Use of glycoside compounds in preparing drugs for treating atherosclerosis

Abstract

Use of glycoside compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating atherosclerosis. The present invention uses Oil Red O staining of the whole mouse aorta as an indicator to observe the size of lipid plaques on the inner wall of the aorta, and the investigation proves that glycoside compounds have a protective effect on the aorta of atherosclerotic mice, providing an animal efficacy test basis for the development of glycoside compounds as drugs for protecting blood vessels.

Description

Technical Field

[0001] The present invention relates to use of a glycoside compound or a pharmaceutically acceptable salt thereof in preparing a medicine for treating atherosclerosis. Background Art

[0002] Atherosclerosis (AS) is a multifactorial disease affected by environmental and genetic factors and is the main cause of cardiovascular and cerebrovascular diseases. AS is a slowly progressive disease that can cause vascular lesions such as coronary artery stenosis, myocardial ischemic infarction, and cerebral ischemic damage, leading to the occurrence of a variety of cardiovascular and cerebrovascular diseases. Therefore, protecting blood vessels (including but not limited to arteries) plays a very critical role in the prevention and treatment of AS.

[0003] At present, the drugs used to treat atherosclerosis are mainly Western medicines, such as lipid-lowering drugs statins, antiplatelet drugs aspirin, vasodilator drugs nitroglycerin and isopropylamine, thrombolytic drugs urokinase, and anticoagulant drugs heparin. These drugs have different side effects. For example, statins may cause myopathy and liver damage. Antiplatelet drugs have the risk of causing bleeding, and vasodilator drugs can cause or aggravate heart failure, pulmonary edema, and a drop in blood pressure.

[0004] ZL201810651588.5 discloses a glycoside compound that can prevent and treat microvascular diseases, thereby preventing and treating diabetes and its complications. As a new type of compound, the medical use of the glycoside compound needs to be further developed, and there is currently no research report on the use of the glycoside compound in the treatment of artery-related diseases. Summary of the invention

[0005] To solve the above problems, the present invention provides a use of a glycoside compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating atherosclerosis. The structural formula of the glycoside compound is shown in formula (I):

[0006]

[0007] Wherein, R1~R7 are independently selected from H, C1~C6 alkyl, C2~C6 alkenyl or C2~C6 alkynyl.

[0008] Furthermore, the structural formula of the glycoside compound is shown in formula (II):

[0009]

[0010] Furthermore, the structural formula of the glycoside compound is as shown in formula (III) or its enantiomer or diastereoisomer, or its racemic mixture, or its isotopologue:

[0011]

[0012] Furthermore, the structural formula of the glycoside compound is as shown in formula (IV) or its enantiomer or diastereoisomer, or its racemic mixture, or its isotopologue:

[0013]

[0014] Furthermore, the drug is a drug that reduces lipid deposition in blood vessels.

[0015] Furthermore, the drug is a drug that reduces lipid deposition in the aorta.

[0016] The present invention also provides a drug for treating atherosclerosis, which is an oral preparation or injection prepared by using a glycoside compound or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients; the structural formula of the glycoside compound is shown in formula (I):

[0017]

[0018] Wherein, R1~R7 are independently selected from H, C1~C6 alkyl, C2~C6 alkenyl or C2~C6 alkynyl.

[0019] Furthermore, the structural formula of the glycoside compound is shown in formula (II):

[0020]

[0021] Furthermore, the structural formula of the glycoside compound is as shown in formula (III) or its enantiomer or diastereoisomer, or its racemic mixture, or its isotopologue:

[0022]

[0023] Furthermore, the structural formula of the glycoside compound is as shown in formula (IV) or its enantiomer or diastereoisomer, or its racemic mixture, or its isotopologue:

[0024]

[0025] The use of the glycoside compounds of the present invention in preparing drugs for treating atherosclerosis, using Oil Red O staining of the whole mouse aorta as an indicator to observe the size of lipid plaques on the inner wall of the aorta, proves that the glycoside compounds have a protective effect on the aorta of atherosclerotic mice, and provides a new option for treating atherosclerosis.

[0026] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0027] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Structural confirmation diagram of glycoside compounds

[0029] Figure 2 D at 25℃ 2 O Glycosides 1 H NMR spectrum

[0030] Figure 3 D at 25℃ 2 O Glycosides 13 C NMR spectrum

[0031] Figure 4 Mass spectrum of glycoside compounds.[MH]-=359.0984,Found:359.0978

[0032] Figure 5 HPLC chromatogram of glycoside compounds

[0033] Figure 6 UV-visible spectrum of glycoside compounds (0.05mM, λmax1=219nm, λmax2=278nm)

[0034] Figure 7 Circular dichroism spectra of glycoside compounds (0.3mM)

[0035] Figure 8 Fluorescence spectrum of glycoside compounds (0.05mM, λex=220nm)

[0036] Fig. 9 Whole-body staining of aorta in each group DETAILED DESCRIPTION

[0037] Example 1

[0038] 1. Methods

[0039] Apolipoprotein E (ApoE) is a polymorphic protein that participates in the transformation and metabolism of lipoproteins. When ApoE is missing, a series of changes occur in the metabolism and transport of lipoproteins in animals, resulting in a decrease in the clearance rate of cholesterol. Animals with ApoE deficiency develop spontaneous atherosclerosis. - / - Mice are a commonly used animal model of atherosclerosis.

[0040] The present invention uses 10-week-old C57BL / 6 pure line apolipoprotein E gene knockout (Apo E- / -) mice for all groups except the blank control group; wild-type C57BL / 6 mice are used for the blank control group. Atherosclerotic lesions are induced by feeding with a high-fat diet for 8 weeks, and the drug is administered once a day by oral gavage at 18 weeks of age. The mice are dissected at 26 weeks of age, and the aorta is stained as a whole to evaluate the effect of glycoside compounds (structural formula such as Formula IV) on Apo E - / - Effects of atherosclerosis on the progression of mouse arterial disease, specific aorta whole-body staining method:

[0041] 1) Aorta stripping: After the experiment, the mouse was dissected, and the aorta was stripped from the mouse together with the heart, and the remaining tissues outside the aorta were removed;

[0042] 2) Cut the aorta longitudinally: Place it in a 6*6cm cell culture dish, add saline to fill the aorta, and cut the aorta longitudinally with microscissors;

[0043] 3) Staining: Transfer the cut aorta to a new cell culture dish and add Oil Red O staining solution. Remove the staining solution after 10 minutes and differentiate it with 70% alcohol until the normal tissue turns milky white. Rinse the aorta with distilled water and take pictures.

[0044] 2. Trial Grouping and Medication

[0045] The experimental animals were randomly grouped according to the weight results. Mice with a weight far from the mean or due to fighting injuries or death were not included in the experiment. There were 12 mice in each group. The blank control group and the model group were given distilled water, and the drug-treated group (glycoside compound shown in formula IV and simvastatin) was given according to the dosage design table. The glycoside compound shown in formula IV can be obtained by the preparation method reported in patent ZL201810652319.0. The detection and identification results of the glycoside compound shown in formula IV are shown in Figures 1 to 8 .

[0046] Table 1. Animal grouping and drug dosage design

[0047]

[0048] 3. Results

[0049] During the high-fat diet period, all groups of mice - / - Except for seborrheic alopecia in mice, no other obvious abnormal reactions were observed in mice in each group, and no obvious abnormalities were found in gross anatomy, indicating that the test drug had no obvious toxic side effects on animals.

[0050] The specific results of aorta staining in each group are shown in Fig. 9 After 16 weeks of high-fat diet feeding (26 weeks of age), no atherosclerotic plaques were found in the aorta of wild-type C57BL / 6 mice (blank control group), and Apo E - / - The mice (model group) formed an atherosclerotic disease model; compared with the model group, the lipid plaques in the aorta of the mice in the simvastatin group were reduced, and the lipid plaques in the glycoside compound IV administration group (80 mg / kg) were also reduced, indicating that the glycoside compound IV administration group has the effect of reducing lipid deposition in blood vessels and protecting blood vessels (including but not limited to the aorta), and the glycoside compound IV administration group has the effect of treating atherosclerotic diseases.

[0051] In summary, the present invention confirms that glycoside compound IV has a certain effect of reducing lipid deposition and protecting blood vessels (including but not limited to the aorta) through the whole-body staining test of the aorta in the atherosclerotic mouse model, thereby reducing the incidence of atherosclerosis, alleviating the degree of lesions, and further reducing the incidence of vascular lesions such as coronary artery stenosis, myocardial ischemic infarction and cerebral ischemic injury, so that it has comprehensive development and application prospects in the treatment of atherosclerotic diseases.

Claims

1. Use of a glycoside compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating atherosclerosis, Features: The structural formula of the glycoside compound is shown in formula (I):

2. The use according to claim 1, Features: The drug is a drug that reduces lipid deposition in blood vessels.

3. The use according to claim 2, Features: The drug is a drug that reduces lipid deposition in the aorta.

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