Cyclopentane ether derivatives, processes for their production,

Details Cyclopentane ether derivatives, processes for their production, Cyclopentane ether derivatives, processes for their production,

1994-12-14

1997-04-29

Carr, Deborah D.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546257, 548252, 548237, 549357, 549397, 554103, 554104, 554105, 554106, 554114, 554 88, 554221, 554222, 560 15, 560 24, 560121, C07D21500

Patent

active

056250673

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/DE91/00925 filed Nov. 23, 1991.


SPECIFICATION

The invention relates to cyclopentane ether derivatives, processes for their production, as well as their use as auxiliary agents for pharmacological studies and as medicinal agents.
Cyclopentane derivatives have been the subject of intensive scrutiny in recent years because prostaglandins derived from the cyclopentane system, such as, for example, PGA.sub.2, PGB.sub.2, PGE.sub.2, 6-oxo-PGE.sub.1, PGD.sub.2, PGF.sub.2.alpha., PGJ.sub.2,and their analogs exhibit a great variety of biological effects, for example, on the cardiovascular, CNS, or immune system.
It has been found surprisingly that, by the introduction of an ether residue in position 9 (prostaglandin numbering) of the prostane skeleton in combination with a great variety of different structural features in the bottom chain, as well as in the 11 position, chemically and metabolically stable prostaglandin analogs are obtained capable of antagonizing the pharmacological properties of the unstable thromboxane A.sub.2 (TXA.sub.2) and, respectively, PGH.sub.2, as well as its stable analogs, such as, for example U46619 or U44069 on the receptor.
Consequently, the compounds of this invention represent valuable auxliary agents for the selective therapy of diseases that can be traced back to an excess of TXA.sub.2 and, respectively, PGH.sub.2.
The invention relates to cyclopentane ether derivatives of Formula I ##STR2## wherein R.sup.1 means ##STR3## wherein R.sup.5 can be hydrogen or C.sub.1 -C.sub.10 -alkyl optionally substituted by halogen, phenyl, C.sub.1 -C.sub.4 -alkoxy or di-(C.sub.1 -C.sub.4)-alkylamino, C.sub.5 -C.sub.6 -cycloalkyl, C.sub.7 -C.sub.16 -aralkyl, Y-substituted-phenacyl or-C.sub.6 -C.sub.12 -aryl, or a 5- or 6-membered heterocyclic residue with at least one N, O or S atom, or --CONHR.sup.7 wherein R.sup.7 means hydrogen, C.sub.1 -C.sub.10 -alkanoyl or C.sub.1 -C.sub.10 -alkanesulfonyl, ##STR4## R.sup.3 is hydrogen, F, R.sup.6 or OR.sup.6, A is a direct bond, (Z)--CH.dbd.CH--, (E)--CH.dbd.CH--. --C.dbd.C--, --(CH.sub.2).sub.n --V--(CH.sub.2).sub.q --V group, a free or functionally modified hydroxymethylene group, a free or functionally modified ##STR5## group wherein the hydroxy group can in each case be in the .alpha.- or .beta.-position, atoms, a branched saturated alkylene group, or a straight-chain or branched unsaturated alkylene group of 2-5 carbon atoms which can optionally be substituted by fluorine atoms, ##STR6## m is 0 to 2, V is an O or S atom, hydrogen, C.sub.1 -C.sub.5 -alkyl, halogen, or trifluoromethyl, -cycloalkyl, ##STR7## r is 1 or 2, Y.sub.1 and Y.sub.2, being identical or different, mean Y, --CH.sub.2 --OR.sup.6 COOR.sup.6 or C.sub.1 -C.sub.10 -alkyl, -C.sub.12 -aryl or C.sub.7 -C.sub.16 -aralkyl and, if R.sup.5 means hydrogen, .alpha.-, .beta.- or .gamma.-cyclodextrin clathrates, and also the liposome-encapsulated compounds of Formula I.
The definition of 5- or 6-membered heterocyclic residue concerns heterocycles containing at least one hetero atom, preferably nitrogen, oxygen, or sulfur, and being mono- or bicyclic. Examples that can be mentioned are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, quinolyl, isoquinolyl.
Suitable alkyl groups R.sup.4, R.sup.5, R.sup.6 and Y are straight- or branched-chain alkyl groups of 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
The alkyl groups R.sup.4, R.sup.5, R.sup.6 and Y can be substituted by halogen atoms, hydroxy groups, C.sub.1 -C.sub.4 -alkoxy groups, C.sub.6 -C.sub.12 -aryl groups which can be substituted by halogen, di-(C.sub.1 -C.sub.4)-alkylamines and tri-(C.sub.1 -C.sub.4)-alkylammonium. Alkyl groups which are monosubstituted are preferred.
Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
Preferred alkyl groups R.sup.4, R.sup.5, R.sup.6 and Y are those of 1-4 carbon atoms, such as,

REFERENCES:
Cave et al., JCS, Perkins I, pp. 646-652 1981.
Cave et al., "Total Synthesis of Prostaglandin-F.sub.2.alpha., and the 9,O-Benzyl Derivatives of Prostaglandins-F.sub.2 .alpha., -F.sub.1 .alpha., -D.sub.2, and -D.sub.1 ", Journal of Chemical Society (1981), pp. 646-652, see the whole article.

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