Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-03
1998-01-20
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546 77, 514284, A61K 3147
Patent
active
057102759
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to new 7.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 art reveals that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, 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 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.
A number of 4-aza steroid compounds are known in the art as 5.alpha.-reductase inhibitors. For example, See 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., U.S. Pat. No. 4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et al. describe 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be useful in the treatment of DHT-related hyperandrogenic conditions.
However, despite the suggestion in the prior art that hyperandrogeneic diseases are the result of a single 5.alpha.-reductase, there are 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 of rats. The sequence of this rat gene was later used to select 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 O. Wilson indicates that the 5.alpha.-reductase 1 enzyme may be associated with hair follicles.
Thus, the art supports the existence of at least two genes for 5.alpha.-reductase and two distinct isozymes of 5.alpha.-reductase in humans. Both forms are present in prostatic tissue although reductase 2 is the more abundant. The other isozyme, 5.alpha.-reductase 1, is believed to be more abundant in scalp tissue.
In the treatment of hyperandrogenic disease conditions, e.g. benign pros
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Bakshi Raman K.
Graham Donald W.
Harris Georgianna S.
Patel Gool F.
Rasmusson Gary H.
Daus Donald G.
Fitch Catherine D.
Merck & Co. , Inc.
Nicholson William H.
Winokur Melvin
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