Azasteroids as inhibitors of rat prostatic 5 alpha-reductase

• Published in: Journal of medicinal chemistry Vol. 27; no. 12; pp. 1690 - 1701
• Main Authors: Rasmusson, G H, Reynolds, G F, Utne, T, Jobson, R B, Primka, R L, Berman, C, Brooks, J R
• Format: Journal Article
• Language: English
• Published: United States 01.12.1984
• Subjects: 5-alpha Reductase Inhibitors; Animals; Azasteroids - chemical synthesis; Azasteroids - pharmacology; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Optical Rotation; Oxidoreductases - antagonists & inhibitors; Prostate - enzymology; Rats; Steroids, Heterocyclic - chemical synthesis; Structure-Activity Relationship; X-Ray Diffraction
• ISSN: 0022-2623
• DOI: 10.1021/jm00378a028

A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).