Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1988-11-23
1991-06-11
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514573, 560121, 562503, C07C17700, A61K 31557
Patent
active
050232738
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new 6-oxo-prostaglandin E derivatives, process for their production as well as their use as pharmaceutical agents.
From the very voluminous prior art of prostaglandins, especially of the E type and their analogs, it is known that this substance class because of its biological and pharmacological properties is suitable for therapy and prophylaxis of thromboses, infarcts and other cardiovascular diseases. Structural changes therefore have the aim of extending the duration of action, of increasing the selectivity of the effectiveness and at the same time of reducing the effective dose.
It has now been surprisingly found that by the introduction of a three-fold bond in the 18, 19 or 19, 20 and/or 13, 14 position as well as the introduction of a methyl group in the 16 and/or 20 position of the lower chain of the 6-oxo-prostaglandin E.sub.1 analogs the effectiveness can be improved, the selectivity increased and the duration of action extended.
The compounds according to the invention act for inhibition of thrmobocyte aggregation, reduction of blood pressure and for vasodilation and bronchodilation. They are also suitable for inhibition of gastric acid secretion as well as cytoprotection on stomach, heart, liver, pancreas and kidneys.
The invention relates to 6-oxo-prostaglandin E.sub.1 derivatives of formula I, ##STR2## in which R.sup.1 means the radical COOR.sup.2 with R.sup.2 meaning a hydrogen atom, a C.sub.1 -C.sub.10 alkyl, a C.sub.5 -C.sub.6 cycloalkyl or a C.sub.6 -C.sub.10 aryl group or a heterocyclic radical, or the radical CONHSO.sub.2 R.sup.5 with R.sup.5 as C.sub.1-10 alkyl, C.sub.5-6 cycloalkyl or C.sub.6-10 aryl, functionally modified ##STR3## group, and the OH group can be in the alpha or beta position, respectively, and optionally substituted C.sub.6 -C.sub.10 aryl group or a heterocyclic group, bases as well as alpha, beta or gamma cyclodextrin clathrates of the compounds of formula I.
As alkyl groups R.sup.2 and R.sup.5 are understood straight-chain or branched-chain alkyl groups with 1-10 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
The alkyl groups R.sub.2 can optionally be substituted once or several times by halogen atoms, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, optionally substituted C.sub.6 -C.sub.10 aryl groups, di-C.sub.1 -C.sub.4 alkylamines and tri-C.sub.1 -C.sub.4 alkyl ammonium. Those alkyl groups that are substituted once are preferred.
As substituents there can be mentioned, for example, fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
There can be mentioned as preferred alkyl groups R.sup.2 those with 1-4 carbon atoms such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl and butyl.
As aryl groups R.sup.2 and R.sup.5 both substituted and unsubstituted aryl groups are suitable such as, for example, phenyl, alpha or beta naphthyl. These groups can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with 1-4 carbon atoms each, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 carbon atoms. Substituents in the 3 and 4 position on the phenyl ring, e.g., by fluorine, chlorine, alkoxy or trifluoromethyl or the 4 position by hydroxy are preferred.
The cycloalkyl groups R.sup.2 and R.sup.5 can contain 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. As examples there can be mentioned cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.
5- or 6-membered heterocycles are suitable as heterocyclic groups R.sup.2, which preferably contain a heteroatom, preferably nitrogen, oxygen or sulfur. There can be mentioned as examples 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
The hydroxy groups R.sup.4 and in W can be functionally modified, for example by etherification or esterification, and the free or modified hydroxy groups in W can be in the alpha or beta
REFERENCES:
patent: 4205178 (1980-05-01), Axen
patent: 4235930 (1980-11-01), Skuballa
patent: 4315013 (1982-02-01), Skuballa
patent: 4560786 (1985-12-01), Skuballa
patent: 4783480 (1988-11-01), Wakatsuka
Klar Ulrich
Schillinger Ekkehard
Skuballa Werner
Sturzebecher Claus-Steffen
Thierauch Karl-Heinz
Gerstl Robert
Schering Aktiengesellschaft
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