Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-11-23
2003-11-04
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06642220
ABSTRACT:
The present invention relates to a compound.
In particular the present invention relates to a compound and to a pharmaceutical composition comprising the 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 4hydroxyandrostenedione
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”).
Some of the compounds disclosed in PCT/GB92/01587 are shown in FIG.
1
.
It is known that 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 mM. 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 promoter 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 inhibition
8,12
, and that EMATE and its oestradiol congener may possess oestrogenic activity
13
.
The present invention seeks to provide novel compounds suitable for the inhibition of E1-STS but preferably wherein those compounds have no, or a minimal, oestrogenic effect.
According to a first aspect of the present invention there is provided a sulphanate compound suitable for use as an inhibitor of oestrone sulphatase, wherein the compound has the Formula I; wherein A is a first group; B is an aryl ring structure having at least 4 carbon atoms in the ring and wherein the ring B is substituted in at least the 2 position and/or the 4 position with an atom or group other than H; X is a sulphamate group; wherein group A and ring B together are capable of mimicking the A and B rings of oestrone; and wherein group A is attached to at least one carbon atom in ring B.
The term “mimic” as used herein means having a similar or different structure but having a similar functional effect. In otherwords, group A and ring B together of the compounds of the present invention are bio-isosteres of the A and B rings of oestrone.
A key advantage of the present invention is that the sulphamate compounds of the present invention can act as EL-STS inhibitors.
Another advantage of the compounds of the present invention is that they may be potent in vivo and that they may have less oestrogenic activity than the known compounds and can therefore be deemed to be a “non-oestrogenic compound”. The term “non-oestrogenic compound” as used herein means a compound exhibiting no or substantially no oestrogenic activity.
The present invention therefore provides sulphamate compounds which may have a reduced oestrogenic activity.
Another advantage is that the compounds may not be capable of being metabolised to compounds which display or induce hormonal activity.
The compounds of the present invention are also advantageous in that they may be orally active.
The compounds of the present invention are further advantageous in that they may have an irreversible effect.
In a preferred embodiment, the-sulphamate compounds of the present invention are useful for the treatment of breast cancer.
In addition, the sulphamate compounds of the present invention are useful for the treatment of non-malignant conditions, such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
The sulphamate compounds of the present invention are also believed to have therapeutic uses other than for the treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases.
Preferably, the sulphamate group is at position 3 of the ring B.
Preferably, the ring B has six carbon atoms in the ring.
Preferably, the compound has the Formula II; wherein X is the sulphamate group; A is the first group; R
1
and/or R
2
is a substituent other than H; wherein R
1
and R
2
may be the same or different but not both being H; and wherein optionally group A is attached to at least one other carbon atom in ring B.
Preferably, group A is additionally attached to the carbon atom at position 1 of the ring B.
Preferably, group A and ring B are a steroid ring structure or a substituted derivative thereof.
Preferably, the compound has the Formula IV; wherein X is the sulphamate group; R
1
and/or R
2
is a substituent other than H; wherein R
1
and R
2
may be the same or different but not both being H; and wherein Y is a suitable linking group.
Suitable linking groups for Y include groups made up of at least any one or more of C, O, N, and S. The linking groups can also comprise H. The linking group may also increase the size of the ring (i.e. the D ring). Preferably, however, the D ring comprising Y is a five-membered ring.
Preferably, Y is —CH
2
— or —C(O)—.
Preferably, Y is —C(O)—.
Preferably, the compound has the Formula V; wherein X is the sulphamate group; R
1
and/or R
2
is a substituent other than H; and wherein R
1
and R
2
may be the same or different but not both being H.
The term “sulphamate” as used herein includes an ester of sulphamic acid, or an ester of an N-substituted derivative of sulphamic acid, or a salt thereof.
Preferably, the sulphamate group has the Formula III.
In Formula III, each of R
3
and R
4
is independently selec
Lloyd Potter Barry Victor
Reed Michael John
Badio Barbara P.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Sterix Limited
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