Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-02
1997-05-13
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
056293186
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/11155 filed Nov. 18, 1993.
BACKGROUND OF THE INVENTION
The present invention is concerned with the use of 17.beta.-N-monosubstituted-carbamoyl-4-aza-5.alpha.-androst-1-en-3-one compounds as testosterone-5.alpha.-reductase inhibitors for the treatment of chronic prostatitis.
DESCRIPTION OF THE PRIOR ART
Prostatitis in general constitutes about 10 to 15% of all urological practice. This category of poorly understood syndromes can be characterized by evidence of prostatic inflammation and by the presence or absence of white blood cells in prostatic fluid and/or pain associated with the prostate. Within this group of syndromes, the origins of chronic idiopathic prostatitis, asymptomatic prostatitis, and prostatodynia are problematic and are probably the least understood. The origin of these diseases have been attributed to some undefinable bacterial or viral infection, but this has never been proven. These syndromes do not exist prior to puberty but have a peak incidence between the ages of 18 and 50. It is possible that these three specific entities actually represent the same disease process in different phases or forms. Suggestions as to the origins of these conditions have included a chemical imbalance in the prostate, infection undetected by current microbiological methods, and autoimmunity to the prostate gland itself.
What is desired from a therapeutic standpoint is a drug that effectively shuts down the prostate metabolically to inhibit growth and lessen the activity of the prostatitis condition. Particularly what is desired is a drug that blocks the action of the prostatic enzyme that utilizes blood testosterone.
An anti-androgenic agent such as this with minimal side effects, i.e. feminization, is reasonably believed would be of value in the treatment of these common but complexing disorders. It is further believed that a drug which can decrease prostate size, decrease the production of prostate secretions and of substances which might cause inflammation, may very well lead to a cessation of the specific symptoms of prostatitis.
It is known in the art that the principal mediator of androgenic activity in some target organs is 5.alpha.-dihydrotestosterone (DHT), and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfe et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17.beta.-carboxylate was a testosterone-5.alpha.-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17.beta.-carboxylic acid are both active inhibitors of testosterone-5.alpha.-reductase in vitro. They further demonstrated that topical application of either testosterone or 5.alpha.-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17.beta.-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5.alpha.-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5.alpha.-reductase.
A number of 4-aza steroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60, No. 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, U.S. Pat. Nos. 4,377,584, 4,220,775, 4,760,071, 4,859,681 and 5,049,562 of Rasmusson et al. describe a group of 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be usefu
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Gormley Glenn J.
Stoner Elizabeth
Criares Theodore J.
Fitch Catherine D.
Merck & Co. , Inc.
Winokur Melvin
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