Novel Valdecoxib Derivates by Ruthenium-catalyzed 1,3-Dipolar Cycloaddition of Nitrile Oxides with Alkynes - Synthesis and COX-2 Inhibition Affinity.

Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven, partly novel aryl alkynes. Application of Ru(II)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC50=0.042–0.073 µM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl-substituted compounds displayed almost no COX activity. The application of fluoro-substituted nitrile oxides resulted in enhanced COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers for positron emission tomography.