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Carbamate-chalcones cholinesterase inhibitors as well as preparation method and application thereof

The technology of carbamate and phenyldimethyl carbamate is applied in the field of carbamate-chalcone cholinesterase inhibitor and preparation thereof, and can solve the problem that the disease state cannot be fundamentally improved or terminating the progression of the disease, etc.

Inactive Publication Date: 2016-09-28
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although acetylcholinesterase inhibitors aimed at increasing the level of choline in the brain can improve the cognitive ability and daily behavior of patients, and delay the symptoms of AD, they are only effective in the treatment of mild to moderate AD, and cannot fundamentally improve the symptoms of AD. Disease state or process of terminating disease

Method used

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  • Carbamate-chalcones cholinesterase inhibitors as well as preparation method and application thereof
  • Carbamate-chalcones cholinesterase inhibitors as well as preparation method and application thereof
  • Carbamate-chalcones cholinesterase inhibitors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Preparation of Intermediates (M1-M10):

[0150] 5-Acetyl-1,3-phenylene bis(dimethylcarbamate) (M1)

[0151] 5-Acetyl-1,3-phenylene bis(ethyl(methyl)carbamate) (M2)

[0152] 3-Acetyldimethylcarbamate (M3)

[0153] 3-Acetylethyl (methyl) carbamate (M4)

[0154] 4-Acetyldimethylcarbamate (M5)

[0155] 4-Acetoethyl(methyl)carbamate (M6)

[0156] 2-Acetyldimethylcarbamate (M7)

[0157] 2-Acetoethyl (methyl) carbamate (M8)

[0158] 3-Acetylphenyldimethylcarbamate (M9)

[0159] 3-Acetylisopropylcarbamate (M10)

[0160] General synthesis steps of M1-M10: (0.044mol) hydroxyacetophenone, (0.785eq, 0.035mol) K 2 CO 3 / 1.5H 2 O, (0.215eq, 0.009mol) anhydrous K 2 CO 3 and (0.144eq, 0.0063mol) pyridine in an appropriate amount of ethyl acetate, stirred evenly, and heated to 70°C; (1.5eq, 0.066mol) carbamoyl chloride was stirred evenly in an appropriate amount of ethyl acetate, and added dropwise to the above solution, React at 70°C (the reaction time is determined by mon...

Embodiment 2

[0162] Preparation of intermediates (M11-M14):

[0163] 4-Formylphenyldimethylcarbamate (M11)

[0164] 4-Formylethyl (methyl) carbamate (M12)

[0165] 3-Formylphenyldimethylcarbamate (M13)

[0166] 3-Formylethyl (methyl) carbamate (M14)

[0167] General synthesis steps of M11-M14: (0.044mol) hydroxybenzaldehyde, (0.785eq, 0.035mol) K 2 CO 3 / 1.5H 2 O, (0.215eq, 0.009mol) anhydrous K 2 CO 3 and (0.144eq, 0.0063mol) pyridine in an appropriate amount of ethyl acetate were stirred evenly, and heated to 70°C; (1.5eq, 0.066mol) carbamoyl chloride was stirred evenly in an appropriate amount of ethyl acetate, and added dropwise to the above solution, React at 70°C (the reaction time is determined by monitoring the TLC plate). After the reaction, add water equal to the volume of the reaction solution, and stir at 70°C for 1.5h; cool to room temperature, extract and collect the organic phase, and wash each part with 2wt% sulfuric acid and water. After two times, they were dried ...

Embodiment 3

[0169] Synthesis of intermediate (E)-1-(3-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (compound represented by chemical structural formula N1):

[0170] At room temperature, dissolve (0.4425g, 2mmol) intermediate M4 in 5ml of methanol and stir evenly, drop 4ml of 8wt% KOH solution into it, and dissolve (0.2440g, 3.6mmol) p-methoxybenzaldehyde in methanol Drop into the above solution, stir at room temperature for 72 hours, concentrate in vacuo to remove the solvent, add 90ml of dichloromethane and 90ml of water, collect the organic phase, wash with water three times, dry over anhydrous magnesium sulfate, suction filter, concentrate, and dry to obtain a brown oil, which is washed by Column chromatography (petroleum ether: ethyl acetate = 15:1 ~ 6:1) gave 233.7 mg of light yellow solid product N1 with a yield of 45.9%. M.P.126.5-128.3℃.1H NMR(400MHz,DMSO)δ9.76(s,1H),7.84(d,J=8.7Hz,2H),7.70(s,2H),7.60(d,J=7.7Hz, 1H),7.44(s,1H),7.36(t,J=7.9Hz,1H),7.08–6.97(m,3H),3.83(s,3H).1...

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Abstract

The invention discloses a class of carbamate-chalcone cholinesterase inhibitors and a preparation method and application thereof, belonging to the field of medicinal chemistry. The general chemical structure formula of the cholinesterase inhibitor of the present invention is shown in formula (I), wherein A, B, V, X, Y, and Z are as defined in the present invention. The carbamate-chalcone cholinesterase inhibitor of the present invention has stronger acetylcholinesterase inhibitor activity, butyrylcholinesterase inhibitory activity and selective inhibition of butyrylcholinesterase activity, It has lower neurotoxicity and can be applied to the preparation of medicines for treating and preventing diseases caused by cholinesterase.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of carbamate-chalcone cholinesterase inhibitors and a preparation method and application thereof. Background technique [0002] Alzheimer's disease, referred to as AD, is a neurodegenerative disease characterized by progressive memory and cognitive dysfunction. The pathological changes of AD include cholinergic system dysfunction, deposition of aggregated β-amyloid (Aβ), hyperphosphorylation of Tau protein, etc. Although many factors have been found to be associated with the pathogenesis of AD, its etiology and pathogenesis have not yet been fully understood. At present, most of the drugs used to treat AD clinically belong to the single-target therapeutic drugs. One class is acetylcholinesterase inhibitors for the purpose of increasing the level of choline in the brain, including tacrine, donepezil, Rivastigmine and Galanthamine. The other is the NMDA rec...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/06A61P25/28
CPCC07C271/44
Inventor 王领谭文田艺广
Owner SOUTH CHINA UNIV OF TECH
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