Histidine derivatives, preparation process and uses

Histidine derivatives and processes of preparing the histidine derivatives. The histidine derivatives can be used to combat free radicals. The histidine derivatives may be used in cosmetic and/or dermatological compositions.

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):
 ##STR1##
 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:"
EQU --NH--CO--, --SO.sub.2, --NH--CO--CO--, --O--CO--CO--,
 R' represents an optionally hydroxylated, saturated or unsaturated, linear
 or branched C.sub.6 to C.sub.22 alkyl radical or a C.sub.6 to C.sub.22
 aminoalkyl radical, the amine functional group optionally being protected
 in the acetamide form or substituted by one or two lower alkyl groups,
 Q.sup.+ represents H.sup.+ 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.sup.+) 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.sup.+) can be chosen from alkali metal or alkaline
 earth metal cations, such as Na.sup.+ or K.sup.+, or Q.sup.+ can be an
 NH.sub.4.sup.+ 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-.beta.-alanyl-L-histidine,
 N-dodecylaminocarbonyl-.beta.-alanyl-L-histidine,
 N-octylsulphonyl-.beta.-alanyl-L-histidine,
 N-dodecylsulphonyl-.beta.-alanyl-L-histidine, and
 N-dodecylaminooxalyl-.beta.-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 solvent of a compound of formula (II)
 ##STR2##
 in which n', n, R, R' and X have the same meanings as in the above formula
 (I), and Y is a conventional activating group for the acidic functional
 group.
 Reactions for the activating the --COOH acidic groups are well known to
 those skilled in the art. Reference may be made, for example, to Advanced
 Organic Chemistry, Jerry March, 3rd Edition, 1985, pp. 370-377,
 incorporated herein by reference. "Coupling agent" is understood to mean
 any compound which can substitute the OH group of the compound of formula
 (IV) and then be substituted subsequently by the amino acid which it is
 desired to graft, for example histidine. Coupling agents are described in
 Advanced Organic Chemistry, J. March. 3rd Edition, 1985, p. 372,
 incorporated herein by reference. A particularly preferred coupling agent
 is 2-(5-norbomene-2,3-dicarboximido)-1,1,3,3-tetramethylammonium
 tetrafluoroborate.
 The starting histidine, comprising an asymmetric carbon, is used in the
 pure optical form or in the mixed optical form (D; L; D, L), depending on
 the desired optical form of the compound of formula (I).
 Examples of the solvent include dichloromethane, 1,2-dichloroethane,
 1,1,1-trichloroethane, chloroform, acetonitrile, toluene, dioxane,
 tetrahydrofuran, 1,2-dimethoxyethane, cyclohexane, dimethylformamide,
 water or a mixture of these solvents.
 The reaction is carried out at a temperature preferably of between
 -10.degree. C. and +40.degree. C. and more preferably between 20.degree.
 C. and 30.degree. C.
 The reaction can be carried out in the presence of a base. The base may be
 chosen from alkali metal or alkaline earth metal hydroxides, sodium
 hydrogen carbonate, alkali metal alkoxides, alkaline hydrides or tertiary
 amines, such as pyridine, diisopropylechylamine or triethylamine. Sodium
 hydrogen carbonate is a preferred base.
 Another subject-matter of the present invention is a composition
 comprising, in a physiologically acceptable medium, a compound of formula
 (I) as defined above. The composition comprising the compound can be
 provided in particular in the form of a cosmetic or pharmaceutical
 composition respectively comprising a cosmetically or pharmaceutically
 acceptable medium. In the compositions according to the invention, the
 compounds of formula (I) are generally present at a concentration of
 0.001% to 15% by weight and preferably of 0.01% to 5% by weight with
 respect to the total weight of the composition. These weight % ranges
 include all specific values and subranges therebetween, including 0.005,
 0.02, 0.05, 1, 2, 8, 10 and 12% by weight.
 These compositions can be prepared according to the usual methods known to
 a person skilled in the art. They can be in the form of a lotion, gel,
 water-in-oil or oil-in-water emulsion, microemulsion, milk or cream,
 powder, paste, solid stick, spray or aerosol foam.
 Another subject-matter of the invention is the use of the compounds of
 formula (I) as agent for combating free radicals and in particular as
 agent for combating free radicals which deactivates singlet oxygen, in
 particular in a cosmetic or pharmaceutical composition.
 The invention also relates to the use of the compounds of formula (I) in a
 cosmetic or pharmaceutical composition for the treatment of keratinous
 substances against the effects of ageing. "Keratinous substances" is
 understood to mean the skin, hair, nails, body hairs, mucous membranes and
 semimucous membranes, such as the lips.
 The compounds of formula (I) constitute anionic amphiphilic lipids which
 can be included in a vesicular system.
 The compositions comprising the compounds according to the invention can
 also comprise, in a known way, one or more active compounds having a
 cosmetic and/or pharmaceutical activity which, depending on their
 solubility characteristics, can be located in different places. For
 example, in the case of dispersions of vesicles comprising an encapsulated
 aqueous phase, it the active principles are fat-soluble, they can be
 present in the lipid phase constituting the layer(s) of the vesicles or in
 the droplets of water-immiscible liquid stabilized by the vesicles. If the
 active principles are water-soluble, they can be present in the
 encapsulated aqueous phase of the vesicles or in the continuous aqueous
 phase of the dispersion. If the active principles are amphiphilic, they
 are distributed between the lipid phase and the encapsulated aqueous phase
 with a partition coefficient which varies according to the nature of the
 amphiphilic active principle and the respective compositions of the lipid
 phase and of the encapsulated aqueous phase. The active principles are
 generally positioned in the lipid phase of the layers and/or in the phase
 encapsulated by the layers.
 The compositions according to the invention to may also comprise,
 formulation additives having neither a cosmetic activity nor a
 pharmaceutical activity of their own but which are of use in the
 formulation of the compositions. Mention may be made, among these
 additives, for example, of gelling agents, polymers, preservatives,
 colorants, opacifiers and fragrances.
 The cosmetic or pharmaceutical compositions according to the invention may
 be provided, for example, in the form of shampoos or conditioners, of
 cleansing compositions, of creams for caring for the skin or hair, of
 antisun compositions, of shaving creams or foams, of body deodorants, of
 compositions for oral use, of hair dyeing compositions or of make up
 compositions, for example.
 The histidine derivatives of the present invention may be used to protect
 substrates against free radicals. Here, an effective amount of the
 histidine derivative(s) is applied to the substrate. Suitable substrates
 include skin and hair.
 The histidine derivatives of the present invention may be used to protect
 compositions against the effects of free radicals. An effective amount of
 the histidine derivative(s) is incorporated into the compositions. For
 example, the composition may contain 0.001% to 15% by weight of the
 histidine derivative(s).
 Having generally described this invention, a further understanding can be
 obtained by reference to certain specific examples which are provided
 herein for purposes of illustration only and are not intended to be
 limiting unless otherwise specified.

##STR3##
 a) Synthesis of N-octylsulphonyl-.beta.-alanine
 2 g (22.45 mmol) of P-alanine are dissolved in 1 equivalent of 1N sodium
 hydroxide solution in a three-necked flask equipped with two 250 ml
 dropping funnels and with a glass electrode for measuring the pH. 1
 equivalent of 1-octanesulphonyl chloride in tetrahydrofuran is introduced
 dropwise into the reaction mixture at room temperature. The pH is
 maintained above 9 by the simultaneous addition of 1 equivalent of 1N
 sodium hydroxide solution. After stirring for 3 hours at room temperature,
 the mixture is acidified with approximately 1.1 equivalents of a 3N
 hydrochloric acid solution. The heterogeneous mixture is extracted with
 100 ml of ethyl acetate. The organic phase is washed with 3 times 20 ml of
 water, dried over sodium sulphate and then evaporated to dryness. The
 solid residue is taken up in heptane and is then filtered off and dried
 under vacuum. 1.6 g of a white product are obtained, i.e. a yield of 30%.
 Melting point: 121.8.degree. C. (Mettler FPR9)
 Elemental analysis (C.sub.11 H.sub.2,NO.sub.4 S, MW=265.372)

C H N O S
 % calculated 49.79 8.74 5.28 24.12 12.08
 % found 49.72 8.76 5.24 24.18 12.10
 b) Synthesis of N-octylsulphonyl-.beta.-alanyl-L-histidine
 4 g (15 07 mmol) of N-octylenlphonyl-.beta.-alanine are dissolved in 50 ml
 of tetrahydrofuran and 1 equivalent of triethylamine in a 100 ml
 three-necked flask equipped with a thermometer and with a 10 ml dropping
 funnel. 1 equivalent of pivaloyl chloride is then introduced at a
 temperature of 5.degree. C. The mixture is 12 subsequently stirred for 1
 hour at a temperature of 20.degree. C. A solution comprising 1.2
 equivalents of histidine and 1.2 equivalents of sodium hydroxide in 20 ml
 of water is prepared and then run dropwise into the reaction mixture while
 maintaining the temperature below 30.degree. C. After stirring for 6
 hours, the mixture is neutralized with 1 equivalent of SN hydrochloric
 acid. The solvent is evaporated and then 50 ml of water are introduced.
 The precipitate is filtered off, washed with water and then dried under
 vacuum over phosphorus pentoxide. The crude product is washed with acetone
 and then recrystallized from 95.degree. ethanol. 1.6 g of a white product
 are obtained, i.e. a yield of 27%.
 Analyses
 Melting point: 146.8.degree. C. (Mettler FP89)
 Thin layer chromatography (SiO.sub.2), eluent NH.sub.4 OH 6/CH.sub.3 OH
 47/CH.sub.2 Cl.sub.2 47: R.sub.f =0.74 (iodine visualization)
 Elemental analysis (C.sub.17 H.sub.30 N.sub.4 O.sub.5 S, MW=402.513)

##STR4##
 a) Synthesis of N-octylaminocarbonyl-.beta.-alanine 4 g (24.67 mmol) of 1,1
 '-carbonyldiimidazole are dissolved in 40 ml of dimethylformamide in a 100
 ml three-necked flask under a nitrogen atmosphere. 4 g (24.67 mmol) of
 octylamine are then introduced. After stirring for 45 minutes at room
 temperature, a solution of 2.4 g (1.1 equivalents) of P-alanine in 10 ml
 of aqueous sodium hydroxide solution (1.1 equivalents) is added dropwise
 to the preceding mixture. The mixture becomes heterogeneous, which mixture
 is subsequently neutralized with a concentrated hydrochloric acid solution
 diluted by half. The precipitate is filtered off, washed with water and
 then dried under vacuum over phosphorus pentoxide. 4.9 g of a white
 product are obtained, i.e. a yield of 82%.
 Analyses:
 Melting point: 136.9.degree. C. (Mettler FPB9)
 Elemental analysis (C.sub.12 H.sub.24 N.sub.2 O.sub.3, MW=244.333)

C H N O
 % calculated 58.99 9.9 11.47 19.64
 % found 58.82 9.96 11.12 19.61
 b) Synthesis of N-octylaminocarbonyl-.beta.-alanyl-L-histidine
 3 g (12.28 mmol) of N-octylaminocarbonyl-.beta.-alanine are dissolved in 60
 ml of tetrahydrofuran and 1 equivalent of triethylamine in a 100 ml
 three-necked flask equipped with a thermometer and with a 10 ml dropping
 funnel. 1 equivalent of pivaloyl chloride is then introduced at a
 temperature of 5.degree. C. The mixture is subsequently stirred for 1 hour
 at a temperature of 20.degree. C. A solution comprising 1.2 equivalents of
 histidine and 1.2 equivalents of sodium hydroxide in 20 ml of water is
 prepared and then run dropwise into the reaction mixture while maintaining
 the temperature below 30.degree. C. After stirring for 6 hours, the
 mixture is neutralized with 1 equivalent of 5 N hydrochloric acid. The
 solvent is evaporated and then 50 ml of water are introduced. The
 precipitate is filtered off, washed with water and then dried under vacuum
 over phosphorus pentoxide. The crude product is washed with acetone and
 then recrystallized from 95.degree. ethanol. 1.4 g of a white product are
 obtained, i.e. a yield of 30%.
 Analyses:
 Melting point: 199.6.degree. C. (Mettler FP89)
 Thin layer chromatography (SiO.sub.2), eluent NH.sub.4 OH 6/CH.sub.3 OH
 47/CH.sub.2 Cl.sub.2 47: R.sub.f =0.82 (iodine visualization).
 Elemental analysis (C.sub.18 H.sub.31 N.sub.5 O.sub.4, MW=381.474)

C H N O
 % calculated 56.68 8.19 18.36 16.78
 % found 54.41 8.19 17.09 17.96
 Obviously, numerous modifications and variations of the present invention
 are possible in light of the above teachings. It is therefore to be
 understood that within the scope of the appended claims, the invention may
 be practiced otherwise than as specifically described herein.
 This application is based on French Patent Application Serial No. 98-06538,
 filed on May 25, 1998, and incorporated herein by reference.