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Manipulation of androgen receptors in treatment of hair loss

United States Patent     5,510,351

Graham, et al.     Apr. 23, 1996

17-Ethers and thioethers of 4-aza-steroids. Asteroids as 5A-reductase inhibitors.



Graham; Donald W. (Mountainside, NJ); Aster; Susan D. (Teaneck, NJ); Hagmann; William (Westfield, NJ); Tolman; Richard L. (Warren, NJ).



Merck & Co., Inc. (Rahway, NJ).



The portion of the term of this patent subsequent to Nov. 10, 2014 has been disclaimed


Appl. No:




Nov. 14, 1994


Related U.S. Application Data:

Continuation-in-part of Ser No. 886,021, May 20, 1992, abandoned.

Intl. Cl.: A61K 31/58

Current U.S. Cl.: 514/253; 514/241; 514/261; 514/269; 514/284; 544/198; 544/242; 544/264; 544/336; 546/77

Field of Search: 546/77; 514/284, 253; 544/336



Described are delta 17 and delta 20 olefinic and saturated 17 Beta-substituted 4-aza-5 alpha-androstan-3-ones and related compounds having 5 alpha reductase inhibitors for treatment of benign prostatic hyperplasia and other hyperandrogenic related disorders.

14 Claims, No Drawings

References Cited:

U.S. Patent Documents

4,220,775      Sept., 1980      Rasmusson et al.      546/77

4,337,584      Mar., 1983      Rasmusson et al.      546/77

4,596,812      Jun., 1986      Chidsey, III et al.

4,732,897      Mar., 1988      Cainelli et al.      546/77

4,760,071      Jul., 1988       Rasmusson et al.      546/71

4,859,681      Aug., 1989      Rasmusson et al.      546/77

4,882,319      Nov., 1989      Holt et al.      514/71

4,888,336      Dec., 1989      Holt et al.      546/77

4,910,226      Mar., 1990      Holt et al.      514/319

5,049,562      Sept., 1991      Rasmusson et al.      546/77

5,084,574      Jan., 1992      Bhattacharya et al.

5,110,939      May, 1992      Holt et al.

5,116,983      May, 1992      Bhattacharya et al.

5,120,742      Jun., 1992      Rasmusson et al.      514/284

5,175,155      Dec., 1992      Juniewicz et al.      514/284

Foreign Patent Documents

0004949      Oct., 1979      EP

0200859      Nov., 1986      EP

0277002      Jun., 1988      EP

1465544      Nov., 1965      FR

WO93/23039      Nov., 1993      WO

94/00125      Jan., 1994     WO

Other References

Burger, “Medicinal Chemistry 2d Ed” Interscience N.Y., 1960 p. 42.

Stinson “Prostate Drug Proscar Cleared for Marketing”, Chem & Engineering News, Jun. 29, 1992, pp. 7-8.

Diani et al., “Hair Growth Effects of Oral Administration of Finasteride, A Steroid 5a-Reductase Inhibitor, Alone and in Combination with Topical Minoxidil in the Balding Stumptail MaCaque”, J. Clin. & Endoc. & Metab. 74: 345-350 (1992).

Geldof “Consideration of the use of 17Beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha androstan-3-one (4MA) a 5 alpha-reductase inhibitor in prostate cancer therapy” J. Cancer Res. Clin. Oncol. 118: 50-55 (1992).

Rasmusson, et al., “Azasteroids as Inhibitors of Rat Prostatic 5-alpha Reductase” J. Med. Chem. 27: 1690-1701 (1984).

Rasmusson, et al., “Azasteroids, Structure Activity Relationships for Inhibition of 5a-Reductase and of Androgen Receptor Binding” J. Med. Chem. 29: 2298-2315 (1986).

Helliker “Alopecia Sufferers Seek to Suffer Less and not in Silence”, Wall Street Jour. 7 Jun. 1991, pp. A1 & A7.

Back, “Oxidation of Azasteroid Lactams and Alcohols with Benzeneselenic Anhydride”, J. Org. Chem. 46: 1442-1446 (1981).

Back et al., “N-Chloroazasteroids: A Novel Class of Reactive Steroid Analogues. Preparation, Reaction with Thiols, and Photochemical Conversion to Electrophilic N-Acyl Imines” J. Organic Chem. 541: 1904-1910 (1989).

Kadohama et al., “Retardation of Prostate Tumor Progression in the Noble Rat by 4-Methyl-4-aza-Steroidal Inhibitors of 5alpha-reductase”, JNCI, 74(2): 475-486 (1985).

Liang et al., “Species Differences in Prostatic 5alpha-Reductase of Rat, Dog and Human”, Endocrinology 117(2): 571-579 (1985).

Brooks et al., “Prostatic Effects Induced in Dogs by Chronic or Acute Oral Administration of 5alpha-Reductase Inhibitors”, The Prostate 9: 65-75 (1986).

Brooks et al., “Effect of Castration, DES, Flutamide, and the 5alpha-Reductase Inhibitor MK-906, on the Growth of the Dunning Rat Prostatic Carcinoma, R-3327”, The Prostate 18:215-227 (1991).

LaBrie et al., “Combination Therapy in Prostate Cancer”, The Lancet Nov. 8, 1986, pp. 1095-1096.
Primary Examiner: Daus; Donald G.
Attorney, Agent or Firm: Fitch; Catherine D., Giesser; Joanne M., Winokur; Melvin


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