WO2020062780A1 - 防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用 - Google Patents

防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用 Download PDF

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WO2020062780A1
WO2020062780A1 PCT/CN2019/076751 CN2019076751W WO2020062780A1 WO 2020062780 A1 WO2020062780 A1 WO 2020062780A1 CN 2019076751 W CN2019076751 W CN 2019076751W WO 2020062780 A1 WO2020062780 A1 WO 2020062780A1
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ischemic
acyl
structural formula
thrombosis
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钟诗龙
马红坤
张姗姗
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百迈康生物医药科技(广州)有限公司
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • 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

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  • the invention relates to the field of pharmaceutical technology, in particular to a medicament for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis and its application.
  • Ischemic heart disease also known as coronary heart disease, includes atherosclerotic lesions of coronary arteries that cause narrowing or obstruction of the lumen of the blood vessels and cause heart disease caused by myocardial ischemia, hypoxia or necrosis.
  • Ischemic encephalopathy refers to stenosis or occlusion of cerebral blood vessels, resulting in blockage of cerebral blood flow and cerebral ischemia, hypoxia, softening and even necrosis, resulting in cerebral vascular dysfunction and related symptoms. Ischemic encephalopathy includes ischemic stroke, cerebral thrombosis, cerebral embolism, lacunar ischemic stroke, multiple ischemic stroke, and minor stroke.
  • indole-3-methanol (INDOLE-3-CARBINOL; INDOLE-3-METHANOL; I3C) is relatively high in most cruciferous vegetables, which can be obtained from cruciferous vegetables (such as broccoli, radish and broccoli, etc.) ).
  • Indole-3-methanol has a variety of promising biological properties, and has anti-cancer, antioxidant and anti-inflammatory activities. Previous studies have shown that indole-3-methanol can inhibit the occurrence and development of head and neck cancer, skin cancer, liver cancer, breast cancer and other tumors. Since indole-3-methanol is derived from food, it has almost no side effects and has great development prospects.
  • the purpose of the present invention is to provide medicines and applications for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis, so as to solve the problems mentioned in the background art.
  • the present invention provides the following technical solutions:
  • a drug for preventing or treating ischemic heart disease or ischemic encephalopathy or thrombosis comprising indole-3-methanol and its derivative, or diindolemethane and its derivative.
  • indole-3-methanol having the following structural formula (I) and derivatives thereof in the preparation of a medicine for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis,
  • R1, R2, R4, R5, R6, and R7 are respectively H, phenyl, benzoyl, Cl-C1O acyl, halogen substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy One.
  • R1 is one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group, and R2, R4, R5, R6, and R7 are all hydrogen.
  • R5 is one of a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, a Cl-C1O alkyl group, and a Cl-C1O acyl group; R1, R2, R4, R6, R7 Both are hydrogen.
  • R1 is one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group
  • R5 is a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, a Cl-C1O alkyl group
  • One of Cl-C1O alkoxy and Cl-C1O acyl, R2, R4, R6, and R7 are all hydrogen.
  • R1 is one of phenyl, benzoyl, halogen substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, and Cl-C1O acyl
  • R5 It is one of a hydroxyl group, a methoxy group, and a Cl-C1O acyl group
  • R2, R4, R6, and R7 are all hydrogen.
  • diindolemethane and its derivative having the following structural formula (II) in the preparation of a medicine for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis,
  • Rl, R2, R4, R5, R6, R7, Rl ', R2', R4 ', R5', R6 ', R7' are H, phenyl, benzoyl, halogen substituent, nitro, Cl -C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl.
  • R1 and R1 ' are one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group, and R2, R4, R5, R6, R7, R2', R4 ', R5' , R6 'and R7' are all hydrogen.
  • R5 and R5 ′ are one of a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, a Cl-C1O alkyl group, and a Cl-C1O acyl group, R1, R2, and R4. , R6, R7, R1 ', R2', R4 ', R6', R7 'are all hydrogen.
  • R1 and R1 ′ are one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group
  • R5 and R5 ′ are a hydroxyl group, a methoxy group, a halogen substituent, a nitro group
  • One of Cl-C1O alkyl, Cl-C1O alkoxy, and Cl-C1O acyl, R2, R4, R6, R7, R2 ', R4', R6 ', and R7' are all hydrogen.
  • R1 and R1 ′ are one of phenyl, benzoyl, halogen substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, and Cl-C1O acyl R5 and R5 'are hydroxy, methoxy, Cl-C1O acyl, R2, R4, R6, R7, R2', R4 ', R6', R7 'are all hydrogen.
  • the present invention conducted an experiment on the effect of indole-3-methanol on the survival rate of myocardial cells damaged by ischemia and hypoxia, and the results show that indole-3-methanol can increase the survival rate of myocardial cells damaged by ischemia and hypoxia
  • the ROS value (intracellular active oxygen level) of ischemic hypoxic myocardial cells can significantly increase the total SOD activity and inhibit active oxygen-induced lipid peroxidation, indicating that indole-3-methanol can prevent myocardial injury heart disease.
  • the in vitro myocardial cell culture experiment of the present invention shows that indole-3-methanol can improve the survival rate of myocardial cells damaged by ischemia and hypoxia; increase the level of reactive oxygen species (ROS) and the activity of superoxide dismutase (SOD) ; Inhibit lipid peroxidation.
  • ROS reactive oxygen species
  • SOD superoxide dismutase
  • the B-ultrasonic examination of the small animal heart revealed differences in left ventricular systolic function between the experimental animal groups; indole-3-methanol significantly improved the cardiac function of the ischemic myocardial rat model;
  • the negative control group significantly increased the ratio of heart to body weight.
  • I3-C 20mg / kg and I3-C 50mg / kg significantly reduced the increase in the ratio of heart to body weight caused by ISO.
  • the SD rats were administered with gastric prophylaxis for 7 consecutive days.
  • the number of dead rats in the I3C low-dose group (20mg / kg) and the I3C high-dose group (50mg / kg) was significantly less than the model group (P ⁇ 0.05).
  • the results showed that I3C was in the low-dose (20mg / kg) and I3C high-dose ( 50mg / kg) have the effect of preventing death risk.
  • the I3C can be used as a therapeutic drug to treat atherosclerosis.
  • the present invention studies the pharmacological effects of indole-3-methanol in the treatment of ischemic encephalopathy in rat models, and the results show that the indole-3-methanol can be used as a therapeutic drug to treat ischemia such as cerebral infarction Encephalopathy.
  • the present invention investigated the effect of indole-3-methanol on adenosine diphosphate (ADP) -induced platelet aggregation in human platelet-rich plasma (PRP) in vitro, and found that I3C can inhibit ADP in human PRP in a dose-dependent manner Induced platelet aggregation.
  • the indole-3-methanol can inhibit platelet aggregation.
  • the indole-3-methanol has obvious protective effect on ischemic heart and brain tissues, and can prepare drugs for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis.
  • Figure 1 is the effect of I3C on the survival rate of myocardial cells injured by ischemia and hypoxia.
  • Figure 2 is the effect of I3C on the level of reactive oxygen species (ROS) in myocardial cells damaged by ischemia and hypoxia.
  • ROS reactive oxygen species
  • Figure 3 is the effect of I3C on the superoxide dismutase (SOD) in myocardial cells damaged by ischemia and hypoxia.
  • Figure 4 is the effect of I3C on myocardial lipid peroxidation induced by ischemia and hypoxia.
  • Figure 5 is the effect of I3C on death in ischemic myocardial model rats.
  • FIG. 6 is a cardiac function experiment of I3C improving ischemic myocardial rat model.
  • FIG. 7 is an I3C improvement cardiac function experiment in a rat model of ischemic myocardium.
  • LVFS left ventricular shortening fraction
  • FIG. 8 is a graph showing that I3C significantly reduces the heart weight / body weight ratio of a rat model of ischemic myocardium.
  • Figure 9 shows that I3C reduces infarct volume after rat middle cerebral artery occlusion.
  • Figure 10 is the effect of I3C on ADP-induced platelet aggregation in human platelet-rich plasma.
  • indole-3-methanol having the following structural formula (I) and derivatives thereof in the preparation of a medicine for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis,
  • R1, R2, R4, R5, R6, and R7 are respectively H, phenyl, benzoyl, Cl-C1O acyl, halogen substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy One.
  • R1 is one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group, and R2, R4, R5, R6, and R7 are all hydrogen.
  • R5 is one of a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, a Cl-C1O alkyl group, and a Cl-C1O acyl group, and R1, R2, R4, R6, and R7 are all hydrogen. .
  • R1 is one of phenyl, benzoyl, and Cl-C1O acyl
  • R5 is hydroxyl, methoxy, halogen substituent, nitro, Cl-C1O alkyl, and Cl-C1O
  • R2, R4, R6, and R7 are all hydrogen.
  • R1 is one of a phenyl group, a benzoyl group, a halogen substituent, a nitro group, a Cl-C1O alkyl group, a Cl-C1O alkoxy group, and a Cl-C1O acyl group
  • R5 is a hydroxyl group
  • One of methoxy and Cl-C1O acyl, R2, R4, R6, and R7 are all hydrogen.
  • diindolemethane and its derivative having the following structural formula (II) in the preparation of a medicine for preventing and treating ischemic heart disease or ischemic encephalopathy or thrombosis,
  • Rl, R2, R4, R5, R6, R7, Rl ', R2', R4 ', R5', R6 ', R7' are H, phenyl, benzoyl, halogen substituent, nitro, Cl -C1O alkyl, Cl-C1O alkoxy, Cl-C1O acyl.
  • R1 and R1 ' are one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group, and R2, R4, R5, R6, R7, R2', R4 ', R5', R6 ' And R7 'are both hydrogen.
  • R5 and R5 ′ are one of a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, a Cl-C1O alkyl group, and a Cl-C1O acyl group, and R1, R2, R4, R6, R7, R1 ', R2', R4 ', R6', R7 'are all hydrogen.
  • R1 and R1 ′ are one of a phenyl group, a benzoyl group, and a Cl-C1O acyl group
  • R5 and R5 ′ are a hydroxyl group, a methoxy group, a halogen substituent, a nitro group, and a Cl-C1O
  • R2, R4, R6, R7, R2 ', R4', R6 ', R7' are all hydrogen.
  • R1 and R1 ′ are one of phenyl, benzoyl, halogen substituent, nitro, Cl-C1O alkyl, Cl-C1O alkoxy, and Cl-C1O acyl, R5 And R5 'are hydroxy, methoxy, Cl-C1O acyl, R2, R4, R6, R7, R2', R4 ', R6', R7 'are all hydrogen.
  • the medicament also includes a pharmaceutically acceptable carrier for indole-3-methanol and its derivatives.
  • the carrier includes a beverage or food.
  • the medicament of Examples 1-11 can be used to prepare a medicament for the prevention and treatment of ischemic heart disease or ischemic encephalopathy or thrombosis.
  • the ischemic heart disease includes: coronary atherosclerotic heart disease, thrombosis due to inflammation, Ischemic heart disease caused by stenosis or occlusion caused by embolism or injury;
  • the ischemic encephalopathy includes: cerebral infarction, ischemic stroke, cerebral thrombosis, cerebral embolism, lacunar ischemic stroke, Multiple ischemic stroke and minor stroke;
  • the thrombosis includes: venous thrombosis, thrombosis during extracorporeal circulation surgery, thrombosis during hemodialysis, and thrombosis during arrhythmia.
  • the study was divided into a negative control group, an ischemia and hypoxia model group (without drug intervention, 5% CO2 calming and ischemia and hypoxia for 6 hours), a low I3C (100nm / ml) group, and a medium I3C (200nm / ml) group. , I3C high-dose group (400nm / ml).
  • the negative control group was cultured in a common carbon dioxide incubator with DMEM / F-12 medium containing 10% fetal bovine serum.
  • the ischemia-hypoxia model group, I3C low-dose group, middle-dose group, and high-dose group were cultured in serum-free DMEM sugar-free medium.
  • the I3C low-dose group, middle-dose group, and high-dose group were treated with I3C at a concentration of 100nm / ml, 200nm / ml, and 400nm / ml, and then placed in an anaerobic bag, and the anaerobic bag was placed in a 37 ° C incubator. Incubate for 6 hours. Cells treated with ischemia and hypoxia were used for experimental detection.
  • the culture medium was changed to a DMEF / F-12 medium containing an appropriate amount of CCK-8 reagent. After incubation at 37 ° C for 2 hours, the absorbance was measured at 450 nm with a microplate reader to measure cell viability. The results are shown in Fig. 1.
  • the survival rate of the ischemia-hypoxia model group was significantly lower than that of the negative control group, and each concentration of indole-3-methanol significantly improved the cell survival rate.
  • the total SOD activity in the cells of the ischemia-hypoxia model group was significantly lower than that in the negative control group, while the total SOD activity in the cells of each concentration group of indole-3-methanol was significantly higher than that of the ischemia-hypoxia model group. (P ⁇ 0.05).
  • SD rats Sixty Sprague-Dawley (SD) rats were randomly divided into four groups of 12 each, including: saline control group, ischemic hypoxia model group, I3C low-dose group (20mg / kg), I3C high-dose Group (50mg / kg).
  • the I3C low-dose group (20mg / kg) and the I3C high-dose group (50mg / kg) were given I3C intragastrically for 7 days before isoproterenol (ISO) was used to prepare an ischemic myocardial rat model. Then, subcutaneous injection of ISO 5mg / kg / day, and I3C gavage at the same time, once a day for 7 days; I3C gavage alone for 15 days.
  • ISO isoproterenol
  • the rats in the normal saline control group were not subcutaneously injected with ISO, and were not given intragastrically with I3C.
  • Rats in the ischemia and hypoxia model group were injected subcutaneously with ISO 5 mg / kg / day for 7 days, and I3C was not administered to the stomach during the whole course.
  • the effects of I3C on the survival of rats in each group were observed, and the rats' B-ultrasound was performed before the rats were sacrificed. Finally, the rats were sacrificed, and the heart was taken and weighed to illustrate the condition of cardiac hypertrophy.
  • the remaining surviving rats underwent cardiac B-ultrasound examination at the end of the experiment, and the ejection fraction (LVEF) and left ventricular shortening fraction (LVFS) were used to evaluate the cardiac function level of the model rats.
  • the results are shown in Figure 6-7.
  • the LVEF and LVFS of the rats in the ischemic hypoxia model group the indole-3-methanol low and high dose groups were reduced to varying degrees (P ⁇ 0.05), indicating that ISO can damage the heart of rats Features.
  • the LVEF and LVFS of the indole-3-methanol low and high dose groups were increased.
  • Indole-3-methanol can improve cardiac function in rat models of ischemic myocardium: ISO action weakens rat heart function, I3C action can reduce this damage, and I3C concentration increases, and protective effect increases.
  • Left ventricular ejection fraction LVEF 55-80% Left ventricular shortening rate LVFS 30%.
  • the rats were sacrificed, and the rat hearts were quickly opened to remove the remaining blood in the heart cavity with normal saline.
  • the filter paper was blotted and the hearts were weighed.
  • the results are shown in Figure 8.
  • the ratio of heart to body weight in the ischemic hypoxia model group was significantly increased compared with the negative control group.
  • the I3-C20mg / kg and I3-C50mg / kg groups had significantly lower heart-to-body weight ratios than the ischemia-hypoxia model group, proving that I3C can significantly improve cardiac hypertrophy caused by subcutaneous injection of ISO.
  • indole-3-methanol can significantly improve cardiac function, reduce cardiac weight / weight ratio, and reduce mortality in ischemic myocardial rat models.
  • I3C was given orally by oral gavage 2 hours after ischemia or at reperfusion. Treatment continued once a day for 14 days. After the surgical incision, the rats in the sham operation group were cut through the middle cerebral artery but not ligated and closed.
  • the MCAO model group rats were orally administered with a solvent containing no I3C.
  • the I3C low-dose group, the I3C middle-dose group, and the I3C high-dose group were orally administered with I3C 10 mg / kg, 20 mg / kg, and 50 mg / kg, respectively, once a day for 14 days.
  • rats were euthanized, and brain tissue was collected for determination of infarct volume. Rat brains of each group were frozen at -20 ° C for 5 minutes and cut into 2 mm thick coronal sections.

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Abstract

本发明公开了防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用，所述药物包含吲哚-3-甲醇及其衍生物，或二吲哚甲烷及其衍生物；所述药物还包括其药学上可接受的载体，所述载体包括饮料或食物；所述药物可用于治疗和预防冠状动脉粥样硬化性心脏病，因炎症血栓、栓塞或损伤导致管腔狭窄或闭塞而引起的缺血心脏病，血栓形成、以及脑梗，缺血性脑中风，脑血栓，脑栓塞，腔隙性缺血性脑中风，多发性缺血性脑中风及小中风。

Description

防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用 技术领域
本发明涉及制药技术领域，具体是一种防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用。
背景技术
近年来，随着社会经济发展、饮食习惯及环境的改变、生活节奏的加剧以及人口老龄化进程的加速，全世界范围内心脑血管疾病，冠心病和脑中风的发病率和死亡率呈现出逐年上升的趋势。根据《中国心血管病报告2016》推算冠状动脉粥样硬化性心脏病患病人数达到1100万。缺血性心脏病，亦称冠心病，包括冠状动脉血管发生动脉粥样硬化病变而引起血管腔狭窄或阻塞，造成心肌缺血、缺氧或坏死而导致的心脏病。其他疾病包括炎症、栓塞等也可导致管腔狭窄或闭塞，而引起缺血心肌病。缺血性脑病指脑血管狭窄或闭塞，导致脑血流阻断而使脑组织发生缺血缺氧、软化甚至坏死，致使脑血管功能障碍，引起相关症状。缺血性脑病包括缺血性脑中风、脑血栓、脑栓塞、腔隙性缺血性脑中风和多发性缺血性脑中风及小中风。
尽管目前在治疗策略和手段上已经取得了很大的进步，缺血性心脏病或缺血性脑病患者的预后仍然比较差。因此寻找新的能够防治血栓形成、减少缺血缺氧心肌细胞或脑细胞死亡，从而减少心肌梗死面积和脑梗面积的药物具有重要临床意义。
吲哚-3-甲醇(INDOLE-3-CARBINOL；INDOLE-3-METHANOL；I3C)在大多数十字花科蔬菜中的含量相对较高，可从十字花科蔬菜(如西兰花、萝卜和花椰菜等)中提取而得。吲哚-3-甲醇具有多种有前途的生物学特性，具有抗癌、抗氧化和抗炎活性。以往研究表明吲哚-3-甲醇能够抑制头颈部癌、皮肤癌、肝癌、乳腺癌等多种肿瘤的发生和发展。由于吲哚-3-甲醇来源于食物，几乎无副作用，具有极大的发展前途。
目前尚未见有关用吲哚-3-甲醇在防治缺血性心脏病或缺血性脑病中应用的报道。
发明内容
本发明的目的在于提供防治缺血性心脏病或缺血性脑病或血栓形成的药物及应用，以解决上述背景技术中提出的问题。
为实现上述目的，本发明提供如下技术方案：
防治缺血性心脏病或缺血性脑病或血栓形成的药物，所述药物包含吲哚-3-甲醇及其 衍生物，或二吲哚甲烷及其衍生物。
一种具有下述结构式(I)的吲哚-3-甲醇及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
Figure PCTCN2019076751-appb-000001
其中，Rl、R2、R4、R5、R6、R7分别为H、苯基、苯甲酰基、Cl-C1O酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基中的一种。
进一步的，所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7均为氢。
进一步的，所述结构式(I)中，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7均为氢。
进一步的，所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
进一步的，所述结构式(I)中，R1为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
一种具有下述结构式(II)的二吲哚甲烷及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
Figure PCTCN2019076751-appb-000002
其中，Rl、R2、R4、R5、R6、R7、Rl’、R2’、R4’、R5’、R6’、R7’分别为H、苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种。
进一步的，所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7、R2’、R4’、R5’、R6’、R7’均为氢。
进一步的，所述结构式(II)中，R5和R5’同时为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7、Rl’、R2’、R4’、R6’、R7’均为氢。
进一步的，所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
进一步的，所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、Cl-C1O酰基，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
与现有技术相比，本发明的有益效果是：
1)本发明进行了吲哚-3-甲醇对缺血缺氧损伤心肌细胞的存活率影响的实验，结果表明，吲哚-3-甲醇可提高缺血缺氧损伤心肌细胞的存活率，提高缺血缺氧心肌细胞的ROS值(细胞内活性氧的水平)，能够明显提高总SOD活力，抑制活性氧诱导的脂质过氧化，表明吲哚-3-甲醇可预防心肌损伤性心脏病。
2)本发明通过体外心肌细胞培养实验，结果显示，吲哚-3-甲醇可以提高缺血缺氧损 伤心肌细胞的存活率；提高活性氧(ROS)水平和超氧化物歧化酶(SOD)活性；抑制脂质过氧化作用。
3)本发明的实验中，小动物心脏B超检查发现实验动物各组之间左心收缩功能的差异；吲哚-3-甲醇显著提高缺血性心肌大鼠模型的心功能；模型组较阴性对照组明显增加心脏与体重的比值，I3-C 20mg/kg、I3-C 50mg/kg能明显降低ISO引起的心脏与体重的比值增加；连续7天给SD大鼠灌胃预防给药，I3C低剂量组(20mg/kg)和I3C高剂量组(50mg/kg)死亡大鼠数量显著少于模型组(P<0.05)，结果表明I3C在低剂量(20mg/kg)和I3C高剂量(50mg/kg)时均有防治死亡风险作用。所述的I3C可作为治疗药物应用于治疗动脉粥样硬化。
4)本发明研究了吲哚-3-甲醇在大鼠模型中治疗缺血性脑病的药理作用，结果显示，所述的吲哚-3-甲醇可作为治疗药物应用于治疗脑梗等缺血性脑病。
5)本发明研究了吲哚-3-甲醇对体外人富含血小板的血浆(PRP)中二磷酸腺苷(ADP)诱导的血小板聚集的影响，发现I3C可以剂量依赖性地抑制人PRP中ADP诱导的血小板聚集。所述的吲哚-3-甲醇可以抑制血小板聚集。
6)所述的吲哚-3-甲醇对缺血心脏和脑组织具有明显的保护作用，可制备防治缺血性心脏病或缺血性脑病或血栓形成的药物。
附图说明
图1是I3C对缺血缺氧损伤心肌细胞的存活率的影响。
图2是I3C对缺血缺氧损伤心肌细胞内活性氧(ROS)水平的影响。
图3是I3C对缺血缺氧损伤心肌细胞内超氧化物歧化酶(SOD)的影响。
图4是I3C对缺血缺氧损伤心肌细胞内脂质过氧化的影响。
图5是I3C对缺血性心肌模型大鼠死亡的影响。
图6是I3C改善缺血性心肌大鼠模型的心功能实验，各实验组的大鼠左室射血分数(LVEF)的值。
图7是I3C改善缺血性心肌大鼠模型的心功能实验，各实验组的大鼠左室缩短分数(LVFS)的值。
图8是I3C显著降低缺血性心肌大鼠模型的心脏重量/体重比值。
图9是I3C减少大鼠大脑中动脉闭塞术后梗死体积。
图10是I3C对人富含血小板的血浆中ADP诱导的血小板聚集的影响。
具体实施方式
下面结合具体实施方式对本专利的技术方案作进一步详细地说明。
实施例1
一种具有下述结构式(I)的吲哚-3-甲醇及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
Figure PCTCN2019076751-appb-000003
其中，Rl、R2、R4、R5、R6、R7分别为H、苯基、苯甲酰基、Cl-C1O酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基中的一种。
实施例2
在实施例的基础上。所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7均为氢。
实施例3
在实施例1的基础上。所述结构式(I)中，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7均为氢。
实施例4
在实施例1的基础上。所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
实施例5
在实施例1的基础上。所述结构式(I)中，R1为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
实施例6
一种具有下述结构式(II)的二吲哚甲烷及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
Figure PCTCN2019076751-appb-000004
其中，Rl、R2、R4、R5、R6、R7、Rl’、R2’、R4’、R5’、R6’、R7’分别为H、苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种。
实施例7
在实施例6的基础上。所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7、R2’、R4’、R5’、R6’、R7’均为氢。
实施例8
在实施例6的基础上。所述结构式(II)中，R5和R5’同时为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7、Rl’、R2’、R4’、R6’、R7’均为氢。
实施例9
在实施例6的基础上。所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧 基、Cl-C1O酰基中的一种，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
实施例10
在实施例6的基础上。所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、Cl-C1O酰基，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
实施例11
在实施例1的基础上。所述药物还包括吲哚-3-甲醇及其衍生物药学上可接受的载体。所述载体包括饮料或食物。
实施例1-11的药物可用于制备防治缺血性心脏病或缺血性脑病或血栓形成的药物，所述的缺血性心脏病包括：冠状动脉粥样硬化性心脏病，因炎症血栓、栓塞或损伤导致管腔狭窄或闭塞而引起的缺血心脏病；所述的缺血性脑病包括：脑梗，缺血性脑中风，脑血栓，脑栓塞，腔隙性缺血性脑中风，多发性缺血性脑中风及小中风；所述的血栓形成包括：静脉血栓形成、体外循环手术时血栓形成、血液透析时血栓形成、心律失常时血栓形成。
实验例1吲哚-3-甲醇(I3C)提高细胞存活力实验
建立实验模型：取1-3日龄SD乳鼠，无菌条件取心脏，在PBS中清洗，剪碎，移入5ml含有15％的胰酶离心管，常温消化5分钟，同时用巴氏吸管轻轻吹打2-3分钟，每次消化后收集上清液，适量血清中止消化，重复6-8次，至无沉淀，4℃，1400转，离心10mn。收集细胞沉淀调节细胞密度为10 -6。用含有10％胎牛血清的DMEM/F-12培养基培养，第三天用于实验。研究分为阴性对照组、缺血缺氧模型组(不给予药物干预，5％CO2安宁包缺血缺氧6h)、I3C低剂量(100nm/ml)组、I3C中剂量(200nm/ml)组、I3C高剂量组(400nm/ml)。阴性对照组采用含有10％胎牛血清的DMEM/F-12培养基于普通二氧化碳培养箱培养。缺血缺氧模型组、I3C低剂量组、中剂量组、高剂量组采用无血清的DMEM无糖培养基培养。I3C低剂量组、中剂量组、高剂量组分别用浓度为100nm/ml、200nm/ml、400nm/ml的I3C处理细胞后，放在厌氧袋中，厌氧袋放在37℃的培养箱中培养6小时。缺血缺氧处理后的细胞用作实验检测。
细胞经过缺血缺氧处理后，将培养液换成含有适量CCK-8试剂的DMEF/F-12培养液。37℃接着培养2小时，用酶标仪在450nm检测吸光度，用作检测细胞存活力。结果如图1所示，缺血缺氧模型组存活率明显低于阴性对照组，吲哚-3-甲醇各浓度均能明显提高细胞存活率，单因素方差分析P<0.05。
实验例2吲哚-3-甲醇(I3C)提高缺血缺氧心肌细胞的ROS值(细胞内活性氧的水平)实验
按照实验例1中的方法采用建立实验模型。采用DCFH-DA荧光探针检测细胞内活性氧水平。原代心肌细胞种于96孔板，第三天心肌细胞密度达到80％左右。根据ROS试剂盒说明书，用荧光酶标仪检测细胞内活性氧水平，结果如图2所示，缺血缺氧模型组细胞内活性氧水平明显低于阴性对照组，吲哚-3-甲醇各浓度均能明显提高细胞内活性氧水平，单因素方差分析P<0.05。
实验例3吲哚-3-甲醇(I3C)提高SOD活性实验
按照实验例1中的方法采用建立实验模型。超氧化物歧化酶(SOD)对机体的氧化与抗氧化平衡起着至关重要的作用。此酶能清除超氧阴离子自由基，保护细胞免受损伤。采用黄嘌呤氧化酶法(羟胺法)测定SOD活力，每毫克组织蛋白在1ml反应液中抑制率达50％时所对应的SOD量为一个SOD活力单位(U)。结果如图3所示，缺血缺氧模型组细胞内总SOD活力明显低于阴性对照组，而吲哚-3-甲醇各浓度组细胞内总SOD活力较缺血缺氧模型组显著升高(P<0.05)。
实验例4吲哚-3-甲醇(I3C)抑制脂质过氧化实验
按照实验例1中的方法采用建立实验模型。机体通过酶系统与非酶系统产生氧自由基，后者能攻击生物膜中的多不饱和脂肪酸(PUFA)，引发脂质过氧化，并因此形成脂质过氧化物丙二醛(MDA)。MDA可与硫代巴比妥缩合，形成红色产物，在532nm处有最大吸收峰。结果如图4所示，缺血缺氧模型组细胞脂质过氧化明显高于阴性对照组，而吲哚-3-甲醇各浓度均能明显降低细胞内脂质过氧化水平(P<0.05)，表明吲哚-3-甲醇可抑制活性氧诱导的脂质过氧化。
实验例5吲哚-3-甲醇(I3C)显著提高缺血性心肌大鼠模型的心功能、降低心脏重量/体重比值和减少死亡率实验
将Sprague-Dawley(SD)大鼠60只，随机分为4组，每组12只，包括：生理盐水对照组，缺血缺氧模型组，I3C低剂量组(20mg/kg)，I3C高剂量组(50mg/kg)。I3C低剂量组(20mg/kg)、I3C高剂量组(50mg/kg)在异丙肾上腺素(ISO)制备缺血性心肌大鼠模型前，连续给予I3C灌胃给药7天，进行预防给药；然后皮下注射ISO 5mg/kg/天，同时灌胃I3C，每天进行一次，持续7天；再单独I3C灌胃给药15天。生理盐水对照组大鼠不进行皮下注射ISO，全程不给予I3C灌胃。缺血缺氧模型组大鼠皮下注射ISO 5mg/kg/天，持续7天，全程不给予I3C灌胃。观察I3C对各组大鼠生存的影响，最后处死大鼠前进行大鼠心脏B超检查。最后处死大鼠，留取心脏，进行心脏称重，用于说明心脏肥厚情况。
大鼠在行心脏B超检查前，对照组，缺血缺氧模型组，I3C低剂量组(20mg/kg)和I3C高剂量组(50mg/kg)大鼠分别死亡0只、8只、4只和2只。卡方精确概率检验显示I3C低剂量组(20mg/kg)和I3C高剂量组(50mg/kg)死亡大鼠数量均显著少于缺血缺氧模型组(P<0.05)。结果见图5，I3C在低剂量(20mg/kg)和I3C高剂量(50mg/kg)时均有防治死亡风险作用。
其余存活大鼠在实验结束后行心脏B超检查，用射血分数(LVEF)和左室缩短分数(LVFS)评估模型大鼠心功能水平。结果见图6-7。与阴性对照组比较，缺血缺氧模型组、吲哚-3-甲醇低、高剂量组大鼠的LVEF和LVFS均有不同程度的减小(P<0.05)，表明ISO可损害大鼠心功能。与缺血缺氧模型组相比，吲哚-3-甲醇低、高剂量组大鼠的LVEF和LVFS均有增加。吲哚-3-甲醇能改善缺血性心肌大鼠模型的心功能：ISO作用使大鼠心功能减弱，I3C作用能减弱这种损伤，并且I3C浓度增加，保护作用增大。左室射血分数LVEF 55-80％左室缩短率LVFS 30％左右。
完成心脏B超检查后，处死大鼠，迅速开胸取出大鼠心脏，用生理盐水冲洗尽心腔剩余血液，滤纸吸干后心脏称重。结果见图8，缺血缺氧模型组大鼠心脏与体重的比值较阴性对照组明显增加。I3-C20mg/kg、I3-C50mg/kg组大鼠心脏与体重的比值较缺血缺氧模型组明显减小，证明I3C能够明显改善皮下注射ISO引起的心脏肥厚。
上述结果表明，吲哚-3-甲醇能显著提高缺血性心肌大鼠模型的心功能、降低心脏重量/体重比值和减少死亡率。
实验例6吲哚-3-甲醇(I3C)减少大鼠大脑中动脉闭塞术后梗死体积实验
将雄性SD大鼠分成5组(每组6只)，分别是假手术组(生理盐水)，模型组，I3C 低剂量组(10mg/kg)，I3C中剂量组(20mg/kg)，I3C高剂量组(50mg/kg)。用腔内缝线闭塞法封闭右侧大脑中动脉制备大鼠大脑中动脉闭塞(MCAO)模型。在局部缺血2小时后或在再灌注时通过口服强饲法口服给予I3C。治疗持续每天一次，持续14天。假手术组大鼠在手术切开后，大脑中动脉过线但不结扎封闭，切口缝合后，正常饮食，全程不给予I3C。MCAO模型组大鼠口服强饲法口服给予不含I3C的溶剂。I3C低剂量组、I3C中剂量组和I3C高剂量组分别口服强饲法口服给予I3C 10mg/kg、20mg/kg和50mg/kg治疗，每天一次，持续14天。最后一次给药1小时后，对大鼠实施安乐死，并收集脑组织，用于测定梗塞体积。将每组的大鼠脑在-20℃下冷冻5分钟并切成2mm厚的冠状切片。将切片在37℃下在磷酸盐缓冲盐水(PBS，pH 7.4)中的2％三苯基四唑氯化物(TTC)溶液中温育20分钟。捕获这些切片的彩色图像，并使用合适的软件计算梗塞的大小。结果见图9，假手术组无脑梗塞，模型组脑梗塞体积达30％，显著高于假手术组(P<0.05)；与模型组相比较，三个I3C剂量组(10、20和50mg/kg)均显著减少与MCAO大鼠梗塞体积(P<0.05)。
实验例7吲哚-3-甲醇(I3C)剂量依赖性地抑制血小板聚集实验
取健康志愿者血液到含有1000U肝素钠/ml(0.9％盐水)溶液的塑料注射器中。先4℃下1200rpm离心5分钟，取血浆，然后在1600rpm离心10分钟，获得含血小板的血浆(PRP)。I3C低剂量组(1μM)，I3C中剂量组(10μM)，I3C高剂量组(50μM)分别在500μlPRP中加入浓度为1μM、10μM、50μM的I3C，搅拌混匀，空白对照加不含I3C的溶剂。5分钟后，各组在1200rpm下搅拌，并向血小板中加入10μM ADP，刺激后检测5分钟光透射的变化。结果见图10，与空白对照相比，I3C剂量依赖性地抑制人PRP中ADP诱导的血小板聚集(P<0.05)。
上面对本专利的较佳实施方式作了详细说明，但是本专利并不限于上述实施方式，在本领域的普通技术人员所具备的知识范围内，还可以在不脱离本专利宗旨的前提下作出各种变化。

Claims (11)

  1. 防治缺血性心脏病或缺血性脑病或血栓形成的药物，其特征在于，所述药物包含吲哚-3-甲醇及其衍生物，或二吲哚甲烷及其衍生物。
  2. 一种具有下述结构式(I)的吲哚-3-甲醇及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
    Figure PCTCN2019076751-appb-100001
    其中，Rl、R2、R4、R5、R6、R7分别为H、苯基、苯甲酰基、Cl-C1O酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基中的一种。
  3. 根据权利要求2所述的应用，其特征在于：所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7均为氢。
  4. 根据权利要求2所述的应用，其特征在于：所述结构式(I)中，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7均为氢。
  5. 根据权利要求2所述的应用，其特征在于：所述结构式(I)中，R1为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
  6. 根据权利要求2所述的应用，其特征在于：所述结构式(I)中，R1为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5为羟基、甲氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7均为氢。
  7. 一种具有下述结构式(II)的二吲哚甲烷及其衍生物在制备防治缺血性心脏病或缺血性脑病或血栓形成药物中的应用，
    Figure PCTCN2019076751-appb-100002
    其中，Rl、R2、R4、R5、R6、R7、Rl’、R2’、R4’、R5’、R6’、R7’分别为H、苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种。
  8. 根据权利要求7所述的应用，其特征在于：所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R2、R4、R5、R6、R7、R2’、R4’、R5’、R6’、R7’均为氢。
  9. 根据权利要求7所述的应用，其特征在于：所述结构式(II)中，R5和R5’同时为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O酰基中的一种，R1、R2、R4、R6、R7、Rl’、R2’、R4’、R6’、R7’均为氢。
  10. 根据权利要求7所述的应用，其特征在于：所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
  11. 根据权利要求7所述的应用，其特征在于：所述结构式(II)中，R1和Rl’为苯基、苯甲酰基、卤素取代基、硝基、Cl-C1O烷基、Cl-C1O烷氧基、Cl-C1O酰基中的一种，R5和R5’为羟基、甲氧基、Cl-C1O酰基，R2、R4、R6、R7、R2’、R4’、R6’、R7’均为氢。
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