Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1998-01-08

1999-11-30

Dodson, Shelley A.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, A01N 4500, C07C40100

Patent

active

059943327

DESCRIPTION:

BRIEF SUMMARY
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 antiinflammatory 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 (Alzheimers 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: ##STR2## in which formula X is hydrogen or hydroxy; R.sup.1 and R.sup.2 stand for methyl or ethyl, or, when taken together with the carbon atom bearing the group X, can form a C.sub.3 -C.sub.5 carbo-cyclic ring; Q is either a single bond or a C.sub.1 -C.sub.8 hydrocarbylene in which one of any methylene groups not directly bonded to the carbonyl group may optionally be replaced by an oxygen atom (or methyl by hydroxy); Y is either a single bond or C.sub.1 -C.sub.8 hydrocarbylene.
In the context of this invention, the expression hydrocarbylene indicates the diradical obtained after removal of 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of Q and Y (when not a single bond) include, but are not limited to, methylene, ethylene, CH.dbd.CH, C.dbd.C, trimethylene, CH.dbd.CHCH.sub.2, CH.sub.2 CH.dbd.CH, C.tbd.CCH.sub.2, CH.sub.2 --C.tbd.C, analogously derived C.sub.4 --(tetramethylene) and C.sub.5 -diradicals, and additionally, for Q: O--CH.sub.2, O--CH.sub.2 CH.sub.2, CH.sub.2 --O--CH.sub.2 CH.sub.2, CH.sub.2 CH.sub.2 --O--CH.sub.2, CH(OEt)--C.dbd.CH, CH(OH)--CH.sub.2, CH(OEt)--C.tbd.C, and for Y: phenylene (o-, m-, p-).
The compounds of the invention can comprise more than one diastereoisomeric form (e.g. E or Z configurations when a double bond is present in the group Q or Y; R and S configurations when a branching carbon is present). 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 which can be reconverted to hydroxy groups in vivo are also within the scope of the invention.
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 cosolvent 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 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

REFERENCES:
Yoshida et al., Biological activity of Vit D derivatives, J. Pharmacobio-Dyn., 7(12), 962-8, 1984.
Masuda et al., In vitro metab. of the anti-psoriatic Vit. D analog, J. Biol. Chem., 269(7), 4794-803, 1994.
Makino et al., Secondary hyperparathyroidism Inhibitors, JP 07242550 A2, 1995.
Takahashi et al., 1,3-(OH)2 -cholestadiene derivatives, JP 02250865 A2, Oct. 8, 1990.
Schnoes et al., 1-hydroxy-25-keto-27-nor-cholecalciferol, WO 8002502, Nov. 1980.

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