17-Ethers and thioethers of 4-aza-steroids

United States Patent     5,536,727

Witzel, et al.     Jul. 16, 1996

 

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

 

Inventors:

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

 

Assignee:

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

 

Appl. No:

335,792

 

Filed:

Nov. 10, 1984

 

Related U.S. Application Data:

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

Intl. Cl.: C07D 241/12, A61K 31/495

Current U.S. Cl.: 544/336; 544/405; 544/406; 546/77

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

 

Abstract:

Described are new 17.beta.-ester, amide and ketone 4-aza-5a-androstan-3-ones and related compounds and their use as 5a-reductase inhibitors for treatment of benign prostatic hyperplasia and other hyperandrogenetic related disorders.

3 Claims, No Drawings

References Cited:

U.S. Patent Documents

4,377,584      Mar., 1983      Rasmusson et al.      514/284

4,732,897      Mar., 1988      Cainelli et al.      514/228.2

4,760,071      Jul., 1988      Rasmusson et al.      514/284

4,859,681      Aug., 1989      Rasmusson      514/284

4,882,319      Nov., 1989      Holt      514/119

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

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

5,110,939      May, 1992      Holt      548/250

5,116,983      May, 1992      Bhattacharya      546/77

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

5,138,063      Aug., 1992      Rasmusson et al.

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

5,278,159      Jan., 1994      Bakshi et al.

5,300,294      Apr., 1994      Johnson

5,302,621      Apr., 1994      Kojima et al.

Foreign Patent Documents

0200859      Nov., 1986      EP

93-23051     Nov., 1993     WO

WO93/23420     Nov., 1993     WO

Other References

Stinson, Chem. Eng. News, Jun. 29, ’92 pp. 7-8.

Helliker, Wall Street Jour. 7 Jun. ’91, pp. A1 and A7 (1991).

Diani et al., Jour. of Clin. & Metab. vol. 74 pp. 345-350 (1992).

Rasmusson et al. Jour Med Chem vol. 29 pp. 2298-2315 (1986).

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

Rasmusson et al Jour Med Chem vol. 27 pp. 1690-1701 (1984).

Back, Jour Org Chem vol. 46 pp. 1442-1446 (1981).

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

Burger, Medicinal Chem. 2nd Ed Interscience, N.Y. 1960, p. 42.

Geldof, “Consideration of the Use of 17-Beta-N,N-diethyl Carbamoyl-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).

Liang et al. “Species Differences in Prostatic Steroid 5alpha-reductases of Rat, Dog and Human”, Endocrinology, vol. 117, No. 2, pp. 571-579 (1985).

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

Back et al., “N-chloroazasteroids: A Novel Class of Reactive Steroid Analogous Preparation, Reaction with Thiols and Photochemical Conversion to Electrophilic N-acyl Imines”, J. Org. Chem. 54: 1904-1910 (1989).

Stinson, “Prostate Drug Proscar Cleared for Marketing”, Chem. Eng. News, 1992, pp. 7-8.

Diani et al., “Hair Growth Effects of Oral Administration of finasteride . . . “, Jour. Clinincal Endoc. & Metab. 74: 345-350 (1992).

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

Rasmusson et al., “Azasteroids as Inhibitors of Rat Prostate 5-alpha Reductase”, J. Med. Chem. 27: 1690-1701 (1984).
Primary Examiner: Daus; Donald G.
Attorney, Agent or Firm: Giesser; Joanne M., Fitch; Catherine D., Winokur; Melvin