Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1999-03-12
2000-07-11
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514100, 514284, 514453, 546 23, 546 77, 549220, 549277, 549384, A61K 3135, A61K 3147, C07D31178, C07D22118
Patent
active
060873477
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel 3-substituted-D-homo-1,3,5(10)-estratriene derivatives. More particularly, it relates to estratriene derivatives of the formula ##STR2## wherein one of A and B represents C.dbd.O or CH.sub.2 and the other represents O or NH; and R represents --SO.sub.2 NR.sup.1 R.sup.2 or --PO(OM).sub.2 in which R.sup.1 and R.sup.2 each independently represent a hydrogen atom or a lower alkyl group and M represents a hydrogen atom or an alkali metal; provided that, when one of A and B represents NH, the other represents C.dbd.O.
BACKGROUND ART
Estrone sulfate, which is an intermediate product in the steroid metabolism within the human body, is hydrolyzed by estrone sulfatase present in the living body to yield estrone in free form. It is also known that, in the living body, this estrone is further converted reversibly into estradiol by the action of 17.beta.-hydroxysteroid dehydrogenase. These estrogens formed in the steroid metabolism, such as estrone and estradiol, are considered to be closely associated with diseases such as breast cancer, uterine cancer, ovarian cancer, endometriosis, adenomyosis uteri and mastopathy.
Accordingly, it is believed that, if the action of estrone sulfatase can be effectively inhibited, this would be effective for the treatment of diseases associated with estrogens. From this point of view, several compounds having an inhibitory effect on estrone sulfatase, as typified by estrone-3-sulfamate, have been proposed (see the pamphlet of International Publication of PCT Application No. WO93/05064).
However, estrone-3-sulfamate has the disadvantage that it causes an increase in liver weight as observed after the administration of estrogens.
It has now been found that novel 3-substituted-D-homo-1,3,5(10)-estratriene derivatives of the above formula (I) in which an oxygen or nitrogen atom is introduced into the D ring exhibit a powerful inhibitory effect on estrone sulfatase without causing an increase in liver weight.
Thus, the present invention provides estratriene derivatives of the above formula (I).
DISCLOSURE OF THE INVENTION
The term "lower" as used herein means that the groups or compounds modified by this term have not more than 6 carbon atoms and preferably not more than 4 carbon atoms.
In the above formula (I), examples of the "lower alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-hexyl, and examples of the "alkali metal" include sodium and potassium.
Consequently, examples of the substituent group represented by R include --SO.sub.2 NH.sub.2, --SO.sub.2 NHCH.sub.3, --SO.sub.2 NHC.sub.2 H.sub.5, --SO.sub.2 NHC.sub.3 H.sub.7, --SO.sub.2 N(CH.sub.3).sub.2, --SO.sub.2 N(C.sub.2 H.sub.5).sub.2, --PO(OH).sub.2, --PO(OH)(ONa), --PO(ONa).sub.2 and --PO(OK).sub.2.
A particularly preferred group of compounds represented by the above formula (I) is those of formula (I) in which R is --SO.sub.2 NH.sub.2.
Moreover, a particularly preferred group of compounds represented by the above formula (I) is those of formula (I) in which A is C.dbd.O or CH.sub.2 and B is O.
According to the present invention, compounds of the above formula (I) may be prepared by ##STR3## wherein A and B have the same meanings as described previously, with amidosulfonic acid chloride of the formula ##STR4## wherein R.sup.1 and R.sup.2 have the same meanings as described previously, or and, if necessary, treating the reaction product with an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide).
The aforesaid reactions (a) and (b) may be carried out in an inert solvent selected, for example, from amides such as dimethylformamide and N-methylpyrrolidone, alkyl halides such as dichloromethane and dichloroethane, and organic bases such as pyridine, optionally in the presence of an alkali such as sodium hydride, sodium methoxide, potassium butoxide or potassium hydroxide, or an organic base such as triethylamine or 2,6-di-tert-butyl-4-methylpyridine, at a reaction temperature ranging from about -20.degree. C
REFERENCES:
patent: 3865833 (1975-02-01), Chorvat et al.
Fujii Tomohito
Iwashita Shigeki
Kawachi Tomoko
Koizumi Naoyuki
Mieda Mamoru
Dentz Bernard
Teikoku Hormone Mfg. Co. Ltd.
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