Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective NK1 antagonists

Abstract Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK 1 antagonists that includes 3 and 4 . Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK 1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1- b ][1,5]oxazocine, 17 , was found to contain the optimal ring tether size (8) for retaining NK 1 activity, was more NK 1 versus NK 2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32 , which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2- f ][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK 1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK 1 pharmacophore model and present a further refinement of that model.