9-substituted bicyclo[3.3.0]octane derivatives, process for thei

Details 9-substituted bicyclo[3.3.0]octane derivatives, process for thei 9-substituted bicyclo[3.3.0]octane derivatives, process for thei

1993-06-11

1995-04-11

Dees, Jose G.

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

Organic compounds

Carboxylic acid esters

562430, 564 86, 564 87, 548215, 548250, 549377, C07C30702

Patent

active

054059887

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The invention relates to 9-substituted bicyclo[3.3.0]octane derivatives, process for their production as well as their use as auxiliary agents for pharmacological studies and as pharmaceutical agents.
Bicyclo[3.3.0]octane derivatives have been intensively dealt with in recent years, since carbacyclins derived from the bicyclo[3.3.0]octane system, such as, e.g., iloprost or cicaprost or other analog isocarbacyclins, constitute biologically very potent as well as chemically and partially also metabolically stable prostacyclin-mimetic agents.
It has been found, surprisingly, that by the introduction of a suitable radical in 9-position (prostaglandin numbering system), chemically and metabolically stable carbacyclin analogs are obtained which, in addition, are able to antagonize the pharmacological properties of unstable thromboxane A.sub.2 (TXA.sub.2) or PGH.sub.2 as well as its stable analogs, such as, e.g., U46619 or U44069.
The compounds of this invention therefore constitute valuable auxiliary agents for selective treatment of diseases which are attributable to a deficiency of endogenous PGI.sub.2 and/or an excess of TXA.sub.2 or PGH.sub.2.
The invention relates to 9-substituted bicyclo[3.3.0]octane derivatives of formula I, ##STR2## as well as their enantiomers, in which at most one double bond lies between the carbon atoms of centers a-b or b-c or b-d, ##STR3## and R.sup.2 can mean hydrogen or C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.7 -C.sub.16 aralkyl, optionally substituted by halogen, phenyl, C.sub.1 -C.sub.4 alkoxy or di-(C.sub.1 -C.sub.4)-alkylamino, phenacyl or C.sub.6 -C.sub.12 aryl substituted by Y or a 5- or 6-membered heterocyclic radical with at least one N, O or S atom, or --CONHR.sup.3 with R.sup.3 meaning hydrogen, C.sub.1 -C.sub.10 alkanoyl or C.sub.1 -C.sub.10 alkanesulfonyl, group, hydroxy group, and the OH group can be in .alpha.- or .beta.-position, --R.sup.7, ##STR4## m means 0 to 2 A means a cis or trans CH.dbd.CH or a --C.tbd.C group, ##STR5## group, and the OH group can be in .alpha.- or .beta.-position, D and E together mean a bond or R.sup.9 and R.sup.10 are the same or different and mean hydrogen, chlorine or bromine, or a C.sub.1 -C.sub.5 alkyl group or ##STR6## R.sup.5 means a hydrogen atom, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 cycloalkyl or C.sub.6 -C.sub.12 aryl substituted by Y, NO.sub.2, COOR.sup.8 or C.sub.1 -C.sub.10 alkyl, C.sub.7 -C.sub.16 aralkyl optionally substituted by halogen and, if R.sup.2 means hydrogen, their salts with physiologically compatible bases, as well as the .alpha.-, .beta.- or .gamma.-cyclodextrin clathrates, as well as the compounds of formula I encapsulated with liposomes.
The definition of 5- or 6-membered heterocyclic radical relates to heterocycles, which contain at least one heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl.
As alkyl groups R.sup.2, R.sup.5, R.sup.8 and Y, straight-chain or branched-chain alkyl groups with 1-10 C atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl, are suitable.
Alkyl groups R.sup. 2, R.sup.5, R.sup.8 and Y can be substituted by halogen atoms, hydroxy groups, C.sub.1 14 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. Those alkyl groups which are singly substituted are preferred.
As substituents, for example, there can be mentioned fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
As preferred alkyl groups R.sup.2, R.sup.5, R.sup.8 and Y, those with 1-5 C atoms, such as, e.g., methyl, ethyl, propyl, isobutyl, butyl, chloroethyl, hydroxyethyl and 1- and 2-hydroxypropyl can be mentioned.
As alkylene groups D, straight-chain or branched-chain alkylene groups with 1-10 C atoms, such as, for example, methylene, ethylene,

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