Dual neurokinin NK1/NK2 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.