Histidine derivatives, preparation process and uses

Details Histidine derivatives, preparation process and uses Histidine derivatives, preparation process and uses

1999-05-25

2001-01-30

Jones, Dameron (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S401000, C424S408000, C424S409000, C548S339100

Reexamination Certificate

active

06180116

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel histidine derivatives and to processes of preparing the histidine derivatives. The present invention also relates to cosmetic or dermatological compositions containing these compounds. The compounds may be used as agents for combating free radicals.
2. Discussion of the Background
Sunlight, heat, atmospheric pollution and, in particular, smoke and tobacco are known to bring about the formation of free radicals. They mainly originate from molecular oxygen. Mention may be made of the following free radicals:
singlet oxygen: highly oxidizing, highly toxic and with a very short lifetime, the product of the excitation of molecular oxygen by light photons;
the superoxide radical anion: the product of the addition of an electron to oxygen, which can give rise to the production of highly reactive hydroxyl radicals;
the hydroxyl radical: highly oxidizing and the most toxic to cells.
The formation of these radical species results in particular in the oxidation of cutaneous lipids. Living cells, in particular those of the skin, scalp and certain mucous membranes, are particularly sensitive to these free radicals, which is reflected by an accelerated ageing of the skin, with a complexion lacking radiance and premature formation of wrinkles or fine lines, and also by a decrease in the vigor and a lacklustre appearance of the hair. It is therefore particularly important to protect the skin, hair and mucous membranes from these free radicals. It is known that some antioxidants can inhibit the formation of free radicals. Thus, carnosine, or N-p-alanyl-L-histidine, which is a natural dipeptide found in the muscles of numerous vertebrates, is known for its activity in combating free radicals, in particular in combating singlet oxygen (E. Decker and H. Faraji, JAOCS, Vol. 67, No. 10, 650-652, 1990). Its use as an antioxidizing agent or as an agent for combating free radicals in cosmetics is described in WO-A-92/09298. However, carnosine exhibits problems of decomposition on contact with the skin, caused by enzymes present in the skin and in particular proteases, which results in a significant loss in its activity.
Histidine derivatives are also known, such as, for example, the derivatives N-(4-amino-1-oxobutyl)-L-histidine, -(5-amino-1-oxopentyl)-L-histidine and N-(6-amino-1-oxohexyl)-L-histidine disclosed in RU2084457. However, due to their physicochemical nature, these histidine derivatives are unsatisfactory in protecting non-polar compounds from oxidation.
Accordingly, there remains a need for compounds which are useful for combating free radicals.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide compounds which combat free radicals with respect to oxidizable non-polar compounds and, in particular, effectively deactivate singlet oxygen.
It is another object of the invention to provide compositions containing the compounds which may be used for cosmetic and/or dermatological applications.
It is still another object of the invention to provide methods of making the compounds.
The present invention is based on the unexpected discovery that novel histidine derivatives exhibit excellent activity in combating free radicals with respect to oxidizable non-polar compounds and are highly effective in deactivating singlet oxygen. These compounds may, therefore, be used in cosmetics and in pharmaceuticals; they are readily applicable to the skin.
Accordingly, the object of the invention, and others, may be accomplished with novel histidine derivatives corresponding to the following general formula (I):
where
n is an integer ranging from 0 to 5,
n′ is an integer ranging from 1 to 16,
R represents a side chain of an amino acid,
X represents a radical chosen from the radicals of formulae, read from left to right:”
—NH—CO—, —SO
2
, —NH—CO—CO—, —O—CO—CO—,
R′ represents an optionally hydroxylated, saturated or unsaturated, linear or branched C
6
to C
22
alkyl radical or a C
6
to C
22
aminoalkyl radical, the amine functional group optionally being protected in the acetamide form or substituted by one or two lower alkyl groups,
Q
+
represents H
+
or an organic or inorganic carton, or an addition salt of a compound of formula (I) with an organic or inorganic acid.
The objects of the invention may also be accomplished with a process for making the histidine derivatives.
The objects of the invention may also be accomplished with a composition comprising the histidine derivative as in a physiologically acceptable medium.
The objects of the invention may also be accomplished with a method of combating free radicals by applying the histidine derivatives to substrates to be protected against free radicals. In a preferred embodiment, the substrate may be skin and/or hair.
The objects of the invention may also be accomplished with a method of protecting a composition from free radicals by incorporating the histidine derivative into the composition.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The organic cation (Q
+
) can be ammoniums comprising a residue chosen from basic amino acids, such as lysine or arginine, or from amino alcohols, such as glucamine, N-methylglucamine or 3-amino-1,2-propanediol. The inorganic cation (Q
+
) can be chosen from alkali metal or alkaline earth metal cations, such as Na
+
or K
+
, or Q
+
can be an NH
4
+
ion.
The addition salts with an acid may be chosen, for example, hydrochlorides, hydrobromides, sulphates, tartrates or acetates.
The compounds of formula (I) comprise at least one asymmetric carbon in their chemical structure. The invention relates both to the compounds with a D configuration or with an L configuration and to their mixtures, in particular a racemic mixture of the D and L compounds.
In the present invention, the preferred compounds of formula (I) satisfy at least one of the following:
(1) R′ denotes a saturated, linear or branched alkyl radical having from 8 to 18 carbon atoms,
(2) n is an integer from 1 to 5, and/or
(3) n′ is an integer ranging from 1 to 11.
In the present invention, preferable linear or branched alkyl radicals having from 6 to 22 carbon atoms include hexyl, octyl, nonyl, 2-ethylhexyl, dodecyl, hexadecyl and octadecyl radicals.
The lower alkyl groups generally comprise from 1 to 6 carbon atoms. For example, the lower alkyl group includes methyl, ethyl, propyl, iospropyl, tert-butyl and hexyl radicals.
Examples of linear alkyl radicals having from 6 to 22 carbon atoms include the octyl, dodecyl, hexadecyl and octadecyl radicals.
Examples of the branched alkyl radicals having from 6 to 22 carbon atoms include 2-methylpentyl, 1-methylhexyl and 3-methylheptyl radicals. “Unsaturated alkyl radical” is preferably understood to mean a linear or branched radical having from 6 to 22 carbon atoms and comprising one or more double bonds.
The side chains of an amino acid correspond to the side chains of any one of the natural amino acids. The identity of the side chains of the natural amino acid side chains is described in L. Stryer,
Biochemistry
, Third Edition, incorporated herein by reference in its entirety. Thus, R can represent in particular hydrogen or a methyl or isopropyl radical. R can therefore be nonpolar, polar but uncharged, or negatively or positively charged side chains.
Examples of the preferred compounds corresponding to the general formula (1) include:
N-octylaminocarbonyl-&bgr;-alanyl-L-histidine,
N-dodecylaminocarbonyl-&bgr;-alanyl-L-histidine,
N-octylsulphonyl-&bgr;-alanyl-L-histidine,
N-dodecylsulphonyl-&bgr;-alanyl-L-histidine, and
N-dodecylaminooxalyl-&bgr;-alanyl-L-histidine.
Another subject-matter of the present invention is a process for the preparation of the compounds of formula (I). This process comprises the reaction with histidine in an inert s

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