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Abstract

The structural requirements for strong ganglion-blocking activity and long duration of action amongst some lower homologues of mecamylamine, together with the discovery of similar activities amongst isomers with enlarged ring structures, are described. In both series of compounds it was found that the successive introduction of C-methyl groups surrounding the nitrogen atom resulted in a progressive increase in ganglion-blocking activity and duration of action.The pharmacology of the potent ganglionblocking compound pempidine, 1,2,2,6,6-pentamethylpiperidine, has recently been described (Corne and Edge, 1958; Spinks, Young, Farrington, and Dunlop, 1958).The independent discovery of the properties of this compound by Spinks and Young (1958) originated from their observation that secondary and tertiary aliphatic amines in which the basic group is sterically hindered by attachment to a tertiary carbon atom have a modest level of ganglion-blocking activity.By contrast, we first studied structure-activity relationships amongst certain aminobicyclo[2,2,1]heptanes which were lower homologues of R=H or alkyl aminobicyclo-[2,2,1]heptanes. N atom is exocyclic bicyclo[3,2,1 ]azaoctanes. N atom is endocyclic mecamylamine. During this work we unexpectedly encountered a chemical route to bicyclo[3,2,1]azaoctanes, isomeric compounds in