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Prodrug of flavonoids and application of prodrug

A technology of compounds and prodrugs, applied in the field of prodrugs of flavonoids, can solve the problems of low bioavailability, poor solubility and the like

Active Publication Date: 2015-08-26
BEIJING SHENOGEN PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] However, although the above-disclosed flavonoids have good pharmaceutical activity, these compounds have a common disadvantage: poor solubility in water, and the bioavailability of the prepared oral preparations is very low after biological administration

Method used

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  • Prodrug of flavonoids and application of prodrug
  • Prodrug of flavonoids and application of prodrug
  • Prodrug of flavonoids and application of prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of Alcoradine

[0065] Acradine, also known as icariin, is extracted and separated from the traditional Chinese medicine Epimedium, and its structure is shown in the following formula (G).

[0066]

[0067] The preparation method of icariin is disclosed in the patent whose publication number is CN101302548. In the method, icariin is used as a raw material, hydrolyzed by β-glucosidase, the precipitate obtained by centrifuging the hydrolyzed product is dissolved in acetone, and the supernatant is obtained by centrifuging and filtering. The supernatant obtained by centrifugation is then recrystallized with water to obtain pure icariin, which is in the form of yellow powder crystals. The icariin in the present invention was purchased from Shaanxi Jiahe Plant Chemical Co., Ltd., with a purity of 90%.

Embodiment 2

[0069] 3,5-Dihydroxy-8-(3-methyl-2-butenyl)-2-(4-methoxyphenyl)-7-(4H-chromen-4-one)phosphonic acid di Synthesis and identification of sodium ester (formula I compound), synthetic route is as follows:

[0070]

[0071] Compound H 3,5-dihydroxy-8-(3-methyl-2-butenyl)-2-(4-methoxybenzene Preparation of diethyl)-7-(4H-benzopyran-4-one)phosphate

[0072] Compound G 3,5,7-trihydroxy-8-(3-methyl-2-butenyl)-2-(4-methoxyphenyl)-7-(4H-benzopyran-4 -ketone) (7.4g, 20mmol, 1.0eq) was dissolved in 100ml of anhydrous tetrahydrofuran (THF), added DIPEA (15ml, 83.7mmol, 4.2eq), stirred well, added DMAP (0.24g, 2mmol, 10%mol), Cool down to -10°C, slowly add CCl dropwise 4 (3ml, 31mmol, 1.5eq), 10ml of anhydrous THF solution of diethyl phosphite (3.32g, 2.4mmol, 1.2eq), slowly rise to room temperature for reaction, thin-layer chromatography (silica gel plate loading material, developing agent is acetic acid Ethyl ester and petroleum ether 1:2, 254nm ultraviolet lamp color) monitor un...

Embodiment 3

[0094] 3,5-Dihydroxy-8-(3-methyl-2-butenyl)-2-(4-methoxyphenyl)-7-(4H-benzene Preparation, synthesis and identification of pyran-4-one) sodium sulfate

[0095]

[0096] Compound G (3.68g, 10mmol, 1.0eq) was dissolved in 40ml of dry pyridine / dimethylformamide (DMF) (1:1 v / v), slowly added in batches to pyridine sulfur trioxide complex (C 5 h 5 NSO 3 ) (4.8g, 30mmol, 6.0eq), after the addition is complete, keep away from light, heat and stir the reaction at 50-60°C, thin-layer chromatography (silica gel plate loading material, developing agent is ethyl acetate and petroleum ether 2:1, 254nm UV Light color) Monitor until compound G disappears completely, the reaction solution naturally cools down to room temperature, cools down to 0°C in an ice bath, slowly adds 30ml of water under stirring and stirs for 30 minutes, adjusts the pH value to 13 with 1mol / l NaOH, evaporates to dryness and removes Pyridine and DMF, add 40ml of water, add dropwise 1mol / l sulfuric acid to acid...

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Abstract

The invention provides a prodrug of flavonoids and pharmaceutically acceptable salt or solvate of the prodrug. The prodrug is shown in a formula I in the specification. The prodrug of the flavonoids is prepared by substituting sulfate or sulfate ester, carbonate or carbonic ester and phosphate or phosphate ester for hydrogen of hydroxyl. The prodrug overcomes defects of poor water solubility and low bioavailability of original flavonoids.

Description

technical field [0001] The invention relates to a prodrug of a flavonoid compound and its application, belonging to the field of medicine. Background technique [0002] Flavonoids are a class of compounds that exist in nature and have a 2-phenylchromone core, as shown in the following formula (A). Because there is a ketone carbonyl group in the molecule of this kind of compound, the first oxygen atom is basic and can form a salt with strong acid, and its hydroxyl derivatives are mostly yellow, so they are called flavones. [0003] [0004] Studies have shown that flavonoids have a variety of biological activities, such as cardiovascular system activity, antibacterial and antiviral activity, antitumor activity, antioxidant free radical activity, anti-inflammatory and analgesic activity, and liver protection activity. [0005] At present, more and more specific flavonoids have entered the drug development process and made progress in research and development. For example,...

Claims

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Application Information

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IPC IPC(8): C07F9/655C07D311/30C07D405/12A61K31/661A61K31/4545A61K31/496A61K31/352A61P35/00
Inventor 王永钢张建存孟坤
Owner BEIJING SHENOGEN PHARMA GRP
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