Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-05-17
1996-10-01
Prior, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514176, 514177, 514182, 514284, 514563, 546 77, 562498, 552502, 552506, 552521, 552524, 552540, 552546, 552548, 552552, 552553, 552554, 552556, 552557, 552558, 552599, 552600, 552601, 552606, 552607, 552610, 552611, A61K 3156, A61K 3158, C07J 4100, C07J 900
Patent
active
055611249
DESCRIPTION:
BRIEF SUMMARY
CONTINUING DATA
This application is a 371 of PCT application PCT/US93/11235.
1. Field of the Invention
The present invention relates to novel substituted 17-.alpha. acyl steroidal 5.alpha.-reductase inhibiting compounds, pharmaceutical compositions containing these compounds and methods for using these compounds to inhibit steroid 5.alpha.-reductase. Also invented are novel processes useful in preparing these compounds.
2. 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 prostatic hypertrophy 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 testis. 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 17.beta.-acyl steroidal derivatives.
A number of substituted 17.beta.-acyl steroidal 5.alpha.-reductase inhibiting compounds are know in the art. For example,
U.S. Pat. No. 4,760,071 describes a class of substituted 17.beta.-acyl-4-aza-steroidal 5.alpha.-reductase inhibiting compounds.
U.S. Pat. No. 4,970,204 describes a class of substituted 17.beta.-acyl-3-nitro steroidal 5.alpha.-reductase inhibiting compounds.
U.S. Pat. No. 5,017,568 describes a class of substituted 17.beta.-acyl-3-carboxylic acid steroidal 5.alpha.-reductase inhibiting compounds.
U.S. Pat. No 4,954,446 describes a class of substituted 17.beta.-acyl A ring aryl 3-carboxylic acid steroidal 5.alpha.-reductase inhibiting compounds.
U.S. Pat. No. 4,970,205 describes a class of substituted 17.beta.-acyl A ring aryl 3-sulfonic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 4,910,226 describes a class of substituted 17.beta.-acyl A nor 2-carboxylic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 4,937,237 describes a class of substituted 17.beta.-acyl A ring aryl 3-phosphonic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 4,882,319 describes a class of substituted 17.beta.-acyl A ring aryl 3-phosphinic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 5,026,882 describes a class of substituted 17.alpha.-acyl 3-phosphinic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 4,946,834 describes a class of substituted 17.beta.-acyl 3-phosphonic acid steroidal 5.alpha. reductase inhibiting compounds.
WO 91/19732 describes a class of substituted 17.beta.-acyl 3-acetic acid steroidal 5.alpha. reductase inhibiting compounds.
U.S. Pat. No. 5,100,917 describes substituted 175.beta.-acyl A nor 3-carboxylic acid steroidal 5.alpha. reductase inhibiting compounds.
WO 91/267098-36 describes a class
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J. Steroid Biochem, Molec. Biol. vol. 37, No. 4, pp. 575-579 1990.
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J. Med. Chem. 33 pp. 937-942 1990.
J. of Chromatography, 631 (1993) 251-254.
Dustman Wayne J.
Lentz Edward T.
Prior Kimberly J.
Venetianer Stephen
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