Application of compound SP3 in preparation of medicine for treating cardiovascular diseases

Abstract

The invention discloses an application of a compound in preparation of a medicine for treating cardiovascular diseases, the compound is SP3, and the structural formula is shown in the specification. The compound can obviously reduce the myocardial infarction area and ischemia area after myocardial ischemia reperfusion, has a myocardial protection effect, and particularly has a better effect on ischemic heart disease.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to application of a compound SP3 in preparation of a drug for treating cardiovascular diseases and a pharmaceutical composition thereof. BACKGROUND

[0002] Coronary atherosclerotic heart disease (coronary heart disease) is also called ischemic heart disease, which is caused by myocardial ischemia and hypoxia due to coronary atherosclerosis, and is a global cardiovascular disease. Myocardial infarction is one of the most serious manifestations, which causes serious damage to coronary microcirculation, leading to massive death of myocardial cells due to ischemia and hypoxia, and leads to the introduction of percutaneous coronary intervention and surgical coronary artery bypass grafting to enable early reperfusion of infarct blood, but the ischemic area of the heart muscle will further trigger ischemia-reperfusion injury. The prevalence of cardiovascular disease in China is in a continuous upward phase, and it is estimated that there are 330 million people with cardiovascular disease, of which 11.39 million have coronary heart disease, 8.9 million have heart failure, and 4.87 million have atrial fibrillation. From July 2021 to June 2022, the “China Residents Cardiovascular and Cerebrovascular Event Surveillance” project found that the crude incidence of cardiovascular disease among residents aged 18 and over in China was 600.9 / 100,000 (age-standardized incidence was 411.8 / 100,000), of which the crude incidence of acute myocardial infarction was 79.7 / 100,000 (age-standardized incidence was 55.8 / 100,000). Cardiovascular disease has become the leading cause of death among urban and rural residents in China due to illness, with high incidence, high mortality and disability rate, and poor prognosis, posing a great challenge to the development of treatment and prevention strategies.

[0003] After myocardial infarction, the structure and subcellular changes of the matrix gradually affect heart function, and trigger a series of reactions, including inflammation, apoptosis, ferroptosis, autophagy, mitochondrial dysfunction, etc., and further lead to myocardial fibrosis. To prevent further damage after myocardial ischemia, blood flow should be restored as soon as possible in the early stage of ischemia, and thrombolytic therapy or percutaneous coronary intervention is often used in clinic to reduce infarct size and relieve symptoms. However, the current strategy also has the disadvantages of narrow treatment window and easy bleeding. Therefore, it is an urgent problem to find new targets for treatment, drugs with new mechanisms of action and fewer adverse reactions.

[0004] Stimulator of interferon genes (STING) is a transmembrane protein that activates downstream signal transduction after palmitoylation, plays an important role in maintaining cell homeostasis, metabolism and chronic inflammation, and many studies have shown that the activation of STING is related to inflammatory diseases, anti-tumor immunity and adriamycin-induced cardiotoxicity. The first inflammation reaction is started after myocardial ischemia. The literature has reported that the STING inhibitor H-151 can significantly reduce myocardial fibrosis after myocardial ischemia reperfusion and protect myocardial function. However, H-151 has the disadvantages of short half-life and poor water solubility, so it is of great significance to develop a STING inhibitor with higher bioavailability. SUMMARY

[0005] The purpose of the present application is to overcome the problems existing in the prior art cardiovascular disease treatment drugs, provide the application of a compound SP3 and a pharmaceutical composition thereof in the preparation of a drug for treating cardiovascular diseases, which has a significant myocardial protective effect and can significantly reduce the myocardial infarction area and ischemic area, and can be used for preventing or treating myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, sudden death coronary heart disease and the like.

[0006] In order to achieve the above-mentioned purpose, the first aspect of the present application discloses the application of a compound SP3 in the preparation of a drug for treating cardiovascular diseases.

[0007] Preferably, the cardiovascular disease is ischemic heart disease.

[0008] Preferably, the ischemic heart disease includes myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, sudden death coronary heart disease.

[0009] The present application discloses the application of a compound SP3 in the preparation of a drug for reducing the myocardial infarction area.

[0010] The present application discloses the application of a compound SP3 in the preparation of a drug for reducing the myocardial infarction ischemic area.

[0011] Preferably, the myocardial infarction is caused by myocardial ischemia reperfusion.

[0012] The present application provides a pharmaceutical composition for treating cardiovascular diseases, wherein the active ingredient comprises a compound SP3, and further comprises a pharmaceutically acceptable carrier and / or adjuvant; specifically, the pharmaceutical composition for treating cardiovascular diseases is composed of a compound SP3 and a pharmaceutically acceptable carrier and / or adjuvant.

[0013] Preferably, the pharmaceutical composition is a solvent or a diluent.

[0014] Preferably, the pharmaceutical composition is a preparation suitable for oral, rectal, topical, buccal, sublingual, subcutaneous, intramuscular, intravenous administration.

[0015] Preferably, the pharmaceutical composition is a tablet, a capsule, a dispersible powder or granules.

[0016] Preferably, the pharmaceutical composition is an injection preparation.

[0017] In the present application, the chemical structural formula of the compound SP3 is as follows: .

[0018] By the above technical solution, the area of myocardial infarction and ischemia can be significantly reduced, and the myocardial protection effect is achieved, especially for ischemic heart disease. The prepared drug can be used for treating myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, sudden death coronary heart disease and the like. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 It is a nuclear magnetic chart of the compound SP3.

[0020] Figure 2 It is an Evans Blue / TTC double staining diagram of the sham group, the model group, the SP3 group and the H-151 group in Example 2 of the present application.

[0021] Figure 3 It is a statistical diagram of the compound SP3 for reducing the area of myocardial infarction and ischemia in Example 2 of the present application. DETAILED DESCRIPTION

[0022] The specific embodiments of the present application are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present application, and are not used to limit the present application.

[0023] The present application will be described in detail by examples below. In the following examples, each material used is commercially available unless otherwise specified, the method used is a conventional method in the art unless otherwise specified, the animal experiment conforms to the relevant requirements of Suzhou University, and the data statistical analysis is a conventional technique.

[0024] The present application provides a drug SP3 for treating cardiovascular diseases and the use of the compound SP3 in the preparation of a drug for treating cardiovascular diseases, and the structural formula of SP3 is as follows: .

[0025] In the present application, preferably, the cardiovascular disease is ischemic heart disease.

[0026] The ischemic heart disease is not particularly limited, and includes, but is not limited to, myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, sudden coronary death. In the present application, preferably, the ischemic heart disease includes myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, sudden coronary death.

[0027] In the present application, the type of the preparation of the medicament is not particularly limited, and can be a preparation suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. In the present application, the pharmaceutical composition is a solvent or diluent.

[0028] In the present application, preferably, the medicament is a preparation suitable for oral, rectal, topical, buccal, sublingual, subcutaneous, intramuscular, intravenous administration. The most suitable route can depend on the condition and disorder of the recipient. The preparation can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy.

[0029] The preparation suitable for oral administration described above can be in the form of discrete units such as capsules or tablets, powders or granules, solutions or aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, containing predetermined amounts of active ingredient. The active ingredient can also be presented in a bolus, electuary or paste. In the present application, preferably, the pharmaceutical composition is a tablet, capsule, dispersible powder or granules.

[0030] The tablets described above can be compressed or moulded, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated to provide sustained, delayed or controlled release of the active ingredient.

[0031] The preparations for parenteral administration described above include aqueous and non-aqueous sterile injection solutions containing anti-oxidants, buffers, bacteriostatic agents and solutes. The preparations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickening agents.

[0032] In the present application, preferably, the pharmaceutical composition is in the form of an injection preparation.

[0033] The various dosage forms of the pharmaceutical composition of the present application described above can be prepared according to methods well known in the art of pharmacy.

[0034] 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 application belongs.

[0035] The application will be further described with reference to the following examples and drawings, in which the raw materials used are commercially available products, and the specific preparation procedures and performance testing, statistical analysis are conventional techniques.

[0036] Preparation of Synthesis Example SP3

[0037] 3-methoxy-4-[[4-(trifluoromethyl)phenyl]amino]cyclobut-3-ene-1,2-dione (b2): 4-(trifluoromethyl)aniline (p-trifluoromethylaniline, 1.0 g, 6.2 mmol) was dissolved in anhydrous ethanol (20 mL), then 3,4-dimethoxycyclobut-3-ene-1,2-dione (882 mg, 6.2 mmol) was added, and then stirred at room temperature for 4 h, and the reaction was completed by TLC detection, and a yellow solid (1.4 g, 83%) b2 was obtained by filtration.1H NMR (300 MHz, CDCl3) δ 7.71 - 7.59 (m, 2H), 7.48 - 7.34 (m, 2H), 4.54 (s, 3H). LCMS (ESI / APCI) m / z: 271.9 [M + H] + .

[0038] b2 (500 mg, 1.84 mmol) was dissolved in a mixed solvent of toluene N,N-dimethylformamide (19 / 1, 20 mL), 1H-indol-6-amine (6-aminoindole, 245 mg, 1.84 mmol), Zn(CF3SO3)2 (135 mg, 0.37 mmol) were added, and stirred at 100°C for 12 hours, and the reaction was completed by TLC detection, and a brown solid (80 mg, 12%) 3-((1H-indol-6-yl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (SP3) was obtained by filtration. Figure 1 The product NMR chart is as follows: 1 H NMR (400 MHz, DMSO- d6) δ 11.19 (s, 1H), 10.30 (s, 1H), 10.17 (s, 1H),7.74 – 7.71 (m, 2H), 7.71 – 7.68 (m, 2H), 7.68 – 7.66 (m, 1H), 7.52 (d, J =8.4 Hz, 1H), 7.30 (t, J = 2.7 Hz, 1H), 7.08 (dd, J = 8.5, 2.1 Hz, 1H), 6.39(s, 1H).LCMS (ESI / APCI) m / z: 369.9 [M - H] + . Purity: 96%.

[0039] Example 1 Protective effect of SP3 on acute phase of myocardial ischemia reperfusion in mice Male C57 mice were randomly divided into sham group, model group, SP3 administration group (10 mg / kg), H-151 administration group (10 mg / kg), 10 in each group.

[0040] According to the conventional method, the mouse myocardial ischemia reperfusion model (MI / R) was made by occluding the left anterior descending branch of the coronary artery. After ischemia for 30 min, reperfusion, and tail vein injection after reperfusion, the above-mentioned groups were given solvent (0.9% sodium chloride aqueous solution containing 1% DMSO and 1% Tween 20) control, SP3 solution and H-151 solution respectively; 24 h later, the mice were opened and the heart vessels were ligated again, 1% Evans Blue 200 μL was injected into the apex of the heart, the heart was taken out, frozen at-40℃ for 60 min, sectioned, placed in 1% TTC phosphate buffer (pH 7.4), incubated at 37℃ for 10 min, scanned by image acquisition system, and then the myocardial infarction area and ischemic area were calculated by Image J to observe the effect of SP3 on myocardial infarction area and ischemic area in acute phase of myocardial ischemia reperfusion.

[0041] Figure 2 The above-mentioned compound SP3 for reducing Evans Blue / TTCs double staining diagram in acute phase of myocardial ischemia reperfusion in mice, Figure 3 Evans Blue / TTCs double staining result statistical diagram, respectively indicating infarction area (myocardial infarct size), ischemic risk area (area at risk, AAR) and the ratio of infarction area to ischemic risk area; mean±SD, n=10; compared with the model group, * P <0.05, **P <0.01, *** P <0.001. Compound SP3 can reduce myocardial infarction and ischemic area in the acute phase of myocardial ischemia-reperfusion in mice, and its efficacy is superior to that of H-151, an existing compound that targets the Cys91 site of STING, blocks its binding to cGAMP, and inhibits STING oligomerization and downstream signaling pathways.

[0042] The above results indicate that SP3 has a protective effect on myocardial ischemia and can be used for the prevention and treatment of this type of disease.

[0043] Example 2 Comparison of Pharmacokinetic Properties of SP3 and H-151 Healthy male wild-type C57BL / 6 mice weighing 20-25 g were selected and fasted for 12 h before the experiment (with free access to water). The following dosing regimen was used: (1) Mice were randomly divided into four groups (n = 3 / group / time point) and given a single injection of H-151 or SP3 solution via the tail vein at a dose of 10 mg / kg. (2) Blood sample collection: Whole blood was collected from the orbital venous plexus into heparinized anticoagulant tubes at 0 (baseline), 5, 15, and 30 min after administration. The blood was centrifuged at 4000 × g for 10 min at 4°C to separate the plasma and aliquot into pre-cooled Eppendorf tubes. (3) Brain tissue processing: Mice were killed 30 min after administration, and the whole brain tissue was quickly dissected and weighed, and then homogenized in saline solution (150 mg / mL).

[0044] (4) Biological sample analysis Plasma and brain homogenate supernatant samples were detected by high performance liquid chromatography tandem mass spectrometry (LC-MS / MS) The following parameters were calculated based on the non-compartmental model: maximum plasma drug concentration, area under the plasma drug concentration-time curve, mean residence time (extrapolated to infinity), half-life, apparent clearance, etc.

[0045] Table 1 is a schematic comparison of the pharmacokinetic properties of H-151 and SP3. It can be seen from the table that compared with H-151, SP3 has a significantly lower systemic clearance (CL_obs), an increased systemic exposure (AUC), and a slower elimination (t 1 / 2 The results showed that SP3 prolonged the duration of drug action, increased bioavailability, and further enhanced efficacy.

[0046] Table 1. Comparison of pharmacokinetic properties of H-151 with SP3

[0047] The preferred embodiments of the present application have been described in detail above, but the present application is not limited thereto. Various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be considered as disclosed by the present application and fall within the protection scope of the present application.

Claims

1. Use of a compound SP3 in the preparation of a drug for treating cardiovascular diseases, characterized in that: The chemical structure of compound SP3 is as follows: 。 2. The use according to claim 1, characterized in that The cardiovascular disease is ischemic heart disease.

3. The use according to claim 2, characterized in that The ischemic heart disease includes one or more of myocardial infarction, stable angina pectoris, unstable angina pectoris, heart failure, ischemic cardiomyopathy, and sudden coronary death.

4. A pharmaceutical composition for treating cardiovascular diseases, wherein the active ingredient of the pharmaceutical composition for treating cardiovascular diseases comprises compound SP3, characterized in that: The chemical structural formula of the compound SP3 is as follows: 。 5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition for treating cardiovascular diseases further comprises a pharmaceutically acceptable carrier and / or excipient.

6. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is a preparation suitable for oral, rectal, topical, buccal, sublingual, subcutaneous, intramuscular, and intravenous administration.

7. Use of compound SP3 in the preparation of a drug for reducing myocardial infarction area, characterized in that: The chemical structural formula of the compound SP3 is as follows: 。 8. Use of compound SP3 in the preparation of a drug for reducing the ischemic area of ​​myocardial infarction, characterized in that: The chemical structural formula of the compound SP3 is as follows: 。 9. The use according to claim 7 or 8, characterized in that Myocardial infarction is caused by myocardial ischemia and reperfusion.

10. A method for preparing compound SP3, characterized in that: The method comprises the following steps: using 3-methoxy-4-[[4-(trifluoromethyl)phenyl]amino]cyclobut-3-ene-1,2-dione and 6-aminoindole to prepare compound SP3.

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