Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5 alpha-androstan-3-ones as inhibitors of human 5 alpha-reductases and antagonists of the androgen receptor.

A number of 17β-(N-alkyl/arylformamido)- and 17β-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5α-steroids were prepared from 17β-hydroxy-4-azasteroids and evaluated as inhibitors of human 5α-reductase and antagonists of the androgen receptor. Jones' oxidation of 17β-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc) 3 /NaBH 3 CN to give 17β-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH 4 . Formylation of amines 10-27 gave 17β-(N-alkylformamides) 28-41; however, acylation afforded 17β-(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide (4-MA; IC 50 =4.15 nM), 17β-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5α-reductase, IC 50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type 1 enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC 50 s=9.57 and 16-9 nM, respectively), showed also strong inhibitory activity (IC 50 s=14.0 and 18-4 nM, respectively) for human type II 5α-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide (MK-906; IC 50 s=4.53 nM). Other compounds in this series showed moderate activities (IC 50 >100 nM) on the typeII enzyme-17β-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5α-reductase with IC 50 s of 1.77, 2.42, 2-93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107). The inhibition of DHT action on the proliferation of the androgen-sensitive cancer cells by formamido compounds showed moderate to good activity, IC 50 values ranging from 45 to 100 nM as compared to hydroxyflutamide (IC 50 =52.5 nM)