No abstract

With the aim of developing new radioligands for in vivo studies of substance P receptors using positron emission tomography or single photon emission computed tomography, 2- and 3-halo naphthyridone-6-carboxamide derivatives were synthesized. Their affinities toward the target receptors were evaluated on CHO cells and compared to the unsubstituted analogue EP 00652218 (IC(50) = 100 nM +/- 20). The IC(50) value was not altered in the case of 2-chloro compound 1 (IC(50) = 100 nM +/- 15) and only slightly reduced for the 2-fluoro and -iodo analogues 6 and 8 (IC(50) = 500 nM +/- 80). A drastic reduction in binding (IC(50)> 1000 nM) was observed for the halogenated compounds 2-5, 7, and 9.

Pyridine-2,3-dicarboxylic acids bearing an halogen in the position a or b to the nitrogen atom were synthesized by oxidation of the corresponding quinolines. Two methods, using either ozone followed by hydrogen peroxide or ruthenium tetroxide under catalytic conditions were used. Diacids 1b,c and 2a-c substituted in 6-position by a chlorine or bromine and in 5-position by a fluorine, chloride or bromine, respectively, were isolated in yields ranging from 46-71%. Yields of 6-fluoro and 6-or 5-iodo diacids 1a,d and 2d did not exceed 30%.