Prostacyclins and pharmaceuticals containing the same

Details Prostacyclins and pharmaceuticals containing the same Prostacyclins and pharmaceuticals containing the same

1987-05-18

1989-06-13

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514 63, 514460, 514569, 514573, 514621, 514623, A61K 31557

Patent

active

048393886

DESCRIPTION:

BRIEF SUMMARY
[TECHNICAL FIELD]

This invention relates to novel prostacyclins and uses in which they are employed as crisulation ameliorating pharmaceuticals for blood flow ameliorating, antithrombus and the like, or antiulcer pharmaceuticals.


[BACKGROUND ART]

Prostacyclin (hereinafter written as PGI.sub.2) has been known as a natural physiologically active substance and has the structure shown by the following formula: ##STR2## Its chemical name is (5Z,13E)-(9.alpha.,11.alpha.,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-die nic acid. PGI.sub.2 exists within the vascular walls and has the potent aggregation inhibiting effect of platelet as well as relaxing effect of smooth muscle of peripheral artery [Nature, 263, p. 663 (1976)].
PGI.sub.2 exhibiting such effects is useful for prophylaxis and therapy of cerebral thrombosus, myocardial infarction and acute stenocardia induced by exasperation of platelet aggregation and further increase of thrombotic tendency, expected to be applicable for prophylaxis and therapy of arteriosclerotic diseases and desired to be developed as the so-called blood circulation ameliorating pharmaceuticals.
Also, prostaglandins containing PGI.sub.2 are known to have gastric mucosa protective effect and blood flow increasing effect within gastric mucosa ['83 Inflammation Seminar "Prostaglandin" Pretext page 50 (Sponsored by Society of Inflammation of Japan)], and PGI.sub.2 exhibiting such effects can be expected to be applicable for prophylaxis and therapy of gastrointestinal ulcers, typically stomach ulcer.
However, PGI.sub.2 is a remarkably unstable substance and this has been an obstacle against practical application as pharmaceuticals.
In order to overcome such obstacle, studies have been made about stable analogues in which the oxygen atom between the carbon atoms at the 6- and 9-positions in PGI.sub.2 is replaced with carbon atom. The carbacyclin type compounds [Japanese Provisional Patent Publication No. 130543/1979] shown by the formula (III) as represented by OP-41483 [Japanese Provisional Patent Publication No. 130543/1979] and 9(0)-methano-.DELTA..sup.6 PGI.sub.1 represented by the formula (IV) [Japanese Provisional Patent Publication No. 32436/1981] are all chemically stable PGI.sub.2 analogue compounds. Also, 9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 (isocarbacyclin, formula (V)) in which the 5-position double bond in 9(0)-methanoprostacyclin (carbacyclin) is transferred to the 6(9.alpha.) position is also chemically sufficiently stable and has been reported as a PGI.sub.2 analogue compound having potent physiological activities [Japanese Provisional Patent Publication No. 137445/1984]. ##STR3##


[DISCLOSURE OF THE INVENTION]

The present inventors have made extensive studies in order to provide prostacyclins which are stable, substantially free from decomposition at room temperature and have excellent pharmacological properties, and consequently created novel prostacyclins and found that said compounds have potent platelet aggregation inhibiting effect, hypotensive effect, vasodilative effect and antiulcer effect, and are also low in toxicity, to accomplish the present invention.
That is, the present invention concerns prostacyclins represented by the [I]: ##STR4## [wherein R.sup.1 represents --CO.sub.2 R.sup.5 group (in the group, R.sup.5 represents a hydrogen atom, or a straight or branched alkyl group having 1 to 12 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms which may be unsubstituted or substituted by at least one alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted phenyl group, or a monoequivalent cation), or --CONR.sup.6 R.sup.7 group (in the group, R.sup.6 and R.sup.7 each may be the same or different, represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted 5 -to 6-membered ring combined with nitrogen atom bonded thereto which may have further hetero atoms); A is alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group havi

REFERENCES:
patent: 4632997 (1986-12-01), Shibasaki
patent: 4699921 (1987-10-01), Shibasaki
Chemistry Letters, No. 4, Apr. 1986, pp. 559-562.

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