Vitamin D analogues

Details Vitamin D analogues Vitamin D analogues

1992-03-17

1995-02-07

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

053875826

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a hitherto unknown class of compounds which shows an immunomodulating effect 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 autoimmune diseases, including diabetes mellitus, hypertension, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, and/or imbalance in the immune system.
The compounds of the present invention are represented by the general formula I ##STR2## in which R.sup.1 and R.sup.2 may be the same or different and stand for hydrogen, lower alkyl, lower cycloalkyl, or, taken together with the carbon atom (starred in formula I), bearing the groups X, R.sup.1 and R.sup.2 can form a C.sub.3 -C.sub.8 carbocyclic ring; X stands for hydrogen or hydroxy, R.sup.3 and R.sup.4, which may be the same or different stand for hydrogen, lower alkyl or halogen, n is 0, 1 or 2 and m is 0, 1 or 2.
In the context of this invention, the expression "lower alkyl" indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 5 carbon atoms, and the expression "lower cyclo-alkyl" indicates a saturated or unsaturated C.sub.3 -C.sub.7 carbocyclic ring.
As can be seen from formula I, depending on the meanings of X, R.sup.1 and R.sup.2 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.
Compounds of formula 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 (X =OH) by enzymatic hydroxylation after administration to the patient.
It has recently been shown that 1.alpha.,25-dihydroxyvitamin 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-1 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, 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 cancer and psoriasis.
Also, the use of 1,25(OH).sub.2 D.sub.3 for the treatment of hypertension and diabetes mellitus has been suggested.
However, the therapeutic possibilities in such indications of 1,25(OH).sub.2 D.sub.3 are severely limited by the well known potent effect of this hormone on calcium metabolism; elevated blood concentrations will rapidly give rise to hypercalcemia. Thus, this compound and its potent synthetic analogues are not completely satisfatory for use as drugs in the treatment of e.g. psoriasis, cancer or immune diseases which may require continuous administration of the drug in relatively high doses.
A number of oxa-analogues of vitamin D.sub.3 are

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