Application of terpineol compound in preparation of medicine for treating heart diseases

Abstract

The invention discloses application of terpinenol compounds in preparation of medicines for treating heart diseases, in particular to preparation of medicines for resisting heart failure. After doxorubicin-induced chronic heart failure rat models are administered, the terpinenol compound can obviously increase the maximum rising rate and the maximum decreasing rate of left ventricular internal pressure in the doxorubicin-induced chronic heart failure rat models, increase the rat heart ejection fraction in the chronic heart failure rat models, relieve the heart hemodynamics of the chronic heart failure rats to a certain extent, and improve the curative effect of the doxorubicin-induced chronic heart failure rats. Experimental evidence is provided for clinical application of the terpinenol compound to treatment of heart failure, and the terpinenol compound has good application and development prospects.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to the application of terpinenol compounds in the preparation of medicines for treating heart diseases. Background Art

[0002] Heart failure (HF) refers to abnormal changes in the heart pump function under the action of multiple pathogenic factors, resulting in an absolute decrease in cardiac output or a relative insufficiency that cannot meet the metabolic needs of the body's tissue cells. It has a high morbidity and mortality rate, which has seriously endangered human health and caused huge clinical pressure and economic costs. Various heart diseases such as coronary heart disease, hypertension, valvular heart disease, cardiomyopathy, myocarditis and congenital heart disease are the main causes of heart failure. Heart failure is not an independent disease, but the terminal stage of various cardiovascular diseases. Its mechanism is mainly related to myocardial systolic and diastolic dysfunction, myocardial hypertrophy, fibrosis, myocardial cell apoptosis and activation of the neuro-endocrine system. Therefore, the effective prevention and treatment of heart failure is a medical problem that has attracted worldwide attention.

[0003] α-Terpinenol is an active ingredient extracted from mugwort oil, and its chemical name is α,α,4-trimethyl-3-cyclohexene-1-methanol. Reference 1 (Chen Yan, Zhang Lu-Lu. Recent updates on bioactive properties of α-terpineol. Journal of Essential Oil Research, 35, 274-288, 2023, doi: 10.1080 / 10412905.2023.2196515) discloses that α-terpinenol has the effects of protecting the cardiovascular system, improving cardiac function, reducing myocardial hypertrophy, enhancing vasodilation and lowering blood pressure. Intravenous injection of α-terpinenol in rats can lead to hypotension, tachycardia and decreased peripheral vascular resistance. In addition, α-terpinenol can also alleviate isoproterenol-induced myocardial cell hypertrophy, reduce the area of ​​myocardial infarction in rats, reduce myocardial fiber rupture, and inhibit inflammatory cell infiltration and myocardial necrosis.

[0004] Publication No. CN106380400A discloses a terpinenol compound and its preparation method and application. By derivatizing α-terpinenol, a series of terpinenol compounds are obtained, which effectively improve the anti-asthma and anti-pulmonary hypertension effects of such compounds. However, it has not yet been studied whether terpinenol compounds can play a role in the preparation and treatment of heart diseases. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the use of terpinenol compounds in the preparation of drugs for treating heart diseases. The terpinenol compounds improve cardiac diastolic function by alleviating cardiac hemodynamics in a rat model of heart failure.

[0006] The use of terpinenol compounds in the preparation of drugs for treating heart diseases, wherein the structural formula of the terpinenol compounds is as shown in Formula I or Formula II,

[0007]

[0008] Wherein, in Formula I, R is C 12 ~C 16 Alkyl, -NR 1 R 2 、-SR 3 OR 4 ;

[0009] R 1 , R 2 , R 3 and R 4 independently selected from C1-C6 alkyl or -NO2, wherein the C1-C6 alkyl may be substituted by OH; or the R 1 , R 2 Together with the nitrogen connecting them, they form a five-membered ring or a six-membered ring, and the five-membered ring or the six-membered ring may contain one O or C=O.

[0010] More preferably, the R is C 12 H 25 , C 16 H 33 or one of the following groups,

[0011]

[0012] in, Indicates the connection location.

[0013] The structures of the terpinenol compounds in the present invention are shown in the table below.

[0014] Table 1: Names and structures of terpinenol compounds

[0015]

[0016]

[0017] Preferably, the heart disease is heart failure.

[0018] Preferably, the drug for treating heart disease comprises a preparation of a terpinenol compound and a pharmaceutically acceptable carrier or excipient.

[0019] Preferably, the dosage form of the preparation is one of injection, capsule, tablet, spray, aerosol, and oral solution.

[0020] More preferably, the preparation is in the form of an oral solution, and the dosage of the terpinenol compound is 5 to 500 mg.

[0021] Preferably, the terpinenol compound is formulated into an oral solution and administered sublingually. Within this dosage range, the terpinenol compound can significantly increase the maximum rate of increase of left ventricular intraventricular pressure.

[0022] More preferably, the terpinenol compound is T-1, T-2, T-3 or T-4, and the dosage of the terpinenol compound is 20 mg.

[0023] Preferably, in a rat model of chronic heart failure, sublingual administration of the above compound at a dose of 20 mg can significantly increase the maximum rate of increase of left ventricular pressure, wherein T-1 and T-2 can also significantly increase the maximum rate of decrease of left ventricular pressure and improve cardiac diastolic function.

[0024] Preferably, the dosage form of the preparation is an aerosol, and the raw material components of the aerosol include the above-mentioned terpinenol compound, a propellant and a solvent.

[0025] Preferably, the aerosol can spray the terpinenol compound in a mist form by means of the pressure of the propellant, and the aerosolized compound can be inhaled orally to achieve the purpose of drug administration.

[0026] More preferably, the propellant is a hydrofluoroalkane, such as tetrafluoroethane, tetrafluoropropylene, difluoroethane or heptafluoropropane.

[0027] More preferably, the solvent is ethanol or propylene glycol.

[0028] More preferably, the weight ratio of the terpinenol compound to the propellant is 1:5-50.

[0029] More preferably, the dosage of the terpinenol compound is 4 to 200 mg.

[0030] Within the above dosage range, terpinenol compounds can increase the cardiac ejection fraction of rats with heart failure.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The invention discloses that terpinenol compounds can be used to prepare drugs for treating heart diseases, especially for preparing drugs for treating heart failure. After administration, the terpinenol compounds can alleviate the cardiac hemodynamics of rats with chronic heart failure to a certain extent and improve the cardiac diastolic function, which provides experimental evidence for the clinical application of terpinenol compounds in treating heart failure and has good application development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a statistical chart of the changes in rat body weight for 6 consecutive weeks since the intraperitoneal injection of doxorubicin, where the horizontal axis represents the number of weeks.

[0034] Figure 2 Representative ultrasound images of the heart of rats in the normal group in the doxorubicin-induced heart failure model.

[0035] Figure 3 Representative ultrasound images of the rat heart in the model group of doxorubicin-induced heart failure model.

[0036] Figure 4 Representative ultrasound images of the rat hearts in the digoxin group in the doxorubicin-induced heart failure model.

[0037] Figure 5 Representative ultrasound images of the rat heart in the high-dose T-1 group in the doxorubicin-induced heart failure model.

[0038] Figure 6 Representative ultrasound images of the rat heart in the low-dose T-1 group in the doxorubicin-induced heart failure model. DETAILED DESCRIPTION

[0039] The present invention will be further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited to the following examples.

[0040] The synthesis method of the terpinenol compounds involved in the present invention refers to the patent specification with publication number CN106380400A.

[0041] The raw materials used in the present invention are all commercially available.

[0042] 1. Effects of terpinenol compounds on cardiac function in heart failure model mice

[0043] 1. Experimental steps

[0044] SD rats (male, 250±20g, certificate number NO1911070128, provided by the Animal Center of Zhejiang Institute of Traditional Chinese Medicine) were randomly divided into 7 groups, 10 rats in each group, namely normal group (G1), model group (G2), digoxin administration group (G3), T-1 administration group (G4), T-2 administration group (G5), T-3 administration group (G6) and T-4 administration group (G7). Except for the normal group, the rats in the other 6 groups were intraperitoneally injected with 2.5 mg / kg of doxorubicin solution once a week for 6 weeks. During the experiment, the body weight, mental state, activity, food intake, coat color and death of all rats were regularly observed. Starting from the 5th week of modeling, the compound was administered sublingually (T-1, T-2, T-3, and T-4 were prepared at 0.2 g / mL, 100 uL / mouse, and administered sublingually orally), and digoxin 0.045 mg / kg was administered orally by gavage. The normal group and the model group did not receive any treatment, and the intervention lasted for 2 weeks.

[0045] 2. Index detection

[0046] (1) General behavior observation

[0047] Starting from the day of intraperitoneal injection of doxorubicin, the diet and weight changes, behavioral activity sensitivity and mental state, the occurrence of edema, changes in the skin and hair, defecation and other general conditions of the rats in each group were regularly observed and recorded throughout the experiment.

[0048] Observation results: During the modeling period, rats with heart failure had no obvious abnormal symptoms in the first 3 weeks. Some rats began to show mild ascites from the 4th week, and obvious ascites and death occurred in the 5th week. The hair of rats with ascites stood up, their hair color and gloss were poor, and their movements were slow. Those with severe ascites died.

[0049] Figure 1 This is a statistical chart of the changes in rat body weight for 6 consecutive weeks since the intraperitoneal injection of doxorubicin. As shown in the figure, during the experiment, the body weight of rats in each group gradually increased. The increase in rat body weight was not only related to the amount of feed intake, but also related to ascites in rats with heart failure. In the later stage of the experiment, rats with severe ascites also gained weight faster, but there was no significant difference in body weight among the groups.

[0050] (2) Heart function test

[0051] Preparation of 0.1% heparin sodium solution: The specification of heparin sodium is 2mL / 12500 units. 12500 units contain 100mg heparin sodium. The content of heparin sodium injection is 50mg / mL. When preparing, take 0.6mL injection solution and dilute to 30mL with normal saline for use.

[0052] After the last administration, rats in each group were anesthetized by intraperitoneal injection of 10% urethane 1.3 mL / rat, fixed on the operating table in the supine position, and electrocardiogram electrodes were inserted subcutaneously in the limbs to record the electrocardiogram. Left ventricular catheterization: After the electrocardiogram stabilizes, the neck is shaved, disinfected, and the skin is cut open. The right common carotid artery is bluntly separated, the distal end is ligated, and the proximal end is blocked with an artery clamp to block the blood flow. A small opening is cut between the two toward the heart, and a catheter inhaled with 0.1% sodium heparin solution is inserted into the common carotid artery. When the catheter and artery are inserted about 1 cm, the surgical thread is used to fix the catheter and artery, and the artery clamp is released. The pressure transducer is input into the physiological recorder. After the graph on the display stabilizes, the cardiac catheter is inserted into the left ventricular cavity. After stabilization for 5 minutes, the cardiac contraction is measured. Functional indicators (such as the maximum rate of increase of left ventricular intracardiac pressure (+dp / dtmax), left ventricular systolic pressure (LVSP)), myocardial diastolic function indicators (such as left ventricular end-diastolic pressure (LVEDP), maximum rate of decrease of left ventricular intracardiac pressure (-dp / dtmax)), heart rate (HR), the results are shown in Table 2, the measurement data are expressed as ±SD, SPSS19.0 data analysis software was used for one-way analysis of variance and rank sum test for comparison among the groups, P<0.05 was considered statistically significant.

[0053] Table 2 shows the effects of each drug group on cardiac function in rat heart failure model

[0054]

[0055] Note:" △ ", compared with the normal group, p < 0.05; " * ”, compared with the model group, p<0.05.

[0056] Cardiac function tests found that the maximum rise / fall rate of left ventricular pressure (±dp / dtmax) in rats with heart failure was significantly reduced, and compounds T-1, T-2, T-3, and T-4 could significantly increase the maximum rise rate of left ventricular pressure (+dp / dtmax), among which compounds T-1 and T-2 could also significantly increase the maximum fall rate of left ventricular pressure (-dp / dtmax). Terpinenol compounds can alleviate the cardiac hemodynamics of rats with chronic heart failure to a certain extent and improve cardiac diastolic function.

[0057] (3) Observation of organ lesions in rats

[0058] During the rat autopsy process, it was observed that the rats in the doxorubicin-induced heart failure model had obvious ascites, which was dark red and milky white, with enlarged liver and fat deposits on the edges of the kidneys. The positive drug and terpinenol compound administration groups all had the above-mentioned doxorubicin-induced heart failure model symptoms. In this experiment, the drugs were administered at the same time as the doxorubicin model was established, and the accumulation of doxorubicin in the heart of the drug-administered group was significantly improved compared with the modeling group.

[0059] 2. Effects of different doses of T-1 on cardiac function in heart failure model mice

[0060] 1. Experimental steps

[0061] Preparation of T-1 aerosol: weigh 1 part of T-1 by weight, add 2 times the amount of anhydrous ethanol, stir for 5 minutes to dissolve T-1 in ethanol, add the mixed solution of T-1 and ethanol (1.5 g) into an aluminum can, seal the aluminum can and the valve, and fill it with 17 parts of HFA-134a, about 8.5 g per bottle.

[0062] SD rats (male, 200±20 g, purchased from Hangzhou Medical College, production license number SCXK(Zhejiang)2019-0002, raised in the Experimental Animal Center of Zhejiang Institute of Traditional Chinese Medicine, use license number SYXK(Zhejiang)2019-0010) were randomly divided into 5 groups, namely, normal group, model group, digoxin group, T-1 low-dose group and T-1 high-dose group, with 10 rats in the normal group and 12 rats in each of the other groups.

[0063] Except for the normal group, rats in the other groups were intraperitoneally injected with 2.5 mg / kg of adriamycin solution once a week for 6 weeks. The normal group was not treated.

[0064] Drug intervention: From the 31st day of the rat experiment, each group was administered with the corresponding drug. Digoxin was administered with 0.009 mg / mL digoxin solution, 10 mL / kg intragastric volume, and the oral dose for rats was 0.09 mg / kg. T-1 aerosol was administered by spray, low dose 1 spray / rat (4.18 mg / rat), high dose 2 sprays / rat (8.36 mg / rat)

[0065] The drugs were administered for 10 consecutive days, and the normal control group and the model group were given 2 mL of saline per day. From the beginning to the end of the experiment, the animals in each group were given normal diet and normal drinking water.

[0066] 2. Index detection

[0067] (1) General behavior observation

[0068] Starting from the day of intraperitoneal injection of doxorubicin, the entire experimental process was regularly observed and recorded, with attention paid to the diet and weight changes of each group of rats, the sensitivity of behavioral activities and mental state, the occurrence of edema, changes in the skin and hair, breathing, defecation, and death.

[0069] During the modeling period, rats with heart failure had no obvious abnormal symptoms in the first 3 weeks. Some rats began to show mild ascites in the 4th week, and obvious ascites and death occurred in the 5th week. Edema, fur color and glossiness of the drug-treated group were improved compared with the model group.

[0070] (2) Heart function test

[0071] After 7 days of administration, the rats were subjected to echocardiography examination: M-mode echocardiography was used to measure the left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular ejection fraction (LVEF), and left ventricular shortening fraction (LVFS) of the rats in each group. The results are shown in Table 3 and Figures 2 to 6 shown.

[0072] Table 3 shows the effects of different doses of T-1 on cardiac function in rats with heart failure

[0073]

[0074] Note:" ΔΔ "Compared with the normal group, P < 0.01;" * ", compared with the model group, P < 0.05, " ** ”, compared with the model group, P<0.01.

[0075] Figures 2 to 6 These are representative images of rat cardiac ultrasound in the normal group, model group, digoxin group, T-1 high-dose group, and T-1 low-dose group in the adriamycin-induced heart failure model. Figure 2 , Figure 3 As shown in Table 3, the ejection fraction of rats with heart failure was reduced (P < 0.01), indicating that the cardiac pumping function of rats with chronic heart failure was reduced; Figures 4 to 6 As shown, all drug-treated groups could increase the cardiac ejection fraction of rats with heart failure (P<0.01, 0.05).

[0076] (3) Electrocardiogram

[0077] After the rat heart function test was completed, the electrocardiogram test was performed. The rats in each group were anesthetized with 10% chloral hydrate (350 mg / kg) by intraperitoneal injection and fixed on the operating table in the supine position. The II lead electrocardiogram test was performed using an electrocardiogram sensor, and the experimental results are shown in Table 4.

[0078] Table 4 shows the effects of different doses of T-1 on the electrocardiogram of rats with heart failure

[0079]

[0080] Note:" ΔΔ "Compared with the normal group, P < 0.01," Δ "Compared with the normal group, P < 0.05;" * ”, compared with the model group, P<0.05.

[0081] As shown in Table 2, the P, R, and T waves in the electrocardiogram of heart failure rats were significantly increased (P < 0.05). High doses of T-1 could significantly alleviate the increase of P waves (P < 0.05), but had no significant effect on R and T waves.

[0082] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. The use of terpinenol compounds in the preparation of drugs for treating heart diseases, characterized in that: The structural formula of the terpinenol compound is shown in Formula I or Formula II. Wherein, in Formula I, R is C 12 ~C 16 Alkyl, -NR 1 R 2 、-SR 3 OR 4 ; R 1 , R 2 , R 3 and R 4 independently selected from C1-C6 alkyl or -NO2, wherein the C1-C6 alkyl may be substituted by OH; or the R 1 , R 2 Together with the nitrogen connecting them, they form a five-membered ring or a six-membered ring, and the five-membered ring or the six-membered ring may contain one O or C=O.

2. The use according to claim 1, characterized in that: The R is C 12 H 25 , C 16 H 33 or one of the following groups, in, Indicates the connection location.

3. The use according to claim 1, characterized in that: The heart disease is heart failure.

4. The use according to claim 1, characterized in that: The medicine for treating heart disease comprises a preparation made of terpinenol compounds and pharmaceutically acceptable carriers or excipients.

5. The use according to claim 4, characterized in that: The dosage form of the preparation is one of injection, capsule, tablet, spray, aerosol and oral liquid.

6. The use according to claim 5, characterized in that: The dosage form of the preparation is oral liquid, and the dosage of the terpinenol compound is 5 to 500 mg.

7. The use according to claim 5, characterized in that: The dosage form of the preparation is an aerosol, and the raw material components of the aerosol include a terpinenol compound shown in Formula I or Formula II, a propellant and a solvent.

8. The use according to claim 7, characterized in that: The propellant is hydrofluoroalkane, and the solvent is ethanol or propylene glycol.

9. The use according to claim 8, characterized in that: The weight ratio of the terpinenol compound to the propellant is 1:5-50.

10. The use according to claim 7, characterized in that: The dosage of the terpinenol compound is 4 to 200 mg.

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