Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-01-06
1995-08-08
Goldberg:, Jerome
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
H61K 31445
Patent
active
054399211
DESCRIPTION:
BRIEF SUMMARY
This application is a continuation of PCT/GB91/01099 filed Jul. 5, 1991.
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to the treatment of prostatic cancer and benign prostatic hypertrophy.
2. Description of Related Art
Conditional neoplasms are those that only grow to certain specific environmental conditions. Androgen-dependent neoplasms fall into such a category, being dependent upon a source of androgens to stimulate their proliferation. Without a source of androgens, they persist but do not proliferate. It is this rationale that supports the initial approach of orchidectomy in the treatment of prostatic cancer, withdrawing the principal source of androgens. Alternatively oestrogen therapy is as effective as orchidectomy, suppressing testicular activity and therefore androgen production by inhibiting the production of pituitary gonadotrophins. There is still some proliferation of prostatic neoplasms after orchidectomy or drug-induced castration, herein collectively referred to as "therapeutic castration", this being partly due to the androgens being secreted by the adrenal gland.
Endocrine therapy, either using androgen antagonists or synthetic oestrogens as described hereinafter, is commonly practised in the treatment of prostatic cancer, both in conjunction with, and independently of therapeutic castration. Oestrogen therapy can be used as described above in depressing testicular activity, and also to treat patients who have suffered a relapse after orchidectomy, as oestrogens have shown a direct regressive effect on the carcinomas of such relapsed patients.
The major drawback in oestrogen therapy is the increased incidence of fatal thromboembolitic disease. Nevertheless, some 60% of patients obtain some relief with diethylstilboestrol, a synthetic oestrogen, a third of whom become refractory and die within two years. Flutemide and cyproterone acetate are two non-steroidal compounds that antagonize androgens; this property also offsets the feedback of androgens in the hypothalamus, stimulating an increase in the levels of luteinzing hormone (LH). The compounds are therefore not appropriate for use in non-castrate patients. Aminoglutethimide (AG) has been tried in the treatment of prostatic cancer as it blocks the side chain cleavage of cholesterol by inhibiting the enzyme desmolase. The results in a reduction of androgens, oestrogens and cortisol. A wide range of trials have been performed, the results of which indicate that some benefit s derived from the use of AG in orchidectomized patients in relapse (Chang A.Y. et al. Am. J. Clan. Oncol. 12 (4) 358-60 (1989)). The use of AG has been combined with hydrocortisone (as a cortisol replacement) but side effects such as skin rashes, lethargy and thrombocytopenia have still been observed (Elomaa I. et al. Eur. Urol. 14 (2) 104-6 (1988)). The actual mechanism through which AG is effective in the treatment of prostatic cancer is debated. Dowsett M. et al. (Br. J. Cancer 57 (2) 190-2 (1988)) do not attribute it to a lowering of adrenal androgen secretion, whereas others in this field do. Overall, the need for cortisol replacement therapy and the undesirable side effects limit the use of AG in treating prostatic cancer.
Additional prior art is referred to in a separate section after "Summary of the Invention", without which its context would not be clear.
SUMMARY OF THE INVENTION
After a trial on 10 post menopausal women with breast cancer it has been found that pyridoglutethemide (3-ethyl-3-(4-pyridyl) glutarimide), a specific aromatase inhibitor, causes a significant reduction in androgens. This was an unexpected observation as androgens are aromarase substrates and blockade of aromatase would not be expected to have an effect on androgen levels. In the light of this finding, simple derivatives of 3-ethyl-3-(4-pyridyl)glutarimide having a substituent in the pyridine ring ortho to the N-atom, would be expected to exhibit the same effect.
Accordingly the invention provides the use of compounds of the formula (I) ##STR2## whe
REFERENCES:
patent: 3944671 (1976-03-01), Dziemian et al.
Leung, Chui-Sheung et al "Analogues of 3-Ethyl-3-(4-pyridyl) . . . ", J. Med. Chem. 1987, 30, pp. 1550-1553.
J. E. F. Reynolds "Martindale--The Extra Pharmacopoeia" edition 29, 1989, Pharmaceutical Press (London, GB), No. 1803, Aminoglutethimide pp. 596-598.
M. R. G. Robinson "Aminoglutethimide: Medical Adrenalectomy . . . " British Jour. of Urology, vol. 52 No. 4, 1980, pp. 328-329.
Weatherall, D. J. et al (Eds) "Medical aspects of neoplasis", Oxford Textbook of Medicine, vol. 1 sections 1-12 and Index, pp. 4.143-4.145. (1987).
British Technology Group Limited
Goldberg: Jerome
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