7-substituted oxa- or azasteroid compound

Details 7-substituted oxa- or azasteroid compound 7-substituted oxa- or azasteroid compound

1995-03-24

1996-07-23

Rizzo, Nicholas

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546 61, A61K 31565, C07J 3100

Patent

active

055391273

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel 7-substituted oxa- or azasteroid compounds having an aromatase-inhibiting action, and more detailedly relates to a steroid compound represented by the formula ##STR2## wherein R.sup.1 denotes --S--R.sup.2, --S(O)m--R.sup.3 or an aralkyl group, with a hydroxyl, amino or lower alkoxycarbony group; a lower alkenyl group; an aralkyl group; an aryl group optionally substituted with halogen atom(s), or amino, di-(lower alkyl )amino, lower alkoxy or lower alkyl group(s); an acyl group; or a lower alkoxycarbonyl group, amino or lower alkoxycarbonyl group; a lower alkenyl group; an aralkyl group; an aryl group optionally substituted with halogen atom(s), or amino, di-(lower alkyl) amino, lower alkoxy or lower alkyl group(s); or an acyl group, 7-positions of the steroid skeleton mean that a double bond can exist there, provided that the 6- and 7-positions is assumed to denote a single bond, and 2-positions is assumed to denote a single bond.


BACKGROUND OF INVENTION

Biosynthesis of estrogens can be carried out by means such that androgens are subjected to oxidation and elimination of formic acid by an enzyme called aromatase, and aromatized. Therefore, if the action of aromatase can effectively be inhibited, it is expected to be useful for treatment of diseases caused by estrogens, and in line with this expectation, several aromatase inhibitors have already been found to be effective for treatment of breast cancer and prostatic hypertrophy.
Aromatase inhibitors are also effective for treatment of other diseases caused by estrogens, for example uterine cancer, ovarian cancer, endometriosis, male gynecomastia, male e infertility related to oligospermia, etc.
As known steroid aromatase inhibitors, there have, for example, been known testolactone (Merck Index, 10th edition, 8999), 4-hydroxy-4-androstene-3,17-dione and its esters (U.S. Pat. No. 4,235,893), 1-alkylandrosta-1,4-diene-3,17-dione derivatives (Japanese Laid-Open Patent Publication No. 13796/1985), 4-substituted androstene-3,17-dione derivatives (Japanese Laid-Open Patent Publication No. 189295/1986), 6-methyleneandrosta-1,4-diene-3,17-dione derivatives (Japanese Laid-Open Patent Publication No. 12797/1987), 16-oxaandrosta-1,4-diene-3,17-dione (Journal of Medicinal Chemistry, 32, 651, (1989)), 7.alpha.-substituted thioandrostenedione derivatives (Journal of Medicinal Chemistry, 21, 1007, (1978)), etc.
However, these steroid aromatase inhibitors, when administered into living bodies, are liable to be inactivated through metabolism, and are still not satisfactory for clinical use.
The present inventors found that a series of steroid compounds wherein a hetero atom is introduced into the ring D part and the 7-position of the steroid skeleton is substituted with a specific substituent have a very excellent aromatase-inhibiting activity, and moreover, are slow to undergo inactivation through metabolism.


DISCLOSURE OF INVENTION

In this description, the term "lower" means that the carbon atom number of groups or compounds to which this term is attached is 6 or less, preferably 4 or less.
In the above formula (I), the "lower alkyl group" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups, etc., the "lower alkoxy group" includes, for example, methoxy, ethoxy, n-propoxy, n-butoxy groups, etc., the "lower alkenyl group" includes, for example, vinyl, all yl groups, etc., the "lower alkoxycarbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl groups, etc., and the "aralkyl group" includes, for example, benzyl, 4-methoxybenzyl, phenethyl groups, etc.
The "lower alkyl group optionally substituted with a hydroxyl, amino or lower alkoxycarbonyl group" includes, for example, besides the above-mentioned unsubstituted lower alkyl groups. 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, groups, etc., and the "aryl group optionall

REFERENCES:
patent: 4116978 (1978-09-01), Cimarusti et al.
patent: 4235893 (1980-11-01), Brodie et al.
patent: 4591585 (1986-05-01), Kerb et al.
patent: 4757061 (1988-07-01), Faustini et al.
patent: 4808616 (1989-02-01), Buzzetti et al.
patent: 5219879 (1993-06-01), Ko et al.
patent: 5227375 (1993-07-01), Labrie et al.
Sherwin et al., "Effects of Steroid D-Ring Modification on Suicide Inactivation and Competitive Inhibition of Aromatase by Analogues of Androsta-1,4-diene-3,17-dione", Journal of Medicinal Chemistry, 1989, 32, pp.651-658.
Brueggemeier et al., "Synthesis and Biochemical Evaluation of Inhibitors of Estrogen Biosynthesis", Journal of Medicinal Chemistry, 1978, vol. 21, No. 10, pp. 1007-1011.

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