Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

2000-04-05

2002-06-04

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

06399797

ABSTRACT:

This invention relates to a hitherto unknown class of compounds that show strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating and anti-inflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterised by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and other disturbances of keratinisation, HIV-associated dermatoses, wound healing, cancer, including skin cancer, and of diseases of, or imbalance in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythematosus, diabetes mellitus and chronic dermatoses of autoimmune type, e.g. scieroderma and pemphigus vulgaris, and inflammatory diseases, such as rheumatoid arthritis, as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, cognitive impairment or senile dementia (Alzheimer's disease) and other neurodegenerative diseases, hypertension, acne, alopecia, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
The compounds of the invention constitute a novel class of vitamin D analogues represented by the general formula I:
in which formula X is hydrogen or hydroxy or protected hydroxy; R
1
and R
2
stand for hydrogen, methyl or ethyl, or, when taken together with the carbon atom bearing the group X, R
1
and R
2
can form a C
3
-C
5
carbocyclic ring; Q is a C
3
-C
6
hydrocarbylene, hydrocarbylene indicating the diradical obtained after removal of 2 hydrogen atoms from a straight or branched, saturated or unsaturated hydrocarbon, in which one of any CH
2
groups may optionally be replaced by an oxygen atom or a carbonyl group, such that the carbon atom (C-22) directly bonded to C-20 is an sp
2
or sp
3
hybridised carbon atom, i.e. bonded to 2 or 3 other atoms; and in which another of the CH
2
groups may be replaced by phenylene, and where Q may optionally be substituted with one or more hydroxy or C
1
-C
4
-alkoxy groups.
Examples of I include, illustratively but not limitingly, the horizontal entries in Table 1 (p. 12), where for convenience Q is considered to be a composite of segments Qa through Qf, with any blank spaces being understood as direct bond, such that Qa is directly bonded to C-20, and R
1
is the same as R
2
unless otherwise noted. Thus, segments within Q such as methylene, methene (in contiguous pairs, i.e. carbon atoms connected by double bonds), methyne (in contiguous pairs, i.e. carbon atoms connected by triple bonds), phenylene (illustrated by m-phenylene), alkylidene (illustrated by 1,1-propylidene), hydroxymethylene, alkoxymethylene (illustrated by ethoxymethylene), keto, and oxa may be combined to produce side chains that are in fact identical (apart from the 17,20-double bond) to those already known from a variety of active vitamin D analogues.
The compounds of the invention can comprise more than one diastereoisomeric form (e.g. E or Z configuration of the 17,20-double bond and also of any non-ring double bond present in the group Q; R and S configurations when a hydroxy group or an alkoxy group or a branching atom is present in Q). The invention covers all these diastereoisomers in pure form and also mixtures thereof. In addition, prodrugs of I in which one or more of the hydroxy groups are masked as groups that can be reconverted to hydroxy groups in vivo could also be envisaged.
The compounds I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.
A number of vitamin D analogues have been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity in vitro as compared with the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safely be administered. One of the first of these to appear, calcipotriol (INN) or calcipotriene (USAN), has been developed on the basis of this selectivity and is now recognised world-wide as an effective and safe drug for the topical treatment of psoriasis.
A study with another analogue selected on this basis supports the concept that systemically administered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K. W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992)).
Promising immunosuppressive activities of vitamin D analogues have been reviewed (Binderup, L., Biochem. Pharmacol. 43, 1885-1892 (1992)). Thus, a series of 20-epi-vitamin D analogues has been identified as potent inhibitors of T-lymphocyte activation in vitro (Binderup, L. et al, Biochem. Pharmacol. 42, 1569-1575 (1991)). Two of these analogues, MC 1288 and KH 1060, systemically administered, have shown immunosuppressive activities in vivo in experimental animal models. Additive or synergistic effects were observed in combination with low-dose cyclosporin A. KH 1060, alone or in combination with cyclosporin A, has also been shown to prevent autoimmune destruction of transplanted islets in diabetic NOD mice (non-obese diabetic mice) (Bouillon, R. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 551-552). MC 1288 was able to prolong survival of cardiac and small bowel grafts in rats (Johnsson, C. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Fla., Walter de Gruyter, Berlin, 1994, pp 549-550). However, in all these studies, the dosages of the analogues that produced significant immunosuppression also induced increases in serum calcium levels. There is therefore a continuing need for new analogues with high potency showing an acceptable combination of prolonged therapeutic activity and minimum toxic effects.
The present invention provides a hitherto undisclosed series of vitamin D analogues which is characterised by the presence of a double bond between C-17 and C-20.
21-Nor-17(20)-ene vitamin D analogues are described in EP 0 717 034, but the only previously described vitamin D analogues with a C-17,20 double bond and the C-21 methyl group preserved are those with a C-22,23 triple bond (WO 94/01398). The compounds of the present invention extend the range of side chain types to comprise a more comprehensive selection of side chains known from prior art vitamin D analogues.
These compounds have been discovered to possess exceptionally high immunosuppressive activities together with high tumour cell proliferation inhibiting activities.
The following standard abbreviations are used throughout this disclosure:
18C6=18-Crown-6
AIBN=2,2′-azobisisobutyronitrile
b.p.=boiling point
Bu=n-butyl
Bu
t
=tert-butyl
DIBAH=diisobutylaluminium hydride
DMAP=4-dimethylaminopyridine
DMF=N,N-dimethylformamide
DMR=Dess-Martin-Reagent=1,1,1-triacetoxy-1,1-dihydro-1,2-benz-iodoxol-3(1H)-one
Et=ethyl
Ether=diethyl ether
Fg=functional group
LDA=lithium diisopropylamide
Lg=leaving group
Me=methyl
m.p.=melting point
PCC=pyridinium chlorochromate
PDC=pyridinium dichromate
Ph=phenyl
PPTS=pyridinium p-toluenesulfonate
Py=pyridine
r.o.s.=“r

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