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Multi-target tacrine derivative and preparation method and application thereof

A technology of pharmaceutical preparations and reactions, applied in the field of biomedicine

Active Publication Date: 2019-12-10
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no relevant report on HDAC8

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  • Multi-target tacrine derivative and preparation method and application thereof
  • Multi-target tacrine derivative and preparation method and application thereof
  • Multi-target tacrine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Example 1: Synthesis of target compound H1-H7

[0136] Intermediate 2-aminobenzoic acid (6), 9-chloro-1, 2, 3, 4-tetrahydroacridine (8) and 6,9-dichloro-1, 2, 3, 4-tetrahydroacridine (9) Preparation

[0137] Add 2-aminobenzonitrile (5g, 42.3mmol) and potassium hydroxide (23.7g, 423mmol) into 30ml water, reflux at 100°C for 5h, cool to room temperature after the reaction, adjust pH=7-8 with dilute hydrochloric acid In between, intermediate 6 was obtained after drying to obtain 4.5g, intermediate 6 (2g, 16.9mmol) and cyclohexanone (2g, 20.3mmol) or intermediate 7 (2g, 11.65mmol) and cyclohexanone (2.28 g, 23.3mmol), slowly add 8ml of phosphorus oxychloride solution dropwise under ice bath conditions, and heat to reflux at 100°C for 6h. After the reaction is over, the reaction solution is slowly dropped into warm water after cooling to 60°C, stirring, intermediate 9. It can be precipitated directly, 3.5g after filtration and drying, and the intermediate 8 is adjusted to be ne...

Embodiment 2

[0193] Example 2: Synthesis of target compounds I1-I7

[0194] (E)-methyl 4-(3-oxo-3-((3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)amino)prop-1-en-1-yl) benzoate(19a)

[0195] (E)-4-(3-oxo-3-((3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)amino)prop-1-ene- 1-yl)methyl benzoic acid (19a)

[0196] First, (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid (0.16g, 0.784mmol) was dissolved in 10ml of dichloromethane, and TBTU (0.302g, 0.941mmol) was added to activate at room temperature for 40min, TLC Detection of activation is complete, Intermediate 12 (0.2g, 0.784mmol) is dissolved in dichloride and added to the activated acid, reacted at room temperature for 5h, TLC detects that the reaction is complete, the solid impurities in the reaction solution are filtered out, and the organic layer is collected. The organic layer was washed with saturated NaHCO3 aqueous solution (50ml*3), saturated brine (50ml*3), water (50ml*2), the organic layer was collected and dried over anhydrous magn...

Embodiment 3

[0236] Example 3: Synthesis of target compound J1-J4

[0237] methyl 3-((2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)propanoate(20a)

[0238] 3-((2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)propionic acid methyl ester (20a)

[0239] Dissolve Intermediate 10 (1g, 4.1mmol) in 12ml of tetrahydrofuran, add methyl 3-bromopropionate (0.7g, 4.1mmol), K2CO3 (1.7g, 12.3mmol), add 4ml of water, and heat at 70°C Reflux for 12h, TLC detects the completion of the reaction. When the reaction solution is cooled to room temperature, add 100ml of dichloromethane, wash with saturated brine (50ml*3), collect the organic layer, dry with anhydrous magnesium sulfate, evaporate under reduced pressure, and purify by column chromatography to obtain yellow The oily product 20a (0.8g) has a yield of 59.7%.

[0240] methyl 3-((2-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)propanoate(20b)

[0241] Methyl 3-((2-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)propionat...

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Abstract

The invention provides a multi-target tacrine derivative and a preparation method and application thereof. The compound has the structure shown in a formula (I) (please see the specification in the formula (I)), wherein n is a natural number greater than 1; m is 1 or 2; p is 0 or 1; R1 is H or halogen; and Y is selected from the following structures (please see the specification for the structures) or, a pharmaceutically acceptable salt of a compound in a formula (X). According to the compound, activity of histone deacetylase (HDACs), acetylcholinesterase (AChE) or butyryl cholinesterase (BChE) can be effectively inhibited.

Description

Technical field [0001] The present invention relates to the field of biomedicine, in particular to a multi-target type tacrine derivative and a preparation method and application thereof. Background technique [0002] Disclosure of the background information is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an acknowledgement or in any form suggesting that the information constitutes the prior art known to those of ordinary skill in the art. [0003] Alzheimer’s disease (AD) is an age-related neurodegenerative disease, commonly known as Alzheimer’s. In general, people over 65 years of age, the incidence of the disease will increase with age, about 5% of people over 65 years of age, and rise to 20% of people over 85 years of age. The occurrence and development of Alzheimer's disease involve many factors, including genes, environment and internal environment of the body. Its clinical manifestations ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D219/12C07D401/12A61K31/473A61K31/506A61K31/497A61P25/28
CPCA61P25/28C07D219/12C07D401/12
Inventor 吴敬德徐阿娜何峰张祥娜冉莹瑛魏超
Owner SHANDONG UNIV
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