Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1995-03-16
1997-09-02
Prior, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
552653, C07C40100
Patent
active
056631570
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01735 filed Jun. 30, 1993, published as WO94/00429, Jan. 6, 1994.
22-En-25-oxa Derivatives in the Vitamin D Series, Process for their Production, Pharmaceutical Preparations Containing these Derivatives as well as their Use as Pharmaceutical Agents
This invention relates to 22-en-24a-oxa derivatives in the vitamin D series of general formula I ##STR2## in which
R.sup.1, R.sup.2 and R.sup.4, independently of one another, each mean a hydrogen atom, an alkanoyl group with 1 to 9 carbon atoms or an aroyl group,
R.sup.3 mean a hydrogen atom each or a linear or branched alkyl group each with 1 to 4 carbon atoms, a trifluoromethyl group each or a saturated or unsaturated carbocyclic or heterocyclic 3-, 4-, 5- or 6-membered ring formed together with the tertiary carbon atom, and
X means an alkylene radical --(CH.sub.2).sub.n --with n=1, 2 or 3, a process for their production, pharmaceutical preparations that contain these compounds as well as their use for the production of pharmaceutical agents.
The alkanoyl groups possible for radicals R.sup.1, R.sup.2 and R.sup.4 are derived especially from saturated alkanecarboxylic acids and the aroyl group from the benzoic acid.
As alkyl groups for R.sup.3, first of all the methyl, ethyl or propyl group or a cyclopropyl or cyclopentyl ring formed together with the tertiary carbon atom are suitable.
Preferred according to this invention are 22-en-25-oxa compounds 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 for a methyl, ethyl or propyl group each and X stands for CH.sub.2 .
Especially preferred are the compounds:
(5Z,7E,22E)-(1S,3R)-24-(2-Hydroxy-2-methylpropoxy)-9,10-secochola-5,7,10(19 ),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-24-(2-ethyl-2-hydroxybutoxy)-9,10-secochola-5,7,10(19), 22-tetraene-,1,3-diol,
(5Z,7E,22E)-(1S,3R)-24-(2-hydroxy-2-propylpentoxy)-9,10-secochola-5,7,10(19 ),22-tetraene-,1,3-diol. 22-en-24b-oxa derivatives in the vitamin D series have already been described (Schering AG, PCT application WO 91/12238).
Natural vitamins D.sub.2 and D.sub.3 (cf. general formula XV) are biologically inactive per se and are converted to their biologically active metabolites only after hydroxylation in 25-position in the liver or in 1-position in the kidney. The action of vitamins D.sub.2 and D.sub.3 consists in the stabilization of the plasma-Ca.sup.++ and plasma-phosphate level; they counteract a decline of the plasma-Ca.sup.++ level. ##STR3## Ergocalciferol: R.sup.a .dbd.R.sup.b .dbd.H, R.sup.c .dbd.CH.sub.3 Vitamin D.sub.2 Double bond C.dbd.22/23 .dbd.H .dbd.H Calcitriol
In addition to their pronounced effect on the calcium and phosphate metabolism, vitamin D.sub.2 and D.sub.3 and its 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, Editors H. L. J. Makin, 2nd Edition, Blackwell Scientific Publications 1984, pp. 71-116).
But when using vitamin D, overdosage symptoms can occur (hypercalcemia).
1.alpha.-Cholecalciferols hydroxylated in 24-position already follow from DE-AS 25 26 981; they have a lower toxicity than the corresponding nonhydroxylated 1.alpha.-cholecalciferol. The hydroxylated compounds show a selective activation of the 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 in humans and animals caused by abnormal cell proliferation and/or cell differentiation.
For various 1,25-dihydroxy-homo-vitamin D derivatives, a dissociation relative to the properties of bone absorption effect and HL-60 cell differentiation has already recently been mentioned by De Luca. The bone absorption effect in vitro is a direct measurement in this case for the calcium mobilization in vivo.
The vitamin D activity of the compounds according to the invention is determined by a calcitri
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Haberey Martin
Kirsch Gerald
Neef Gunter
Schwarz Katica
Steinmeyer Andreas
Prior Kimberly J.
Schering Aktiengesellschaft
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