Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1991-02-17
1992-05-12
Cintins, Marianne
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552540, C07J 5100, A61K 3156
Patent
active
051128152
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel 9.alpha.-hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid derivatives of the formula (I), ##STR2## wherein M stands for hydrogen C.sub.1-4 alkyl or a pharmaceutically acceptable cation, as well as pharmaceutical compositions containing these compounds.
The invention also relates to processes for preparing the compounds of the formula (I) by a microbial degradation of .beta.-sitosterol or .beta.-sitosterol-containing sterols of plant origin followed, if desired, by salt formation or esterification, and for preparing pharmaceutical compositions containing the compounds of the formula (I).
The pharmaceutically acceptable salts of the compounds of the formula (I) include those formed with inorganic or organic cations such as sodium, potassium, calcium, magnesium, aluminium, zinc, ammonium, ethylenediaminium, tris(hydroxymethyl)-aminomethane or tetramethylammonium.
The compounds of the formula (I) of this invention, wherein M is as defined above, are new and possess valuable pharmacological properties. They also serve as starting materials for preparing pharmaceutically important steroid derivatives.
It is known that bacteria using sterols as carbon source degrade both the steroid skeleton and the side-chain. The mechanism of the degradation of the side-chains of sterols was elucidated by C. J. Sih and co-workers [J. Am. Chem. Soc. 89, 1957 (1967); ibid. 104, 4718 (1982); ibid 104, 4720 (1982)]. The degradation of the side-chain of cholesterol begins with hydroxylation at the end of the side-chain. The oxidation of the hydroxyl group on the carbon atom in position 26 leads to the formation of a carboxylic acid which is degraded by the .beta.-oxidation mechanism characteristic of fatty acids, resulting in a gradual shortening of the side-chain. The degradation of the side-chain of .beta.-sitosterol having an ethyl group on the carbon atom in position 24 differs from that of cholesterol in that the bacteria degrading the side-chain introduce a carboxyl group on the carbon atom in position 28 attached to the carbon atom in position 24, then cleave the bond between the carbon atoms in positions 24 and 28 by a .beta.-oxidation mechanism.
The enzymatic transformations affecting the steroid skeleton, which run parallel with the degradation of the side-chain, lead to the cleavage of the skeleton followed by a complete degradation of the ring system. The cleavage happens in such a way that steroid derivatives with the structure of 9 .alpha.-hydroxy-1,4-dien-3-one are formed from the sterols followed by a spontaneous rearrangement to yield therapeutically worthless seco-steroids in which the bond between the carbon atoms in positions 9 and 10 in ring B of the skeleton is cleaved [R. M. Dodson and R. D. Muir: J. Am. Chem. Soc. 83, 4627 (1961); K. Schubert and co-workers: Z. Naturforsch. 15b, 584 (1960)].
In the 1970s strains with changed genetic properties were prepared from sterol-utilizing bacteria by mutagenic treatments. These strains, having no active enzymes to catalyze the reactions initiating the degradation of the steroid skeleton.
It has also known that the cell wall of bacteria can be completely or partially removed by enzymatic hydrolysis under iso-osmotic conditions when protoplasts [J. Tomcsik and S. Guex-Holzer: Schweiz. Z. Allg. Path. Bact. 15, 517 (1952); C. Weibull: J. Bacteriol. 66, 688 (1953)] or spheroplasts [H. Sato and co-workers: Canad. J. Microbiol. 11, 807 (1965)] are formed the cell wall of which can be regenerated. The polyethylene-glycol-induced fusion of protoplasts or spheroplasts involves events of genetic recombination resulting in cells with new genetic information [K. Fodor and L. Alfoldi: Proc. Natl. Acad. Sci. USA 73, 2147 (1976); P. Schaeffer and co-workers: Proc. Natl. Acad. Sci. USA 73, 2151 (1976); N. Rastogi and co-workers: J. Gen. Microbiol. 129, 1227 (1983); ibid. 137a, 135 (1986)].
Using the method of G. E. Peterson and co-workers [J. Lipid Reasearch 3, 275 (1962)] we isolated sitosterol-degrading microorganisms from various soil samples. Of the
REFERENCES:
patent: 4062880 (1977-12-01), Antosz et al.
Ambrus Gabor
Hajos Gyorgy
Horvath Gyula
Ilkoy Eva
Javor Andras
Cintins Marianne
Cook R.
Richer Gedeon Vegyeszet
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