Substituted flavonoids and preparation method, application and pharmaceutical composition thereof

A technology of flavonoids, substituents, applied in the fields of medicinal chemistry and pharmacotherapeutics

Inactive Publication Date: 2008-09-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But despite this, only Zileuton is the only 5-LOX inhibitor that is actually marketed for clinical use. Ther

Method used

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  • Substituted flavonoids and preparation method, application and pharmaceutical composition thereof
  • Substituted flavonoids and preparation method, application and pharmaceutical composition thereof
  • Substituted flavonoids and preparation method, application and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Synthesis of 5,7-dihydroxy-3-(3-methylbut-2-enyl)-2-phenyl-4H-chromen-4-one (compound 1):

[0111] Step (1): Dissolve 0.5g of ethyl 3-oxo-3-phenylpropionate in 5mL of DMF to obtain a colorless clear liquid, add 0.4g of potassium carbonate and 3,3-dimethylallyl bromide under stirring at room temperature 0.305mL, react overnight at room temperature. The next day, add 20 mL of water to the system, transfer to a separatory funnel, extract three times with 30 mL of ethyl acetate, combine the organic phases, wash twice with 25 mL of water, twice with 20 mL of saturated saline, and dry over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated to dryness to obtain the crude product as viscous oil, which was purified by column chromatography to obtain 575 mg of the pure product, with a yield of 85%. 1 H NMR (CDCl 3 , 300M): δ8.24(d, J=7.2Hz, 2H), 7.57(t, J=7.2Hz, 1H), 7.45(t, J=7.5Hz, 2H), 5.10(t, J=7.2Hz , 1H), 4.29(t, J=7.5Hz, 1H), 4.1...

Embodiment 2

[0114] 5,7-dihydroxy-3-(3-methylbut-2-enyl)-2-(2,4,5-trimethoxyphenyl)-4H-chromen-4-one (compound 2) Synthesis of:

[0115] Step (1): According to the literature method [Kumazawa, T. et al. Carbohydr. Res. 2000, 329, 507.], the double MOM-protected trihydroxyacetophenone was prepared.

[0116]Step (2): Dissolve 3.1g of double-MOM-protected trihydroxyacetophenone in 20mL of anhydrous DMF, slowly drop 1.5g of sodium hydride in DMF solution under ice cooling, and then add 2,4,5-trimethoxy 3.0 g of benzoyl chloride was reacted overnight at room temperature. Add 50mL of cold water at 0-10°C to the system, extract with 50mL of ethyl acetate, combine the organic phases, wash with 50mL of water and 50mL of saturated brine, and dry over anhydrous magnesium sulfate. The desiccant was filtered off, and the product obtained by evaporating the solvent to dryness could be directly used in the next reaction with a yield of 97%. 1 H NMR (CDCl 3 , 300M): δ13.42(s, 1H), 7.56(s, 1H), 6.48(s,...

Embodiment 3

[0120] 5-Hydroxy-3-(3-methylbut-2-enyl)-4-oxo-2-(2,4,5-trimethoxyphenyl)-4H-benzopyran-7-substituted Synthesis of mesylate (compound 3):

[0121] Dissolve 100mg of compound 2 in 2ml of anhydrous tetrahydrofuran, add 20μL of methanesulfonyl chloride and 34μL of triethylamine under ice cooling, react at room temperature until the raw materials disappear, evaporate the solvent, add 10mL of water to the system, extract with 15mL of ethyl acetate, and the organic phase successively Wash twice with 20 mL of water and 20 mL of saturated saline, and dry over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated to dryness to obtain a crude product, which was recrystallized from a mixed solvent of ethyl acetate and petroleum ether (V: 1 / 3) to obtain 107 mg of a pure product with a yield of 90%. 1 H NMR (CDCl 3 , 300M): δ13.15(s, 1H), 6.86(s, 1H), 6.84(s, 1H), 6.66(s, 1H), 6.60(s, 1H), 5.07(t, J=6.6Hz, 1H), 3.97(s, 3H), 3.85(s, 3H), 3.79(s, 3H), ...

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PUM

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Abstract

The invention provides a substituted flavonoid in formula (I), and pharmaceutically acceptable salt, solvate and hydrate thereof, wherein the definitions of R1-R10, X and Y are described in specification. Pharmacological experiment indicates that the compound is 5-lipoxidase strong inhibitor. Therefore, the flavonoid is expected to be applied in the preparation of drugs for preventing and/or treating inflammation diseases, immunological diseases such as asthma, anaphylaxis, etc., and cardiovascular disease. The invention also provides the preparation method of the flavonoid.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to substituted flavonoids, their preparation methods, and their use as 5-lipoxygenase inhibitors in the preparation, treatment and / or prevention of inflammatory diseases, immune diseases such as asthma and allergies, and Use in medicine for cardiovascular diseases and pharmaceutical compositions comprising such compounds. Background technique [0002] 5-lipoxygenase (5-lipoxygenase, 5-LOX) is a member of the lipoperoxidase family, widely present in animal and plant tissues. Lipoperoxidase catalyzes the oxidation of polyunsaturated fatty acids (eg, arachidonic acid, AA) with 1,4-cis-pentadiene moieties to produce their peroxidation products. When AA in human body is formed by phospholipid membrane A 2 After release, 5-LOX oxidizes its C-5 position to generate 5-hydroxyperoxytetraenoic acid (5-HPETE), which is subsequently dehydrated to generate t...

Claims

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Application Information

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IPC IPC(8): C07D311/30C07D493/04A61K31/352A61K31/5355A61P29/00A61P37/00A61P9/00
Inventor 柳红蒋华良朱维良郑鸣芳郑明月罗小民沈建华陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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