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A kind of bis-o-hydroxyacetophenone gemini compound and its preparation method and application

A technology of o-hydroxyacetophenone and hydroxyacetophenone is applied in the field of di-o-hydroxyacetophenone twin drug compounds and their preparation, and can solve the problems of many toxic and side effects, poor long-term efficacy of AD patients, complex etiology of AD and the like , to achieve the effect of strong antioxidant activity

Inactive Publication Date: 2021-04-20
NANYANG NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The etiology of AD is complex, and its pathogenesis has not been fully elucidated so far, but studies have shown that the level of acetylcholine in the brain of patients is reduced, excessive production and deposition of β-amyloid protein, metal ion metabolism disorders, Ca 2+ Balance disorder, neurofibrillary tangles caused by hyperphosphorylation of tau-protein, hyperactivity of glutamate receptors, oxidative stress to produce a large number of reactive oxygen species (ROS) and free radicals, and neuroinflammation are factors in the pathogenesis of AD. play an important role in the process
In response to the above-mentioned pathogenic factors, researchers adopted the traditional "one drug, one target" drug design strategy, and discovered a large number of drugs with high activity and high selectivity for a certain target, such as: cholinesterase inhibitors and NMDA receptors Antagonists, etc. These drugs have a single target, more toxic and side effects in clinical use, and poor long-term curative effect on AD patients.

Method used

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  • A kind of bis-o-hydroxyacetophenone gemini compound and its preparation method and application
  • A kind of bis-o-hydroxyacetophenone gemini compound and its preparation method and application
  • A kind of bis-o-hydroxyacetophenone gemini compound and its preparation method and application

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Embodiment 1

[0032] General method for the preparation of embodiment 1 bis-o-hydroxyacetophenone gemini drug compound Ia

[0033] Add 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of the corresponding dibromocompound (2), 3mmol of anhydrous potassium carbonate and 50ml of acetonitrile in the reaction flask, after stirring evenly, heat up and reflux and stir for 2.0 to 72 hours ( The reaction process is tracked by TLC); after the reaction, evaporate the solvent to dryness under reduced pressure, add 80ml of deionized water, extract three times with 200mL of dichloromethane, wash with saturated sodium chloride after the organic layer is combined, dry and filter through anhydrous sodium sulfate , two 2-hydroxyacetophenone gemini compounds (Ia) are evaporated to dryness under reduced pressure, and the residue is purified by column chromatography (petroleum ether: acetone=100:1v / v) to obtain the corresponding two 2-hydroxyacetophenone Ketogemide compound Ia, the yield is 15%-65%, and its chemica...

Embodiment 2

[0054] General method for the preparation of embodiment 2 two o-hydroxyacetophenone gemini compounds (Ib)

[0055]Add 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of the corresponding dibromoalkylamine compound (3), 5mmol of anhydrous potassium carbonate and 20ml of acetonitrile in the reaction flask, stir evenly, and then heat up and reflux to stir for 2.0 to 72 hours (the reaction process was tracked by TLC); after the reaction, the solvent was evaporated under reduced pressure, 80ml of deionized water was added, extracted three times with 200mL of dichloromethane, the organic layers were combined and washed with saturated sodium chloride, washed with anhydrous sodium sulfate Drying and filtering, two 2-hydroxyacetophenone gemini compounds (Ib) are evaporated to dryness under reduced pressure, and the residue is purified by column chromatography (petroleum ether: acetone=100:1v / v) to obtain the corresponding two 2-hydroxyl Acetophenone gemini compound (Ib), yield 10%-55%, it...

Embodiment 3

[0061] General method for the preparation of embodiment 3 two o-hydroxyacetophenone gemini compounds (Ic)

[0062] Add 2.0mmol of 2-hydroxyacetophenone (1), 10mmol of the corresponding ethyl bromoalkylate (4), 5mmol of anhydrous potassium carbonate and 20ml of acetonitrile in the reaction flask, stir evenly, and then raise the temperature and reflux to stir for 2.0-72 hours (the reaction process was tracked by TLC); after the reaction, the solvent was evaporated under reduced pressure, 80ml of deionized water was added, extracted three times with 200mL of dichloromethane, the organic layers were combined and washed with saturated sodium chloride, washed with anhydrous sodium sulfate Dry and filter, evaporate the solvent from ethyl ferulamide-O-alkanoate under reduced pressure, and purify the residue by column chromatography (petroleum ether: acetone=100:1v / v) to obtain the corresponding ferulamide-O-alkane Acetate ethyl ester, then add 20mL methanol and 10mmol30% LiOH solution...

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Abstract

The invention relates to a bis-o-hydroxyacetophenone gemini compound and its preparation method and use, belonging to the field of medicinal chemistry. The invention uses 2-hydroxyacetophenone derivatives as starting materials and prepares the compound in a suitable solvent and alkaline conditions. The following reaction will generate di-o-hydroxyacetophenone gemini compounds connected by different linkers. This compound has pleiotropic functions and is expected to be used in medicine to treat and / or prevent neurodegenerative-related diseases. Such neurodegenerative-related diseases Including Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, vascular dementia, neuropathic pain, glaucoma, etc., for the effective treatment of related geriatric diseases , and lay the foundation for improving the healthy living standards of residents.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a bis-o-hydroxyacetophenone gemini compound and its preparation method and application. Background technique [0002] Alzheimer's disease (AD) is one of the diseases with the highest morbidity and mortality among the elderly. According to the "2015 Global Alzheimer's Report" released by Alzheimer's Disease International (ADI), more than 46 million people in the world suffered from dementia in 2015. It is predicted that by 2050, the world's There will be 131.5 million people suffering from dementia, and the incidence rate of dementia patients in China has reached 6.61%. With the prolongation of the average life expectancy, the disease has developed into a major burden on the society and the medical care system, and has brought heavy mental and economic pressure to the society, patients and their families. Therefore, it is of great significance to research and devel...

Claims

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Application Information

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IPC IPC(8): C07C49/84C07C217/22C07C235/10C07C45/64C07C213/08C07C231/02A61K31/12A61K31/138A61K31/165A61P25/28A61P25/16A61P25/14A61P25/00A61P27/06A61P25/04
CPCC07C49/84C07C217/22C07C235/10
Inventor 桑志培王柯人柳文敏于林涛王慧娟马倩文韩雪叶梦瑶
Owner NANYANG NORMAL UNIV
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