Novel 9-substituted carbacyclin derivatives, processes for their

Details Novel 9-substituted carbacyclin derivatives, processes for their Novel 9-substituted carbacyclin derivatives, processes for their

1989-03-22

1991-10-01

Brust, Joseph Paul

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...

549425, 549483, 549488, 552 4, 552 10, A61K 31655, C07C24706, C07C24710

Patent

active

050534009

DESCRIPTION:

BRIEF SUMMARY
The invention relates to novel 9-substituted carbacyclin derivatives, processes for their preparation, as well as their use as medicinal agents.
U.S. Pat. No. 4,420,632 describes 9-alkylated carbacyclin derivatives exhibiting antithrombotic, antisecretory and bronchodilating properties. They show furthermore thrombocyte-aggregation-inhibiting activity.
It has been found that carbacyclin analogs chain-lengthened in the 9-position and having a reactive group in the .omega.-position can be bound to polymeric carriers with an only small loss of biological activity. The compounds according to this invention are suitable for inhibiting thrombocyte aggregation, for lowering blood pressure via vasodilation, for inhibiting gastric acid secretion, as well as, after chemical linkage to proteins, for the preparation of antibodies to carbacyclins.
The invention concerns carbacyclin derivatives of Formula I ##STR2## wherein Y.sub.1 is the residue -CH.sub.2 -X-(CH.sub.2).sub.n -R.sub.1 or the residue ##STR3## n is 1 or 3, R.sub.1 is the residue ##STR4## the residue -COCH.sub.3, COOR.sub.2 wherein R.sub.2 can mean hydrogen or alkyl of 1-10 carbon atoms optionally substituted by halogen, phenyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -dialkylamino, cycloalkyl, aryl, or a heterocyclic residue; or the residue CONHR3 wherein R3 means hydrogen or an alkanoyl or alkanesulfonyl residue of respectively 1-10 carbon atoms, R.sub.9 is the residue -Z-(CH.sub.2)m-R.sub.6, -CH.sub.2 -group, cis-CH.dbd.CH- or trans-CH.dbd.CH-, functionally modified ##STR5## wherein the OH-group can be in the .alpha.- or .beta.-position, D is the group a straight-chain, saturated alkylene group of 1-5 carbon atoms, a branched, saturated or a straight-chain or branched, unsaturated alkylene group of 2-5 carbon atoms which can optionally be substituted by fluorine atoms, o is 1, 2 or 3, R.sub.7 means a hydrogen atom, an alkyl group of 1-5 carbon atoms or halogen, carbon atoms, or an optionally substituted aryl group of 6-10 carbon atoms, or a heterocyclic group, compatible bases, and their cyclodextrin clathrates.
Suitable alkyl groups R.sub.2 are considered to be straight- or branched-chain alkyl groups of 1-10carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
The alkyl groups R.sub.2 can optionally be mono- to polysubstituted by halogen atoms, C.sub.1 -C.sub.4 -alkoxy groups, phenyl and di-C.sub.1 -C.sub.4 -alkylamines. Those alkyl grops that are monosubstituted are preferred.
Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. Preferred alkyl groups R.sub.2 are those of 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.
Suitable aryl groups R.sub.2 are substituted as well as unsubstituted aryl groups, e.g. phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups of 1-4 carbon atoms each, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or alkoxy group of 1-4 carbon atoms.
The substituents in the 3- and 4-positions on the phenyl ring are preferred, e.g. by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.
The cycloalkyl group R.sub.2 can contain in the ring 4-10, preferably 5 and 6 carbon atoms. The rings can be substituted by alkyl groups of 1-4 carbon atoms. Examples that can be cited are cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.
Suitable heterocyclic groups R.sub.2 are 5- and 6-membered heterocycles containing at least one hetero atom, preferably nitrogen, oxygen or sulfur. Examples that can be cited are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and others.
The acid residue R.sub.3 can be physiologically compatible acid residues. Preferred acids are organic carboxylic acids and sulfonic acids of 1-10 carbon atoms pertaining to the aliphatic, cycloaliphatic, aromatic, aromatic-al

REFERENCES:
patent: 4487960 (1984-12-01), Lin
patent: 4588823 (1986-05-01), Aristoff
"The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals" (Cyclodextrins), 1989; p. 425, Compound No. 2724, Eleventh Edition.

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