2,4-bis-substituted acetophenone compound, optical isomers and pharmaceutically acceptable salts thereof and application of 2,4-bis-substituted acetophenone compound and optical isomers and pharmaceutically acceptable salts thereof

A technology of optical isomers and acetophenone, applied in the field of derivatives of acetophenone, can solve the problems of complex pathogenesis, inability to effectively control or cure AD, and difficult to contain or reverse the development of AD disease.

Active Publication Date: 2017-12-01
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Currently, the main marketed drugs for the treatment of senile dementia are five acetylcholinesterase (AChE) inhibitors and one N-methyl-D-aspartic acid (NMDA) receptor antagonist, However, all of them can only delay the symptoms of mild or moderate AD patients, and it is difficult to curb or reverse the development of AD.
[0004] Studies have shown that the pathogenesis of AD is very complex, so the use of single-target drugs cannot effectively control or cure AD

Method used

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  • 2,4-bis-substituted acetophenone compound, optical isomers and pharmaceutically acceptable salts thereof and application of 2,4-bis-substituted acetophenone compound and optical isomers and pharmaceutically acceptable salts thereof
  • 2,4-bis-substituted acetophenone compound, optical isomers and pharmaceutically acceptable salts thereof and application of 2,4-bis-substituted acetophenone compound and optical isomers and pharmaceutically acceptable salts thereof
  • 2,4-bis-substituted acetophenone compound, optical isomers and pharmaceutically acceptable salts thereof and application of 2,4-bis-substituted acetophenone compound and optical isomers and pharmaceutically acceptable salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Embodiment 1: the preparation of 3-(1-hydroxyl) ethylphenol (IIIa)

[0089] With 150.00g (1.10mol) 3-hydroxyacetophenone compound (corresponding to R in formula II 3 (for methyl) was dissolved in 500ml of tetrahydrofuran, and 51.00g (1.30mol) of sodium borohydride was added in batches in an ice bath, stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction, tetrahydrofuran was removed by rotary evaporation, sodium borohydride was quenched with ice water, and dilute hydrochloric acid was added dropwise until the pH value reached 5-6. The aqueous layer was extracted three times with ethyl acetate, and the combined ethyl acetate layer was dried over anhydrous sodium sulfate, then concentrated and evaporated to dryness to obtain a pale yellow solid IIIa with a yield of 83.1%.

[0090] 1 H-NMR (δ, CDCl 3 ):7.23(s,1H,-OH),7.08(dd,1H,J 1 =J 2 =8.0Hz, ArH), 6.77(s,1H,ArH),6.73(d,1H,J=8.0Hz,ArH),6.59(dd,1H,J 1 =8.0 Hz,J 2 =1.6Hz, ArH...

Embodiment 2

[0091] Embodiment 2: the preparation of 3-(1-hydroxyl) ethyl ethyl benzoate (IVa)

[0092] Dissolve 126.60g (0.90mol) of compound IIIa in 500ml of potassium hydroxide solution with a concentration of 5.50mol / L at 0°C, add 113ml (1.17mol) of acetic anhydride dropwise with stirring at 0°C, complete the dropwise addition within half an hour and store at room temperature Stir for 2h. After the reaction, the reaction system was extracted three times with ethyl acetate, and the mixed ethyl acetate layer was extracted three times with saturated sodium bicarbonate, saturated sodium chloride and water, respectively, and then dried with anhydrous sodium sulfate, concentrated and evaporated to dryness. Yellow liquid IVa, yield 76.3%.

[0093] [M+H] + =181.

Embodiment 3

[0094] Embodiment 3: the preparation of 3-(1-chloro) ethyl ethyl benzoate (Va)

[0095] 125.50g (0.70mol) of compound IVa was dissolved in 500ml redistilled dichloromethane and 123ml (1.61mol) redistilled N,N-dimethylformamide (DMF) mixed solution, and 67ml ( 1.05mol) redistilled thionyl chloride and stirred for 2h. After the reaction, slowly add saturated sodium carbonate solution dropwise at 0°C to adjust the pH value of the reaction system to 7-8. Afterwards, it was extracted three times with ethyl acetate, and the mixed ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain Va, a brownish-yellow liquid, with a yield of 91.8%.

[0096] [M+H] + =199.

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Abstract

The invention relates to a 2,4-bis-substituted acetophenone compound and optical isomers and pharmaceutically acceptable salts thereof. The invention further discloses an application of the 2,4-bis-substituted acetophenone compound and the optical isomers and pharmaceutically acceptable salts thereof in the aspect of treatment of neural degeneration diseases. The novel compounds have acetylcholinesterase inhibition activity and A beta aggregation inhibiting ability, and hydrolyzates of the novel compounds further have a metal ion chelation action, so that the novel compounds can be used for carrying out treatment from a plurality of targets and have a better application prospect in the treatment of the neural degeneration diseases.

Description

technical field [0001] The present invention relates to a derivative of acetophenone, in particular to a 2,4-disubstituted acetophenone compound and its optical isomer, pharmaceutically acceptable salt and application. Background technique [0002] At present, the problem of population aging in my country is becoming more and more serious. The "2011 Statistical Bulletin on the Development of China's Aging Work" shows that by the end of 2011, the number of people aged 60 and over in the country has reached 185 million, and has entered an aging society. Among them, degenerative diseases such as senile dementia are common diseases and frequently-occurring diseases of the elderly. The incidence rate of people over 65 years old is 8%, 20% over 75 years old, and up to 40% over 85 years old. [0003] Currently, the main marketed drugs for the treatment of senile dementia are five acetylcholinesterase (AChE) inhibitors and one N-methyl-D-aspartic acid (NMDA) receptor antagonist, Ho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07D295/205C07D295/03A61P25/28A61P25/16
CPCC07C271/44C07D295/03C07D295/205
Inventor 黄文海沈正荣王尊元马臻梁美好章迟啸
Owner ZHEJIANG ACAD OF MEDICAL SCI
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