroke, and the inhibition rate of cerebral infarction in the testosterone propionate group (78.34%) is stronger than that in the positive drug group (53.07%), which proves that testosterone propionate is more effective than the positive drug. good curative effect.
综上所述，本发明通过采用MCAO脑缺血再灌注损伤动物模型评价哈西奈德、***和丙酸***对缺血性脑卒中治疗效果，实验结果显示哈西奈德、***和丙酸***具有治疗缺血性脑卒中的作用，哈西奈德及其衍生物也具有治疗缺血性脑卒中的作用，在临床上具有广阔的应用前景。To sum up, the present invention evaluates the therapeutic effect of hacinide, prednisone and testosterone propionate on ischemic stroke by using MCAO cerebral ischemia-reperfusion injury animal model. And testosterone propionate has the effect of treating ischemic cerebral apoplexy, and hacinide and its derivatives also have the effect of treating ischemic cerebral apoplexy, and have broad application prospect in clinical.
凡技术人员按照本发明的思路在现有技术上通过逻辑分析、推断和实验得出的技术方案，均属于权利要求书中保护的范围。All technical solutions obtained by technical personnel through logical analysis, inference and experimentation in the prior art according to the idea of the present invention belong to the scope of protection in the claims.

Claims (10)

  1. 哈西奈德及其衍生物用于制备治疗和/或预防脑血管疾病药物中的应用，其特征在于，所述的哈西奈德及其衍生物具有式(Ⅰ)所示的结构通式：The application of hacinide and its derivatives in the preparation of medicines for the treatment and/or prevention of cerebrovascular diseases, characterized in that said hacinide and its derivatives have the general structural formula shown in formula (I):
    Figure PCTCN2021082818-appb-100001
    Figure PCTCN2021082818-appb-100001
    其中，所述的哈西奈德及其衍生物可为其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐；Wherein, the hacinide and its derivatives may be in the form of tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts;
    R 1和R 2分别独立的选自H、-C＝C； R 1 and R 2 are independently selected from H, -C=C;
    R 3选自为H或卤素； R is selected from H or halogen;
    R 4选自H、-OH或-C＝OH； R4 is selected from H, -OH or -C=OH;
    R 5和R 6分别独立的选自H、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧酰基、C 2-6烯基、C 2-6炔基、C 1-6烷基酰基、芳香酰基、C 6-10芳基、C 5-6环烷基，或R 5和R 6连接形成饱和或不饱和的5或6元碳环或杂环基或含烷基取代的碳环或杂环基，其中R 5和R 6中的烷基被1-3个下列的取代基取代：羟基、卤素。 R 5 and R 6 are each independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyacyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl acyl, aromatic acyl, C 6-10 aryl, C 5-6 cycloalkyl, or R 5 and R 6 are connected to form a saturated or unsaturated 5- or 6-membered carbon A cyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl groups in R 5 and R 6 are substituted with 1-3 of the following substituents: hydroxy, halogen.
  2. 如权利要求1所述的应用，其特征在于，所述的R 5和R 6分别独立选自H、-OH、-NH 2、C 1-6烷基、C 1-4烷氧基、C 1-4烷氧酰基、C 2-4烯基、C 2-4炔基、C 1-4烷基酰基、苯基酰基、苯基、C 5-6环烷基，或R 5和R 6连接形成饱和或不饱和的5或6元碳环或杂环基或含烷基取代的碳环或杂环基，其中R 5和R 6中所述烷基可被1-3个下列的取代基取代：羟基、卤素。 The application according to claim 1, wherein said R 5 and R 6 are independently selected from H, -OH, -NH 2 , C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxyacyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl acyl, phenyl acyl, phenyl, C 5-6 cycloalkyl, or R 5 and R 6 Linked to form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group, wherein the alkyl group in R 5 and R 6 may be substituted with 1-3 of the following Base substitution: hydroxyl, halogen.
  3. 如权利要求2所述的应用，其特征在于，The application of claim 2, wherein:
    R 5和R 6分别选自H、-OH、-NH 2、-COH、CH 3CO-、-CO-CH 2OH、-O-C(O)CH 2CH 3、-CH 2-C≡CH、-(CH 2) 5CH 3、-(CH 2) 4CF 3、环己基-、-CH 2-(CH 2) 3-CH 2-、-C(O)-CF 3、-C(O)-Ph、其中所述烷基被1-3个下列的取代基取代：羟基、卤素。 R 5 and R 6 are independently selected from H, -OH, -NH 2 , -COH, CH 3 CO-, -CO-CH 2 OH, -OC(O)CH 2 CH 3 , -CH 2 -C≡CH, -(CH 2 ) 5 CH 3 , -(CH 2 ) 4 CF 3 , cyclohexyl-, -CH 2 -(CH 2 ) 3 -CH 2 -, -C(O)-CF 3 , -C(O) -Ph, wherein the alkyl group is substituted with 1-3 of the following substituents: hydroxy, halogen.
  4. 如权利要求3所述的应用，其特征在于，所述的哈西奈德及其衍生物选自以下化合物：Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Pregn-4-ene-3,20-dione,21-hydroxy-；Androst-4-en-3-one,17-(1-oxopropoxy)-,(17β)-；Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-；Pregn-4-ene-3,20-dione,11,17,21-trihydroxy-, (11β)-；Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-；Pregna-1,4-diene-3,11,20-trione,17,21-dihydroxy-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α)-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-；Pregna-1,4-diene-3,20-dione,9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-；Androst-4-en-3-one；Androst-4-en-3-one,17-methylene-；Androst-4-ene-3,17-dione；Androst-4-ene-3,16-dione；Androst-4-en-3-one,17-hydroxy-,(17α)-；Androst-4-ene-3,11-dione；Androst-4-en-3-one,17β-amino-；Androst-4-en-3-one,17-chloro-,(17α)-；Androst-4-ene-3,11,16-trione；Pregn-4-en-20-yn-3-one,(17α)-。The application according to claim 3, characterized in that, the hacinide and its derivatives are selected from the following compounds: Pregn-4-ene-3,20-dione,21-chloro-9-fluoro-11- hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-; Pregn-4-ene-3,20-dione,21-hydroxy-; Androst-4-en-3 -one,17-(1-oxopropoxy)-,(17β)-; Pregn-4-ene-3,11,20-trione,17,21-dihydroxy-; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11β)-; Pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-,(11β)-; Pregna-1,4-diene- 3,11,20-trione,17,21-dihydroxy-; Pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-,(11β,16α )-; Pregna-1,4-diene-3,20-dione,9-fluoro-11,16,17,21-tetrahydroxy-,(11β,16α)-;Pregna-1,4-diene-3,20 -dione,9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(11β,16α)-;Androst-4-en-3-one;Androst-4 -en-3-one,17-methylene-;Androst-4-ene-3,17-dione;Androst-4-ene-3,16-dione;Androst-4-en-3-one,17-hydroxy- ,(17α)-;Androst-4-ene-3,11-dione;Androst-4-en-3-one,17β-amino-;Androst-4-en-3-one,17-chloro-,(17α )-; Androst-4-ene-3,11,16-trione; Pregn-4-en-20-yn-3-one,(17α)-.
  5. 如权利要求1-4任一项所述的应用，其特征在于，所述的脑血管疾病为脑卒中、脑缺血、脑梗塞。The application according to any one of claims 1-4, wherein the cerebrovascular disease is stroke, cerebral ischemia, and cerebral infarction.
  6. 如权利要求5所述的应用，其特征在于，所述的脑卒中包括出血性脑卒中和/缺血性脑卒中。The application of claim 5, wherein the stroke includes hemorrhagic stroke and/or ischemic stroke.
  7. 如权利要求6所述的应用，其特征在于，所述的脑卒中为缺血性脑卒中。The application according to claim 6, wherein the stroke is ischemic stroke.
  8. 哈西奈德及其衍生物用于制备治疗和/或预防神经功能损伤药物中的应用。The application of hacinide and its derivatives in the preparation of medicines for treating and/or preventing nerve function damage.
  9. 哈西奈德及其衍生物用于制备治疗和/或预防脑缺血再灌注损伤药物中的应用。The application of hacinide and its derivatives in the preparation of medicaments for treating and/or preventing cerebral ischemia-reperfusion injury.
  10. 如权利要求1-4任一项所述的应用，其特征在于，所述的哈西奈德及其衍生物可以为散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂。The application according to any one of claims 1-4, wherein the hacinide and its derivatives can be powders, tablets, granules, capsules, solutions, emulsions, suspensions, injection.
PCT/CN2021/082818 2021-03-24 2021-03-24 Application of halcinonide and derivatives thereof for preparing drug treating and/or preventing cerebrovascular disease WO2022204827A1 (en)

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