Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-05-06
1999-03-23
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 78, 546 77, A01N 4342, C07D22102
Patent
active
058860053
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the inhibition of 5.alpha.-reductase, and more particularly, the inhibition of 5.alpha.-reductase isozyme type 1.
BACKGROUND OF THE INVENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Androgenic alopecia is also known as androgenetic alopecia. 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., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5.alpha.-dihydrotestosterone ("DHT") , formed locally in the target organ by the action of 5.alpha.-reductase, which converts testosterone to DHT. Inhibitors of 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5.alpha.-reductase 1 (or 5.alpha.-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5.alpha.-reductase 2 (or 5.alpha.-reductase type 2).
Since 5.alpha.-reductase type 1 and type 2 convert testosterone to DHT, inhibition of either or both of the isozymes would serve to alleviate the conditions and diseases mediated by DHT. The present invention addresses this by providing novel compounds that are active as inhibitors of 5.alpha.-reductase type 1.
SUMMARY OF THE INVENTION
The novel compounds of the present invention are those of structural formula I: ##STR2## or a pharmaceutically acceptable salt or ester thereof, and are inhibitors of 5.alpha.-reductase, particularly 5.alpha.-reductase type 1. The compounds of formula I are useful in the oral, systemic, parenteral or topical treatment of hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia which includes female and male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the treatment of prostatic carcinoma, as well as in the treatment of prostatitis.
Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of 5.alpha.-reductase type 1. It is an additional object of this invention to provide methods of using the compounds of formula I for the treatment of hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia, male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the prevention and treatment of prostatic carcinoma, as well as the treatment of prostatitis. It is a further obje
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Aster Susan D.
Graham Donald W.
Daus Donald G.
Fitch Catherine D.
Merck & Co. , Inc.
Winokur Melvin
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