Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1983-12-30
1987-01-20
Jiles, Henry R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514382, 514460, 514469, 260465F, 548253, 548252, 549414, 549415, 549465, 560 56, 562466, 564172, 540596, 540607, 558416, 558123, 558419, A61K 3144, C07D307935
Patent
active
046380027
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new 2,3,4-trinor-1,5-inter-m-phenylene-prostacyclin-I.sub.2 analogues, a process for the preparation thereof and pharmaceutical compositions containing the same.
According to an aspect of the present invention there are provided new 2,3,4-trinor-1,5-inter-m-phenylene-PGI.sub.2 analogues of the Formula I ##STR2## wherein A stands for carboxy, cyano, tetrazolyl or --COOR.sup.3 or --CONR.sup.1 R.sup.2 ; acceptable cation; optionally substituted by carboxy, hydroxy, phenyl or C.sub.2-5 alkoxycarbonyl; or C.sub.1-4 alkylsulfonyl; or containing 3-6 carbon atoms; optionally interrupted by one or more oxygen atom or --CH.dbd.CH-- or --C.tbd.C-- group and/or optionally substituted by halogen; or a phenyoxymethyl group optionally substituted by halogen or trifluoromethyl; or an alkenyloxymethyl group containing 3-5 carbon atoms; alkoxy; alkanoylamido; unsbustituted or not interrupted by an oxygen atom or a --CH.dbd.CH-- or --C.tbd.C-- group; or a phenyoxymethyl group optionally substituted by halogen or trifluoromethyl, then carboxy or --COOR.sup.3 and salts thereof formed with pharmaceutically acceptable cations.
The prostacyclin analogues of the Formula I possess various valuable pharmacological properties. It is known that prostacyclin is a substance which occurs in nature and is biologically highly active. Prostacyclin plays a role in the regulation of haemostasis (antiaggregation, desaggregation), exhibits useful peripherial vasodilating effect as well as a generally acknowledged cytoprotective activity (Prostaglandins 1976, 12, 915-928; J. Am. Chem. Soc. 1977, 99, 2006; Pharmacol. Rev. 1968, 20, 1. )
The greatest drawback of the therapeutical use of prostacyclin resides in its great instability due to the enolether structural unit. Thus the half-period of the sodium salt of prostacyclin in aqueous solution at a pH value of 7 amounts to 3 minutes (Prostaglandins 1978, 15, 943).
Research in the field of prostacyclin analogues has been directed from the very beginning to the preparation of stable compounds having high prostacyclin activity.
According to DOS No. 3.029.984 the unstable prostacyclin structure can be stabilized by substituting the carbon chain between carbon atoms 1 and 5 (according to the numbering used in prostaglandin chemistry) by an aromatic ring. The derivatives thus obtained exhibit anti-aggregation and hypotensive effects and influence the heart rate; the said derivatives are more stable than PGI.sub.2 occurring in nature. Compounds having substantially similar structure are disclosed in DOS No. 2.945.781. The said prostacyclin derivatives contain 1,2-phenylene group and according to the disclosure of DOS No. 2.945.781 they exert smooth muscle stimulating, blood platelet aggregation inhibiting and hypotensive effects, they inhibit the secretion of gastric acid, exhibit an antiasthma effect, heal the lesions caused by non-steroidal anti-inflammatory agents and show an antidermatosis effect as well. The strength and duration of the activities is, however, not disclosed in the cited references.
According to European Patent Application No. 0,062,902 the ratio of the hypotensive and blood platelet aggregation inhibiting effects can be shifted in favor of the latter activity by introducting into the lower side-chain an alkyl group being longer than that of natural PGI.sub.2 or an amino or optionally a phenyl or benzyl group.
The strength of the above two basic biological activities can be altered to a still larger extent by replacing the vinylene group in position 13, 14 (according to the numbering used in prostaglandin chemistry) by a halogenated vinylene group or an acetylene group and simultaneously using a side-chain being longer or comprising an aromatic group, respectively (European Patent Application No. 82,110,986). The antiaggregation effect of the said compounds is approximately similar to that of PGI.sub.2 while--on the other hand--the undesired hypotensive effect is about 200-230 times weaker than that of PGI.sub.2.
It has been surprisingly found that the new 2
REFERENCES:
patent: 4372971 (1983-02-01), Seipp et al.
patent: 4451483 (1984-05-01), Szekely et al.
patent: 4479945 (1984-10-01), Szekely et al.
Bertok Bela
Botar Sandor
Dolgos nee Kekesi Krisztina
Gajary Antal
Kovacs Gabor
Chinoin Gyogyszer - es Vegyeszeti Termekek Gyara Rt.
Dentz Bernard I.
Dubno Herbert
Jiles Henry R.
Ross Karl F.
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