Compound, pharmaceutical composition, and use thereof in preparation of drugs for treating cardiovascular and cerebrovascular diseases

Abstract

The present invention relates to the technical field of medicine, and discloses a compound, a pharmaceutical composition, and a use thereof in preparation of drugs for treating cardiovascular and cerebrovascular diseases. The present invention provides a flavonoid compound for treating cardiovascular and cerebrovascular diseases and a pharmaceutical composition thereof. The flavonoid compound can significantly reduce a cerebral infarction area of model group mice, and can be used for treating cardiovascular and cerebrovascular diseases.

Description

Compounds, pharmaceutical compositions and their use in the preparation of drugs for treating cardiovascular and cerebrovascular diseases Technical Field

[0001] This invention belongs to the field of pharmaceutical science, and more specifically, relates to compounds, pharmaceutical compositions and their use in the preparation of drugs for treating cardiovascular and cerebrovascular diseases. Background Technology

[0002] Cardiovascular and cerebrovascular diseases are a collective term for diseases of the heart and brain blood vessels. They are a group of diseases caused by insufficient blood supply due to blood vessel blockage, leading to tissue damage. These include myocardial infarction, chronic heart failure, coronary heart disease, ischemic stroke, peripheral arterial disease, deep vein thrombosis, and pulmonary embolism, and are the leading cause of death worldwide. Statistics show that approximately 17.9 million people died from cardiovascular and cerebrovascular diseases in 2016, accounting for 31% of all deaths globally. Of these, 85% died from heart disease and stroke.

[0003] Stroke, also known as cerebrovascular accident, is an acute cerebrovascular disease caused by the sudden rupture or blockage of blood vessels in the brain, leading to brain tissue damage. It includes ischemic and hemorrhagic strokes, with ischemic strokes accounting for 85% of cases. Current treatment strategies for ischemic stroke primarily focus on two aspects: first, improving cerebral blood circulation, including intravenous thrombolytic enzymes, arterial thrombectomy, and anticoagulation; and second, using neuroprotective agents such as edaravone (ED) and butylphthalide (NBP) to protect nerve tissue by scavenging free radicals and preventing oxidative damage. Despite these current treatment strategies, the mortality rate of ischemic stroke remains high, necessitating better treatment options. Only by rapidly restoring blood supply to the ischemic area can the neurological deficit after ischemia be minimized. While thrombolytic therapy can quickly restore blood supply to the ischemic area, its narrow time window and numerous contraindications significantly limit its clinical application. Therefore, promoting the establishment of collateral circulation and angiogenesis is crucial for the recovery of neurological function. Early collateral circulation in ischemic stroke depends on the opening of the original vascular network, which varies from person to person and is difficult to intervene in. Later collateral circulation establishment depends on angiogenesis. Angiogenesis helps blood flow bypass the blocked segment to reach brain tissue, improving blood perfusion in the ischemic area and reducing infarct size. It also promotes neuronal remodeling and functional recovery. Therefore, we are developing novel compounds based on mechanisms that promote angiogenesis. Summary of the Invention

[0004] This invention provides a novel compound that, by promoting angiogenesis, improves blood perfusion in ischemic areas, and reduces infarct size, thereby achieving the goal of preventing or treating cardiovascular or cerebrovascular diseases, especially ischemic stroke. Based on this:

[0005] One of the objectives of this invention is to provide new compounds that have preventive or therapeutic effects on cardiovascular or cerebrovascular diseases, especially stroke.

[0006] A second objective of this invention is to provide the use of the compound in the prevention or treatment of cardiovascular or cerebrovascular diseases, particularly stroke.

[0007] A third objective of this invention is to provide a pharmaceutical composition containing the above-mentioned compounds that has a preventive or therapeutic effect on cardiovascular or cerebrovascular diseases, especially stroke.

[0008] The fourth objective of this invention is to provide the use of the above-mentioned pharmaceutical composition in the prevention or treatment of cardiovascular or cerebrovascular diseases, especially stroke;

[0009] Based on the above objectives, the core problem that this invention aims to solve is: addressing the unsatisfactory effects of existing drug treatments.

[0010] [1. Compound of Formula I]

[0011] The first aspect of this invention provides a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, with the following structure:

[0012] In the formula: R1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino;

[0013] R2 and R3 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, Fmoc-aminoacyl, aminoacyl or groups having one of the following general formulas:

[0014] R4 and R5 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups.

[0015] According to any embodiment of the first aspect of the invention, the compound thereof or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R1 is selected from OH, F, Cl, Br, I.

[0016] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0017] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0018] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0019] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from the α-side chain of one of the natural amino acids.

[0020] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0021] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is methyl.

[0022] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0023] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3.

[0024] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R3 is selected from H, C1-C4 alkyl groups or groups having one of the following general formulas:

[0025] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0026] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R3 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0027] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from the α-side chain of one of the natural amino acids.

[0028] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R3 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0029] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3, and R6 is methyl.

[0030] According to any embodiment of the first aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R3 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0031] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3.

[0032] According to any embodiment of the first aspect of the invention, the compound thereof or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R3 is hydrogen.

[0033] Cellular experiments have shown that the Formula I compound of this invention can simultaneously promote angiogenesis, provide neuroprotection, and reduce inflammation, which is beneficial for the prevention and treatment of cardiovascular and cerebrovascular diseases. In the occurrence, development, treatment, and prognosis of cardiovascular and cerebrovascular diseases, including cardiovascular diseases or cerebrovascular diseases, especially ischemic stroke, the synergistic effect of promoting angiogenesis, neuroprotection, and anti-inflammation aims to prevent or treat cardiovascular or cerebrovascular diseases, especially ischemic stroke. The Formula I compound in the composition promotes nerve cell growth and the secretion of neurotrophic factors, reduces inflammatory responses and nerve damage, and promotes nerve repair, providing a multi-target synergistic solution for the prevention and / or treatment of cardiovascular or cerebrovascular diseases, especially stroke.

[0034] [2. Compound of Formula II]

[0035] A second aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, having the following structure:

[0036] In the formula: R1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino;

[0037] R2 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, Fmoc-aminoacyl, aminoacyl or a group having one of the following general formulas:

[0038] R4 and R5 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups.

[0039] It should be noted that, as in any embodiment of the first aspect of the present invention, or any embodiment of the second aspect of the present invention, the aminoacyl group is a group having the following general formula:

[0040] R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0041] As described in any embodiment of the first aspect of the present invention above, or in any embodiment of the second aspect of the present invention, the Fmoc-aminoacyl group is a group having the following general formula:

[0042] R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0043] According to any embodiment of the second aspect of the present invention, the compound thereof or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R1 is selected from OH, F, Cl, Br, I.

[0044] According to any embodiment of the second aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C6 alkyl groups or groups having one of the following general formulas:

[0045] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0046] According to any embodiment of the second aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0047] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

[0048] According to any embodiment of the second aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0049] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from the α-side chain of one of the natural amino acids.

[0050] According to any embodiment of the second aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having one of the following general formulas:

[0051] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3, while R6 is hydrogen.

[0052] According to any embodiment of the second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein R2 is selected from C1-C4 alkyl groups or groups having the following general formulas:

[0053] R4 and R5 are each independently selected from hydrogen, deuterium, or CH3.

[0054] According to any embodiment of the second aspect of the present invention, the compound thereof or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, wherein the compound is any one of formula II-a, II-b, II-c, II-d, II-e, II-f:

[0055] Cellular experiments have shown that the compound of formula II of this invention can simultaneously achieve angiogenesis promotion, neuroprotection, and anti-inflammatory effects, which are beneficial for the prevention and treatment of cardiovascular and cerebrovascular diseases. In the occurrence, development, treatment, and prognosis of cardiovascular and cerebrovascular diseases, including cardiovascular diseases or cerebrovascular diseases, especially ischemic stroke, the synergistic effects of promoting angiogenesis, neuroprotection, and anti-inflammatory action achieve the goal of preventing or treating cardiovascular or cerebrovascular diseases, especially ischemic stroke. The compound of formula II in the composition promotes nerve cell growth and the secretion of neurotrophic factors, reduces inflammatory responses and nerve damage, and promotes nerve repair, providing a multi-target synergistic solution for the prevention and / or treatment of cardiovascular or cerebrovascular diseases, especially stroke.

[0056] This invention has discovered that some flavonoids not only promote angiogenesis but also possess protective effects against OGD / R-induced damage at levels almost identical to those of stroke drugs, such as apigenin, represented by Formula II-a. Furthermore, compared to apigenin, compounds represented by Formula II-a, such as II-b, II-c, II-d, II-e, and II-f, exhibit stronger blood-brain barrier crossing ability and better bioavailability. These compounds are ideal for treating cardiovascular and cerebrovascular diseases, including cardiovascular or cerebrovascular diseases, particularly stroke, and possess excellent protective effects against OGD / R-induced damage and promote angiogenesis, making them ideal for the prevention and / or treatment of cardiovascular and cerebrovascular diseases, particularly stroke, and especially ischemic stroke.

[0057] As mentioned in this article, "cardiovascular and cerebrovascular diseases" refers to a general term for diseases of the heart and brain blood vessels, broadly encompassing ischemic or hemorrhagic diseases of the heart, brain, and other tissues caused by conditions such as hyperlipidemia, high blood viscosity, atherosclerosis, and hypertension. Specifically, it includes cardiovascular diseases or cerebrovascular diseases.

[0058] As discussed in this article, "cardiovascular disease" refers to diseases of the heart or blood vessels, also known as circulatory system diseases, which are a series of diseases involving the circulatory system. Specifically, these include chronic heart failure, myocardial infarction, coronary heart disease, ischemic stroke, peripheral arterial vascular disease, deep vein thrombosis, and pulmonary embolism.

[0059] As described in this article, "chronic heart failure" also refers to the gradual appearance and persistence of symptoms and signs of heart failure (such as shortness of breath, fatigue, and edema of the limbs) on the basis of pre-existing chronic heart disease.

[0060] As mentioned in this article, "myocardial infarction," "myocardial infarction," or "myocardial rupture" refers to a serious coronary heart disease caused by acute blockage of the coronary arteries (the arteries that supply blood to the heart), resulting in ischemic necrosis of part of the myocardium. It is common in the elderly and manifests as severe chest pain.

[0061] As mentioned in this article, "coronary heart disease" generally refers to coronary atherosclerotic heart disease. Coronary heart disease is a heart disease caused by atherosclerotic lesions in the coronary arteries, leading to narrowing or blockage of the blood vessel lumen, resulting in myocardial ischemia, hypoxia, or necrosis.

[0062] As described in this article, "peripheral arterial vascular disease" is a chronic ischemic disease of the limbs, characterized by narrowing and blockage of antegrade blood flow in major systemic arteries other than the brain and coronary circulation system.

[0063] As discussed in this article, "cerebrovascular disease" refers to brain dysfunction caused by cerebrovascular lesions or blood flow obstructions due to various reasons, including neurological dysfunction caused by vascular occlusion, vascular rupture, vascular wall damage, or abnormal blood components. Examples include asymptomatic cerebrovascular diseases, transient ischemic attacks, stroke, cerebrovascular dementia, hypertensive encephalopathy, and cerebral infarction.

[0064] As mentioned in this article, "stroke" is a general term for acute cerebrovascular diseases of the brain. Stroke is also known as "cerebrovascular accident" or "stroke", and specifically includes hemorrhagic stroke and ischemic stroke.

[0065] As described in this article, "ischemic stroke" refers to a stroke caused by insufficient blood supply to neurons due to vascular blockage, also known as "cerebral infarction," "cerebral infarction," or "cerebral stroke."

[0066] The term "prevention" as used herein refers to administering the compounds or pharmaceutical compositions of the present invention to a subject before the onset of the disease or symptoms, in order to avoid the occurrence of the disease or symptoms or to reduce the risk of the occurrence of the disease or symptoms.

[0067] The “reduction of the risk of disease or symptoms” mentioned herein refers to a subject’s likelihood of developing a disease or symptoms being lower than that of an equivalent control individual, for example, the subject being given the compound or pharmaceutical composition of the present invention while the control was not treated or received a drug.

[0068] As used herein, the term "treatment" refers to the relief of symptoms or complications by suppressing, alleviating, or eradicating a disease state or its symptoms, to delaying disease progression, and / or to curing or eliminating the disease. Patients wishing to be treated are preferably mammals, particularly humans.

[0069] As described herein, the term "therapeutic and / or preventative effective amount" for the pharmaceutical compositions of the present invention refers to an amount sufficient to cure, alleviate, or partially prevent the clinical manifestations of a given disease and its complications in a therapeutic intervention including administration of the composition. An amount sufficient to achieve the above is defined as a "therapeutic and / or preventative effective amount." The effective amount for each purpose will depend on the severity of the disease or lesion and the subject's weight and general condition. However, it should be recognized that the total daily dosage of the pharmaceutical compositions of the present invention must be determined by the attending physician within the bounds of reliable medical judgment. For any specific patient, the specific therapeutically effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific pharmaceutical composition used; the specific pharmaceutical composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific pharmaceutical composition used; the duration of treatment; other drugs used in combination with or concurrently with the pharmaceutical composition used; and similar factors known in the medical field. For example, it is practiced in the art to start the dose of the pharmaceutical composition below the level required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0070] The term “treatment of disease” refers to reducing the frequency or severity of at least one symptom or sign of a disease or condition experienced by a subject.

[0071] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt of a compound of the present invention, which has the desired pharmaceutical activity and is biologically and otherwise undesirable. Acidic salts include inorganic acid salts and organic acid salts. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, and methanesulfonic acid; organic acids include, but are not limited to, acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

[0072] Preferably, the pharmaceutically acceptable salt is a hydrochloride salt.

[0073] As described herein, when a compound of Formula I or Formula II has isomers, such as optical isomers, stereoisomers, positional isomers, etc., any isomers and mixtures of isomers are included within the scope of a compound of Formula I or Formula II. For example, when a compound of Formula I or Formula II has an optical isomer, the optical isomer separated from the racemic mixture is also included within the scope of a compound of Formula I or Formula II. These isomers can be obtained as separate products by synthetic or separation methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0074] Compounds of Formula I, II, II-a, II-b, II-c, II-d, II-e, and II-f may be in crystalline or amorphous form. When the compound is crystalline, both single crystals and mixtures of crystals are included within the scope of the compound. Crystals can be prepared by crystallization methods known per se.

[0075] Compounds of Formula I, II, II-a, II-b, II-c, II-d, II-e, and II-f can be pharmaceutically acceptable cocrystals or cocrystal salts. In this document, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more specific solids, each possessing different physical properties (e.g., structure, melting point, heat of fusion, etc.) at room temperature. Cocrystals and cocrystal salts can be prepared using co-crystallization methods known per se.

[0076] Compounds of Formula I, Formula II, Formula II-a, Formula II-b, Formula II-c, Formula II-d, Formula II-e, and Formula II-f can be solvates (e.g., hydrates, etc.) or non-solvents, both of which are included within the scope of compounds of Formula I or Formula II.

[0077] Isotopes can be used (e.g.) 2 H, 3 H, 14 C, etc.) etc. are labeled as compounds of formula I, formula II, formula II-a, formula II-b, formula II-c, formula II-d, formula II-e, and formula II-f.

[0078] Deuterated compounds (of which) 1 H has been transformed 2 H(D) is also included in the range of compounds of formula I, formula II, formula II-a, formula II-b, formula II-c, formula II-d, formula II-e, and formula II-f.

[0079] According to any embodiment of the first or second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof may be administered as a single dose selected from any of the following numerical ranges: 0.03-300 mg, 0.05-280 mg, 0.08-250 mg, 0.1-220 mg, 0.15-200 mg, 0.2-180 mg, 0.25-150 mg, 0.3-100 mg, 0.35-80 mg, 0.4-50 mg, 0.45-30 mg, 0.5-20 mg, 0.8-20 mg, 1-20 mg, 1.5-20 mg, 2-10 mg, 2-8 mg, 2-6 mg, 2.5-5 mg, 2.5-4 mg.

[0080] Satisfactory results are obtained when administered as a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0081] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0082] According to any embodiment of the first or second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof is administered at a dose selected from any of the following numerical ranges: 0.01-5 mg / Kg, 0.01-4 mg / Kg, 0.01-3 mg / Kg, 0.01-2 mg / Kg, 0.01-1 mg / Kg, 0.01-0.5 mg / Kg, 0.01-0.2 mg / Kg, 0.01-0.1 mg / Kg.

[0083] Satisfactory results are obtained when administered as a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0084] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0085] According to any embodiment of the first or second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, is administered to a mammal, particularly a human, at a dose of 0.005 to 0.5 mg / kg / day / person.

[0086] Preferably, the medication is administered to the patient at a dose of 0.01–0.25 mg / kg / day / person.

[0087] Preferably, the drug is administered to the patient at a dose of 0.01–0.1 mg / kg / day / person. Within the above dosage range, the pharmaceutical composition did not exhibit any toxic side effects.

[0088] [3. Uses of the compound]

[0089] A third aspect of the present invention provides the use of the compound described in any embodiment of the first or second aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, for the preparation of a medicament for cardiovascular and cerebrovascular diseases, wherein the cardiovascular and cerebrovascular diseases include cardiovascular diseases or cerebrovascular diseases.

[0090] Experiments show that the use of the compound described in any embodiment of the first or second aspect of the present invention, or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, and mixtures thereof, in the preparation of drugs for cardiovascular and cerebrovascular diseases, can simultaneously achieve the effects of promoting angiogenesis, neuroprotection and anti-inflammatory effects.

[0091] The compounds described in any embodiment of the first or second aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, are used to prepare drugs for cardiovascular or cerebrovascular diseases. These drugs, in the course of the occurrence, development, treatment, and prognosis of cardiovascular or cerebrovascular diseases, particularly ischemic stroke, achieve the purpose of preventing or treating cardiovascular or cerebrovascular diseases, particularly ischemic stroke, through the synergistic effects of promoting angiogenesis, neuroprotection, and anti-inflammation. The compounds described in any embodiment of the first aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, or the compounds described in any embodiment of the second aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, provide a multi-target synergistic prevention and / or treatment solution for cardiovascular or cerebrovascular diseases, particularly stroke, by promoting nerve cell growth and neurotrophic factor secretion, reducing inflammatory responses, and reducing nerve damage and neurorepair.

[0092] The compounds of the first aspect or the second aspect of the present invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, can also be used as agents for the prevention or treatment of TNF-α-related inflammatory diseases. In this context, TNF-α-related inflammatory diseases are inflammatory diseases that arise in the presence of TNF-α and are treated by the inhibitory effect of TNF-α. Examples of inflammatory diseases include diabetic complications (e.g., retinopathy, nephropathy, neuropathy, megavascular disease), myocarditis, cardiomyopathy, heart failure, ischemic heart disease, rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, swelling, neuralgia, pharyngitis, cystitis, hepatitis, pneumonia, gastric mucosal damage (including gastric mucosal damage caused by aspirin), and so on.

[0093] The compounds described in any embodiment of the first or second aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, can also be used as agents for the prevention or treatment of IL-1β-related inflammatory diseases. In this document, IL-1β-related inflammatory diseases are inflammatory diseases that arise in the presence of IL-1β and are treated by the inhibitory effect of IL-1β.

[0094] The compounds described in any embodiment of the first or second aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, can also be used as agents for the prevention or treatment of IFN-γ-related inflammatory diseases. In this document, IFN-γ-related inflammatory diseases are inflammatory diseases that arise in the presence of IFN-γ and are treated by IFN-γ inhibition.

[0095] The compounds described in any embodiment of the first or second aspect of this invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, have apoptosis-inhibiting activity and are also used as agents for the prevention or treatment of diseases associated with increased apoptosis. Examples of diseases associated with increased apoptosis, as described herein, include ischemic diseases such as myocardial infarction, stroke, atherosclerosis, etc.

[0096] The compounds described in any embodiment of the first or second aspect of the present invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, and mixtures thereof, are also used for the prevention and inhibition of the gradual development of secondary diseases, such as cerebrovascular diseases (e.g., stroke) and cardiovascular diseases (e.g., myocardial infarction).

[0097] According to any embodiment of the third aspect of the present invention, the cerebrovascular disease includes: a cerebrovascular disease characterized by increased cerebral inflammation; or a cerebrovascular disease characterized by increased infarct volume; or a cerebrovascular disease characterized by reduced or interrupted cerebral blood flow; or a cerebrovascular disease characterized by rupture of cerebral blood vessels; or a cerebrovascular disease characterized by hemorrhage caused by rupture of cerebral blood vessels.

[0098] Existing research has found that cerebrovascular diseases are typically characterized by increased brain inflammation, increased infarct volume, reduced or interrupted cerebral blood flow, ruptured cerebral blood vessels, and hemorrhage caused by ruptured cerebral blood vessels. Cell experiments of this invention show that the compound of formula I or formula II of this invention has a significant inhibitory effect on brain inflammation. Further animal experiments show that the compound described in any embodiment of the first or second aspect of this invention, or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, and mixtures thereof, have a significant inhibitory effect on the infarct volume in mouse models.

[0099] According to any embodiment of the third aspect of the present invention, the cerebrovascular disease includes: ischemic cerebrovascular disease; or hemorrhagic cerebrovascular disease; or atherosclerosis, stenosis or occlusion of the head and neck arteries.

[0100] According to any embodiment of the third aspect of the present invention, the stroke is an ischemic stroke.

[0101] According to any embodiment of the third aspect of the present invention, the cardiovascular disease includes: a cardiovascular disease characterized by angina pectoris; or a cardiovascular disease characterized by myocardial infarction; or a cardiovascular disease characterized by ischemic cardiomyopathy; or a cardiovascular disease characterized by chronic heart failure.

[0102] According to any embodiment of the third aspect of the present invention, the cardiovascular disease is any one, two or more of chronic heart failure, myocardial infarction, coronary heart disease, and peripheral arterial vascular disease.

[0103] The compounds of this invention can be effectively used as agents to inhibit or improve the gradual development and worsening of cardiovascular diseases, such as cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, weakened vasodilation, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc.

[0104] [4. Pharmaceutical Composition]

[0105] A fourth aspect of the present invention provides a pharmaceutical composition comprising: a compound described in any embodiment of the first or second aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0106] A fourth aspect of the present invention provides a pharmaceutical composition comprising a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, and a pharmaceutically acceptable carrier or diluent;

[0107] A fourth aspect of the present invention provides a pharmaceutical composition comprising a compound of formula II-b or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, and a pharmaceutically acceptable carrier or diluent;

[0108] A fourth aspect of the present invention provides a pharmaceutical composition comprising a compound as shown in Formula II-d or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, and a pharmaceutically acceptable carrier or diluent;

[0109] The pharmaceutical composition refers to a pharmaceutical composition in which the active ingredient is a compound or a pharmaceutically acceptable equivalent (a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof and a mixture thereof) described in any embodiment of the first or second aspect of the present invention, and which contains one or more pharmaceutically acceptable carriers or diluents.

[0110] The term "pharmaceutically acceptable carrier or diluent" as used in this invention refers to excipients, additives, or solvents commonly used in pharmaceutical preparations, including but not limited to lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, gums, fatty acids, fatty acid amines, glyceryl monostearate or glyceryl distearate, phospholipids, olive oil, peanut oil, syrups, colorants, flavoring agents, preservatives, water, ethanol, propanol, physiological saline, and glucose solution.

[0111] According to any embodiment of the fourth aspect of the present invention, the pharmaceutical composition is in a single-dose form, wherein the single-dose form contains 0.03-300 mg of the following substances: the compound of any embodiment of the first or second aspect of the present invention or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof (hereinafter referred to as: active ingredient).

[0112] The active ingredient contained in the pharmaceutical composition is administered as a single dose selected from any of the following numerical ranges: 0.03-300 mg, 0.05-280 mg, 0.08-250 mg, 0.1-220 mg, 0.15-200 mg, 0.2-180 mg, 0.25-150 mg, 0.3-100 mg, 0.35-80 mg, 0.4-50 mg, 0.45-30 mg, 0.5-20 mg, 0.8-20 mg, 1-20 mg, 1.5-20 mg, 2-10 mg, 2-8 mg, 2-6 mg, 2.5-5 mg, 2.5-4 mg.

[0113] Satisfactory results are obtained when administered as a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0114] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0115] According to any embodiment of the fourth aspect of the present invention, the active ingredient contained in the pharmaceutical composition is administered at a dose selected from any of the following numerical ranges: 0.01-5 mg / Kg, 0.01-4 mg / Kg, 0.01-3 mg / Kg, 0.01-2 mg / Kg, 0.01-1 mg / Kg, 0.01-0.5 mg / Kg, 0.01-0.2 mg / Kg, 0.01-0.1 mg / Kg.

[0116] Satisfactory results are obtained when administered at the above dosage, preferably once, two, or three times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dosage may be reduced proportionally.

[0117] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention is applied to mammals, particularly humans, wherein the active ingredient is administered to the patient at a dose of 0.005 to 0.5 mg / kg / day / person.

[0118] Preferably, the active ingredient is administered to the patient at a dose of 0.01 to 0.25 mg / kg / day / person.

[0119] Preferably, the active ingredient is administered to the patient at a dose of 0.01 to 0.1 mg / kg / day / person; when administered within the above-mentioned dose range, the pharmaceutical composition has not shown any toxic side effects.

[0120] According to any embodiment of the fourth aspect of the present invention, the mass percentage of the active ingredient in the pharmaceutical composition is selected from any of the following numerical ranges: 1–99 wt%, 30–99 wt%, 30–95 wt%, 30–90 wt%, 30–85 wt%, 30–80 wt%, 30–75 wt%, 30–70 wt%, 30–65 wt%, 30–60 wt%, 30–55 wt%, 30–50 wt%, 40–99 wt%, 40–95 wt%, 40–90 wt%, 40–85 wt%, 40–80 wt%, 40–75 wt%, 40–70 wt%, 40–65 wt%, 40–60 wt%, 40–55 wt%, 40–50 wt%. 50~99wt%, 50~95wt%, 50~90wt%, 50~85wt%, 50~80wt%, 50~75wt%, 50~70wt%, 50~6 5wt%, 50~60wt%, 50~55wt%, 60~99wt%, 60~95wt%, 60~90wt%, 60~85wt%, 60~80wt%, 60~75wt%, 60~70wt%, 60~65wt%, 70~99wt%, 70~95wt%, 70~90wt%, 70~85wt%, 70~8 0wt%, 70~75wt%, 80~99wt%, 80~95wt%, 80~90wt%, 80~85wt%, 90~99wt%, 90~95wt%.

[0121] As a preferred embodiment of any aspect of the fourth aspect of the present invention, the concentration (drug loading concentration) of the active ingredient in the pharmaceutical composition is selected from any of the following numerical ranges: 0.01-10 mg / mL, 0.01-8 mg / mL, 0.01-5 mg / mL, 0.01-3 mg / mL, 0.01-2 mg / mL, 0.01-1 mg / mL, 0.1-10 mg / mL, 0.1-8 mg / mL, 0.1-5 mg / mL, 0.1- 3mg / mL, 0.1-2mg / mL, 0.1-1mg / mL, 1-10mg / mL, 1-8mg / mL, 1-5mg / mL, 1-3mg / mL, 1-2mg / mL, 2-10mg / mL , 2-8mg / mL, 2-5mg / mL, 2-3mg / mL, 4-10mg / mL, 4-8mg / mL, 4-5mg / mL, 6-10mg / mL, 6-8mg / mL, 8-10mg / mL.

[0122] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention further includes at least one combination drug.

[0123] According to any embodiment of the fourth aspect of the present invention, the combination drug is selected from any one, two or more of the following: combination drugs with anti-cerebral thrombosis effect, combination drugs with antiplatelet effect, combination drugs with thrombolytic effect, combination drugs with antioxidant effect, combination drugs with anticoagulant effect, and combination drugs with cholesterol-lowering effect.

[0124] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention further includes at least one cerebrovascular disease treatment agent.

[0125] According to any embodiment of the fourth aspect of the present invention, the cerebrovascular disease treatment agent is selected from any one, two or more of the following: a cerebrovascular disease treatment agent characterized by inhibiting or reducing or alleviating cerebral inflammation; or a cerebrovascular disease treatment agent characterized by inhibiting or reducing or alleviating cerebral infarction volume; or a cerebrovascular disease treatment agent characterized by inhibiting or reducing or alleviating reduced cerebral blood flow; a cerebrovascular disease treatment agent characterized by inhibiting or reducing or alleviating cerebral blood flow interruption; or a cerebrovascular disease treatment agent characterized by inhibiting or reducing or alleviating cerebral blood vessel rupture.

[0126] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention, the combination drug, and / or other cerebrovascular disease treatment agents, and / or cardiovascular disease treatment agents include any one, two or more of butylphthalide, edaravone, dextroborneol, aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, heparin, warfarin, dabigatran, apixaban, rivaroxaban and atorvastatin.

[0127] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention further includes at least one substance having neuroprotective function.

[0128] In the pharmaceutical composition, the total weight is the sum of the weights of the active ingredients; wherein the content of the active ingredients can be any value taken from any of the following numerical ranges: 1-99%, 30-90wt%, 30-85wt%, 30-80wt%, 30-75wt%, 30-70wt%, 30-65wt%, 30-60wt%, 30-55wt%, 35-90wt%, 35-85wt%, 35-80wt%, 35-75wt%, 35-70wt%. %, 35-65wt%, 35-60wt%, 35-55wt%, 35-50wt%, 40-90wt%, 40-85wt%, 40-80wt%, 40-75wt%, 40-70wt%, 40-65w t%, 40-60wt%, 40-55wt%, 40-50wt%, 40-45wt%, 45-90wt%, 45-85wt%, 45-80wt%, 45-75wt%, 45-70wt%, 45-65 wt%, 45-60wt%, 45-55wt%, 45-50wt%, 50-90wt%, 50-85wt%, 50-80wt%, 50-75wt%, 50-70wt%, 50-65wt%, 50-6 0wt%, 50-55wt%,, 55-90wt%, 55-85wt%, 55-80wt%, 55-75wt%, 55-70wt%, 55-65wt%, 55-60wt%, 60-90wt%, 60 -85wt%, 60-80wt%, 60-75wt%, 60-70wt%, 60-65wt%, 65-90wt%, 65-85wt%, 65-80wt%, 65-75wt%, 65-70wt%, 7 0-90wt%, 70-85wt%, 70-80wt%, 70-75wt%, 75-90wt%, 75-85wt%, 75-80wt%, 80-90wt%, 80-85wt%, 85-90wt%.

[0129] The compounds of the present invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof and mixtures thereof, can be used in combination with pharmaceuticals, such as agents for the treatment of diabetes, agents for the treatment of diabetic complications, agents for the treatment of hyperlipidemia, agents for the treatment of arteriosclerosis, agents for the treatment of hypertension, agents for the treatment of obesity, diuretics, agents for the treatment of gout, agents for the treatment of thrombosis, anti-inflammatory agents, chemotherapeutic agents, immunotherapeutic agents, agents for the treatment of osteoporosis, agents for the treatment of dementia, agents for the treatment of erectile dysfunction, agents for the treatment of urinary incontinence / frequency, agents for the treatment of dysuria, etc. (hereinafter referred to as concomitant drugs). These concomitant drugs can be low molecular weight compounds, high molecular weight proteins, peptides, antibodies, vaccines, etc.

[0130] There are no restrictions on the timing of administration of the above-mentioned combined medications. The compounds of the present invention or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers thereof, mixtures thereof, or pharmaceutical compositions, and the combined medications may be administered simultaneously or at different times. The dosage of the combined medications may be based on clinical dosage and may be appropriately determined according to the recipient, route of administration, disease, combination, etc. The above-mentioned combined medications may be a combination of two or more of them in suitable proportions.

[0131] Examples of the above-mentioned administration modes include the following: (1) administering a single formulation obtained by simultaneously processing the compound or pharmaceutical composition of the present invention and a syndicated drug; (2) administering two formulations of the compound or pharmaceutical composition of the present invention and a syndicated drug prepared separately via the same route of administration; (3) administering two formulations of the compound or pharmaceutical composition of the present invention and a syndicated drug prepared separately via the same route of administration in an alternating manner; (4) administering two formulations of the compound or pharmaceutical composition of the present invention and a syndicated drug prepared separately via different routes of administration; (5) administering two formulations of the compound or pharmaceutical composition of the present invention and a syndicated drug prepared separately via different routes of administration in an alternating manner (e.g., administering in the order of the compound or pharmaceutical composition of the present invention and the syndicated drug, or administering in the reverse order), etc.

[0132] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention includes a powder, granule, tablet, pill, capsule, sustained-release agent, controlled-release agent, injection, infusion or suspension.

[0133] The pharmaceutical composition may be specifically formulated for administration via a suitable route of administration, such as oral, rectal, nasal, pulmonary, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, with injection being preferred. It should be understood that the preferred route of administration depends on the overall condition and age of the treated subject, the nature of the disease or condition being treated, and the selected active ingredient.

[0134] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention is in the form of an injection.

[0135] When the compounds of the present invention are administered parenterally, they are generally given in the form of a liquid formulation (e.g., an injection).

[0136] As an injectable preparation, it can be administered intravenously, subcutaneously, intradermally, intramuscularly, or by infusion. As a sustained-release formulation, it can be administered via iontophoresis. This injectable preparation is prepared using methods known in the art, namely, by dissolving, suspending, or emulsifying a compound of formula I or formula II in a sterilized aqueous or oily liquid.

[0137] The pharmaceutical composition according to any embodiment of the fourth aspect of the present invention further comprises a solvent.

[0138] According to any embodiment of the fourth aspect of the present invention, the solvent of the pharmaceutical composition is selected from one or more of alcohol solvents, ether solvents, ketone solvents, and sulfide compound solvents.

[0139] Preferably, the alcohol solvent includes one or more of ethanol, isopropanol, ethylene glycol, propylene glycol, and polyethylene glycol; the ether solvent includes one or more of ethylene glycol monoethyl ether and ethylene glycol monobutyl ether; the ketone solvent includes one or more of acetone and N-methyl-2-pyrrolidone; and the sulfide compound solvent includes dimethyl sulfoxide (DMSO).

[0140] Furthermore, aqueous solutions for injection can be physiological saline, isotonic solutions containing glucose or other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride, etc.), etc., and can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80), etc. As oily liquids, sesame oil, soybean oil, etc., can be used, and can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. Additionally, buffer solutions (e.g., phosphate buffer, sodium acetate buffer), soothing agents (e.g., benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (e.g., human serum albumin, polyethylene glycol, etc.), preservatives (e.g., benzyl alcohol, phenol, etc.) can be mixed with it. The prepared injections are generally filled into vials.

[0141] [5. Uses of the composition]

[0142] The fifth aspect of the present invention provides the use of the compound described in any embodiment of the first or second aspect, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof or a mixture thereof, or the pharmaceutical composition described in any embodiment of the fourth aspect, in the preparation of a medicament for the treatment of cardiovascular or cerebrovascular diseases.

[0143] According to any embodiment of the fifth aspect of the present invention, the cerebrovascular disease includes: a cerebrovascular disease characterized by increased inflammation in the brain; or a cerebrovascular disease characterized by increased infarct volume; or a cerebrovascular disease characterized by reduced or interrupted blood flow in the brain; or a cerebrovascular disease characterized by rupture of a cerebral blood vessel; or a cerebrovascular disease characterized by hemorrhage caused by rupture of a cerebral blood vessel.

[0144] According to any embodiment of the fifth aspect of the present invention, the cerebrovascular disease includes: ischemic cerebrovascular disease; or hemorrhagic cerebrovascular disease; or atherosclerosis, stenosis or occlusion of the head and neck arteries.

[0145] According to any embodiment of the fifth aspect of the present invention, the cerebrovascular disease is stroke.

[0146] According to any embodiment of the fifth aspect of the present invention, the stroke is an ischemic stroke.

[0147] According to any embodiment of the fifth aspect of the present invention, the cardiovascular disease includes: a cardiovascular disease characterized by angina pectoris; or a cardiovascular disease characterized by myocardial infarction; or a cardiovascular disease characterized by ischemic cardiomyopathy; or a cardiovascular disease characterized by chronic heart failure.

[0148] According to any embodiment of the fifth aspect of the present invention, the cardiovascular disease is any one, two or more of chronic heart failure, myocardial infarction, coronary heart disease, and peripheral arterial vascular disease.

[0149] The definitions of “cardiovascular disease,” “cerebrovascular disease,” “stroke,” “ischemic stroke,” “chronic heart failure,” “myocardial infarction,” “coronary heart disease,” and “peripheral arterial vascular disease” used in this article are the same as those described above.

[0150] [6. Medicine Box]

[0151] The sixth aspect of the present invention provides a medicine box comprising one or more single-dose units of a compound described in any embodiment of the first aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, or a mixture thereof; or comprising one or more single-dose units of a compound described in any embodiment of the second aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, or a mixture thereof; or comprising one or more single-dose units of a pharmaceutical composition described in any embodiment of the fourth aspect of the present invention, and instructions for use in treating a disease.

[0152] [7. Uses for the treatment or prevention of cardiovascular and cerebrovascular diseases]

[0153] The seventh aspect of the present invention provides the use of the compound described in any embodiment of the first aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer or mixture thereof, or the compound described in any embodiment of the second aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer or mixture thereof (hereinafter referred to as: active ingredient), or the pharmaceutical composition described in any embodiment of the fourth aspect of the present invention in the prevention or treatment of cardiovascular and cerebrovascular diseases.

[0154] According to any embodiment of the seventh aspect of the present invention, the cerebrovascular disease includes: a cerebrovascular disease characterized by increased cerebral inflammation; or a cerebrovascular disease characterized by increased infarct volume; or a cerebrovascular disease characterized by reduced or interrupted cerebral blood flow; or a cerebrovascular disease characterized by rupture of cerebral blood vessels; or a cerebrovascular disease characterized by hemorrhage caused by rupture of cerebral blood vessels.

[0155] According to any embodiment of the seventh aspect of the present invention, the cerebrovascular disease includes: ischemic cerebrovascular disease; or hemorrhagic cerebrovascular disease; or atherosclerosis, stenosis or occlusion of the head and neck arteries.

[0156] According to any embodiment of the seventh aspect of the present invention, the cerebrovascular disease includes any one, two or more of transient ischemic attack, cerebral infarction, stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, chronic cerebral ischemia, cerebral hemorrhage, cerebral hemorrhage, and subarachnoid hemorrhage.

[0157] According to any embodiment of the seventh aspect of the present invention, the stroke is an ischemic stroke.

[0158] According to any embodiment of the seventh aspect of the present invention, the cardiovascular disease includes: a cardiovascular disease characterized by angina pectoris; or a cardiovascular disease characterized by myocardial infarction; or a cardiovascular disease characterized by ischemic cardiomyopathy; or a cardiovascular disease characterized by chronic heart failure.

[0159] According to any embodiment of the seventh aspect of the present invention, the cardiovascular disease is any one, two or more of chronic heart failure, myocardial infarction, coronary heart disease, and peripheral arterial vascular disease.

[0160] According to any embodiment of the seventh aspect of the invention, the active ingredient is applied to a mammal, particularly a human, wherein the active ingredient is administered to the patient at a dose of 0.005 to 0.5 mg / kg / day / person.

[0161] Preferably, the active ingredient is administered to the patient at a dose of 0.01 to 0.25 mg / kg / day / person.

[0162] Preferably, the active ingredient is administered to the patient at a dose of 0.01–0.1 mg / kg / day / person. When administered within the above-mentioned dosage range, the pharmaceutical composition has not exhibited any toxic side effects.

[0163] [definition]

[0164] As used herein, the term "solvent" refers to a compound that carries solvent molecules; for example, the solvate may be a hydrate.

[0165] In this invention, the term "comprising" or "containing" indicates that various ingredients may be used together in the composition of this invention. Therefore, the terms "consistent with..." and "composed of..." are included in the term "comprising" or "containing".

[0166] In this invention, a "pharmaceuticalally acceptable" ingredient is a substance that is suitable for humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., has a reasonable benefit / risk ratio.

[0167] The actual dosage level and route of administration of the active ingredient (compound of formula I or II, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, or mixture thereof) in the pharmaceutical composition of the present invention can be modified so that the resulting amount of active ingredient can effectively achieve the desired therapeutic response in a specific patient. The dosage level must be selected based on the activity of the specific active ingredient, the route of administration, the severity of the condition being treated, and the patient's condition and medical history. However, it is the practice in the art to start the dosage of the active ingredient below the level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0168] The definition of "treatment" as described here is the same as that mentioned above. 3. Beneficial effects

[0169] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0170] (1) Existing positive drugs mostly prevent or treat cardiovascular and cerebrovascular diseases such as ischemic stroke by inhibiting nerve cell death through neuroprotective and anti-inflammatory effects. This invention discovers a new compound within the formula I range that has both anti-inflammatory and neuroprotective effects, as well as angiogenesis-promoting effects. The anti-inflammatory, neuroprotective and angiogenesis-promoting effects work synergistically to inhibit heart and brain damage, thereby achieving the purpose of preventing or treating cardiovascular and cerebrovascular diseases such as ischemic stroke.

[0171] (2) Cell experiments show that the compounds within the scope of Formula I of the present invention have the following effects: the anti-inflammatory effect of traditional flavonoids; promoting nerve cell proliferation and nerve synapse growth; promoting angiogenesis and protecting against ischemic-like injury; these effects indicate that the compounds within the scope of Formula I have the potential for application in the prevention and treatment of cardiovascular and cerebrovascular diseases.

[0172] (3) The present invention investigated the anti-ischemic effect of compounds within the general formula range of Formula I using an in vitro ischemia-reperfusion model; the results showed that compounds within the general formula range of Formula I have a significant protective effect on neurons.

[0173] (4) Animal experiments further showed that in the mouse tMCAO stroke model, the application of compounds within the scope of Formula I of the present invention can significantly reduce the percentage of cerebral infarction volume in mice with cerebral ischemia; compounds within the scope of Formula I provide an effective solution for the prevention and treatment of stroke.

[0174] (5) Flavonoids such as apigenin (as shown in formula II-a) not only promote angiogenesis but also have a protective effect against OGD / R-induced damage at almost the same level as stroke drugs. Furthermore, compared to apigenin (as shown in formula II-a), compounds such as those shown in formulas II-b, II-c, II-d, II-e, and II-f have a stronger ability to cross the blood-brain barrier and better bioavailability, making them ideal drugs for the treatment of cardiovascular and cerebrovascular diseases, including cardiovascular or cerebrovascular diseases, especially stroke. They also have good protective effects against OGD / R-induced damage and promote angiogenesis, making them ideal drugs for the prevention and / or treatment of cardiovascular and cerebrovascular diseases, including cardiovascular or cerebrovascular diseases, especially stroke, and even more so ischemic stroke.

[0175] (6) Based on the effects of compounds within the general formula range of Formula I on promoting angiogenesis and protecting against ischemic-like injury, compounds of Formula I and pharmaceutical compositions containing compounds of Formula I are beneficial in reducing the probability of secondary stroke.

[0176] (7) Based on the effects of compounds within the general formula range of Formula I on promoting angiogenesis and protecting against ischemic-like injury, Formula I compounds and pharmaceutical compositions containing Formula I compounds are beneficial to improving collateral circulation, especially cerebral collateral circulation, restoring blood oxygen supply, realizing blood supply, and thus inhibiting heart and brain injury. They provide a multi-target synergistic prevention and / or treatment solution for cardiovascular and cerebrovascular diseases, especially chronic heart failure, myocardial infarction, and stroke. Attached Figure Description

[0177] Figures 1-5 illustrate the effects of apigenin (Api, formula II-a), butylphthalide (NBP), and edaravone-dexborneol (ED) on angiogenesis, anti-ischemic injury, and anti-inflammation.

[0178] Figure 1 shows the effects of the normal control group (labeled Ctrl), different concentrations of butylphthalide (1 μM and 3 μM, labeled NBP-1 and NBP-3, respectively), different concentrations of edaravone-dexborneol (30 μM and 100 μM, labeled ED-30 and ED-100, respectively), and apigenin (0.3 μM, 1 μM, and 3 μM, labeled Api-0.3, Api-1, and Api-3, respectively) on the proliferation of human umbilical vein endothelial cells (HUVECs).

[0179] Figure 2 shows the effects of the normal control group (labeled Ctrl), the oxygen-glucose deprivation injury group (OGD / R), and different concentrations of butylphthalide (1 μM and 3 μM, labeled NBP-1 and NBP-3, respectively), different concentrations of edaravone-dexborneol (30 μM and 100 μM, labeled ED-30 and ED-100, respectively) under OGD / R injury on vascular endothelial cell survival (anti-ischemic-like injury).

[0180] Figure 3 shows the effects of the normal control group (labeled Ctrl), the TNF-α injury group (labeled TNFα), and the different concentrations of butylphthalide (1 μM and 3 μM, labeled NBP-1 and NBP-3, respectively), the different concentrations of edaravone-dexborneol (30 μM and 100 μM, labeled ED-30 and ED-100, respectively), and the apigenin group (0.3 μM, 1 μM, and 3 μM, labeled Api-0.3, Api-1, and Api-3, respectively) on vascular endothelial cell survival (anti-inflammatory);

[0181] Figure 4 shows the effects of the normal control group (labeled Ctrl), the IL-1β injury group (labeled IL-1β), and the different concentrations of butylphthalide (1 μM and 3 μM, labeled NBP-1 and NBP-3, respectively), the different concentrations of edaravone-dexborneol (30 μM and 100 μM, labeled ED-30 and ED-100, respectively), and the apigenin group (0.3 μM, 1 μM, and 3 μM, labeled Api-0.3, Api-1, and Api-3, respectively) on vascular endothelial cell survival (anti-inflammatory);

[0182] Figure 5 shows the effects of the normal control group (labeled Ctrl), the IFN-γ injury group (labeled IFN-γ), and the different concentrations of butylphthalide (1 μM and 3 μM, labeled NBP-1 and NBP-3, respectively), the different concentrations of edaravone-dexborneol (30 μM and 100 μM, labeled ED-30 and ED-100, respectively), and the apigenin group (0.3 μM, 1 μM, and 3 μM, labeled Api-0.3, Api-1, and Api-3, respectively) on vascular endothelial cell survival (anti-inflammatory);

[0183] Figures 6-10 show the effects of EW223 (Formula II-b) and apigenin (Api, Formula II-a) on three aspects: angiogenesis, anti-ischemic injury, and anti-inflammation.

[0184] Figure 6 shows the effects of the blank control group (labeled Ctrl), the apigenin group (concentration 3 μM, labeled Api-3), and different concentrations of EW223 (concentrations 0.3 μM, 1 μM, and 3 μM, labeled EW223-0.3, EW223-1, and EW223-3) on the proliferation of human umbilical vein endothelial cells (HUVECs).

[0185] Figure 7 shows the effects of the normal control group (labeled Ctrl), the oxygen-glucose deprivation injury group (labeled OGD / R), the apigenin group under OGD / R injury (concentration 3 μM, labeled Api-3), and different concentrations of EW223 (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW223-0.3, EW223-1, EW223-3) on vascular endothelial cell survival (anti-ischemic injury).

[0186] Figure 8 shows the effects of the normal control group (labeled Ctrl), the TNF-α injury group (labeled TNFα), the apigenin group under TNF-α injury (concentration 3 μM, labeled Api-3), and different concentrations of EW223 (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW223-0.3, EW223-1, EW223-3) on vascular endothelial cell survival (anti-inflammatory);

[0187] Figure 9 shows the effects of the normal control group (labeled Ctrl), the IL-1β-damaged group (labeled IL-1β), the apigenin group under IL-1β damage (concentration 3 μM, labeled Api-3), and different concentrations of EW223 (concentrations 0.3 μM, 1 μM, and 3 μM, labeled EW223-0.3, EW223-1, and EW223-3) on vascular endothelial cell survival (anti-inflammatory);

[0188] Figure 10 shows the effects of the normal control group (labeled Ctrl), the IFN-γ injury group (labeled IFN-γ), the apigenin group under IFN-γ injury (concentration 3 μM, labeled Api-3), and different concentrations of EW223 (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW223-0.3, EW223-1, EW223-3) on vascular endothelial cell survival (anti-inflammatory);

[0189] Figures 11-15 show the effects of EW231 (Formula II-d) and EW223 (Formula II-b) on three aspects: angiogenesis, anti-ischemic injury, and anti-inflammation.

[0190] Figure 11 shows the effects of the blank control group (labeled Ctrl), the EW223 group (concentration 3 μM, labeled EW223-3), and different concentrations of EW231 groups (concentrations 0.3 μM, 1 μM, and 3 μM, labeled EW231-0.3, EW231-1, and EW231-3) on the proliferation of human umbilical vein endothelial cells (HUVECs).

[0191] Figure 12 shows the effects of the normal control group (labeled Ctrl), the oxygen-glucose deprivation injury group (labeled OGD / R), and the EW223 group (concentration 3 μM, labeled EW223-3) under OGD / R injury, as well as different concentrations of EW231 groups (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW231-0.3, EW231-1, EW231-3) on the survival of vascular endothelial cells (HBMEC) (anti-ischemic injury).

[0192] Figure 13 shows the effects of the normal control group (labeled Ctrl), the TNF-α injury group (labeled TNFα), the EW223 group under TNF-α injury (concentration 3 μM, labeled EW223-3), and different concentrations of EW231 groups (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW231-0.3, EW231-1, EW231-3) on vascular endothelial cell survival (anti-inflammatory);

[0193] Figure 14 shows the effects of the normal control group (labeled Ctrl), the IL-1β-damaged group (labeled IL-1β), the IL-1β-damaged EW223 group (concentration 3 μM, labeled EW223-3), and different concentrations of EW231 groups (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW231-0.3, EW231-1, EW231-3) on vascular endothelial cell survival (anti-inflammatory);

[0194] Figure 15 shows the effects of the normal control group (labeled Ctrl), the IFN-γ injury group (labeled IFN-γ), the EW223 group under IFN-γ injury (concentration 3 μM, labeled EW223-3), and different concentrations of EW231 groups (concentrations 0.3 μM, 1 μM, 3 μM, labeled EW231-0.3, EW231-1, EW231-3) on vascular endothelial cell survival (anti-inflammatory);

[0195] Figures 16-19 show the effects of the blank control group (labeled Ctrl), EW231 (Formula II-d, concentration 3 μM, labeled EW231), EW223 (Formula II-b, concentration 3 μM, labeled EW223), apigenin group (Formula II-a, concentration 3 μM, labeled Api), and VEGF-A (vascular endothelial growth factor) group (20 ng / mL) on the formation of tubular structures in vascular endothelial cells.

[0196] Figure 16. Tubular structure under a fluorescence microscope;

[0197] Figure 17. Total length of the tubular structure;

[0198] Figure 18 Number of lumens;

[0199] Figure 19 shows the number of branches.

[0200] Figures 20-21 illustrate the roles of EW231 (Formula II-d), EW223 (Formula II-b), and RA (retinoic acid) in promoting the proliferation of neural stem cells (NSCs) and the growth of neural synapses.

[0201] Figure 20 shows the effects of the blank group (Vehicle), RA group (concentration 5 μM), EW223 group (concentration 5 μM), and EW231 group (concentration 5 μM) on promoting neural synapse growth.

[0202] Figure 21 shows the effects of the blank group (Vehicle), RA group (concentration 5 μM), EW223 group (concentration 5 μM, labeled EW223-5) and EW231 group (concentration 5 μM, labeled EW231-5) on promoting neural synapse growth.

[0203] Figures 22-27 show the effects of EW223 (Formula II-b) on tMCAO model mice, where:

[0204] Figures 22 and 23 show the TTC staining results (Figure 22) and statistical graph (Figure 23) of the blank group (Veh) and the treatment group (concentration 0.2 mg / kg, 0.67 mg / kg, labeled EW223-0.2, EW223-0.67) or butylphthalide group (concentration 6 mg / kg, labeled NBP) under the tMCAO model 3 days after administration.

[0205] Figures 24 and 25 show the cerebral blood flow test results one week after administration to the sham surgery group (Sham), the blank group under the tMCAO model (Veh), and the treatment group under the tMCAO model given EW223 (concentrations of 0.2 mg / kg, 0.67 mg / kg, and 2 mg / kg, labeled as EW223-0.2, EW223-0.67, and EW223-2) or the butylphthalide group (concentration of 6 mg / kg, labeled as NBP).

[0206] Figure 26 shows the Y-maze behavioral data of mice in the sham-operated group (Sham), the blank group under the tMCAO model (Veh), and the treatment group under the tMCAO model that was given EW223 (concentrations of 0.2 mg / kg, 0.67 mg / kg, and 2 mg / kg, labeled as EW223-0.2, EW223-0.67, and EW223-2) or the butylphthalide group (concentration of 6 mg / kg, labeled as NBP).

[0207] Figure 27 shows the open field behavioral data of mice in the sham-operated group (Sham), the blank group under the tMCAO model (Veh), and the treatment group under the tMCAO model that was given EW223 (concentrations of 0.2 mg / kg, 0.67 mg / kg, and 2 mg / kg, labeled as EW223-0.2, EW223-0.67, and EW223-2) or the butylphthalide group (concentration of 6 mg / kg, labeled as NBP).

[0208] Figure 28. Nuclear magnetic resonance spectrum of product II-d prepared in Example 1 ( 1 HNMR);

[0209] Figure 29. Nuclear magnetic resonance spectrum of product II-e prepared in Example 1 ( 1 HNMR);

[0210] Figure 30. Nuclear magnetic resonance spectrum of product II-c prepared in Example 1 ( 1 HNMR);

[0211] Figure 31 shows the nuclear magnetic resonance spectrum of product II-b prepared in Example 1. 1 HNMR). Detailed Implementation

[0212] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0213] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0214] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable.

[0215] Concentration, content, percentage content, and other numerical data may be presented in range format herein. It should be understood that such range format is used solely for convenience and brevity and should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges encompassed within the range, as if each value and subrange were explicitly stated. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly stated limits of 1 to 4.5, but also individual numbers (such as 2, 3, 4) and subranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges that describe only a single value, such as "less than about 4.5," which should be interpreted to include all the aforementioned values ​​and ranges. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0216] Butylphthalide, purchased from WuXi AppTec, 1g specification.

[0217] Edaravone-dexborneol, wherein the molar ratio of edaravone to dexborneol is 4:1; edaravone was purchased from MCE, catalog number: HY-B0099; dexborneol was purchased from Sigma, catalog number: 420247; the concentration of the edaravone-dexborneol group in the examples is the concentration of edaravone.

[0218] RA (retinoic acid), purchased from MCE, product number: HY-14649.

[0219] The compound shown (apigenin, Api) was provided by MCE with a purity ≥99.5%.

[0220] The compound shown (EW223) was provided by Shanghai Dongxi Zhihui Biopharmaceutical Co., Ltd., with a purity ≥98%. It was prepared to the required concentration by mixing 5% NMP + 50% PEG400 + 45% PG (5% N-Methylpyrrolidone, 50% Polyethylene glycol 400 and 45% Propylene glycol).

[0221] The present invention will be further described below with reference to specific embodiments. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0222] Example 1

[0223] Compound preparation examples

[0224] Synthesized compound 3:

[0225] Potassium hydroxide (7.8 g, 140.2 mmol, 2.5 eq) was dissolved in 112 ml of water and slowly added at room temperature to an ethanol (110 ml) solution of compound 1 (2'-hydroxy-4',6'-dimethoxyacetophenone, CAS: 90-24-4, purchased from Shanghai Haohong Biomedical Technology Co., Ltd.) (11.0 g, 56.1 mmol, 1.0 eq) and compound 2 (p-fluorobenzaldehyde, CAS: 459-57-4, 7.6 g, 61.7 mmol, 1.1 eq). The reaction was purged with nitrogen and stirred at 40 °C for 12 hours. TLC showed that the reaction was basically complete, and mass spectrometry showed the formation of products. The reaction solution was poured into ice water, and the pH was adjusted to 3-4 with 6N hydrochloric acid. During this process, a large amount of yellow solid precipitated. The solution was filtered, the filter cake was washed with water, and then the filter cake was collected and dried to obtain compound 3 (16.3 g, 96%) as a yellow solid.

[0226] The reaction conditions shown on the TLC plate were as follows: TLC: petroleum ether: ethyl acetate = 10:1, UV 254nm;

[0227] Rf(compound 1) = 0.6; Rf(compound 3) = 0.5. LC-MS: 303.0, [M+1] + .

[0228] Synthesized compound 4:

[0229] Compound 3 (4.1 g, 13.6 mmol, 1.0 eq) was dissolved in 50 mL of dimethyl sulfoxide solution. Elemental iodine (69.1 mg, 0.3 mmol, 0.02 eq) was added at room temperature. The reaction was purged with nitrogen and stirred at 120 °C for 5 h. TLC showed the reaction was essentially complete, and mass spectrometry showed product formation. The reaction was cooled to room temperature and poured into saturated sodium sulfite (~40 mL). The mixture was stirred for 20 minutes, during which a large amount of yellow solid precipitated. The mixture was filtered, the filter cake was washed with water, and then collected and dried to give compound 4 (3.5 g, 86%) as a yellow solid.

[0230] TLC: dichloromethane: methanol = 20:1, UV 254nm;

[0231] Rf(compound 3) = 1.0; Rf(compound 4) = 0.5. LC-MS: 30 1.0 [M+1] + .

[0232] Synthetic product II-b:

[0233] Compound 4 (3.2 g, 10.7 mmol, 1.0 eq) was dissolved in 35 mL of 48% hydrobromic acid aqueous solution. The reaction was purged with nitrogen and stirred continuously at 100 °C for 60 h. TLC showed that the reaction was essentially complete, and mass spectrometry showed the formation of the product. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, and the resulting organic phase was washed successively with brine, dried over sodium sulfite, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give product II-b (2.2 g, 76%) as a yellow solid.

[0234] The reaction conditions shown on the TLC plate were as follows: TLC: dichloromethane: methanol = 20:1, UV 254nm;

[0235] Rf(compound 4) = 0.5; Rf(compound II-b) = 0.6. LC-MS: 273.0, [M+1] + .

[0236] Furthermore, Figure 31 shows the nuclear magnetic resonance spectrum of product II-b prepared in this embodiment: 1 H NMR (400MHz, DMSO-d6) δ12.78 (s, 1H), 10.90 (s, 1H), 8.13 (dd, J = 8.8, 5.6Hz, 2H), 7.39(t,J=8.8Hz,2H),6.95(s,1H),6.50(d,J=2.0Hz,1H),6.19(d,J=2.0Hz,1H).

[0237] Synthesized compound 6:

[0238] Compound 7 (p-nitrophenyl chloroformate, CAS: 7693-46-1, purchased from Anhui Zesheng Technology Co., Ltd.) (5.0 g, 24.8 mmol, 1.0 eq) was dissolved in 50 mL of dioxane solution. Methylamine hydrochloride (1.7 g, 24.8 mmol, 1.0 eq) was added at room temperature. The reaction was purged with nitrogen and stirred at 80 °C for 12 h. TLC showed the reaction was essentially complete, and mass spectrometry showed product formation. The reaction was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give compound 6 (2.7 g, 55%) as a yellow solid.

[0239] The reaction conditions shown on the TLC plate were as follows: TLC: petroleum ether: ethyl acetate = 3:1, UV 254nm;

[0240] R f (Compound 7) = 0.6; R f (Compound 6) = 0.3. LC-MS: 197.0 [M+1] + .

[0241] Synthetic product II-d:

[0242] Compound II-b (800.0 mg, 2.9 mmol, 1.0 eq) was dissolved in 10 mL of tetrahydrofuran solution. Compound 6 (576.4 mg, 2.9 mmol, 1.0 eq) and N,N-diisopropylethylamine (1.9 g, 14.6 mmol, 5.0 eq) were added at room temperature, and the mixture was stirred at 40 °C for 12 h. TLC showed the reaction was essentially complete, and mass spectrometry showed product formation. The reaction was then purged with nitrogen, cooled to room temperature, and quenched with water. The product was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give the final product II-d (140.1 mg, 14%) as a yellow solid with a purity >99%.

[0243] The reaction conditions shown on the TLC plate were as follows: TLC: dichloromethane: methanol = 20:1, UV 254nm;

[0244] Rf(compound II-b) = 0.6; Rf(compound II-d) = 0.7. LC-MS: 330.0, [M+1] + ;

[0245] Furthermore, Figure 28 shows the nuclear magnetic resonance spectrum of product II-d prepared in this embodiment: 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.17(dd,J=8.8,5.2Hz,2H),7.87(d,J=4.8Hz,1H),7.41(t ,J=8.8Hz,2H),7.10(s,1H),7.03(d,J=2.0Hz,1H),6.57(d,J=2.0Hz,1H),2.66(d,J=4.8Hz,3H).

[0246] Synthetic product II-e:

[0247] Intermediate product 4 was dissolved in 48% aqueous hydrobromic acid solution, the reaction was carried out under nitrogen gas and stirred continuously at 100°C for 48 h, and the crude product obtained after treatment and separation was purified by silica gel column chromatography to obtain product II-e with a purity >95%.

[0248] LC-MS: 287.00, [M+1] + .

[0249] Figure 29 shows the nuclear magnetic resonance spectrum of product II-e obtained in this embodiment: 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.20–8.14(m,2H),7.42(t,J=8.8Hz, 2H),7.03(s,1H),6.81(d,J=2.4Hz,1H),6.39(d,J=2.4Hz,1H),3.86(s,3H).

[0250] Synthetic product II-c:

[0251] Compound II-b was dissolved in 10 ml of tetrahydrofuran solution, and dimethylcarbamoyl chloride and sodium hydride were added at room temperature. The mixture was stirred at 40 °C for 12 h. The crude product obtained after treatment and separation was purified by silica gel column chromatography to obtain product II-c with a purity >97%.

[0252] LC-MS: 344.25, [M+1] + .

[0253] Figure 30 shows the nuclear magnetic resonance spectrum of product II-c obtained in this embodiment: 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.18(dd,J=8.8,5.2Hz,2H),7.42(t,J=8.8Hz,2H ), 7.11 (s, 1H), 7.08 (d, J = 2.0Hz, 1H), 6.63 (d, J = 2.0Hz, 1H), 3.02 (s, 3H), 2.91 (s, 3H).

[0254] Synthetic product II-f:

[0255] Compound II-b was dissolved in N,N-dimethylformamide (DMF) solution, and N-(tert-butoxycarbonyl)glycine, N,N-diisopropylethylamine (DIEA) and the polypeptide condensation reagent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) were added at room temperature to give intermediate 8. The Boc was removed with trifluoroacetic acid (TFA) and dichloromethane (DCM) to give final product II-f.

[0256] Example 2

[0257] Specific experimental methods

[0258] Vascular endothelial cell proliferation experiment

[0259] HUVEC cells were seeded at 3000 cells / well in 96-well plates and cultured for 24 h. Then, the culture medium was replaced with Ham's F-12K containing 0.2% FBS and 50 ng / mL heparin sodium for 6 h of starvation. After 6 h, the test compound was added and the cells were cultured for another 48 h. After 48 h, cell proliferation was assessed using the CTG method (Cell Titer-Glo Luminescent Assay, DD1101-02, Novizan).

[0260] OGD / R (Oxygen-glucose deprivation / reperfusion) induced vascular endothelial cell injury experiment

[0261] HUVEC cells were seeded at a rate of 4000 cells / well in 96-well plates and cultured normally for 24 hours. After 24 hours, the culture medium was replaced with sugar-free DMEM (11966025, Gibco) containing the test compound, and the plates were placed in an anaerobic incubator. After 4 hours, the culture medium was replaced with normal culture medium containing the test compound, and the plates were placed in a normal incubator for another 24 hours. Cell viability was assessed using the CTG method.

[0262] TNF-α-induced vascular endothelial cell injury experiment

[0263] HUVEC cells were seeded at 4000 cells / well in 96-well plates and cultured for 24 h. The culture medium was then replaced with Ham's F-12K medium containing 0.2% FBS, 50 ng / mL heparin sodium, and 20 ng / mL bFGF for 12 h of starvation. Then, 3 ng / mL TNF-α and the test compound were added, and the treatment continued for another 24 h. After 24 h, cell viability was assessed using the CTG method.

[0264] IL-1β-induced vascular endothelial cell injury experiment

[0265] HUVEC cells were seeded at 4000 cells / well in 96-well plates and cultured for 24 h. The culture medium was then replaced with Ham's F-12K medium containing 0.2% FBS, 50 ng / mL heparin sodium, and 20 ng / mL bFGF for 12 h of starvation. Then, 10 ng / mL IL-1β and the assay compound were added, and the treatment continued for another 24 h. After 24 h, cell viability was assessed using the CTG method.

[0266] IFN-γ-induced vascular endothelial cell injury experiment

[0267] HUVEC cells were seeded at 4000 cells / well in 96-well plates and cultured for 24 h. The culture medium was then replaced with Ham's F-12K medium containing 0.2% FBS, 50 ng / mL heparin sodium, and 20 ng / mL bFGF for 12 h of starvation. Then, 5 ng / mL IFN-γ and the assay compound were added, and the treatment continued for another 24 h. After 24 h, cell viability was assessed using the CTG method.

[0268] Tubular structure formation experiment

[0269] The culture medium for HUVEC cells was replaced with Ham's F-12K medium containing 1% FBS and 50 ng / mL heparin sodium, and the cells were starved for 3 hours.

[0270] Adhesive application: Apply Matrigel (354230, Corning) at 50 μL per well of the 96-well plate and place at 37°C for 30 min to allow the adhesive to solidify.

[0271] Preparation of the test compound: Prepare the test compound at a 10-fold concentration, adding 11 μL of 10× test compound to each well.

[0272] After digesting and starving HUVEC cells, centrifuge at 1000 rpm for 5 minutes, resuspend in Ham's F-12K medium containing 1% FBS and 50 ng / mL heparin sodium, and count the cells.

[0273] Seed cells at a density of 10,000 cells per well, with 100 μL of cell suspension per well, and incubate at 37°C for 6 hours.

[0274] Six hours later, Calcein AM (C2012, Beyotime) was added for staining, and the images were taken using an Olympus IX73 microscope (4× objective).

[0275] Neural synapse growth

[0276] SHSY-5Y neural cells were seeded at 50,000 cells / well in 10% FBS MEM / F12 medium in 24-well plates and cultured for 24 hours. The following day, the cells were treated with the test compound in 1% FBS MEM / F12 medium. After 24 hours of compound treatment, cell morphology was observed under an inverted microscope, and images were taken at random from 10 fields of view per well. To determine neurite growth, the lengths of the five longest neurites in each well were calculated using an ImageJ plugin, and the average neurite length was statistically analyzed from data obtained from at least three independent replicate experiments.

[0277] Preparation of a mouse model of transient middle cerebral artery occlusion (tMCAO)

[0278] C57BL / 6J mice were randomly divided into 6 groups: Sham group (solvent), tMCAO+Veh group (solvent), tMCAO+NBP (positive control drug, butylphthalide) group, and tMCAO+EW223 (0.20 mg / kg, 0.67 mg / kg, 2.0 mg / kg) group. After 2 hours of ischemia, the mice were randomly assigned to groups and injected via tail vein with solvent, NBP, or EW223 once daily for 7 consecutive days. Tissue samples were collected 4 hours after the last injection.

[0279] Establishment of a mouse model of transient middle cerebral artery embolism (tMCAO model):

[0280] (1) Before the tMCAO surgery, the mice were fasted for 12 hours but allowed to drink water. Then they were anesthetized with isoflurane inhalation (4% for induction, 2% for maintenance), fixed in a supine position, and a midline incision was made in the neck to expose the right common carotid artery (CCA), external carotid artery (ECA) and internal carotid artery (ICA).

[0281] (2) Ligate the proximal ends of the ECA and CCA with sutures, and keep the distal end of the CCA with sutures. Temporarily clamp the ICA with a mini arterial clamp.

[0282] (3) Make a small incision 3 mm from the bifurcation of the ECA, insert a 2 mm silicone-coated suture plug through the incision, and gently push the suture plug (Huayang, 14-3003). Open the arterial clamp on the ICA, allowing the suture plug to enter the middle cerebral artery (MCA) along the ICA. Secure the suture with a spare suture. The distance from the bifurcation of the CCA to the point of resistance (the origin of the middle cerebral artery) is approximately 8 mm.

[0283] (4) Use the spare suture at the distal end of the CCA to tie and fix the suture plug and the CCA, and then suture.

[0284] (5) During reperfusion, mice were anesthetized with isoflurane (4% for induction, 2% for maintenance), the cervical suture incision was opened, the suture plug was gradually pulled out until it was completely removed from the ECA, the ECA stump was electrocoagulated with an electrocoagulator, the cervical incision was sutured again, and povidone-iodine was applied for disinfection. After surgery, the animals were kept at body temperature by irradiating with a heater for 4 hours, and were kept in individual cages for 24 hours without food but without water.

[0285] Intravenous administration began 2 hours after model establishment, once daily for 7 days. On day 8, open field tests and Y-maze tests were performed. A final dose was administered after analysis, followed by cerebral blood flow testing. Perfusion sampling was performed 4 hours after administration.

[0286] cerebral infarction volume measurement

[0287] The brain was harvested on the third day after surgery. The intact brain tissue was frozen at -20℃ for 20 minutes. Coronal brain slices were cut from the forebrain and divided into 6 slices, each slice being 2mm thick.

[0288] Brain slices were placed in six-well plates containing 0.2% TTC solution (prepared with physiological saline) and incubated at 37°C in the dark for 15 minutes. The plates were then removed, and the brain slices were gently turned over with forceps to ensure even contact with the staining solution. After 15 minutes, the TTC staining solution was aspirated, and the brain slices were fixed with 4% paraformaldehyde solution. Images were taken after 30 minutes, and the images were analyzed using Image Pro Plus image analysis software to determine the area of ​​cerebral infarction. Normal brain tissue areas were shown in red, while infarcted and surrounding areas were shown in white. The cerebral infarction volume ratio was calculated using the following formula: Cerebral infarction volume ratio % = Infarct volume / Volume of the non-infarcted hemisphere × 100.

[0289] Mouse Y-maze Behavior

[0290] The mouse Y-maze apparatus consists of three identical arms, each 40cm × 3cm × 12cm and positioned at 120° to each other. The mouse is placed within the central triangular area with its head facing one of the arms and explores freely within the Y-maze for 5 minutes. The spontaneous alternation response rate is then calculated. Spontaneous alternation response rate = number of alternations / (total number of arm entries n - 2) × 100.

[0291] In the open field experiment, mice were placed in the corner of an opaque open field box (50cm×50cm×50cm) under a camera, with their heads facing the corner. The light intensity was 100±5 lux. The mice were allowed to move freely in the open field box for 1 hour. The total distance and time the mice traveled in the central area (21cm×21cm) were recorded.

[0292] Cerebral blood flow detection

[0293] Mice were anesthetized using a RWD Life Science R540 Pro anesthesia machine (3% isoflurane in the air) and maintained with 1.2-1.5% isoflurane. They were fixed in a prone position within a stereotactic frame (RWD Life Science) and their body temperature was maintained at 37°C using a heating pad. Laser speckle flow imaging was performed on the seventh day after tMCAO modeling. The scalp was opened to expose the skull, and the probe was positioned 10 cm above the skull. The camera magnification was set to 4.3, and the region of interest (ROI) was selected. Using a laser speckle flow imaging system (RWD Life Science RFLSI III), the camera aperture was adjusted to match the speckle size to the pixel size (2048*2048). Images were acquired at 10 frames per second (5 ms exposure time), uniformly illuminating the skull surface under 780 nm laser diode conditions and a laser intensity of 110 mW. Blood perfusion was continuously recorded for 1 minute, and the average value was used as the baseline cerebral blood flow level for analysis of cerebral blood flow changes.

[0294] Statistical analysis

[0295] All data are presented as mean ± SEM. All charts were created using GraphPad Prism 8.4.0. One-way ANOVA was used to evaluate the infarct volume ratio, brain water content, total exploration time, discrimination index, and rotator results, combined with Turkey's post-hoc test. Animal survival rate was assessed using the Kaplan-Meier test. Neurological function scores were evaluated using the Kruskal-Wallis nonparametric test. A p-value < 0.05 was considered statistically significant.

[0296] Experimental results

[0297] Figures 1-5 illustrate the effects of apigenin (Api, formula II-a), butylphthalide (NBP), and edaravone-dexborneol (ED) on angiogenesis, anti-ischemic injury, and anti-inflammation. Further details are also provided.

[0298] Figure 1 shows the effects of the blank control group, different concentrations of butylphthalide (1 μM, 3 μM), different concentrations of edaravone-dexborneol (30 μM, 100 μM), and apigenin (0.3 μM, 1 μM, 3 μM) on the proliferation of human umbilical vein endothelial cells (HUVECs). As can be seen from Figure 1, compared with the blank control group, apigenin promoted the proliferation of vascular endothelial cells, while butylphthalide and edaravone-dexborneol did not.

[0299] Figure 2 shows the effects of different concentrations of butylphthalide (1 μM, 3 μM), edaravone-dextrin (30 μM, 100 μM), and apigenin (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-ischemic injury) in the normal control group, the oxygen-glucose deprivation injury (OGD / R) group, and under OGD / R injury. As can be seen from Figure 2, in the OGD / R injury model, apigenin has a better protective effect on vascular endothelial cells and alleviates damage caused by oxygen-glucose deprivation compared to butylphthalide and edaravone-dextrin.

[0300] Figure 3 shows the effects of different concentrations of butylphthalide (1 μM, 3 μM), edaravone-dextrin (30 μM, 100 μM), and apigenin (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory) under TNF-α injury, as well as on the survival of vascular endothelial cells under TNF-α injury. As can be seen from Figure 3, compared with butylphthalide and edaravone-dextrin, apigenin has a better protective effect on vascular endothelial cells and alleviates TNF-α-induced injury.

[0301] Figure 4 shows the effects of the normal control group, the IL-1β-damaged group, and different concentrations of butylphthalide (1 μM, 3 μM), different concentrations of edaravone-dextrin (30 μM, 100 μM), and apigenin (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory) under IL-1β-damaged conditions. As can be seen from Figure 4, compared with the IL-1β-damaged group, apigenin has a protective effect on vascular endothelial cells and alleviates IL-1β-induced damage, while butylphthalide and edaravone-dextrin have no such effect.

[0302] Figure 5 shows the effects of the normal control group, the IFN-γ injury group (IFN-γ), and the different concentrations of butylphthalide (1 μM, 3 μM), edaravone-dexborneol (30 μM, 100 μM), and apigenin (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory) under IFN-γ injury. As can be seen from Figure 5, compared with the IFN-γ injury group, apigenin has a protective effect on vascular endothelial cells and alleviates IFN-γ-induced damage, while butylphthalide and edaravone-dexborneol have no such effect.

[0303] Figures 6-10 show the effects of EW223 (Formula II-b) and apigenin (Api, Formula II-a) on three aspects: angiogenesis, anti-ischemic injury, and anti-inflammation. Further:

[0304] Figure 6 shows the effects of the blank control group, the apigenin group (3 μM), and different concentrations of EW223 (0.3 μM, 1 μM, 3 μM) on the proliferation of human umbilical vein endothelial cells (HUVECs). As can be seen from Figure 6, compared with the blank control group, EW223 had the same effect on promoting endothelial cell proliferation as apigenin, and there was no statistically significant difference compared with the apigenin group.

[0305] Figure 7 shows the effects of the normal control group, the oxygen-glucose deprivation injury group (OGD / R), and the apigenin group (3 μM) and different concentrations of EW223 (0.3 μM, 1 μM, 3 μM) under OGD / R injury on vascular endothelial cell survival (anti-ischemic-like injury). As can be seen from Figure 7, compared with the OGD / R injury group, EW223, like apigenin, has the effect of protecting vascular endothelial cells and alleviating oxygen-glucose deprivation-induced injury.

[0306] Figure 8 shows the effects of the normal control group, the TNF-α injury group (TNFα), the apigenin group under TNF-α injury (3 μM), and different concentrations of EW223 (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 8, compared with the TNF-α injury group, EW223, like apigenin, has the effect of protecting vascular endothelial cells and alleviating TNF-α-induced damage.

[0307] Figure 9 shows the effects of the normal control group, the IL-1β-damaged group (IL-1β), the apigenin group (3 μM) under IL-1β damage, and different concentrations of EW223 (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 9, compared with the IL-1β-damaged group, EW223, like apigenin, has a protective effect on vascular endothelial cells and alleviates IL-1β-induced damage.

[0308] Figure 10 shows the effects of the normal control group, the IFN-γ injury group (IFN-γ), the apigenin group under IFN-γ injury (3 μM), and different concentrations of EW223 (0.3 μM, 1 μM, 3 μM) on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 10, compared with the IFN-γ injury group, EW223, like apigenin, has a protective effect on vascular endothelial cells and alleviates IFN-γ-induced damage.

[0309] Figures 11-15 show the effects of EW231 (Formula II-d) and EW223 (Formula II-b) on three aspects: angiogenesis, anti-ischemic injury, and anti-inflammation. Further:

[0310] Figure 11 shows the effects of the blank control group, the EW223 group (3 μM), and different concentrations of EW231 (0.3 μM, 1 μM, 3 μM) on the proliferation of human umbilical vein endothelial cells (HUVECs). As can be seen from Figure 11, compared with the blank control group, EW231 had the same effect on promoting endothelial cell proliferation as EW223, and there was no statistically significant difference between the two groups.

[0311] Figure 12 shows the effects of the normal control group, the oxygen-glucose deprivation injury group (OGD / R), and the EW223 group (3 μM) and different concentrations of EW231 (0.3 μM, 1 μM, 3 μM) under OGD / R injury on vascular endothelial cell survival (anti-ischemia-like injury). As can be seen from Figure 12, compared with the OGD / R injury group, EW231, like EW223, has a protective effect on vascular endothelial cells and alleviates oxygen-glucose deprivation-induced injury.

[0312] Figure 13 shows the effects of the normal control group, the TNF-α injury group (TNFα), and the EW223 group (3 μM) and different concentrations of EW231 (0.3 μM, 1 μM, 3 μM) under TNF-α injury on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 13, compared with the TNF-α injury group, EW231, like EW223, has the effect of protecting vascular endothelial cells and alleviating TNF-α-induced damage.

[0313] Figure 14 shows the effects of the normal control group, the IL-1β-damaged group (IL-1β), and the EW223 group (3 μM) and different concentrations of EW231 (0.3 μM, 1 μM, 3 μM) under IL-1β damage on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 14, compared with the IL-1β-damaged group, EW231, like EW223, has the effect of protecting vascular endothelial cells and alleviating IL-1β-induced damage.

[0314] Figure 15 shows the effects of the normal control group, the IFN-γ injury group (IFN-γ), and the EW223 group (3 μM) and different concentrations of EW231 (0.3 μM, 1 μM, 3 μM) under IFN-γ injury on vascular endothelial cell survival (anti-inflammatory). As can be seen from Figure 15, compared with the IFN-γ injury group, EW231, like EW223, has a protective effect on vascular endothelial cells and alleviates IFN-γ-induced damage.

[0315] Figures 16–19 show the effects of blank control group (Ctrl), EW231 (Formula II-d) 3 μM, EW223 (Formula II-b) 3 μM, apigenin group (Api, Formula II-c) 3 μM, and positive control group (VEGF-A) 20 ng / mL on the formation of tubular structures in vascular endothelial cells.

[0316] As shown in Figures 16-19, compared with the blank control group, the positive control VEGF significantly promoted the formation of tubular structures by vascular endothelial cells. EW231 also promoted the formation of tubular structures by vascular endothelial cells, but its effect was not statistically different from that of EW223 and apigenin. These results indicate that the three compounds, EW231, EW223, and apigenin, can all significantly promote the formation of tubular structures by vascular endothelial cells, as evidenced by a significant increase in the total length (Figure 17), tube number (Figure 18), and branch points (Figure 19) of the tubular structures, with similar degrees of effect.

[0317] Figures 20-21 illustrate the roles of EW231 (Formula II-d), EW223 (Formula II-b), and RA (retinoic acid) in synaptic growth:

[0318] Figures 20-21 show the effects of the blank control group (Vehicle), RA group, EW223 group (EW223-5, indicating EW223 concentration of 5 μM), and EW231 group (EW231-5, indicating EW231 concentration of 5 μM) on promoting synaptic growth. As can be seen from Figures 20 (representative figure) and 21 (statistical figure), compared with the blank control group, the positive control RA significantly promoted the growth of synapses of nerve cells. At this time, both EW223 and EW231 showed significant effects in promoting the growth of synapses of nerve cells.

[0319] Figures 22-27 show the effects of EW223 (Formula II-b) on tMCAO model mice.

[0320] Figures 22 and 23 show representative TTC staining results (Figure 22) and statistical graphs (Figure 23) 3 days after administration of EW223 in the tMCAO group (Veh) and the tMCAO model group treated with EW223 (EW223, 0.2 or 0.67 mg / kg) or the butylphthalide group (NBP, 6 mg / kg). As can be seen from Figures 22 and 23, compared with the Veh group, EW223 significantly reduced the infarct area in the ischemic region; compared with the NBP group, EW223 showed a superior reduction in infarct area.

[0321] Figures 24 and 25 show representative graphs (Figure 24) and statistical graphs (Figure 25) of cerebral blood flow detection results one week after administration to the sham-operated group (Sham), the tMCAO group (Veh), and the tMCAO model group treated with EW223 (0.2 mg / kg, 0.67 mg / kg, 2 mg / kg) or the butylphthalide group (NBP, 6 mg / kg). Figures 24 and 25 show that compared with the Veh group, EW223 significantly increased cerebral blood flow, while NBP had no significant effect on improving cerebral blood flow.

[0322] Figure 26 shows the Y-maze behavioral data of mice in the sham-operated group (Sham), the tMCAO group (Veh), and the tMCAO model treated with EW223 (0.2 mg / kg, 0.67 mg / kg, 2 mg / kg) or butylphthalide group (NBP, 6 mg / kg). As shown in Figure 26, the total distance traveled by mice in the Veh group decreased, and the number of alternations was reduced. EW223 significantly improved post-injury behavior, increasing both the total distance traveled and the number of alternations, compared to butylphthalide.

[0323] Figure 27 shows the behavioral data of mice in the open field test under the sham-operated group (Sham), the tMCAO group (Veh), and the tMCAO model treated with EW223 (0.2 mg / kg, 0.67 mg / kg, 2 mg / kg) or butylphthalide (NBP, 6 mg / kg). As shown in Figure 27, the proportion of time spent in the central region of the open field chamber decreased in the Veh group. EW223 significantly improved post-injury behavior and increased the proportion of time spent in the central region compared to butylphthalide.

[0324] The above description provides an illustrative overview of the present invention and its embodiments. This description is not restrictive, and the embodiments shown are merely one example of the invention's implementation. Actual implementations are not limited to these examples. Therefore, if those skilled in the art are inspired by this description and design similar implementations and examples without departing from the spirit of the invention, such designs should fall within the scope of protection of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, characterized in that, The structure of the compound is shown in the following formula: R1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino. R2 and R3 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, Fmoc-aminoacyl, aminoacyl, or groups having one of the following formulas: R4 and R5 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof and mixtures thereof, characterized in that, The R1 is selected from OH, F, Cl, Br, and I; R2 and R3 are each independently selected from C1-C6 alkyl groups or groups having one of the following formulas: R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from H, substituted or unsubstituted aliphatic side chains, or substituted or unsubstituted aromatic side chains.

3. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof and mixtures thereof, characterized in that, R2 and R3 are each independently selected from H, C1-C4 alkyl groups, or groups having one of the following formulas: R4 and R5 are each independently selected from hydrogen, deuterium, or CH3; R6 is selected from the α-side chain of one of the natural amino acids.

4. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof and mixtures thereof, characterized in that, R1 is selected from fluorine and hydroxyl groups; R2 is selected from C1-C4 alkyl groups or groups having one of the following formulas: R4 and R5 are each independently selected from hydrogen or CH3; R6 is hydrogen; and R3 is hydrogen.

5. A compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, characterized in that, The structure of the compound is shown in the following formula: R1 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino. R2 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, Fmoc-aminoacyl, aminoacyl or a group having one of the following general formulas: R4 and R5 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups.

6. The compound according to claim 5, or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof and mixtures thereof, characterized in that, R1 is selected from fluorine and hydroxyl groups; R2 is selected from C1-C4 alkyl groups or groups having one of the following formulas: R4 and R5 are each independently selected from hydrogen or CH3; R6 is hydrogen.

7. A compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, or a mixture thereof, characterized in that, The compound is any one of formulas II-a, II-b, II-c, II-d, II-e, and II-f:

8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof or a mixture thereof, and a pharmaceutically acceptable carrier or diluent.

9. A pharmaceutical composition comprising a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof or a mixture thereof, and a pharmaceutically acceptable carrier or diluent; 10. A pharmaceutical composition comprising a compound of formula II-b or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof or a mixture thereof, and a pharmaceutically acceptable carrier or diluent; 11. A pharmaceutical composition comprising a compound of formula II-d or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof and mixtures thereof, and a pharmaceutically acceptable carrier or diluent; 12. The pharmaceutical composition according to any one of claims 8 to 11, characterized in that, The pharmaceutical composition is in a single-dose form, wherein the single-dose form contains 0.03 mg to 300 mg of the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof or a mixture thereof, and a pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition according to any one of claims 8 to 12, characterized in that, The mass percentage of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer and mixture thereof in the pharmaceutical composition is 1 to 99 wt%.

14. The pharmaceutical composition according to any one of claims 8 to 13, characterized in that, The drug loading concentration of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof in the pharmaceutical composition is 0.01 to 10 mg / mL.

15. The pharmaceutical composition according to any one of claims 8 to 14, characterized in that, It also includes agents selected from at least one of the following: Combination drugs; Other treatments for cerebrovascular diseases; Cardiovascular disease treatment agents.

16. The pharmaceutical composition according to any one of claims 15, characterized in that, The other cerebrovascular disease treatment agents are selected from any one, two, or more of the following: A therapeutic agent for cerebrovascular diseases characterized by inhibiting, reducing, or alleviating inflammation in the brain; A therapeutic agent for cerebrovascular diseases characterized by inhibiting, reducing, or alleviating the volume of cerebral infarction; Treatment agents for cerebrovascular diseases characterized by inhibiting, reducing, or alleviating reduced blood flow to the brain; A therapeutic agent for cerebrovascular diseases characterized by inhibiting, reducing, or relieving cerebral blood flow interruption; A therapeutic agent for cerebrovascular diseases characterized by inhibiting, reducing, or alleviating cerebral hemorrhage.

17. The pharmaceutical composition according to claim 15 or 16, characterized in that, The combination drugs are selected from any one, two, or more of the following: Combination drugs with anti-cerebral thrombosis effects; Combination drugs with antiplatelet activity; Combination drugs with thrombolytic effects; Combination drugs with antioxidant effects; Combination drugs with anticoagulant effects; Combination drugs that have cholesterol-lowering effects.

18. The pharmaceutical composition according to any one of claims 15 to 17, characterized in that, The combination drugs or other cerebrovascular disease treatment agents or cardiovascular disease treatment agents mentioned include any one, two or more of butylphthalide, edaravone, dextroborneol, aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, heparin, warfarin, dabigatran, apixaban, rivaroxaban and atorvastatin.

19. The pharmaceutical composition according to any one of claims 8 to 18, characterized in that, The dosage form of the pharmaceutical composition is selected from one or more of the following: powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion, or suspension.

20. The pharmaceutical composition according to claims 8 to 18, wherein the dosage form of the pharmaceutical composition is an injection; the pharmaceutical composition further comprises a solvent.

21. The pharmaceutical composition according to claim 20, characterized in that, The solvent is selected from one or more of alcohol solvents, ether solvents, ketone solvents, and sulfide compound solvents; Preferably, the alcohol solvent includes one or more of ethanol, isopropanol, ethylene glycol, propylene glycol, and polyethylene glycol; The ether solvents include one or more of ethylene glycol monoethyl ether and ethylene glycol monobutyl ether; The ketone solvents include one or more of acetone and N-methyl-2-pyrrolidone; The solvent for the sulfide compounds includes dimethyl sulfoxide.

22. The use of the compound of any one of claims 1 to 7 or its pharmaceutically acceptable salt, ester, hydrate, solvate or its tautomer or mixture thereof, or the use of the pharmaceutical composition of any one of claims 8 to 21 for the preparation of a medicament for the prevention or treatment of cardiovascular and cerebrovascular diseases, wherein the cardiovascular and cerebrovascular diseases include cardiovascular diseases or cerebrovascular diseases.

23. The use according to claim 22, characterized in that, The cerebrovascular diseases mentioned include: Cerebrovascular diseases characterized by increased inflammation in the brain; or Cerebrovascular diseases characterized by an increase in the volume of cerebral infarction; or Cerebrovascular diseases characterized by reduced or interrupted blood flow to the brain; or Cerebrovascular diseases characterized by rupture of cerebral blood vessels; Cerebrovascular diseases characterized by hemorrhage caused by ruptured blood vessels in the brain.

24. The use according to claim 22, wherein the cerebrovascular disease comprises: Ischemic cerebrovascular disease; or Hemorrhagic cerebrovascular disease; or Atherosclerosis, stenosis, or occlusion of the arteries in the head and neck.

25. The use according to claim 22, characterized in that, The cerebrovascular diseases mentioned include any one, two or more of the following: transient ischemic attack, cerebral infarction, stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, chronic cerebral ischemia, cerebral hemorrhage, cerebral hemorrhage, and subarachnoid hemorrhage.

26. The use according to claim 25, characterized in that, The stroke mentioned is ischemic stroke.

27. The use according to claim 22, characterized in that, The cardiovascular diseases mentioned include: Cardiovascular diseases characterized by angina pectoris; or Cardiovascular diseases characterized by myocardial infarction; or Cardiovascular diseases characterized by ischemic cardiomyopathy; or Cardiovascular disease characterized by chronic heart failure.

28. The use according to claim 22, characterized in that, The cardiovascular diseases mentioned are selected from chronic heart failure, myocardial infarction, coronary heart disease, and peripheral arterial vascular diseases.

29. A pillbox comprising one or more single-dose units of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof or a mixture thereof, or a pharmaceutical composition comprising one or more single-dose units according to any one of claims 8 to 21, and instructions for use in treating a disease.

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