Prostaglandin derivatives

Details Prostaglandin derivatives Prostaglandin derivatives

1995-01-19

1996-02-13

Killos, Paul J.

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

Organic compounds

Carboxylic acid esters

562503, C07C17700, A61K 31557

Patent

active

054912547

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/00938 Jul. 8, 1993.



TECHNICAL FIELD

The present invention relates to novel prostaglandin (hereinafter abbreviated as PG) derivatives.


BACKGROUND ART

PG exhibits a variety of important physiological activities in a trace amount. For its diversity, natural PG analogues and a vast number of derivatives thereof have been studied on synthesis and biological activities, with attempts to apply these compounds to pharmaceuticals. These studies are reported in many publications and Japanese Patent Application KOKAI No. 52-100446, Japanese Patent Application KOHYO No. 2-502009 (WO 89/00559), etc.
The compounds of the present invention are broadly covered by Formula I described in Japanese Patent Application KOHYO No. 2-502009 supra but there is no specific description on these compounds in the specification.
An object of the present invention is to provide compounds which possess much more potent pharmacological activities than PG derivatives known so far.


Disclosure of Invention

As a result of extensive studies, the present inventors have found that some particular compounds exhibit extremely excellent activities for improving renal diseases, ischemic heart diseases and heart failure, though these compounds broadly fall within Formula I but are not concretely described in the specification supra. The present invention has thus been attained.
That is, the present invention relates to PG derivatives represented by formula: ##STR2## wherein R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and salts thereof.
In the present invention, the alkyl group is used to mean a straight or branched alkyl group.
The compounds of the present invention shown by formula (I) can be prepared by, e.g., the following processes. ##STR3## wherein R.sup.1 has the same significance as R, except for a hydrogen atom; TBS represents a t-butyldimethylsiloxy group; and EE represents an ethoxyethyl group.
That is, the compound of formula (II) is reacted with the compound of formula (III) to introduce the w-side chain of PG and thus obtain the compound of formula (IV). On the other hand, (Z)-1-iodo-3-(1-ethoxyethyloxy)-1-propene is reacted with t-butyl lithium and lithium 2-thienylcyanocuprate. The resulting product is reacted with the compound of formula (IV) obtained above, Whereby the s-side chain of PG is introduced to give the compound of formula (V). The compound of formula (V) is then reduced stereo-selectively with lithium tri-sec-butylborohydride to obtain the compound of formula (VI). Thereafter the ethoxyethyl protective group is removed to give the compound of formula (VII). The compound of formula (VII) is reacted with a compound represented by formula: compounds of formula (VIII). Then the hydroxy group in the compounds of formula (VIII) is tosylated with p-toluenesulfonyl chloride followed by reacting the tosylated compound with tetra-n-butylammonium chloride. From the resulting chlorosubstituted compound the protective groups of the hydroxy groups are removed with hydrogen fluoride/ pyridine to give the compounds of formula (Ia) (the compounds of formula (I) wherein R is other than a hydrogen atom). The compounds of formula (I) wherein R is a hydrogen atom can be obtained by hydrolyzing the compounds of formula (Ia) (which correspond to the compounds of formula (Ib)) with lithium hydroxide .


BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter the present invention is described in more detail, with reference to the examples and test examples.


EXAMPLE 1



Preparation of
3-oxa-9-deoxy-9.beta.-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-13,14-d idehydro-PGF.sub.2 .alpha. t-butyl ester (Compound 1)
Note) In the nomenclature of compounds, the term "nor." in "16,17,18,19,20-pentanor" is used to mean that carbon chains at the position are missing (carbon chains from the 16 to 20 position are absent).
(1) In 28.8 ml of benzene was dissolved 3.61 g of (3S)-3-(t-butyldimethylsiloxy)-3-cyclohexylprop-1-yne. n-Butyl lithium (1.95M, hexane solution, 6.4 ml) was add

REFERENCES:
patent: 5204371 (1993-04-01), Skuballa et al.

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