Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-26
1998-12-15
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514344, 514640, 514824, 546330, 546334, 546335, 546336, 546337, 558 87, 558168, 558175, A61K 3144, A61K 3121
Patent
active
058497714
DESCRIPTION:
BRIEF SUMMARY
The invention relates to phosphorylated nitrone derivatives which can be employed as traps for free radicals.
Because of their physicochemical properties, such compounds are greatly sought after in the fields of cosmetology and of medicine.
It has been demonstrated in particular that, under the action of many intracellular processes, the oxygen conveyed in the body by respiration can be reduced to various reactive oxygen-containing species, prooxidants of the O.sub.2.sup..- type (the superoxide radical), HO.sup.. (the hydroxyl radical) and HOO.sup.. (the perhydroxyl radical).
In a normal situation these species are rapidly removed by reaction with enzymatic or nonenzymatic antioxidant substances such as catalase, superoxide dismutase, glutathione peroxidase, glutathione, vitamin E or ascorbate, with the result that the stationary concentration of reactive oxygen-containing species in the human biological media is very low.
It happens, however, that an imbalance is established between antioxidants and prooxidants, resulting in an abnormal increase in the proportion of prooxidants. This is then spoken of as a situation of oxidative stress.
Such a situation has harmful consequences, since the oxygen-containing free radicals thus generated, which are highly unstable, react quite indiscriminately with a large number of the compounds present in the cell medium, namely proteins, amino acids, carbohydrates, DNA bases and organic acids and especially lipids, which are polyunsaturated fatty acids. The resulting damage entails, for example, the inactivation of many enzymes as well as changes involving the permeability and the fluidity of the cell membranes.
It has been possible to demonstrate that various cardiovascular pathological states such as coronary ischaemia, arteriosclerosis and infarctus involve an oxidative stress, that is to say an overproduction of radicals of the O.sub.2.sup..-, HOO.sup.. and HO.sup.. type. The same applies in the case of many inflammatory or infectious processes or of cell aging.
More than any other organ, the brain is sensitive to this oxidative stress state since the disturbances due to the uncontrolled proliferation of oxygen-containing free radicals result in an irreversible neuronal degeneracy.
Now, the brain is particularly vulnerable, insofar as it contains a high proportion of peroxidizable fatty acids and many regions which are very rich in iron (in the form of ferritin), which, acting as catalyst in the production of the oxygen-containing toxic species, contributes to the worsening of this oxidative stress state. Similarly, the rarity of the antioxidant substances where the brain is concerned cannot but help to facilitate the establishment of the oxidative stress state.
It is consequently understandable that the search for efficient traps for free radicals has developed. As a matter of fact, a simple means of curbing the proliferation of these toxic radicals is to bring them into contact with a substance which is sufficiently reactive to enter into competition with the other cell constituents.
Hitherto, a specific nitrone, .alpha.-phenyl-tert-butylnitrone (PBN) has been found particularly effective as an antioxidant exogenous substance capable of reversing the harmful effects of oxygen-containing free radicals, regardless of whether the latter have been generated during a cerebral ischaemia-reperfusion sequence (J. M. Carney et al.; J. of Mol. Neurosc. 1991, 3, 45-57) or following cerebral aging (J. M. Carney et al., Proc. Natl. Acad. Sci. USA, 88, 1991, 3633-3636). However, the low stability of the resulting adducts, obtained by the action of PBN on the various free radicals, has encouraged the present inventors to develop novel molecules which can also be employed as traps for free radicals but which are endowed with better physicochemical properties.
As a result of intensive research they have discovered new phosphorylated nitrones exhibiting a high stability, a good solubility in biological media, a good lipophilicity so as to be able to penetrate the membrane wall, and r
Cerri Viviane
Finet Jean-Pierre
Tordo Paul
Tuccio Beatrice
Zeghdaoui Abdelhamid
Centre National de la Recherche Scientifique (C.N.R.S.)
O'Sullivan Peter
LandOfFree
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