Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation

A kind of cyclic aminomethylpyrone and base methyl technology is applied in the field of 6-aryl 3-cyclic aminomethylpyrone derivatives and their preparation, which can solve the problem of large toxic and side reactions for patients, affecting the dosage and Scope of use and sales, etc.

Inactive Publication Date: 2007-12-26
赵昱
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, because of its strong inhibitory activity on BuChE, taccolin has very obvious hepatotoxicity in clinical use, and the problem of severe toxic and side effects in patients is inevitable, which affects its dosage, scope of use and sales.

Method used

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  • Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation
  • Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation
  • Preparation and application of a category of 6 - aryl - 3 - cycroamido methyl pyrone derviation

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0063] Preparation Example 1: Preparation of Compound I-0 (ethyl 2-methylacetoacetate):

[0064]

[0065] In 300 milliliters of ethanol, add 13.8 grams of metal sodium (600 mmol), after completely dissolving, add dropwise 80 ml (600 mmol) of ethyl acetoacetate, heat up and reflux for 1 hour, dropwise add 50 ml of iodomethane (660 mmol), reflux for two hours, cool Return to room temperature, remove ethanol by rotary evaporation, add water and extract with ether (5×50ml), combine organic phases, dry over anhydrous sodium sulfate, filter with suction, remove ether by rotary evaporation, distill under reduced pressure, collect 78-80°C (13mmHg) fraction , to obtain 87.63 grams of colorless transparent liquid, the separation yield Y=50.71%.

preparation example 2

[0066] Preparation Example 2: Preparation of Compound I-1 [with (2-methyl-3-oxo-5-hydroxyl-5-(3',4',5'-trimethoxyphenyl)-pentanoic acid ethyl ester) For example]:

[0067]

[0068]Under ice-salt bath cooling conditions, 5.78 g (37.5 mmol) of ethyl 2-methylacetoacetate was added dropwise to 2.3 g of sodium hydride (95.8 mmol) in tetrahydrofuran suspension (140 ml), and then 2.5 M 28ml (70.2mmol) of n-hexane solution of butyllithium, after ten minutes, dropwise add 5.88 grams (30mmol) of tetrahydrofuran solution (10ml) of 3,4,5-trimethoxybenzaldehyde, continue to react for 15 minutes, add to the reaction system Add saturated aqueous ammonium chloride solution (30ml), extract with diethyl ether (3×50ml), combine organic phases, wash with saturated brine (3×20ml), dry over anhydrous sodium sulfate, suction filter, silica gel column chromatography (petroleum ether / ethyl acetate: 2 / 1) 7.572 g of yellow oily liquid was obtained, and the separation yield Y=72.11%.

[0069] Rf (e...

preparation example 3

[0070] Preparation Example 3: Preparation of Compound I-2 [taking (2-methyl-3-hydroxyl-5-hydroxyl-5-(3',4',5'-trimethoxy)-ethyl valerate) as an example 】:

[0071]

[0072] In an ice-water bath, 3.06 g (9 mmol) of intermediate I-1 was dissolved in tetrahydrofuran (67.5 ml) and methanol (27 ml), and 1.04 g (27 mmol) of sodium borohydride was slowly added to react for 30 minutes. Add 30 ml of saturated aqueous ammonium chloride solution, extract with ether (3×40 ml), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and remove ether by rotary evaporation to obtain 3.22 g of crude product, which is directly carried out to the next reaction.

[0073] Rf (ethyl acetate / petroleum ether: 1 / 1): 0.35.

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Abstract

This invention relates to compounds with 6-aryl-3-cycloaminomethyl pyrone structure, their preparation method and their application. Pharmacological activity experiments show that the compounds have a high activity in selectively inhibiting AChE while no obvious activity in inhibiting BuChE. The activity of the compounds in inhibiting AChE is higher than huperzine A. Mouse in vivo tests show that the compounds do not have acute toxicity or abnormal reaction phenomenon, and the compounds can be used as a kind of new drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the fields of organic chemistry, medicinal chemistry and pharmacology, in particular, the invention relates to 6-aryl 3-ring aminomethylpyrone derivatives capable of preventing and treating senile dementia and organic dementia and their preparation Methods and uses. According to the pharmacological activity test, this type of compound has a strong inhibitory activity on acetylcholinesterase, and has a very weak inhibitory effect on acylcholinesterase. In vivo tests, this type of compound was given to ICR mice by intragastric administration of 2.0g / kg and intraperitoneal injection Administration of 0.5g / kg has no toxicity, and it can be expected to be used as a drug for preventing and treating senile dementia. Background technique [0002] As the world enters an aging society, the incidence of Alzheimer's disease is increasing year by year. Alzheimer's disease has become the fourth cause of death after heart disease, malignant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06C07D405/14A61K31/496A61K31/4427A61P25/28
Inventor 赵昱白骅蒋翔锐
Owner 赵昱
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