Stereoselective preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a potent and orally active dual neurokinin NK(1)/NK(2) receptor antagonist.

In a program aimed at the development of neurokinin antagonists, N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK(1)/NK(2) receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-d-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK(1) (pK(i) = 8.38) and NK(2) (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK(1) and NK(2) receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.