WO2018145364A1 - 3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用 - Google Patents

3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用 Download PDF

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WO2018145364A1
WO2018145364A1 PCT/CN2017/082826 CN2017082826W WO2018145364A1 WO 2018145364 A1 WO2018145364 A1 WO 2018145364A1 CN 2017082826 W CN2017082826 W CN 2017082826W WO 2018145364 A1 WO2018145364 A1 WO 2018145364A1
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trihydroxyisoflavone
methoxy
platelet aggregation
μmol
daidzein
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PCT/CN2017/082826
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English (en)
French (fr)
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赖仞
申传斌
吕秋敏
刘明
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中国科学院昆明动物研究所
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Priority to US16/325,595 priority Critical patent/US20190183851A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—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 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

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  • the invention belongs to the field of biomedicine, and particularly relates to the application of 3,4,7-trihydroxyisoflavone or 3-methoxyglycin in the preparation of a medicament for inhibiting platelet aggregation and thrombosis.
  • a thrombus is a small coagulation plaque formed by the bloodstream at the surface of the endovascular surface of the cardiovascular system or at the site of repair.
  • thrombus is the final product of the cascade of coagulation systems. It consists mainly of deposited platelets, insoluble fibrin, accumulated white blood cells and red blood cells. Platelet aggregation is one of the initial steps in the hemostasis process and one of the important factors in thrombosis.
  • the formation of blood clots in blood vessels can impede the flow of blood flow, and even lead to complete occlusion of blood vessels.
  • the exfoliation and detachment of blood vessels from the inner wall of blood vessels can easily form a migratory embolism.
  • the cardiovascular and cerebrovascular diseases caused by this include myocardial infarction, cerebral thrombosis, arterial thromboembolism and venous thromboembolism.
  • the formation of thrombotic diseases is a multi-factor change process in which genetic and environmental factors interact and interact. Its pathogenesis is diverse, and it is often repetitive.
  • the comprehensive incidence rate is the highest among various diseases. In recent years, the incidence rate has gradually increased, and the onset time is younger, which is a serious threat to human health. It is a contemporary medical research and drug research and development. One of the highlights and hot spots.
  • the drugs used for the prevention and treatment of thrombotic diseases are mainly anticoagulant drugs, thrombolytic drugs and anti-platelet aggregation drugs, but common antithrombotic drugs such as aspirin and clopidogrel often produce pharmacodynamic effects. Side effects such as weakening, gastrointestinal irritation and neutropenia, in addition, aspirin, clopidogrel and other drugs can also increase the risk of bleeding, which seriously affects the clinical use and life of patients.
  • an object of the present invention is to provide an application of 3,4,7-trihydroxyisoflavone or 3-methoxyglycin in inhibiting platelet aggregation, which can reduce the risk of bleeding, safely use, and expand Clinical and medical use.
  • the present invention provides the following technical solutions:
  • the present invention provides the use of 3,4,7-trihydroxyisoflavone or 3-methoxysuccinone for the preparation of a medicament for inhibiting platelet aggregation, wherein the 3,4,7-trihydroxyisoflavone has the formula I Structure 3-methoxy soyin has the structure shown in formula II:
  • the platelet aggregation is induced by collagen and adenosine diphosphate.
  • the dosage form of the medicament is an oral dose.
  • the 3,4,7-trihydroxyisoflavone is administered in a dose of ⁇ 10 ⁇ mol/kg according to patients of different body weights.
  • the 3-methoxy daidin is administered in a dose of ⁇ 100 ⁇ mol/kg according to patients of different body weights.
  • the present invention provides the use of 3,4,7-trihydroxyisoflavone and 3-methoxysulphonin for the preparation of a medicament for preventing and/or treating thrombosis; the 3,4,7-trihydroxyisoflavone and 3
  • the structural formula of methoxysuccinim is as described in the application.
  • the thrombus is caused by platelet aggregation.
  • the dosage form of the medicament is an oral dose.
  • the 3,4,7-trihydroxyisoflavone is administered in a dose of ⁇ 100 ⁇ mol/kg according to patients of different body weights.
  • the 3-methoxy daidin is administered in a dose of ⁇ 300 ⁇ mol/kg according to patients of different body weights.
  • the present invention provides the use of 3,4,7-trihydroxyisoflavone or 3-methoxysuccinone for the preparation of a medicament for inhibiting platelet aggregation, wherein the 3,4,7-trihydroxyisoflavone has the formula I Structure, the 3-methoxyglycin has the structure shown in Formula II.
  • the 3,4,7-trihydroxyisoflavone or 3-methoxysuccinone has a significant inhibitory effect on platelet aggregation, and the example bleeding test shows that 3,4,7-trihydroxyisoflavone and 3-methyl None of the mice administered with oxydionin showed significant hemorrhagic activity, while the same concentration of clopidogrel in the control group had very significant hemorrhagic activity, indicating that the present invention provides 3,4,7-trihydroxyl.
  • Application of isoflavones or 3-methoxysuccinin in inhibiting platelet aggregation which can reduce the risk of bleeding, safe use, expand clinical and medical Drug use.
  • Figure 1 is a graph showing the inhibitory effect of 3,4,7-trihydroxyisoflavone in collagen-induced platelet aggregation in Example 1;
  • Example 2 is a graph showing the inhibitory effect of 3-methoxyglycinin in collagen-induced platelet aggregation in Example 1;
  • Figure 3 is a graph showing the inhibitory effect of 3,4,7-trihydroxyisoflavone on ADP-induced rat tail thrombus in Example 1;
  • Figure 4 is a graph showing the inhibitory effect of 3-methoxyglycinin in Example 1 on ADP-induced rat tail thrombosis;
  • Figure 5 is a graph showing the inhibition of carrageenan-induced rat tail thrombus by 3,4,7-trihydroxyisoflavone and 3-methoxysuccinide in Example 2;
  • Figure 6 is a graph showing changes in the inhibition of carrageenan-induced rat tail thrombus by the use of 3,4,7-trihydroxyisoflavone in Example 2;
  • Figure 7 is a graph showing changes in the inhibition of carrageenan-induced rat tail thrombus in Example 2.
  • Figure 8 is a graph showing the effect of 80 mg/kg 3,4,7-trihydroxyisoflavone and clopidogrel on tail bleeding time in mice in Example 3;
  • Figure 9 is a graph showing the effect of 80 mg/kg 3-methoxy daidin and clopidogrel on tail bleeding time in mice in Example 3.
  • the present invention provides the use of 3,4,7-trihydroxyisoflavone or 3-methoxysuccinone for the preparation of a medicament for inhibiting platelet aggregation, wherein the 3,4,7-trihydroxyisoflavone has the formula I Structure, the 3-methoxyglycin has the structure shown in Formula II:
  • the platelet aggregation is preferably induced by collagen and adenosine diphosphate.
  • the collagen and adenosine diphosphate induction mechanism is such that the two compounds inhibit the binding of platelets to their platelet membrane receptors, thereby inhibiting platelet aggregation.
  • the collagen is preferably carrageenan or cross-dish gum.
  • the induced concentration of the collagen is preferably 0.5 to 0.8 ⁇ g/mL, and more preferably 0.6 ⁇ g/mL.
  • the adenosine diphosphate inducing concentration is preferably from 50 to 100 ⁇ mol/L, more preferably 70 ⁇ mol/L.
  • the dosage form of the drug is preferably an oral agent.
  • the 3,4,7-trihydroxyisoflavone is preferably used in a dose of ⁇ 10 ⁇ mol/kg for patients of different body weights; more preferably 20 ⁇ mol/kg to 100 ⁇ mol/kg, and most preferably 60 ⁇ mol/kg, that is, each patient
  • the molar dose of kilograms is ⁇ 10 ⁇ mol/kg, and the molar amount of the drug is determined according to patients of different qualities.
  • the source of the 3,4,7-trihydroxyisoflavone is not particularly limited, and a source of 3,4,7-trihydroxyisoflavone well known to those skilled in the art may be used.
  • the 3,4,7-trihydroxyisoflavone is purchased from Beijing Puyihua Technology Co., Ltd.
  • the 3-methoxy soyin is preferably used in a dose of ⁇ 100 ⁇ mol/kg, more preferably 120 ⁇ mol/kg to 300 ⁇ mol/kg, and most preferably 200 ⁇ mol/kg, which is administered per kilogram of the patient.
  • the molar amount is ⁇ 100 ⁇ mol/kg, and the molar amount of the drug is determined according to patients of different qualities.
  • the source of the 3-methoxyglycin is not particularly limited, and a source of 3-methoxysuccinone well known to those skilled in the art may be used.
  • the 3-methoxy soy is purchased from Beijing Puyihua Technology Co., Ltd.
  • the oral agent further includes a medically acceptable adjuvant.
  • the auxiliary materials include a solvent, a propellant, a solubilizer, a co-solvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, Flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, consumer Foaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retarders, and the like.
  • the oral administration agent is administered once a day, and 3 to 7 days is a course of treatment.
  • the present invention provides the use of 3,4,7-trihydroxyisoflavone and 3-methoxysulphonin for the preparation of a medicament for preventing and/or treating thrombosis; the 3,4,7-trihydroxyisoflavone and 3
  • the structural formula of methoxysuccinim is as described in the application.
  • the thrombus is preferably caused by aggregation of platelets.
  • the dosage form of the drug is preferably an oral agent.
  • the dose of the 3,4,7-trihydroxyisoflavone to patients of different body weights is preferably ⁇ 100 ⁇ mol/kg, more preferably 150 ⁇ mol/kg to 400 ⁇ mol/kg, and most preferably 250 ⁇ mol/kg, ie, per patient
  • the molar dose of kilograms is ⁇ 100 ⁇ mol/kg, and the molar amount of the drug is determined according to patients of different qualities.
  • the 3-methoxy soyin is preferably administered to a patient of different body weights of ⁇ 300 ⁇ mol/kg, more preferably 300 ⁇ mol/kg to 500 ⁇ mol/kg, and most preferably 400 ⁇ mol/kg, that is, the patient is administered per kilogram.
  • the molar amount is ⁇ 300 ⁇ mol/kg, and the molar amount of the drug is determined according to patients of different qualities.
  • the oral agent further includes a medically acceptable adjuvant.
  • the auxiliary materials include a solvent, a propellant, a solubilizer, a co-solvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, Flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, consumer One or more of a foaming agent, a thickener, an inclusion agent, a moisturizer, an absorbent, a diluent, a flocculating agent and a deflocculating agent, a filter aid, and a release retardant.
  • the invention also provides a preparation method of the oral agent, comprising the following mass percentage components: 5-20% active ingredient, 2-10% disintegrant, 0.2-2% lubricant, 0.1-1.5 % of the glidant and 0 to 0.5% of the additive, the balance being a mixture of fillers to prepare an oral preparation; the active ingredient is 3,4,7-trihydroxyisoflavone or 3-methoxy daidin.
  • the oral administration agent is administered once a day, and 3-7 days is a course of treatment.
  • Healthy human platelets were diluted with plasma to 2.5 x 10 8 /mL. Take 300 ⁇ L of plasma-rich platelets, add different concentrations of samples for 5 min at 37 ° C, add 70 ⁇ mol / L of ADP to induce aggregation, and plot the aggregation curve within 5 min on the platelet aggregation instrument. Platelet aggregation without sample treatment was used as a control.
  • Each 1.5mL EP tube is filled with 1.4mL platelets (concentrated platelet plasma), centrifuged at room temperature 400g for 5min, and the supernatant is discarded;
  • Flavone and 3'-methoxydaidzein inhibited aggregation of platelets induced by ADP in a gradient-dependent manner. 300 ⁇ M inhibits aggregation of about 50% of platelets, while 100 ⁇ M of 3,4,7-trihydroxyisoflavone inhibits aggregation of about 50% of platelets.
  • the first group was the saline control group, and the sample group was administered with 33, 100, 300 ⁇ mol/kg concentration of 3,4,7-trihydroxyisoflavone and 3-methoxy daidin respectively.
  • the positive control used 300 ⁇ mol/kg chloropyridin. Gray gavage.
  • carrageenan (carrageenan, type I, Sigma) was injected intraperitoneally from the mice at a dose of 40 mg/kg, due to the low temperature environment.
  • the thrombosis rate was >90% and the feeding temperature used was 18 °C.
  • the mean length of thrombus formation was determined after 24 h according to the color change of the tail skin.
  • the inhibition rate of thrombus by oral administration of 3,4,7-trihydroxyisoflavone and 3-methoxydextrin increased with increasing concentration.
  • oral administration of 300 ⁇ mol/kg 3-methoxysuccinin and 100 ⁇ mol/kg 3,4,7-trihydroxyisoflavone significantly inhibited the formation of rat tail thrombus, 300 ⁇ mol/kg 3,4,7
  • the mean thrombus length of the gynol isoxygen in the gavage group was lower than 300 ⁇ mol/kg clopidogrel in the gavage group (Fig. 5 to Fig. 7).
  • mice Male C57BL/6 (18-20g) was given in 8 groups. The test sample and the control group were administered by intragastric administration. After 3, 6 and 12 hours of administration, the mice were placed in a self-made special holder to make the tail. Pass through the trimmed 1mL pipette tip, cut off the tip of the tail with a sterile blade, immediately immerse the rat tail in physiological saline at 37 °C, and observe the stop time of the bleeding. .
  • the 3,4,7-trihydroxyisoflavone group showed no significant bleeding activity at various time points compared with the unadministered group, and the same concentration of chlorine was observed.
  • the pyridine-administered group had very significant hemorrhagic activity.
  • the 3-methoxydiprin group showed no significant bleeding activity at various time points compared with the unadministered group, and the same concentration of clopidogrel was given.
  • the drug group has very obvious bleeding activity.

Abstract

本发明提供了3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集的药物中的应用，所述3,4,7-三羟基异黄酮具有式Ⅰ所示结构，所述3-甲氧基大豆素具有式Ⅱ所示结构。所述3,4,7-三羟基异黄酮或3-甲氧基大豆素人对血小板聚集有明显的抑制作用，同时实施例出血实验表明，3,4,7-三羟基异黄酮和3-甲氧基大豆素给药的小鼠均没有表现出明显的出血活性，而对照组同样浓度的氯吡格雷给药组有非常明显的出血活性，这说明本发明提供3,4,7-三羟基异黄酮或3-甲氧基大豆素在抑制血小板聚集中的应用，所述药物的应用能够降低出血风险，使用安全，扩大临床和医药用途。

Description

3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用 技术领域
本发明属于生物医学领域，具体涉及3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用。
背景技术
血栓是血流在心血管系统血管内面剥落处或修补处的表面所形成的小凝血斑块。在凝血生理过程中，血栓是凝血系统级联反应的最终产物，它主要由沉积的血小板，不溶性纤维蛋白，积聚的白细胞和红细胞组成。血小板聚集是止血过程的起始步骤之一，也是血栓形成的重要因素之一。血管中血栓的形成会阻碍血流的流动，甚至导致血管的完全闭塞，血栓从血管内壁剥落和脱离容易形成游走型栓塞。由此引发的心脑血管疾病包括心肌梗死、脑血栓、动脉血栓栓塞和静脉血栓栓塞等。血栓疾病形成是由遗传和环境因素相互作用、相互影响的多因素变化过程。其发病形式多样，而且往往具有反复性，综合发病率高居各种疾病之首，近年来还有发病率逐渐增加，发病时间年轻化的趋势，严重威胁着人类健康，是当代医学研究和药物研发的重点和热点之一。
目前临床上用于预防和治疗血栓性疾病的药物主要有抗凝血类药物，溶血栓类药物和抗血小板聚集类药物，但是常见的抗血栓药物如阿司匹林、氯吡格雷等往往会产生药效减弱、肠胃刺激和粒细胞减少等副作用，另外，阿司匹林、氯吡格雷等药物还会造成出血风险增加，这严重影响临床使用和患者的生命健康。
发明内容
有鉴于此，本发明的目的在于提供3,4,7-三羟基异黄酮或3-甲氧基大豆素在抑制血小板聚集中的应用，所述药物的应用能够降低出血风险，使用安全，扩大临床和医药用途。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集的药物中的应用，所述3,4,7-三羟基异黄酮具有式Ⅰ所示结构，所 述3-甲氧基大豆素具有式Ⅱ所示结构：
Figure PCTCN2017082826-appb-000001
优选的，所述血小板聚集由胶原和二磷酸腺苷诱导产生。
优选的，所述药物的剂型为口服剂。
优选的，所述3,4,7-三羟基异黄酮按照不同体重的患者给药量≥10μmol/kg。
优选的，所述3-甲氧基大豆素按照不同体重的患者给药量≥100μmol/kg。
本发明提供了3,4,7-三羟基异黄酮及3-甲氧基大豆素在制备预防和/或治疗血栓的药物中的应用；所述3,4,7-三羟基异黄酮和3-甲氧基大豆素的结构式如所述应用中的结构。
优选的，所述血栓为由血小板聚集引起。
优选的，所述药物的剂型为口服剂。
优选的，所述3,4,7-三羟基异黄酮按照不同体重的患者给药量≥100μmol/kg。
优选的，所述3-甲氧基大豆素按照不同体重的患者给药量≥300μmol/kg。
本发明提供了3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集的药物中的应用，所述3,4,7-三羟基异黄酮具有式Ⅰ所示结构，所述3-甲氧基大豆素具有式Ⅱ所示结构。所述3,4,7-三羟基异黄酮或3-甲氧基大豆素人对血小板聚集有明显的抑制作用，同时实施例出血实验表明，3,4,7-三羟基异黄酮和3-甲氧基大豆素给药的小鼠均没有表现出明显的出血活性，而对照组同样浓度的氯吡格雷给药组有非常明显的出血活性，这说明本发明提供3,4,7-三羟基异黄酮或3-甲氧基大豆素在抑制血小板聚集中的应用，所述药物的应用能够降低出血风险，使用安全，扩大临床和医 药用途。
附图说明
图1为实施例1中3,4,7-三羟基异黄酮在胶原诱导的血小板聚集中的抑制作用；
图2为实施例1中3-甲氧基大豆素在胶原诱导的血小板聚集中的抑制作用；
图3为实施例1中3,4,7-三羟基异黄酮在对ADP诱导的鼠尾血栓的抑制作用；
图4为实施例1中3-甲氧基大豆素在对ADP诱导的鼠尾血栓的抑制作用；
图5为实施例2中3,4,7-三羟基异黄酮和3-甲氧基大豆素在对角叉菜胶诱导的鼠尾血栓的抑制图片；
图6为实施例2中3,4,7-三羟基异黄酮在对角叉菜胶诱导的鼠尾血栓的抑制的变化情况；
图7为实施例2中3-甲氧基大豆素在对角叉菜胶诱导的鼠尾血栓的抑制的变化情况；
图8为实施例3中80mg/kg 3,4,7-三羟基异黄酮和氯吡格雷对小鼠尾出血时间的影响；
图9为实施例3中80mg/kg 3-甲氧基大豆素和氯吡格雷对小鼠尾出血时间的影响。
具体实施方式
本发明提供了3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集的药物中的应用，所述3,4,7-三羟基异黄酮具有式Ⅰ所示结构，所述3-甲氧基大豆素具有式Ⅱ所示结构：
Figure PCTCN2017082826-appb-000002
Figure PCTCN2017082826-appb-000003
本发明中，所述血小板聚集优选由胶原和二磷酸腺苷诱导产生。所述胶原和二磷酸腺苷诱导机理是所述两种化合物抑制血小板与其血小板膜受体的结合，从而抑制血小板聚集。所述胶原优选为卡拉胶或交叉菜胶。所述胶原的诱导浓度优选为0.5～0.8μg/mL，更优选为0.6μg/mL。所述二磷酸腺苷诱导浓度优选为50～100μmol/L，更优选为70μmol/L。
本发明中，所述药物的剂型优选为口服剂。
本发明中，所述3,4,7-三羟基异黄酮对不同体重的患者用药量优选≥10μmol/kg；更优选为20μmol/kg～100μmol/kg，最优选为60μmol/kg，即患者每千克给药摩尔量≥10μmol/kg，根据不同质量的患者来确定用药的摩尔量。所述3,4,7-三羟基异黄酮的来源没有特殊限制，采用本领域技术人员所熟知的3,4,7-三羟基异黄酮的来源即可。本发明实施例中，所述3,4,7-三羟基异黄酮购于北京普益华科技有限公司。
本发明中，所述3-甲氧基大豆素对不同体重的患者用药量优选≥100μmol/kg，更优选为120μmol/kg～300μmol/kg，最优选为200μmol/kg，即患者每千克给药摩尔量≥100μmol/kg，根据不同质量的患者来确定用药的摩尔量。所述3-甲氧基大豆素的来源没有特殊限制，采用本领域技术人员所熟知的3-甲氧基大豆素的来源即可。本发明实施例中，所述3-甲氧基大豆素购于北京普益华科技有限公司。
本发明中，所述口服剂还包括医学上接受的辅料。所述辅料包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。
本发明中，所述口服剂的用药频率为每日一次，3～7d为一个疗程。
本发明提供了3,4,7-三羟基异黄酮及3-甲氧基大豆素在制备预防和/或治疗血栓的药物中的应用；所述3,4,7-三羟基异黄酮和3-甲氧基大豆素的结构式如所述应用中的结构。
本发明中，所述血栓为优选由血小板聚集引起。
本发明中，所述药物的剂型优选为口服剂。
本发明中，所述3,4,7-三羟基异黄酮对不同体重的患者用药量优选≥100μmol/kg，更优选为150μmol/kg～400μmol/kg，最优选为250μmol/kg，即患者每千克给药摩尔量≥100μmol/kg，根据不同质量的患者来确定用药的摩尔量。
本发明中，所述3-甲氧基大豆素对不同体重的患者用药量优选≥300μmol/kg，更优选为300μmol/kg～500μmol/kg，最优选为400μmol/kg，即患者每千克给药摩尔量≥300μmol/kg，根据不同质量的患者来确定用药的摩尔量。
本发明中，所述口服剂还包括医学上接受的辅料。所述辅料包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂和释放阻滞剂中的一种或多种。
本发明还提供了所述口服剂的制备方法，包括下列质量百分含量组分：5～20％的活性成分，2～10％的崩解剂，0.2～2％的润滑剂，0.1～1.5％的助流剂及0～0.5％的添加剂，余量为填充剂混合，制成口服剂；所述活性成分为3,4,7-三羟基异黄酮或3-甲氧基大豆素。
本发明中，所述口服剂的用药频率为每天一次，3-7天为一个疗程。
下面结合实施例对本发明提供的3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
健康人血小板用血浆稀释至2.5×108个/mL。取富血浆血小板300μL，加入不同浓度样品37℃保温5min后，添加70μmol/L的ADP诱导聚集，在血小板聚集仪上绘制5min内的聚集曲线。以没有样品处理过的血小板聚集为对照。
检测胶原诱导的血小板聚集使用洗涤的人血小板。如图1和图2所示， 3,4,7-三羟基异黄酮及其类似物以梯度依赖的方式抑制由0.6μg/mL胶原诱导的血小板的聚集。20μM的3-甲氧基大豆素能抑制约50％的血小板的聚集，而20μM的3,4,7-三羟基异黄酮能完全抑制的血小板的聚集。血小板洗涤方法如下：
a.每个1.5mLEP管装1.4mL血小板(浓缩血小板血浆)，室温400g离心5min，弃上清；
b.每管用0.5mL台式A液重悬血小板，把两管重悬的血小板合并到新的1.5mLEP管，混匀，400g室温离心5min；
c.每管用1mL台式A液重悬血小板，移到新的EP管中400g室温离心5min；
d.每管用1mL台式B液重悬血小板，并用台式B液调整血小板到适当的浓度。
Figure PCTCN2017082826-appb-000004
如图3和图4所示分别表示3,4,7-三羟基异黄酮(3’,4’,7-Trihydroxyiso
flavone)和3-甲氧基大豆素(3’-methoxydaidzein)以梯度依赖的形式抑制由ADP诱导的血小板的聚集。300μM的能抑制约50％的血小板的聚集，而100μM的3,4,7-三羟基异黄酮能抑制约50％的血小板的聚集。
实施例2
卡拉胶致鼠尾血栓模型
实验动物用雄性昆明小鼠，体重20-25g，饲养一周后，随机分组(n＝10)。第1组为生理盐水对照组，样品组分别使用33、100、300μmol/kg浓度3,4,7-三羟基异黄酮和3-甲氧基大豆素灌胃，阳性对照使用300μmol/kg氯吡格雷灌胃。灌胃给药处理30min后，以40mg/kg的剂量从小鼠腹腔注射卡拉胶(carrageenan，type I，Sigma)，由于在低温环境下， 血栓形成率>90％，所用饲养温度为18℃。24h后根据尾部皮肤颜色变化测定血栓形成的平均长度。口服3,4,7-三羟基异黄酮和3-甲氧基大豆素对血栓的抑制率随着浓度的增加变大。和阴性对照组相比，口服300μmol/kg3-甲氧基大豆素和100μmol/kg 3,4,7-三羟基异黄酮都能显著抑制鼠尾血栓的形成，其中300μmol/kg 3,4,7-三羟基异黄酮灌胃组平均血栓长度要低于300μmol/kg氯吡格雷灌胃组(图5～图7)。
实施例3
3,4,7-三羟基异黄酮和3-甲氧基大豆素的出血风险评估
雄性C57BL/6(18-20g)8只一组，测试样品及对照组通过灌胃给药，给药3、6、12小时后，将小鼠置于自制的专用固定器中，使其尾部穿过修剪后的1mL移液器枪头，用消毒保险刀片切去尾尖5mm，立即将鼠尾浸入37℃的生理盐水中，以血流停止时间为指标，观察记录断尾出血停止的时间。
结果如图8所示，在80mg/kg剂量时，3,4,7-三羟基异黄酮组与未给药组相比在各个时间点都没有表现出明显的出血活性，而同样浓度的氯吡格雷给药组有非常明显的出血活性。结果如图9所示，在80mg/kg剂量时，3-甲氧基大豆素组与未给药组相比在各个时间点都没有表现出明显的出血活性，而同样浓度的氯吡格雷给药组有非常明显的出血活性。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集的药物中的应用，所述3,4,7-三羟基异黄酮具有式Ⅰ所示结构，所述3-甲氧基大豆素具有式Ⅱ所示结构：
    Figure PCTCN2017082826-appb-100001
  2. 根据权利要求1所述的应用，其特征在于，所述血小板聚集由胶原和二磷酸腺苷诱导产生。
  3. 根据权利要求1或2所述的应用，其特征在于，所述药物的剂型为口服剂。
  4. 根据权利要求3所述的应用，其特征在于，所述3,4,7-三羟基异黄酮按照不同体重的患者给药量≥10μmol/kg。
  5. 根据权利要求3所述的应用，其特征在于，所述3-甲氧基大豆素按照不同体重的患者给药量≥100μmol/kg。
  6. 3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备预防和/或治疗血栓的药物中的应用；所述3,4,7-三羟基异黄酮和3-甲氧基大豆素的结构式如权利要求1所述应用中的结构。
  7. 根据权利要求6所述的应用，其特征在于，所述血栓为由血小板聚集引起。
  8. 根据权利要求6或7所述的应用，其特征在于，所述药物的剂型为口服剂。
  9. 根据权利要求8所述的应用，其特征在于，所述3,4,7-三羟基异黄酮按照不同体重的患者给药量≥100μmol/kg。
  10. 根据权利要求8所述的应用，其特征在于，所述3-甲氧基大豆素按照不同体重的患者给药量≥300μmol/kg。
PCT/CN2017/082826 2017-02-09 2017-05-03 3,4,7-三羟基异黄酮或3-甲氧基大豆素在制备抑制血小板聚集和血栓药物中的应用 WO2018145364A1 (zh)

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Publication number Priority date Publication date Assignee Title
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KR20120020904A (ko) * 2010-08-31 2012-03-08 (주)아모레퍼시픽 다이하이드로다이드제인을 포함하는 혈액 순환 개선용 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055072A1 (en) * 2001-01-16 2002-07-18 Novogen Research Pty Ltd Regulation of lipids and/or bone density and compositions therefor
KR20120020904A (ko) * 2010-08-31 2012-03-08 (주)아모레퍼시픽 다이하이드로다이드제인을 포함하는 혈액 순환 개선용 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WENWEN JIANG: "The effects of twelve representative flavonoids on tissue factor expression in human monocytes: Structure-activity relationships", THROMBOSIS - RESEARCH, vol. 124, no. 6, 14 July 2009 (2009-07-14), pages 714 - 720, XP026765647 *

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