Cyclooxygenase 2 COX-2 Inhibitor NSAIDs

The discovery that a subtype cycloxygenase enzyme, COX-2, does not inhibit the formation of stomach-protecting prostaglandins paved the way for a series of NSAIDS whose stracmres depart markedly from the carboxylic acid-based drugs 

The nucleus of the one-time widely prescribed prescribed COX-2 inhibitor, rofecoxib, better known by its trade name Vioxx , actually comprises a butenolide rather than a classical heterocycle. The drug was withdrawn from the market at full flood due to an unexpectedly high incidence of adverse cardiovascular side effects. The compound is included at this point to emphasize the breadth of the SAR for COX-2 anti-inflammatory agents. Reaction of phenylacetic acid (35-1) with ethyl bro-moacetate in the presence of triethylamine leads to the formation of the ester (35-2). Treatment of that intermediate with a strong base generates a carbanion at the benzyhc position in an intramolecular reaction, this attacks the terminal ester carbonyl to yield the butenolide (35-3). Reaction of that compound with triflic anhydride converts the 

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