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Tacrine-heteroauxin heterozygous compound as well as preparation method and application thereof

An indole acetic acid and compound technology, which is applied in the directions of organic chemistry, drug combination, nervous system diseases, etc., can solve the problems of large liver toxicity and side effects, and achieves the effect of simple preparation method and easy availability of raw materials

Inactive Publication Date: 2018-03-20
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its hepatotoxic side effects are relatively large, and it has been withdrawn from clinical use.
However, scientists have not stopped their research on tacrine derivatives. They have designed and synthesized a batch of tacrine diads or hybrids by using the design method of tacrine, in order to obtain a new type of tacrine with higher efficacy and less side effects. Cholinesterase Inhibitors

Method used

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  • Tacrine-heteroauxin heterozygous compound as well as preparation method and application thereof
  • Tacrine-heteroauxin heterozygous compound as well as preparation method and application thereof
  • Tacrine-heteroauxin heterozygous compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1: the preparation of formula I compound

[0025]

[0026] Dissolve 175mg indoleacetic acid (1, 1 equivalent) in 5ml dichloromethane, add 103mg N,N-diisopropylethylamine and 304mg 2-(7-azobenzotriazole)-tetramethyluronium hexafluoro Phosphate ester, stirred at room temperature for 3 h, and TLC detected that the reaction was complete. Add the corresponding tacrine derivative (2, 1 equivalent) dissolved in dichloromethane to the above reaction solution, stir at room temperature for three hours, TLC detects that the reaction is complete, concentrate the reaction solution under reduced pressure, and separate and purify by silica gel chromatography to obtain the corresponding A compound of formula I, wherein n=1-7. The specific compounds are as follows:

[0027] Compound of formula I-1

[0028] White solid (172mg, 43.3%), melting point 202.1-203.5°C. 1 H NMR (600MHz, MeOD) δ8.32(d, J=8.4Hz, 1H), 7.82(t, J=8.4Hz 1H), 7.70(d, J=8.4Hz, 1H), 7.51(t, J= 7.8Hz...

Embodiment 2

[0041] Example 2: Cholinesterase inhibitory activity

[0042] Reagents: acetylcholinesterase (AChE) or butyrylcholinesterase (BChE), thioacetylcholine iodide (ATC) or thiobutyrylcholine iodide (BUC) as substrate, and 5,5-Dithiobis(2-nitrobenzoic acid) (DTNB) was purchased from Sigma. The AChE and BChE inhibitory activities were measured with reference to the method reported by Ellan et al. (Ellman, G.L. et al. Biochem. Pharmacol. 1961, 7, 88.). Add 40 μL of phosphate buffer (pH=8.0) to each well of a 96-well plate, and then add 10 μL of 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 M solutions of Formula I or blank control into the corresponding air , followed by adding 10 μL of AChE and incubating on a shaker at 37°C for 5 min. Add 20 μL of DTNB solution and incubate on a shaker at 37°C for 5 minutes, then add 10 μL of substrate ATC or BUC and incubate on a shaker at 37°C for 3 minutes, measure the absorbance at 412 nm with a microplate reader, and calculate the effec...

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Abstract

The invention discloses tacrine-heteroauxin heterozygous as well as a preparation method and application thereof, and belongs to the field of medicine synthesis. A structural formula of the compound is shown in a formula (I) which is shown in the description, wherein n is equal to 1 to 7. The compound is not reported in literatures, and has better AChE and BChE double inhibition activity, and potential application prospect on treating AD (Alzheimer's disease).

Description

technical field [0001] The invention relates to a series of tacrine-indole acetic acid hybrids and their preparation methods and applications, belonging to the field of drug synthesis. Background technique [0002] Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically manifested as cognitive impairment, decreased ability of daily life, and various neuropsychiatric symptoms. There is no effective treatment. According to statistics from the World Alzheimer's Association, there were about 46 million AD patients in the world in 2015. With the aging population getting worse, the number of AD patients will reach 138 million by 2050. [0003] The etiology and pathogenesis of AD are extremely complex, and cholinergic neuron damage is an earlier recognized pathogenesis of AD. Cholinesterase can hydrolyze the neurotransmitter acetylcholine (ACh), which in turn leads to a decrease in the synthesis, release and uptake of acetylcholine, resulting in ...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/473A61P25/28A61P25/00
Inventor 张华江成世朱孔凯成志强宋佳丽李越费艳李美娇王溪
Owner UNIV OF JINAN
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