Synthesis and analgetic activity of some 5-aryl-2-azabicyclo[3.2.1]octanes

Abstract

A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.

A Facile Synthesis of a Polyhydroxylated 2-Azabicyclo[3.2.1]octane

“…Remarkably few examples of this ring system have been reported. , While the synthesis of the trans -6,7-diol [3.2.1] azabicycle has been reported, the route is low yielding and does not allow for the introduction of the 4-hydroxyl group. An alternative synthesis prepared a lactone derivative of 3 , which incorporated the 4-hydroxyl group, but the synthesis is quite long and low yielding .…”

Intramolecular Michael-type additions. IV. Synthesis of 2-azabicyclo[3.2.1]oct-3-enes from 4-chloroalkyl-1,4-dihydropyridines

“…Only saturated derivatives appear to have been evaluated for pharmacological activity, prompted by structural relationships to pempidine (26) or the benzomorphan system (27). Reports describe assessment of hypotensive (28,29), analgesic (30)(31)(32), narcotic antagonist (27), and ganglionblocking activity (26).…”