Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-09-15
1997-11-04
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552610, 552548, 540110, A61K 3156, C07J 300, C07J 4300
Patent
active
056839952
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to certain novel 17.alpha. and 17.beta. substituted acyl-3-carboxy 3,5-diene steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-.alpha.-reductase. Also invented are novel intermediates and processes useful in preparing these compounds.
DESCRIPTION OF RELATED ART
The class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertropy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer.
Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-.alpha.-reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-.alpha.-reduced analogue, in these tissues but not in others such as muscle and testes. Steroid 5-.alpha.-reductase is a Nicotinamide Adenine dinucleotide Phosphate(NADPH)dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by the discovery of a genetic steroid 5-.alpha.-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11:637-648.
Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme. Among the most potent inhibitors identified to date are 3-carboxy-androsta-3,5-diene steroidal derivatives.
A number of 5-.alpha.-reductase inhibitors are known in the art. For example,
1. Bioinorganic Chemistry, 17, pp. 372-376 (1986), by B. W. Metcalf, et al. describes the inhibition of human steroid 5.alpha. reductase (EC 1.3.1.30) by 3 androstene-3-carboxylic acids;
2. Biochemistry (1990) Vol. 29, pp. 2815-2824, by M. A. Levy, et al, M. A. Levy, et al. describes the mechanism of enzyme inhibitor interation in the inhibition or rat liver steroid 5.alpha. reductase by 3-androstene-3-carboxylic acids;
3. J. Med. Chem. (1990) Vol. 33, pp. 943-950 (1990), by D. A. Holt, et al, describes the inhibition of steroid 5.alpha. reductase by unsaturated 3-carboxysteroids;
4. J. Steroid Biochem, Vol. 34, Nos. 1-6, pp. 571-575 (1989), by M. A. Levy, et al, describes the interaction mechanism between rat prostatic steroid 5-alpha reductase and 3-carboxy-17.beta.-substituted steroids;
5. J. Med. Chem. (1990) Vol. 33, pp. 937-942, by D. A. Holt, et al, describes the new steroid class of A ring aryl carboxylic acids;
6. TIPS (December 1989) Vol. 10, pp. 491-495, by D. W. Metcalf, et al, describes the effect of inhibitors of steroid 5.alpha. reductase in benign prostatic hyperplasia, male pattern baldness and acne; and
7. EPO Publn. No. 0 289 327, to D. A. Holt, et al. (SmithKline Beckmann) describes steroidal 3-carboxylic acid derivatives as useful 5.alpha. reductase inhibitors.
8. EPO Publn. No. 0 343 954 A3, to D. A. Holt, et al., (SmithKline Beckmann) describes steroidal 3-carboxylic acid derivatives as useful 5-.alpha.-reductase inhibitors.
9. EPO Publn. No. 0 465 142 A1, to G. H. Rasmusson, et al, (Merck & Co. Inc.) describes steroidal 3-carboxylic acid derivatives as useful 5.alpha.-reductase inhibitors.
However, none of the above references specifically suggest that any of the novel steroidal 17.alpha. or 17.beta.-substituted acyl-3
REFERENCES:
patent: 4954446 (1990-09-01), Holt et al.
patent: 5017568 (1991-05-01), Holt et al.
patent: 5032586 (1991-07-01), Metcalf et al.
patent: 5041433 (1991-08-01), Holt et al.
patent: 5137882 (1992-08-01), Holt et al.
patent: 5196411 (1993-03-01), Rasmusson et al.
patent: 5212166 (1993-05-01), Panzeri et al.
J. Med. Chem. 33, pp. 943-950 (1990).
J. Med. Chem. 33, pp. 937-942 (1990).
Biochemistry, vol. 29, No. 11, pp. 2815-2830 (1990).
Holt Dennis Alan
Levy Mark Alan
Berch Mark L.
Dustman Wayne J.
Kifle Bruck
Kinzig Charles M.
Lentz Edward T.
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