Use of terpene alcohol compound in preparation of drug for treating heart diseases

Abstract

Disclosed is use of a terpene alcohol compound in the preparation of a drug for treating heart diseases, in particular in the preparation of an anti-heart failure drug.

Description

Application of terpinenol compounds in the preparation of drugs for treating heart disease Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the use of terpinenol compounds in the preparation of drugs for treating heart diseases. Background Technology

[0002] Heart failure (HF) refers to an abnormal change in the heart's pumping function under the influence of various pathogenic factors, resulting in an absolute reduction or relative insufficiency of cardiac output, which cannot meet the metabolic needs of the body's tissues and cells. It has a high incidence and mortality rate, seriously endangering human health and causing enormous clinical pressure and economic costs. Coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, myocarditis, and congenital heart disease are the main causes of HF. HF is not an independent disease, but rather the end stage of various cardiovascular diseases. Its mechanisms are mainly related to myocardial systolic and diastolic dysfunction, myocardial hypertrophy, fibrosis, cardiomyocyte apoptosis, and activation of the neuroendocrine system. Therefore, effective prevention and treatment of HF is a medical challenge of global concern.

[0003] α-Terpineol is an active ingredient extracted from Artemisia argyi oil, with the chemical name 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-terpineol has protective effects on the cardiovascular system, improves cardiac function, reduces myocardial hypertrophy, enhances vasodilation, and lowers blood pressure. Intravenous injection of α-terpineol in rats resulted in hypotension, tachycardia, and a decrease in peripheral vascular resistance. Furthermore, α-terpineol can alleviate isoproterenol-induced cardiomyocyte hypertrophy, reduce the area of ​​myocardial infarction in rats, reduce myocardial fiber breakage, and inhibit inflammatory cell infiltration and myocardial necrosis.

[0004] Publication number CN106380400A discloses a terpinenol compound, its preparation method, and its applications. Through the derivatization of α-terpinenol, a series of terpinenol compounds were obtained, effectively enhancing their anti-asthmatic and anti-pulmonary hypertension effects. However, whether terpinenol compounds can play a role in the preparation of treatments for heart diseases has not yet been investigated. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides the application of terpinenol compounds in the preparation of drugs for treating heart diseases. Terpinenol compounds improve cardiac diastolic function by alleviating cardiac hemodynamics in a rat model of heart failure.

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

[0007] In Equation I, R is C 12 ~C 16 Alkyl, -NR 1 R 2 -SR 3 or -OR 4 ;

[0008] R 1 R 2 R 3 and R 4 Independently selected from C1-C6 alkyl groups or -NO2, wherein the C1-C6 alkyl groups may be substituted with OH; or the R 1 R 2 Together with the N connecting them, they form a quinary or hexagram, which may contain an O or C=O.

[0009] More preferably, R is C 12 H 25 C 16 H 33 Or one of the following groups,

[0010] in, Indicates the connection location.

[0011] The structures of the terpinenol compounds in this invention are shown in the table below.

[0012] Table 1: Names and structures of terpinenol compounds

[0013] Preferably, the heart disease is heart failure.

[0014] Preferably, the medicament for treating heart disease comprises a formulation made of terpinenol compounds and a pharmaceutically acceptable carrier or excipient.

[0015] Preferably, the dosage form of the preparation is one of injection, capsule, tablet, spray, aerosol, or oral liquid.

[0016] More preferably, the dosage form of the preparation is an oral liquid, and the dosage of the terpinenol compound is 5-500 mg.

[0017] In a preferred embodiment, 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 pressure.

[0018] 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.

[0019] In a preferred embodiment, in a rat model of chronic heart failure, sublingual administration of the above compounds at a dose of 20 mg significantly increased the maximum rate of increase of left ventricular pressure. Among them, T-1 and T-2 also significantly increased the maximum rate of decrease of left ventricular pressure and improved cardiac diastolic function.

[0020] Preferably, the formulation is an aerosol, and the raw material components of the aerosol include the above-mentioned terpinen alcohol compounds, propellants, and solvents.

[0021] In a preferred embodiment, the aerosol can use the pressure of the propellant to spray terpinen alcohol compounds into a mist, which can then be inhaled orally to achieve the purpose of drug administration.

[0022] More preferably, the propellant is a hydrofluoroalkane, such as tetrafluoroethane, tetrafluoropropylene, difluoroethane, or heptafluoropropane.

[0023] More preferably, the solvent is ethanol or propylene glycol.

[0024] More preferably, the weight ratio of the terpinenol compound to the propellant is 1:5 to 50.

[0025] More preferably, the dosage of the terpinenol compound is 4–200 mg.

[0026] Within the above dosage range, terpinenol compounds can increase the cardiac ejection fraction in rats with heart failure.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention discloses that terpinenol compounds can be used to prepare drugs for treating heart diseases, especially drugs for treating heart failure. After administration of terpinenol compounds, cardiac hemodynamics in rats with chronic heart failure can be alleviated to a certain extent, and cardiac diastolic function can be improved. This provides experimental evidence for the clinical application of terpinenol compounds in the treatment of heart failure and has good application development prospects. Attached Figure Description

[0029] Figure 1 shows the weight change of rats over 6 consecutive weeks from the date of intraperitoneal injection of doxorubicin, where the horizontal axis represents the number of weeks.

[0030] Figure 2 shows a representative echocardiogram of the normal group in the doxorubicin-induced heart failure model.

[0031] Figure 3 shows a representative echocardiogram of the rats in the model group of the doxorubicin-induced heart failure model.

[0032] Figure 4 shows a representative echocardiogram of the digoxin group in the doxorubicin-induced heart failure model.

[0033] Figure 5 shows a representative echocardiogram of rats in the T-1 high-dose group in the doxorubicin-induced heart failure model.

[0034] Figure 6 shows a representative echocardiogram of rats in the T-1 low-dose group in the doxorubicin-induced heart failure model. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0036] The synthesis method of the terpinenol compounds involved in this invention is based on the patent specification with publication number CN106380400A.

[0037] All raw materials used in this invention are commercially available.

[0038] I. Effects of terpinenol compounds on cardiac function in a rat model of heart failure

[0039] 1. Experimental Procedure

[0040] Male SD rats (250±20g, certificate number NO1911070128, provided by the Animal Center of Zhejiang Academy of Traditional Chinese Medicine) were randomly divided into 7 groups of 10 rats each: normal control group (G1), model group (G2), digoxin-treated group (G3), T-1 treatment group (G4), T-2 treatment group (G5), T-3 treatment group (G6), and T-4 treatment group (G7). Except for the normal control group, the other 6 groups of rats were intraperitoneally injected with doxorubicin solution 2.5mg / kg once a week for 6 weeks. During the experiment, the body weight, mental state, activity, food intake, coat color, and mortality of all rats were observed regularly. Starting from week 5 of modeling, the compounds were administered sublingually (T-1, T-2, T-3, and T-4 were prepared as 0.2 g / mL, 100 uL / animal, and administered orally sublingually), and digoxin was administered orally by gavage at a dose of 0.045 mg / kg. The normal group and the model group received no treatment. The intervention lasted for 2 weeks.

[0041] 2. Indicator Testing

[0042] (1) General behavioral observation

[0043] From the date of intraperitoneal injection of doxorubicin, the rats in each group were regularly observed and recorded throughout the experimental process, including changes in diet and weight, behavioral agility and mental state, presence of edema, changes in skin and hair, and general condition such as bowel movements.

[0044] Observation results: During the modeling period, no obvious abnormal symptoms were observed in the heart failure rats in the first 3 weeks. In the 4th week, some rats showed mild ascites. In the 5th week, obvious ascites and death occurred. The ascites rats had upright hair, poor coat color and luster, and slow movement. Those with severe ascites died.

[0045] Figure 1 shows the statistical chart of rat weight changes over 6 consecutive weeks from the date of intraperitoneal injection of doxorubicin. As shown in the figure, the weight of rats in each group gradually increased during the experiment. The increase in rat weight was not only related to the amount of feed ingested, but also to the 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 weight among the groups.

[0046] (2) Cardiac function test

[0047] Preparation of 0.1% heparin sodium solution: Heparin sodium specification 2mL / 12500 units, 12500 units contains 100mg of heparin sodium, so the content of heparin sodium injection is 50mg / mL. When preparing, take 0.6mL of injection solution and dilute it to 30mL with physiological saline for later use.

[0048] After the last administration, rats in each group were anesthetized with an intraperitoneal injection of 1.3 mL / rat of 10% urethane, fixed in a supine position on the operating table, and ECG electrodes were inserted subcutaneously into the limbs for ECG recording. Left ventricular cannulation: After the ECG stabilized, the neck was shaved, disinfected, and the skin was cut open. The right common carotid artery was bluntly dissected, the distal end was ligated, and the proximal end was clamped to block blood flow. A small incision was made between the two ends towards the heart, and a catheter aspirated with 0.1% heparin sodium solution was inserted into the common carotid artery. When the catheter was inserted to about 1 cm, it was fixed with surgical sutures. The arterial clamp was released, and the data was input into a physiological recorder via a pressure transducer. After the image on the monitor stabilized, the cardiac catheter was further inserted into the left ventricular cavity. After stabilization for 5 minutes, cardiac contraction was measured. Functional indicators (e.g., maximum rate of rise of left ventricular pressure (+dp / dtmax), left ventricular systolic pressure (LVSP)), myocardial diastolic function indicators (e.g., left ventricular end-diastolic pressure (LVEDP), maximum rate of fall of left ventricular pressure (-dp / dtmax)), and heart rate (HR) were included. The results are shown in Table 2. Quantitative data are expressed as ±SD. One-way ANOVA and rank-sum test were performed using SPSS 19.0 data analysis software for comparisons between groups. P < 0.05 was considered statistically significant.

[0049] Table 2 shows the effects of each drug administration group on the cardiac function of the rat heart failure model Note: " △ ", compared with the normal group, p < 0.05; " * ", compared with the model group, p < 0.05.

[0050] Cardiac function detection found that the maximum rate of rise / fall of left ventricular pressure (±dp / dtmax) in heart failure rats was significantly decreased. Compounds T-1, T-2, T-3, and T-4 could significantly increase the maximum rate of rise of left ventricular pressure (+dp / dtmax). Among them, compounds T-1 and T-2 could also significantly increase the maximum rate of fall of left ventricular pressure (-dp / dtmax). Terpenoid alcohols could relieve the cardiac hemodynamics of rats with chronic heart failure to a certain extent and improve cardiac diastolic function.

[0051] (3) Observation of rat organ lesions

[0052] During the dissection of rats, it was observed that the rats with adriamycin-induced heart failure model had obvious ascites, the ascites was dark red and milky white, the liver was enlarged, and there was adipose growth on the edge of the kidneys. The positive drug and each terpenoid alcohol compound administration group had the above symptoms of the adriamycin-induced heart failure model. In this experiment, drugs were administered while the adriamycin model was established, and the accumulation of adriamycin in the heart in the administration group was significantly improved compared with the model group.

[0053] II. Effects of different administration doses of T-1 on the cardiac function of rats with heart failure model

[0054] 1. Experimental procedures

[0055] Preparation of T-1 aerosol: By weight, weigh 1 part of T-1, 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) to an aluminum can, seal the aluminum can and the valve, and fill with 17 parts of HFA-134a, about 8.5 g per bottle.

[0056] SD rats (male, 200 ± 20 g, purchased from Hangzhou Medical College, production license number SCXK(Zhe)2019-0002, raised in the Experimental Animal Center of Zhejiang Academy of Traditional Chinese Medicine, use license number SYXK(Zhe)2019-0010) were randomly divided into 5 groups, namely the normal group, the model group, the digoxin group, the low-dose T-1 group, and the high-dose T-1 group. There were 10 rats in the normal group and 12 rats in each of the other groups.

[0057] Except for the normal group, rats in the other groups were intraperitoneally injected with adriamycin solution at 2.5 mg / kg once a week for a total of 6 weeks. The normal group was not treated.

[0058] Drug intervention: Starting from day 31 of the rat experiment, each treatment group was administered the corresponding drug. Digoxin was administered by gavage at a volume of 10 mL / kg, with the oral dose being 0.09 mg / kg. T-1 aerosol was administered via spray, with the low dose being 1 spray / rat (4.18 mg / rat) and the high dose being 2 sprays / rat (8.36 mg / rat).

[0059] The drugs were administered continuously for 10 days. The normal control group and the model group were given 2 mL of physiological saline per animal per day. From the beginning to the end of the experiment, all animals were given normal food and water.

[0060] 2. Indicator Testing

[0061] (1) General behavioral observation

[0062] From the date of intraperitoneal injection of doxorubicin, the entire experimental process was regularly observed and recorded, paying attention to changes in diet and weight, behavioral agility and mental state, presence of edema, changes in skin and hair, respiration, defecation and urination, and death of rats in each group.

[0063] During the modeling period, the heart failure rats showed no obvious abnormal symptoms in the first 3 weeks. Starting from the 4th week, some rats showed mild ascites, and by the 5th week, obvious ascites and death occurred. The edema, coat color, and luster of the drug-treated group were improved compared with the model group.

[0064] (2) Cardiac function test

[0065] Seven days after drug administration, rats underwent echocardiography: M-mode echocardiography was used to measure the left ventricular end-diastole diameter (LVIDd), left ventricular end-systole diameter (LVIDs), left ventricular ejection fraction (LVEF), and left ventricular ejection fractional shortening (LVFS) in each group of rats. The results are shown in Table 3 and Figures 2-6.

[0066] Table 3 shows the effects of different doses of T-1 on cardiac function in rats with heart failure. 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.

[0067] Figures 2-6 show representative echocardiograms of rats in the doxorubicin-induced heart failure model, including the normal group, model group, digoxin group, high-dose T-1 group, and low-dose T-1 group. As shown in Figures 2 and 3 and Table 3, the ejection fraction of the heart in heart failure rats was decreased (P < 0.01), indicating reduced cardiac pumping function in rats with chronic heart failure. As shown in Figures 4-6, all treatment groups increased the ejection fraction of the heart in heart failure rats (P < 0.01, 0.05).

[0068] (3) Electrocardiogram (ECG) detection

[0069] After completing the cardiac function test in rats, electrocardiogram (ECG) was performed. Rats in each group were anesthetized by intraperitoneal injection of 10% chloral hydrate (350 mg / kg) and fixed in a supine position on the operating table. ECG was performed using an ECG sensor in lead II. The experimental results are shown in Table 4.

[0070] Table 4 shows the effects of different doses of T-1 administration on the electrocardiograms of rats with heart failure. 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.

[0071] As shown in Table 2, the P, R, and T waves were significantly elevated in the electrocardiogram of rats with heart failure (P < 0.05). High dose of T-1 could significantly alleviate the elevation of P waves (P < 0.05), but had no significant effect on R and T waves.

[0072] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The application of terpinenol compounds in the preparation of drugs for treating heart diseases, characterized in that, The structural formulas of the terpinenol compounds are shown in Formula I or Formula II. In Equation I, R is C 12 ~C 16 Alkyl, -NR 1 R 2 -SR 3 or -OR 4 ; R 1 R 2 R 3 and R 4 Independently selected from C1-C6 alkyl groups or -NO2, wherein the C1-C6 alkyl groups may be substituted with OH; or the R 1 R 2 Together with the N connecting them, they form a quinary or hexagram, which may contain an O or C=O.

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

3. The application according to claim 1, characterized in that, The heart disease mentioned is heart failure.

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

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

6. The application according to claim 5, characterized in that, The formulation is an oral liquid, and the dosage of the terpinenol compound is 5-500 mg.

7. The application according to claim 5, characterized in that, The formulation is in the form of an aerosol, and the raw material components of the aerosol include terpinenol compounds represented by Formula I or Formula II, a propellant, and a solvent.

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

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

10. The application according to claim 7, characterized in that, The dosage of the terpinenol compounds is 4–200 mg.

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