Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-02-09
2002-11-19
Davis, Brian J. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S039000, C560S041000, C560S042000
Reexamination Certificate
active
06482855
ABSTRACT:
The subject-matter of the present invention is novel compounds of the type of esters derived from alkylenediaminediacetic acid or alkylenediaminetriacetic acid and in particular their use in cosmetic and pharmaceutical compositions, in particular for protecting the body against oxidative stress.
Oxidative stress characterizes a certain number of physiological and physiopathological situations during which there exists an imbalance in the antioxidant/prooxidant balance. This imbalance is reflected essentially by uncontrolled oxidative processes within living tissues which involve oxygen-comprising free radicals and which lead to the formation of oxidative damage in biological molecules and macromolecules.
A certain number of physiopathological situations induce, promote, accompany and/or are the direct consequence of oxidative stress. They are in particular inflammation, ageing, neurodegenerative diseases, exposure to UV radiation and to ionizing radiation, carcinogenesis, or the toxicity and/or mode of action of certain medicaments.
It is known that, during oxidative stress, iron is released from its normal storage sites, such as ferritin, and then becomes available to participate in certain reactions, in particular in Fenton and Haber-Weiss reactions, thus making possible the formation of hydroxyl radicals, the latter being known to be responsible for much oxidative damage.
Compounds, in particular synthetic compounds, which make it possible to protect the body against oxidative stress have been sought for a long time.
These compounds can be grouped into the following main classes:
antilipoperoxidizing agents, such as vitamin E, trolox or butylhydroxytoluene,
biological reducing agents, such as reduced glutathione and its derivatives or vitamin C and its derivatives,
singlet oxygen deactivators (quenchers), such as &bgr;-carotene,
systems capable of decomposing hydrogen peroxide and in particular enzymes, such as catalase or peroxidases, in the presence of their co-substrates,
systems for protecting against the superoxide anion, such as superoxide dismutase (SOD) or SOD-like materials, such as the Mn-desferal complex or copper diisopropyl salicylate,
systems capable of decomposing organic hydroperoxides, such as glutathione peroxidase or selenium-based model systems,
iron-chelating agents, such as desferal or certain hydroxypyridinones.
However, none of the known iron-chelating agents proved to be really satisfactory for the purpose of protecting the body with regard to hydroxyl radicals. Most of these protective compounds are toxic because of interference with the normal metabolism of iron, which limits their use.
Patent Application WO-94/11338 discloses novel iron-chelating agents which are effective against oxidative stress. These compounds, which are capable of forming complexes with iron, have low stability constants, which consequently decreases the toxicity risks associated with their use.
The action of these compounds is based on a novel concept, that of iron-chelating agents which can be activated in a situation of oxidative stress.
The advantage of these compounds is in particular that of limiting the potential side effects. This is because, in a normal situation, these compounds have an affinity for iron which is sufficiently weak not to displace iron from transport proteins, such as transferrin, unlike certain other powerful chelating agents, such as desferal or HBED, which have high stability constants (greater than 10
30
). In a situation of oxidative stress, these compounds are specifically oxidized by H
2
O
2
to species having a strong affinity for iron which prevent its participation in the formation of HO
•
, resulting in the term “of activation in a situation of oxidative stress”.
A number of in vitro experiments have confirmed the advantage of these compounds as protective agents with regard to the induction of oxidative damage catalysed by iron in the various classes of biological molecules.
However, the protective effect of these compounds of the prior art on cultured cells remains relatively modest because their bioavailability remains low, even when the compounds are provided in the form of alkyl esters.
The aim of the present invention is to solve this problem by providing novel compounds which are effective against oxidative stress and which confer very effective protection against the toxicity of H
2
O
2
on cultured cells.
The subject-matter of the invention is therefore a compound of formula (I):
in which:
R
1
, R
2
and R
3
are, independently of one another, chosen from H, OH or a linear or branched C
1
-C
8
alkoxy radical
R
4
and R
5
are, independently of one another, chosen from H or a linear or branched C
1
-C
4
alkyl radical; it being possible for R
4
and R
5
, taken together, to form a 5- or 6-membered ring
X
1
and X
2
are, independently of one another, chosen from:
a —(CO)NR
6
R
7
group in which R
6
and R
7
are, independently of one another, chosen from H or a linear or branched C
1
-C
4
alkyl radical; it being possible for R
6
and R
7
, taken together, to form a 5- or 6-membered ring, or
an —O(CO)R
8
group in which R
8
is chosen from H or a linear or branched C
1
-C
8
alkyl radical
Z is chosen from a group of formula A or a group of formula B
in which:
R′
1
, R′
2
and R′
3
are, independently of one another, chosen from H, OH or a linear or branched C
1
-C
8
alkoxy radical
X′ is either a —(CO)NR′
4
R′
5
group in which R′
4
and R′
5
are, independently of one another, chosen from H or a linear or branched C
1
-C
4
alkyl radical; it being possible for R′
4
and R′
5
, taken together, to form a
5-
or 6-membered ring; or an —O(CO)R′
6
group in which R′
6
is chosen from H or a linear or branched C
1
-C
8
alkyl radical and its organic or inorganic salts.
Another subject-matter of the invention is a process for the preparation of the above compounds in which a salt, for example a sodium salt or a hydrochloride, of an N,N′-dibenzylalkylenediamine-N,N′-diacetic acid derivative or N-benzylalkylenediamine-N,N′,N′-triacetic acid derivative is reacted with 2 to 4 equivalents of a substituted halomethyl derivative.
Another subject-matter of the invention is a cosmetic or pharmaceutical composition comprising, in a cosmetically or pharmaceutically acceptable vehicle, at least one compound of above formula (I).
Another subject-matter of the invention is the use of the compounds of formula (I) as antioxidizing agent.
Another subject-matter of the invention is the use of the compounds of formula (I) in a cosmetic composition for treating oxidative stress and/or for treating the effects of exposure to the sun and/or for preventing ageing, in particular of the skin or hair.
Another subject-matter of the invention is the use of the compounds of formula (I) for the preparation of a pharmaceutical composition intended to treat oxidative stress, in particular related to certain pathological conditions, and/or intended to treat pathological situations, such as cancers, inflammatory conditions, reinfusion ischaemia, iron overloads or degenerative diseases of the nervous system, and/or intended to treat the effects of exposure to ionizing or solar radiation, and/or intended to treat the effects of the use of certain medicaments which generate free radicals, and/or intended to prevent ageing, in particular of the skin or hair.
It has therefore been found that the compounds of the invention exert a protective effect at low concentrations, of the order of a few micromoles per liter, whereas the compounds of the closest prior art, such as WO 94/11338, only exert an effect at much higher concentrations, of the order of a millimole per liter.
The compounds according to the invention are therefore much more effective than those of the prior art with respect to the protection of cultured cells against the toxicity of H
2
O
2
.
The compounds according to the invention are therefore esters of N,N′-dibenzylalkylenediamine-N,N′-diacetic a
Dumats Jacqueline
Galey Jean-Baptiste
Davis Brian J.
L'Oreal (S.A.)
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