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Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof

A technology of andrographolide, nitric oxide, applied in the direction of organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problem of cell apoptosis without any protective effect, and achieve the effect of protecting islet beta cells

Active Publication Date: 2013-09-18
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Zumsteg et al. used iNOS and Fas knockout islet β cells to study the effects of nitric oxide and Fas on cytokine-induced β-cell injury, and found that reducing nitric oxide can partially protect islet β-cells from cytokine-induced damage. Apoptosis, but no protection against apoptosis induced by cross-linking of Fas and FasL on the cell surface

Method used

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  • Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof
  • Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof
  • Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0056] The preparation of embodiment 1 compound AndroII:

[0057] Add 3 mL of toluene, 0.4 mL of DMSO, 2,2-dimethoxypropane (0.2 mL, 0.85 mmol), pyridinium p-toluenesulfonate (3 mg, 0.88 mmol), and andrographolide (150 mg, 0.43 mmol) into 20 mL of In the reaction flask, react at 81°C for 1 h. After the reaction was complete, it was cooled to room temperature, and 0.1 mL of triethylamine was added to terminate the reaction. The reaction mixture was diluted with toluene (20 mL), washed with water (15 mL), and the organic layer was washed with anhydrous Na 2 SO 4 After drying and concentrating, the obtained pale yellow solid was washed with diethyl ether to obtain white solid compound AndroII (135 mg, 80.8%) (Srinivase et al., Bioorg. Med. Chem. Lett. 2004, 14, 4711-4717).

[0058]

Embodiment 2

[0059] The preparation of embodiment 2 compound 4b (as figure 1 shown):

[0060] Dissolve 5-bromovaleric acid (500mg, 2.76mmol) in 10mL of anhydrous acetonitrile, then add dropwise an acetonitrile solution of silver nitrate (934mg, 5.52mmol) to the reaction solution, after the addition is complete, heat up to 70°C to avoid light Reaction 6h. After the reaction, the reaction solution was cooled, filtered, concentrated, and the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, the combined organic layers were washed with anhydrous Na 2 SO 4 After drying and concentrating, the light yellow liquid 5-nitroxyvaleric acid was obtained, which was directly used in the next reaction. 5-Nitroxyvaleric acid was dissolved in 5 mL of dichloromethane, DIEA (0.16 mL, 0.92 mmol) and HBTU (350 mg, 0.92 mmol) were added at room temperature, and stirred at room temperature for 1 h. The reaction solution was washed with water (3×5 ...

Embodiment 3

[0064] The preparation of embodiment 3 compound 6b (as figure 2 shown):

[0065] 4-Bromo-2-butenoic acid (330 mg, 2.0 mmol) was dissolved in 5 mL of dichloromethane, DIEA (0.38 mL, 2.2 mmol) and HBTU (834 mg, 2.2 mmol) were added at room temperature, and stirred at room temperature for 1 h. The reaction solution was washed with water (3×5 mL), and the organic layer was kept for later use. Compound 2 (390 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, 4 mL of water and 300 mg of sodium bicarbonate were added. Under the condition of ice bath, DBU (0.4 mL, 2.7 mmol) and the organic layer were added to the reaction liquid, and the reaction was carried out for 40 min under the condition of ice bath. Stand to separate the liquid, the organic layer was washed 3 times with 10 mL of 1% acetic acid aqueous solution, and anhydrous Na 2 SO 4 After drying and concentration, the resulting mixture was separated on a silica gel column (PE:EA=2:1) ​​to obtain compound 6a (300 mg,...

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Abstract

The invention discloses an andrographolide derivative nitric oxide donor compound as well as a preparation method and an application thereof. The derivative has a structure expressed by a formula (I), wherein R1 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, R2 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, R3 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, and at least one of R1, R2 and R3 is a functional group capable of releasing nitric oxide or an organic acid radical substituted by nitroxide group. The andrographolide derivative nitric oxide donor compound can be used for preparing medicaments for treating diabetes, medicaments for treating cardiovascular diseases, antimicrobial medicaments and antiviral medicaments. The medicaments can be prepared to tablets, capsules, granules, fine granules, powder, pills, patches, oral liquid or injection.

Description

technical field [0001] The invention belongs to the technical field of traditional Chinese medicine, and in particular relates to an andrographolide nitric oxide donor compound, a preparation method thereof and an application in pharmacy. Background technique [0002] The chemical name of Andrographolide is 3-[2-[decahydro-6-hydroxy-5-(hydroxymethyl)-5,8α-dimethyl-2-methylene-1-naphthyl]ylidene Ethyl]dihydro-4-hydroxyl-2(3H)-furanone, a diterpene lactone compound extracted from Andrographis paniculata, is one of its main active ingredients. [0003] Research on the hypoglycemic effect of andrographolide: Modern pharmacological studies have shown that the extract of the traditional Chinese medicine Andrographis paniculata, andrographolide and its derivatives all have hypoglycemic effect, and can be used for the prevention and treatment of diabetes. Zhang et al. found that oral administration of different doses of Andrographis paniculata ethanol extract significantly reduced ...

Claims

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Application Information

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IPC IPC(8): C07D307/60A61K31/365A61P3/10A61P9/00A61P31/00A61P31/12
CPCY02P20/55
Inventor 王玉强孙业伟杜恩明于沛张高小
Owner JINAN UNIVERSITY
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