Azasteroids as inhibitors of rat prostatic 5.alpha.-reductase

Abstract

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).

Synthesis of 5,6,6-[2H3]finasteride and quantitative determination of finasteride in human plasma at picogram level by an isotope-dilution mass spectrometric method

“…In the first step three deuterium atoms were introduced: first at position 6 by isotopic exchange in 2H20 and CH3COOEH and then at position 5 and 6 by reduction with 2H 2 of the 5-6 double bound. The IR, IH-NMR, ~3C-NMR and MS spectra of deuterated compound 1 were identical with the spectra reported for the hydrogenated compound [1,12]. The molecular ion in the MS spectrum at 322 m/z, the absence in the ~3C-NMR spectrum of the C5 and C6 signals at 60.03 and 26.54 ppm, respectively, and the lack in the 1H-NMR spectrum of the signal at 2.95 ppm corresponding to the H-C5 hydrogen are consistent with the introduction of three deuterium atoms at the positions 5,6,6.…”

“…3-Oxo-4-aza-5-androstene-17fl-carboxylic acid (0.81 g, 2.55 mmol), prepared according to the procedure described by Rasmusson et al [1,12] was stirred in 2H20 for 16 h at room temperature and, after filtration, in CH3COO2H (12 ml) for 3 h. Then, the CH3COO2H solution was maintained for 48 h under 2H z (3 atm) at 60°C in the presence of Pt20 (0.12 g, 0.53 mmol). The solution was then filtered, evaporated and washed with water affording 5,6,6-[ H3]-3-oxo-4-aza-androstane-17fl-carboxylic acid (1) (90% yield, 2.29 mmol).…”

Long-Term Urodynamic Effects of Finasteride in Benign Prostatic Hyperplasia: A Pilot Study

“…Much larger multicentre studies have demonstrated an overall response rate after 2 years of therapy of around 60% [19,20], Huggins and Stevens [7] demonstrated that human BPH tissue shows predominant loss of the epithe lial, as opposed to the stromal, tissue component follow ing androgen deprivation as a result of orchiectomy. Stud ies with finasteride in experimental animals have indi cated similar findings [24], Since the relative proportion of epithelium to stroma varies in man from prostate to prostate, it might be anticipated that those individuals sustained reduction, and flow rates and voiding pressures entered the non-obstructed range for this age group. We suggest that finasteride has a place in the management of BPH, but that therapy needs to be continued for at least 24 months before maximal effect is observed.…”

A novel bridged-A-ring steroid

“…The enzyme steroid 5t~-reductase converts the substrate testosterone into dihydrotestosterone (Brooks, Berman, Hichens, Primka, Reynolds & Rasmussen, 1982). Inhibition of this enzyme is of considerable interest (Rasmussen, Reynolds, Utne, Jobson, Primka, Berman & Brooks, 1984) since elevated levels of dihydrotestosterone have been linked to such undesirable androgenic activities in man as acne, male-pattern baldness and benign prostatic * Department of Physical & Structural Chemistry.…”

“…In connection with an interest in inhibition of steroid 5a-reductase, the report of Rasmussen et al (1984) regarding the inhibitory activity of a 19-nor analog in a series of 4-aza steroids was intriguing. In the testosterone series, the solid-state structure of the 19-nor analog shows the steroidal A ring arched towards the fl face relative to the parent testosterone molecule (Duax & Norton, 1975).…”