Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-11
1999-12-14
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514255, 514256, 514262, 514265, 514266, 514269, 514272, 514274, 514275, 544265, 544266, 544268, 544276, 544277, 544301, 544311, 544312, 544316, 544317, 544319, 544320, 544322, 544323, 544329, 544332, C07D22102, A61K 31435
Patent
active
060018445
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel compounds, novel compositions, methods of their use and methods of their manufacture where such compounds are generally pharmacologically useful as agents in therapies for diseases relating to hyperandrogenic stimulation, particularly caused by excessive accumulation of testosterone ("T") dihydrotestosterone ("DHT") and similar androgenic hormones in the metabolic system.
The novel compounds of the present invention are especially useful in the prevention and treatment of prostatic carcinoma, and they may also be useful in the treatment and prevention of other hyperandrogenic diseases such as acne vulgaris, seborrhea, female hirsutism, also called androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia.
The compounds of the present invention are 3-oxo-4-azasteroids, particularly 17-substituted, 4-aza-5.alpha.-androstan-3-one derivatives.
Finasteride, (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-3-one ) as shown below, is a potent inhibitor of the human prostate enzyme. ##STR2## Under the trade name PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions; see e.g. U.S. Pat. No. 4.760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published Oct. 5, 1988; EP 0 285,383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276.
Finasteride is a 5.alpha.-reductase inhibitor. The enzyme 5.alpha.-reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below: ##STR3##
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5.alpha.-reductase. Inhibitors of testosterone-5.alpha.-reductase prevent or lessen symptoms of hyperandrogenic stimulation in these organs.
There are two isozymes of 5.alpha.-reductase in humans. One isozyme (type 1) predominates in sebacious glands of facial and skin tissue and is relatively insensitive to finasterides, the other (type 2) predominates in the prostate and is potently inhibited by finasteride. European patent publication EP 0 547 691 discloses 17-substituted 4-aza-5.alpha.-androstan-3-one derivatives useful in the treatment of prostatic carcinoma.
European Patent Publication 0 484 094 discloses 4-azasteroid compounds with 17-aryl carboxamide substitutions.
Other attempts to provide a chemotherapeutic agent to counter the desirable results of hyperandrogenicity led to the discovery of steroidal antiandrogens such as: hydroxy-flutamide (the active form of flutamide), and Casodex.TM.(the trademark for ICI 176,334 from Imperial Chemical Industries PLC.) ##STR4##
For the treatment of advanced prostatic carcinoma, therapy has included castration by surgery (orchidectomy) or by using an LHRH agonist.
There remains a need for an agent which approaches the treatment of hyperandrosgenic diseases by inhibiting both the isozymes of 5.alpha.-reductase. The present invention provides for such compounds.
SUMMARY OF THE INVENTION
The novel compounds of the present invention are those of structural Formula (I) ##STR5## and a pharmaceutically acceptable salts and esters thereof which are potent antiandrogens. These compounds inhibit 5.alpha.-reductase type 1 and type 2. The compounds of structural Formula I are useful in the systemic, including oral, and parenteral, including topical, treatment and prevention of hyperandrogenic conditions including prostatic carcinoma, benign prostatic hyperplasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenetic alopecia) which includes male- and female-pattern baldness, female hirs
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Tolman et al., "4-Methyl-3-oxo-4-aza-5alpha-androst-1-en17beta-N-aryl-carboxamides: An approach to combined androgen blockade"; Mar. 1997 issue of J. Steroid Biochem & Molec. Bio. vol. 60, No. 5-6 pp. 303-309.
Bakshi Raman K.
Sahoo Soumya P
Tolman Richard L.
Coleman Brenda
Durette Philippe L.
Fitch Catherine D.
Merck & Co. , Inc.
Shah Mukund J.
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