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N-(3-pyridine formyloxy)-3,5-dimethyl-1-amantadine for curing senile dementia or pharmaceutical salt thereof

A medicinal salt and amidation reaction technology is applied in the application field of preparing a drug for treating senile dementia, and can solve the problems of increased risk of dementia, blocked amyloid synthesis and the like

Active Publication Date: 2009-01-21
XIAN LIJUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, epidemiological studies have shown that high cholesterol levels can promote the production of amyloid, which increases the risk of dementia by 3 to 4 times. Animal experiments have found that once cholesterol intake is blocked, the synthesis of amyloid in the hippocampus is blocked.

Method used

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  • N-(3-pyridine formyloxy)-3,5-dimethyl-1-amantadine for curing senile dementia or pharmaceutical salt thereof
  • N-(3-pyridine formyloxy)-3,5-dimethyl-1-amantadine for curing senile dementia or pharmaceutical salt thereof
  • N-(3-pyridine formyloxy)-3,5-dimethyl-1-amantadine for curing senile dementia or pharmaceutical salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Preparation of N-(3-pyridyloxy)-3,5-dimethyl-1-adamantanamine by DCC / DMAP method (active ester method)

[0069] 2.46g (0.02mol) of nicotinic acid and 4.32g (0.02mol) of memantine hydrochloride were dissolved in dry 120mL DMF at room temperature, 0.30g (0.002mol) of DMAP was added dropwise after adding 2.30mL of anhydrous TEA, 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 solution: petroleum ether-acetone), to obtain N-(3-pyridineformyloxy)-3,5 - Dimethyl-1-adamantanamine, colorless viscous substance, 3.58 g, yield 63%.

[0070] MS (EI), m / z: 284 (M + ), 269 (M + -CH 3 ), 178 (C 12 h 20 NO + ), 106(C ...

Embodiment 2

[0076] Preparation of N-(3-pyridyloxy)-3,5-dimethyl-1-adamantanamine by CDI / DMAP method (active ester method)

[0077] 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 dropwise a mixed solution of 1.08g (5mmol) of memantine hydrochloride in 2.30mL of anhydrous TEA and 25mL of DMF solution, stir overnight at room temperature, concentrate under reduced pressure, add an appropriate amount of ethyl acetate, filter, and 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 solution: petroleum ether-acetone), to obtain N-(3-pyridineformyloxy)-3,5 - Dimethyl-1-adamantanamine, colorless viscous substance, 0.99 g, yield 70%.

Embodiment 3

[0079] Preparation of N-(3-pyridineformyloxy)-3,5-dimethyl-1-adamantanamine by mixed acid anhydride method

[0080] Dissolve 0.32g (2.60mmol) niacin in an appropriate amount of anhydrous CH under ice-salt bath 2 Cl 2 1mL (7.18mmol) TEA and 0.4mL (3.13mmol) anhydrous benzenesulfonyl chloride were slowly added dropwise in sequence, stirred for 1h, and 0.40g (1.86mmol) of memantine hydrochloride and TEA’s CH 2 Cl 2 The mixed solution was stirred for 3 h, concentrated under reduced pressure, added an appropriate amount of ethyl acetate, filtered, followed by water, 0.1N HCl, saturated NaHCO 3 , saturated brine for 3 times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a red oil, which was separated and purified by column chromatography (silica gel H, eluent: petroleum ether-acetone mixed solvent) to obtain N-(3-pyridinemethyl Acyloxy)-3,5-dimethyl-1-adamantanamine, colorless viscous substance, 0.41 g, yield 77%.

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Abstract

The invention relates to a N-(3-pyridine methoxy)-3,5-dimethyl-1-amine diadamantane for treatment of Alzheimer's Disease or a salt thereof for medicinal purpose, and also relates to the method for synthesizing the compound or the salt thereof for medicinal purpose, as well as the application in the preparation of drugs for treatment of Alzheimer's Disease, particularly, the compound is a synergetic prodrug produced through chemical coupling of amido link between nicotinic acid and amine diadamantane hydrochloric, on one hand, the prodrug not only avoids the side effects caused by nicotinic acid which is orally taken, but also implements cooperative dual effects on prevention and treatment of Alzheimer's disease by nicotinic acid and amine diadamantane, thereby improving the treatment effect of amine diamantine hydrochloric on Alzheimer's Disease; on the other hand, the enhanced molecular solubility of amine diadamantane in lipid facilitates the passage of the prodrug through a blood-brain barrier, increases the distribution concentration of the prodrug in the cerebrospinal fluid, thereby accomplishing the aim of reducing the peripheral side effects of the drug.

Description

technical field [0001] The present invention relates to N-(3-pyridineformyloxy)-3,5-dimethyl-1-adamantamine or a pharmaceutically acceptable salt thereof, and also relates to a synthesis method of said compound and its use in the preparation and treatment of senile dementia application in disease medicine. Background technique [0002] Alzheimer's disease is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. With the acceleration of the aging process of the population, its incidence has shown an obvious upward trend. And the number four killer after a stroke. The main manifestations of the disease include memory and cognitive dysfunction (including memory loss, orientation loss, thinking and judgment loss, etc.), reduced daily life ability, and even abnormal mental behavior symptoms, so it is difficult to care for patients. The pressure on families and society in the "April 21" Chinese model ...

Claims

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Application Information

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IPC IPC(8): C07D213/82A61K31/455A61P25/28
Inventor 熊晓云邹永吴秦黄朝招明高朱杰吴玉梅
Owner XIAN LIJUN PHARMA CO LTD
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