SYNTHESIS OF NOVEL OXIMES OF 2-ARYL-6-METHOXY-3,4-DIHYDRONAPHTHALENE AND THEIR EVALUATION AS INHIBITORS OF 17-ALPHA-HYDROXYLASE-C17,20-LYASE (P450-17)

The synthesis and biological evaluation of oximes of 2-aryl-6-methoxy- 3,4-dihydronaphthalene (7a, 7b, 14a, 14b) as nonsteroidal inhibitors o f 17 alpha-hydroxylase-C17,20-lyase (P450 17, CYP 17) is described. Th e target compounds were synthesized and identified by H-1 NMR and MS. The preparation of the key intermediates 5a and 5b was accomplished by coupling 4a and 4b with 1 ,4-dihydronaphthalene-2-trifluoromethanesul fonate) using the palladium complex Pd(PPh3)(4) as catalyst. Hydrolysi s of 5a and 5b in THF-HCl solution at room temperature gave the corres ponding keto compounds 6a and 6b. The other important intermediates - the substituted (E)-2-methylene-1-tetralones 10a and 10b - were obtain ed by condensation of 1-tetralone with the corresponding aromatic alde hydes (9a and 9b). Hydrogenation (H-2), followed by reduction (NaBH4), and subsequent hydrolysis and elimination led to the keto compounds 1 3a and 13b. The title compounds, the oximes 7a, 7b and 14a, 14b were f ormed by reaction of hydroxylamine hydrochloride with the correspondin g keto compounds. Using a microsomal fraction of human testicular enzy me, 7a, 7b, 14a, and 14b inhibited the target enzyme only marginally.