22-thio vitamin D derivatives

Details 22-thio vitamin D derivatives 22-thio vitamin D derivatives

1995-04-11

1996-09-10

Prior, Kimberly J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, A61K 3159, C07C40100

Patent

active

055545998

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of international application PCT/DK93/00425 filed Dec. 17, 1993.
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 ##STR2## in which formula Y is sulfur, S(O), or S(O).sub.2 ; R stands for C.sub.1 -C.sub.3 alkyl; or ##STR3## can form a C.sub.3 -C.sub.8 carbocyclic ring; Q is a C.sub.1 -C.sub.8 hydrocarbylene diradical.
In the context of this invention, the expression hydrocarbylene diradical indicates the residue after removal of 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated hydrocarbon.
Examples of R include, but is not limited to, methyl, trifluoromethyl, ethyl, normal- and isopropyl.
Examples of Q include, but are not limited to, methylene, ethylene, tri-, tetra-, and pentamethylene, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --CH.dbd.CH--, --CH.sub.2 --C.tbd.C--, --CH.sub.2 CH.sub.2 --C.tbd.C--, phenylene (C.sub.6 H.sub.4 ; ortho, meta, para), --CH.sub.2 --(C.sub.6 H.sub.4)-- (ortho, meta, para), and --(C.sub.6 H.sub.4)--CH.sub.2 -- (ortho, meta, para).
The compounds of the invention comprise more than one stereoisomeric form (e.g., R or S configuration at C-20; E or Z configuration when a double bond is present in the group Q). The invention covers all these stereoisomers in pure form and 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.
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 cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis.
Also, the use of 1,25(OH).sub.2 D.sub.3, or its pro-drug 1.alpha.--OH--D.sub.3, for the treatment of hypertension (Lind, L. et al., Acta Med. Scand. 222, 423-427 (1987)) and diabetes mellitus (Inomata, S. et al., Bone Mineral 1, 187-192 (1986)) has been suggested. Another indication for 1,25(OH).sub.2 D.sub.3 is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with 1,25(OH).sub.2 D.sub.3 may promote hair growth (Editorial, Lancet, March 4, p. 478 (1989)). Also, the fact that topical application of 1,25(OH).sub.2 D.sub.3 reduces the size

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