Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

No abstract

No abstract

No abstract

Oxidative ring closure of alkyl-substituted 2-hydroxyacetophenone trifluoromethanesulfonate esters (triflates) occurs upon exposure to base in anaerobic DMF at 20-90 degrees C. Alkyl substitution is required for ring closure. A migrated enol triflate product forms at lower temperature in high yield via migration of the trifluoromethanesulfonate in the unsubstituted and monoalkyl-substituted cases. The alkyl-substituted enol triflates also enter into the benzofuran-3-one ring-forming process under thermal cyclization conditions. Potential mechanistic pathways are evaluated.