Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1995-03-20
1997-06-17
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514284, 546 23, 546 77, A61K 31435, C07D22102
Patent
active
056397410
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to novel amino substituted 4-azasteroidal 5.alpha.-reductase inhibitors.
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-azasteroid compounds are known in the art as 5.alpha.-reductase inhibitors. For example, See U.S. Pat. Nos. 2,227,876, 3,239,417, 3,264,301 and 3,285,918; French Patent No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60, 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, 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 hyperandrogenic 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 abundant 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 whi
REFERENCES:
patent: 2227876 (1941-01-01), Bolt
patent: 3239417 (1966-03-01), DiTullio et al.
patent: 3264301 (1966-08-01), Dorrenboos
patent: 3285918 (1966-11-01), Doorenboos et al.
patent: 4220775 (1980-09-01), Rasmusson et al.
patent: 4317817 (1982-03-01), Blohm et al.
patent: 4377584 (1983-03-01), Rasmusson et al.
patent: 4596812 (1986-06-01), Chidsey, III et al.
patent: 4732897 (1988-03-01), Cainelli et al.
patent: 4760071 (1988-07-01), Rasmusson et al.
patent: 4845104 (1989-07-01), Carlin et al.
patent: 4859681 (1989-08-01), Rasmusson et al.
patent: 4882319 (1989-11-01), Holt et al.
patent: 4910226 (1990-03-01), Holt et al.
patent: 5049562 (1991-09-01), Rasmusson et al.
patent: 5110939 (1992-05-01), Holt et al.
patent: 5116983 (1992-05-01), Bhattacharya et al.
patent: 5494914 (1996-02-01), Labrie et al.
Li et al., J. Med. Chem. 1995, pp. 1158-1173, "Synthesis and in Vitro Activity of 17Beta-(N-alkyl/arylformamido)-and 17Beta-[N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5alpha-androsta n-3-ones as Inhibitors of Human 5alpha-Reductases and Antagonists of the Androgen Receptor" .
The Daily (Tuesday, May 7, 1996), "New Data on Proscar, Abbott's Hytrin Show Conflicting Results".
Wall Street Journal (Tuesday, May 7, 1996), "Study Finds Abbott's Prostate Drug is Much More Effective than Merck's," p. B4.
Endo., vol. 91, No. 2, pp. 427-437 (1972) by Neri, et al., "A Biological Profile of a Non-steroidal Antiandrogen, SCH 13521 . . . ".
Steroids, 14, 269-283(1969), by Nayfeh, et al., "Metabolism of Progesterone by Rat Testicular Homogenates-III".
Endo., vol. 92, p. 1216 (1973) by Voight & Hsia (See disclosure in Reference AP).
J. Pharm. Sci., 62, No. 4, pp. 638-640 (1973) by Doorenbos & Solomons, "Synthesis & Antimicrobial Properties of 17 Beta-Isopentyloxy-4-Aza-5 Alpha-Androstane and the 4-Methyl Derivative".
J. Pharm. Sci., 60, No. 8, pp. 1234-1235 (1971) by Doorenbos & Brown, "4,17 Alpha-Dimethyl-4-Aza-5-Alpha-Androstan-17 beta-ol Acetate & Related Azasteroids".
J. Pharm., 63, No. 4, pp. 620-622 (1974) by Doorenbos & Kim, "Synthesis & Evaluation of Antimicrobial Properties of Amidinoazaandrostanes and Guanidinoazaandrostantes".
J. Med. Chem. (1986) 29 (11): pp. 2298-3115 by Rasmusson, et al., "Aza Steroids: Structure-Activity Relationships . . . ".
Prostate (1986) 9 (1): pp. 65-75 by Brooks, et al., "Prostatic Effects Induced in Dogs By . . . 5 alpha-Reductase Inhibitors".
Steroids (1986) 47 (1) .sunburst.pp. 1-19 by Brooks, et al., "5 Alph-Reductase Inhibitory . . . Activities of Some 4-Aza-Steroids in the rat".
Endocr. (1985) 117 (2): pp. 571-579, by Liang, et al., "Species Differences in Prostatic Steroidal 5 Alpha-Reductases of Rat, Dog and Human".
J. Med. Chem. (1984) 27 (12).sunburst.pp. 1690-1701, by Rasmusson, et al., "Azasteroids as Inhibitors of Rat Prostatic 5 alpha-reductase".
J. Org. Chem. (1981) vol. 46, No. 7, pp. 1442-1446, T. Back, et al., "N-Chloroazasteroids . . . ".
Chem. Abstracts, vol. 95, 109055j, by T. Liang, et al. "Inhibition of 5 Alpha-Receptor Binding . . . by a 4-Methyl-4-Aza-Steroid".
JNCI, vol. 74, No. 2, pp. 475-481 (Feb. 1985), by N. Kadohama, et al., "Retardation of Prostate Tumor Progression in the Noble Rat by 4-Methyl-4-Aza-Steroidal Inhibitors of 5 Alpha-Reductase".
The Prostate, vol. 10, pp. 189-197 (1987) by G. Andriole, et al., "The Effect of 4MA . . . on the Growth of . . . Human Tumors . . . ".
J. Endocr., vol. 57, pp. 111-121 (1973) by K. D. Bingham, et al., "The Metabolism of Testosterone by Human Male Scalp Skin".
Toxicol. Appl. Pharmacol., vol. 103, pp. 222-227 (1990) by G. L. Kedderis, et al., "Studies With Nitrogen-Containing Steroids . . . ".
Bioinorganic Chemistry, 17, pp. 372-376 (1986) by B. W. Metcalf, et al., "Patent Inhibition of Human Steroid . . . by 3-Androstene-3-Carboxylic Acid".
Biochemistry, 1990, vol. 29, pp. 2815-2824, by M. A. Levy, et al., "Inhibition of Rat Liver Steroid 5 Alpha-Reductase . . . ".
J. Med. Chem., 1990, vol. 33, pp. 943-950, by D. A. Holt, et al., "Steroidal A Ring Car
Bergman Jeffrey P.
Tolman Richard L.
Witzel Bruce E.
Daus Donald G.
Fitch Catherine D.
Giesser Joanne M.
Merck & Co. , Inc.
Winokur Melvin
LandOfFree
17-amino substituted 4-azasteroid 5.alpha.-reductase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 17-amino substituted 4-azasteroid 5.alpha.-reductase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 17-amino substituted 4-azasteroid 5.alpha.-reductase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2157873