SYNTHESIS OF PERHYDRO-1,4-ETHANO-1,5-NAPHTHYRIDINE AND PERHYDRO-4,7-ETHANOPYRROLO[3,2-B]PYRIDINE DERIVATIVES - POTENTIAL NK1-RECEPTOR ANTAGONISTS - X-RAY MOLECULAR-STRUCTURES OF -OXO-8-PHENYLPERHYDRO-1,4-ETHANO-1,5-NAPHTHYRIDINE AND -7,8-DIPHENYLPERHYDRO-1,4-ETHANO-1,5-NAPHTHYRIDINE

Derivatives of perhydro-1,4-ethano-1,5-naphthyridine and 4.7-ethanopyr rolo[3.2-b]pyridine were designed and synthesized as conformationally constrained analogues of the potent NK1-receptor antagonist CP-96,345. 2-Benzylidenequinuclidin-3-one 1 was used as the common starting mate rial: (i) heterocyclizations of compound 1 with N-(carbamoylmethyl)pyr idinium chloride gave unsaturated pyridone derivatives which, after ca talytic hydrogenation, afforded 1,5-naphthyridines, and (ii) functiona lization of compound 1 by nucleophilic 1.4-addition reactions, followe d by reductive cyclizations, gave quinuclidine derivatives with fused five- or six-membered rings. The cyclization reactions proceeded stere oselectively and the relative stereochemistries were determined by a c ombination of molecular mechanics calculations, X-ray crystallography, and NMR spectroscopy. The biological activities of the synthesized de rivatives were evaluated by binding studies to human NK1-receptors in UC11MG cells. The compounds had low to moderate affinity for the NK1-r eceptor.