Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-21
1997-12-02
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514284, A61K 3158
Patent
active
056938101
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to new 17.beta.-carboxanilides of 4-aza-5.alpha.-androstan-3-ones and related compounds and the use of such compounds as 5.alpha.-reductase inhibitors.
DESCRIPTION OF THE PRIOR ART
The art reveals that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hyperplasia, are the result of hyperandrogenetic 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 at., Endo., Vol. 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 in the art that the principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5.alpha.-dihydrotestosterone, 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 will serve to prevent or lessen symptoms of hyperandrogenetic stimulation.
For example, 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 and the articles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med. Chem. 29, 2998-2315 (1986) of Rasmusson, et al., and U.S. Pat. No. 4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et at., and EP Publication No. 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.
However, none of the above references specifically describe the compounds of the instant invention, which are selective and potent inhibitors of 5.alpha.-reductase in humans, as well as animals, i.e. dogs, which are exceptionally active.
SUMMARY OF THE INVENTION
The present invention discloses novel anilide derivatives of 17.beta.-carboxy-4-aza-5.alpha.-androstan-3-ones which are useful for inhibiting the 5.alpha.-reductase enzyme in prostatic tissue and isozymes thereof. They are also particularly effective in selectively inhibiting mammalian 5.alpha.-reductase for the treatment of benign prostatic hyperplasia in humans and dogs, acne, female hirsutism, androgenic alopecia, i.e., male pattern baldness and treatment of prostatic carcinoma.
In accordance with the present invention there is provided novel anilides of 17.beta.-carboxy-4-aza-5.alpha.-androstan-3-one and related compounds of the formula: ##STR2## wherein:
R is H, CH.sub.3, or C.sub.2 H.sub.5 ;
R.sub.1 is H, C.sub.1 -C.sub.10 alkyl, or phenyl; and
X, Y and Z independently represent --H; --OH; --NH.sub.2 ; SH; --SC.sub.1 -C.sub.4 alkyl;
--CO.sub.2 H; --CN; --C.sub.2 -C.sub.10 acyl; --C.sub.7 -C.sub.15 aroyl; straight or branched chain alkyl having 3, 4, 5, 6, 7, or 8 carbon atoms; --C.sub.3 -C.sub.8 cycloalkyl; -C.sub.6 -C.sub.14 aryl; heteroaryl; heteroaroyl; --C.sub.7 -C.sub.10 aralkyl; --CONR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 independently are H, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.6 -C.sub.14 aryl, or R.sup.2 and R.sup.3 together with the nitrogen to which they are attached form a 5-7 membered saturated heterocyclic ring containing 1-2 nitrogen atoms, and 0-1 oxygen atoms; or C.sub.1 -C.sub.10 alkyl, and pr
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Bakshi Raman K.
Patel Gool F.
Rasmusson Gary H.
Daus Donald G.
Fitch Catherine D.
Merck & Co. , Inc.
Winokur Melvin
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