Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1999-04-30

2001-10-30

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

06310226

ABSTRACT:

This invention relates to a hitherto unknown class of compounds which shows 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 characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and other disturbances of keratinization, 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. scleroderma and pemphigus vulgaris, and inflammatory diseases, such as rheumatoid arthritis and asthma, 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; R
1
and R
2
which may be the same or different, stand for hydrogen or C
1
-C
5
hydrocarbyl; or R
1
and R
2
, taken together with the carbon atom bearing the group X, can form a C
3
-C
8
carbocyclic ring, Q is methylene, ethylene, tri- or tetra-methylene and may optionally be substituted with an oxy group, —OR
3
, in which R
3
is hydrogen, methyl or ethyl; Y is either a single bond or C
1
-C
2
hydrocarbylene; and one or more carbons within R
1
, R
2
, and/or Y may optionally be substituted with one or more fluorine atoms, or with a hydroxyl group.
In the context of this invention, the expression hydrocarbyl (/hydrocarbylene) indicates the radical (/diradical) obtained after removal of 1 (/2) hydrogen atom(/s) from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of R
1
and R
2
when taken separately include, but are not limited to, hydrogen, methyl, trifluoromethyl, hydroxymethyl, ethyl, (1- or 2-)hydroxyethyl, vinyl, ethynyl, normal-, iso- and cyclopropyl, propen-2-yl, and 3-pentyl. Examples of R
1
and R
2
when taken together include ethylene, tri-, tetra- and pentamethylene.
Examples of Q with an oxy substituent include but are not limited to, hydroxymethylene, (1- or 2-)hydroxyethylene, (1-, 2- or 3-)hydroxytrimethylene, and corresponding diradicals in which the hydroxy is etherified with methyl or ethyl.
Examples of Y (when not a single bond), include but are not limited to, methylene, hydroxymethylene, difluoromethylene, ethylene, ethylidene (:CH—CH
3
), CH═CH, C—C, (1- or 2-)hydroxyethylene.
The compounds of the formula I comprise more than one diastereo-isomeric form (E and Z configurations of the side chain double bond, and additionally for example R and S configurations at the carbon bearing the group X when R
1
and R
2
are different from each other and from X, and E or Z configurations when a double bond is present in the groups Y or R(1 or 2)). 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 are also envisaged.
The compounds I in which X is hydroxy are the preferred ones, but the compounds I in which X is hydrogen are actually another type of prodrug. These compounds are relatively inactive in vitro, but are converted to active compounds of formula I by enzymatic side chain hydroxylation at one or more sites in the —(Y)CHR
1
R
2
portion of the molecule after administration to the patient.
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 that 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 recently 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 recognized world-wide as an effective and safe drug for the topical treatment of psoriasis.
A study with another analogue (EB 1089) 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 (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 an acceptable combination of prolonged therapeutic activity and minimum toxic effects.
The compounds of the present invention provide a hitherto undisclosed series of 1&agr;-hydroxy-20-epi-vitamin D analogues characterised by the presence of a distal carbon-carbon double bond in the side chain, i.e. positioned in such a way that no double-bonded atom is directly connected to C-20. [A series of 20-epi-vitamin D analogues that contain no side chain double bond or a 22,23-double bond (C-22 is bonded directly to C-20) is disclosed in International Patent Application with Publication number WO91/00271. Reports of compounds having the natural configuration at C-20 and containing a 23,24- or a 24,24a-double bond have appeared (Uskokovic, M. R. et al. In: Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application, edited by Norman, A. W., Bouillon, R. and Thomasset, M. Berlin: Walter de Gruyter, 1991, pp. 139-145, Baggiolini E. G.; et al. U.S. Pat. No. 5,087,619-A (1992), Chodynski M. et al., Steroids 56, 311-315 (1991)).] Since the filing of the present application, an application has been published (Kutner, A.; et al. EP 742,203 (1996)) disclosing a series that appears fo

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