阅读说明：本技术 二蒽酮类化合物在制备预防和/或治疗心肌缺血性疾病及其相关病症的药物中的应用 (Application of dianthrone compound in preparation of medicine for preventing and/or treating myocardial ischemic diseases and related diseases thereof ) 是由 马双成 孙华 魏锋 杨建波 欧阳婷 汪褀 陈子涵 王莹 宋云飞 陈智伟 高慧宇 于 2021-09-14 设计创作，主要内容包括：本发明提供了二蒽酮类化合物在制备预防和/或治疗心肌缺血性疾病及其相关病症的药物中的应用,属于生物医药技术领域。本发明提供了二蒽酮类化合物在制备预防和/或治疗心肌缺血性疾病及其相关病症的药物中的应用；所述二蒽酮类化合物包括Trans-大黄素二蒽酮和/或Cis-大黄素二蒽酮。本发明提供了二蒽酮类化合物在制备预防和/或治疗心肌缺血性疾病及其相关病症的药物中的应用。由实施例的结果表明,相较于地尔硫卓,二蒽酮类化合物在药理上具有以下显著活性：显著改善心肌缺血小鼠心电图ST段抬高情况,降低血清心肌损伤生物标记物cTn-T水平,降低心肌酶水平,改善心肌缺血损伤状态。(The invention provides an application of dianthrone compounds in preparing medicines for preventing and/or treating myocardial ischemic diseases and related diseases, belonging to the technical field of biological medicines. The invention provides application of dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases and related diseases thereof; the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone. The invention provides application of dianthrone compounds in preparation of medicines for preventing and/or treating myocardial ischemic diseases and related diseases thereof. The results of the examples show that compared with diltiazem, the dianthrone compound has the following significant activity in pharmacology: obviously improve the ST-segment elevation condition of the electrocardiogram of the myocardial ischemia mouse, reduce the cTn-T level of a serum myocardial injury biomarker, reduce the myocardial enzyme level and improve the myocardial ischemia injury state.)

1. The application of dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases and related diseases;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

2. The use according to claim 1, wherein when the dianthrone compounds include Trans-emodin dianthrone and Cis-emodin dianthrone, the ratio of the amounts of the substances of Trans-emodin dianthrone and Cis-emodin dianthrone is 1 (0.5-1).

3. The use according to claim 2, wherein the substance amounts of Trans-emodin dianthrone and Cis-emodin dianthrone are in a ratio of 56: 38.

4. The use according to any one of claims 1 to 3, wherein the ischemic myocardial disease and its associated disorders include one or more of coronary heart disease, arrhythmia, heart failure, myocardial infarction and angina pectoris.

5. The use according to any one of claims 1 to 4, wherein the mass percentage of the dianthrone compound in the medicament is 0.1% to 95%.

6. The use according to claim 5, wherein the content of dianthrone compounds in the medicament is 30-90% by mass.

7. The use according to any one of claims 1 to 4, wherein the medicament is in a dosage form selected from the group consisting of oral preparation, external preparation, injection and cavity administration preparation.

8. The use according to claim 7, wherein the oral formulation comprises a tablet, capsule, pill, granule, oral liquid or suspension.

9. The use of claim 7, wherein the injection comprises a liquid injection, a powder injection or an infusion solution.

Technical Field

The invention relates to the technical field of biological medicines, in particular to application of dianthrone compounds in preparing medicines for preventing and/or treating myocardial ischemic diseases and related diseases thereof.

Background

Cardiovascular diseases are serious diseases threatening the life and health of human beings, and become the single largest cause of death worldwide, and the death number caused by cardiovascular diseases accounts for about 30 percent of the total death number worldwide in 2014. With the social progress and the improvement of the living standard of people, the cardiovascular disease rate of countries with low income and medium income is increasing at an incredible speed, and the change is accelerating, in China, the cardiovascular disease incidence and the mortality are in a continuous rising trend in recent years, and the incidence age is gradually reduced. Among cardiovascular diseases, myocardial ischemic heart disease is the focus of cardiovascular diseases, can be developed into angina pectoris, arrhythmia, myocardial infarction and heart failure, is the main cause of disability and death in the global scope, and seriously harms human health. The effective reduction of damage caused by myocardial ischemia has become a hot problem in the medical world today.

Myocardial ischemia refers to a pathological state in which the blood flow of coronary arteries is reduced, the oxygen supply of cardiac muscles is reduced, the energy metabolism of cardiac muscles is abnormal, and the normal work of the heart cannot be supported, which is caused by various reasons. Common causes are atherosclerosis (95-99%), inflammation (rheumatic, syphilitic, kawasaki disease, and vasoocclusive vasculitis), spasm, embolism, spontaneous dissection, connective tissue disease, trauma, and congenital malformations. The pathogenesis is considered to be related to apoptosis, calcium ion overload, oxidative stress, inflammation and the like caused by myocardial ischemia.

The dianthrone compounds have a plurality of pharmacological effects such as antidepressant, antitumor and antiviral effects, but the application of the dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases is not reported.

Disclosure of Invention

The invention aims to provide application of dianthrone compounds in preparing medicines for preventing and/or treating myocardial ischemic diseases and related diseases.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides application of dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases and related diseases thereof;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

Preferably, when the dianthrone compound comprises Trans-emodin dianthrone and Cis-emodin dianthrone, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is 1 (0.5-1).

Preferably, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is 56: 38.

Preferably, the myocardial ischemic disease and its related disorders include one or more of coronary heart disease, arrhythmia, heart failure, myocardial infarction and angina pectoris.

Preferably, the mass percent of the dianthrone compound in the medicine is 0.1-95%.

Preferably, the mass percentage of the dianthrone compound in the medicine is 30-90%.

Preferably, the dosage form of the medicament comprises an oral preparation, an external preparation, an injection or a cavity administration preparation.

Preferably, the oral preparation comprises tablets, capsules, pills, granules, oral liquid or suspension.

Preferably, the injection comprises water injection, powder injection or infusion solution.

The invention provides application of dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases and related diseases thereof; the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone. The invention provides application of dianthrone compounds in preparation of medicines for preventing and/or treating myocardial ischemic diseases and related diseases thereof. The results of the examples show that compared with diltiazem, the dianthrone compound has the following significant activity in pharmacology: obviously improve the ST-segment elevation condition of the electrocardiogram of the myocardial ischemia mouse, reduce the cTn-T level of a serum myocardial injury biomarker, reduce the myocardial enzyme level and improve the myocardial ischemia injury state.

Drawings

FIG. 1 shows the effect of Isoproterenol (ISO) -induced changes in the ST segment of the II-lead electrocardiogram of mice with myocardial ischemia (n-4), (b), (c), (d) and (d) in)^*P is less than 0.05, compared with a blank control group;^#p is less than 0.05, and is compared with a model group; ) (ii) a

FIG. 2 shows the effect of Isoproterenol (ISO) on serum myocardial injury biomarker cTn-T (n-7 ∞ to E)10)，(^*P is less than 0.05, compared with a blank control group;^#p is less than 0.05, and is compared with a model group; ) (ii) a

FIG. 3 shows the effect of Isoproterenol (ISO) on serum-induced myocardial ischemia CK-MB (n: 7-10) in mice^*P is less than 0.05, compared with a blank control group;^#p is less than 0.05, and is compared with a model group; ).

Detailed Description

The invention provides application of dianthrone compounds in preparing medicaments for preventing and/or treating myocardial ischemic diseases and related diseases thereof;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

In the invention, the chemical structural formula of the Trans-emodin dianthrone (HSW-W-25) is shown as a formula I; the chemical structural formula of the Cis-emodin dianthrone (HSW-W-26) is shown as a formula II;

the sources of Cis-emodin dianthrone and Trans-emodin dianthrone are not particularly limited in the present invention and are derived from conventional commercial sources or prepared according to methods well known in the art.

In the present invention, the Trans-emodin dianthrone is a mixture of racemates of Trans-emodin dianthrone; the Cis-emodin dianthrone is a meso-form mixture of the Cis-emodin dianthrone.

In the invention, when the dianthrone compound comprises Trans-emodin dianthrone and Cis-emodin dianthrone, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is preferably 1 (0.5-1), and more preferably 56: 38.

In the present invention, the myocardial ischemic disease and its related disorders preferably include one or more of coronary heart disease, arrhythmia, heart failure, myocardial infarction and angina pectoris.

In the present invention, the mass percentage of the dianthrone compound in the drug is preferably 0.1% to 95%, more preferably 30% to 90%, and most preferably 50% to 80%.

In the present invention, the dosage form of the drug preferably includes an oral preparation, a topical preparation, an injection or a cavity administration preparation.

In the present invention, the oral formulation preferably includes a tablet, a capsule, a pill, a granule, an oral liquid or a suspension.

In the invention, the injection preferably comprises water injection, powder injection or infusion solution.

In the present invention, the dosage form of the drug preferably includes a gaseous dosage form, a liquid dosage form, a solid dosage form or a semisolid dosage form.

In the present invention, the gaseous dosage form preferably comprises an aerosol or spray.

In the present invention, the liquid dosage form preferably includes a solution, an emulsion, a suspension, an injection, an eye drop, a nasal drop, a lotion or a liniment. In the present invention, the solution preferably comprises a true solution or a colloidal solution; the emulsion preferably comprises o/w type living compound emulsion or w/o type living compound emulsion; the injection preferably comprises water injection, powder injection or infusion solution.

In the present invention, the solid dosage form preferably comprises tablets, capsules, granules, powders, pellets, dripping pills, suppositories, films, patches or powder sprays; in the present invention, the tablet preferably includes a general tablet, an enteric coated tablet, a buccal tablet, a dispersible tablet, a chewable tablet, an effervescent tablet or an orally disintegrating tablet. In the present invention, the capsule preferably includes a hard capsule, a soft capsule or an enteric capsule.

In the present invention, the semisolid dosage form preferably comprises an ointment, gel or paste.

In the present invention, the dosage form of the drug preferably includes a general formulation, a sustained release formulation, a controlled release formulation, a targeted formulation or a microparticle delivery system.

In the present invention, the medicament preferably further comprises pharmaceutically acceptable excipients.

In the present invention, when the dosage form of the drug is preferably a tablet, the auxiliary material preferably includes one or more of a diluent, a binder, a wetting agent, a disintegrant, a lubricant, and a glidant.

In the present invention, the diluent preferably includes one or more of starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and calcium carbonate; the humectant preferably comprises one or more of water, ethanol and isopropanol; the binder preferably comprises one or more of starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, acrylic resins, carbomers, polyvinylpyrrolidone and polyethylene glycol; the disintegrant preferably comprises one or more of dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester and sodium dodecyl sulfate; the lubricant preferably comprises one or more of talc, silica, stearate, tartaric acid, liquid paraffin and polyethylene glycol; the glidant preferably comprises one or more of talc, silicon dioxide, stearate, tartaric acid, liquid paraffin and polyethylene glycol.

In the present invention, the tablet preferably includes a coated tablet, and the coated tablet preferably includes a sugar-coated tablet, a film-coated tablet or an enteric-coated tablet.

In the present invention, the tablet preferably comprises a single-layer tablet or a multi-layer tablet.

In the present invention, when the dosage form of the drug is preferably a capsule, the adjuvant preferably includes one or more of a diluent, a glidant, a wetting agent, a binder, and a disintegrant.

In the present invention, when the dosage form of the drug is preferably an injection, the solvent of the injection preferably includes one or more of water, ethanol, isopropanol, and propylene glycol; the auxiliary materials of the injection preferably comprise one or more of solubilizer, cosolvent, pH regulator and osmotic pressure regulator. The solubilizer preferably comprises one or more of poloxamer, lecithin and hydroxypropyl-beta-cyclodextrin, and the cosolvent preferably comprises one or more of poloxamer, lecithin and hydroxypropyl-beta-cyclodextrin; the pH regulator preferably comprises one or more of phosphate, acetate, hydrochloric acid and sodium hydroxide; the osmolality adjusting agent preferably comprises one or more of sodium chloride, mannitol, glucose, phosphate and acetate.

In the invention, when the dosage form of the medicament is preferably a freeze-dried powder injection, the auxiliary material preferably comprises a propping agent. The proppant preferably comprises mannitol and/or glucose.

In the present invention, the adjuvant of the drug preferably further comprises one or more of a coloring agent, a preservative, a fragrance and a flavoring agent.

The method of administration of the drug is not particularly limited in the present invention, and a method of administration known in the art may be used.

In the present invention, the route of administration of the drug preferably includes enteral administration or parenteral administration. The enteral administration preferably comprises oral administration or rectal administration; said parenteral administration preferably comprises: intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin or vagina.

In the present invention, the drug is preferably administered at a daily dose of 0.001 to 150mg/kg body weight, more preferably 0.1 to 100mg/kg body weight, still more preferably 1 to 60mg/kg body weight, and most preferably 2 to 30mg/kg body weight, and the above dose may be administered in one dosage unit or divided into several dosage units depending on the clinical experience of the doctor and the administration regimen including the use of other therapeutic means.

The medicine of the invention can be taken alone or combined with other therapeutic medicines or symptomatic medicines. When the medicament of the invention has synergistic effect with other therapeutic drugs, the dosage of the medicament is adjusted according to actual conditions.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The following examples and pharmacological activity experiments are intended to further illustrate the invention, but are not intended to limit the invention in any way. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the full names or corresponding Chinese names of the partial substances are as follows:

HSW-W-25: trans-emodin dianthrone

HSW-W-26: cis-emodin dianthrone

HSW-W-25/26: trans-emodin dianthrone and Cis-emodin dianthrone (dianthrone for short)

Control: blank control

Model: model comparison

ISO: isoproterenol

CK-MB: creatine kinase-isoenzyme

cTn-T: troponin T

The room temperature described in the examples below is as conventional in the art and is typically 15-25 ℃.

Experimental example 1 Activity of HSW-W-25/26 (dianthrone) on Isoproterenol (ISO) -induced myocardial ischemia model in mice

The experimental method comprises the following steps:

the male Kunming mouse is randomly divided into 4 groups after adapting to the environment, wherein the 4 groups are respectively a blank control group, an ISO model group and 20 mg.kg of ISO + diltiazem^-1Positive control group, ISO + dianthrone 10mg kg^-1And (4) grouping. The dianthranone group mice are intragastrically administrated for 1 time per day with corresponding dose, diltiazem group is intraperitoneally administrated for 1 time per day, blank control group and model group mice are administrated with the same amount of solvent, and the dosage is 10 mL/kg^-1The administration was continued for 10 days. On day 4 of administration, mice in each group were injected subcutaneously with ISO 40mg kg^-1One time, 5 to 10 days IS of drug administrationThe administration concentration of O-type injection is adjusted to 20mg/kg^-1All the animals were molded 2h after the administration, and were treated 2h after the last day of the administration to ISO molding. The animal body weight was recorded during the experiment, the final body weight was 33.2 + -1.9 g in the blank control group, 30.7 + -1.9 g in the model group, and 29.6 + -2.1 g in the HSW-W-25/26 (dianthrone) group. The animal was in good condition and did not die.

And (3) electrocardiogram detection: one day before the experiment, 4 mice in each group are randomly selected, and after 0.5h of modeling, II-lead electrocardiogram is recorded, and ST elevation condition is analyzed.

Myocardial injury biomarker and myocardial enzyme assay: blood is taken from the orbit of the mouse, the mouse is kept stand for 2h at room temperature, serum is separated by centrifugation at 3500rpm for 20min, and the content of CK-MB and cTn-T in the serum is determined according to the specification of an ELISA kit.

The experimental results are as follows:

effect of HSW-W-25/26 (dianthrone) on II-lead electrocardiogram of mice with myocardial ischemia induced by Isoproterenol (ISO)

Electrocardiographic examination is the most common non-invasive method for diagnosing myocardial ischemia. The results are shown in fig. 1, after ISO administration, the mouse electrocardiogram is caused to show ST segment continuous arch back elevation, typical myocardial ischemic change is shown, ST segment elevation degree (delta ST) is calculated, and ST segment is elevated from 0.06 +/-0.02 MV to 0.10 +/-0.02 MV. The results are shown in table 1, with the ISO model group being significantly elevated compared to the blank control group. The HSW-W-25/26 (dianthrone) 10mg/kg can obviously reduce the ST-segment elevation of the electrocardiogram caused by ISO, and has statistical difference compared with a model group. The activity is better than that of a positive control medicament diltiazem 20 mg/kg.

Effect of HSW-W-25/26 (dianthrone) on serum myocardial injury biomarker cTn-T in mice with myocardial ischemia induced by Isoproterenol (ISO)

When the myocardium is necrotized, some protein substances contained in the myocardium are released from myocardial tissues and appear in peripheral circulating blood, and can be used as a judgment index of myocardial damage. Troponin (Tn) is a regulatory protein of myocardial tissue contraction, and cardiac troponin (cTn) is different from Tn in skeletal muscle in molecular structure and immunology, so that the troponin (Tn) is unique to cardiac muscle and is a first-choice marker for judging most specificity and sensitivity of myocardial necrosis. cTn has three subtypes, cTnT, cTnI, and cTnC. cTn-T has high diagnostic value for early and late myocardial necrosis.

The results are shown in fig. 2 and table 1, and ISO causes a significant increase in the mouse serum cardiac muscle injury biomarker cTn-T, which is statistically different compared to the blank control group. 10mg/kg of HSW-W-25/26 (dianthrone) can obviously reduce the level of serum cTn-T, reduce the serum cTn-T from 298.10 +/-37.21 ng/L to 253.04 +/-32.73 ng/L, and has activity superior to that of diltiazem 20 mg/kg.

Influence of HSW-W-25/26 (dianthrone) on the content of serum myocardial enzyme CK-MB in mice with myocardial ischemia caused by Isoproterenol (ISO)

Serum creatine kinase-isozyme (CK-MB) is another clinical specificity and sensitivity index for determining myocardial necrosis. The results are shown in fig. 3 and table 1, and Isoproterenol (ISO) can cause the mouse to have significantly increased CK-MB activity in serum, and compared with a blank control group, the activity is statistically different. 10mg/kg of HSW-W-25/26 (dianthrone) remarkably reduces the CK-MB level of serum raised by ISO, reduces the CK-MB level from 7.56 +/-1.05 ng/mL to 6.11 +/-0.81 ng/mL, and has activity superior to that of diltiazem 20 mg/kg.

TABLE 1HSW-W-25/26 Activity test on isoproterenol-induced myocardial ischemia model in mice

Serial number	ΔST/MV	Troponin T/ng/L	CK-MB/ng/mL
				Blank control group	0.06±0.02	258.88±30.43	6.40±0.93
Model set	0.10±0.02	298.10±37.21	7.56±1.05
				Diltiazem	0.07±0.05	273.93±36.17	7.11±1.63
Dianthrones	0.06±0.03	253.04±32.73	6.11±0.81

The results of table 1 and fig. 1-3 show that, compared with diltiazem, dianthrone compounds have the following significant activity in pharmacology: obviously improve the ST-segment elevation condition of the electrocardiogram of the myocardial ischemia mouse, reduce the cTn-T level of a serum myocardial injury biomarker, reduce the myocardial enzyme level and improve the myocardial ischemia injury state.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.