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Usnic acid derivatives, and preparation method and applications thereof in Alzheimer's disease drugs

A derivative, usnic acid technology, applied in the field of structural modification of natural compounds, can solve problems such as difficulty in simplification of natural products, difficulty in the source and de novo synthesis of natural products, lack of cytotoxicity or research on the improvement effect of animal models, etc.

Active Publication Date: 2020-02-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason is the source of natural products and the difficulty of de novo synthesis
The lack of structure-activity relationship analysis also makes it difficult to simplify the subsequent natural products
At the same time, the reported natural product inhibitors lack studies on their cytotoxicity or improvement effects in animal models, which limits their further application

Method used

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  • Usnic acid derivatives, and preparation method and applications thereof in Alzheimer's disease drugs
  • Usnic acid derivatives, and preparation method and applications thereof in Alzheimer's disease drugs
  • Usnic acid derivatives, and preparation method and applications thereof in Alzheimer's disease drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Compound (4) of Example 1: (R,E)-6-acetyl-7,9-dihydroxy-2-(1-((5-hydroxypentyl)amino)ethylene)-8,9b- Preparation of dimethyldibenzo[b,d]furan-1,3(2H,9bH)-dione.

[0079] 100 mg (+)-usnicic acid (0.290 mmol, 1.0 eq) was suspended in 5 mL of absolute ethanol, and 0.033 mL of 5-amino-1-pentanol (0.320 mmol, 1.1 eq) was slowly added dropwise while stirring. After the dropwise addition, the reaction was carried out at 80°C under the protection of argon for 4 h until the completion of the reaction was monitored by a spot plate. After the solution was cooled to room temperature, it was acidified with 1N hydrochloric acid solution, the mixture was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated, mixed and passed through a silica gel column, and the petroleum ether / ethyl acetate product system was obtained to obtain t...

Embodiment 2

[0080]Example 2 compound (5): (R, E)-6-acetyl-2-(1-((5-chloro-2-hydroxyphenyl)amino)ethylene)-7,9-dihydroxy- Preparation of 8,9b-dimethyldibenzo[b,d]furan-1,3(2H,9bH)-dione.

[0081] Preparation process is with example 1. The starting material was replaced with 4-chloro-2-aminophenol. The yield is about 89%, yellow solid. m.p.154-155℃. 1 H NMR (500MHz, DMSO-d 6 )δ14.53(bs,1H),13.40(s,1H),12.02(s,1H),10.62(s,1H),7.47(d,J=3.5Hz,1H),7.30(dd,J=8.5 ,3.5Hz,1H),7.03(d,J=8.5Hz,1H),6.00(s,1H),2.66(s,3H),2.52(s,3H),1.99(s,3H),1.71(s ,3H). 13 C NMR (126MHz, DMSO-d 6 )δ201.43,198.58,189.99,174.98,174.16,163.05,157.97,156.18,151.19,129.59,127.06,124.72,122.92,118.24,106.98,105.51,103.00,102.73,101.46,57.22,32.09,31.53,20.79,7.99.

Embodiment 3

[0082] Example 3 compound (6): (R, E)-6-acetyl-2-(1-((4-chloro-2-hydroxyphenyl)amino)ethylene)-7,9-dihydroxy- Preparation of 8,9b-dimethyldibenzo[b,d]furan-1,3(2H,9bH)-dione.

[0083] Preparation process is with example 1. The starting material was replaced with 2-amino-5-chlorophenol. The yield is about 84%, yellow solid. m.p.147-149℃. 1 H NMR (500MHz, DMSO-d 6 )δ14.52(bs,1H),13.40(s,1H),12.03(s,1H),10.87(s,1H),7.36(d,J=8.5Hz,1H),7.05(d,J=2.3 Hz,1H),6.98(dd,J=8.5,2.3Hz,1H),5.98(s,1H),2.66(s,3H),2.51(s,3H),1.98(s,3H),1.71(s ,3H). 13 C NMR (126MHz, DMSO-d 6 )δ201.40,198.51,189.99,174.83,174.13,163.04,157.97,156.17,152.99,133.43,128.74,122.84,119.72,116.65,106.97,105.51,103.02,102.72,101.44,57.19,32.11,31.52,20.81,7.99.

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Abstract

The invention discloses usnic acid derivatives, and a preparation method and applications of the usnic acid derivatives in Alzheimer's disease drugs, derivatives and pharmaceutically acceptable saltsthereof. The usnic acid derivatives comprise compounds with structures represented as general formula (I) or general formula (II), wherein R is selected from H, C5-C8 alkyl, polysubstituted benzene ring and polysubstituted heterocyclic ring. The usnic acid derivatives prepared by the invention can inhibit tau protein aggregation and neuroinflammation, and have a good application prospect in preparation of drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention relates to structural modification of natural compounds, specifically usnic acid derivatives and their preparation methods and their application in Alzheimer's disease medicine. Background technique [0002] Alzheimer's Disease (AD) is a neurodegenerative disease. Currently there are two main hypotheses for AD pathology: Aβ deposition and tau protein neurofibrillary tangles. Due to successive failures in the development of Aβ drugs, the tau protein hypothesis has gradually attracted the attention of drug developers. Tau protein is a microtubule-associated protein, which mainly plays a role in maintaining the stability of microtubules. In the AD brain, tau protein is hyperphosphorylated, detaches from microtubules and aggregates to form neurotoxic neurofibrillary tangles (NTFs), and microtubules depolymerize and lose function. The degree of neurofibrillary tangles is highly correlated with the progress of AD, so it is of great significa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/91C07D405/12C07D417/12C07D491/048A61P25/28A61P25/00
CPCC07D491/048C07D307/91C07D405/12C07D417/12A61P25/28A61P25/00
Inventor 孔令义王小兵石存剑
Owner CHINA PHARM UNIV
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