Cyclic organoselenium compounds, their preparation and their...

Details Cyclic organoselenium compounds, their preparation and their... Cyclic organoselenium compounds, their preparation and their...

2000-05-16

2003-02-25

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S359000, C544S001000, C548S121000, C549S015000, C549S032000

Reexamination Certificate

active

06525040

ABSTRACT:

This application is a 371 of PCT/EP97/07295 filed Dec. 23, 1997.
The principal objects of the present invention are:
novel cyclic organoselenium compounds;
the use of said novel compounds as antioxidant;
pharmaceutical compositions containing them;
a method of preparation of said novel compounds.
STATE OF THE PRIOR ART
In aerobic organisms, during the metabolism of oxygen, very reactive entities are generated whose accumulation causes deleterious effects. These organisms possess a system of regulation, composed of enzymes and small is molecules which enable controlling the production of these reactive oxygen entities. Amongst the various components of this regulation system, often called Antioxidant Defense System, glutathione peroxidases play a central role in the prevention of <<oxidative stress>> and its deleterious consequences. These antioxidant and cytoprotecting enzymes enable degrading the endogenous or exogenous cytotoxic hydroperoxides.
These enzymes catalyse the reduction of hydrogen peroxide (reaction 1) or that of organic hydroperoxides (reaction 2) by reduced glutathione (GSH):
reaction 1:
H
2
O
2
+2GSH→2H
2
O+GSSG
reaction 2:
ROOH+2GSH→ROH+H
2
O+GSSG
The active sites of these enzymes all contain one essential selenium atom in the form of a selenocysteine residue incorporated in the polypeptide chain.
The selenium is incorporated from selenite salts, or selenate salts, or L-seleno-methionine salts arising from food (see C. K. Chow and J. Jeng; in Selenium in Medicine and Biology, M. D. Spallholz and H. E. Ganther Eds.; (1986); Academic Press). In situations of selenium deficiency in the diet, the concentrations and activities of these glutathione peroxidases gradually decrease (see Y. X. Wang and J. Kiem.; Biological Trace Elements Res.; (1988); 15; 89 and see R. Reiter and A. Wendel; Biochem. Pharmacol.; (1983); 32; 3063-3067); this leads to an acute susceptibility to the oxidative stress (see D. B. Coursin and H. P. Cihla, Thorax, (1996), 51, 479-483). The provision of selenium in the diet is therefore a limiting factor in the biosynthesis of glutathione peroxidases.
The protecting role of glutathione peroxidases, in situations wherein the production of hydroperoxides rises, has been demonstrated following experiments of direct intracellular micro-injection of the enzyme of erythrocyte origin which have enabled demonstrating its cytoprotective effect upon the viability of fibroblasts or endothelial cells exposed to an oxidative stress (see C. to Michiels et al.; Experiment. Cell Res.; (1988); 179; 581-589). On the other hand, it has been shown that the survival of human fibroblasts is appreciably lowered when glutathione peroxidase is inhibited (see C. Michiels et al., J. Eur. Biochem., 1988, 177, 435-441).
Furthermore, the glutathione peroxidases are themselves particularly sensitive to an over-production of hydroperoxides and are rapidly inhibited under these conditions (see H. Ochi et al., Arch. of Biochem. Biophys., (1992), 294, 2, 407-411).
A certain number of pathologies such as certain ischemic cardiomyopathies for example (see J. Chaudiére, in Biologie des lipides chez l'Homme, L. Doustes-Blazy and F. Mendy eds, Edition Médicale Internationale—Paris, (1988), 137-154 and see D. Vitoux et al.; Ann. Biol. Clin.; (1996); 54; 5; 181-187) are associated with a lowering of glutathione peroxidase activity.
The demonstration of the essential role of the selenium at the active centre of these ubiquitous enzymes (see J. T. Rotruck, in Selenium in Biology and Medicine, Spallholz, J. E. Martin, J. L. Ganther H. I. eds., Avi Publishing Co, Wesport, (1981), 10-16) as well as the importance of the selenium in the regulation of oxidative damages generated during certain pathologies (see Cadenas, E. and Sies, H., Adv. Enz. Regul., (1985), 23, 217-237 and see Ursini, F., Bindoli, A., Chem. Phys. Lipids, (1987), 44, 255-276) has enabled the emergence of a novel class of organoselenium compounds as potential drugs.
Two types of compounds have been designed and prepared to this end.
On one side, modified macromolecules possessing a selenium atom introduced chemically such as selenosubtilisin (see Z. P. Wu and D. Hilvert, J. Am. Chem. Soc., (1990), 112, 5647-5648) or even a seleno-abzyme (see G. M. Luo et al., Biochem. Biophys. Res. Comm., 1994, 198, 3, 1240-1247). However, the use of proteins with a therapeutic aim is difficult to envisage for the following reasons:
their biostability is often insufficient;
an efficient method for ensuring their intra-cellular targeting does not exist;
they cannot be administered orally.
On the other side, synthetic molecules of low molecular weight have been synthetized, of which 2-phenyl-1,2-benzisoselenazolin-3-one (ebselen) (see H. Sies, Free Rad. Biol. Med., (1993), 14, 313-323) was the first compound described as having a glutathione peroxidase activity. Homologs of said ebselen, i.e. 2H-3,4-dihydro-1,2-benzoselenazin-3-ones, have also been described by Pierre V. Jacquemin et al. in Tetrahedron Letters, (1992), Vol. 33, No. 27, 3863-3866. In fact, several organoselenium derivatives have been described as glutathione peroxidase mimics, i. e. capable of reducing hydroperoxides in the presence of a biological thiol such as glutathione or lipoic acid (see I. A. Cotgreave et al., Biochem. Pharmacol., (1992), 43, 793-802 and C. M. Andersson et al., Free Rad. Biol. Med., (1994), 16, 17-28 and S. R. Wilson et al., J. Am. Chem. Soc., (1989), 111, 5936-5939 and V. Galet et al., J. Med. Chem., (1994), 37, 2903-2911). The patent application WO-A-95/27706 describes compounds of benzisoselenazoline and benzisoselenazine structure having a glutathione peroxidase activity inter alia.
These organoselenium compounds, which are mimics of glutathione peroxidase, invariably produce catalytic intermediates of the selenol and/or diselenide type.
Amongst these, 2-phenyl-1,2-benzisoselenazolin-3-one (ebselen) and some of its derivatives do not seem to have any major toxic effect (see A. Wendel et al.; Biochem. Pharmacol.; (1984); 33; 3241-3245 and S. D. Mercurio and G. F. Combs; Biochem. Pharmacol.; (1986); 35; 4505-4509). 2-Phenyl-1,2-benzisoselenazolin-3-one (ebselen) is however very little soluble in water, even in the presence of an excess of glutathione GSH, which limits its pharmacological applications.
The biochemical and pharmacological properties of the organoselenium compounds which have been synthesised and studied have been recently reviewed (see M. J. Pamham and E. Graf; Progress in Drug Res.; (1991); 36; 9-47 and M. J. Pamham, Exp. Opin. Invest. Drugs, (1996), 5, 7, 861-570).
One of the aims of the present invention is to design organoselenium compounds having a catalytic activity of the glutathione peroxidase type in the presence of physiological concentrations of glutathione GSH.
These compounds must be able to penetrate the target tissues or cells, be soluble in water at active concentrations and must not efficiently reduce oxygen into toxic by-products.
These aims are attained by virtue of the present invention which resides on the design of cyclic organoselenium compounds whose antioxidant and cytoprotecting activities have been demonstrated by the Applicant and which are given below.
DESCRIPTION OF THE INVENTION
The aim of the present invention is:
1) to solve the novel technical problem consisting of providing novel cyclic heteroaryl selenium compounds having a very good antioxidant and cytoprotecting activity, thus constituting valuable active principles of pharmaceutical compositions;
2) to solve the novel technical problem above according to a solution which includes a method of preparation of these novel compounds which is easy to carry out.
The technical problems set forth above are solved for the first time in a simultaneous manner by the present invention in a simple way; the method of preparation of said novel compounds being relatively easy to carry out and giving good yields.
According to its first aspect, the present invention thus relates to novel cyclic organoselenium compou

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