Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1992-07-23

1994-12-20

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

053746295

DESCRIPTION:

BRIEF SUMMARY
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 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.
The compounds of the present invention are represented by the general formula I ##STR2## in which formula X is hydrogen or hydroxy; Y is oxygen or sulphur or oxidized sulphur (S(O) or S(O.sub.2)); R.sup.1 and R.sup.2, which may be the same or different, stand for hydrogen or C.sub.1 -C.sub.6 hydrocarbyl; 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; Q is a C.sub.1 -C.sub.8 hydrocarbylene diradical. R.sup.3 is hydrogen or C.sub.1 -C.sub.6 hydrocarbyl. R.sup.1, R.sup.2 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms. n is 0 or 1.
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 Q include methylene, di-, tri- and tetra-methylene, --CH.sub.2 --CH.dbd.CH--, --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), and
Examples of R.sup.3 include (apart from hydrogen) methyl, normal-butyl and phenyl.
As can be seen from formula I, depending on the meanings of R.sup.1, R.sup.2, R.sup.3 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 and also mixtures of diastereoisomers. In addition, derivatives 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 ("bioreversible derivatives or prodrugs of I").
The term "bioreversible derivatives or prodrugs of I" includes, but is not limited to, derivatives of the compounds of formula I in which one or more hydroxy groups have been transformed into --O-acyl or --O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo.
The compounds I in which X is hydrogen are another type of prodrug. 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, indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases and rejection of transplants. In addition, other conditions characterized by an abnormal interleukin production, e.g. inflammatory diseases such as rheumatoid arthritis may be treated with 1,25(OH).sub.2 D.sub.3.
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, an

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