Synthesis
The hydrolysis of 1-formamido-3,5-dimethyladamantane-1-formamido-3,5-dimethyladamantane (industrial grade, 70% purity, 2 mmol, calculated as 100% purity) was performed using a selected base (6 mmol) in a selected solvent (10 ml) or solvent system (10 ml). The reaction was monitored by taking aliquots after the time shown in the examples. The aliquots were partitioned between toluene and water. The organic phase was separated and dried over anhydrous Na2SO4, and the obtained compound was confirmed as 3,5-dimethyladamantane by gas chromatography. Furthermore, researchers synthesized 3,5-dimethyladamantane using a one-pot method, reacting o-iodophenol with ethyl propynate in the presence of triethylamine using toluene as solvent. This method effectively avoids the problem of using highly toxic diazo compounds during the reaction, has fewer reaction steps, shorter reaction time, simpler operation, higher yield, and allows for more convenient molecular structure modification and alteration of the target compound, providing guidance for the synthesis of similar compounds.
Figure 3, Synthetic Route of Memantine
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
History
Memantine was first synthesized, patented, and described by Eli Lilly and Company in 1963 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. By 1972, it was discovered to have central nervous system (CNS) activity, and was developed by Merz for treatment of neurological diseases, such as Parkinson's disease. Memantine was first studied in the treatment of Alzheimer's disease in 1986.
The drug was first marketed for dementia in 1989 in Germany under the name Axura. Memantine was approved in the European Union in 2002 and in the United States in 2003.
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.
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.
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.
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.
