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

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.