Study On Design And Synthesis Of Memantine Hydrochloride And Its Derivatives

Alzheimer's disease (AD) is a neurodegenerative disease, which seriously affects old people's health and quality of lives. In recent years, more attentions are paided on the study and development for these drugs, but it is still one of serious challenges that drug studies encount because the pathogenesis of AD is uncertain.Memantine hydrochloride, which is uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with middle affinity and can protect neurocyte from overexcitation caused by glutamic acid, is used for moderate and severe AD. Some problems, e.g., high energy consumption, high pollution and high costs, exist in the preparation of memantine hydrochloride. In order to resolve these problems, we designed a novel preparation routine comprised by nitration, reduction and salification instead of previous four-step process (halogenation, Ritter reation, hydrolysis and salification). The conditions of nitration were optimized by orthogonal experimental design, and the total yield of memantine hydrochloride reached 80.87%.Some nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce inflammation and formation of senile plaque in AD brains. However, long-term use of NSAIDs will lead to serious gastrointestinal side effects. Target compounds I and IV had been designed by coupling memantine and NSAIDs directly or with linker applying principle of hybridization. In order to increase the capabilities of drugs through the blood-brain barrier, II and III were designed by means of amino acid-specific carrier-mediated transport system. Sixteen novel compounds had been synthesized and their structures were identified by 1HNMR, IR and HR-MS. Many efforts had been made to synthesize target compounds and to study the mechanism by which some byproducts formed.