Delta-17 and delta-20 olefinic and saturated 17 beta-substituted

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

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514241, 514261, 514269, 514284, 544242, 544264, 544198, 544336, 546 77, A61K 3158

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055103510

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BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention is directed to new delta-17 and delta-20 olefinic and saturated 17.beta.-substituted 4-aza-5.alpha.-androstan-3-ones and related compounds and the use of such compounds as 5.alpha.-reductase inhibitors.


DESCRIPTION OF THE PRIOR ART

The an reveals that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endo., Vol. 91. No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It is now known in the art that the principal mediator of androgenic activity in some target organs. e.g. the prostate, is 5.alpha.-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It is also known that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. For example, a number of 4-aza steroid compounds are known which are 5.alpha.-reductase inhibitors.
See the following Merck & Co., Inc. patents, U.S. Pat. Nos. 4,377,584, 4,220,775, 4,859,681,4,760,071 and the articles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med. Chem. 29, 2998-2315 (1986) of Rasmusson, et al., and U.S. Pat. No. 4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et al. which describe 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones said to be useful in the treatment of DHT-related hyperandrogenic conditions.
Further there is the suggestion in the early prior art that hyperandrogenic diseases are the result of a single 5.alpha.-reductase. However, there are later reports regarding the presence of other 5.alpha.-reductase isozymes in both rats and humans. For example, in human prostate, Bruchovsky, et al. (See J. Clin. Endocrinol. Metab. 67, 806-816, 1988) and Hudson (see J. Steroid Biochem. 26, p 349-353, 1987) found different 5.alpha.-reductase activities in the stromal and epithelial fractions. Additionally, Moore and Wilson described two distinct human reductases with peaks of activities at either pH 5.5 or pH 7-9. (See J. Biol. Chem. 251, 19, p. 5895-5900, 1976.)
Recently. Andersson and Russell isolated a cDNA which encodes a rat liver 5.alpha.-reductase (see J. Biol. Chem. 264 pp. 16249-55 (1989). They found a single mRNA which encodes both the liver and prostatic reductases in rats. This rat gene was later used to identify a human prostatic cDNA encoding a 5.alpha.-reductase termed "5.alpha.-reductase 1". (See Proc. Nat'l. Acad. Sci. 87, p. 3640-3644. 1990.)
More recently, a second, human prostatic reductase (5.alpha.-reductase 2) has been cloned with properties identified with the more abundant form found in crude human prostatic extracts. (See Nature. 354, p. 159-161, 1991.)
Further, "Syndromes of Androgen Resistance"--The Biology of Reproduction, Vol. 46, p. 168-173 (1992) by Jean 0. Wilson suggests that the 5.alpha.-reductase 1 enzyme is associated with hair follicles.
Thus, the an supports the existence of at least two genes for 5.alpha.-reductase and two distinct isozymes of 5.alpha.-reductase in humans. Both isozymes are believed to be present in prostatic tissue in which, 5.alpha.-reductase 2, is the more abundant, while the other isozyme, 5.alpha

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