6,8-substituted naringenin derivative and use thereof

Patent metadata

Field	Value
Publication number	US-2016130245-A1
Application number	US-201314784036-A
Country	US
Kind code	A1
Filing date	Jan 18, 2013
Priority date	Dec 19, 2012
Publication date	May 12, 2016
Grant date	—

Abstract

Disclosed in the present invention are a 6,8-substituted naringenin derivative as shown in formula (I):

in which A 6 and A 8 in formula (I) are respectively selected from H, halogen, hydroxyl, an alkyl group with 1-3 carbon atoms, and a straight-chain alkenyl, alcohol group, aldehyde group, or carboxylic acid group containing 2-3 carbon atoms, obtained by modifying naringenin as lead compound, or a pharmaceutically acceptable salt thereof, a preparation method therefor and use thereof in preparation of drugs for improving the function of the respiratory system and relieving cough.

First claim

1 . A 6,8-substituted naringenin derivative as shown in general formula (1):

wherein A6 and A8 are respectively selected from H, halogen, hydroxyl, an alkyl group with 1-3 carbon atoms, and a straight-chain alkenyl group, alcohol group, aldehyde group or carboxylic acid group containing 2-3 carbon atoms; or a pharmaceutically acceptable salt thereof.

2 . The derivative according to claim 1 , wherein the alkyl group with 1-3 carbon atoms is methyl, ethyl or propyl.

3 . The derivative according to claim 1 , wherein the straight-chain alkenyl group, alcohol group, aldehyde group or carboxylic acid group containing 2-3 carbon atoms is straight-chain allyl, ethanol group, acetaldehyde group, or acetic acid group.

4 . The derivative according to claim 1 , wherein the halogen is selected from F, CI, Br or I.

5 . The derivative according to claim 1 , wherein the derivative is one of 8-n-propylnaringenin, 6-n-propylnaringenin, 6-bromo-8-allylnaringenin, 6-allyl-8-bromonaringenin, 6-allyl-8-chloronaringenin, 8-propyl-6-chloronaringenin, 6-chloro-8-allylnaringenin, 6-allyl-8-hydroxynaringenin, 6-propyl-8-chloronaringenin, 6-allyl-8-iodonaringenin, naringenin-8-acetaldehyde, naringenin-6-acetaldehyde, naringenin-8-acetic acid, 8-chloro-naringenin-6-acetic acid, or 6-chloro-naringenin-8-acetic acid.

6 - 7 . (canceled)

8 . A pharmaceutical preparation with the derivative according to claim 1 , or a pharmaceutically acceptable salt thereof single or in combination as active ingredient(s).

9 . The pharmaceutical preparation according to claim 8 , wherein the pharmaceutical preparation is in a pharmaceutically acceptable dosage form, and the active ingredient is present in an amount of 0.1-95% by weight of the pharmaceutical preparation.

10 . A method for preparing the derivative according to claim 1 , comprising:
(1) preparing the intermediate compounds 8-allylnaringenin and 6-allylnaringenin of the derivative, specifically by subjecting a known compound 7-allyloxynaringenin as starting material to Claisen rearrangement in toluene, to obtain two isomers that are 8-allylnaringenin and 6-allylnaringenin respectively; (2) as required by the position of the modifying group to be introduced, dissolving the intermediate compound 8-allylnaringenin or 6-allylnaringenin obtained in step (1) in ethanol, adding a catalytic amount of 10% Pd/C, hydrogenating for 20 hrs under normal pressure, filtering under suction, and purifying the filtrate by silica gel column chromatography eluting with a mixed solvent of petroleum ether and ethyl acetate, to obtain 8-n-propylnaringenin and 6-n-propylnaringenin respectively; (3) as required by the position of the modifying group to be introduced, dissolving the intermediate compound 8-allylnaringenin or 6-allylnaringenin obtained in step (1) in tetrachloromethane and dimethyl formamide, halogenating with N-halosuccinimide, and after the reaction is complete, purifying the reaction solution by silica gel column chromatography eluting with a mixed solvent of petroleum ether and ethyl acetate, to obtain an allylnaringenin derivative substituted with halogen at position 6 or 8 respectively; (4) as required by the position of the modifying group to be introduced, dissolving the derivative substituted with a propyl group at position 8 or 6 obtained in step (2) in tetrachloromethane and dimethyl formamide, halogenating with equivalent amount of N-halosuccinimide, and after the reaction is complete, purifying the reaction solution by silica gel column chromatography eluting with a mixed solvent of petroleum ether and ethyl acetate, to obtain a propylnaringenin derivative substituted with halogen at position 6 or 8 respectively; (5) dissolving the intermediate compound 8-allylnaringenin or 6-allylnaringenin obtained in step (1) in dichloromethane and tetrahydrofuran, cooling the solution to −70° C. in a dry ice-acetone bath under neat nitrogen atmosphere, then introducing ozone continuously for 2 hrs until the solution becomes blue colored and no discoloration occurs in ten minutes after the introduction of ozone is complete, whereupon introducing air for 15 min, then adding a reducing agent dimethyl sulfide, gradually heating to room temperature, mixing the resulting product with silica gel and purifying by silica gel column chromatography, to obtain a naringenin derivative substituted with an aldehyde group at position 8 or 6 respectively; (6) dissolving the allylnaringenin derivative substituted with halogen at position 6 or 8 obtained in step (3) in ethyl acetate, then adding m-chloroperoxybenzoic acid, heating to reflux for 48 hrs, filtering under suction, concentrating the filtrate, and then purifying the residue by silica gel column chromatography, to obtain an allylnaringenin derivative substituted with a hydroxyl group at position 6 or 8 respectively; (7) dissolving the naringenin derivative substituted with an aldehyde group at position 8 obtained in step (5) in ethanol, adding aminosulfonic acid, adding sodium chlorite dropwise at freezing point, and after complete reaction, mixing the resulting product with silica gel and purifying by silica gel column chromatography, to obtain a naringenin derivative substituted with chloro at position 6 and with a carboxylic acid group at position 8, and dissolving the naringenin derivative substituted with an aldehyde group at position 6 obtained in step (5) in ethyl acetate, adding aminosulfonic acid, adding sodium chlorite dropwise at freezing point, and after complete reaction, mixing the resulting product with silica gel and purifying by silica gel column chromatography, to obtain a naringenin derivative substituted with chloro at position 8 and with a carboxylic acid group at position 6; and (8) dissolving the naringenin derivative substituted with an aldehyde group at position 8 obtained in step (5) in ethyl acetate, adding aminosulfonic acid, adding sodium chlorite dropwise at freezing point, and after the reaction is completed in 0.5 hr, mixing the sample with silica gel and purifying by silica gel column chromatography, to obtain a naringenin derivative substituted with H at position 6 and with a carboxylic acid group at position 8.

Assignees

• Su Weiwei
• Wang Yonggang
• Wu Zhong
• Univ Sun Yat Sen

Inventors

• Su Weiwei
• Wang Yonggang
• Wu Zhong

Classifications

• A61P11/14

  Antitussive agents · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• C07D311/32 Primary

  2,3-Dihydro derivatives, e.g. flavanones · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title