A class of compounds based on flavonoid apigenin linked to citric acid

Abstract

The present invention discloses a class of flavonoid compound apigenin linked to citric acid, which is characterized by having the following general formula (molecular formula: C 21 H 16 O 11 ). Apigenin has a certain uric acid-lowering effect. At the same time, the added citric acid group also has a certain uric acid-lowering effect, thereby enhancing the uric acid-lowering activity of apigenin. This greatly increases the market prospects of apigenin modifications and is expected to contribute to future uric acid-lowering products.

Description

Technical Field

[0001] The present invention relates to a class of compounds based on flavonoid compound apigenin linked to citric acid. Background Art

[0002] Hyperuricemia refers to high levels of uric acid in the blood. This symptom is caused by the body producing too much uric acid or the kidneys excreting too little uric acid, which leads to supersaturation of uric acid in the extracellular fluid, causing the uric acid content in the blood to rise above the healthy standard. Hyperuricemia can be divided into two categories: primary and secondary. Excluding other diseases, hyperuricemia caused by congenital purine metabolism disorders and uric acid excretion defects is called primary hyperuricemia or gout. Secondary hyperuricemia is caused by reduced uric acid excretion caused by kidney disease or certain drugs, myeloproliferative diseases and tumors. Secondary hyperuricemia is caused by increased uric acid production caused by kidney disease or certain drugs, myeloproliferative diseases and chemotherapy. Epidemiological and clinical studies have shown that hyperuricemia is closely related to a series of cardiovascular diseases, such as coronary heart disease, hypertension, heart failure, stroke and atherosclerosis, and has great damage to human liver, kidneys, joints and other organs.

[0003] Apigenin, also known as apigenin, is a naturally occurring flavonoid compound that is widely found in a variety of fruits, vegetables and beans, with the highest content in celery. Existing studies have found that apigenin can significantly inhibit the activity of xanthine oxidase, and its uric acid-lowering effect is similar to allopurinol. At present, foreign countries have developed health products specifically for gout patients with celery seeds as the main ingredient. Citric acid is mainly found in the peel and juice, accounting for about 10% of the dry weight of lemons. It is the most representative acidic substance in lemons. Studies have shown that it can alkalize urine and promote the excretion of uric acid. We enhance the uric acid-lowering effect of apigenin by adding citric acid groups. Summary of the invention

[0004] The problem to be solved by the present invention is to propose an innovative solution to the shortcomings of the above-mentioned prior art, especially a solution with better uric acid lowering effect.

[0005] To solve the above problems, the present invention adopts the following scheme: a flavonoid compound apigenin linked to citric acid compound, characterized in that its molecular formula is: C 21 H 16 O 11 , whose structural formula is:

[0006]

[0007] A preparation method based on a flavonoid compound apigenin linked to citric acid, characterized in that it comprises the following steps:

[0008]

[0009] Dissolve citric acid and oxalyl chloride in benzene, mix and stir, and after the reaction is completed, remove excess benzene and oxalyl chloride by vacuum evaporation.

[0010] Convert the carboxylic acid bond of citric acid into acyl chloride. Citric acid has three carboxylic acid bonds, and what we need is citric acid chloride generated by replacing one of the acyl chloride bonds.

[0011] The evaporated solid was dissolved in 1,2-dichloroethane, apigenin and catalyst 4-dimethylaminopyridine were added, the reaction was stirred continuously, and then quenched with pH 7.0 phosphate buffer (0.1 M), and then extracted with CH2Cl2 to obtain an organic layer containing compound 1 (a class of flavonoid compound apigenin linked to citric acid compounds).

[0012] The catalyst 4-dimethylaminopyridine was quenched and the pH was adjusted. The organic layer extracted with CH2Cl2 contained compound 1 and some impurities soluble in the organic solvent CH2Cl2, as well as a small amount of impurities soluble in water.

[0013] The organic layer was washed with water to remove water-soluble impurities, and then the organic layer was taken and dried over anhydrous NaSO4, filtered to remove NaSO4, and vacuum evaporated to remove the organic solvent CH2Cl2. Finally, silica gel column chromatography was used for purification to obtain a pure product, Compound 1 (a class of compounds based on the flavonoid compound apigenin linked to citric acid).

[0014] Furthermore, a preparation method based on the flavonoid compound apigenin linked to citric acid compound is characterized in that in step three of the synthesis and preparation method based on the flavonoid compound apigenin linked to citric acid compound, the organic layer is washed at least three times with water.

[0015] Furthermore, a class of applications based on the flavonoid compound apigenin connected with citric acid compounds is characterized in that a class of applications based on the flavonoid compound apigenin connected with citric acid compounds is used to prepare uric acid-lowering drugs.

[0016] The technical effects of the present invention are as follows: apigenin has a certain uric acid lowering effect, and the added citric acid group also has a certain uric acid lowering effect, thereby enhancing the uric acid lowering activity of apigenin, which greatly increases the market prospects of apigenin modifications and is expected to contribute to future uric acid lowering products. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 These are the levels of blood uric acid, urine uric acid and 24-hour urine creatinine in each group of mice. DETAILED DESCRIPTION

[0018] Example: Preparation of Compound 1.

[0019]

[0020] Get 192mg of citric acid (1mmol), add 6.0mL of benzene and 400 μ L (4.6mmol) of oxalyl chloride therein.This mixture was stirred at room temperature for 2.5 hours, after stirring finished, mixed solution was spin-dried for solvent in vacuum on rotary evaporator, then the solid after spin-dried was dissolved in 10mL 1,2-ethylene dichloride.270mg apigenin and 300mg (2mmol) 4-dimethylaminopyridine were dissolved in 5mL 1,2-ethylene dichloride and then added in mixed solution.This mixture was stirred for 5 minutes, then quenched with 2mL phosphate buffer (0.1M) of pH 7.0, and used CH Cl Extraction.The organic layer was washed with water three times, and after washing three times with anhydrous NaSO for organic layer Drying and spin-dried in vacuum in rotary evaporator.Unpurified product was purified by silica gel column chromatography, 345mg product was obtained.

[0021] Comparative experiment:

[0022] Fifty mice were randomly divided into normal group, model group, allopurinol group (5 mg / kg) and low-dose and high-dose groups of compound 1 (40 and 80 mg / kg) according to body weight, with 10 mice in each group. Except for the normal group, the mice in the other groups were injected with potassium oxonate 250 mg / kg through the tail vein to replicate the hyperuricemia model. One hour after modeling, the mice in each administration group were given the corresponding drugs, and the mice in the normal group and model group were given equal volumes of normal saline, once a day for 7 consecutive days. One hour after the last administration, blood was collected from the ocular venous plexus of mice in each group, centrifuged (centrifugal radius of 10 cm, 3000r / min, the same below) for 10 minutes, and serum was collected for standby use. After that, the mice were killed by dislocating the cervical vertebra, and the liver and kidney tissues of the mice were taken on the ice table, frozen with liquid nitrogen, and stored in a -80℃ refrigerator for standby use. On the 6th day of administration, 5 mice in each group were placed in metabolic cages 1 hour after administration. After 1 day of adaptation, 24h urine was collected on the 7th day of administration. The urine was centrifuged for 10 min, the supernatant was taken, the urine volume was measured, and serum was taken. The blood uric acid, urine uric acid, and 24-hour urine creatinine levels of each group of mice were determined according to the instructions of the kit.

[0023]

[0024] Table 1: Serum uric acid, urine uric acid, and 24-hour urine creatinine levels in each group of mice

[0025] go through Figure 1 Compared with Table 1, it can be clearly found that compound 1 (a class of compounds based on the flavonoid compound apigenin linked to citric acid) has a significant effect in lowering uric acid, which greatly increases the market prospects of apigenin modifications and is expected to contribute to future uric acid lowering products.

Claims

1. A class of compounds based on flavonoid apigenin and citric acid, characterized in that: Its molecular formula is: C 21 H 16 O 11 , whose structural formula is:

2. The method for preparing a flavonoid compound apigenin linked to citric acid according to claim 1, characterized in that: The steps include:

1. Dissolve citric acid and oxalyl chloride in benzene, mix and stir, and after the reaction is completed, remove excess benzene and oxalyl chloride by vacuum evaporation; 2. Dissolve the evaporated solid in 1,2-dichloroethane, add apigenin and catalyst 4-dimethylaminopyridine, stir the reaction continuously, then quench with 0.1M phosphate buffer at pH 7.0, and then extract with CH2Cl2 to obtain an organic layer containing a class of flavonoid compound apigenin linked to citric acid; 3. Wash the organic layer with water to remove water-soluble impurities, then take the organic layer and dry it with anhydrous NaSO4, filter to remove NaSO4, vacuum evaporate to remove the organic solvent CH2Cl2, and finally purify it using silica gel column chromatography to obtain a pure product of a class of flavonoid compound apigenin linked to citric acid compounds.

3. The preparation method according to claim 2, characterized in that: In step 3, the organic layer is washed with water at least three times.

4. The use of a flavonoid compound apigenin linked to citric acid according to claim 1 in the preparation of uric acid-lowering drugs.

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