Ginkgolide derivatives and a process for preparing them

Details Ginkgolide derivatives and a process for preparing them Ginkgolide derivatives and a process for preparing them

1994-07-05

1995-11-14

Ivy, C. Warren

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549348, C07D31306, C07D30793, C07D49322

Patent

active

054668298

DESCRIPTION:

BRIEF SUMMARY
This application is filed under 35 USC 371 of PCT/KR92/00043, filed Sep. 18, 1992.


TECHNICAL FIELD

The present invention relates to new ginkgolide derivative, having valuable PAF-antagonistic activity, of formula (I) as below and a process for preparing them, especially a process for preparing Ginkgolide B derivatives by separating only one component of ginkgolide, not mixture. ##STR2##


BACKGROUND ART

The ginkolides, a terpenoid compounds, from the roots and leaves of the Ginkgo tree are the substances having very characteristic chemical structure. Among ginkgolides being isolated from the natural substance by Nakanishi in 1967, 4 kinds of ginkgolide were determined and named the Ginkgolide A, B, C and M by characteristic of its chemical structure, and after the Ginkgolide J was identified by Weing in 1987. General chemical structure of these ginkgolides are the formula A as below. ##STR3## in which X.sub.1, X.sub.2, and X.sub.3 are hydrogen or hydroxy of the same or not.
The above ginkgolides of the formula A are indicated in the following Table 1 as below by way of substituent X.sub.1, X.sub.2, and X.sub.3.


TABLE 1 ______________________________________ Ginkgolide X.sub.1 X.sub.2 X.sub.3 ______________________________________ A H OH H B OH OH H C OH OH OH M OH H OH J H OH OH ______________________________________
Especially, the studies about them are going on progress, becauce it has been found recently that ginkgolides have PAF-antagonistic activity.
Meanwhile, Barquet of Institute of Henri Beaufour Company in France synthesized new derivatives that substituted hydroxy group in 1- and 10-carbon of the ginkgolide structure with methoxy or ethoxy group by treating the ginkgolide with diazoalkane. (Brit. pat. appl. 2,211,841)
It is well known that these ginkgolides are distinguished from the difference of having or not hydroxy group in 1, 3, and 7-carbon in its chemical structure, but it is very difficult to separate them into each substance because of very similar chemical properties.
Therefore, the pure individual substance was separated by passing through silicagel column [K. Nakanish, Pure Appl. Chem. 1967. 89-113] or ion exchange resin such as Cephadex-LH-20 by Weing et al., two or three times, [Liebigs. Ann. Chem, 1987. 521-526] after several times of fractional recrystallization using the difference of the solubility coming from the difference of hydroxy group.
But, these usual methods for separating using the fractional recrystallization have very low efficiency because of similar properties of each component. Especially because the Ginkgolide A and B have similar properties, R.sub.f values for the Ginkgolide A and B by thin layer chromatography(silicagel plate, developing solvent; toluene:acetone=7:3) is nearly no difference as each 0.32 and 0.30, and so they could not be seperated by passing through silicagel column. So there am much difficulty, e.g. they have a uneconomical defect that repeated it several times or used high price ion exchange resin such as Cephadex-LH-20, for separation.
Moreover, recently the effectiveness of ginkgolides are increasing as time goes on, and it has been found that the activity of the Ginkgolide B among them is superior to compared with another 4 kinds of ginkgolide. But the Ginkgolide A, B, and C mixture is used as a drag [Brit. pat. Appl. 2,162,062A], because the method for effective separation was not developed.
Therefore, it is necessary to separate the pure one component of the Ginkgolide B, because the Ginkgolide A and C have relatively low activity than the Ginkgolide B, and also it is necessary to separate for using characteristics of each component. So if they am separated each component of the ginkgolide with simple, easy and economical, a new field for the utilization of the ginkgolides will open up.
Therefore, we, inventors, perfected the present invention by finding out that it is possible to effectively separate the ginkgolide derivatives into each component by substituting the hydroxy group, availing of the chemical struct

REFERENCES:
patent: 5089636 (1992-02-01), Kwak et al.
Corey et al., "Total Synthesis of Ginkgolide A," Tetrahedron Letters, Pergamon Press; Oxford, N.Y.; vol. 29; No. 25, pp. 3205-3206 (1988).
Corey et al., "Simple Analogs of Ginkgolide B Which Are Highly Active Antagonists Of Platelet Activating Factor" Tetrahedron Letters, Pergamon Press; Oxford, N.Y.; vol. 30; No. 49, pp. 6959-6962 (1989).
Chemical Abstracts, vol. 110, No. 15 (1989), 134,946m.
Chemical Abstracts, vol. 113, No. 9 (1990), 78,720f.
Weinges et al., "Chemistry Of Ginkgolides, II [1].-Isolation And Structural Elucidation Of A New Ginkgolide", Liebigs Ann. Chem., vol. 5, pp. 522-526 (English Translation), 1987.

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