Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2<i>S</i>,3<i>R</i>)-3-(3,4- Difluorophenyl)-2-(4-fluorophenyl)-4- hydroxy-<i>N</i>-((3<i>S</i>)-1-methyl-2-oxo-5- phenyl-2,3-dihydro-1<i>H</i>-benzo[<i>e</i>][1,4]- diazepin-3-yl)butyramide by Use of an Asymmetric Ireland−Claisen Rearrangement

Abstract

Novel benzodiazepine-containing gamma-secretase inhibitors for potential use in Alzheimer's disease have been designed that incorporate a substituted hydrocinnamide C-3 side chain. A syn combination of alpha-alkyl or aryl and beta-hydroxy or hydroxymethyl substituents was shown to give highly potent compounds. In particular, (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyramide (34) demonstrated excellent in vitro potency (IC(50) = 0.06 nM). 34 could also be selectively methylated to give [(3)H]-28, which is of use in radioligand binding assays.