AROMATASE INHIBITORS - SYNTHESES AND STRUCTURE-ACTIVITY STUDIES OF NOVEL PYRIDYL-SUBSTITUTED INDANONES, INDANS, AND TETRALINS

The (E)-2-(4-pyridylmethylene)-1-indanones (E)-1-(E)-5[(E)-1, H; (E);2 , 4-OCH3; (E)-3, 5-OCH3; (E)-4, 4-OH; (E)-5,5-OH] were obtained by ald ol condensation of the corresponding 1-indanones with 4-pyridinecarbox aldehyde, and in case of the OH compound (E)-4 subsequent ether cleava ge of (E)-2. The synthesis of the (Z)-isomers (Z)-1-(Z)-3 [(Z)-1, H; ( Z)-2, 4-OCH3; (Z)-3, 5-OCH3] was accomplished by UV irradiation of the corresponding (E)-isomers. Catalytic hydrogenation of (E)-1-(E)-3 gav e the 2-(4-pyridylmethyl)-1-indanones 6-8 (6, H; 7, 4-OCH3; 8, 5-OCH3) . The 2-(4-pyridylmethyl)-substituted indans 11-13 (11, H; 12, 4-OCH3; 13, 5-OCH3) and the tetralins 16-19 (16, H; 17, 5-OCH3; 18, 6-OCH3; 1 9, 7-OCH3) were obtained by reduction of the corresponding ketones usi ng N2H4/KOH. The 2-(4-pyridylmethyl)-substituted indanones 9 (4-OH) an d 10 (5-OH), indans 14 (4-OH) and 15 (5-OH), and tetralins 20-22 (20, 5-OH; 21, 6-OH; 22, 7-OH) were synthesized by ether cleavage of the co rresponding OCH3 compounds. All compounds showed inhibition of human p lacental aromatase exhibiting relative potencies from 0.9 [(E)-4] to 1 63 [18; aminoglutethimide (AC) potency E 1]. Compounds 13 and 18 showe d competitive type of inhibition and a type II difference spectrum, in dicating the interaction of the pyridyl-N with the central Fe(III) ion of the cytochrome P450 heme component. Only the OH-substituted indans and tetralins inhibited bovine adrenal desmolase with maximum activit y shown by 20 and 22 (12% inhibition, 25 mu M; AG, 53 % inhibition, 25 mu M). In vivo, however, all tested aromatase inhibitors (6, 8, 10, 1 4, 15, 18 and 20) were less active than AG concerning the inhibition o f the uterotrophic activity of androstenedione (6, 8, 10, 15), the red uction of the plasma estradiol concentration (14, 20), and the mammary carcinoma (MC) inhibiting properties (18, 20; androstenedione-stimula ted juvenile rats, pregnant mares' serum gonadotropin-primed rats as w ell as dimethylbenzanthracene-induced MC of the Sprague-Dawley rat, po stmenopausal experiment). Since no affinity to the estrogen receptor w as demonstrated (20), estrogenic effects as a cause for the poor tumor inhibiting activity have to be excluded.