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17-ester, amide, and ketone derivatives of 3-oxo-4-azasteroids as 5A-reductase inhibitors


United States Patent 5,510,485
Graham, et. al. Apr. 23, 1996

17-ester, amide, and ketone derivatives of 3-oxo-4-azasteroids 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, 1994

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

References Cited | [Referenced By:]


U.S. Patent Documents

 

4,377,584 Mar., 1983 Rasmusson 514/284
4,732,897 Mar., 1988 Cainelli et al.
4,760,071 Jul., 1988 Rasmusson et al.
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


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




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