Dual neurokinin NK 1/NK 2 antagonists: N-[( R, R)-( E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl- N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[ N′-3,5-bis(trifluoromethyl)benzoyl- N-arylmethyl- N′-methylhydrazino]- N-[( R)-2-oxo-azepan-3-yl]propionamides

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(trifluoromethyl)benzamide ( 1), attempts to improve the NK 2 affinity have resulted in the discovery of N-[( R,R)-( E)-1-(3,4-dichlorobenzyl)-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′-3,5-bis(trifluoromethyl)benzoyl- N-(3,4-dichlorobenzyl)- N′-methylhydrazino]- N-[( R)-2-oxo-azepan-3-yl]propionamide ( 22), a potent and fairly balanced NK 1/NK 2 antagonist.