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Two acetaldehyde dehydrogenase agonists, and preparation method and application thereof

A compound and pharmaceutical technology, applied in the field of medicine, can solve the problems of loss and decrease of ALDH2 enzyme activity, etc., and achieve the effect of simple preparation method, cheap and easy-to-obtain raw materials, and high yield

Inactive Publication Date: 2014-07-16
高尔医药科技(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 12th exon base A of the ALDH2*1 gene was replaced by G to become the ALDH2*2 gene. This substitution resulted in the mutation of the glutamic acid residue at position 504 to lysine (E504K). We call this A mutation called E487K mutation, this mutation makes the activity of ALDH2 enzyme decreased or even completely lost

Method used

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  • Two acetaldehyde dehydrogenase agonists, and preparation method and application thereof
  • Two acetaldehyde dehydrogenase agonists, and preparation method and application thereof
  • Two acetaldehyde dehydrogenase agonists, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of 3,4-methylenedioxybenzylamine:

[0033] Add 300ml of anhydrous isopropyl ether to a 250ml three-necked bottle, cool to -5°C to 0°C, add 12g (90mmol) of aluminum trichloride and 5.2g (136mmol) of lithium aluminum tetrahydrogen, stir for 5 minutes with magnetic force, and control the temperature Between -5°C and 0°C, a mixed solution of 10 g (68 mmol) of 3,4-(methylenedioxy)benzonitrile and 300 ml of isopropyl ether was added dropwise. The reaction mixture was stirred for 10 hours and quenched with methanol at 0°C. The reaction mixture was basified with 1M aqueous NaOH and extracted with ethyl acetate. Combine the organic layers, wash with water and saturated sodium bicarbonate solution, dry the organic layer over anhydrous magnesium sulfate, distill off the ethyl acetate under normal pressure, and distill under reduced pressure with a vacuum pump to collect 9.1 g of 10 mmHg fraction at 136-138 ° C, with a yield of 88.5%. 1H NMR (300MHz, DMSO) 1.73 (brs, ...

Embodiment 2

[0035] Preparation of SL-D021:

[0036]Add 20ml of water and 2g (0.0132mol) of 3,4-methylenedioxybenzylamine to a 100ml three-neck flask under stirring, wait until the temperature in the reaction flask drops to 5-10 degrees, stir magnetically for 2 minutes in an ice bath, drop Add 1.93 g (0.0148 mol) of furoyl chloride, and dropwise add acid chloride and sodium hydroxide solution (0.6 g, 0.015 mol of sodium hydroxide plus 2.5 ml of water). After the addition is complete, continue stirring for 30 minutes, and monitor by TLC until the end of the reaction. Stop the reaction, filter, and wash the filter cake successively with 3ml×2 water, 3ml×2 water, 5% HCl 5ml, and 3ml×2 water to obtain a crude product. The crude product was recrystallized from methanol to obtain 2.9 g of pure product. Yield 91%, mp: 114-116°C. 1 HNMR (300MHz, CDCl 3 )4.51(d,J=5.7Hz,2H),5.94(s,2H),6.48-6.50(m,1H),6.66(brs,1H),6.75-6.79(m,2H),6.82-6.84(m ,1H), 7.13(d,J=3.6Hz,1H),7.41(d,J=0.9Hz,1H). HRMS:m / z2...

Embodiment 3

[0038] Preparation of SL-D022:

[0039] Add 20ml of water and 2g (0.0132mol) of 3,4-methylenedioxybenzylamine to a 100ml three-neck flask under stirring, wait until the temperature in the reaction flask drops to 5-10 degrees, stir magnetically for 2 minutes in an ice bath, drop Add 2.35g (0.0148mol) of 3-fluorobenzoyl chloride, and dropwise add acid chloride and sodium hydroxide solution (0.6g 0.015mol of sodium hydroxide plus 2.5ml of water). end point of the reaction. Stop the reaction, filter, and wash the filter cake successively with 3ml×2 water, 3ml×2 water, 5% HCl 5ml, 3ml×2 water, and dry the crude product. The crude product was recrystallized from methanol to obtain 2.6 g of pure product. Yield 72%, mp: 124-126°C. 1 HNMR (300MHz, CDCl 3 )4.29(d,J=6.0Hz,2H),5.91(d,J=1.2Hz,2H),6.14(brs,1H),6.64-6.69(m,2H),6.70-6.73(m,2H), 6.92-6.93(m,1H),6.96-6.99(m,1H),7.22-7.27(m,1H).HRMS:m / z274.79(M+H) ＋ .

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Abstract

The invention relates to the technical field of medicines, and specially relates to two acetaldehyde dehydrogenase agonists, and a preparation method and application thereof. Specifically, the invention relates compounds shown as a formula I and a formula II, a preparation method of the compounds, and application of the above two compounds and pharmaceutically acceptable inorganic or organic salts to prepare ALDH2 agonists and to prepare medicines for treating alcohol poisoning and to prepare medicines for alleviating alcoholism. The formula I and the formula II are shown in the specification.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to two acetaldehyde dehydrogenase agonists, a preparation method and application thereof. Background technique [0002] Existing studies have shown that normal adults who drink a small amount of alcohol can accelerate blood circulation, have the effects of promoting blood circulation, dredging collaterals and dispelling cold, eliminating fatigue, and promoting sleep. With the increase of people's demand for alcohol, the impact of alcohol on human health has attracted widespread attention. Excessive drinking can cause nausea, vomiting and other discomfort symptoms. Long-term excessive drinking can damage internal organs such as liver, stomach, spleen, etc. Diseases such as liver cirrhosis. Alcoholism, especially acute alcoholism, is increasing day by day, which can cause a series of social problems. The World Health Organization (WHO) points out: alcoholism is the first public haz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12C07D317/58A61K31/36A61P39/02
CPCC07D317/58C07D407/12
Inventor 苏定冯刘爱军刘建国刘霞苏一凌吴波吕加国
Owner 高尔医药科技(上海)有限公司
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