Compounds with a sulfamate group

Details Compounds with a sulfamate group Compounds with a sulfamate group

1998-09-02

2000-07-04

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549285, 549278, 549280, 549292, 514453, 514455, A61K 31353, C07D31128, C07D31134

Patent

active

060839783

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a compound.
In particular the present invention relates to a pharmaceutical composition comprising the compound.
Breast and endometrial cancers are major causes of death in Western women. In particular, tumours in endocrine-dependent tissues, such as the breast and endometrium, occur most frequently in postmenopausal women at a time when the ovaries have ceased their production of oestrogens.
Evidence suggests that oestrogens are the major mitogens involved in stimulating and promoting the growth of tumours in endocrine-dependent tissues, such as the breast and endometrium.sup.21. Although plasma oestrogen concentrations are similar in women with or without breast cancer, breast tumour oestrone and oestrone levels are significantly higher than in normal breast tissue or blood. In addition, in postmenopausal women oestrogens continue to be produced by extraglandular production in adipose tissue but also in normal and malignant breast tissues.sup.22.
FIGS. 1 and 2 are schematic diagrams showing some of the enzymes involved in the in situ synthesis of oestrone from oestrone sulphate, oestradiol and androstenedione.
In FIG. 2, which schematically shows the origin of oestrogenic steroids in postmenopausal women, "ER" denotes Oestrogen Receptor, "DHA/-S" denotes Dehydroepiandrosterone/-Sulphate, "Adiol" denotes Androstenediol. "E1-STS" denotes Oestrone Sulphatase, "DHA-STS" denotes DHA-sulphatase, "Adiol-STS" denotes Adiol Sulphatase, and "17B-HSD" denotes Oestradiol 17B-hydroxysteroid dehydrogenase.
As can be seen, the main two enzymes that are involved in the peripheral synthesis of oestrogens are the aromatase enzyme an the enzyme oestrone sulphatase.
In short, the aromatase enzyme converts androstenedione, which is secreted in large amounts by the adrenal cortex, to oestrone. Recent reports have suggested that some flavones could inhibit aromatase activity.sup.35.36.
Much of the oestrone so formed, however, is converted to oestrone sulphate (E1S) and there is now a considerable body of evidence showing that E1S in plasma and tissue acts as a reservoir for the formation of oestrone by the action of oestrone sulphatase.sup.23.
In this regard, it is now believed that the oestrone sulphatase (E1-STS) pathway--i.e. the hydrolysis of oestrone sulphate to oestrone (E1S to E1) is the major source of oestrogen in breast tumours.sup.1.2. This theory is supported by a modest reduction of plasma oestrogen concentration in postmenopausal women with breast cancer treated by aromatase inhibitors, such as aminoglutethimide and 4-hydroxyandrostenedione.sup.3.4 and also by the fact that plasma E1S concentration in these aromatase inhibitor-treated patients remains relatively high. The Ion half-life of E1S in blood (10-12 h) compared with the unconjugated oestrogen (20 min).sup.5 and high levels of steroid sulphatase activity in liver and, normal and malignant breast tissues, also lend support to this theory.sup.6.
Thus, oestrogen formation in malignant breast and endometrial tissues via the sulphatase pathway makes a major contribution to the high concentration of oestrogens which are present in these tumours.sup.24.25.
PCT/GB92/01587 teaches novel steroid sulphatase inhibitors and pharmaceutical compositions containing them for use in the treatment of oestrone dependent tumours, especially breast cancer. These steroid sulphatase inhibitors are sulphamate esters, such as N,N-dimethyl oestrone-3-sulphamate nd, preferably, oestrone-3-sulphamate (otherwise known as "EMATE").
EMATE is a potent E1-STS inhibitor as it displays more than 99% inhibition of E1-STS activity in intact MCF-7 cells at 0.1 .mu.M. EMATE also inhibits the E1-STS enzyme in a time-dependent and concentration-dependent manner, thereby indicating that it acts as an active site-directed inactivator.sup.7.3.
Although EMATE was originally designed for the inhibition of E1-STS, it also inhibits dehydroepiandrosterone sulphatase (DHA-STS), which is an enzyme that is believed to have a pivotal role in regulating the biosynthesis of the

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