Prostaglandin I.sub.2 derivatives

Details Prostaglandin I.sub.2 derivatives Prostaglandin I.sub.2 derivatives

1993-04-09

1995-05-16

Gerstl, Robert

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D307935

Patent

active

054162319

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel prostaglandin I.sub.2 derivatives. More particularly, the present invention relates to prostaglandins I.sub.2 having a halogen atom, particularly a fluorine atom, on the carbon atom corresponding to the 7-position of natural prostaglandin I.sub.2 and having a cycloalkylene group in the .alpha.-chain, and their esters and salts, which will hereinafter be referred to generally as prostaglandin I.sub.2 derivatives. Further, the present invention relates to pharmaceutical compositions containing such prostaglandin I.sub.2 derivatives as active ingredients. In this specification, prostaglandin may sometimes be referred to simply as PG.


BACKGROUND ART

Natural PGI.sub.2 is a local hormone product in vivo mainly at the endothelium of arterial vessels, and it is an important factor for controlling cell functions in vivo by its strong physiological activities such as an anti-platelet activity and a vasodilating activity. There has been an attempt to use it directly as a drug (P. J. Lewis, J. O. Grandy et al, Clinical Pharmacology of Prostacyclin Raven Press, N.Y., 1981). However, natural PGI.sub.2 has in its molecule a vinyl ether bond which is susceptible to hydrolysis and is readily deactivated under a neutral or acidic condition. Thus, because of its chemical instability, it can not be regarded as a good compound for a drug. Therefore, studies have been made to develop chemically stable synthetic PGI.sub.2 derivatives having physiological activities equal to natural PGI.sub.2. Among them, there is a report on a case wherein a fluorine atom was introduced to various sites ("Journal of Synthetic Organic Chemistry, Jpn", vol 42, 794 (1984), and 7-fluoro-PGI.sub.2 derivatives having fluorine introduced at the 7-position have been reported (Japanese Unexamined Patent Publications No. 171988/1982 and No. 243079/1985). Further, PGI.sub.2 derivatives having a cycloalkyl group introduced to the .omega.-side chain in order to improve the pharmacological effect and stability, have been reported (Japanese Unexamined Patent Publication No. 163365/1984). However, there has been no report on PGI.sub.2 having a cycloalkyl group introduced to the .alpha.-side chain or on derivatives thereof.


DISCLOSURE OF INVENTION

The present inventors have conducted extensive researches and as a result, have found that by introducing a cycloalkyl structure to the .alpha.-side chain of PGI.sub.2 and introducing a halogen atom on the carbon atom corresponding to the 7-position of natural PGI.sub.2, strong inhibitory activities on platelet aggregation and anti-anginal activities can be obtained, and yet these compounds have high stabilities. As the halogen atom, a fluorine atom is preferred, and the number is preferably one.
Thus, the present invention provides a novel prostaglandin I.sub.2 derivative selected from a prostaglandin I.sub.2 having a halogen atom on the carbon atom corresponding to the 7-position of natural prostaglandin I.sub.2 and having a cycloalkylene group in the .alpha.-chain, and its esters and salts.
The present invention also provides a pharmaceutical composition for prophylaxis and treatment of circulatory diseases, which contains such a prostaglandin I.sub.2 derivative as an active ingredient.


DETAILED DESCRIPTION OF THE INVENTION

In PGI.sub.2 in the present invention, the bivalent hydrocarbon moiety in the .alpha.-chain corresponding to the trimethylene group at the 2- to 4-position of natural PGI.sub.2 is preferably a C.sub.3-8 cycloalkylene group, or a bivalent hydrocarbon group having a methylene group or a dimethylene group bonded to at least one bond of such a cycloalkylene group.
The hydrocarbon group corresponding to the n-pentyl group at the 16- to 20-position of natural PGI.sub.2 is a monovalent organic group of various types, including an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group and a substituted aryl group. A alkyl group, a cycloalkyl-substituted alkyl group and a cycloalkyl group ar

REFERENCES:
patent: 4273784 (1981-06-01), Bollinger
Journal of Pharmacology and Experimental Therapeutics, vol. 206, No. 1, Jul. 1978 (Baltimore, US) B. H. Crane et al.: "Effect of prostaglandin I.sub.2 and analogs on platelet aggregation and smooth muscle contraction", pp. 132-138.

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