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New xanthine oxidase inhibitor

A flavonoid and pharmaceutical technology is applied to the application of a pharmaceutical composition in the preparation of uric acid-lowering drugs. It can solve the problem that the selectivity of the pharmacological action of apigenin needs to be improved

Inactive Publication Date: 2016-12-07
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the selectivity of the pharmacological action of apigenin needs to be improved

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Example 1 5, the synthesis of 7-dihydroxy-4'-(1-carboxymethoxy) flavone (I-1)

[0016] 1.1 Preparation of 7-methoxymethyleneoxy-5,4'-dihydroxyflavone (i)

[0017] Add 50 mL of anhydrous DMF to a 250 mL three-necked flask, and add 10 g (37 mmol) of apigenin and 4.1 g (29.6 mmol) of anhydrous potassium carbonate under stirring in an ice bath. Under the protection of argon, 2.97 g (37 mmol) of chloromethyl methyl ether was slowly added dropwise to the reaction system. After the dropwise addition, the ice bath was removed, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction, potassium carbonate was removed by filtration, 50 mL of water was added, and the pH was adjusted to neutral with dilute hydrochloric acid. Add ethyl acetate and extract (100 mL×3). The ethyl acetate layer was washed successively with saturated sodium chloride solution and water, and dried over anhydrous sodium sulfate. Anhydrous so...

Embodiment 2

[0024] Embodiment 2 5, the synthesis of 7-dihydroxy-4'-(3-carboxypropoxyl) flavone (I-2)

[0025] Referring to Example 1.2, replace ethyl 2-bromoacetate with ethyl 4-bromobutyrate, and react with compound i to obtain 7-methoxymethyleneoxy-5-hydroxyl-4'-(3-ethoxycarbonyl Propoxy) flavone (ii-2), yield: 43%.

[0026] Referring to Example 1.3, ii-2 was demethoxymethylene with 3N hydrochloric acid to obtain 5,7-dihydroxy-4'-(3-ethoxycarbonylpropoxy)flavone (iii-2), producing rate of 85%.

[0027] Referring to Example 1.4, iii-2 was hydrolyzed with potassium carbonate base to obtain 0.18 g of a yellow solid of I-2, namely 5,7-dihydroxy-4'-(3-carboxypropoxy)flavone, with a yield of 90%. Melting point: 232-233°C, 1 H NMR (400MHz, DMSO-d 6 ): δ = 1.95-1.99 (2H, m), 2.41 (2H, t), 4.10 (2H, t), 6.20 (1H, d, J = 2.24Hz), 6.51 (1H, d, J = 2.24Hz) , 6.88(1H, s), 7.11(2H, d, J=8.96Hz), 8.03(2H, d, J=8.96Hz), 10.87(1H, s), 12.19(1H, s), 12.93ppm(1H , s); HRMS-ESI(MeOH): m / z[M-H] - C ...

Embodiment 3

[0028] Example 3 5,7-dihydroxy-4,-(4-carboxybutoxy)flavone (I-3) synthesis

[0029] Referring to Example 1.2, replace ethyl 2-bromoacetate with ethyl 5-bromovalerate, and react with compound i to obtain 7-methoxymethyleneoxy-5-hydroxyl-4'-(4-ethoxycarbonyl Butoxy)flavone (ii-3), yield: 46%.

[0030] Referring to Example 1.3, ii-3 was demethoxymethyleneized with 3N hydrochloric acid to obtain 5,7-dihydroxy-4'-(4-ethoxycarbonylbutoxy)flavone (iii-3), producing The rate is 95%.

[0031] Referring to Example 1.4, iii-3 was hydrolyzed with potassium carbonate base to obtain 0.18 g of a yellow solid of I-3, namely 5,7-dihydroxy-4'-(4-carboxybutoxy)flavone, with a yield of 90%. Point: 202-204°C, 1 H NMR (400MHz, DMSO-d 6): δ=1.64-1.68 (2H, m), 1.74-1.78 (2H, m), 2.30 (2H, t), 4.09 (2H, t), 6.20 (1H, d, J=2.24Hz), 6.51 ( 1H, d, J = 2.24Hz), 6.88 (1H, s), 7.11 (2H, d, J = 8.96Hz), 8.03 (2H, d, J = 8.96Hz), 10.87 (1H, s), 12.00 ( 1H, s), 12.94ppm (1H, s); HRMS-ESI (MeOH): m / z [M-H...

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Abstract

The present invention provides a new apigenin derivative having a selective xanthine oxidase inhibition effect and represented by a formula I, or a pharmaceutically acceptable salt thereof, wherein R is H or C1-C5 straight or branched chain alkyl, and n is an integer from 1-10. The formula I is defined in the specification.

Description

technical field [0001] The present invention relates to new flavonoid derivatives with xanthine oxidase inhibitory activity and their non-toxic pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds as active ingredients, as well as the flavonoid derivatives and their non-toxic Toxic pharmaceutically acceptable salts and applications of pharmaceutical compositions containing these compounds as active ingredients in the preparation of uric acid-lowering medicines. Background technique [0002] Apigenin is one of the most widely studied flavonoids, which has various biological activities, such as anti-inflammatory, anti-oxidative, anti-tumor effects, etc. In vitro studies have shown that apigenin also has xanthine oxidase inhibitory activity and α-glucosidase inhibitory activity. [0003] [0004] However, the selectivity of the pharmacological action of apigenin needs to be improved. Contents of the invention [0005] The p...

Claims

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Application Information

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IPC IPC(8): C07D311/30A61K31/352A61P19/06
Inventor 仲伯华苏卓然樊士勇史卫国姚宜山贾红新
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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