Vitamin-D amide derivatives

Details Vitamin-D amide derivatives Vitamin-D amide derivatives

1996-11-20

1998-09-22

Clardy, S. Mark

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

514167, C07C40100, A01N 4500

Patent

active

058115625

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel vitamin D analogues, more particularly to 1.alpha.-hydroxy vitamin D.sub.3 analogues having a modified side chain at the 17-position.
Vitamin D.sub.3 which has the formula ##STR2## is well known to play a vital role in the metabolism of calcium, by promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus and stimulating mobilisation of calcium from the bone fluid compartment in the presence of parathyroid hormone.
Following the discovery that the D vitamins are hydroxylated in vivo, at the 25-position in the liver and at the 1.alpha.-position in the kidney, the resulting 1 .alpha.,25-dihydroxy metabolite being the biologically active material, much attention has been given to hydroxylated vitamin D analogues, initially with the intention of achieving enhanced effects on calcium metabolism. The subsequent findings that 1.alpha.,25-dihydroxy vitamin D.sub.3 exhibits cell modulating activity, including immunosuppressive and immunopotentiating effects, led to further investigations in a search for analogues exhibiting a high level of such activity coupled with a reduced effect on calcium metabolism, since the use of such compounds for cell modulating purposes may otherwise be precluded by unacceptable hypercalcaemia and cumulative toxicity problems as a result of their effects on calcium metabolism.
A review of previous work in this area is contained in WO 93/09093, the contents of which are incorporated herein by reference. This review identifies a number of vitamin D analogues which appear to show cell modulating activity at a similar level to that of 1.alpha.,25-dihydroxy vitamin D.sub.3 ; however, these analogues also appear still to show appreciable effects on calcium metabolism, such activity being attenuated by at most two orders of magnitude relative to that of 1.alpha.,25-dihydroxy vitamin D.sub.3. Use of such analogues may therefore give rise to cumulative toxicity problems if the compounds are used in long term therapy, particularly where systemic application is required.
It has been suggested that the attenuated calcium effect of such vitamin D analogues may in fact be due merely to more rapid metabolism of the analogue, this reducing the amount of the drug circulating in the body (see e.g. Bouillon et al., J. Bone Miner. Res. (1991), 6, p 1051 and Dusso et al., Endocrinology (1991), 128, p 1687). The cell modulating effect may similarly be reduced in vivo so that one may require larger systemic dosages than are suggested by in vitro test results.
In the above-mentioned WO 93/09093 there are described and claimed a number of 1.alpha.-hydroxy vitamin D derivatives and 20-epi analogues thereof in which the 17-position side chain terminates in an optionally N-substituted or N,N-disubstituted carbamoyl group. Such vitamin D amide derivatives exhibit minimal effect on calcium metabolism, e.g. having insignificant effects on serum calcium and phosphorus levels in rats even when administered in amounts of 100 times a conventional dosage for 1.alpha.,25-dihydroxy vitamin D.sub.3, but may have a potent cell modulating effect, for example as evidenced by eliciting cell differentiation and maturation, inhibiting proliferation and/or by activating monocytes; they accordingly exhibit an advantageous therapeutic ratio of cell modulating to calcaemic activity. The cell modulating activity of the compounds is most surprising given that they possess sizeable vitamin D-like side chains which do not carry a hydroxyl group at the 24- or 25- positions and which in many cases are not capable of being hydroxylated at these positions; previous findings had strongly suggested the need for such a hydroxyl group in order to obtain cell modulating activity. Furthermore, other workers had found the presence of an amide group in the 17-position side chain of corresponding 1.alpha.-unsubstituted compounds to have an antagonist effect characterised by anti-vitamin D activity (see U.S. Pat. No. 4,217,288).
The present invention is based o

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