Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1994-04-04

1995-08-29

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, C07C40100

Patent

active

054460344

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/DK93/00105.
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, and a number of disease states including diabetes mellitus, hypertension, acne, alopecia, skin ageing, imbalance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and cancer, and for promoting osteogenesis and treating osteoporosis.
The compounds of the invention constitute a novel class of vitamin D analogues and 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 a C.sub.1 -C.sub.6 hydrocarbyl radical; or R.sup.1 and R.sup.2 taken together with the carbon atom (starred in formula I) bearing the group X, can form a C.sub.3 -C.sub.8 carbocyclic ring; R.sup.3 stands for hydrogen or a C.sub.1 -C.sub.10 hydrocarbyl radical or for YR.sup.4 in which Y stands for the radicals --CO--, --CO--O--, --CO--S--, --CS--, --CS--O--, --CS--S--, --SO-- or --SO.sub.2 --, and R.sup.4 stands for hydrogen or a C.sub.1 -C.sub.10 hydrocarbyl radical; Q is a single bond or a C.sub.1 -C.sub.8 hydrocarbylene diradical. R.sup.1, R.sup.2, R.sup.3 and/or Q may be optionally substituted with one or more deuterium or 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 (apart from hydrogen), but are not limited to, methyl, trifluoromethyl, ethyl, vinyl, normal-, iso- and cyclo-propyl, and 1-methylvinyl.
Examples of R.sup.1 and R.sup.2 when taken together include di-, tri-, tetra- and penta-methylene.
Examples of R.sup.3 and R.sup.4 include (apart from hydrogen), but are not limited to, methyl, trifluoromethyl, ethyl, propyl, normal-, iso- and cyclopropyl, normal-, iso-, sec-, and tert-butyl, normal- and iso-pentyl, phenyl and benzyl.
Examples of Q include a single bond, methylene, di-, tri- and tetra-methylene, --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 --C.tbd.C--, --CH.dbd.CH--CH.sub.2 --, --C.tbd.C--CH.sub.2 --, 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).
As can be seen from formula I, depending on the meanings of R.sup.1, R.sup.2, R.sup.3, Q and X the compounds of the invention can comprise several diastereoisomeric forms (e.g. R or S configuration at the starred carbon atom). The invention covers all these diastereoisomers in pure form as well as mixtures of diastereoisomers.
In particular, both diastereoisomers having the two possible configurations at the carbon atom marked "22" are included. These are referred to as isomer A and isomer B.
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.
Compounds of formula I in which X is hydrogen also may act as prodrugs, as these compounds are relatively inactive in vitro, but are converted to active compounds of formula I by enzymatic hydroxylation after administration to the patient.
It has recently 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

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