Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-07-15
1997-10-14
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
548202, 548203, 548235, 5483351, 5483411, A61K 3158
Patent
active
056772939
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
It is estimated that 75% of prostatic cancers are sensitive to levels of androgens, more specifically testosterone. (Van Wauwe, J. P. and Janssen, P. A. J., J. Med. Chem., (1989), 32, 2233). It is well established that reduction of serum testosterone levels is useful in the treatment of such prostatic cancers. In clinical practice, this has been accomplished for example by orchiectomy or by diethylstilbestrol treatment. However, the first approach is often psychologically unacceptable while a number of side effects are associated with the second approach.
The cytochrome P-4501.sub.17 .alpha. monooxygenase enzyme system catalyzes the 17.alpha.-hydroxylation of C.sub.21 steroids and also catalyzes the oxidative cleavage of the C.sub.17-20 bond. (Blohm, T. R. et al., Biochem. Biophys. Res. Commun., (1989), 162, 1571). More specifically the steroid C.sub.17-20 lyase activity of cytochrome P-450.sub.17.alpha. catalyzes the conversion of the C.sub.21 steroids pregnenolone and progesterone to the C.sub.19 steroids dehydroepiandrosterone and androstenedione, which are the precursors of the androgens, 5.alpha.-dihydrotestosterone and testosterone. Androstenedione and testosterone, in turn, are the precursors of the estrogens, estrone and estradiol. Thus, inhibition of the steroid C.sub.17-20 lyase can reduce formation of the androgens as well as the estrogens. As a result of this effect, the search for effective and selective inhibitors of the steroid C.sub.17-20 lyase enzyme is expanding. (Laughton, C. A. and Neidle, S., Biochem. Biophys. Res. Commun., (1990), 171, 1160). C.sub.17-20 lyase inhibitors would be useful for treating various androgen-dependent disorders. More particularly, such compounds would be useful in the treatment of prostatic carcinoma, benign prostatic hyperplasia, male-pattern baldness and virilism and hirsutism (in women). In addition, C.sub.17-20 lyase inhibitors would also be useful in the treatment of estrogen-dependent disorders, such as estrogen dependent breast cancer.
Thus, in light of the drawbacks associated with diethylstilbestrol treatment or orchiectomy, there has been an ongoing search for effective inhibitors of steroid C.sub.17-20 lyase. The present invention relates to C.sub.17 heterocyclic steroids and also to a method for using such compounds as effective steroid C.sub.17-20 lyase inhibitors. More particularly, the present invention relates to the treatment of androgen dependent disorders.
SUMMARY OF THE INVENTION
The present invention relates to compounds having the following general formula I: ##STR1## wherein - - - represents a single or double bond; alkyl;
The present invention further provides a method of inhibiting the steroid C.sub.17-20 lyase activity in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound of formula II: ##STR2## wherein - - - represents a single or double bond; ##STR3## wherein Q is O, S or NR;
The present invention further provides a method of inhibiting the steroid C.sub.17-20 lyase activity in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound of formula (I).
The present invention further provides a method of treating a patient suffering from an androgen dependent disorder comprising administering to said patient an effective inhibitory amount of a compound of formulas (I) or (II).
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "C.sub.1 -C.sub.4 alkyl" refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. The term "halogen" or "halo" refers to a chlorine, bromine or iodine atom.
The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three dimensional structures are called configurations.
It is understoo
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Burkhart Joseph P.
Gates Cynthia A.
Peet Norton P.
Lentz Nelson L.
Merrell Pharmaceuticals Inc.
Owens Amelia
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