Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1982-09-28
1984-04-10
Roberts, Elbert L.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
424177, C07J 900
Patent
active
044420374
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to water-soluble derivatives of cholesterol and more particularly to water-soluble derivatives of 7-hydroxycholesterol.
BACKGROUND ART
It is known that the immunoregulatory substance isolated from the Cohn IV, paste of human serum is 7-hydroxycholesterol and effective not only as an immunoregulatory agent, particularly acting to regulate cell-mediated immunity, but also as an anti-inflammatory agent (Japanese Patent Application Laid-open No. 104735/1978).
DISCLOSURE OF INVENTION
Since 7-hydroxycholesterol, a compound very valuable as a medicine, is sparingly soluble in water, the present inventors made intent studies aiming at development of its derivatives having improved water solubility.
As a result, the aim has been attained by finding out new compounds, complexes of albumin with organic dibasic acid half esters of 7-hydroxycholesterol.
Thus, the object of this invention is to provide said complexes, which are represented by the formula ##STR1## wherein R is phenylene or (CH.sub.2).sub.m, of which m indicates 0 or an integer of 1-5, P is albumin residue, and n is a number of 20-200, which indicates the number of moles of the steroid, shown in the bracket, binding to mole of albumin.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 show results of gel filtration of the respective compounds obtained by reacting 1 part of albumin and 3 parts of albumin, respectively, to 1 part of 7-hydroxycholesterol-3-succinic acid half ester .
In these figures, concentrations of albumin are represented by measured values of the O.D. (optical density) at 280 nm ( ), concentrations of 7-hydroxycholesterol-3-succinic acid half ester are represented by measured values of the O.D. at 640 nm ( ) after development of color by the Lubschutz reaction, and peak A, peak B, and V.sub.o correspond to the complex, the unreacted albumin, and the void volume, respectively.
BEST MODE FOR CARRYING OUT THE INVENTION
An organic dibasic acid half ester of 7-hydroxycholesterol, used as a starting material in this invention, which is represented by the formula ##STR2## wherein R is as defined above, can be prepared from 7-ketocholesterol by esterifying it with a reactive derivative of the corresponding organic dibasic acid in the presence of a tertiary amine, followed by the reduction with a complex metal hydride (Japanese Patent Application No. 7676/1979). Preferred organic dibasic acids used include succinic acid and phthalic acid, and preferred starting materials include 7-hydroxycholesterol-3-succinic acid half ester, 7-hydroxycholesterol-3-phthalic acid half ester, and 7.beta.-hydroxycholesterol-3-phthalic acid half ester.
The compounds of this invention are conveniently produced by uniform reaction of half esters above mentioned with albumin in a mixture of water and a water-misible organic solvent such as dioxane, tetrahydrofuran, or dimethylsulfoxide. Water is a good solvent for albumin and the organic solvent is so for the half ester. Thus, the reaction is carried out in such a way that such an organic solvent is added to an aqueous solution of albumin and then a solution of the half ester in the organic solvent is added to the resulting mixture with stirring or in the reverse addition order. Organic solvent to water ratios allowing enough uniform progress of the reaction are acceptable, which are 1:1-10.
The albumin to be used may be of human or bovine serum, and it is not particularly restricted as far as purified for therapeutic purposes. Needless to say, those of human derivation are preferred. The purity of the albumin is preferably not less than 80% as measured by the electrophoretic method. The amount of albumin used for preparation is chosen from within the range of 0.2-10 parts by weight for part by weight of the organic dibasic acid half ester of 7-hydroxycholesterol, so that the complex having a desired binding ratio can be obtained. An increase in the proportion of albumin makes the water-solubility of the half ester increased, but this is unfavorable with respect
REFERENCES:
patent: 4304726 (1981-12-01), Arakawa et al.
patent: 4379779 (1983-04-01), Rao et al.
Arakawa Yoshio
Funakoshi Satoshi
Suyama Tadakazu
Takanabe Atsuyuki
Uemura Yahiro
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