SYNTHESIS OF NEW STEROIDAL ISOXAZOLES - INHIBITORS OF ESTROGEN SYNTHASE

A novel class of steroidal A/B ring isoxazoles have been prepared by t wo independent reaction schemes using 3 beta,17 beta-diacetoxyandrost- 5-ene (1) and 3 beta,17 beta-diacetoxyandrost-4-en-6-one (4) as synthe tic precursors. The key common intermediate in these syntheses, 3 beta ,17 beta-diacetoxyandrost-4-eno[6,5,4-c,d] isoxazole (3), was prepared by synthetic methods described in both schemes. Further chemical modi fication of 3 yielded 3 beta,17 beta-dihydroxyandrost-4-eno[6,5,4-c,d] isoxazole (6), androst-3,17-dione-4-eno[6,5,4-c,d] isoxazole (7), and 17 beta-hydroxyandrost-3-one-4-eno[6,5,4-c,d] isoxazole (9). Human pl acental estrogen synthase (aromatase) bioassays were conducted to obta in the following IC50 values resulting from a 50% reduction of enzymat ic activity: 6, 120.5 mu M; 7, 1.889 mu M. 9, 18.57 mu M. (C) 1998 Els evier Science Ltd. All rights reserved.