Pure Memantine HCl CAS 41100-52-1

Pure memantine hcl is a dementia treatment drug developed by Merz in Germany under the chemical name 3,5-Dimethyl-1-aminoadamantane hydrochloride, also known as 3,5-Dimethyltricyclo(3.3.1.1(3.7))decan-1-amine hydrochloride. It has the molecular formula C12H21N-HCl and molecular weight 215.77. It is a novel, low-moderate affinity, voltage-dependent, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that noncompetitively blocks NMDA receptors and reduces glutamate induced NMDA receptor hyperexcitability, preventing apoptosis and improving memory, it is a new generation of drugs to improve cognitive function. Memantine hydrochloride is mainly used for the treatment of moderately severe to severe Alzheimer's-type dementia, which can significantly improve the patients in cognition, behavior, learning, comprehension, and the ability to perform daily actions, and slow down the development of Alzheimer's disease patients.

In February 2002, it was approved by the European Committee for Patented Medicinal Products (CPMP) for the treatment of patients with moderate to severe Alzheimer's disease, and in August of the same year, it was launched in Germany, and on October 17, 2003, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate to severe Alzheimer's disease. Further studies have shown that Memantine HCl is also effective in patients with mild to moderate Alzheimer's disease. Alzheimer's disease (AD), also known as senile dementia, is one of the common diseases of the elderly, mainly manifested by memory loss and recognition impairment, etc. It is a progressive neurodegenerative degenerative disease. Currently, cholinesterase inhibitors (donepezil, carboplatin, galantamine) and Pure memantine HCl are approved for the treatment of Alzheimer's disease.

Pure memantine HCl is primarily used in the treatment of dementia in Alzheimer's disease (AD), particularly moderate to severe Alzheimer's-type dementia. It is a novel, low-moderate affinity, voltage-dependent, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, which is able to reduce glutamate-induced NMDA receptor hyperexcitability and prevent apoptosis by non-competitive blockade of the NMDA receptor, thereby improving memory.

In addition, Memantine HCl can also be used for the treatment of Parkinson's disease or Parkinson's syndrome, etc. However, Memantine HCl is not suitable for all conditions. People with epilepsy and susceptibility to epilepsy, those with a history of convulsions, renal insufficiency, mild to moderate hepatic insufficiency, patients with severe psychiatric disorders, as well as those with cardiovascular disorders need to be cautious about the use of this medication. It is also contraindicated in people who are allergic to the active ingredient of the product or its excipients, as well as in people with severe hepatic insufficiency.

There are two commonly used specifications: Memantine hcl 5 mg and memantine hcl 10 mg.

Memantine Hydrochloride, as a non competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has become one of the core drugs for treating neurodegenerative diseases worldwide since its approval by the European Medicines Agency (EMA) in 2002 and certification by the US Food and Drug Administration (FDA) in 2003. Its unique pharmacological mechanism - by regulating the balance of glutamatergic neurotransmission, it not only inhibits neurotoxicity caused by excessive excitation, but also preserves the physiological functions required for normal learning and memory, making it an important treatment for Alzheimer's disease (AD) and related cognitive disorders.

Core indication: Whole course management of Alzheimer's disease

 

1. Frontline treatment for moderate to severe Alzheimer's disease
Pure memantine hcl is the first NMDA receptor antagonist approved by the FDA for the treatment of moderate to severe Alzheimer's disease, and its efficacy has been validated through multiple phase III clinical trials. For example, a randomized controlled trial involving 252 patients with moderate to severe Alzheimer's disease showed that after 24 weeks of continuous use of 20mg/day metformin hydrochloride, patients' cognitive function score (ADAS Cog) improved by 2.1 points compared to baseline, and their daily living ability scale (ADCS-ADL) score increased by 1.8 points, significantly better than the placebo group. Its mechanism of action lies in:

 

Inhibition of glutamate excitotoxicity: In AD patients, there is an abnormal increase in glutamate levels in the brain, which leads to overactivation of NMDA receptors and overload of calcium ion influx, triggering neuronal apoptosis. Meijingang reduces calcium ion influx and protects neuronal structural integrity by non competitive blockade of receptor channels.
Regulating neurotransmitter balance: In AD patients, the degeneration of the cholinergic system leads to a deficiency of acetylcholine (ACh), and memantine can increase the release of presynaptic membrane ACh and enhance the sensitivity of postsynaptic membrane NMDA receptors to ACh, forming a "glutamate cholinergic" synergistic regulatory effect.

 

2. Early intervention for mild to moderate Alzheimer's disease
Although initially approved for moderate to severe AD, subsequent studies have confirmed its early intervention value. A multicenter trial involving 403 patients with mild to moderate AD showed that after 12 months of combined use of memantine (20mg/day) and cholinesterase inhibitors (such as donepezil), patients' cognitive function scores improved by an additional 1.5 points compared to the monotherapy group, and the incidence of psychological and behavioral symptoms (such as anxiety and agitation) decreased by 32%. This suggests that Meijingang can delay disease progression through multi-target regulation, especially suitable for patients with rapidly progressing AD.

 

3. Adjuvant treatment for vascular dementia
Vascular dementia (VaD) is caused by cerebrovascular disease and often coexists with AD pathology (mixed dementia). The therapeutic effect of Meijingang in VaD stems from its dual role:
Improving cerebral hemodynamics: By regulating NMDA receptors in endothelial cells, inhibiting vascular spasm caused by calcium overload, and increasing cerebral blood flow.
Inhibit neuroinflammation: reduce the activation of microglia, decrease the release of inflammatory factors (such as IL-1 β, TNF - α), and protect neurovascular units.
A trial involving 321 VaD patients showed that after 6 months of treatment with memantine, the MMSE score of patients increased by 1.2 points, and the improvement rate of daily living ability reached 45%, significantly better than the control group.

Extended application: cognitive enhancement across disease domains

 

1. Parkinson's disease dementia (PDD) and Lewy body dementia (DLB)
PDD and DLB are characterized by cognitive fluctuations, visual hallucinations, and motor disorders, and their pathological mechanisms involve an imbalance of the cholinergic glutamatergic system. Meijingang improves visual hallucinations (28% reduction in incidence) and cognitive fluctuations (40% reduction in duration) by antagonizing D4 dopamine receptors and reducing excessive activation of the prefrontal cortex. An open label study targeting DLB patients showed that after 12 weeks of treatment with memantine, the Neuropsychiatric Inventory (NPI) score decreased from 28.5 to 18.2 without worsening motor symptoms.

 

2. Cognitive impairment after traumatic brain injury (TBI)
Long term cognitive impairment after TBI is closely related to glutamate excitotoxicity. Meijingang has been shown to reduce hippocampal neuron death and improve spatial memory ability in TBI animal models. In clinical studies, patients with mild TBI showed a 15% increase in attention test scores and a 22% decrease in working memory error rates after using Mexicam (10mg/day) for 3 months.

 

3. Cognitive impairment in schizophrenia
Schizophrenia patients have cognitive deficits such as working memory and executive function, which are partially related to insufficient glutamatergic transmission in the prefrontal cortex. Meijingang improves cognitive flexibility (such as increasing the accuracy of Wisconsin Card Sorting Test by 18%) and attention persistence (shortening the response time of continuous operation tasks by 120ms) by enhancing the function of NMDA receptors in the prefrontal cortex. It should be noted that its antipsychotic effect is weak and is usually used as an adjuvant therapy.

Pure memantine HCl was synthesized by seven main methods, and the following is the main statement of the synthetic route by acetonitrile method.

 (1)1-Bromo-3,5-dimethyladamantane was obtained by substituting 1,3-dimethyladamantane with bromine.

 (2)Then acetamidated to obtain 1-acetamido-3,5-dimethyladamantane.

 (3)Hydrolyzed under alkaline conditions.

 (4)Acidification to a salt, Memantine HCl.

Catalyst and temperature are two important factors in the synthesis of Memantine HCl by acetonitrile method. Catalyst is mainly used to promote the reaction rate and increase the yield and purity of the product. For the acetonitrile method, concentrated sulfuric acid is usually used as a catalyst because it can effectively promote the amidation reaction.

As for the temperature, it affects the rate of the reaction and the quality of the product. In the process of synthesizing Memantine HCl by acetonitrile method, the temperature of the reaction needs to be controlled to ensure that the reaction can be carried out smoothly, and at the same time to avoid too high temperature leading to the occurrence of side reactions. The specific reaction temperature may vary according to the specific reaction conditions and raw materials used, so it needs to be adjusted according to the experimental conditions in the actual operation.

In addition, the following points need to be noted during the synthesis process:

• The quality and purity of the raw materials have a great influence on the quality and yield of the final product, so high-quality raw materials need to be selected.
• During the reaction process, the reaction time and reaction conditions need to be strictly controlled to ensure the completeness of the reaction and the purity of the product.
• For the waste gas, waste liquid and solid waste generated, reasonable treatment is needed to prevent harm to the environment and human body.

It should be noted that although the acetonitrile method is an effective method for the synthesis of Memantine HCl, it may need to be adjusted and optimized according to the specific situation in practice.

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