Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-15
1997-04-15
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546109, 514298, C07D22112, C07D40112
Patent
active
056211040
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 selective inhibition of the isozyme 5.alpha.-reductase 1.
BACKGROUND OF THE INVENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness (alopecia) and benign prostatic hyperplasia, 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'-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 ferns 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, formed locally in the target organ by the action of testosterone-5.alpha.-reductase. Inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with epidermal tissues, especially in scalp tissues. This form is conventionally designated as 5.alpha.-reductase 1, while the isozyme that principally interacts with the prostatic tissues is designated as 5.alpha.-reductase 2. Both isozymes are active in the prostatic tissues. Thus, in the treatment of hyperandrogenic disease conditions e.g. benign prostatic hyperplasia (BPH), it would be desirable to have one drug entity which is active against both isozymes in the prostate to significantly inhibit dihydrotesterone production, while also having another drug entity which is highly selective for inhibiting the isozyme 5.alpha.-reductase 1 associated with the scalp, for use in treating conditions of the skin and scalp, e.g. acne and alopecia in males and hirsutism in females. Additionally, such a selective 5.alpha.-reductase 1 inhibitor could also be used in combination with finasteride (PROSCAR.RTM.), which is highly selective for 5.alpha.-reductase 2, for combination therapy in the treatment of BPH. Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of one or both 5.alpha.-reductase isozymes. It is an additional object of this invention to provide compounds that are useful in the treatment and/or prevention of benign prostatic hyperplasia. It is an additional object of this invention to provide compounds that are useful in the treatment of female hirsutism, male pattern baldness, acne, androgenetic alopecia, prostatic cancer, and insufficient plasma levels of high density lipoproteins. The compounds of the invention have utility in one or more of the aforementioned areas.
SUMMARY OF THE INVENTION
The compounds of the present invention are those of the general structural formula I: ##STR1## or a pharmaceutically acceptable salt or ester thereof, wherein hydrogen and C.sub.1-6 alkyl; C.sub.1-6 alkoxyl and C.sub.1-6 alkylcarbonyloxy; C.sub.1-6 alkoxyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, halogen, cyano, C.sub.1-6 alkylcarbonyl, Ar-carbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylaminocarbonyl, Ar-aminocarbonyl and di-C.sub.1-6 alkylaminocarbonyl; and
DETAILED DESCRIPTION OF THE INVENTION
Salts encomp
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Levy et al.
Graham Donald W.
Hagmann William K.
Fitch Catherine D.
Merck & Co. , Inc.
Rotman A.
Rotman Alan L.
Winokur Melvin
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