Steroidal Antiandrogens and 5α-Reductase Inhibitors

Abstract

The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high inhibitory activity for the enzyme 5α-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5α-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5α-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5α-reductase inhibitor, has greatly alleviated the symptons associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone ·or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and aproximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17α­acyloyloxy-6-halo (chloro, bromo) 16 β-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5α-reductase inhibitors and showed a slightly higher inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperlasia. In another study we synthesized several new 4-halo (bromo and chloro) 17α-benzoyloxy and also 4-halo-17α-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17a-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17a-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17α-acetoxy (58, 59) and the 17α-benzoyloxy-4-chloro analog 63 showed a very high inhibitory activity for the enzyme 5α-reductase type 2 "figure 15".