Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-06-24
2001-07-03
Moezie, F. T. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S018700, C514S019300, C514S400000, C514S556000, C514S844000, C514S944000, C514S945000, C514S946000, C514S947000, C424S043000, C424S401000, C424S489000, C424S455000, C424S450000
Reexamination Certificate
active
06255344
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel histidine derivatives and to a process for their preparation. The invention also relates to cosmetic or dermatological compositions comprising these compounds. The invention also relates more particularly to the use of these compounds as anti-free-radical agents.
Solar radiation, heat, atmospheric pollution and, in particular, smoke and tobacco are known to lead to the formation of free radicals. They originate to a large extent from molecular oxygen.
Mention may be made of the following free radicals:
singlet oxygen, which is highly oxidizing, highly toxic and has a very short lifetime, produced by the excitation of molecular oxygen with photons of light;
the superoxide anion radical, produced by the addition of an electron to oxygen and capable of giving rise to the production of highly reactive hydroxyl radicals;
the hydroxyl radical, which is highly oxidizing and the most toxic to cells.
The formation of these radical species leads in particular to oxidation of the lipids in the skin.
Live cells, in particular those in the skin, the scalp and certain mucous membranes, are particularly sensitive to these free radicals, which is reflected in accelerated ageing of the skin, with a complexion lacking radiance and early formation of wrinkles and fine lines, and also by a reduction in the vigour and a dull appearance of the hair.
It is thus seen that it is particularly important to protect the skin, the hair and the mucous membranes against these free radicals.
2. Description of the Related Art
It is known that certain antioxidants are capable of inhibiting the formation of free radicals.
Thus, carnosine, or N-&bgr;-alanyl-L-histidine, which is a natural dipeptide found in the muscles of many vertebrates, is known for its anti-free-radical activity, in particular its activity against singlet oxygen (E. Decker and H. Faraji, JAOCS, vol. 67, No. 10, 650-652, 1990). Its use as an antioxidant or as anti-free-radical agent in cosmetics is also known from patent application WO-A-92/09298. However, when in contact with the skin, carnosine displays degradation problems caused by the enzymes present in the skin and in particular proteases, which leads to a substantial loss of its activity.
Carnosine derivatives are also known, such as, for example, the N-acyl carnosine derivatives described in patent FR-C-2,496,660. Products with antioxidant activity, obtained by coupling fatty acids and carnosine and used in cosmetic preparations, have been described in patent application FR-A-2,668,365. However, such carnosine derivatives also have the same problem of instability in the presence of the enzymes present in the skin.
BRIEF SUMMARY OF THE INVENTION
The Applicant has discovered, unexpectedly, novel histidine derivatives which display greater stability on contact with the enzymes present in the skin, and in particular proteases, than do the known derivatives of the prior art, while at the same time having good anti-free-radical activity and in particular having a good property of efficacy in the deactivation of singlet oxygen. They can thus be used in cosmetics and pharmacy: they are easy to apply to the skin.
DETAILED DESCRIPTION OF THE INVENTION
The Applicant has found that such results can be obtained with lipodipeptide histidine derivatives containing a carbamate function.
A subject of the invention is thus novel histidine derivatives corresponding to the general formula (I) below:
in which:
R denotes a linear or branched, saturated or unsaturated alkyl radical containing from 6 to 22 carbon atoms,
n is an integer from 1 to 16,
Q
+
represents H
+
or an organic or inorganic cation, and the addition salts with an acid.
According to the invention, R preferably denotes a linear or branched, saturated alkyl radical containing from 8 to 18 carbon atoms and n is an integer ranging from 1 to 11.
The organic cation can be chosen from ammoniums containing a residue chosen from basic amino acids such as lysine or arginine, or alternatively from amino alcohols such as glucamine, N-methylglucamine or 3-amino-1,2-propanediol.
The inorganic cation can be chosen from alkali metal or alkaline-earth metal cations such as Na
+
or K
+
, or can be the NH
4
+
ion.
The addition salts with an acid are chosen, for example, from the hydrochlorides, hydrobromides, sulphates, tartrates and acetates.
The compounds of formula (I) containing an asymmetric carbon in their structure comprise the compounds of D configuration, of L configuration or of D,L configuration.
Among the preferred compounds corresponding to the general formula (I), mention may be made in particular of:
N-octyloxycarbonyl-&bgr;-alanyl-L-histidine,
N-dodecyloxycarbonyl-&bgr;-alanyl-L-histidine,
N-2-ethylhexyloxycarbonyl-&bgr;-alanyl-L-histidine hydrochloride,
N-hexadecyloxycarbonyl-&bgr;-alanyl-L-histidine.
A subject of the present invention is also the process for preparing the compounds of formula (I). This process consists in reacting, in an inert solvent, a compound of formula (II)
X representing a halogen atom, in particular a chlorine atom, or a radical derived from an azole, in particular a radical originating from an imidazole such as that of formula (III):
and R having the same meaning given in formula (I) above,
either (A) with carnosine,
or (B), in a first step, with an amino acid of formula:
H
2
N—(CH
2
)
n
—COOH
to form a compound of formula (IV) below:
R and n having the same meanings as those given in formula (I) defined above,
and, in a second step, in reacting histidine with the compound of formula (IV) in the presence of a coupling agent.
The term “coupling agent” refers to any compound capable of substituting the OH group in the compound of formula (IV), and then of being subsequently substituted with histidine. Coupling agents are mentioned in “Advanced Organic Chemistry, J. March, 3rd edition, 1985, page 372 ”. 2-(5-Norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate can be used in particular as a coupling agent.
The starting histidine and carnosine, each containing an asymmetric carbon, are used in the pure optical form or as a mixture (D; L; D,L) depending on the desired optical form of the compound of formula I.
Dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chloroform, acetonitrile, toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclohexane, water or a mixture of these solvents can be used as inert solvent.
The reaction is carried out at a temperature preferably between −10° C. and +40° C., and more preferably between 20° C. and 30° C.
The reaction can be carried out in the presence of a base. This can be chosen from alkali metal or alkaline-earth metal hydroxides, sodium hydrogen carbonate, alkali metal alkoxides, alkaline hydrides and tertiary amines such as pyridine or triethylamine. Sodium hydrogen carbonate is preferably used.
The present invention also relates to a composition comprising, in a physiologically acceptable medium, a compound of formula (I) as defined above.
The composition comprising the said compound can be, in particular, in the form of a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically acceptable medium, respectively.
In the compositions according to the invention, the compounds of formula (I) are generally present at a concentration of from 0.01% to 15% by weight, and preferably from 0.1% to 5% by weight, relative to the total weight of the composition.
These compositions can be prepared according to the usual methods known to those skilled in the art. They can be in the form of a lotion, a gel, a water-in-oil or oil-in-water emulsion, a microemulsion, a milk, a cream, a powder, pastes, a solid stick, a spray or an aerosol mousse.
A subject of the invention is also the use of the compounds of formula (I) as anti-free-radical agents, and in particular as anti-free-radical agents for deactivating singlet oxygen, and in particular in a cosmetic or pharmaceutical composition.
The invention
Bordier Thierry
Philippe Michel
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
L'Oreal (S.A.)
Moezie F. T.
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