Prostaglandin E.sub.1 analogues

Details Prostaglandin E.sub.1 analogues Prostaglandin E.sub.1 analogues

1993-10-19

1995-09-12

Gerstl, Robert

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

Organic compounds

Carboxylic acid esters

556441, 562503, C07C40500

Patent

active

054498155

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP92/00514 filed Apr. 21, 1992.


TECHNICAL FIELD

The present invention relates to novel prostaglandin (hereinafter referred to as PG) E.sub.1 analogues.


BACKGROUND ART

Since PG's exhibit various important biological effects in a trace amount, investigations have been made of the synthesis and biological activity of natural PG's and a large number of PG analogues with the intention of use as medicines.
Especially, PGE.sub.1 is now commercially available as a drug for the improvement of peripheral circulatory disturbances because of having characteristic effects such as blood platelet aggregation inhibiting effect and blood pressure reducing effect, and therefore, a large number of PGE.sub.1 analogues have also been studied. However, the prior art PGE.sub.1 analogues are quickly metabolized in vivo and thereby have drawbacks such as lack of duration of the effect. Furthermore, the prior art PGE.sub.1 analogues cannot be administered orally in a sufficiently high amount to obtain the satisfactory effects because of causing diarrhea as a side-effect.
On the other hand, the known 13, 14-didehydro PGE.sub.1 analogues in which the double bond between the 13- and 14-positions of PGE.sub.1 is replaced by a triple bond include 13,14-didehydro PGE.sub.1 methyl ester and 6-hydroxy-13,14-didehydro PGE.sub.1.
An object of the present invention is to provide novel PGE.sub.1 analogues which have more excellent pharmaceutical effects, longer duration of the effect and less side-effects than the prior art PGE.sub.1 analogues.


DISCLOSURE OF THE INVENTION

As a result of continued extensive research, the present inventors have found that the specific compounds having a triple bond between the 13- and 14-positions of the PGE.sub.1 analogues, and a methyl group at the 17-position can solve the above-mentioned problems, and have accomplished the present invention.
The present invention is directed to a PGE.sub.1 analogue represented by the formula: ##STR2## (wherein R.sup.1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an allyl group, and R.sup.2 is an alkyl group having 3 to 6 carbon atoms or an alkenyl group having 3 to 6 carbon atoms), or a salt thereof.
In the present invention, the alkyl group having 1 to 6 carbon atoms refers to a straight or branched chain alkyl group (e.g. a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an n-pentyl group and an isopentyl group). The alkyl group having 3 to 6 carbon atoms and the alkenyl group having 3 to 6 carbon atoms refer to a straight or branched chain alkyl group.
The salt of the compound of Formula (I) refers to salts thereof when R.sup.1 is a hydrogen atom, for example, salts with metals (e.g. sodium, potassium and aluminium), or salts with organic amines (e.g. trialkylamine).
The compounds of Formula (I) can be prepared easily, for example, by the following processes: ##STR3## (wherein, R.sup.3 and R.sup.4 are the same or different, and are each a hydroxyl protecting group, R.sup.5 and R.sup.6 are the same or different, and are each an alkyl group having 1 to 10 carbon atoms, R.sup.7 is the same as R.sup.1, except a hydrogen atom, and R.sup.2 is as defined above. The hydroxyl protecting group refers to those usually used in the field of prostaglandins, such as a t-butyldimethylsilyl group, a triethylsilyl group, a phenyldimethylsilyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a methoxymethyl group, an ethoxyethyl group and a benzyl group).
1 First, the known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of an organic aluminium compound of Formula (III) in an inert solvent (e.g. benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at a temperature of -10 to 30.degree. C., preferably 0.degree. to 10.degree. C., according to the method of Sato et al. [Journal of Organic Chemistry, vol. 53, page 5590 (1988)] to give a compound of Formula (IV) stereo-specifically.
The organic aluminium c

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