17-Azolyl steroids useful as androgren synthesis inhibitors

Details 17-Azolyl steroids useful as androgren synthesis inhibitors 17-Azolyl steroids useful as androgren synthesis inhibitors

1999-05-27

2001-03-13

Shah, Mukund J. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S284000, C540S002000, C540S094000, C540S098000, C546S061000

Reexamination Certificate

active

06200965

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel 17-azolyl steroids which are useful as androgen synthesis inhibitors, as well as methods for the use of the same to reduce plasma levels of testosterone and/or dyhydrotestosterone, and to treat prostate cancer and benign prostatic hypertrophy.
BACKGROUND OF THE INVENTION
Breast cancer kills 45,000 women per year. In addition, prostate cancer now ranks as the most prevalent cancer in men. Approximately 160,000 new cases are diagnosed with prostate cancer each year. Of these, 35,000 will die of metastatic disease.
It has been proposed that selective aromatase (estrogen synthetase) inhibitors to control estrogen production would be useful agents for treatment of breast cancer in women (Bolla et al,
N. Eng. J. Med.,
337:295-300 (1997)). In addition, in men, aromatase inhibitors may be useful for conditions associated with estrogen excess, such as gynecomastia and oligospermia (Coen et al,
New Eng. J. Med.,
324:317-322 (1991); and Hsiang et al,
J. Steroid Biochem.,
26:131-136 (1987)). It has also been suggested that aromatase inhibitors might be useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH) (Henderson,
Annals Med.,
23:201-203 (1991)).
Compounds which are potent and selective inhibitors of aromatase have been reported (Schwarzel et al,
Endocrinol.,
92:866-880 (1973)). The most active of those inhibitors, 4-hydroxyandrostene-3,17-dione (4-OHA) (Brodie et al,
J. Steroid Biochem.,
7:787-793 (1976)), was found to act by rapid competitive inhibition, followed by inactivation of the enzyme in vitro, which appeared to be long-lasting or irreversible (Brodie et al,
Steroids,
38:693-702 (1981)). Enzyme inhibitors with these properties are thought to bind to the active site of the enzyme, are likely to be quite specific, and should have long-lasting effects in vivo due to inactivation of the enzyme (Sjoerdsma,
Clin. Pharmacol. Ther.,
30:3 (1981)). It was also demonstrated that 4-OHA reduces peripheral plasma estrogen levels, and causes significant regression of breast cancers in postmenopausal patients with advanced metastatic disease who have relapsed from other hormonal treatment, such as ovariectomy and tamoxifen. 4-OHA has both oral and parenteral activity, and is without significant side-effects in these patients (Goss et al,
Cancer Res.,
46:4223-4826 (1986); and Coombes et al,
Steroids,
50:245-252 (1987)). 4-OH-A, also known as formastane, was approved in 1995 for the treatment of breast cancer in many countries worldwide, including most European countries and Canada. It was the first new treatment for breast cancer in 10 years.
In men, estrogens are produced by the testes, and by peripheral aromatization of adrenal androgens. Testosterone is the major product of the testis, and is converted in the prostate by 5&agr;-reductase to the more potent androgen, dihydrotestosterone (DHT) (Bruchovsky et al,
J. Biol. Chem.,
243:2012-2021 (1968)). While androgens are of primary importance in the growth of normal prostate, BPH and prostatic cancer, several lines of evidence suggest that estrogens may also have a role (Mawhinney et al,
Adv. Sex Horm. Res.,
2:41-209 (1976)).
4-OHA also inhibits 5a-reductase in vitro, although with less potency than it inhibits aromatase (Brodie et al,
Cancer Res.,
49:6551-6555 (1989b)). Because of these two activities, the possibility that 4-OHA might be effective in prostatic cancer was explored in a small group of men with advanced disease. Subjective responses were observed in 80% of these patients, although there was no clear evidence of objective remissions (Shearer et al,
In:
4-
hydroxyandrostenedione—A New Approach to Hormone
-
Dependent Cancer,
Eds. Coombes et al, pages 41-44 (1991)). Estrogen levels were reduced as expected but, DHT concentrations were unchanged in the patients. The latter finding, in addition to the weak androgenic activity of 4-OHA, may have determined the lack of objective responses.
Chemotherapy is usually not highly effective, and is not a practical option for most patients with prostatic cancer because of the adverse side-effects which are particularly detrimental in older patients. However, the majority of patients initially respond to hormone ablative therapy (McGuire, In:
Hormones and Cancer,
Eds. Iacobelli et al, Raven Press, New York, Vol. 15, pages 337-344 (1980)) although they eventually relapse, as is typical with all cancer treatments. Current treatment by orchidectomy or administration of gonadotropin-releasing hormone (GnRH) agonists result in reduced androgen production by the testis, but does not interfere with androgen synthesis by the adrenals. Following 3 months of treatment with a GnRH agonist, testosterone and DHT concentrations in the prostate remained at 25% and 10%, respectively, of pretreatment levels (Forti et al,
J. Clin. Endocrinol. Metab.,
68:461-468 (1989)). Similarly, about 20% of castrated patients in relapse had significant levels of DHT in their prostatic tissue (Geller et al,
J. Urol.,
132:693-696 (1984)). These finding suggest that the adrenals contribute precursor androgens to the prostate. This is supported by clinical studies of patients receiving combined treatment with either GnRH or orchidectomy and an anti-androgen, such as flutamide, to block the actions of androgens, including adrenal androgens. Such patients have increased progression-free survival time compared to patients treated with GnRH agonist or orchidectomy alone (Crawford et al,
N. Engl. J. Med.,
321:419-424 (1989); and Labrie et al,
Cancer Suppl.,
71:1059-1067 (1993)).
Although patients initially respond to endocrine therapy, they frequently relapse. It was reported recently that in 30% of recurring tumors of patients treated with endocrine therapy, high-level androgen receptor (AR) amplification was found (Visakorpi et al,
Nature Genetics,
9:401-406 (1995)). Also, flutamide tends to interact with those mutant AR, and stimulate prostatic cell growth. This suggests that AR amplification may facilitate tumor cell growth in low androgen concentrations. Thus, total androgen blockade as first line therapy may be more effective than conventional androgen deprivation by achieving maximum suppression of androgen concentrations which may also prevent AR amplification. It is presently unclear whether sequential treatment with different agents can prolong the benefits of the initial therapy. This strategy has been found effective in breast cancer treatment. New agents which act by different mechanisms could produce second responses in a portion of relapsed patients. Although the percentage of patients who respond to second-line hormonal therapy may be relatively low, a substantial number of patients may benefit because of the high incidence of prostatic cancer. Furthermore, there is the potential for developing more potent agents than current therapies, none of which are completely effective in blocking androgen effects.
Human cytochrome 17&agr;-hydroxylase/C
17,20
-lyase (hereinafter “P450
17&agr;
”) is a key enzyme in the biosynthesis of androgens, and converts the C
21
steroids (pregnenolone and progesterone) to the C
19
androgens, dehydroepiandrosterone (DHEA), 5-androstenediol (A-diol), testosterone, and 5 androstenedione in the testis and adrenals. Some inhibitors of P450
17&agr;
have been described (Barrie,
J. Steroid Biochem.,
33:1191-1195 (1989); McCague et al,
J. Med. Chem.,
33:3050-3055 (1990); Jarman et al,
J. Med. Chem.,
33:2452-2455 (1990); Ayub et al,
J. Steroid Biochem.,
28:521-531 (1987); Nakajin et al,
Yakugaku Zasshi.
(
Japan
), 108:1188-1195 (1988); Nakajin et al,
Chem. Pharm. Bull.
(
Tokyo
), 37:1855-1858 (1989); Angelastro et al,
Biochem. Biophys. Res. Commun.,
162:1571-1577 (1989); Potter et al,
J. Med. Chem.,
38:2463-2471 (1995); and Rowlands et al,
J. Med. Chem.,
38:4191-4197 (1995)). Ketoconazole, an active imidazole fungicide, has been used to reduce testosterone biosynthesis in the treatment of patients with advanced prostatic cancer (Trachtenberg,
J. Urol

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