Memantine Chemical Properties

Melting point:

258 °C

Boiling point:

239.8±8.0 °C(Predicted)

Density 

1.046

refractive index 

nD25 1.4941

storage temp. 

Keep in dark place,Inert atmosphere,2-8°C

solubility 

Chloroform (Slightly), DMSO (Slightly)

form 

Solid

pka

10.79±0.60(Predicted)

color 

Colorless Oil to Off-White Waxy

BCS Class

1?

CAS DataBase Reference

19982-08-2(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Safety Statements 

24/25

Hazardous Substances Data

19982-08-2(Hazardous Substances Data)

MSDS

• Language:English Provider:1,3-Dimethylaminoadamantane

Memantine Usage And Synthesis

Description

Memantine is a potent antagonist of the N-methyl-D-aspartate (NMDA) receptor. Experimentally, memantine inhibits and reverses the abnor-mal activity of a protein phosphatase (PP-2A) that leads to tauhyperphosphorylation and to neurofibrillary degeneration inAD. Memantine is effective and well toler-ated in patients with severe AD and wasapproved by the FDA for the treatment of moderate-to-severe AD.

Originator

Akatinol,Merz,W. Germany,1983

Uses

antiulcer

Uses

Recent phase 3 clinical trials have shown that Memantine is an effective way of treatment of both mild and moderate-to-severe Alzheimer''s disease and possibly vascular dementia (multi-infarct dementia). Memantine’s method of action involves an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission.

Definition

ChEBI: A primary aliphatic amine that is the 3,5-dimethyl derivative of 1-aminoadamantane. A low to moderate affinity uncompetitive (open-channel); NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.

Application

Memantine has been used in patients with VaD basedon its experimental efficacy in animal models of ischaemiclesions.Memantine acts on potentially contributing factorssuch as neuronal depolarization，mitochondrial dysfunc-tion, magnesium effects on NMDA receptors and chronicglutamatergic overstimulation; it also has shown positiveeffects on long-term potentiation and cognitive tests in stan-dard animal models of impaired synaptic plasticity.

Manufacturing Process

A mixture of 24 g of 1,3-dimethyladamantane and 80 ml of bromine was refluxed for 6 hours. The reaction product mixture was cooled, taken up in about 200 ml of chloroform, and poured onto ice. The excess bromine was removed by adding sodium hydrosulfite. The chloroform layer was separated from the aqueous layer, dried, concentrated in vacuo, and distilled at reduced pressure to yield 30.5 g of product having a boiling point of about 118°C at 5- 6 mm; nD25 = 1.5169-1.5182. The product was identified by nuclear magnetic resonance (NMR) and elemental analyses as 1-bromo-3,5- dimethyladamantane.
A mixture of 20 g of 1-bromo-3,5-dimethyladamantane, 75 ml of acetonitrile, and 150 ml of concentrated sulfuric acid was allowed to react overnight at ambient room temperature. The red reaction product mixture was poured over crushed ice, and the white solid which precipitated was taken up in benzene and the benzene solution dried over sodium hydroxide pellets. The benzene solution was filtered from the drying agent and evaporated to dryness in vacuo to yield 18.2 g of product having a melting point of about 97°C and identified by infrared spectrum as 1-scetamido-3,5-dimethyladamantane.
A mixture of 18 g of 1-acetamido-3,5-dimethyladamantane, 38 g of sodium hydroxide, and 300 ml of diethylene glycol was refluxed for a period of 6 hours. The reaction product mixture was cooled and poured onto about 2,000 ml of crushed ice. The basic solution thus obtained was extracted five times with 250 ml portions of benzene and the aqueous layer was discarded. The combined benzene extracts were dried over sodium hydroxide and the dried benzene solution concentrated in vacuo to give a crude oil weighing 14 g and having nD25 = 1.4941, A 4 g sample of the crude oil was dissolved in ether and the solution saturated with anhydrous hydrogen chloride. The solid which precipitated was filtered off and recrystallized from a mixture of alcohol and ether to yield product weighing 3.5 g and melting at 258°C.
It was identified by analysis as 1-amino-3,5-dimethyladamantane hydrochloride.

Therapeutic Function

Spasmolytic

Biological Activity

An antagonist at the NMDA receptor, binding to the ion channel site. Used in the treatment of Parkinsonism.

Clinical Use

NMDA-receptor antagonist:
Treatment of moderate to severe dementia in Alzheimer’s disease

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: increased risk of CNS toxicity with ketamine – avoid.
Analgesics: increased risk of CNS toxicity with dextromethorphan – avoid.
Dopaminergics: possibly enhances effects of dopaminergics and selegiline; increased risk of CNS toxicity with amantadine – avoid.

Metabolism

Memantine undergoes partial hepatic metabolism to form mainly three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitrosodeaminated memantine. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.

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