Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-11-10
1996-11-26
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540 2, 540 15, 540107, 546 78, 546 14, 562499, C07J 7300
Patent
active
055787266
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to a new process for preparing 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 hyperandrogenetic 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'-trifluoromethylisobutyranilide. 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. which describe 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones said to be useful in the treatment of DHT-related hyperandrogenetic conditions.
However, despite the suggestion in the prior art that hyperandrogenetic 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, more adundant reductase (5.alpha.-reductase 2) has been cloned from human prostate with properties identified with the 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 in which, 5.alpha.-reductase 2, is the more abundant, and the other isozyme, 5.alpha.-reductase 1, is believed to be more abundant in scalp tissue.
In the treatment of hyperandrog
REFERENCES:
patent: 4139619 (1979-02-01), Chidsey, III
patent: 4220775 (1980-09-01), Rasmusson et al.
patent: 4377584 (1983-03-01), Rasmusson et al.
patent: 4760071 (1988-07-01), Rasmusson et al.
patent: 4859681 (1989-08-01), Rasmusson et al.
patent: 4888336 (1989-12-01), Holt et al.
patent: 5049562 (1991-09-01), Rasmusson et al.
patent: 5237064 (1993-08-01), Bakshi et al.
patent: 5237065 (1993-08-01), Holt
patent: 5278159 (1994-01-01), Bakshi et al.
Rasmusson et al. "Azasteroids: Structure-Activity Relationships for Inhibition of 5 .alpha.-Reductase and of Androgen-Receptor Binding", J. Med. Chem. 29 (11): 2298-2315 (1986).
Rasmusson et al. "Azasteroids as Inhibitors of Rat Prostatic 5 .alpha.-Reductase", J. Med. Chem. 27 (12): 1690-1701 (1984).
Stinson, "Prostate Drug Proscar Cleared for Marketing" Chem. Eng. News, Jun. 29, 1992, pp. 7-8.
Helliker, "Alopecia Sufferers Seek to Suffer Less, and Not in Silence,", Wall Street Journal, 7 Jun. 1991, pp. A1 and A7.
Diani et al., "Hair Growth Effects of Oral Administration of Finasteride, a Steroind 5 .alpha.-Reductase Inhibitor Alone and in Combination with Topical Minoxidil in the Balding Stumptail Macaque", J. Clin. Endocrin. and Metabl., 74(2):345-350 (1990).
Back et al., "N-Chloroazasteroids: A Novel Class of Reactive Steroid Analogues Preparation, Research with Thiols, and Photochemical Conversion to Electrophilic N-Acyl Imines", J. Org. Chem. 54: 1904-1910 (1989).
Back "Oxidation of Lactams and Alcohols with Benezene Selenic Anhydride", J. Org. Chem. 46: 1442-1446 (1981).
Bakshi Raman K.
Rasmusson Gary H.
Daus Donald G.
Fitch Catherine D.
Giesser Joanne M.
Merck & Co. , Inc.
Winokur Melvin
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