Flavonoid glycoside derivative as well as preparation method and application thereof
By preparing flavonoid glycoside derivatives, the shortcomings of existing antihypertensive drugs in the treatment of refractory hypertension have been overcome, achieving a more effective blood pressure lowering effect, especially a significant improvement in systolic blood pressure.
Patent Information
- Application Number
- CN202511307121.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-13
- Publication Date
- 2025-12-02
AI Technical Summary
Existing antihypertensive drugs have clinical application limitations in treating refractory hypertension, necessitating the development of safer and more effective antihypertensive drugs.
By preparing a flavonoid glycoside derivative, compound 3, which has excellent blood pressure lowering effect, was generated by reacting compound 1 and compound 2 with tert-butyl hydrogen peroxide in a specific solvent.
Flavonoid glycoside derivatives exhibit a significant effect in reducing systolic blood pressure, which is superior to the traditional drug nifedipine, and have potential clinical application prospects.
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Figure CN121045203A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a flavonoid glycoside derivative, and more particularly to a flavonoid glycoside derivative, its preparation method and application, belonging to the field of pharmaceutical synthesis technology. Background Technology
[0002] Hypertension is the leading manageable risk factor for cardiovascular and cerebrovascular events worldwide, with approximately half of patients exhibiting refractory hypertension, meaning their blood pressure remains high even after treatment with a combination of three or more antihypertensive drugs. This uncontrolled hypertension can lead to organ damage, cardiovascular disease, stroke, heart attack, and heart failure. Although five major classes of antihypertensive drugs (diuretics, beta-blockers, calcium channel blockers, ACEIs / ARBs, and renin inhibitors) are currently widely used, their respective clinical application limitations necessitate the development of new antihypertensive drugs with improved safety profiles. Among these, targeted structural modification of bioactive substances is an effective approach to reducing side effects and improving therapeutic efficacy. Summary of the Invention
[0003] To address the above technical problems, this invention proposes a flavonoid glycoside derivative, its preparation method, and its application.
[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows: Based on the first aspect of the present invention, a flavonoid glycoside derivative having the following molecular structural expression is provided: .
[0005] Based on a second aspect of the present invention, a method for preparing a flavonoid glycoside derivative is also provided, comprising the following reaction process expression: ; The method includes the following steps: Compound 1 and compound 2 (4-amino-6-chloro-1,3-benzenedisulfonamide) were mixed and dissolved, and tert-butyl hydrogen peroxide was added and heated to prepare compound 3, namely the flavonoid glycoside derivative.
[0006] In the preparation method provided by this invention, compound 1 can be extracted from hawthorn leaves with reference to known techniques, such as dissolving in an organic solvent under reflux and then separating and purifying by column chromatography (doi.org / 10.1002 / rcm.9033); compound 2 is sulfanilamide (scientific name: 4-amino-6-chloro-1,3-benzenedisulfonamide), which is widely available in the market.
[0007] As a preferred embodiment, the molar ratio of compound 1 to compound 2 is 1:(0.4-0.6), for example, 1:0.45, 1:0.5, 1:0.55, etc.
[0008] As a preferred embodiment, the amount of tert-butyl hydroperoxide added is 1.5-2.5 times the amount of 1 mole of the compound, for example, 1.8 times, 2 times, 2.2 times, 2.4 times, etc.
[0009] As a preferred embodiment, the reaction solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, and diethylene glycol dimethyl ether.
[0010] As a preferred embodiment, the reaction is carried out at a temperature of 100-150℃ with stirring for 10-30 hours. Preferred reaction temperatures include, for example, 110℃, 120℃, 120℃, and 140℃. Preferred reaction times include, for example, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 26 hours, and 28 hours.
[0011] As a preferred embodiment, after the reaction is complete, the reaction solution is poured into ice water to stop the reaction. The purification method of the product is one or a combination of evaporation, extraction, column chromatography, and recrystallization. Conventional purification methods can be generally adjusted and replaced, and will not be elaborated further.
[0012] The preparation method provided by this invention can easily obtain the target product through a one-step process, which has typical application advantages.
[0013] Based on a third aspect of the present invention, the use of the flavonoid glycoside derivatives as described above and the flavonoid glycoside derivatives prepared by the method described above in the preparation of antihypertensive drugs is also provided.
[0014] The flavonoid glycoside derivatives provided by this invention have been found to have excellent antihypertensive effects during long-term research, especially in reducing systolic blood pressure, and have potential clinical application prospects. Attached Figure Description
[0015] Figure 1 This is a dotted line graph showing the changes in systolic blood pressure in each group of mice during the experimental testing process. Detailed Implementation
[0016] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.
[0017] Unless otherwise specified, the raw materials and reagents used in the following embodiments of the present invention can be obtained commercially. The method for obtaining compound 1 is as follows: 20 kg of hawthorn leaves were pulverized using a cell wall breaker and extracted three times by reflux with 80% ethanol for 30 min each time. The extracts were combined and concentrated under reduced pressure. The concentrated extract was suspended in water and subjected to AB-8 macroporous adsorption resin column chromatography, eluted with 55% ethanol, and the solvent was evaporated under reduced pressure to obtain a mixture. The mixture was loaded onto a silica gel column and eluted with a gradient of CHCl3–CH3OH at ratios of 50:1, 20:1, and 10:1 to obtain crude extracts A, B, and C, respectively. Crude extract C was loaded onto a silica gel column and eluted with a gradient of CHCl3–CH3OH. The eluents of [CHCl3–CH3OH (15:1→9:1)] were combined and then subjected to polyamide column chromatography, eluted with H2O–EtOH (3:2) to obtain compound 1.
[0018] The 1H NMR spectrum of compound 1 was identified using an NMR spectrometer, as follows: 1 H NMR (600 MHz, DMSO-d6) δ 11.28 (s, 1H), δ 8.91 (s, 1H), 7.85 –7.79 (m, 2H), 6.94 – 6.88 (m, 2H), 6.69 (s, 1H), 6.62 (s, 1H), 4.81 – 4.74(m, 1H), 4.55 – 4.48 (m, 1H), 4.18 (dddd, J = 7.4, 6.5, 4.0, 2.7 Hz, 2H), 4.01 – 3.91 (m, 2H), 3.74 – 3.62 (m, 2H), 3.46 (d, J = 16.5 Hz, 1H), 3.26 (t,J = 5.3 Hz, 1H).
Example 1
[0019] 1H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.91 (s, 1H), 8.37 (s,1H), 7.98 (s, 1H), 7.85 – 7.79 (m, 2H), 7.50 (s, 1H), 7.37 (s,1H), 6.94 –6.88 (m, 2H), 6.69 (s, 1H), 6.62 (s, 1H), 5.83 (d, J = 7.7 Hz, 1H), 5.43 (d,J = 6.8 Hz, 1H), 5.06 (ddd, J = 7.9, 6.8, 3.0 Hz, 1H), 4.84 (d, J = 5.1 Hz,1H), 4.42 (d, J = 5.6 Hz, 1H), 4.32 (td, J = 6.2, 5.0 Hz, 1H), 4.28 – 4.21(m, 2H), 3.67 (d, J = 16.5 Hz, 1H), 3.47 (d, J = 16.3 Hz, 1H).
Example 2
[0020]
Example 3
[0021]
Application Example
[0022] Drug administration: During the experimental feeding process, mice in the normal group were fed a normal diet, while mice in other groups were continuously fed a high-salt diet. In addition, mice in each group were administered the following dosages by gavage once a day: low-dose experimental group 1 mg / kg flavonoid glycoside derivative (prepared in Example 1), medium-dose experimental group 2 mg / kg flavonoid glycoside derivative (prepared in Example 1), high-dose experimental group 5 mg / kg flavonoid glycoside derivative (prepared in Example 1), positive control group 5 mg / kg nifedipine, raw material group 2.5 mg / kg compound 1 and 2.5 mg / kg compound 2, and model group and normal group were given an equal volume of physiological saline.
[0023] During the 40-day experimental period, the systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) of mice in each group were measured. The average values were recorded in Tables 1 and 2, respectively. The changes in systolic blood pressure in Table 1 were plotted as a dotted line graph, as shown below. Figure 1 As shown.
[0024] Table 1
[0025] Table 2
[0026] The test results above show that the flavonoid glycoside derivatives provided by this invention have excellent antihypertensive effects, and at the same drug concentration, they have a more significant effect on improving systolic blood pressure than the positive control drug nifedipine, and are expected to have potential clinical applications.
[0027] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.
Claims
1. A flavonoid glycoside derivative, characterized in that, It has the following molecular structural expression: 。 2. A method for preparing a flavonoid glycoside derivative, characterized in that, The reaction process has the following expression: ； The method includes the following steps: Compound 1 and Compound 2 were mixed and dissolved, and tert-butyl hydrogen peroxide was added and the mixture was heated to prepare Compound 3, which is the flavonoid glycoside derivative.
3. The method for preparing flavonoid glycoside derivatives according to claim 2, characterized in that, The molar ratio of compound 1 to compound 2 is 1:(0.4-0.6).
4. The method for preparing flavonoid glycoside derivatives according to any one of claims 1-3, characterized in that, The amount of tert-butyl hydroperoxide added is 1.5-2.5 times the amount of 1 mole of the compound.
5. The method for preparing flavonoid glycoside derivatives according to any one of claims 1-4, characterized in that, The reaction solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, and diethylene glycol dimethyl ether.
6. The method for preparing flavonoid glycoside derivatives according to any one of claims 1-5, characterized in that, The reaction is carried out at a temperature of 100-150℃ with stirring for 10-30 hours.
7. The method for preparing flavonoid glycoside derivatives according to any one of claims 1-6, characterized in that, After the reaction is complete, pour the reaction solution into ice water to stop the reaction.
8. The use of a flavonoid glycoside derivative as described in claim 1 and a flavonoid glycoside derivative prepared by the method of any one of claims 2-7 in the preparation of antihypertensive drugs.