Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-09-28
1996-05-21
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549384, C07D31178, A61K 3135
Patent
active
055190510
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 92/00364 filed Mar. 26, 1992.
TECHNICAL FIELD
This invention relates to novel oxa- or azasteroid derivatives having an aromatase inhibition action, and relates in more detail to steroid derivatives represented by the formula ##STR2## wherein
R.sup.1 denotes a hydrogen atom or a lower alkyl group;
R.sup.2 denotes a hydrogen atom, a halogen atom, or a hydroxyl, mercapto or amino group which may optionally be acylated or lower alkylated;
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 denote one of the following (a) to (d):
(a) R.sup.3 and R.sup.5 each denote a hydrogen atom, and R.sup.4 and R.sup.6 each denote a hydrogen atom, a halogen atom or a lower alkyl group,
(b) R.sup.3 and R.sup.6 each denote a hydrogen atom, and R.sup.4 and R.sup.5 combine to denote a single bond, a methylene group or a dihalomethylene group,
(c) R.sup.3 and R.sup.4 combine to denote an oxo group or a methylene group, and R.sup.5 and R.sup.6 each denote a hydrogen atom,
(d) R.sup.3 denotes an acyloxy group, R.sup.4 and R.sup.5 combine to denote a single bond, and R.sup.6 denotes a hydrogen atom;
A denotes C.dbd.O, CH.sub.2, C.dbd.CH.sub.2 or C.dbd.CH-lower alkyl;
B denotes O, NH or N-lower alkyl;
X does not exist, or denotes C.dbd.O or CH.sub.2 ;
n denotes 2 or 3 when X does not exist, or denotes 1 or 2 when X denotes C.dbd.O or CH.sub.2 ; and
the broken line between the 1- and 2-positions of the steroid skeleton means that a double bond may optionally exist there,
provided that the cases of the following (i) to (v) are excluded:
(i) the case where each of R.sup.1 to R.sup.6 is a hydrogen atom, A is C.dbd.O, B is O, X is C.dbd.O, n is 1, and a double bond exists between the 1- and 2-positions of the steroid skeleton,
(ii) the case where each of R.sup.1 to R.sup.6 is a hydrogen atom, A is C.dbd.O, B is O or NH, X is C.dbd.O, n is 1, and the 1- and 2-positions of the steroid skeleton are combined by a single bond,
(iii) the case where each of R.sup.1, R.sup.2, R.sup.3 and R.sup.6 is a hydrogen atom, R.sup.4 and R.sup.5 combine to denote a single bond, A is C.dbd.O, B is NH, X is C.dbd.O, n is 2, and the 1- and 2-positions of the steroid skeleton are combined by a single bond,
(iv) the case where B is NH or N-lower alkyl, and X does not exist, and
(v) the case where B is NH or N-lower alkyl, X is CH.sub.2, A is C.dbd.O, C.dbd.CH.sub.2 or C.dbd.CH-lower alkyl.
BACKGROUND ART
Biosynthesis of estrogens occurs when androgens are oxidized with an enzyme called aromatase, formic acid is eliminated, and the androgens are aromatized. Therefore, if it is possible to inhibit the action of aromatase effectively, it is considered to be useful for treatment of diseases caused by excess of estrogens, and, based thereon, it is already revealed that several aromatase inhibitors are useful for treatment of breast cancer and prostatic hypertrophy.
Further, aromatase inhibitors are also useful for treatment of other diseases caused by excess of estrogens, for example, uterine cancer, ovarian cancer, endometriosis, gynecomastia, male infertility based on oligospermia, etc.
As steroidal aromatase inhibitors, there have, for example, been known testolactone (The 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 (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 (J. Med. Chem., 32, 651, (1989)), etc.
On the other hand, as compounds having chemical structure comparatively analogous to that of the compounds of this invention, there have been known 16-azaandrost-4-ene-3,17-dione and 16-methyl-16-azaandrost-4-en-3-one (J. Med. Chem., 10, 177, (1967)), 17-aza-D-homoandrosta-4,6-diene-3,17a-dione (U.S. Pat. No. 3,642,800), 17a-aza-D-homoandrost-4-en-3-one (J. Am. Chem., Soc., 78, 639, (1
REFERENCES:
patent: 3642800 (1972-02-01), Nelson et al.
patent: 4235893 (1980-11-01), Brodie et al.
patent: 4591585 (1986-05-01), Kerb et al.
patent: 4596797 (1986-06-01), Schweikert et al.
patent: 4757061 (1988-07-01), Faustini et al.
patent: 4808616 (1989-02-01), Buzzetti et al.
patent: 5227375 (1993-07-01), Labrie et al.
CA 114 62401
CA 108 183872
CA 106 102579
The Merch Index, 10th Edition, Entry 8999.
Sherwin et al., J. Med. Chem., "Effects of Steroid D-Ring Modification on Suicide Inactivation and Competitive Inhibition of Aromatase by Analogues of Androsta-1, 4-diene-3, 17-dione", vol. 32, pp. 651-658 (1989).
Kierstead et al., J. Med. Chem. "16-Aza Steroids", vol. 10, pp. 177-181 (1967).
Regan et al., J. Am. Chem. Soc., "17-- and 17a-Aza-D-homosteroids", vol. 78, pp. 639-643 (1956).
Suginome et al., J. Org. Chem., "Photoinduced Transformations. 73..sup.1 Transformations of Five-- (and Six--) Membered Cyclic Alcohols into Five-- (and Six--) Membered Cyclic Ethers-A New Method of a Two-Step Transformation of Hydroxy Steroids into Oxasteroids.sup.2 ", vol. 49, pp. 3753-3762 (1984).
Ryan, The Journal of Biological Chemistry, "Biological Aromatization of Steroids", vol. 234, pp. 268-272 (1959).
Thompson et al., The Journal of Biological Chemistry, "The Involvement of Human Placental Microsomal Cytochrome P-450 in Aromatization", vol. 249, pp. 5373-5378 (1974).
Honma Seijiro
Iwashita Shigeki
Kawachi Tomoko
Koizumi Naoyuki
Matsui Teruaki
Geist Gary
Kilby Scalzo Catherine
Teikoku Hormone Mfg. Co. Ltd.
LandOfFree
Oxa- or azasteroid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oxa- or azasteroid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oxa- or azasteroid derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2038388