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Mono-propargylamine modified thiouracil compound, and applications thereof

A technology of pyrimidinethiourea and compounds, applied in the field of anti-Alzheimer's disease drugs, can solve the problems of single target and termination of disease process

Active Publication Date: 2017-07-14
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have a single target and can only control or improve cognitive symptoms, but cannot fundamentally terminate the disease process

Method used

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  • Mono-propargylamine modified thiouracil compound, and applications thereof
  • Mono-propargylamine modified thiouracil compound, and applications thereof
  • Mono-propargylamine modified thiouracil compound, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1-(6-aminopyridin-4-yl)-1H-imidazole-4-carbaldehyde (formula II A The preparation of the shown compound):

[0045] Dissolve 0.96g (10mmol) of 1H-imidazole-4-carbaldehyde in 20ml of DMF, add 1.30g (10mmol) of 4-amino-6-chloropyrimidine, 2.07g (15mmol) of potassium carbonate, and heat up to 100°C , Stir the reaction for 12h. Add an appropriate amount of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, then filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography, eluent: methanol: dichloromethane = 1: 30, to obtain 0.87g of white solid (formula II A shown compound), the yield was 46%.

[0046] 1 H NMR (400MHz, DMSO) δ9.83(s, 1H), 8.70(s, 1H), 8.64(s, 1H), 8.37(s, 1H), 7.35(s, 2H), 6.72(s, 1H) .

Embodiment 2

[0048] 2-(1-(6-aminopyridin-4-yl)-1H-imidazol-4-yl)ethan-1-alcohol (formula II B Compound shown in -1) preparation:

[0049]

[0050] 1.12g (10mmol) of 2-(1H-imidazol-4-yl)ethan-1-ol was dissolved in 20ml of DMF, and 1.30g (10mmol) of 4-amino-6-chloropyrimidine, 3.91g were added successively (12mmol) of cesium carbonate, heated to 140°C, and stirred for 12h. Add an appropriate amount of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, then filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography, eluent: methanol: dichloromethane = 1: 30, to obtain white solid 1.19g (formula II B -1 shown in the compound), the yield was 58%.

[0051] 1 H NMR (400MHz, DMSO) δ8.33(s, 1H), 8.29(s, 1H), 7.54(s, 1H), 7.16(s, 2H), 6.50(s, 1H), 4.74-4.59(m, 1H), 3.70-3.60(m, 2H), 2.66(t, J=6.9Hz, 2H).

Embodiment 3

[0053] 3-(1-(6-aminopyridin-4-yl)-1H-imidazol-4-yl)propan-1-alcohol (formula II B Compound shown in -2) preparation:

[0054]

[0055] 1.26g (10mmol) of 3-(1H-imidazol-4-yl)propan-1-ol was dissolved in 20ml of DMF, and 1.30g (10mmol) of 4-amino-6-chloropyrimidine, 3.91g ( 12mmol) of cesium carbonate, heated to 140°C, and stirred for 12h. Add an appropriate amount of water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, then filter, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography, eluent: methanol: dichloromethane = 1: 30, to obtain 0.90 g of white solid (formula II B -2 shown in the compound), the yield was 41%.

[0056] 1 H NMR (400MHz, DMSO) δ8.33(d, J=1.1Hz, 1H), 8.29(s, 1H), 7.50(s, 1H), 7.13(s, 1H), 6.50(d, J=0.7Hz , 1H), 4.47(t, J=5.2Hz, 1H), 3.44(dd, J=11.7, 6.3Hz, 2H), 2.59-2.51(m, 2H), 1.81-1.69(m, 2H).

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Abstract

The invention relates to a mono-propargylamine modified thiouracil compound, and applications thereof. The structure of the mono-propargylamine modified thiouracil compound is novel; the mono-propargylamine modified thiouracil compound possesses cholinesterase inhibition activity, monoamine oxidase activity, and metal ion chelating properties, is capable of inhibiting generation of metal ion-induced free radicals, and inhibiting metal ion-induced Abeta aggregation, is low in cytotoxicity, and is high in blood brain barrier penetration rate in vitro experiment. Preparation technology is simple; preparation cost is low; and it is promising to prepare multifunctional drugs used for treating, improving and / or preventing Alzheimer disease from the mono-propargylamine modified thiouracil compound.

Description

technical field [0001] The present invention relates to a pyrimidine thiourea compound and its use, in particular to a pyrimidine thiourea compound modified by propargylamine and it can be used as an anti-Alzheimer's disease drug with multiple targets and functions. Background technique [0002] Alzheimer's disease (AD), also known as Alzheimer's disease, is a disease characterized by senile plaques (senile plaques, Sp), neurofibrillary tangles (neurofibrillary tangles, NFT) and loss of hippocampal neurons. of neurodegenerative diseases. The main clinical manifestations are memory loss and cognitive dysfunction, accompanied by a series of psychiatric symptoms. The etiology of AD is complex, and various complex regulatory networks and changes in regulatory factors are involved in the process of occurrence and development. It is difficult for a single-target drug to fundamentally solve the problem. Multi-target therapy designs small-molecule compounds for multiple targets in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P25/28
CPCC07D403/04
Inventor 毛斐徐以香李晓康刘文文李剑
Owner EAST CHINA UNIV OF SCI & TECH
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