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Amino sugar thiazole derivative as well as synthetic method and application thereof

A synthesis method and sugar thiazole technology, applied in the field of drug preparation, can solve the problems such as the inability to prevent the degeneration and death of central cholinergic neurons, the decrease in the efficacy of acetylcholinesterase inhibitors, the large side effects of gastrointestinal irritation, and the like. Scope of application, strong inhibitory activity, effect of reducing production cost

Active Publication Date: 2015-01-21
HUAIHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0004] Although the existing AChE inhibitors have become the mainstream drugs for the treatment of AD, only inhibiting the activity of acetylcholinesterase can only increase the content of acetylcholine, but cannot prevent the progressive degeneration and death of central cholinergic neurons.
With the development of the disease, the central cholinergic neurons undergo progressive degeneration and death, and the efficacy of acetylcholinesterase inhibitors will gradually decrease
Moreover, the existing AChE inhibitors generally have the disadvantages of poor drug selectivity, low bioavailability, large gastrointestinal irritating side effects, narrow therapeutic range, and severe liver cytotoxicity.

Method used

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  • Amino sugar thiazole derivative as well as synthetic method and application thereof
  • Amino sugar thiazole derivative as well as synthetic method and application thereof
  • Amino sugar thiazole derivative as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1, an aminoglucothiazole derivative, its structural formula is as follows formula VII:

[0030]

[0031] Wherein, the R is selected from CH 3 -, n-C 4 h 9 -, C 6 h 5 -, 4-CH 3 C 6 h 4 -, 3-CH 3 C 6 h 4 -, 2-CH 3 C 6 h 4 -, 4-CH 3 OC 6 h 4 -, 3-CH 3 OC 6 h 4 -, 2,3-di-CH 3 OC 6 h 3 -, 4-FC 6 h 4 -, 2-FC 6 h 4 -, 4-ClC 6 h 4 -, 3-ClC 6 h 4 -, 4-BrC 6 h 4 -, 3-BrC 6 h 4 -, 4-NO 2 C 6 h 4 -, 3-NO 2 C 6 h 4 -, 4-OHC 6 h 4 -, 4-NH 2 C 6 h 4 -, 4-PhC 6 h 4 -, 3-C 6 h 4 N-, 2-C 5 h 3 S-.

Embodiment 2

[0032] Embodiment 2, a kind of synthetic method of aminoglucothiazole derivative as described in embodiment 1, its steps are as follows:

[0033] (1) N-(1,3,4,6-tetra-O-benzyl-2-deoxy- β -D-glucopyranose-2-yl)thiourea preparation: first 2-deoxy-2-amino-1,3,4,6-tetra-O-benzyl- β -D-pyranose hydrochloride reacts with benzoyl isothiocyanate, and the product reacts with alkali to obtain glycosylthiourea; 1-benzoyl-3-(1,3,4,6-tetra-O -Benzyl- β The molar ratio of -D-glucopyranose-2-yl)thiourea to base is 1:1, the reaction temperature is 50°C, and the reaction time is 0.5 hours;

[0034] (2) N-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)-2-amino-4-substituted thiazole: 1-benzoyl-3-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)thiourea reacts with 1-bromo-2-substituted ethanone to give N-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)-2-amino-4-substituted thiazole; reaction with ethanol as solvent, N-(1,3,4,6-tetra-O-benzyl-2-deoxy- β The molar ratio of -D-glucopyran...

Embodiment 3

[0035] Embodiment 3, a kind of synthetic method of aminoglucothiazole derivative as described in embodiment 1, its steps are as follows:

[0036] (1) N-(1,3,4,6-tetra-O-benzyl-2-deoxy- β -D-glucopyranose-2-yl)thiourea preparation: first 2-deoxy-2-amino-1,3,4,6-tetra-O-benzyl- β -D-pyranose hydrochloride reacts with benzoyl isothiocyanate, and the product reacts with alkali to obtain glycosylthiourea; 1-benzoyl-3-(1,3,4,6-tetra-O -Benzyl- β The molar ratio of -D-glucopyranose-2-yl)thiourea to base is 1: 2, the reaction temperature is 70°C, and the reaction time is 1.5 hours;

[0037] (2) N-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)-2-amino-4-substituted thiazole: 1-benzoyl-3-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)thiourea reacts with 1-bromo-2-substituted ethanone to give N-(1,3,4,6-tetra-O-benzyl- β -D-glucopyranose-2-yl)-2-amino-4-substituted thiazole; reaction with ethanol as solvent, N-(1,3,4,6-tetra-O-benzyl-2-deoxy- β The molar ratio of -D-glucopyra...

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Abstract

The invention discloses an amino sugar thiazole derivative as well as a synthetic method thereof. When synthesis is carried out, glucosamine hydrochloride is taken as a raw material, and benzyl ether protection is carried out on hydroxy, so that the selective reaction of amino is realized, a novel intermediate glycosyl thiourea-N-(1,3,4,6-tetra-0-benzyl-2-deoxygenation- beta-D-glucopyranose-2-group) thiocarbamide is synthesized, and glycosyl thiazole-N-(1,3,4,6-tetra-0-benzyl-beta-D-glucopyranose-2-group)-2-amido-4-substituted thiazole is synthesized by cyclizing the novel intermediate glycosyl thiourea-N-(1,3,4,6-tetra-0-benzyl-2-deoxygenation beta-D-glucopyranose-2-group) thiocarbamide with 1-bromine-2-substituted ethyl ketone. The synthetic method disclosed by the invention has the advantages of easiness and safety for operation, wide application scope, low cost of the raw material, easiness for raw material obtaining, easiness and convenience for post-processing and high yield, is a fast high-efficiency synthetic method and has a wide application prospect on the aspect of preparing an acetylcholinesterase resistant drug because the synthesized compound has high inhibiting effect on acetylcholinesterase.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to an aminoglucothiazole derivative, and also relates to a preparation method and application of the aminoglucothiazole derivative. Background technique [0002] Alzheimer's disease (AD) is a common brain neurodegenerative disease with a relatively high incidence rate, and has become one of the diseases that seriously threaten human life in modern society. Its clinical manifestations are deteriorating cognition and memory function, progressive decline in the ability of daily life, and various neuropsychiatric symptoms and behavioral disturbances. In developed countries, AD has become the fourth leading cause of death among the elderly after heart disease, cancer, and stroke. In China, the prevalence rate of the elderly over 65 years old is as high as 6.6%. For every 5 years of age increase, the prevalence rate doubles. One in three elderly people over the age of 85 has Alzheimer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00A61P25/28
CPCC07H1/00C07H17/00
Inventor 刘玮炜史大华霍云峰李曲祥张强程峰昌殷龙
Owner HUAIHAI INST OF TECH
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