9-halo-2-prostaglandin derivatives, processes for the preparatio

Details 9-halo-2-prostaglandin derivatives, processes for the preparatio 9-halo-2-prostaglandin derivatives, processes for the preparatio

1985-09-17

1987-10-13

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514573, 514601, 514630, 549415, 560 62, 560118, 560121, 562472, 562500, 562503, 564 98, 564 99, 564217, 564221, C07C17700, A61K 31557

Patent

active

046999205

DESCRIPTION:

BRIEF SUMMARY
The invention relates to novel 9-halo-.DELTA..sup.2 -prostaglandin derivatives, processes for their preparation, as well as their use as medicinal agents.
It is known from the very voluminous state of the art of prostaglandins and their analogs that this class of compounds is suited, based on their biological and pharmacological properties, for the treatment of mammals, including man. The use of these compounds as medicinal agents, however, frequently meets with difficulties. Most of the natural prostaglandins exhibit a period of efficacy which is too short for therapeutic purposes, since they are too rapidly degraded metabolically by various enzymatic processes. All structural modifications serve the purpose of prolonging the duration of efficacy as well as increasing the selectivity of effectiveness.
German Unexamined Laid-Open Applications Nos. 2,950,027 and 3,126,924 disclose prostane derivatives having a chlorine or fluorine atom in the 9-position. It has now been found that a longer period of efficacy, higher selctivity, and improved effectiveness can be attained by the introduction of a double bond into the 2,3-position of the 9-haloprostaglandins.
The invention relates to 9-halo-.DELTA..sup.2 -prostane derivatives of general Formula I ##STR3## wherein
Hal is a fluorine or chlorine atom in the .alpha.- or .beta.-position,
R.sub.1 is the residue OR.sub.2 with R.sub.2 meaning a hydrogen atom, alkyl, cycloalkyl, aryl or a heterocyclic residue; or the residue NHR.sub.3 wherein R.sub.3 means an acid residue or the residue R.sub.2 and
A is a --CH.sub.2 --CH.sub.2 -- or cis--CH.dbd.CH--group,
B is a --CH.sub.2 --CH.sub.2 -- or trans--CH.dbd.CH-- or --C.tbd.C--group,
W is a free or functionally modified hydroxymethylene ##STR4## wherein the respective OH-groups can be in the .alpha.- or .beta.-position,
D and E jointly mean a direct bond or
D is a straight- or branched-chain alkylene group of 1-10 carbon atoms, which can optionally be substituted by fluorine atoms,
E is an oxygen or sulfur atom, a direct bond, a --C.tbd.C--bond or a --CR.sub.6 =CR.sub.7 --group wherein R.sub.6 is a hydrogen atom or an alkyl group and R.sub.7 is a hydrogen atom, an alkyl group or a halogen atom,
R.sub.4 is a free or functionally modified hydroxy group,
R.sub.5 is a hydrogen atom, an alkyl group, a halogen-substituted alkyl group, a cycloalkyl group, an optionally substituted aryl group, or a heterocyclic group, and, if R.sub.2 means a hydrogen atom, the salts
Suitable alkyl groups R.sub.2 are linear or branched alkyl groups of 1-10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl. The alkyl groups R.sub.2 can optionally be mono- to polysubstituted by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups, dialkylamino and trialkylammonium, wherein the single substitution is to be preferred. Examples for substituents are fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. Preferred alkyl groups R.sub.2 that can be cited 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 such as, for example, 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. Preferred are the substituents in the 3- and 4-positions on the phenyl ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl, or in the 4-position by hydroxy.
The cycloalkyl group R.sub.2 can contain 3-10, preferably 5 and 6 carbon atoms in the ring. 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, p

REFERENCES:
patent: 4444788 (1984-04-01), Skulalla
patent: 4562204 (1985-12-01), Wakatsuka

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