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 (4aR,8S,8aR)-6-oxo-8-phenylperhydro-1,4-ethano-1,5-naphthyridine and (4aR,7R,8R,8aR)-7,8-diphenylperhydro-1,4-ethano-1,5-naphthyridine

Abstract

Derivatives of perhydro-1,4-ethano-1,5-naphthyridine and 4,7-ethanopyrrolo[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 material: (i) heterocyclizations of compound 1 with N-(carbamoylmethyl)pyridinium chloride gave unsaturated pyridone derivatives which, after catalytic hydrogenation, afforded 1,5-naphthyridines, and (ii) functionalization of compound 1 by nucleophilic 1,4-addition reactions, followed by reductive cyclizations, gave quinuclidine derivatives with fused five- or six-membered rings. The cyclization reactions proceeded stereoselectively and the relative stereochemistries were determined by a combination of molecular mechanics calculations. X-Ray crystallography, and NMR spectroscopy. The biological activities of the synthesized derivatives were evaluated by binding studies to human NK1-receptors in UC11MG cells. The compounds had low to moderate affinity for the NK1-receptor.