Synthesis and cyclooxygenase inhibitory properties of novel (+) 2-(6-methoxy-2-naphthyl)propanoic acid (naproxene) derivatives

Halomethylation of naproxene (1) occurs regioselectively in position 5 and subsequently - in situ or on treatment with silver nitrate - leads to napro xene-"dimers" with two naproxene units, 5,5'-connected through a ethenylene (3) and a methylene (4) bridge, respectively. Two of the new naproxene der ivatives were screened for their cyclooxygenase inhibitory properties relat ive to naproxene. Both 5-chloromethyl naproxene (2) and 2-(5-((carboxyethyl )-2-methyloxynaphthyl) -6-methoxy-2-naphthyl)propanoic acid (4) were inacti ve in the concentration range of 0.1-10 mu mole against both COX-1 and COX- 2, indicating that bulky substituents in position 5 in naproxene are unfavo urable for both COX-1 and COX-2 inhibition.