Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-09-30
1998-02-03
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
A01N 4500, A61K 3156
Patent
active
057144800
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US95/04023 filed on Mar. 30, 1995, published as WO95/26731 Oct. 12, 1995.
This invention relates to a method of treating cardiovascular disease by employing a steroid 5-.alpha.-reductase inhibiting compound. Advantageously the method of this invention employs 17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-carboxylic acid in the treatment of cardiovascular disease.
BACKGROUND OF THE INVENTION
The class of steroidal horomones 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 production control results in excessive androgen hormone production. For example, ache vulgaris, seborrhea, female hirsutism, prostatic adenocarcinoma, and benign prostatic hypertrophy are correlated with elevated androgen levels. Additionally, the incidence of male pattern baldness has been associated with high androgen levels.
Testosterone (T) 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 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 testis. Steroid 5-.alpha.-reductase is a NADPH-dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by 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.
The fast inhibitor described was 4-androsten-3-one-17.beta.-carboxylic acid by Hisa and Voight in 1973. J. Invest. Dermat, 62:224-227. (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-triane was the next inhibitor to be described and also has found utiltiy as an affinity label for 5-.alpha.-reductase. Robaire, B., et al., (1977), J. Steroid Biochem. 8:307-310. (5a,20-R)-4-diazo-21-hydroxy-20-methlypregnan-3-one has been reported as a potent, time-dependent inhibitor of steroid 5-.alpha.-reductase. Blohm, T. R., et al., (1980), Biochem. Biophys. Res. Comm. 95:273-280; U.S. Pat. No. 4,317,817, Mar. 2, 1982. 17.beta.-N,N-diethylcarbomoyl-4-methyl-4-aza-5-.alpha.-androstan-3-one is exemplary of a group of 4-aza steroid inhibitors of steroid 5-.alpha.-reductase described in U.S. Pat. No. 4,377,584 which issued Mar. 22, 1983, and in Liang, T., et al., (1983), J. Steroid Biochem. 19, 385-390. 17a-acetoxy-6-methylenepregn-4-ene-3,20-dione also has been shown to be a time-dependent inactivator of steroid 5-.alpha.-reductase. Petrow, V., et al., (1981), Steroids 38:121-140.
Among the most potent inhibitors identified to date are 3-carboxy-androsta-3,5-diene steroidal derivatives and 3-carboxy A ring aryl steroidal derivatives.
Additional 5-.alpha.-reductase inhibitors known in the art are; describes the inhibition of human steroid 5-.alpha.-reductase (EC 1.3.1.30) by 3 androstene-3-carboxylic acids; 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; describes the inhibition of steroid 5-.alpha.-reductase by unsaturated 3-carboxysteroids; Levy, et al, describes the interaction mechanism between rat prostatic steroid 5-.alpha.-reductase and 3-carboxy-17.beta.-substituted steroids; describes the new steroid class of A ring aryl carboxylic acids; describes the effect of inhibitors of steroid 5-.alpha.-reductase in benign prostatic hyperplasia, male pattern baldness and
REFERENCES:
patent: 5212166 (1993-05-01), Panzeri et al.
patent: 5422371 (1995-06-01), Liao et al.
Transactions of the American Clinical and Climatological Assoc. 106th Meeting vol. CV Halushka et al., The Gordon Wilson Lecture Regulation of Thromboxane A2 Receptors . . . pp. 95-103, 1994.
Cintins Marianne M.
Dustman Wayne J.
Jones Dwayne C.
Kinzig Charles M.
Lentz Edward T.
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