Dual Neurokinin NK 1 / NK 2 Antagonists : N- [( R , R ) - ( E ) -1-

Abstract

Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(tri-fluoromethyl)benzamide (1), attempts to improve the NK 2 affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichloro-benzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK 2 receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N 0-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N 0-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK 1 /NK 2 antagonist. #