2,6-dioxopiperidine derivatives, their preparation and pharmaceu

Details 2,6-dioxopiperidine derivatives, their preparation and pharmaceu 2,6-dioxopiperidine derivatives, their preparation and pharmaceu

1990-08-22

1991-12-10

Brust, Joseph Paul

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546193, A61K 31445, C07D40104

Patent

active

050718576

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of Invention
This invention relates to derivatives of 2,6-dioxopiperidine, also known as glutarimide, their preparation and pharmaceutical compositions containing them.
2. Description of Prior Art
U.S. Pat. No. 2,673,205 (Ciba) claims 3,3-disubstituted-glutarimides of formula ##STR2## R.sup.1 represents an aliphatic hydrocarbyl group of 1 to 6 carbon atoms and Ar represents a phenyl or pyridyl group, and R.sup.2 represents hydrogen or a substituent group such as alkyl, acyl, phenyl or benzyl. 12 such compounds were prepared, 11 of them being 3-phenyl derivatives (Ar in formula 1=phenyl) and 3-ethyl-3-(3-pyridyl)glutarimide of formula ##STR3## where Et=ethyl. The class of compounds claimed in U.S. Pat. No. 2,673,205 is stated to have an anti-convulsive effect. However, the preferred compound, 3-ethyl-3-phenylglutarimide was subsequently marketed as the sedative and hypnotic agent glutethimide. The later U.S. Pat. No. 2,848,455 (Ciba) claims 3-methyl and -ethyl-3-(4-aminophenyl)glutarimides as anti-convulsive agents. The 3-ethyl compound is known as aminoglutethimide. V. Carelli, Ann. Chim. (Rome) 51, 713-718 (1961), describes "Nota", 3-ethyl-3-(2-pyridyl)-glutarimide, as having a sedative and hypnotic effect. U.S. Pat. No. 3,057,867 claims a large class of N-aminoglutarimides having sedative and anti-convulsive activity.
The present invention is concerned with an entirely different field of therapy, namely anti-cancer therapy, specifically the treatment of oestrogen-dependent tumors. Such tumors are most commonly produced in the breast tissue of female mammals. Within the last 5 years or so aminoglutethimide has come seriously into the reckoning for treatment of advanced breast cancer in post-menopausal patients. Its advantages over tamoxifen have been set out in a recent paper by I. E. Smith et al., British Medical Journal, 283, 1432-1434 (1981). One important factor in the success of aminoglutethimide in this connection is its ability to inhibit in vivo the activity of the enzyme aromatase in peripheral tissue. This enzyme is required for the conversion of androgens into oestrogens. Aminogluthethimide therefore breaks the metabolic pathway to oestrogens. Unfortunately, however, aminoglutethimide also inhibits the enzyme desmolase which is required for the metabolic conversion of cholesterol to corticosteroids. Since the body needs corticosteroids, treatment with aminoglutethimide has to be supplemented by cortisone replacement therapy. Furthermore, depletion of corticosteroids causes a reflex rise in adrenocorticotrophic hormone (ACTH) which stimulates the conversion of cholesterol to pregnenolone by the enzyme desmolase and consequently the production of oestrogen precursors.


SUMMARY OF THE INVENTION

After extensive experiments, we have now found a glutarimide which inhibits aromatase but not desmolase. Moreover, tests indicate that its sedative and anti-convulsant side-effects are lower than that of aminoglutethimide. We have found that the compound can be used successfully in the treatment of mammalian breast cancer. The compound is 3-ethyl-3-(4-pyridyl)glutarimide. Also, certain derivatives thereof, having a substituent group in the pyridine ring ortho to the N-atom inhibit aromatase and show no or insignificant inhibition of desmolase. These compounds are believed to be novel and accordingly the invention provides these compounds which collectively are of general formula ##STR4## wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (which can have a straight or branched chain in the case of propyl and butyl), and their acid addition salts, both per se and for use in the treatment of oestrogen-dependent tumors in mammals.
The compounds of formula (3) are optically active. The invention includes them in the form of their individual optical isomers and mixtures thereof, especially racemates. The R isomers [cf. the R isomer of aminoglutethimide, Graves and Salhanick, Endocrinology 105, 52 (1979)] are expected to show the greater inhibi

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