Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1995-11-07

1998-02-10

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, 568816, 568817, A01N 4500, C07C40100, C07C 3521, C07C 3522

Patent

active

057169454

DESCRIPTION:

BRIEF SUMMARY
This application claims benefit of international application PCT/DK94/00271 filed Jul. 1, 1994.
This invention relates to a hitherto unknown class of compounds which shows antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, of a number of disease states including diabetes mellitus, hypertension, acne, alopecia, skin ageing, imbalance in the immune system, of inflammatory diseases such as rheumatoid arthritis and asthma, of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and cancer, for prevention and/or treatment of steroid induced skin atrophy, and for promoting osteogenesis and treating osteoporosis.
The compounds of the present invention are represented by the general formula I ##STR1## in which formula X is hydrogen or hydroxy; R.sup.1 and R.sup.2 which may be the same or different, stand for hydrogen or C.sub.1 -C.sub.4 hydrocarbyl; or R.sup.1 and R.sup.2 taken together with the carbon atom bearing the group X, can form a C.sub.3 -C.sub.8 carbocyclic ring; Q is a single bond or a C.sub.1 -C.sub.4 hydrocarbylene diradical; R.sup.1, R.sup.2 and/or Q may be optionally substituted with one or more fluorine atoms.
In the context of this invention, the expression hydrocarbyl radical (hydrocarbylene diradical) indicates the residue after removal of 1 (2) hydrogen atom(s) from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of R.sup.1 and R.sup.2 when taken separately include, but are not limited to, hydrogen, methyl, trifluoromethyl, ethyl, vinyl, normal-, iso- and cyclopropyl and propen-2-yl.
Examples of R.sup.1 and R.sup.2 when taken together include ethylene, tri-, tetra- and pentamethylene.
Examples of Q include, but are not limited to, a single bond, methylene, ethylene, trimethylene, dimethylmethylene, CH.dbd.CH, C.tbd.C, CH.sub.2 CH.dbd.CH and CH.sub.2 --C.tbd.C.
The compounds of the invention comprise more than one diastereoisomeric form (e.g., R or S configuration at C-20 and, if R.sup.1 and R.sup.2 are different, at the starred carbon atom; E or Z configuration at the 22,23 double bond and E or Z configuration when a double bond is present in the group 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 which can be reconverted to hydroxy groups in vivo are also within the scope of the invention.
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, where X.dbd.OH, by enzymatic side chain hydroxylation after administration to the patient.
It has been shown that 1.alpha.,25-dihydroxy-vitamin D.sub.3 (1,25(OH).sub.2 D.sub.3) influences the effects and/or production of interleukins (Muller, K. et al., Immunol. Lett. 17, 361-366 (1988)), indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, host versus graft reactions, and rejection of transplants or other conditions characterized by an abnormal interleukin-1 production, e.g. inflammatory diseases such as rheumatoid arthritis and asthma.
It has also been shown that 1,25(OH).sub.2 D.sub.3 is able to stimulate the differentiation of cells and inhibit excessive cell proliferation (Abe, E. et al., Proc. Natl. Acad. Sci., U.S.A. 78, 4990-4994 (1981)), and it has been suggested that this compound might be useful in the treatment of diseases characterized by abnormal c

REFERENCES:
patent: 5145846 (1992-09-01), Baggiolini
patent: 5206229 (1993-04-01), Calverley
patent: 5378695 (1995-01-01), Calverley
patent: 5449668 (1995-09-01), Sestelo

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