A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors

Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor (TM) led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene gamma-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a gamma-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering A beta 40-42, compared to their parent compounds. (c) 2012 Elsevier Ltd. All rights reserved.