Enantioselective Synthesis of Antiinfluenza Compound A-315675

Abstract

Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.

Activity of the Oral Neuraminidase Inhibitor A-322278 against the Oseltamivir-Resistant H274Y (A/H1N1) Influenza Virus Mutant in Mice

“…Two commercially available NA inhibitors, inhaled zanamivir and oral oseltamivir, have demonstrated clinical benefits in the prevention and treatment of seasonal influenza virus infections (1), whereas others are at some stage of development. Among the agents under development is a pyrrolidine-based compound from Abbott Laboratories (A-315675) that showed in vitro activity similar to that of zanamivir and oseltamivir when tested against influenza A (N1, N2, and N9 subtypes) and B viruses (5,9). In addition, A-315675 retains activity against influenza A/H1N1 viruses containing the oseltamivir resistance NA mutations H274Y and N294S, as well as NA enzymes of A/H3N2 viruses containing the oseltamivir resistance NA mutations E119V and N294S.…”

Impact of Reaction Dynamics on Synthesis of Novel Nitrogen containing Aldehydes

“…There are many nitrogen containing chemicals, ranging from simple structural compounds as pyridine to complicated compounds as pharmaceutical ingredients and their number is growing rapidly year by year 2 .Pyrrolidine based compounds have wide application in pharmaceutics ranging from use in the treatment of cancer 3 ,obesity 4 , fungal and viral infections 5 , HIV infection 6 and diabetes [7][8] .Piperazine nucleus is one of the most important heterocycle, exhibiting remarkable pharmacological activities as anthelminitis 9 , anti-HIV agent, antanginals 10 , urological 11 15 . Piperidine is also commonly used in sequencing of DNA 16 and in solid phase peptide synthesis 17 .…”

Efficacy of neuraminidase (NA) inhibitors against H1N1 strains of different geographical regions: an in silico approach

“…Two available NA inhibitors, zanamivir and oseltamivir have been found effective against seasonal infl uenza virus infection [6]. More inhibitors are in the stage of development like pyrrolidine-based compound from Abbott laboratories (A 315675) showing in vitro activity similar to that of zanamivir and oseltamivir against different strains (N1, N2, N9 subtypes) of infl uenza A viruses and B viruses [7,8].…”