Pure Appl. Chem., 2005, Vol. 77, No. 12, pp. 2041-2045
doi: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.
Keywords: antinociceptive; Fused azetidines; neuronal nicotinic receptors; NNR agonists; NNR-based analgesics.