阅读说明：本技术 松萝酸衍生物及其制法和在阿尔茨海默病药物中的应用 (Usnic acid derivative, preparation method thereof and application of usnic acid derivative in Alzheimer disease medicine ) 是由 孔令义 王小兵 石存剑 于 2019-10-22 设计创作，主要内容包括：本发明公开了松萝酸衍生物及其制法和在阿尔茨海默病药物中的应用,衍生物及其药学上可接受的盐,包含结构如通式(I)或通式(II)所示的化合物,其中,R选自H、C<Sub>5</Sub>-C<Sub>8</Sub>烷基、多取代苯环、多取代杂环。本发明所制备的松萝酸衍生物衍生物能抑制tau蛋白聚集和神经炎症,在制备治疗阿尔茨海默病药物中有良好的应用前景。<Image he="254" wi="700" file="DDA0002242412030000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses an usnic acid derivative, a preparation method thereof, application of the usnic acid derivative in Alzheimer disease drugs, the derivative and pharmaceutically acceptable salts thereof, and a compound with a structure shown as a general formula (I) or a general formula (II), wherein R is selected from H, C 5 ‑C 8 Alkyl, polysubstituted benzene ring, polysubstituted heterocycle. The usnic acid derivative prepared by the invention can inhibit tau protein aggregation and neuroinflammation and has good effect in preparing medicaments for treating Alzheimer diseaseGood application prospect.)

1. An usnic acid derivative and a pharmaceutically acceptable salt thereof are characterized by comprising a compound with a structure shown as a general formula (I) or a general formula (II):

wherein R is selected from H, C₅-C₈Alkyl, polysubstituted phenyl and polysubstituted heterocycle.

2. The usnic acid derivative and the pharmaceutically acceptable salt thereof according to claim 1, characterized by comprising a compound having a structure represented by general formula (II), wherein R is 4-benzoic acid, and the structural formula of the complete compound is:

3. usnic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1, characterized in that the derivatives are selected from the following compounds:

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((5-hydroxypentyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-chloro-2-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((4-chloro-2-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((2-hydroxy-5-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((2-hydroxy-4-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((4-hydroxy-2, 6-dimethylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((4-hydroxy-5-isopropyl-2-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((3, 5-di-tert-butyl-4-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((3,4, 5-trimethoxyphenyl) amino) ethylidene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -4- ((1- (6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-1, 3-dioxo-3, 9b dihydrodibenzo [ b, d ] furan-2 (1H) -alkylidene) ethyl) amino) -2-hydroxybenzoic acid

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9b dimethyl-2- (1- ((4- (4-methylpiperazin-1-yl) phenyl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((4- (dimethylamino) phenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((3- (dimethylamino) phenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((3-hydroxypyridin-2-yl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((5-hydroxypyridin-2-yl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-aminopyridin-2-yl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-aminopyrazin-2-yl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- (quinolin-8-ylamino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -2- (1- ((1H-indol-5-yl) amino) ethylene) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((1-methyl-1H-indol-5-yl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- (benzo [ d ] thiazol-5-ylamino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (3-fluorophenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (4-fluorophenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (4- (tert-butyl) phenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

(R) -3- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

(R) -2- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

Ethyl (R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuran [3,2-f ] indazol-1-yl) benzoic acid methyl ester

(R) -8-acetyl-5, 7-dihydroxy-1- (4-methoxyphenyl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- (3-methoxyphenyl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (4- (methylsulfonyl) phenyl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzenesulfonamide

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-4-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-3-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-2-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- (6-methoxypyridin-3-yl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (6-methylpyridazin-3-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyrazin-2-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzonitrile

(R) -8-acetyl-1- (1H-benzo [ d ] imidazol-2-yl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (benzo [ d ] thiazol-2-yl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (4-oxo-3, 4-dihydro-phthalazin-1-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (phenylsulfonyl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1-tosyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- ((4-methoxyphenyl) sulfonyl) -3,4a, 6-trimethyl-1-tosyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one.

4. A process for producing the usnic acid derivative and the pharmaceutically acceptable salt thereof according to claim 1, which is characterized by being selected from any one of the following processes:

(1) adding (+) -usnic acid into a flask, adding absolute ethyl alcohol for suspension, adding different substituted aniline, fatty amine or heterocyclic amine, reacting for 3-5h at 75-85 ℃ under the protection of argon, monitoring the reaction until the reaction is complete, adding HCl solution for acidification, extracting with ethyl acetate, combining ethyl acetate phases, washing an organic phase, drying, concentrating, separating by using a silica gel column chromatography, and eluting with an ethyl acetate/petroleum ether system to obtain a target product; wherein, if the aniline, fatty amine or heterocyclic amine with different substitution is amine hydrochloride, suspending the amine hydrochloride in absolute ethyl alcohol, adding pyridine at 75-85 ℃, stirring until the pyridine is dissolved, adding (+) -usnic acid, reacting for 3-5h under the protection of argon, and the rest steps are the same;

(2) adding (+) -usnic acid into a flask, adding absolute ethyl alcohol for suspension, adding hydrazine hydrate, phenyl hydrazine with different substituents or heterocyclic hydrazine or sulfonyl hydrazine for reaction for 1-3h at 75-85 ℃ under the protection of argon, monitoring the reaction until the reaction is complete, adding HCl solution for acidification, extracting with ethyl acetate, combining ethyl acetate phases, washing an organic phase, drying, concentrating, separating by using a silica gel column chromatography, and eluting with an ethyl acetate/petroleum ether system to obtain a target product; wherein, if hydrazine hydrate, different substituted phenylhydrazines or heterocyclic hydrazines or sulfonyl hydrazides are hydrazine hydrochloride, the hydrazine hydrochloride is firstly suspended in absolute ethyl alcohol, pyridine is added to be stirred at 75-85 ℃ until being dissolved, (+) -usnic acid is added to react for 1-3h under the protection of argon, and the other steps are the same.

5. The method for preparing usnic acid derivatives and pharmaceutically acceptable salts thereof according to claim 4, wherein the washing of the organic phase is washing of the organic phase with a saturated NaCl solution.

6. The process for producing an usnic acid derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein the drying is drying with anhydrous sodium sulfate.

7. Use of the usnic acid derivative or the pharmaceutically acceptable salt thereof according to claim 1 for preparing tau protein inhibitors.

8. Use of the usnic acid derivative and the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a neuroinflammation inhibitor.

9. Use of usnic acid derivatives and pharmaceutically acceptable salts thereof according to claim 1 for the preparation of full-length 2N4R tau protein inhibitors.

10. The use of the usnic acid derivative and the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for treating alzheimer's disease.

Technical Field

The invention relates to structural modification of natural compounds, in particular to an usnic acid derivative, a preparation method thereof and application thereof in medicaments for treating Alzheimer disease.

Background

In the brain of AD, Tau protein is hyperphosphorylated, is separated from microtubules and is aggregated to form Neurofibrillary Tangles (NTFs) with neurotoxicity, microtubules are depolymerized and lose functions, the degree of neurofibrillary tangles is highly related to AD process, so that the drugs for treating AD are designed for Tau protein and have important significance, but AD is a complex neurodegenerative Disease, only Tau protein can effectively block Tau protein pathology, Tau protein is closely related to neuroinflammation, aggregated Tau protein can be used as an inflammation inducing factor to aggravate and treat neuroinflammation, Tau protein can also induce Tau protein hyperphosphorylation and lead Tau protein to promote neuroinflammation, Tau protein aggregation can not particularly promote Tau protein aggregation, Tau protein aggregation can not inhibit neuroinflammation, and Tau protein aggregation can not be used for inducing neuroinflammation and inhibiting neuroinflammation.

The main reason is that the method adopted in screening, namely the thioflavin-T method is easy to have false positive effect, and the referenced existing inhibitor is difficult to modify.

Usnic acid is a secondary metabolite mainly existing in usnic and having extremely high content, and the source of usnic acid is easy to obtain. Usnic acid has excellent anti-inflammatory activity in vitro.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to disclose usnic acid derivatives which are obtained by carrying out structural modification on usnic acid. Another object of the present invention is to provide a process for the preparation of the derivatives. Still another object of the present invention is to indicate that the derivatives can inhibit tau aggregation and neuroinflammation and can be used for the treatment of Alzheimer's disease.

The technical scheme is as follows: the usnic acid derivative and the pharmaceutically acceptable salt thereof comprise a compound with a structure shown as a general formula (I) or a general formula (II):

wherein R is selected from H, C₅-C₈Alkyl, polysubstituted phenyl and polysubstituted heterocycle.

The usnic acid derivative and the pharmaceutically acceptable salt thereof contain a compound with a structure shown as a general formula (II), wherein R is 4-benzoic acid, and the structural formula of the complete compound is as follows:

the usnic acid derivative and the pharmaceutically acceptable salt thereof are selected from the following compounds:

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((5-hydroxypentyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-chloro-2-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((4-chloro-2-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((2-hydroxy-5-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((2-hydroxy-4-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((4-hydroxy-2, 6-dimethylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((4-hydroxy-5-isopropyl-2-methylphenyl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((3, 5-di-tert-butyl-4-hydroxyphenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((3,4, 5-trimethoxyphenyl) amino) ethylidene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -4- ((1- (6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-1, 3-dioxo-3, 9b dihydrodibenzo [ b, d ] furan-2 (1H) -alkylidene) ethyl) amino) -2-hydroxybenzoic acid

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9b dimethyl-2- (1- ((4- (4-methylpiperazin-1-yl) phenyl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((4- (dimethylamino) phenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((3- (dimethylamino) phenyl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((3-hydroxypyridin-2-yl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-2- (1- ((5-hydroxypyridin-2-yl) amino) ethylene) -8,9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-aminopyridin-2-yl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- ((5-aminopyrazin-2-yl) amino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- (quinolin-8-ylamino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -2- (1- ((1H-indol-5-yl) amino) ethylene) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-7, 9-dihydroxy-8, 9 b-dimethyl-2- (1- ((1-methyl-1H-indol-5-yl) amino) ethylene) dibenzo [ b, d ] furan-1, 3(2H, 9bH) -dione

(R, E) -6-acetyl-2- (1- (benzo [ d ] thiazol-5-ylamino) ethylene) -7, 9-dihydroxy-8, 9 b-dimethyldibenzo [ b, d ] furan-1, 3- (2H, 9bH) -dione

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (3-fluorophenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (4-fluorophenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (4- (tert-butyl) phenyl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

(R) -3- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

(R) -2- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzoic acid

Ethyl (R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuran [3,2-f ] indazol-1-yl) benzoic acid methyl ester

(R) -8-acetyl-5, 7-dihydroxy-1- (4-methoxyphenyl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- (3-methoxyphenyl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (4- (methylsulfonyl) phenyl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzenesulfonamide

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-4-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-3-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyridin-2-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- (6-methoxypyridin-3-yl) -3,4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (6-methylpyridazin-3-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (pyrazin-2-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -4- (8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-4-oxo-4, 4 a-dihydro-1H-benzofuro [3,2-f ] indazol-1-yl) benzonitrile

(R) -8-acetyl-1- (1H-benzo [ d ] imidazol-2-yl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-1- (benzo [ d ] thiazol-2-yl) -5, 7-dihydroxy-3, 4a, 6-trimethyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (4-oxo-3, 4-dihydro-phthalazin-1-yl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1- (phenylsulfonyl) -1,4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-3, 4a, 6-trimethyl-1-tosyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

(R) -8-acetyl-5, 7-dihydroxy-1- ((4-methoxyphenyl) sulfonyl) -3,4a, 6-trimethyl-1-tosyl-1, 4 a-dihydro-4H-benzofuro [3,2-f ] indazol-4-one

The preparation method of the usnic acid derivative and the pharmaceutically acceptable salt thereof is selected from any one of the following methods:

(1) adding (+) -usnic acid into a flask, adding absolute ethyl alcohol for suspension, adding different substituted aniline, fatty amine or heterocyclic amine, reacting for 3-5h at 75-85 ℃ under the protection of argon, monitoring the reaction until the reaction is complete, adding HCl solution for acidification, extracting with ethyl acetate, combining ethyl acetate phases, washing an organic phase, drying, concentrating, separating by using a silica gel column chromatography, and eluting with an ethyl acetate/petroleum ether system to obtain a target product; wherein, if the aniline, fatty amine or heterocyclic amine with different substitution is amine hydrochloride, suspending the amine hydrochloride in absolute ethyl alcohol, adding pyridine at 75-85 ℃, stirring until the pyridine is dissolved, adding (+) -usnic acid, reacting for 3-5h under the protection of argon, and the rest steps are the same;

(2) adding (+) -usnic acid into a flask, adding absolute ethyl alcohol for suspension, adding hydrazine hydrate, phenyl hydrazine with different substituents or heterocyclic hydrazine or sulfonyl hydrazine for reaction for 1-3h at 75-85 ℃ under the protection of argon, monitoring the reaction until the reaction is complete, adding HCl solution for acidification, extracting with ethyl acetate, combining ethyl acetate phases, washing an organic phase, drying, concentrating, separating by using a silica gel column chromatography, and eluting with an ethyl acetate/petroleum ether system to obtain a target product; wherein, if hydrazine hydrate, different substituted phenylhydrazines or heterocyclic hydrazines or sulfonyl hydrazides are hydrazine hydrochloride, the hydrazine hydrochloride is firstly suspended in absolute ethyl alcohol, pyridine is added to be stirred at 75-85 ℃ until being dissolved, (+) -usnic acid is added to react for 1-3h under the protection of argon, and the other steps are the same.

The usnic acid derivative and the pharmaceutically acceptable salt thereof are prepared by washing an organic phase with a saturated NaCl solution.

The usnic acid derivatives and the pharmaceutically acceptable salts thereof are dried by anhydrous sodium sulfate.

The usnic acid derivative and the pharmaceutically acceptable salt thereof are applied to preparation of a tau protein inhibitor.

The usnic acid derivative and the pharmaceutically acceptable salt thereof are applied to preparing neuroinflammation inhibitors.

The usnic acid derivative and the pharmaceutically acceptable salt thereof are applied to preparation of a full-length 2N4R tau protein inhibitor.

The usnic acid derivative and the pharmaceutically acceptable salt thereof are applied to the preparation of the medicine for treating the Alzheimer disease.

Has the advantages that: the usnic acid derivative can reduce self-polymerization of AcPHF6 hexapeptide in vitro, and has excellent inhibitory activity on full-length 2N4R tau protein induced by heparin through a CD spectrogram and a transmission electron microscope, has NO obvious cytotoxicity on SH-SY5Y cells, LO2 cells and BV2 cells under the activity test concentration, maintains the anti-inflammatory activity of usnic acid, and inhibits the release amount of NO generated by BV2 cells stimulated by LPS. Animal behavioral experiments show that the compound obviously improves the cognition of rats, so that the compound can be used as a tau protein inhibitor and a neuroinflammation inhibitor to control the development of Alzheimer disease.

Drawings

Figure 1 is a graph of the self-polymerization kinetics of compounds 18 and 30 inhibiting AcPHF 6;

figure 2 is a CD map of compounds 18 and 30 inhibiting self-aggregation of AcPHF 6;

FIG. 3 is a transmission electron microscope image of compounds 18 and 30 inhibiting self-polymerization of AcPHF 6;

FIG. 4 is a graph of inhibition of heparin-induced full-length tau kinetics by Compound 30;

FIG. 5 is the cytotoxicity of compound 30 against SH-SY5Y and LO 2;

FIG. 6 is a graph showing the cytotoxic and LPS inhibitory effects of Compound 30 on BV2 on NO production by BV2 cells;

FIG. 7 shows the behavioral improvement effect of Compound 30 in rats.

Detailed Description

The (+) -usnic acid is purchased from domestic companies, and the preparation method of the example compound 4-50 is as follows: