Prostaglandin derivatives

Details Prostaglandin derivatives Prostaglandin derivatives

1995-04-19

1996-08-13

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514573, 560118, 562500, C01C40500, A61K 31557

Patent

active

055456669

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/01493 filed Oct. 18, 1993.


TECHNICAL FIELD

The present invention relates to novel (9R)-chloro-prostaglandin derivatives.


BACKGROUND ART

Since prostaglandin (hereinafter referred to as PG) shows various important physiological actions in a trace amount, natural PG analogues and a vast number of derivatives thereof have been studied on synthesis and biological activities, with attempt to apply these compounds to pharmaceuticals. The results of the investigations are reported in a number of literature, Japanese Patent Application Kokai (Laid-Open) No. 100446/1977 (U.S. Pat. No. 4,029,681) , Japanese Patent Application Kohyo No. 502009/1990 (WO89/00559), etc. Among these publications, Japanese Patent Application Kohyo No. 502009/1990 discloses a group of PG derivatives which are substituted with a halogen at the 9-position; however, the physiological activities of these PG derivatives are not fully satisfactory.
The object of the present invention is to provide novel PG derivatives having strong ameliorating actions for renal failure, ischemic heart disease and heart failure.


DISCLOSURE OF THE INVENTION

The present inventors made a study and found out that particular PG derivatives which have a chlorine atom of R-configuration at the 9-position and a triple bond between the 13-position and 14-position, have excellent physiological activities, particularly ameliorating actions for renal failure, ischemic heart disease and heart failure. The present invention has been completed based on the finding.
According to the present invention there are provided a prostaglandin derivative represented by formula ##STR2## (wherein R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group, and R.sup.2 represents a cyclohexyl group or a cyclopentylmethyl group), and a salt thereof.
In the present specification, "alkyl group" may be any of a straight chain type and a branched chain type. The C.sub.1 -C.sub.6 alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl groups, etc.
The compound of formula (I) wherein R.sup.1 represents a hydrogen atom, can be present in the form of a free acid, or in the form of a salt. Examples of such a salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; other metal salts such as aluminum salt and the like; ammonium salt; salts with organic amines such as trialkylamine (e.g. triethylamine), pyridine and the like. A pharmaceutically acceptable salt is particularly preferable.
The present compound of formula (I) can be produced, for example, by a process summarized in the following reaction scheme A. ##STR3##
In the above reaction scheme, R.sup.11 represents a C.sub.1 -C.sub.6 alkyl group; TBS represents a tert-butyldimethylsilyl group; and R.sup.2 has the same definition as above.
Each of the first to sixth steps is hereinafter described in more detail.
(First step)
First, a compound of formula (II) known via the process of Sato et al. [J. Org. Chem., Vol. 53, p. 5590 (1988)] is reacted with about 0.8-about 2 equivalents of an organoaluminum compound represented by formula (III) at a temperature of about -10.degree. to about 30.degree. C. in an inert solvent (e.g. toluene, tetrahydrofuran, diethyl ether or the like) to form a compound of formula (IV).
In the above reaction, the organoaluminum compound of formula (III) used as a raw material can be produced, for example, by completely reacting an acetylene compound represented by formula ##STR4## (wherein R.sup.2 and TBS have the same definitions as above), produced by the process of Sato et al. [Tetrahedron Lett., Vol. 30, p. 7083 (1989)] with about 0.8-about 1.5 eguivalents of an alkyllithium (e.g. n-butyllithium, tert-butyllithium or the like) in an inert solvent (e.g. toluene, tetrahydrofuran, diethyl ether, n-hexane or the like) at about -20.degree. to about 30.degree. C., preferably about 10.degr

REFERENCES:
patent: 4029681 (1977-06-01), Smith
J. Org. Chem vol. 53, p. 5590 (1988).
Tetrahedron Lett, vol. 30, p. 7083 (1989).
Tsuchida et al, Arzneim-Forsch, vol. 36 p. 1745, 1986.
Handbook of Physiology (Sec. 8 Renal Physiology) p. 103, 1973.

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