Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-27
1997-12-30
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
424 69, 424401, 514357, 514533, 514564, 514566, 546264, 546335, 560 9, 560 21, 560 22, 560 38, 560 39, 562426, 562435, 562437, 562443, 562444, 562448, 562449, 564370, C07C22916, A61K 31195, A61K 748, C07D21338
Patent
active
057030952
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR93/01109, filed Nov. 10, 1993.
The present invention relates to N-arylmethylene ethylenediaminetriacetate, N-arylmethylene iminodiacetate or N,N'-diarylmethylene ethylenediamineacetate derivatives which are useful in particular for protecting the body against oxidative stress, to their process of preparation and to the pharmaceutical and cosmetic compositions containing such compounds.
In the field of health and cosmetics, the concept of oxidative stress is known, which oxidative stress appears in particular as soon as a disequilibrium exists in the antioxidant/prooxidant balance. This imbalance is reflected in particular in uncontrolled oxidative processes within living tissue which involve oxygenated free radicals and which lead in particular to oxidative damage to biological molecules and macromolecules (Sies, H., in Oxidative Stress, Academic Press Inc. (London) Ltd., 1985).
It is known that various situations cause, promote or accompany oxidative stress or are the consequence thereof; they are in particular exposure to ultraviolet or to ionizing radiation, aging, inflammation, carcinogenesis, ischemic reperfusion situations, or the toxicity and/or method of action of certain medicaments.
During this oxidative stress phenomenon, it is known that iron is released from it usual storage sites, such as ferritin, and, when released, can take part in certain reactions, and in particular the Fenton (1) and Haber-Weiss (2) reactions, which result in the formation of hydroxyl radicals, which radicals are known to be responsible for much oxidative damage (Reif, D. W., Free Rad. Biol. Med. 12, 417-427, 1992).
Oxygen is essential for respiration in aerobic living beings but can be reduced to the superoxide radical O.sub.2 .degree..sup.- in all aerobic cells. This radical can undergo a disproportionation reaction which gives rise to hydrogen peroxide:
In the presence of traces of iron, this superoxide radical can also reduce the Fe.sup.3+ ion:
The Fe.sup.2+ ions thus produced can give rise to the Fenton reaction which produces the hydroxyl radical:
The Haber-Weiss reaction also produces hydroxyl radicals: ##STR1##
The hydroxyl radical OH.degree. can cause very serious damage in the body. It is capable of breaking DNA strands and or detrimentally affecting the gene pool of the living cell. In contrast to H.sub.2 O.sub.2 and to the superoxide radical O.sub.2 .degree..sup.- it is also capable of causing peroxidation of the unsaturated fatty acids. It plays a significant role in skin aging.
It is known that protection of living tissues against attacks by the hydroxyl radical is difficult.
One of the known approaches for self-protection is to use molecules, in particular D-mannitol or DMSO (dimethyl sulfoxide), which are capable of scavenging the hydroxyl radicals. Nevertheless, the hydroxyl radical is such a reactive species that it is necessary to use very large amounts of these scavengers, so as to compete with all the biological molecules which are potential targets for the hydroxyl radical (Halliwell, B., Free Rad. Res. Comms., 9(1), 1-32, 1990). The use of large amounts of these scavengers poses problems of toxicity.
The other known approach for self-protection against hydroxyl radicals is to use chelating agents for iron, in particular deferoxamine or diethylenetriaminepentaacetic acid (DTPA), in order to prevent it from participating in the Fenton and Haber-Weiss reactions.
However, although their complexation constants are high, these chelating agents can be toxic. Thus it is that DTPA has serious side effects, probably partly related to the chelation of metals such as calcium.
Deferoxamine has a presumed chronic toxicity related to its ability to chelate the metals of the active sites of metalloenzymes or hemoproteins, such as hemoglobin.
Moreover, powerful chelating agents, which can complex iron, such as EHPC (ethylenebis-o-hydroxyphenylglycine), are also known to have high acute toxicities.
Finally, HBED-DME, that is to say the dimethyl ester of N,N'-bis(2-hydroxybenzyl)et
REFERENCES:
patent: 4528196 (1985-07-01), Pitt
Sato et al, Chemical Abstracts, vol. 123, abstract 144623 (1994).
Tweedle et al, Chemical Abstracts, vol. 110, abstract 173270 (1988).
Hardegger et al, Chemical Abstract, vol. 68, abstract 50048 (1968).
American Journal of Hematology, vol. 24, No. 3, Mar. 1987, pp. 277-284.
Inorganica Chimica Acta, vol. 138, No. 3, 1987, pp. 215-230.
Chemical Abstracts, vol. 110, No. 3, 27 Mar. 1989, No. 110927.
Pitt, C.G., et al, "Esters and Lactones of Phenolic Amino Carboxylic Acids: Prodrugs for Iron Chelation", J. Med. Chem., vol. 29, No. 7, Jul. 1986, pp. 1231-1237.
Dumats Jacqueline
Galey Jean Baptiste
"L'Oreal"
Raymond Richard L.
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