Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1993-07-19
1995-05-02
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
054119499
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 23-oxa-derivatives in the vitamin D series of formula I ##STR2## in which R.sup.1, R.sup.2 and R.sup.4 independently of one another mean a hydrogen atom or an acyl group with 1 to 9 carbon atoms, with 1 to 4 carbon atoms and X means an alkylene radical--(CH.sub.2).sub.n -- with n=1, 2, 3, and if n=1, R.sup.3 each cannot be a methyl or propyl group, contain these compounds as well as their use for the production of pharmaceutical agents.
The acyl groups possible for radicals R.sup.1, R.sup.2 and R.sup.4 are derived especially from saturated or even unsaturated, straight-chain or branched carboxylic acids or benzoic acid.
As alkyl groups for R.sup.3 methyl, ethyl or propyl groups are first of all suitable.
Preferred, according to this invention, are 23-oxa-vitamin D derivatives of general formula I, in which R.sup.1, R.sup.2 and R.sup.4 stand for a hydrogen atom and R.sup.3 each stands for an ethyl group.
Especially preferred are the compounds 1.alpha.,3.beta.-diol, 1.alpha.,3.beta.-diol, 1.alpha.,3.beta.-diol, 1.alpha.,3.beta.-diol.
Vitamin D derivatives that can be substituted in 1 and 3 position as the compounds according to the invention and the side chain ##STR3## in which Z, i.a., stands for an oxygen atom and R.sup.5 for a straight-chain or branched-chain, optionally substituted aliphatic group with 1 to 12 carbon atoms, are described in EP-A-0078 704. Especially preferred here are the compounds in which Z, i.a., means an oxygen atom and R.sup.5 means the group --CH.sub.2 --C(CH.sub.3).sub.2 OR.sup.6 (R.sup.6 =H, hydroxy protective group).
Natural vitamins D.sub.2 and D.sub.3 (cf. general formula VIII) are in themselves biologically inactive and are converted not until after hydroxylation in 25 position in the liver or in 1 position in the kidneys into their biologically active metabolites. The effect of vitamins D.sub.2 and D.sub.3 consists in the stabilization of the plasma-Ca.sup.++ level and plasma phosphate level; they counteract a drop of the plasma-Ca.sup.++ level. ##STR4##
In addition to their pronounced effect on the calcium and phosphate metabolism, vitamins D.sub.2 and D.sub.3 and their synthetic derivatives also have proliferation-inhibiting and cell-differentiating effects (H. F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, Editor H. L. J. Makin, 2nd Edition, Blackwell Scientific Publications 1984, pp 71-116). However in vitamin D use it is possible to have overdose symptoms (hypercalcemia).
In 24 position hydroxylated 1.alpha.-cholecalciferols are already known from DE-AS 25 26 981; they have less toxicity than the corresponding nonhydroxylated 1.alpha.-cholecalciferol. The hydroxylated compounds show a selective activation of intestinal calcium absorption and a weaker bone absorption effect than 1.alpha.-cholecalciferol.
The 24-hydroxy-vitamin D analogs described in international patent application WO 87/00834 can be used for the treatment of disorders caused by abnormal cell proliferation and/or cell differentiation in humans and animals.
For various 1,25-dihydroxy-homo-vitamin D derivatives a dissociation relative to the properties bone absorption effect and HL-60 cell differentiation recently has been mentioned by De Luca. The bone absorption effect in vitro here is a direct measurement for the calcium mobilization in vivo.
It has now been found that the 23-oxa-vitamin D derivatives of general formula I according to the invention in comparison with vitamin D derivative calcitriol (1.alpha.,25-dihydroxycholecalciferol) surprisingly have a more favorable spectrum of activity. While the effects on the calcium and phosphate metabolism are markedly weakened (reduction of the side effects by overdosage or necessary high dosage), the proliferation-inhibiting and cell-differentiating effects are approximately retained (dissociation).
The vitamin D activity of the compounds according to the invention is determined by the calcitriol receptor test. It is performed by using a specific receptor protein from the intestine of young
REFERENCES:
Kubodera, et al., Chem. Pharm. Bull., 39(12), 1991, pp. 3221-3224.
Haberey Martin
Kirsch Gerald
Neef Gunter
Rach Petra
Schwarz Katica
Kestler Kimberly J.
Richter Johann
Schering Aktiengesellschaft
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