Steroid sulphatase inhibitors

Details Steroid sulphatase inhibitors Steroid sulphatase inhibitors

1994-12-27

1997-02-18

Cook, Rebecca

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514171, 552626, C07J 3100, C07J 5100, A61K 31565

Patent

active

056042159

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/6B92/01586 filed Aug. 28, 1992.


FIELD OF INVENTION

This invention relates to novel compounds for use as 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 W091/13083 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-monoalkyl-thiophosphonate steroid esters as a steroid sulphatase inhibitor, more especially oestrone-3-monomethylthiophosphonate.
Also proposed as antitumour agents (see U.S. Pat. No. 4,150,126) are steroid enol esters of the Formula: ##STR2## wherein: R.sup.1 is (C.sub.2 -C.sub.6) .beta.- or .gamma.-haloalkyl; ##STR3## and X; X is O or S; 3-position and adjacent a double bond in the steroid A ring.
However no mechanistic explanation is given of the antitumour activity of those compounds. In that disclosure brief mention is made that such steroid and esters can be prepared by transesterification inter alia of steroid-3-sulphonates of the Formula: ##STR4## where St is a steroid nucleus as above defined, and R.sup.3 is lower alkyl, optionally containing chloro- or fluoro-substituents, or phenyl, optionally substituted by chloro-, fluoro- or lower alkyl. However, no examples are given of any such steroid-3-sulphonates for use as intermediates in the preparation of the steroid enol esters described in that patent, let alone any suggestion that such steroid-3-sulphonates might themselves inhibit steroid sulphatase activity, and thus be of potential value in the treatment of oestrogen dependent tumours.


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

REFERENCES:
patent: 4150126 (1979-04-01), Fex et al.
Kimura et al, Chem. Pharm. Bull. 21(8) 1720-1726, 1973.
Schwarz et al, Pharmazie 30 pp. 17-21 1975.
Baldwin et al, J. Chem. Soc. (C) 2283-2289, 1968.
Riess et al, Bul. Soc. Chem. Fr., 4933-4941 1965.
Townsley et al, Res. Steroids, 5, 73-78, 1973.
Dibbelt et al, Z. Physiol. Chem. 365, S. 1145-1153, 1984.

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