Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1983-07-27
1985-07-30
Jiles, Henry R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514337, 514422, 514444, 514451, 514459, 514469, 546269, 548525, 549 60, 549214, 549420, 549465, A61K 3134, A61K 31557, C07D307935
Patent
active
045322368
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention relates to novel prostacyclin derivatives, a process for the preparation thereof, as well as use thereof as medicinal agents.
Prostacyclin (PGI.sub.2), one of the primary factors in blood platelet aggregation, has a dilating effect on various blood vessels (Science 196:1072) and thus could be considered as an agent for lowering blood pressure. However, PGI.sub.2 does not possess the stability required for a medicinal agent. Thus, its half-life at physiological pH values and at room temperature is merely a few minutes.
SUMMARY OF THE INVENTION
It has been found that aromatization of the tetrahydrofuran ring in the prostacyclin leads to stabilization of the prostacyclin molecule, the pharmacological spectrum of activity being preserved while the duration of effectiveness of the novel prostacyclins is markedly prolonged.
The compounds of this invention have blood-pressure-lowering and bronchodilatory effects. They are furthermore suitable for inhibiting thrombocyte aggregation, vasodilation, and gastric acid secretion.
The invention relates to prostacyclins of general Formula I ##STR3## wherein R.sub.1 is the residue OR.sub.3 wherein R.sub.3 means hydrogen or alkyl of 1-10 carbon atoms substituted, if desired, by halogen, aryl, C.sub.1 -C.sub.4 -alkoxy, or C.sub.1 -C.sub.4 -dialkylamino; cycloalkyl, aryl, or a heterocyclic residue; or is the residue NHR.sub.4 wherein R.sub.4 means hydrogen, an alkanoyl residue, or an alkanesulfonyl residue of respectively 1-10 carbon atoms, ##STR4## wherein the OH-group can be respectively esterified with a benzoyl or alkanoic acid residue of 1-4 carbon atoms, or can be etherified with a tetrahydropyranyl, tetrahydrofuranyl, C.sub.1 -C.sub.4 -alkoxyalkyl, or tri-(C.sub.1 -C.sub.4 -alkyl)-silyl residue, wherein the free or esterified OH-group can be in the .alpha.- or .beta.-position, atoms, a straight-chain or branched-chain alkenyl group of 2-6 carbon atoms which can be substituted by phenyl, halogen, or C.sub.1 -C.sub.4 -alkyl and, if D and E jointly represent a direct bond, is an alkynyl residue of 2-6 carbon atoms optionally substituted in the 1-position by halogen or C.sub.1 -C.sub.4 -alkyl, residue of 1-4 carbon atoms or which can be etherified with a tetrahydropyranyl, tetrahydrofuranyl, alkoxyalkyl, or trialkylsilyl residue and, if R.sub.3 is hydrogen, the salts thereof with physiologically compatible bases.
DETAILED DISCUSSION
The alkyl group R.sub.3 can be linear or branched alkyl groups of 1-10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, heptyl, hexyl, decyl. The alkyl groups R.sub.3 can optionally be mono- to polysubstituted by halogen atoms, alkoxy groups of 1-4 carbon atoms, optionally substituted aryl groups, dialkylamines, and trialkylammonium of 1-4 carbon atoms. Monosubstituted alkyl groups are preferred. Examples for substituents are fluorine, chlorine, or bromine atoms, phenyl, dimethylamine, methoxy, ethoxy. Preferred alkyl groups R.sub.3 are those of 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, and butyl.
Suitable aryl groups R.sub.3 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 respectively 1-4 carbon atoms, 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, for example, by fluorine, chlorine, alkoxy, or trifluoromethyl or in the 4-position by hydroxy.
The cycloalkyl group R.sub.3 can contain, in the ring, 4-10, preferably 4-6 carbon atoms. The rings can be substituted by alkyl groups of 1-4 carbon atoms. Examples that can be cited are cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and adamantyl.
Suitable as heterocyclic groups R.sub.3 are 5- and 6-membered heterocycles, among which those with a hetero atom,
REFERENCES:
patent: 4256883 (1981-03-01), Nicolaori et al.
Casals-Stenzel Jorge
Haberey Martin
Nickolson Robert
Vorbrueggen Helmut
Dentz Bernard I.
Jiles Henry R.
Schering Aktiengesellschaft
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