Arylpyridone derivatives with acetylcholine esterase inhibition activity

A pyridone and pyridine technology, which is applied in the field of 6-aryl-3-substituted methylene-pyridone derivatives and their preparation, can solve the weakening of conduction signals, the reduction of acetylcholine concentration, and the disorder of acetylcholine synthesis and secretion, etc. question

Inactive Publication Date: 2009-05-27
WENZHOU MEDICAL UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

In the cholinergic model of AD, the main defect is the disorder of acetylcholine synthesis and secretion, and the catabolism of acetylcholine decomposing neurotransmitters is not affected, resulting in a large decrease in the concentration of acetylcholine in the cholinergic synaptic cleft, and to the cerebral cortex. The transmitted signal then weakens

Method used

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  • Arylpyridone derivatives with acetylcholine esterase inhibition activity
  • Arylpyridone derivatives with acetylcholine esterase inhibition activity

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0023] Preparation example 1: Preparation of starting material A (p-methoxyacetophenone):

[0024] p-Methoxyacetophenone

[0025] Methoxybenzene (10.8 g, 0.1 mol) was dissolved in 150 ml of dichloromethane, then anhydrous zinc chloride powder (26.8 g, 0.20 mol) was added, and acetic anhydride (15.3 g, 0.15 moles); after the dropwise addition, the reaction was slowly raised to room temperature for 7 hours, then the reactant was carefully poured into 600 ml of ice water, and extracted 3 times with ethyl acetate; the organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated The crude product was a colorless oil, and after short silica gel column chromatography, the starting material A (p-methoxyacetophenone): 13.1 g, yield 87%); white solid, melting point: 35-38°C. H NMR spectrum 1 H-NMR (400MHz, deuterated chloroform, δ ppm) δ 2.56 (single peak, 3H, COCH 3 ), 3.87 (single peak, 3H, OCH 3 ), 6.93 (doublet, 2H, J=8.4Hz, H-3,5), 7.94 (doublet, 2H, J...

preparation example 2

[0026] Preparation example 2: Preparation of intermediate B (3-cyano-6-(4-methoxyphenyl)-2H-pyridin-2-one):

[0027] 3-cyano-6-(4-methoxyphenyl)-2H-pyridin-2-one

[0028] Sodium metal (2.76 g, 120 mmol) was added to 250 ml of ether, 1 ml of ethanol was added dropwise, and starter A (p-methoxyacetophenone) (100 mmol) and ethyl formate were added dropwise under ice-cooling Ester (150 mmol) mixture, after the dropwise addition, the mixture was stirred for 15 minutes, then warmed up to room temperature and reacted for 1 hour. After diethyl ether was distilled off under reduced pressure, cyanoacetamide (12.6 g, 150 mmol) and water were added to the solid mixture (400ml). After the mixture was refluxed for 8 hours, cooled, acidified with acetic acid, and filtered to obtain a yellow solid, after drying, the initial product was recrystallized from ethanol to obtain intermediate B (3-cyano-6-(4-methoxyphenyl)- 2H-pyridin-2-one): Yield: 56%, pale yellow solid, melting point>250°C;...

preparation example 3

[0029] Preparation example 3: Preparation of intermediate C (3-cyano-6-(4-methoxyphenyl)-2-methoxypyridine):

[0030] 3-cyano-6-(4-methoxyphenyl)-2-methoxypyridine

[0031] Intermediate B (3-cyano-6-(4-methoxyphenyl)-2H-pyridin-2-one) (10 mmol) was prepared in N,N-dimethyldimethylacetal (DMFDMA) ( 1.8 g, 15 mmol) in N,N-dimethylformamide (50 mL) was heated to reflux overnight, and the mixture was poured into ice water. Produce a yellow solid precipitate, filter, wash the filter cake with a small amount of water, dry to obtain a crude product, recrystallize in ethanol to obtain compound intermediate C (3-cyano-6-(4-methoxyphenyl)-2 -methoxypyridine): yield: 89%; white solid; melting point: 137~138°C; R f (Petroleum ether / ethyl acetate 3:1) 0.46; H NMR 1 H-NMR (400MHz, deuterated chloroform, δppm): 3.89 (singlet, 3H, MeO-4'), 4.15 (singlet, 3H, MeO-2), 7.02 (doublet, 2H, J=8.4Hz, H-3', 5'), 7.36 (doublet, 1H, J=8.0Hz, H-5), 7.87 (doublet, 1H, J=8.0Hz, H-4), 8.04 (doublet, ...

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Abstract

The invention relates to the fields of organic chemistry, pharmaceutical chemistry and pharmacology, in particular to an aryl pyridone derivant with the function of inhibiting the activity of acetylcholinesterase, namely a 6-aryl-substituted methylene-pyridone derivant and a medicinal salt thereof. The invention also relates to a method for preparing a compound and medical application thereof. The compound can inhibit activity of acetylcholinesterase and is expected to be used as a drug for preventing and treating senile dementia.

Description

technical field [0001] The present invention belongs to the fields of organic chemistry, medicinal chemistry and pharmacology, in particular, the present invention relates to 6-aryl-3-substituted methylene-pyridone derivatives capable of preventing and treating senile dementia and its preparation method and use . The pharmacological activity test shows that the compound has the activity of inhibiting acetylcholinesterase, and can be expected to be used as a medicine for preventing and treating senile dementia. Background technique [0002] Studies at home and abroad suggest that with the increase of age, the incidence of senile dementia will gradually increase, and the incidence of dementia in the elderly over 80 years old can reach 80%. Alzheimer's disease has become the fourth cause of death after heart disease, malignancy and stroke. At present, the elderly over 60 years old in my country has reached 120 million, and there are about 5 million senile dementia patients. ...

Claims

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Application Information

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IPC IPC(8): C07D213/64A61K31/496A61P25/28
Inventor 李校堃阳应华马建设黄可新董盛谊约阿施·史托克希特赵昱瞿佳
Owner WENZHOU MEDICAL UNIV
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