Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1994-12-27
1997-04-01
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552626, A61K 31165, C07J 100
Patent
active
056165749
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01587.
FIELD OF INVENTION
This invention relates to novel compounds for use a steroid sulphatase inhibitors, and pharmaceutical compositions containing them.
BACKGROUND AND PRIOR ART
Steroid precursors, or pro-hormones, having a sulphate group in the 3-position of the steroid nucleus, referred to hereinafter simply as steroid sulphates, are known to play an important part as intermediates in steroid metabolism in the human body. Oestrone sulphate and dehydroepiandrosterone (DHA) sulphate, for example, are known to play an important role as intermediates in the production, in the body, of oestrogens, such as oestrone and oestradiol. Oestrone sulphate, in particular, is known, for example, to represent one of the major circulating oestrogen precursors particularly in post-menopausal women and oestrone sulphatase activity in breast tumours is 100-1000 fold greater than that of other enzymes involved in oestrogen formation (James et al., Steroids, 50, 269-279 (1987)).
Not only that, but oestrogens such as oestrone and oestradiol, particularly the over-production thereof, are strongly implicated in malignant conditions, such as breast cancer, see Breast Cancer, Treatment and Prognosis: Ed. R. A. Stoll, pp. 156-172, Blackwell Scientific Publications (1986), and the control of oestrogen production is the specific target of many anti-cancer therapies, both chemotherapy and surgical, e.g. oophorectomy and adrenalectomy. So far as endocrine therapy is concerned, efforts have so far tended to concentrate on aromatase inhibitors, i.e. compounds which inhibit aromatase activity, which activity is involved, as the accompanying oestrogen metabolic flow diagram (FIG. 1) shows, in the conversion of androgens such as androstenedione and testosterone to oestrone and oestradiol respectively.
In recently published International Application WO91/13083 a proposal has been made to target a different point in the oestrogen metabolic pathway, or rather two different points, that is to say the conversion of DHA sulphate and oestrone sulphate to DHA and oestrone, respectively, by steroid sulphatase activity, and using 3-monoalkylthiophosphonate steroid esters as a steroid sulphatase inhibitor, more especially oestrone-3-monomethylthiophosphonate.
OBJECTS OF THE INVENTION
A first object of the present invention is to provide new compounds capable of inhibiting steroid sulphatase activity in vitro and in vivo.
A second object of the present invention is to provide new compounds having improved activity as steroid sulphatase inhibitors both in vitro and in vivo.
A third object of the invention is to provide pharmaceutical compositions effective in the treatment of oestrogen dependent tumours.
A fourth object of the invention is to provide pharmaceutical compositions effective in the treatment of breast cancer.
A fifth object of the invention is to provide a method for the treatment of oestrogen dependent tumours in mammals, especially humans.
A sixth object of the invention is to provide a method for the treatment of breast cancer in mammals and especially in women.
SUMMARY OF INVENTION
The invention is based on the discovery of novel compounds having steroid sulphatase inhibitory activity, in some cases, with extremely high activity levels. These compounds are the sulphamic acid esters of polycyclic alcohols, being polycyclic alcohols the sulphate of which is a substrate for enzymes having steroid sulphatase (EC 3.1.6.2) activity, the N-alkyl and N-aryl derivatives of those sulphamic acid esters, and their pharmaceutically acceptable salts.
Broadly speaking, the novel compounds of this invention are compounds of the Formula (I) ##STR2## where: R.sub.1 and R.sub.2 are each independently selected from H, alkyl, cycloalkyl, alkenyl and aryl, or together represent alkylene optionally containing one or more hetero atoms or groups in the alkylene chain; and the sulphate of which is a substrate for enzymes having steroid sulphatase activity (EC 3.1.6.2).
As used herein the reference to polycyc
REFERENCES:
Zeitschrift fur Chemie, Schwarz et al, 14 (1) 1974 pp. 15-16.
Potter Barry V. L.
Reed Michael J.
Cook Rebecca
Imperial College of Science Technology and Medicine
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