Sterols, their fatty acid esters and glucosides; processes for t

Details Sterols, their fatty acid esters and glucosides; processes for t Sterols, their fatty acid esters and glucosides; processes for t

1991-02-15

1993-12-14

Wityshyn, Michael G.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

536 5, 536 62, 552540, 552547, 552544, 552545, 549408, 568824, A61K 3578, C07J 1700

Patent

active

052700410

DESCRIPTION:

BRIEF SUMMARY
INTRODUCTION

The present invention relates to sterols, their fatty acid esters and glucosides; to processes for their preparation; to spontaneously dispersible agents containing these compounds, and to their use for treatment of tumours.
Surprisingly, it has been found that mainly the sterols extracted from the seed of the sunflower (Helianthus annuus L.) and of certain pumpkin species (Cucurbita pepo L. and Cucurbita maxima Duch.), and the glucosides and in particular the fatty acid esters of these sterols, as well as the spontaneously dispersible agents prepared with these compounds, have an outstanding antitumoral action.
No mention is made in the literature that sterols, their glucosides and in particular their fatty acid esters, can be employed for the treatment of tumours.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the melting points and refractive indices of some exemplary sterols according to the present invention;
FIG. 2 shows the density scanning calorimetry graphs for sitosterol and stigmasterol;
FIG. 3 provides the Rf values for some exemplary sterols according to the present invention;
FIG. 4 shows the HPLC analyses for sitosterol and stigmasterol;
FIG. 5 gives the Rf values for stigmasterol-beta-d-glucoside; and
FIG. 6 is a density scanning calorimetry graph for stigmasterol-beta-d-glucoside.


DESCRIPTION OF THE INVENTION

Sterols, their fatty acid esters und glucosides to be used according to the invention can be obtained for example from preferably pregerminated seeds of Helianthus annuus L., Cucurbita pepo L. (varietas styriaca) or Cucurbita maxima Duch., by carrying out the following process steps:
The seeds which have been washed and pregerminated for 2 to 4 days are treated with distilled water which contains 0.1 to 3%, and preferably 0.1 to 1%, of mannitol and 0.1 to 4% of a pharmaceutically acceptable, non-ionic surfactant or surfactant mixture (relative to the pregerminated seeds). The mixture is homogenized in a toothed colloid mill, and the homogenate thus obtained is then centrifuged. The resulting three phases are separated from each other. The bottom phase which contains husk fragments and cell debris is discarded. The upper, oily phase is subjected to an extraction step and then purified by preparative chromatography, while the middle, aqueous phase is first subjected to ultrafiltration and then concentrated in vacuo and lyophilized as a concentrate. (See, in this context, Processing Examples 1 to 3).
The fatty acid esters of sterols, which are preferably to be used according to the invention, can generally also be prepared semisynthetically by the following processes which are known per se: 25.degree.-70.degree. C. with the addition of a catalytic amount of an alcoholate in tetrahydrofuran, benzene, chloroform or dimethylformamide or in a similar indifferent solvent, followed by alcoholysis of the imidazolides formed with a sterol, such as, for example


______________________________________ 24 .beta.-Ethylcholesta - 5,22,25 - trien - 3.beta.-ol (25,27 Dehydroporiferasterol) 24 .beta.-Ethylcholesta - 5,25 (27) - dien - 3.beta.-ol (Clerosterol) 24 z-Ethylidencholest - 5 - en - 3.beta.-ol (Isofucosterol) 24 .alpha.-Ethylcholesta - 5,22 - dien -3.beta.-ol (.DELTA.5-Stigmasterol) 24 .alpha.-Ethylcholest - 5 - en - 3.beta.-ol (.DELTA.5-Sitosterol) 24 .alpha.-Ethylcholest - 7 - en - 3.beta.-ol (.DELTA.7-Sitosterol) cholesta - 8,22 - dien - 3.beta.-ol cholesta - 8,25(27)-dien-3.beta.-ol ______________________________________ indifferent solvent, followed by reaction of the fatty acid chloride formed with a sterol {in this context, see synthesis a)}.
The following straight-chain and branched, saturated and unsaturated fatty acids, inter alia, are suitable for syntheses a) and b):
valeric acid, isovaleric acid, sorbic acid, isocaproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, hexacosanoic acid, octacosanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, tricosanoic acid, penta

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