Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1996-05-29
1998-05-26
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560115, 562503, 562500, 514530, 514573, C07C17700
Patent
active
057568189
DESCRIPTION:
BRIEF SUMMARY
Object of the invention are 9-chloro-prostaglandin analogues, process for their production, as well as their use as pharmaceutical agents.
It is known concerning the extensive prior art of prostaglandins and their analogues that this family of substances is suitable for treating mammals, including humans, because of its biological and pharmacological properties. Their use as pharmaceutical agents encounters difficulties, however. Most natural prostaglandins have too short a duration of action for therapeutic purposes, since they are degraded too quickly by various enzymatic processes. All structural changes therefore have the object of increasing both the duration of action and the selectivity of the action.
It has now been found that the new 9-chloro-prostaglandin analogues have a high-action specificity, better effectiveness, prolonged duration of action and first and foremost greater stability than the natural prostaglandins.
The invention relates to 9-chloro-prostaglandin derivatives of formula I ##STR2## in which X means oxygen or CH.sub.2, and represents hydrogen, and their clathrates with .alpha.-, .beta.- or .gamma.-cyclodextrin.
As alkyl radicals R.sup.1, R2 and R.sup.3, straight-chain or branched C.sub.1 -C.sub.6 alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc., are suitable.
As physiologically compatible bases, e.g., lyes such as KOH, NaOH or alkaline-earth hydroxides such as Ca(OH).sub.2 are suitable.
The invention further relates to a process for the production of 9-chloro-prostaglandin analogues of formula I, characterized in that
a) a compound of formula II ##STR3## in which
R.sup.2 means a straight-chain or branched alkyl group with 1-6 C atoms and
X has the above-indicated meaning, is hydrogenated under protection of the OH groups with dimethyl-tert-butyl silyl chloride in the presence of Pd/C and then the protective groups are removed with tetrabutylammonium fluoride trihydrate or a compound of formula II is hydrogenated in the presence of Pd/C and optionally saponified with lye and compounds with R.sup.1 =H are reacted with diazoalkanes of formula III
The invention also relates to pharmaceutical agents based on compounds of formula I, as well as their cyclodextrin clathrates, with the usual adjuvants and vehicles.
Cyclodextrin clathrates can be obtained analogously to instructions in WO 87/05294.
The 9-chloro-prostaglandin analogues according to the invention are stable PGD.sub.2 derivatives and thus valuable pharmaceutical agents, since in the case of a similar spectrum of activity, they exhibit a significantly improved (higher specificity) and mainly more prolonged action than the corresponding natural prostaglandins.
They are suitable as medicinally valuable active ingredients for use for, e.g., lowering of the blood pressure, the promotion of the blood supply of the skin, luteolysis, inhibition of gastric acid secretion, inhibition of platelet aggregation, treatment of ulcers or cytoprotection.
The compounds according to the invention can also be used in combination with, e.g., .beta.-blockers, diuretic agents, phosphodiesterase inhibitors, calcium antagonists, thromboxane antagonists, thromboxanesynthetase and cyclooxygenase inhibitors, anticoagulant substances, such as also fibrinolytic agents, leukotriene antagonists, leukotriene synthetase inhibitors and antigestagens.
Especially suitable are the compounds according to the invention for topical use, such as, e.g., for promoting the blood supply of the skin and for lowering elevated intraocular pressure (glaucoma) as well as for promoting the renal blood circulation and for use as a diuretic agent.
In rabbits, the topical application of compounds produces a lowering of intraocular pressure.
In monkeys with experimental glaucoma, the topical application of compounds produces a normalization of the pathologically elevated intraocular pressure.
The single dose of the compounds for the use for treating elevated intraocular pressure is 1 ng-100 .m
Buchmann Bernd
Skuballa Werner
Killos Paul J.
Schering Aktiengesellschaft
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