Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Bacterium or component thereof or substance produced by said...
Patent
1981-10-06
1983-03-29
Ford, John M.
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Bacterium or component thereof or substance produced by said...
542429, 549465, A61K 3134, C07D307935
Patent
active
043783708
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention relates to novel prostacyclin derivatives, a process for the preparation thereof, as well as the utilization 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 can be considered a blood-pressure-lowering agent. However, PGI.sub.2 does not have the stability required for a medicinal agent. Thus, the half-life value of PGI.sub.2 at physiological pH values and at room temperature is only a few minutes. Prostacyclin is stabilized by the introduction of a nitrile group at the enol ether double bond, retaining the pharmacological spectrum of efficacy, and markedly prolonging the duration of activity (DOS No. 2,753,244). The additional introduction of fluorine in the 16-position effects a further increase in duration of effectiveness and selectivity.
SUMMARY OF THE INVENTION
The compounds of this invention have a blood-pressure-lowering effect and a bronchodilatory activity. Furthermore, these compounds are suitable for inhibition of thrombocyte aggregation and inhibition of gastric acid secretion.
The invention concerns prostane derivatives of general Formula I ##STR3## wherein R.sub.1 represents the residue OR.sub.3 wherein R.sub.3 can be hydrogen or alkyl of 1-10 carbon atoms, or R.sub.1 is the residue NHR.sub.4 wherein R.sub.4 is an alkanoyl or alkanesulfonyl residue, group, ##STR4## wherein the OH-group can be respectively substituted by alkanoyl of 1-4 carbon atoms and the free or substituted OH-group can be in the .alpha.- or .beta.-position, carbon atoms which can be substituted by phenyl, or a phenyl group, carbon atoms, is hydrogen, the salts thereof with physiologically compatible bases.
DETAILED DISCUSSION
Suitable alkyl groups R.sub.3 are straight-chain or branched-chain alkyl groups of 1-10 carbon atoms, e.g. methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, neopentyl, heptyl, hexyl, decyl. Preferred alkyl groups R.sub.3 are those of 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, isobutyl, butyl.
The alkanoyl residue R.sub.4 can be constituted by physiologically acceptable acid residues derived from the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, trimethylacetic acid, diethylacetic acid, tert.-butylacetic acid. The alkanesulfonyl residues R.sub.4 are derived, for example, from methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, butanesulfonic acid.
Acetyl, propionyl, and butyryl can be named as alkanoyl residues in R.sub.5 and W. Suitable as the alkyl group R.sub.2 are straight-chain and branched-chain, saturated alkyl residues of 1-6 carbon atoms substitutable by phenyl, e.g. methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, phenyl, hexyl, and benzyl.
Suitable as the alkyl group R.sub.6 are straight-chain and branched-chain, saturated alkyl residues of 1-4 carbon atoms. The following can be recited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl.
The alkylene group B can be constituted by straight-chain, saturated alkylene residues of 1-5 carbon atoms, to wit, methylene, ethylene, trimethylene, tetramethylene, pentamethylene.
Inorganic and organic bases are suitable for the salt formation, as they are familiar to those skilled in the art for the formation of physiologically compatible salts. Examples are alkali hydroxides, such as sodium and potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)methylamine, etc.
The invention furthermore relates to a process for the preparation of the prostacyclin derivatives of general Formula I according to this invention, characterized by reacting in a manner known per se a compound of general Formula II ##STR5## where
REFERENCES:
patent: 4219479 (1980-08-01), Vorbrueggen et al.
Casals-Stenzel Jorge
Mannesmann Gerda
Raduechel Bernd
Schillinger Ekkehard
Skuballa Werner
Dentz Bernard
Ford John M.
Schering Aktiengesellschaft
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