Discovery of fused azetidines as novel selective α4β2 neuronal nicotinic receptor (NNR) agonists

Ji, Jianguo; Bunnelle, William H.; Li, Tao; Pace, Jennifer M.; Schrimpf, Michael R.; Sippy, Kevin B.; Anderson, David J.; Meyer, Michael D.

doi:10.1351/pac200577122041

Pure Appl. Chem., 2005, Vol. 77, No. 12, pp. 2041-2045

http://dx.doi.org/10.1351/pac200577122041

Discovery of fused azetidines as novel selective α4β2 neuronal nicotinic receptor (NNR) agonists

Jianguo Ji, William H. Bunnelle, Tao Li, Jennifer M. Pace, Michael R. Schrimpf, Kevin B. Sippy, David J. Anderson and Michael D. Meyer

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept. R47W, Bldg. AP9A, Abbott Park, IL 60064, USA

Abstract: An efficient synthesis of (1R,5S)-6-(5-cyano-3-pyridinyl)-3,6-diaza-bicyclo[3.2.0]heptane A-366833, a novel potent selective neuronal nicotinic receptor (NNR) agonist, is described. The enantiomerically pure pharmacophore benzyl (1S,5S)-3,6-diaza-bicyclo[3.2.0]heptane-3-carbamate was successfully constructed from benzyl N-allyl-N-(2-hydroxyimino-ethyl)-carbamate through a convenient approach including an intramolecular [1,3]-dipolar cycloaddition, reductive ring-opening reaction, chiral resolution, and intramolecular cyclization. Subsequent N-arylation of the pharmacophore with 3-bromo-5-cyanopyridine and N-Cbz deprotection with trifluoroacetic acid furnished A-366833.