LUMIRACOXIB

Description

Lumiracoxib, a selective COX-2 inhibitor discovered and developed by Novartis, was approved in September, 2003 in the UK for the symptomatic relief of osteoarthritis and short term relief of moderate to severe acute pain associated with primary dysmenorrhea, dental surgery and orthopedic surgery. After an initial not approvable letter issued by FDA in September 2003, Novartis expects to re-submit a NDA by early 2006 following the completion of several studies requested by FDA.

Uses

Treatment of rheumatoid arthritis, osteoarthritis, and pain prevention.

Uses

Lumiracoxib is a selective cyclooxygenase-2-(COX-2) inhibitor and an anti-inflammatory agent (1,2,3,4).

Pharmacokinetics

Lumiracoxib is rapidly absorbed, with an oral bioavailability of 74%, and reaches a maximum plasma concentration 2 hour after dosing. It is highly plasma protein bound and has a short elimination half-life of approximately 4 hours, demonstrating linear plasma pharmacokinetics with no accumulation during multiple dosing.

Clinical Use

Lumiracoxib is a selective COX-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. It structurally differs from the other selective COX-2 inhibitors in being a phenylacetic acid with a carboxylic acid group (pKa = 4.7).

Synthesis

Since the original patent on the discovery of lumiracoxib (XIV) disclosed the first synthesis of this compound, several approaches to the synthesis of lumiracoxib (XIV) have been detailed in the subsequent process patent. In all the routes, the key to the synthesis was the ring opening of lactam 121. Coupling of pbromotoluene (116) with 2-chloro-6-fluoroaniline (117) in the presence of palladium catalyst Pd(dba)3, tributyl phosphine and sodium t-butoxide in toluene provided aniline intermediate 118 . Acylation with chloroacetylchloride (119) at 90°C neat gave chloride intermediate 120. Cyclization in the presence of aluminum chloride at 160 to 170°C gave the key lactam 121, which was subsequently opened with sodium hydroxide in boiling ethanol water mixture to provide lumiracoxib (XIV).

Metabolism

Lumiracoxib is extensively metabolized involving oxidation of its 5-Me group and 4′-hydroxylation of the dihalogenated aromatic ring. The major in vitro oxidative pathways is catalyzed primarily by CYP2C9. Lumiracoxib and its metabolites are excreted via renal and fecal routes in approximately equal amounts. The COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. As with other selective coxibs, lumiracoxib exhibits a reduced incidence of gastroduodenal erosions compared with that of naproxen. It was approved for use in the United Kingdom and the United States in 2007.

Raw materials

Preparation Products