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Nitric oxide donor type coumarin derivatives, preparation methods therefor and medicinal use of nitric oxide donor type coumarin derivatives

A technology of coumarin derivatives and body shape, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, and can solve problems such as low bioavailability, limited clinical application, and unstable metabolism in the body

Active Publication Date: 2017-07-14
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the shortcomings of natural coumarin compounds such as insufficient antitumor activity, poor water solubility, unstable metabolism in vivo, and low bioavailability, their clinical application is limited.

Method used

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  • Nitric oxide donor type coumarin derivatives, preparation methods therefor and medicinal use of nitric oxide donor type coumarin derivatives
  • Nitric oxide donor type coumarin derivatives, preparation methods therefor and medicinal use of nitric oxide donor type coumarin derivatives
  • Nitric oxide donor type coumarin derivatives, preparation methods therefor and medicinal use of nitric oxide donor type coumarin derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0508] Synthesis of Coumarin-3-Carboxylic Acid (3)

[0509] In a dry 100mL round bottom flask, add 4.2mL (0.04mol) salicylaldehyde, 8.5mL (0.056mol) diethyl malonate, 25mL absolute ethanol, 2 drops of glacial acetic acid and 0.5mL hexahydropyridine, and heat Reflux for 2h. After cooling, the reactant was poured into water and crystallized in ice water. The crude ethyl coumarin-3-carboxylate was obtained by suction filtration, and 7.5 g of white crystals were obtained by recrystallization, with a yield of 85.4%, m.p.92.0-93.0°C.

[0510] In a 100mL round bottom flask, add 25mL of 95% ethanol and NaOH solution (8g of solid NaOH dissolved in 50mL of water), 6g (0.028mol) of ethyl coumarin-3-carboxylate, and heat to reflux for 15min. The reaction mixture was poured into 70 mL aqueous hydrochloric acid solution with stirring, and crystals were precipitated. Suction-filtered crude coumarin-3-carboxylic acid was recrystallized from 50% ethanol to obtain 5.2 g of white crystal coum...

Embodiment 2

[0520] Referring to the method of Example 1, coumarin-3-formyl chloride and 3,4-diphenylsulfonyl-1,2,5-oxadiazole-2-oxide were prepared.

[0521] Preparation of Aminoethanol Furazan (5)

[0522] Add NaH (142mg, 5.9mmol) and aminoethanol (0.2ml, 3.33mmol) into a 50ml round bottom flask, keep away from light, stir in an ice-salt bath, add furazan dissolved in THF, that is, 3,4-dibenzenesulfonate Acyl-1,2,5-oxadiazole-2-oxide (0.5g, 1.37mmol), keep the reaction on ice bath. TLC detected that the reaction was complete. Water was added to the reaction solution, and after extraction with EtOAc, the organic layer was washed with saturated NaCl, and TLC detected that the organic layer had a single spot. Anhydrous Na 2 SO 4 After drying, it was concentrated to dryness under reduced pressure and weighed 239 mg. Yield 62%.

[0523] Coumarin-3-carboxylic acid-ethanolamine furazan (I 6 )Synthesis

[0524] Dissolve ethanolamine furazan (285mg, 1.0mmol) and triethylamine (0.83ml, 6.0...

Embodiment 3

[0526] Referring to Example 1, 1,4-butynediol furoxan was synthesized.

[0527] Synthesis of 2,4-Dihydroxybenzaldehyde

[0528] Add DMF (19mL, 210mmol) and acetonitrile (100mL) into a 500mL three-necked flask, and stir well at room temperature. Phosphorus oxychloride (19 mL, 250 mmol) was slowly added dropwise in an ice bath, and the addition was completed after 1 h, and then stirred at room temperature for 1 h. Dissolve 1,3-benzenediol (21g, 190mmol) in acetonitrile, and slowly add it dropwise to the reaction solution, a white precipitate is formed. After the dropwise addition, the solution is stirred for 4 hours in an ice bath and 2 hours at room temperature. Filter with suction, wash the filter cake with ice acetone, and vacuum-dry the obtained solid at 50°C to constant weight. Transfer the solid to a 500mL round bottom flask, add 400mL of water, heat and stir at 50°C for 30min, then stir at room temperature for 2h, a pink needle-like solid precipitates. The crude produc...

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Abstract

The invention relates to the fields of pharmacochemistry and pharmacotherapeutics and particularly relates to nitric oxide donor type coumarin derivatives, preparation methods therefor and an application of the nitric oxide donor type coumarin derivatives. The compounds play a role in resisting tumors and can be applied to the preparation of antitumor drugs.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a class of nitric oxide (NO) donor type coumarin derivatives or pharmaceutically acceptable salts thereof, their preparation methods and medical applications, especially in the preparation of anti- Application in tumor medicine. Background technique [0002] Malignant tumors are one of the main killers that endanger human health. There are many kinds of drugs used to treat malignant tumors clinically, but due to their toxic side effects, drug resistance and low selectivity, most cancer patients lack effective treatment. Therefore, there is a long way to go to find new anti-tumor drugs with high efficacy and low side effects. [0003] Natural products have long been recognized as an important source of effective therapeutic drugs. Searching for new drugs or lead compounds from natural products is an important research direction and a very act...

Claims

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Application Information

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IPC IPC(8): C07D413/12A61K31/4245A61K31/454A61K31/496A61K31/5377A61P35/00
CPCC07D413/12
Inventor 何黎琴张灼王蓉柏志伟
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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