Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-01-30
1999-10-19
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514359, 544 1, 548121, C07D29312, C07D29310, C07D42112, A61K 3141
Patent
active
059689200
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of novel compounds with a benzisoselenazoline structure gem-disubstituted in the 3 position and benzisoselenazine compounds gem-disubstituted in the 4 position, as antioxidants, a method for their preparation and pharmaceutical compositions containing these compounds.
PRIOR ART
The majority of mammalian tissues and cells possess enzymes termed glutathione peroxidases which allow endogenous or exogenous cytotoxic hydroperoxides to degrade.
These antioxidizing and cytoprotective enzymes play a central role in preventing "oxidizing stress" and its deleterious consequences.
They catalyse the reduction of hydrogen peroxide (reaction 1) or organic hydroperoxides (reaction 2) by reduced glutathione (GSH):
Glutathione peroxidases are selenium enzymes. Three sub-families have been described: tetrameric structure (see L. Flohe, "Structures and Catalytic Mechanism of Glutathione Peroxidase", in Glutathione Centennial, (1989); N. Taniguchi, T. Higashi, Y. Sakamoto and A. Meister, Eds: Academic Press, pp 103-114); monomeric structure (see F. Ursini et al., Biochem. Biophys. Acta, (1982), 710, pp 197-211); tetrameric enzyme whose N-terminal end is specifically glycosylated (see K. Takahashi et al., J.Biochem, (1990), 108, pp 145-148).
The active sites of these enzymes all possess an essential selenium atom in the form of a selenocysteine residue incorporated into the polypeptide chain.
The essential character of the selenium in the active site is well documented (see J. W. Forstrom et al., Biochemistry (1978), 17, 2639-2644 and A.Wendel et al., Hoppe-Seyler's Z.Physiol.Chem., (1978), 359, pp 1035-1036).
In cases of nutritional deficiency of selenium, the concentrations and activities of the glutathione peroxidases gradually fall (see Y. X. Wang and J. Kiem, Biological Trace Elements Res., (1988), 15, p 89).
Further, controlled mutagenesis experiments have shown that replacement of a selenium atom in the active site by a sulfur atom results in a large fall in catalytic activity (see C. Rocher et al., Eur. J. Biochem., (1992), 205, pp 955-960).
In the human and animal, selenite and selenate salts and L-selenomethionine constitute three natural forms of selenium supply.
The nutritional supply of selenium is a limiting factor in the biosynthesis of glutathione peroxidases, but an increase in the glutathione peroxidase activity with such a supply of selenium follows a rapid saturation curve. Beyond the saturation plateau, an increase in the nutritional supply of selenium results in marked toxicity (see O. A. Levander, Ann. Rev. Nutr., (1987), 7, pp 227-250). The interval between the quantities of selenium required from natural origins and their toxicity limit is thus small.
Experiments involving intra-cellular microinjection of erythrocytic enzyme have shown its very marked protective effect on the viability of fibroblasts or endothelial cells exposed to an oxidizing stress (see C. Michiels et al., Experiment. Cell Res., (1988), 179, pp 581-589).
The use of a glutathione peroxidase of natural origin for therapeutic use is, however, difficult to envisage for the following reasons:
To eliminate these difficulties, a certain number of low molecular weight organoselenium compounds have been synthesized.
The biochemical and pharmacological properties of organoselenium compounds which have been synthesized and studied have recently been reviewed (see M. J. Parnham and E. Graf, Progress in Drug Res., (1991), 36, pp 9-47).
Organoselenium compounds with glutathione peroxidase activity generally produce selenol and/or diselenide type catalytic intermediates.
Of those compounds, 2-phenyl-3-one-benzisoselenazoline(2H) and some of its derivatives do not appear to have a major toxic effect (See A. Wendel et al., Biochem. Pharmacol., (1984), 33, pp 3241-3245 and S. D. Mercurio and G. F. Combs, Biochem. Pharmacol, (1986), 35, pp 4505-4509).
In the presence of excess glutathione GSH, however, 2-phenyl-3-one-benzisoselenazoline(2H) produces a derivative which is only very slightly soluble in water, wh
REFERENCES:
Free Radicals in Inflammatory Bowel Diseases etc.--Arndt et al--Hepato-Gastroenterol 41, 1994, pp. 320-327.
Excessive Production of Reactive Oxygen Metabolites etc. Keshavarzian et al, Gastroenterology 1992, pp. 177-185.
Synthesis of 2H-3,4-Dihydro-1,2-Benzoselenazin-3-One etc.--1992 Jacquemin et al--Tetrahedren Letters, vol. 33, No. 27, pp. 3863-3866.
Seleno-Organic Compounds and the Therapy of Hydroperoxide-Linked etc.--Parnham et al--vol. 30, No. 19, pp. 3095-3102, 1987.
Official Gazette, 1134 OG 198, Jan. 7, 1992.
Yoshikawa et al., Cancer Research 33, 1617-1620, Apr. 15, 1995.
Trush et al., Free Radical Biology & Medicine, vol. 10, pp. 201-209, 1991.
Chaudiere Jean
Erdelmeier Irene
Moutet Marc
Yadan Jean-Claude
Kifle Bruck
Oxis Isle of Man, Limited
Shah Mukund J.
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