Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-24
1998-12-01
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 77, C07D22118, C07D22104, C07D22122, A61K 3144
Patent
active
058439536
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION OF THE INVENTION
This invention relates to novel 7-substituted 4-aza cholanic acid derivatives which are 5.alpha.-reductase inhibitors and their use in the treatment of various disorders associated with an excess of 5.alpha.-reductase.
BACKGROUND OF THE INVENTION
Certain undesirable physiological conditions, including acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostatic hyperplasia and prostatic cancer can be 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 effects 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, such as 4'-nitro-3 '-trifluoromethyl-isobutyranilide, such as described in Neri et al Endocrinology 91, No. 2 (1972). 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.
It is now known that the principal mediator of androgenic activity in some target organs, e.g. the prostate is 5.alpha.-dihydrotestosterone (DHT), and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It is also known that inhibitors of testosterone-5.alpha.-reductase can prevent or lessen the symptoms of hyperandrogenetic stimulation.
A number of 4-aza steroid compounds are known which are 5.alpha.-reductase inhibitors. See the following Merck & Co., Inc. patents: U.S. Pat. Nos. 4,377,584, 4,220,775, 4,859,681, 4,760,071. See also Rasmusson et al., 1984, J. Med. Chem. 27:1690-1701) and Rasmusson et al., 1986, J. Med. Chem. 29:2998-2315, and EP Publication 0 484 094 to Sankyo, which describe 4-aza-17.beta.-substituted 5.alpha.-androstan-3-ones said to be useful in the treatment of DHT-related hyperandrogenic conditions.
Recently, Anderson and Russell isolated a cDNA which encodes a rat liver 5.alpha.-reductase (see J. Biol. Chem. 264:16249-55, 1989). They found that a single mRNA which encodes both the liver and prostatic reductases of rats. The sequence of this rat gene was later used to select a human prostatic cDNA encoding a 5.alpha.-reductase termed "5.alpha.-reductase 1" (Proc. Natl. Sci. USA 87:3640-3644, 1990). More recently, a second human prostatic reductase (5.alpha.-reductase 2) has been cloned with properties identified with the more abundant form found in crude prostatic extracts (see Nature 354:159-161, 1991).
Thus, there are at least two genes for 5.alpha.-reductase and two distinct isozymes of 5.alpha.-reductase in humans. While both forms are present in prostatic tissue, 5.alpha.-reductase 2 is more abundant there. The other isozyme, 5.alpha.-reductase 1 is believed to be more abundant in scalp and skin tissue.
In the treatment of hyperandrogenetic disease conditions, it would be desirable to have one drug entity which is highly selective for inhibiting the scalp and skin associated enzyme 5.alpha.-reductase 1 for the use in treating diseases of the skin and scalp, such as acne and alopecia.
DESCRIPTION OF THE INVENTION
This invention related to the compounds of the formula I ##STR2## wherein: the dotted line indicates that a double bond may be present or absent; CONH(CH.sub.2).sub.2 SO.sub.3 H aralkyl; substituted phenyl moieties;
The compounds of formula I are potent inhibitors of the 5 .alpha.-reductase type 1 isoenzyme, primarily associated with the skin and scalp tissues. As such they are useful for treatment of disorders of the skin and scalp which are related to an excess of DHT, including androgenic alopecia, acne vulgaris, female hirsutism, and seborrhea.
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Carlin Josephine R.
Chiu Shuet-Hing Lee
Graham Donald W.
Tolman Richard L.
Fitch Catherine D.
Merck & Co. , Inc.
Rotman Alan L.
Winokur Melvin
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