Type of aryl benzofuran amidated derivative and medical use thereof

Patent metadata

Field	Value
Publication number	US-11021454-B2
Application number	US-201716075370-A
Country	US
Kind code	B2
Filing date	Jan 19, 2017
Priority date	Feb 3, 2016
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The present invention relates to a type of aryl benzofuran amidated derivatives, the medical use thereof, and the preparation method; said derivatives have antioxidation activity, and xanthine oxidase inhibitory activity, and can be used for antioxidation and for preparing compositions, drugs and health products and treating gout and hyperuricemia.

First claim

What is claimed is:

1. An aryl benzofuran amidated derivative, wherein a structural formula of the aryl benzofuran amidated derivative is shown in formula I:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from the
group consisting of
hydrogen,
hydroxy,
halogen,
nitro,
benzyl,
C 1-4 alkyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, nitro and C 1-2 alkoxy, and
C 1-3 alkoxy unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, nitro and C 1-2 alkoxy;
R 9 is one selected from the group consisting of
hydrogen,
C 1-4 alkyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl and C 1-2 alkoxy,
3-ethyl-1H-indole unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy,
phenyl unsubstituted or substituted by one selected from the group consisting of halogen, hydroxy and C 1-2 alkoxy, and
benzyl unsubstituted or substituted by one selected from the group consisting of halogen, hydroxy and C 1-2 alkoxy,
wherein the X is one selected from the group consisting of F, Cl, and Br; n is 1, 2 or 3; and
R 10 is one selected from the group consisting of
hydrogen,
—COOH,
—COOCH 3 ,
—COOCH 2 CH 3 ,
—COOCH(CH 3 ) 2 ,
—COO(CH 2 ) 2 CH 3 , and
C 1-4 alkyl substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-2 alkoxy.

2. The aryl benzofuran amidated derivative of claim 1 , wherein in the formula:

R 3 or/and R 4 are substituents other than hydroxy;
R 9 or/and R 10 are substituents other than hydrogen;
or, the aryl benzofuran amidated derivative comprises a structural formula:

wherein R 3 , R 4 , and R 6 are each independently C 1-3 alkoxy unsubstituted or substituted by halogen and hydroxyl;
R 9 is one selected from the group consisting of:
hydrogen,
C 1-4 alkyl unsubstituted or substituted by one selected from the group consisting of halogen, and hydroxy,
3-ethyl-1H-indole,
phenyl unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy,
benzyl unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy, and
wherein the halogen is one selected from the group consisting of F, Cl, and Br;
R 10 is one selected from the group consisting of: hydrogen, —COOH, —COOCH 3 , —COOCH 2 CH 3 , —COOCH(CH 3 ) 2 , —COO(CH 2 ) 2 CH 3 , and C 1-4 alkyl substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-2 alkoxy;
or, the aryl benzofuran amidated derivative comprises the structural formula:

wherein R 3 , R 4 , and R 6 are each independently hydroxy;
R 9 is hydrogen; R 10 is hydrogen;
or, the aryl benzofuran amidated derivative comprises the structural formula:

wherein R 3 , R 4 , and R 6 are each independently C 1-3 alkoxy unsubstituted or substituted by halogen and hydroxyl;
R 9 is one selected from the group consisting of:
C 1-4 alkyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, and hydroxy,
3-ethyl-1H-indole unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy,
phenyl unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy,
benzyl unsubstituted or substituted by one selected from the group consisting of halogen and hydroxy, and
wherein the halogen is one selected from the group consisting of F, Cl, and Br; R 10 is one selected from the group consisting: of —COON, —COOCH 3 , —COOCH 2 CH 3 , —COOCH(CH 3 ) 2 , —COO(CH 2 ) 2 CH 3 hydrogen, and C 1-4 alkyl substituted by 1-3 substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, and C 1-2 alkoxy.

3. The synthesis method of claim 1 , comprising the following steps:
(1) mixing salvianolic acid C with a first inorganic base to obtain a first mixture, ultrasonically dissolving the first mixture in a first organic solvent to obtain a second mixture, and heating the second mixture and continuously detecting a reaction of the second mixture; after the reaction is completed, carrying out a first separation and purification method by silica gel column chromatography to obtain an intermediate Tournefolic acid A;
(2) adding SOCl 2 to a second organic solvent under ice bath cooling, and reacting for 30 min to obtain a first solvent, then adding amino compounds selecting from alanine, phenylalanine, cysteine, tyrosine, methionine, tryptophan, and D/L-DOPA to the first solvent to obtain a second solvent, stirring the second solvent at room temperature, concentrating and evaporating the second solvent by a second separation and purification method before washing and drying the second solvent to obtain series of carboxyl-protected amino derivatives;
(3) mixing the intermediate Tournefolic acid A with the series of carboxyl-protected amino derivatives at a mole ratio of 1:(1.1-2) under an action of a condensing agent to be a third mixture, dissolving the third mixture in a third organic solvent to obtain a third solvent, stirring the third solvent at room temperature, and after a reaction and treatment of the third solvent, separating the third solvent by a third separation and purification method by silica gel column chromatography to obtain series of aryl benzofuran amidated derivatives; and
(4) adding an second inorganic base to the series of aryl benzofuran amidated derivatives to be a fourth solvent, ultrasonically dissolving the fourth solvent in a fourth organic solvent to be a fourth solvent, stirring the fourth solvent at room temperature or heating the fourth solvent under reflux, and continuously monitoring a reaction of the fourth solvent by thin layer chromatography (TLC), subjecting the fourth solvent to post-treatment, and then passing the fourth solvent through silica gel column chromatography or preparative high performance liquid chromatography for separation and purification to obtain series of high purity benzofuran amidated derivatives;
wherein each of the first separation and purification method and the third separation and purification method is as follows:
performing separation and purification by silica gel column chromatography, mobile phase gradient elution with chloroform/methanol/formic acid; or using preparative liquid chromatography column for the separation and purification of a sample mixture, wherein the preparative liquid chromatography column is an Agilent Zorbax-C18 column with a column length of 250 mm, an inner diameter of 9.4 mm and a particle size of 5 μm, and chromatographic conditions are: flow rate: 8 mL/min, detection wavelength: 281 nm, column temperature: 30° C., mobile phase: acetonitrile—0.1% formic acid—water.

4. The

Assignees

• Univ China Pharma

Inventors

• Chen Jun

Classifications

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D307/86

  with an oxygen atom directly attached in position 7 · CPC title

• A61P19/06

  Antigout agents, e.g. antihyperuricemic or uricosuric agents · CPC title

• B01D15/26

  characterised by the separation mechanism · CPC title

• C07D307/80 Primary

  Radicals substituted by oxygen atoms · CPC title