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Synergistic precursor medicine compound for treating Alzheimer disease

A compound and drug technology, applied in the field of Alzheimer's disease synergistic prodrug compounds, can solve the problems of large therapeutic dose, facial flushing, induced ulcer disease, etc.

Inactive Publication Date: 2004-11-24
国海证券股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Long-term application of niacin can reduce the incidence or mortality of coronary heart disease, myocardial infarction, and other cardiovascular and cerebrovascular diseases, but because niacin requires a large therapeutic dose (3-6g / day), it is prone to facial flushing and itching , induce ulcer disease, aggravate diabetes and gout and other side effects, which limit its clinical application

Method used

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  • Synergistic precursor medicine compound for treating Alzheimer disease
  • Synergistic precursor medicine compound for treating Alzheimer disease
  • Synergistic precursor medicine compound for treating Alzheimer disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of (1-dimethylphosphoryl-2,2,2-trichloro)-ethyl-1-ol nicotinate (NMF) by acid chloride method

[0036]Under dry and anhydrous conditions, install a drying device and a gas absorption device, add 8 mL of thionyl chloride into the reaction bottle, cool it to about 0 °C with an ice-water bath, stir, and add 0.8 g (6.5 mmol) of nicotinic acid to it, Add 5-7 drops of anhydrous DMF dropwise, and slowly heat up the oil bath to about 77°C to reflux. After 3 hours, distill off excess thionyl chloride under reduced pressure to obtain nicotinyl chloride hydrochloride (light yellow solid). Add an appropriate amount of anhydrous dichloromethane to the dry reaction flask under ice-salt bath, stir vigorously, add 10mL of anhydrous TEA and 1.7g (6.6mmol) metrifosate in 20mL of dichloromethane solution successively dropwise, react for 3h, filter After the filtrate was concentrated under reduced pressure, an appropriate amount of ethyl acetate was added, followed by water, 0....

Embodiment 2

[0038] Preparation of NMF by DCC / DMAP method (active ester method)

[0039] 2.46g (0.02mol) of niacin and 5.15g (0.02mol) of metrifosate were dissolved in dry 120mL DMF at room temperature, 0.30g (0.002mol) of DMAP was added, and stirred evenly. Add 6.19g (0.03mol) DCC solution in 50mL DMF dropwise at 0-5°C, stir overnight at room temperature, filter, concentrate under reduced pressure, add an appropriate amount of ethyl acetate, filter, then water, 0.1N HCl, saturated NaHCO 3 , saturated brine for 3 times, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, flash column chromatography (silica gel H, washing liquid: petroleum ether-acetone), to obtain (1-dimethylphosphoryl-2,2,2- Trichloro)-ethyl-1-ol nicotinate 4.70g (light yellow solid), recrystallized from petroleum ether-acetone mixed solvent to obtain colorless massive crystals. Yield: 65.0%.

Embodiment 3

[0041] CDI / DMAP method (active ester method) to prepare NMF

[0042] Dissolve 0.62g (5mmol) niacin in dry 25mL DMF solution, quickly add 0.81g (0.002mol) CDI and 0.08g (0.5mmol) DMAP, and stir the reaction at 0-5°C for 1h. Add 1.29g (5mmol) of metrifosate in 25mL of DMF dropwise, stir overnight at room temperature, concentrate under reduced pressure, add an appropriate amount of ethyl acetate, filter, and successively add water, 0.1N HCl, saturated NaHCO 3 , saturated brine for 3 times, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, flash column chromatography (silica gel H, washing liquid: petroleum ether-acetone), to obtain (1-dimethylphosphoryl-2,2,2- Trichloro)-ethyl-1-ol nicotinate 1.26g (light yellow solid), recrystallized from petroleum ether-acetone mixed solvent to obtain colorless massive crystals. Yield: 70.0%.

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Abstract

The present invention relates to synergistic precursor medicine compound for treating Alzheimer disease or its salt and their preparation process, and medicine composition containing the compound or its salt and their application in treating Alzheimer disease. Specially, the compound, which is (1-dimethyl phosphoryl-2, 2, 2-trichloro)-ethyl-1-alcohol nicotinate, is formed with nicotinic acid and metrifonate and through ester bond coupling. The compound or its salt of the present invention has excellent effect on treating Alzheimer disease.

Description

field of invention [0001] The invention relates to an Alzheimer's disease synergistic prodrug compound and a preparation method thereof, and also relates to a pharmaceutical composition containing the compound and an application of the compound in preparing a medicine for treating Alzheimer's disease. Specifically, the compound is formed by coupling nicotinic acid and metrifosate via an ester bond, that is, (1-dimethylphosphoryl-2,2,2-trichloro)-ethyl-1-alcohol esters (NMF). Background of the invention [0002] Alzheimer's disease (AD) is the main type of senile dementia. It is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment, accompanied by personality changes and behavioral disorders. . The incidence rate among the elderly around 65 years old is 10%, and the incidence rate among the elderly over 85 years old is 50%. At present, there are 130 million elderly people ...

Claims

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Application Information

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IPC IPC(8): A61K31/662A61P25/28C07F9/58
Inventor 熊晓云邹永朱杰吴玉梅梅其炳陈海生刘及响胡建平
Owner 国海证券股份有限公司
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