Title of article :
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]propionamid
Author/Authors :
Marc Gerspacher، نويسنده , , Luigi La Vecchia، نويسنده , , Robert Mah، نويسنده , , Andreas von Sprecher، نويسنده , , Gary P. Anderson، نويسنده , , Natarajan Subramanian، نويسنده , , Kathleen Hauser، نويسنده , , Heinrich Bammerlin، نويسنده , , Sabine Kimmel، نويسنده , , Viviane Pawelzik، نويسنده , , Karin Ryffel، نويسنده , , Howard A. Ball، نويسنده ,
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 NK2 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 NK2 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 NK1/NK2 antagonist.
