Use of 3-hydroxy-2-aminobenzimidazole derivatives for the preparation of a medicament for the prevention and treatment of myocardial ischemia-reperfusion injury

Abstract

This application relates to the field of biomedical technology, specifically to the application of 3-hydroxy-2-aminobenzimidazole derivatives as ferroptosis inhibitors in the preparation of drugs for preventing and treating myocardial ischemia-reperfusion injury. 3-hydroxy-2-aminobenzimidazole derivatives, as ferroptosis inhibitors, can (1) improve the survival rate of cardiomyocytes after myocardial ischemia-reperfusion and (2) inhibit the generation of lipid free radicals in cardiomyocytes after myocardial ischemia-reperfusion. This invention provides evidence of the inhibitory effect of 3-hydroxy-2-aminobenzimidazole derivatives on cardiomyocyte ferroptosis, providing a theoretical basis for the treatment of myocardial ischemia-reperfusion injury targeting ferroptosis, and particularly for the clinical application of its combination with ferroptosis inhibitors. The 3-hydroxy-2-aminobenzimidazole derivatives include the following compounds:

Description

Technical Field

[0001] This application relates to the field of biomedical technology, specifically to the application of 3-hydroxy-2-aminobenzimidazole derivatives as ferroptosis inhibitors in the preparation of drugs for the prevention and treatment of myocardial ischemia-reperfusion injury. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Myocardial ischemia, also known as coronary heart disease, is one of the most common cardiovascular diseases. Globally, approximately 23.5 million people die from coronary heart disease each year, with myocardial infarction being the second leading cause of death. Myocardial infarction is primarily caused by a reduction or interruption of blood supply to the coronary arteries, leading to ischemia and hypoxia of myocardial cells, ultimately resulting in myocardial cell necrosis. Currently, the main clinical treatment approach is to quickly restore blood flow to the ischemic myocardium, increase blood volume, and improve microcirculation to salvage dying myocardial cells. Therefore, rapid reperfusion is the only effective way to treat acute myocardial infarction. However, numerous studies have found that ischemic myocardial reperfusion itself can induce a series of new pathophysiological changes, further aggravating myocardial tissue cell damage, resulting in reperfusion arrhythmias, myocardial systolic and diastolic dysfunction, metabolic abnormalities, and changes in myocardial ultrastructure, known as myocardial ischemia-reperfusion injury (MIRI). Currently, the factors that induce myocardial ischemia-reperfusion injury and their underlying mechanisms remain unclear. However, existing studies have shown that ferroptosis promotes the progression of myocardial ischemia-reperfusion injury by participating in calcium overload, oxidative stress, and mitochondrial dysfunction.

[0004] Ferrostatin-1 and Liproxstatin-1 are first-generation small-molecule ferroptosis inhibitors that function by scavenging lipid free radical damage to cell membranes and blocking ferroptosis. These inhibitors have well-defined mechanisms of action and structure-activity relationships. However, both compounds suffer from drawbacks, namely short half-lives and relatively high toxicity. Therefore, there is an urgent need for a ferroptosis inhibitor suitable for preventing and treating myocardial ischemia-reperfusion injury. Summary of the Invention

[0005] To overcome the aforementioned problems, this invention provides the application of a 3-hydroxy-2-aminobenzimidazole derivative as a ferroptosis inhibitor in the preparation of drugs for preventing and treating myocardial ischemia-reperfusion injury. Based on research into the mechanism of ferroptosis, this invention, through drug design and cell activity testing, discovered that a 3-hydroxy-2-aminobenzimidazole derivative can act as a targeted inhibitor of ferroptosis, and provides its use in the preparation of drugs for preventing and treating myocardial ischemia-reperfusion injury.

[0006] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides the use of a 3-hydroxy-2-aminobenzimidazole derivative as a ferroptosis inhibitor in the preparation of a medicament for the prevention, improvement, or treatment of myocardial ischemia-reperfusion injury, wherein the 3-hydroxy-2-aminobenzimidazole derivative has the structural formula shown in Formula (I):

[0008]

[0009] R1 is selected from hydrogen, methyl and chlorine, and R2 is selected from hydrogen and methyl.

[0010] In one or more embodiments, the 3-hydroxy-2-aminobenzimidazole derivative includes the following compounds:

[0011]

[0012] Further preferred options are:

[0013] The reason why 3-hydroxy-2-aminobenzimidazole derivatives can act as inhibitors of ferroptosis is that they can block the chain reaction of lipid free radicals, reduce the damage of free radicals to cell membranes, and prevent ferroptosis.

[0014] In one or more embodiments, the 3-hydroxy-2-aminobenzimidazole derivative, in addition to small molecule entities having the above-described structure, the hydrates, solvates, pharmaceutical salts, and pharmaceutical esters of the compound also fall under the same concept as the first aspect of this invention and are part of the technical content protected by this invention.

[0015] In one or more embodiments, the 3-hydroxy-2-aminobenzimidazole derivative acts as a ferroptosis inhibitor and has at least one of the following effects:

[0016] (1) Improve the survival rate of cardiomyocytes after myocardial ischemia-reperfusion;

[0017] (2) Inhibits the generation of lipid free radicals in cardiomyocytes after myocardial ischemia-reperfusion.

[0018] In a second aspect, the present invention provides a medicament for preventing, improving or treating myocardial ischemia-reperfusion injury, wherein the active ingredient of the medicament is the above-mentioned 3-hydroxy-2-aminobenzimidazole derivative.

[0019] In one or more embodiments, the formulation of the drug is selected from gastrointestinal dosage forms or non-gastrointestinal dosage forms.

[0020] Preferably, the above-mentioned gastrointestinal dosage forms include powders, tablets, granules, capsules, sustained-release preparations, solutions, dry suspensions, effervescent tablets, emulsions, and suspensions.

[0021] Preferably, non-gastrointestinal dosage forms include injectable dosage forms (e.g., injections, including various injections such as intravenous injections, intramuscular injections, subcutaneous injections, intradermal injections, and intracavitary injections); respiratory dosage forms (e.g., sprays, aerosols, powders, etc.); skin dosage forms (e.g., topical solutions, lotions, liniments, ointments, plasters, pastes, patches, etc.); mucosal dosage forms (e.g., eye drops, nasal drops, ophthalmic ointments, mouthwashes, sublingual tablets, adhesive tablets, films, etc.); and cavity dosage forms (e.g., suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the rectum, vagina, urethra, nasal cavity, ear canal, etc.).

[0022] A third aspect of the present invention provides a pharmaceutical composition for preventing, improving or treating myocardial ischemia-reperfusion injury, comprising a therapeutically effective amount of the above-described 3-hydroxy-2-aminobenzimidazole derivative.

[0023] The beneficial effects of this invention are mainly reflected in the following aspects: This invention provides evidence of the inhibition of cardiomyocyte ferroptosis by 3-hydroxy-2-aminobenzimidazole derivatives, providing a theoretical basis for the treatment of myocardial ischemia-reperfusion injury targeting ferroptosis, and in particular, providing a basis for its combined use with ferroptosis inhibitors in clinical practice. Attached Figure Description

[0024] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0025] Figure 1 The inhibitory effect of the 3-hydroxy-2-aminobenzimidazole derivative on RSL3-induced lipid free radicals in Experimental Example 2;

[0026] Figure 2 The effect of 3-hydroxy-2-aminobenzimidazole derivative on the relief of myocardial ischemia-reperfusion injury (I / R) in rats was shown in Experiment 3. Detailed Implementation

[0027] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0028] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0029] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0030] Ferrostatin-1 and RSL3 were purchased from Sigma and dissolved in sterile dimethyl sulfoxide (DMSO) to prepare the required concentrations.

[0031] Cardiac cell line culture conditions: RPMI Medium 1640 medium, 37℃, 5% CO2 saturated humidity incubator.

[0032] The statistical analysis used in this invention employed R software, and experimental data are expressed as Mean ± SEM. Tukey's test (ANOVA) was used for inter-group comparisons in cell and animal experiments, while Student's test was used for comparisons between two groups. A p-value < 0.05 was considered statistically significant; different letters indicate p < 0.05.

[0033] Example 1: Preparation of Compound 1

[0034]

[0035] (1) Add 3-methoxy-2-nitrobenzoic acid (10 mmol, 1.97 g), oxalyl chloride (12.8 mmol, 1.62 g) and dichloromethane (20 mL) to a flask, add 1 drop of DMF to initiate the reaction, stir at room temperature for 1 h, and then evaporate the solvent under vacuum to obtain intermediate A.

[0036] (2) Dissolve intermediate A (10 mmol) in 40 mL of dichloromethane and slowly add it dropwise to 80 mL of dichloromethane solution containing o-phenylenediamine (10 mmol, 1.08 g) and triethylamine (12.8 mmol, 1.30 g) using a constant pressure dropping funnel under ice bath conditions. Continue stirring under ice bath conditions for 1 h, then restore the temperature to room temperature and continue stirring for 1 h. When the reaction is complete as detected by TLC, evaporate the solvent under vacuum to obtain crude intermediate B. Purify intermediate B by silica gel column chromatography.

[0037] (3) Add intermediate B (10 mmol, 2.69 g), 48% hydrobromic acid (150 mmol, 25.31 g) and glacial acetic acid (30 mL) to the flask, reflux at 130 °C for 24 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature and evaporate the solvent under vacuum to obtain crude intermediate C.

[0038] (4) Add crude intermediate C (10 mmol), activated carbon powder (100 mmol, 1.20 g), anhydrous ferric chloride (20 mmol, 3.24 g), 85% hydrazine hydrate (100 mmol, 5.88 g) and ethanol-chloroform mixed solution (50 mL, v / v = 3 / 2) to the flask, reflux at 70 °C for 4 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature, filter, evaporate the solvent from the filtrate under vacuum to obtain crude product compound 1, and purify by silica gel column chromatography to obtain compound 1.

[0039] The preparation process includes:

[0040]

[0041] Example 2 Preparation of Compound 2

[0042]

[0043] (1) Take intermediate A (10 mmol) synthesized in step (1) of Example 1 and dissolve it in 40 mL of dichloromethane. Under ice bath conditions, slowly add it dropwise to 80 mL of dichloromethane solution containing 4,5-dimethyl-1,2-phenylenediamine (10 mmol, 1.36 g) and triethylamine (12.8 mmol, 1.30 g) using a constant pressure dropping funnel. Continue stirring under ice bath conditions for 1 h. After restoring the temperature to room temperature, continue stirring for 1 h. When the reaction is complete as detected by TLC, evaporate the solvent under vacuum to obtain crude intermediate D. Purify it by silica gel column chromatography to obtain intermediate D.

[0044] (2) Add intermediate D (10 mmol, 2.97 g), 48% hydrobromic acid (150 mmol, 25.31 g) and glacial acetic acid (30 mL) to the flask, reflux at 130 °C for 24 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature and evaporate the solvent under vacuum to obtain crude intermediate E.

[0045] (3) Add crude intermediate E (10 mmol), activated carbon powder (100 mmol, 1.20 g), anhydrous ferric chloride (20 mmol, 3.24 g), 85% hydrazine hydrate (100 mmol, 5.88 g) and ethanol-chloroform mixed solution (50 mL, v / v = 3 / 2) to the flask, reflux at 70 °C for 4 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature, filter, evaporate the solvent from the filtrate under vacuum to obtain crude product compound 2, and purify by silica gel column chromatography to obtain compound 2. 1 H NMR (400MHz, DMSO) δ12.33(s,1H),9.48(s,1H),7.46-7.22(m,3H),6.74(t,J=7.5Hz,3H),6.51(t,J=7.8Hz,1H),2.32(s,6H).HRMS(ESI)m / z:calcd for C 15 H 15 N3O:[M+H]254.1293; found:254.1287.HPLC purity=94.8%.

[0046] The preparation process includes:

[0047]

[0048] Example 3 Preparation of Compound 3

[0049]

[0050] (1) Take intermediate A (10 mmol) synthesized in step (1) of Example 1 and dissolve it in 40 mL of dichloromethane. Under ice bath conditions, slowly add it dropwise to 80 mL of dichloromethane solution containing 4,5-dichloro-1,2-phenylenediamine (10 mmol, 1.77 g) and triethylamine (12.8 mmol, 1.30 g) using a constant pressure dropping funnel. Continue stirring under ice bath conditions for 1 h. After the temperature is restored to room temperature, continue stirring for 1 h. When the reaction is complete as detected by TLC, evaporate the solvent under vacuum to obtain crude intermediate F. Purify it by silica gel column chromatography to obtain intermediate F.

[0051] (2) Add intermediate F (10 mmol, 3.40 g), 48% hydrobromic acid (150 mmol, 25.31 g) and glacial acetic acid (30 mL) to the flask, reflux at 130 °C for 24 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature and evaporate the solvent under vacuum to obtain crude intermediate G.

[0052] (3) Add crude intermediate G (10 mmol), activated carbon powder (100 mmol, 1.20 g), anhydrous ferric chloride (20 mmol, 3.24 g), 85% hydrazine hydrate (100 mmol, 5.88 g) and ethanol-chloroform mixed solution (50 mL, v / v = 3 / 2) to the flask, reflux at 70 °C for 4 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature, filter, evaporate the solvent from the filtrate under vacuum to obtain crude product compound 3, and purify by silica gel column chromatography to obtain compound 3. 1 H NMR(400MHz,DMSO)δ12.33(s,1H),9.48(s,1H),8.30(s,2H),7.46-7.22(m,3H),6.72(s,2H).HRMS(ESI)m / z:calcd forC 13 H9Cl2N3O: [M+H] 294.0201; found: 294.0183. HPLC purity=96.2%.

[0053] The preparation process includes:

[0054]

[0055] Example 4: Preparation of Compound 4

[0056]

[0057] (1) At room temperature, methyl bromide (10 mmol, 1.71 g) was added to a methanol (50 mL) solution of intermediate B (10 mmol, 2.69 g) and KOH (10 mmol, 0.56 g) synthesized in step (2) of Example 1. The mixture was stirred at room temperature for 4 h. After removing the solvent, the crude product was purified by column chromatography to obtain pure intermediate H.

[0058] (2) The mixture of intermediate H (7.7 mmol, 2.78 g) and HBr (48%, 9.35 g, 115.5 mmol) in acetic acid (5 mL) was heated at 120 °C for 24 h, and the organic phase was evaporated to obtain intermediate I, which is a yellow solid of 3.32 g.

[0059] (3) Add crude intermediate I (10 mmol), activated carbon powder (100 mmol, 1.20 g), anhydrous ferric chloride (20 mmol, 3.24 g), 85% hydrazine hydrate (100 mmol, 5.88 g) and ethanol-chloroform mixed solution (50 mL, v / v = 3 / 2) to the flask, reflux at 70 °C for 4 h, and when the reaction is complete as detected by TLC, cool the reactants to room temperature, filter, and evaporate the solvent from the filtrate under vacuum to obtain crude product compound 4. Purify compound 4 by silica gel column chromatography.1 H NMR (400MHz, DMSO) δ9.54(s,1H),7.65(d,J=7.2Hz,1H),7.49(d,J=7.0Hz,1H),7.40-7.35(m,1H),7.1 9(dq,J=7.3,6.0Hz,2H),6.81-6.68(m,3H),6.53(t,J=7.8Hz,1H),3.95(s,3H)..HRMS(ESI)m / z:calcd forC 14 H 13 N3O:[M+H]240.1137; found:240.1152.HPLC purity=96.8%.

[0060] The preparation process includes:

[0061]

[0062] Experimental Example 1: 3-Hydroxy-2-aminobenzimidazole derivatives inhibit RSL3-induced ferroptosis

[0063] After the cultured cardiomyocytes adhered to the culture medium, they were divided into a control group, experimental group 1, experimental group 2, and experimental group 3. The control group's culture medium contained DMSO. Experimental group 1's culture medium contained RSL3 (1.5 μM, final concentration). Experimental group 2's culture medium contained RSL3 (1.5 μM, final concentration) and gradient concentrations of compound 1, compound 2, compound 3, and compound 4. Experimental group 3's culture medium contained RSL3 (1.5 μM, final concentration) and gradient concentrations of Fer-1. The concentration gradients of compounds 1-4 and Fer-1 in experimental groups 2 and 3 were 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, and 31 nM. The control group, experimental groups 1, 2, and 3 were cultured for 24 hours, and cell viability was detected by CCK-8 assay. The results are shown in Table 1 (data obtained after three replicates). Compounds 1 through 4 effectively inhibited ferroptosis, and their EC50 values ​​were... 50 All values ​​were less than 500 nM, with compound 2 exhibiting the highest activity at 52.5 ± 2.0 nM.

[0064] Table 1. Cell viability results of compounds 1-4

[0065] compound <![CDATA[EC 50 (nM)]]> Compound 1 106.8±25.1 Compound 2 52.5±2.0 Compound 3 257.2±35.9 Compound 4 163.8±16.7 Fer-1 137.9±15

[0066] As shown in Table 1, compounds 1–4 significantly inhibited RSL3-induced cell death (p<0.01), and their activity was comparable to that of the positive control Ferrostatin-1, indicating that 3-hydroxy-2-aminobenzimidazole significantly inhibits RSL3-induced cell ferroptosis.

[0067] Experimental Example 2: 3-Hydroxy-2-aminobenzimidazole derivatives inhibit the generation of lipid free radicals.

[0068] After the cultured cardiomyocytes adhered to the culture medium, they were divided into a control group, experimental group 1, experimental group 2, and experimental group 3. The control group culture medium was supplemented with DMSO; experimental group 1 culture medium was supplemented with RSL3 (1.5 μM, final concentration); experimental group 2 culture medium was supplemented with RSL3 (10 μM) + compound 2 (0.2 μM); and experimental group 3 culture medium was supplemented with RSL3 (10 μM) + Fer-1 (0.2 μM). After 12 h of treatment, C11 staining was performed, and fluorescence images were captured. The results are shown below. Figure 1 As shown. From Figure 1 As can be seen, compared with the control group, RSL3 significantly increased the generation of cell membrane lipid free radicals in experimental group 1, while compared with experimental group 1, cell membrane lipid free radicals were significantly reduced in experimental group 2. This indicates that compound 2 can inhibit RSL3-induced lipid peroxidation, and the inhibitory effect of experimental group 2 is better than that of experimental group 3.

[0069] Experimental Example 3: Alleviating effect of 3-hydroxy-2-aminobenzimidazole derivatives on myocardial ischemia-reperfusion injury (I / R) in rats.

[0070] Animal grouping: Thirty 8-10 week old C57BL / 6 rats were selected and randomly divided into 3 groups, half male and half female. Ten rats were the control group; ten rats were the experimental group 1, which underwent I / R treatment; and ten rats were the experimental group 2, which was injected intraperitoneally with compound 2 (10 mg / kg) before I / R treatment.

[0071] Experimental Group 1: Each rat was fasted for more than 12 hours and anesthetized with 10% chloral hydrate. After anesthesia took effect, the rat was fixed to a splint and connected to a ventilator and electrocardiogram (ECG) for real-time monitoring of its physiological status. The skin was cut open at the 3rd-4th intercostal space on the left side of the rat's chest, and the layers of muscle were separated to expose the ribs. The 3rd and 4th ribs were cut open with scissors, and the chest wall was pulled open to expose the heart. The thymus was clamped with hemostatic forceps, and a 7-0 silk suture was threaded between the left atrial appendage and the pulmonary artery conus. In the ischemia-reperfusion group, the chest was opened after anesthesia, the 3rd-4th ribs were cut, the pericardium was opened, and the heart was exposed. A suture (0-gauge suture) was threaded at the root of the left anterior descending coronary artery and ligated to block blood flow. The ligation was determined by the ST segment elevation on the ECG. The ligation was released 30 minutes later, and reperfusion was determined by the ST segment regression on the ECG. The chest wall was sutured, and the rat resumed spontaneous breathing.

[0072] Experimental group 2: Compound 2 (10 mg / kg) was injected intraperitoneally before I / R treatment.

[0073] Serum myocardial enzyme levels, serum oxidative stress damage indicators, and inflammatory factors were detected in mice from the control group, experimental group 1, and experimental group 2, respectively.

[0074] Three hours after myocardial reperfusion, 2 mL of blood was collected from the left ventricle of rats and centrifuged at 4,500 r / min for 10 min with a centrifugation radius of 15 cm. The supernatant serum was collected, and the levels of inflammatory factors TNF-α, CRP, and IL-6, serum myocardial enzyme indicators LDH and CK, and serum oxidative stress injury indicator MDA were detected using an ELISA kit. The results are shown in Table 2.

[0075] Table 2. Effects of compound 2 on LDH, CK, and MDA activity during myocardial ischemia-reperfusion in mice.

[0076]

[0077] As shown in Table 2, the activities of LDH, CK, and MDA in the experimental group were significantly increased (P < 0.01). After administration of compound 2, the activities of LDH, CK, and MDA in the blood of mice in experimental group 2 decreased (P < 0.05). This indicates that compound 2 can reduce ischemic / reperfusion myocardial injury and exert a protective effect on the myocardium.

[0078] The area of ​​myocardial infarction was measured in mice from the control group, experimental group 1, and experimental group 2, respectively.

[0079] Myocardial infarction area detection: After the experiment, mouse hearts were removed and frozen at -80℃ for 2 hours. Then, the hearts were continuously sliced ​​into 2mm thick slices along the longitudinal axis from the apex to the base. The fifth slice from each heart was placed in a 12-well plate containing 2% TTC solution and incubated at 37℃ in the dark for 15 minutes. The slices were stained with TTC (2,3,5-triphenyltetrazolium chloride) solution and then soaked in 4% paraformaldehyde in the dark for 2 days. Digital photography was used; dead myocardial tissue appeared white, and surviving myocardial tissue appeared red. Image J was used to measure the area of ​​the white area and the total heart area. Myocardial infarction area fraction = (area of ​​white area / total area) × 100%. The results are as follows: Figure 2 As shown. From Figure 2 As can be seen, compared with the control group, the myocardial infarction area fraction of mice in experimental group 1 was increased, and the difference was statistically significant (P < 0.01). However, the myocardial infarction area fraction of mice in experimental group 2 was decreased, and the difference was statistically significant (P < 0.01). Therefore, this further illustrates that compound 2 can reduce ischemic / reperfusion myocardial injury and play a protective role for the myocardium.

Claims

1. Use of 3-hydroxy-2-amino-benzimidazole derivatives as ferroptosis inhibitors for the preparation of a medicament for preventing, ameliorating or treating myocardial ischemia-reperfusion injury, characterized in that, The structural formula of the 3-hydroxy-2-aminobenzimidazole derivative is shown in Formula (Ⅰ): Equation (I); Among them, R1 is selected from hydrogen, methyl and chlorine, and R2 is selected from hydrogen and methyl; The 3-hydroxy-2-aminobenzimidazole derivative, as a ferroptosis inhibitor, has at least one of the following effects: (1) Improve the survival rate of cardiomyocytes after myocardial ischemia-reperfusion; (2) Inhibit the generation of lipid free radicals in cardiomyocytes after myocardial ischemia-reperfusion.

2. Use according to claim 1, wherein The 3-hydroxy-2-aminobenzimidazole derivative is one of the following compounds: 。 3. Use according to claim 2, wherein the compound is ###0002### The 3-hydroxy-2-aminobenzimidazole derivative is one of the following compounds: 。 4. A medicament for preventing, ameliorating or treating myocardial ischemia-reperfusion injury, characterized by comprising the compound of claim 1. The active ingredient of the drug is a 3-hydroxy-2-aminobenzimidazole derivative, the structural formula of which is shown in Formula (I): Equation (I); R1 is selected from hydrogen, methyl and chlorine, and R2 is selected from hydrogen and methyl.

5. The medicament for preventing, ameliorating or treating myocardial ischemia-reperfusion injury according to Claim 4, wherein the medicament is a pharmaceutical composition for oral administration. The 3-hydroxy-2-aminobenzimidazole derivative is one of the following compounds: 。 6. The medicament for preventing, improving, or treating myocardial ischemia-reperfusion injury as described in claim 5, characterized in that, The 3-hydroxy-2-aminobenzimidazole derivative is: 。 7. The medicament for preventing, ameliorating or treating myocardial ischemia-reperfusion injury according to Claim 4, wherein the medicament is a pharmaceutical composition for oral administration. The formulation of the drug is selected from gastrointestinal dosage forms or non-gastrointestinal dosage forms.

8. A pharmaceutical composition for preventing, improving, or treating myocardial ischemia-reperfusion injury, characterized in that, Includes a therapeutically effective amount of a 3-hydroxy-2-aminobenzimidazole derivative, wherein the 3-hydroxy-2-aminobenzimidazole derivative is one of the following compounds: 。 9. The pharmaceutical composition according to claim 8, characterized in that, The 3-hydroxy-2-aminobenzimidazole derivative is: 。

Images