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Recent advances in process development of antiviral agents targeting the influenza virus: Amantadine-Remantadine-derived pharmaceutical agents.

Krishna SarmaPathy

This review summarizes our work on the process development for synthesis of amontidineremantadine. The presented publications have been sorted according to five basic criteria. Influenza is a serious infectious disease, which is life-threatening especially in children, seniors and immunocompromised patients. In addition to vaccination, the development of new anti-influenza agents represents a crucial defense strategy to combat seasonal and pandemic influenza strains. At present most attention is paid to the development of inhibitors of influenza neuraminidase, which has been established as a key drug target for the prophylaxis and treatment of influenza infections. However, the emergence of drug-resistant influenza variants highlights the need of continuously innovative strategies for the development of new drugs with improved antiviral effects, higher safety and increased tolerability. The M2 proton channel of the Influenza A virus is the target of the anti-influenza drugs amantadine and rimantadine. The effectiveness of these drugs has been dramatically limited by the rapid spread of drug resistant mutations, mainly at sites S31N, V27A and L26F in the pore of the channel. Despite progress in designing inhibitors of V27A and L26F M2, there are currently no drugs targeting these mutated channels in clinical trials. The article traces the evolution of various synthesis approaches and provides a comparison for overall yield efficiency. Amantadine hydrochloride is an antiviral drug used in prevention and treatment of influenza A infections. It has also been used for alleviating early symptoms of Parkinson’s disease. Several methods for the preparation of Amantadine hydrochloride have been reported overall yields ranging from 50% to 52%. In this article, we describe procedure for the synthesis of Amantadine hydrochloride from N-(1-adamantyl)acetamide with an improved yield of 60%. The procedure was also optimized to reduce the use of toxic solvents and reagents, rendering it more environmentfriendly. The procedure can be considered as suitable for large-scale production of amantadine hydrochloride.