Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-14
2001-05-29
McKane, Joseph (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S280000
Reexamination Certificate
active
06239169
ABSTRACT:
RELATED APPLICATIONS
This application is the National Phase under 35 U.S.C. §371 of PCT/GB97/00444, filed Feb. 17, 1997, designating the U.S. and claiming priority from GB 9603325.3, filed Feb. 16, 1996.
The present invention relates to a compound.
In particular the present invention relates to a non-steroidal compound and to a pharmaceutical composition comprising the non-steroidal compound.
Evidence suggests that oestrogens are the major mitogens involved in promoting the growth of tumours in endocrine-dependent tissues, such as the breast and endometrium. Although plasma oestrogen concentrations are similar in women with or without breast cancer, breast tumour oestrone and oestradiol levels are significantly higher than in normal breast tissue or blood. In situ synthesis of oestrogen is thought to make an important contribution to the high levels of oestrogens in tumours and therefore specific inhibitors of oestrogen biosynthesis are of potential value for the treatment of endocrine-dependent tumours.
Over the past two decades, there has been considerable interest in the development of inhibitors of the aromatase pathway which converts the androgen precursor androstenedione to oestrone. However, there is now evidence that the oestrone sulphatase (E1-STS) pathway, i.e. the hydrolysis of oestrone sulphate to oestrone (E1S to E1), as opposed to the aromatase pathway, is the major source of oestrogen in breast tumours
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
3.4
and also by the fact that plasma E1S concentration in these aromatase inhibitor-treated patients remains relatively high. The long half-life of E1S in blood (10-12 h) compared with the unconjugated oestrogens (20 min)
5
and high levels of steroid sulphatase activity in liver and, normal and malignant breast tissues, also lend support to this theory
6
. 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 and, 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 &mgr;M. EMATE also inhibits the E1-STS enzyme in a time- and concentration-dependent manner, indicating that it acts as an active site-directed inactivator
7.8
. 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 oestrogenic steroid androstenediol
8.9
. Also, there is now evidence to suggest that androstenediol may be of even greater importance as a promotor of breast tumour growth
10
. EMATE is also active in vivo as almost complete inhibition of rat liver E1-STS (99%) and DHA-STS (99%) activities resulted when it is administered either orally or subcutaneously
11
. In addition, EMATE has been shown to have a memory enhancing effect in rats
14
. Studies in mice have suggested an association between DHA-STS activity and the regulation of part of the immune response. It is thought that this may also occur in humans
15.16
. The bridging O-atom of the sulphamate moiety in EMATE is important for inhibitory activity. Thus, when the 3-O-atom is replaced by other heteroatoms (
FIG. 1
) as in oestrone-3-N-sulphamate (4) and oestrone-3-S-sulphamate (5), these analogues are weaker non-time-dependent inactivators
12
.
Although optimal potency for inhibition of E1-STS may have been attained in EMATE, it is possible that oestrone may be released during sulphatase inhibitions
8.12
, and that EMATE and its oestradiol congener may possess oestrogenic activity
13
.
The present invention therefore seeks to provide compounds suitable for the inhibition of E1-STS but which have no, or a minimal, oestrogenic effect.
According to a first aspect of the present invention there is provided a non-steroidal sulphamate compound suitable for use as an inhibitor of oestrone sulphatase, wherein the compound has a polycyclic ring structure comprising at least a first ring and a second ring; wherein the first ring and the second ring mimic the A and B rings of oestrone; and wherein the polycyclic ring structure is not tetrahydro-naphthol.
Preferably either the first ring or the second ring comprises an &agr;,&bgr;-unsaturated lactone group.
Preferably the first ring is a phenolic ring.
Preferably the compound has a bicyclic ring structure.
Preferably the compound has the general Formula (A) (see FIG.
8
). In Formula (A) R
1
-R
6
are independently selected from H, halo, hydroxy, sulphamate, alkyl and substituted variants or salts thereof; but wherein at least one of R
1
-R
6
is a sulphamate group; and wherein X is any one of 0, S, NH, a substituted N, CH
2
, or a substituted C.
Preferably X is O.
Preferably, if the sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sulphatase (E.C. 3.1.6.2) activity.
In a highly preferred embodiment, the compound is not hydrolysable by an enzyme having steroid sulphatase (E.C. 3.1.6.2) activity.
According to a second aspect of the present invention there is provided a non-steroidal compound wherein the compound has the general Formula (B) (see FIG.
8
). In Formula (B) R
1
-R
6
are independently selected from H, halo, hydroxy, sulphamate, alkyl and substituted variants or salts thereof; but wherein at least one of R
1
-R
6
is a sulphamate group.
According to a third aspect of the present invention there is provided the compound 4-methyl coumarin-7-0-sulphamate.
According to a fourth aspect of the present invention there is provided a non-steroidal compound according to the present invention for use as a pharmaceutical.
According to a fifth aspect of the present invention there is provided a non-steroidal compound according to the present invention for inhibiting oestrone sulphatase
According to a sixth aspect of the present invention there is provided a pharmaceutical composition comprising a non-steroidal compound according to the present invention; and a pharmaceutically acceptable carrier, excipient or diluent.
According to a seventh aspect of the present invention there is provided the use of a non-steroidal compound according to the present invention in the manufacture of a pharmaceutical for inhibiting oestrone sulphatase.
According to an eighth aspect of the present invention there is provided a process for preparing a compound according to the present invention, the process comprising sulphating a coumarin.
According to a ninth aspect of the present invention there is provided a process for preparing a compound according to the present invention, the process comprising sulphamaylating a coumarin.
The alkyl group(s) in Formula (A) or Formula (B) can be any suitable linear or branched alkyl group which may be saturated or unsaturated and/or substituted or non-substituted. The alkyl group may even be a cyclic alkyl group. For example, at least two of R
1-6
are linked to form a further cyclic component.
Preferably R
1
-R
5
are independently selected from H, alkyl and haloalkyl; preferably wherein R
1
-R
5
are independently selected from H, C1-6 alkyl and C1-6 haloalkyl.
Preferably R
1
-R
5
are independently selected from H, C1-3 alkyl and C1-3 haloalkyl.
Preferably R
1
-R
5
are independently selected from H, methyl and halomethyl. Preferably R
6
is OSO
2
NH
2
.
Preferably the compound is any one of the compounds shown as Compounds 12-16 in FIG.
2
.
Preferably the compound is 4-methyl coumarin-7-0-sulphamate.
In Formula (A) or Formula (B), two or more of R
1
-R
6
may be linked together to form an addition
Potter Barry V.
Reed Michael J.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
McKane Joseph
Solola Taofiq A.
Sterix Limited
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