Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
1999-02-19
2002-04-16
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
C552S653000, C514S167000
Reexamination Certificate
active
06372926
ABSTRACT:
This application is a 371 of PCT GB96/03218 Dec. 23, 1996.
This invention relates to new 1-hydroxy pregnacalciferol derivatives, more especially to 1-hydroxy pregnacalciferol derivatives having anti-progesterone activity.
Vitamin D
3
has long been known to play a key role in the metabolism of calcium. The discovery that the D vitamins undergo hydroxylation in vivo led to the synthesis of many analogues of vitamin D whose evaluation indicated that hydroxyl groups at the 1&agr;-position and at either the 24R- or 25-position were essential for the compound or metabolite thereof to exhibit a substantial effect on calcium metabolism.
Subsequent work indicated that the natural metabolite 1&agr;,25-dihydroxy vitamin D
3
exhibited cell modulating activity, including stimulation of cell maturation and differentiation, as well as immunosuppressive effects, and also exhibited an immunopotentiating effect, stimulating the production of bactericidal oxygen metabolites and the chemotactic response of leukocytes.
The therapeutic potential of 1&agr;,25-hydroxy vitamin D
3
in these areas is, however, severely limited by its potent effect on calcium metabolism. Thus dosages at a level sufficient to elicit a desired cell modulating, immunosuppressive or immunopotentiating effect tend to lead to unacceptable hypercalcaemia. Considerable interest has therefore been shown in the synthesis of analogues having reduced effects on calcium metabolism but still exhibiting desired effects on cellular metabolism, e.g. as summarised in WO 95/16672.
DeLuca and coworkers (Tetrahedron Letters 35(15) (1994), pp. 2295-2298 and Program Abstracts, 77th Annual Meeting of the Endocrine Society (1995), Abstract No. P2-662, p.456) have reported that in their investigations of such vitamin D analogues they have tested various 20-oxopregnacalciferols and found them to be inactive as regards effect on calcium metabolism. Noting that these compounds shared some structural features with progesterone and aware of the development of compounds such as RU 486, a 19-nor steroid having the formula
and exhibiting strong anti-progesterone and anti-glucocorticosteroid activities, they also tested these compounds for ability to bind to the progesterone receptor. 20-Oxopregnacalciferols, and to a lesser extent the 22-aldehyde and 22-hydroxy calciferols, were found to bind the progesterone receptor. Of “many other” vitamin D analogues tested no other showed significant binding activity. 1&agr;-Hydroxy-20-oxopregna-calciferol and its corresponding 19-nor analogues are specifically stated not to have such binding effect.
In contrast to RU 486, 20-oxopregnacalciferol is said not to bind to the glutocorticoid receptor but has been found (Program Abstracts, 76th Annual Meeting of the Endocrine Society (1994), Abstract No. 1744, p. 636) to suppress in vitro growth of human breast cancer cells (T47D).
The present invention is based on the surprising finding that a number of 1-hydroxy pregnacalciferols, in complete contradiction to the findings of DeLuca et al., do in fact act as potent antagonists of progesterone activity, for example as evidenced by antifertility (e.g. contraceptive) activity, anti-progesterone assay and inhibition of growth of mammary cancer T47D and MCF-7 cell lines. Even more surprisingly, we have found that the anti-progesterone effects in respect of these 1-hydroxy compounds may exceed those of the corresponding 1-desoxy compounds.
Apart from the compound 1&agr;-hydroxy-20-oxopregnacalciferol, insofar as it may have been disclosed by DeLuca et al., these 1-hydroxy pregnacalciferols and their O-protected derivatives are novel and constitute a feature of the invention.
Thus according to one aspect of the invention there are provided compounds of general formula (I):
(wherein R
1
denotes an optionally protected hydroxyl group or a lower alkoxy group and R
2
denotes a lower alkynyl group optionally substituted by a hydroxyl, protected hydroxyl or lower alkoxy group; or R
1
denotes a group —C(R
A
)(R
B
)CH
3
wherein R
A
is a lower alkynyl group optionally substituted by a hydroxyl, protected hydroxyl or lower alkoxy group and R
B
is an optionally protected hydroxyl group or a lower alkoxy group, or R
A
and R
B
together represent an oxo group, and R
2
denotes a hydrogen atom, an optionally protected hydroxyl group or a lower alkoxy group; and R
3
and R
4
, which may be the same or different, each denote a hydrogen atom or an O-protecting group) and the corresponding 5,6-trans (i.e. 5E-isomers) thereof, with the proviso that when R
1
denotes a group —C(R
A
)(R
B
)CH
3
wherein R
A
and R
B
together denote an oxo group and the group —OR
4
is in the &agr;-configuration then R
2
is other than hydrogen.
Where any of R
1
, R
2
and R
B
denote or contain lower alkoxy groups these may, for example, be C
1-6
alkoxy groups such as methoxy, ethoxy, propoxy and butoxy groups which, where appropriate, may be straight chain or branched.
Where R
2
or R
A
denotes a lower alkynyl group this may, for example, contain up to 6 carbon atoms, and may for example be an alk-l-yn-1-yl group such as ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl or 1-hexynyl, or an &ohgr;-alkynyl group such as propargyl. Hydroxyl or lower alkoxy substituents may be present as in, for example, 3-hydroxypropynyl and 3-methoxypropynyl groups.
Where R
3
and R
4
represent O-protecting groups these may, for example, be cleavable O-protecting groups such as are commonly known in the art. Suitable groups include etherifying groups such as silyl groups (e.g. tri(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl or t-butyldimethylsilyl; tri(aryl)silyl groups such as triphenylsilyl; and mixed alkyl-arylsilyl groups); lower (e.g. C
1-6
) alkyl groups optionally interrupted by an oxygen atom, such as methyl, methoxymethyl or methoxyethoxymethyl; and cyclic groups such as tetrahydropyranyl. Esterifying O-protecting groups include lower (e.g. C
1-6
) alkanoyl such as acetyl, propionyl, isobutyryl or pivaloyl; aroyl (e.g. containing 7-15 carbon atoms) such as benzoyl or 4-phenylazobenzoyl; lower alkane sulphonyl such as (optionally halogenated) methane sulphonyl; and arene sulphonyl such as p-toluene sulphonyl.
O-protected derivatives are useful as intermediates in the preparation of active 1,3&bgr;-diols of formula (I). Additionally, where the O-protecting groups are metabolically labile in vivo, such ethers and esters of formula (I) may be useful directly in therapy.
5,6-Trans isomers of compounds of general formula (I) are useful as intermediates in the preparation of the corresponding 5,6-cis isomers, e.g. as described in greater detail hereinafter. Where R
3
and R
4
denote hydrogen atoms or metabolically labile groups such 5,6-trans isomers may, however, exhibit biological activity, although typically at a lower order of magnitude than corresponding 5,6-cis isomers, and thus may be useful in therapy.
The anti-progestational activity of both 1&agr;-hydroxy-20-oxopregnacalciferol and active compounds of general formula (I) as defined above suggests their use as, for example, antiproliferative agents in, for example, the treatment and/or prevention of hormone responsive tumours or hyperplasias (such as breast, prostate or ovarian cancers, fibroids or endometriosis) or as suppressants of progesterone activity, for instance in oedema, acne, melasma or in fertility control (such as, for example, in inducing abortion or in contraception) in human or animal subjects. The invention accordingly embraces the use of these compounds both in treatment or prophylaxis of the above-mentioned conditions and in the manufacture of medicaments for such treatment or prophylaxis.
Whilst the antiproliferative effect of compounds according to the present invention is somewhat lower than that of 1&agr;-hydroxy vitamin D analogues having cell modulating activity, for example as described in our International Patent Applications Nos. WO-A-9309093, WO-A-9426707, WO-A-9503273, WO-A-9516672 and WO-A-9525718, it is nonetheless significant and may be ther
Hesse Robert Henry
Pechet Maurice Murdoch
Setty Sundara Katugam Srinivasasetty
Bacon & Thomas
Qazi Sabiha
Research Institute for Medicine and Chemistry
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