Potent nonsteroidal progesterone receptor agonists: Synthesis and SAR study of 6-aryl benzoxazines

Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists. the 6-aryl benzoxazines were potent PR agonists. Compounds 4e. 5b, and 6a wish the 2.4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonist in the series with subnanomolar activities (EC50 0.20-0.35 nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED50 of 1.5 mg/kg (vs 5.62 mg/kg for P4). (C) 2002 Elsevier Science Ltd. All rights reserved.