TOPICAL PHARMACEUTICAL COMPOSITION CONTAINING 17-BETA-METHOXYCARBONYL-4-METHYL-4-AZA-5-ALPHA-ANDROST-1-EN-3-ONE

Abstract: 17β-Acyl-4-aza-5α-androst-1-en-3-ones of the formula: wherein R is selected from hydrogen, methyl and ethyl R² is methoxy, a monovalent radical selected from straight and branched chain alkyl of from 1-12 carbons, or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halo (Cl or Br) substituents, aralkyl selected from benzyl and phenethyl and heterocyclic selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl; and R′, R′′ and R′′′ are each selected from hydrogen and methyl and pharmaceutical formulations of the above compounds are active as testosterone 5α-reductase inhibitors and thus are useful for treatment of acne, seborrhea, female hirsutism, and benign prostatic hypertrophy.

Description: The present invention is concerned with a topical pharmaceutical composition comprising 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one. It is well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, and 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'-trifluoromethylisobutyranilide. See Neri et al., Endo. , Vol. 91, No1 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 more recently became known in the art that the principal mediator of androgenic activity in some target organs is 5α-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5α-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5α-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids , 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17β-carboxylate was a testosterone-5α-reductase inhibitor. Then Voigt and Hsia, Endocrinology , 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17β-carboxylic acid are both active inhibitors of testosterone-5α-reductase in vitro . They further demonstrated that topical application of either testosterone or5α-dihydrotestosterone caused enlargement of the female hamster flank organ, or androgen dependent sebaceous structure. However, concomitant administration of 4-androsten-3-one-17β-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5α-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5α-reductase. A number of 4-aza steroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. 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. Patent 4,377,584 and 4,220,775 and EP-A-4949 of Rasmusson et al. describe a group of 4-aza-5α-17β-substituted-5α-androsten-3-ones which are useful in the treatment of hyperandrogenic conditions. Recently, a number of investigators from Merck & Co., Inc. have published regarding the biological activity of 5α-reductase inhibitors. See for example, Rasmusson et al ., J. Med. Chem. 29 : 2298 (1986), Brooks, et al ., The Prostate 9 : 65-75 (1986), Liang et al ., Endrocrinology 117 , No. 2, pp. 571-579 (1985), Rasmusson et al ., J. Med. Chem. 27 : 1690-1701 (1984), Liang et al ., J. Biol. Chem. 259 , No. 2, pp. 734-739 (1984). Rasmusson, et al, J. Med Chem, 29 , 2298-2315 (1986) discloses inter alia 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one. The present invention is concerned with a topical pharmaceutical composition comprising 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one. The preparation of this compound is described in Rasmussen et al., J. Med Chem, 29 , 2298-2315 (1986). These compositions are useful for treating the hyperandrogenic conditions of acne, seborrhea, hirsutism and male pattern baldness. For the treatment of acne vulgaris, seborrhea, female hirsutism, 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one is administered in the formula of pharmaceutical composition comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration. These topical pharmaceutical compositions may be in the form of a cream, ointment, gel or aerosol formulation adapted for application to the skin. These topical pharmaceutical compositions containing said compound ordinarily include about 0.1% to 15%, preferably about 5%, of the active compound, in admixture with about 95% of vehicle.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A topical pharmaceutical composition comprising 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one. The use of 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one for the preparation for a medicament useful for the topical treatment of the hyperandrogenic conditions of acne vulgaris, seborrhea, hirsutism and male pattern baldness. Claim for the following Contracting State : ES A process for the preparation of a topical pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier and a therapeutically effective amount of 17β-methoxycarbonyl-4-methyl-4-aza-5α-androst-1-en-3-one.

Inventors: RASMUSSON, GARY H., REYNOLDS, GLENN F.
Applicants: MERCK & CO. INC.
Application year: 1987
Main classification: C07J73
IPC codes: C07J73, A61K31, A61P13, A61P15, A61P17, A61P5