Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-08-15
1996-08-06
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142282, 5142328, 514253, 514280, 514284, 514410, 540572, 546 42, 546 61, 548418, 548420, A61K 3140, A61K 31435, A61K 3155
Patent
active
055434061
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to certain substituted 17.beta.-substituted-6-azaandrost-4-en-3-ones and their use as 5.alpha.-testosterone reductase inhibitors.
BACKGROUND OF THE INVENTION
Androgens are responsible for many physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone (LH). However, reduction of the 4,5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid 5.alpha.-reductase in target tissues catalyzes conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A. ##STR2## The requirement for DHT to act as an agonist in these target tissues has been highlighted by studies of steroid 5.alpha.-reductase deficient individuals who have vestigial prostate glands and do not suffer from acne vulgaris or male pattern baldness (see McGinley, J., et al, J. Steroid Biochem., 11, 637-648, (1979)). Thus, inhibition of the conversion of testosterone to DHT in these target tissues is anticipated to be useful in the treatment of a variety of androgen responsive diseases, e.g., benign prostatic hypertrophy, prostate cancer, acne, male pattern baldness and hirsutism.
Because of their valuable therapeutic potential, testosterone 5.alpha.-reductase inhibitors [hereinafter "5.alpha.-reductase inhibitors"] have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 224 (1973); Robaire, B., et al., J. Steroid Biochem., 8, 307 (1977); Petrow, V., et al., Steroids, 38, 121 (1981); Liang, T., et al., J. Steroid Biochem., 19, 395 (1983); Holt, D., J. Med. Chem., 33, 937 (1990); U.S. Pat. Nos. 4,377,584 and 5,017,568. Two particularly promising 5.alpha.-reductase inhibitors currently in clinical trials are MK-906 (Merck) and SKF-105657 (SmithKline Beecham), shown in Scheme B. ##STR3##
SUMMARY OF THE INVENTION
One aspect of the present invention are the compounds of formula (I), ##STR4## wherein R.sup.1 and R.sup.2 are, bearing R.sup.1 and R.sup.2 is a single or a double bond, or and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond; halogen atoms, lower cycloalkyl, lower cycloalkyl-lower alkyl, halogen, -(Alk.sup.1).sub.n -CO.sub.2 H, -(Alk.sup.1).sub.n -CO.sub.2 R.sup.7, -(Alk.sup.1).sub.n -Ar.sup.1, -(Alk.sup.1).sub.n -CONR.sup.8 R.sup.9, -(Alk.sup.1).sub.n -NR.sup.8 R.sup.9, -(Alk.sup.1).sub.n -S(O).sub.r R.sup.7, -(Alk.sup.1).sub.n -CN, -(Alk.sup.1)-OH or -(Alk.sup.1).sub.n -OR.sup.7 ; wherein cycloalkyl; cycloalkyl-lower alkyl, -(Alk.sup.1).sub.n -S(O).sub.r R.sup.7, -(Alk.sup.1).sub.n -phthalimidyl, -(Alk.sup.1)-CO.sub.2 H, -(Alk.sup.1).sub.n -CO.sub.2 R.sup.7, -(Alk.sup.1).sub.n -Ar.sup.1, -(Alk.sup.1).sub.n -CONR.sup.8 R.sup.9, -(Alk.sup.1).sub.n -NR.sup.8 R.sup.9, -(Alk.sup.1).sub.n -OH or -(Alk.sup.1).sub.n -OR.sup.7 ; ##STR5## wherein R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl, -(Alk.sup.2).sub.n -CO-thiopyridinyl or -(Alk.sup.2).sub.n -CONR.sup.14 R.sup.15, wherein alkynylene; adamantyl, -Ar.sup.1, benzyl, diphenylmethyl, triphenylmethyl or -(Alk.sup.1).sub.n -norbornyl; or heterocyclic group ##STR6## wherein; Het represents --O--, --CH.sub.2 --, --S(O).sub.r --, --NH-- or --N(-Alk.sup.1 -H)--; optionally substituted with one or more lower alkyl groups;
A second aspect of the invention is a method of inhibiting testosterone-5.alpha.-reductase comprising contacting testosterone-5.alpha.-reductase with a compound of formula (I).
Another aspect of the invention is a method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) to a patient in need of such treatment.
A further aspect comprises pharmaceutical formulations containing a compound of fo
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Andrews Robert C.
Cribbs Cynthia M.
Frye Stephen V.
Haffner Curt D.
Maloney Patrick R.
Brink Robert H.
Dadswell Charles E.
Datlow Philip I.
Glaxo Wellcome Inc.
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