FR2924601A1 - Composition, useful for depigmenting and/or bleaching of human skin, body hair or hair and to prepare dermatological composition, comprises hydroquinone diphosphate compound in a medium - Google Patents

Abstract

Composition comprises at least one hydroquinone diphosphate compound (I) or its salt, its solvates including hydrates, and its optical and geometric isomers, in a medium. Composition comprises at least one hydroquinone diphosphate compound of formula (I) or its salt, its solvates including hydrates, and its optical and geometric isomers, in a medium. R, R 3phosphate group; R 1, R 2H or linear 1-6C, or branched 3-6C alkyl group, optionally substituted by -COOR 4or -CONR 4R 5; and R 4, R 5H or 1-4C alkyl group. An independent claim is included for the hydroquinone diphosphate compound of formula (I). [Image] ACTIVITY : Dermatological. MECHANISM OF ACTION : Tyrosinase inhibitor. The ability of (I) to inhibit tyrosinase was tested in keratinocyte and melanocyte coculture. The results showed that hydroquinone 1,6-O-diphophate tetrasodium salt exhibited an IC 5 0value of 50 mu m.

Description

The present invention relates to a cosmetic composition for depigmenting and / or bleaching the skin comprising a hydroquinone diphosphate as well as certain new compounds.

The color of human skin is a function of various factors including seasons of the year, race and sex; it is mainly determined by the nature and concentration of melanin produced by melanocytes. Melanocytes are the specialized cells that, through the use of particular organelles, melanosomes, synthesize melanin. In addition, at different periods of their life, some people see on the skin and especially on the hands, darker spots and / or more colorful, giving the skin a heterogeneity. These spots are also due to a high concentration of melanin in keratinocytes located on the surface of the skin.

The use of harmless topical depigmenting substances with good efficacy is particularly sought for the treatment of regional hyperpigmentations by melanocytic hyperactivity such as idiopathic melasmas, occurring during pregnancy ("pregnancy mask" or chloasma) or oestro-progestative contraception, hyperpigmentations localized by hyperactivity and benign melanocyte proliferation, such as senile pigmentary spots known as actinic lentigo, accidental hyperpigmentations, possibly due to photosensitization or post-injury wound healing, as well as certain leukoderma, such as than vitiligo. For the latter (the cicatrizations may result in a scar giving the skin a whiter appearance), failing to repigment the damaged skin, it is necessary to depigment the areas of residual normal skin to give the whole of the skin. skin a uniform white hue.

The mechanism of formation of skin pigmentation, that is to say the formation of melanin is particularly complex and involves schematically the following main steps: Trevosine ---> Dopa ---> Dopaquinone --- > Dopachrome ---> Melanine Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxido-reductase EC 1.14.18.1) is the essential enzyme involved in this series of reactions. It catalyzes, in particular, the conversion reaction of tyrosine to Dopa (dihydroxyphenylalanine) by virtue of its hydroxylase activity and the reaction of transformation of Dopa into dopaquinone by virtue of its oxidase activity. This tyrosinase only acts when it is maturing under the influence of certain biological factors.

A substance is recognized as depigmenting if it acts directly on the vitality of the melanogenetic melanocyte melanocytes, and / or if it interferes with one of the stages of melanin biosynthesis by inhibiting one of the enzymes involved in melanogenesis. or by interposing itself as a structural analogue of one of the chemical compounds of the melanin synthesis chain, which chain can then be blocked and thus ensure depigmentation.

The substances most used as depigmenting agents are more particularly hydroquinone and its derivatives, in particular its ethers such as monomethyl ether and hydroquinone monoethyl ether. These compounds, although they have a certain effectiveness, are unfortunately not free of side effects because of their toxicity, which can make their use difficult, even dangerous. This toxicity comes from the fact that they interfere with the fundamental mechanisms of melanogenesis by killing cells that may then disturb their biological environment and therefore force the skin to evacuate them by producing toxins.

Thus, hydroquinone is a particularly irritating and cytotoxic compound for the melanocyte, whose replacement, total or partial has been considered by many authors.

We have thus looked for substances that do not intervene in the mechanism of melanogenesis but act upstream on tyrosinase by preventing its activation and are therefore much less toxic. The kojic acid which complexes copper present in the active site of this enzyme is commonly used as an inhibitor of tyrosinase activation. Unfortunately, this compound is unstable in solution, which somewhat complicates the manufacture of the camp.

There remains the need for a new whitening agent for human skin with action as effective as those known, but not having their disadvantages, that is to say which is non-irritating, non-toxic and / or non-allergenic to the skin, while being stable in a composition, or alternatively which has a reinforced action so that it can be used in a smaller quantity, which considerably reduces the observed side effects. In this regard, it has surprisingly and unexpectedly been found that certain hydroquinone compounds exhibit good depigmenting activity, even at low concentrations, without exhibiting cytotoxicity. More specifically, the subject of the invention is therefore a composition, in particular intended to depigment and / or whiten the skin, comprising, in a physiologically acceptable medium, at least one compound of formula (I) below:

OR R1 R2 OR '(I) wherein:

R and R 'denote a phosphate group; R1 and R2 denote, independently of each other, a hydrogen atom or a C1-C6 or branched C3-C6 linear alkyl group, optionally substituted with a -000R 'or a -CONR'R "group; and R "denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group; As well as their cosmetically acceptable salts, their solvates such as hydrates and their optical and geometrical isomers.

The compounds of formula (I) according to the invention make it possible to depigment and / or effectively lighten the skin of human beings. They are intended to be applied to the skin of individuals with brownish pigmentation spots, senescence spots, or on the skin of individuals wishing to combat the appearance of a brownish color from melanogenesis, for example to following exposure to ultraviolet radiation. The invention therefore also relates to a cosmetic process for depigmenting and / or bleaching human skin comprising applying to the skin a composition as described above. The method is particularly suitable for removing brownish pigment spots and / or senescence spots, and / or for lightening burnished skin.

The subject of the invention is also the cosmetic use of a compound of formula (I) as described above as a bleaching and / or depigmenting agent for the skin, in particular for eliminating pigment spots, senescence spots and or as anti-browning agents.

The invention also relates to the use of a compound of formula (I) as described above for the manufacture of a dermatological composition for de-pigmenting and / or bleaching the skin.

Among the compounds of formula (I), the tetrasodium salt of hydroquinone-1,6-diphosphate has the registry number RN: 857469-10-4 and is described in the article Experiments on the mechanism of action of tetrasodium 2 methyl-1,4-naphthoquinone diphosphate as a nitotic inhibitor and radiosensitizer, using the technique of tissue culture, Mitchell, JS; Simons-Reuss, I.; British Journal of Cancer (1952), 6, p 317-38.

Hydroquinone-1,6-diphosphate (RN: 75805-16-2) is described in US-A-2005/100976 and US-A-2004/0265922.

The subject of the invention is therefore also the compounds of formula (I ') corresponding to the compounds of formula (I) described above with the exception of those for which R1 = R2 = H.

The term alkyl, in the context of the present invention, means a saturated hydrocarbon chain. Among the alkyl groups which are suitable for the implementation of the invention, mention may especially be made of methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl and n-hexyl groups. cyclopropyl, cyclopentyl, cyclohexyl. Among the preferred alkyl groups, mention may be made of the groups methyl, ethyl, iso-propyl and tert-butyl groups, and preferably an ethyl group.

Salts acceptable for non-therapeutic use of the compounds described in the present invention include conventional non-toxic salts of said compounds such as those formed from a mineral base, such as LiOH, NaOH, KOH, Ca (OH) 2, NH4OH, Mg (OH) 2 or Zn (OH) 2; or an organic base such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. This primary, secondary or tertiary alkylamine may comprise one or more nitrogen and / or oxygen atoms and may therefore comprise, for example, one or more alcohol functions; mention may especially be made of 2-amino-methyl-2-propanol, triethanolamine, dimethylamino-2-propanol and 2-amino-2- (hydroxymethyl) -1,3-propanediol. We can also mention lysine or 3- (di methylamino) propylamine.

The solvates acceptable for the non-therapeutic use of the compounds described in the present invention include conventional solvates such as those formed in the last step of preparing said compounds due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water or of linear or branched alcohols, such as ethanol or isopropanol.

In the structure of formula (I) or (I '), the group R 1 is preferably in the 5-position ortho to the group OR.

An advantageous aspect of the invention relates to the compounds of formula (I) in which: R 1 = R 2 = H, or R 1 = H and R 2 denotes a linear C 1 -C 6 or branched C 3 -C 6 alkyl group, optionally substituted with a group -COOR 'or -CONR'R ", R' and R" denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group.

Another particular aspect of the invention relates to the compounds of formula (I) wherein: R 1 = R 2 = H, or R 1 = H and R 2 denotes a linear C 1 -C 6 alkyl group substituted with a group -COO-CH 2 CH 3; R2 being preferably -CH2-COO-CH2CH3. Preferred compounds of formula (I ') are those for which:

R 1 = H and R 2 denotes a linear C 1 -C 6 or branched C 3 -C 6 alkyl group, optionally substituted with a group -OORR 'or -CONR'R ", R' and R" denoting, independently of one of the another, a hydrogen atom or a C1-C4 alkyl group.

The compounds of formula (I ') which are particularly preferred are those for which: R 1 = H and R 2 denotes a linear C 1 -C 6 alkyl group substituted with a degree of addition of COOCH 2 CH 3; R2 being preferably -CH2-COO-CH2CH3.

The compounds of formula (I) and (I ') more particularly preferred are the following:

Hydroquinone 1,6-o-diphosphate (compound 1) or its salts such as its sodium salt: homogentisate diphosphate (OH); In general, the compounds of formula (I) can be prepared by reacting a compound of formula (II) with ethyl or its salts, such as its sodium salt (compound 2): ## STR2 ##

Wherein R1 and R2 have the meaning previously described for the compounds of formula (I),

With phosphorus oxychloride (POCl 3) in the presence of a base such as pyridine, optionally in an inert solvent medium such as tetrahydrofuran. As a base, it is also possible to use a mineral base such as sodium hydroxide, potassium hydroxide, sodium or potassium bicarbonate, sodium carbonate or potassium carbonate.

The reaction can be carried out at a temperature ranging from 0 ° C to 60 ° C.

After reaction, the sodium salt can be formed in methanol with an aqueous solution of sodium hydroxide.

Compounds of formula (II) wherein R 2 denotes a linear C 1 -C 6 or branched C 3 -C 6 alkyl group, substituted with a group -COR 'with R' denoting a C 1 -C 4 alkyl group; or -CONR'R ", R 'and R" denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group; can be obtained, in known manner, by esterification or amidification of the corresponding carboxylic acid.

Another subject of the invention relates to a composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above. In particular, the composition is suitable for application to the skin. The physiologically acceptable medium will preferably be a cosmetically or dermatologically acceptable medium, that is to say without odor, color or unpleasant appearance, and which does not generate tingling, tightness or redness unacceptable to the user.

By physiologically acceptable medium, an environment compatible with keratin materials of human beings such as the skin, the mucous membranes, the nails, the scalp and / or the hair is understood.

The composition according to the invention may be intended for a cosmetic or pharmaceutical application, particularly dermatological. Preferably the composition according to the invention is intended for a cosmetic application.

The quantity of compounds of formula (I) that can be used in the context of the invention obviously depends on the desired effect.

By way of example, this amount may range, for example, from 0.001% to 10% by weight, preferably from 0.01% to 5% by weight, in particular from 0.1% to 2% by weight, relative to the total weight of the composition.

The composition may then comprise all the constituents usually employed in the intended application. It may especially be mentioned water, solvents, oils of mineral, animal and / or vegetable origin, waxes, pigments, fillers, surfactants, cosmetic or dermatological agents, UV filters, polymers , gelling agents, preservatives, perfumes.

Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the advantageous properties of the compounds according to the invention are not, or not substantially, impaired by the addition envisaged. .

The composition according to the invention may be in any galenical form normally used in the cosmetic and dermatological fields; it may especially be in the form of an aqueous solution, hydroalcoholic, optionally gelled, a dispersion of the lotion type possibly two-phase, an oil-in-water or water-in-oil or multiple emulsion, an aqueous gel , an oil dispersion in an aqueous phase using spherules, these spherules may be polymeric nanoparticles such as nanospheres and nanocapsules or, better, lipid vesicles of ionic and / or nonionic type.

When the composition of the invention is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and optional coemulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

This composition may be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a mousse . It can optionally be applied to the skin in the form of an aerosol. It can also be in solid form, and for example in the form of a stick. It can be used as a care product and / or as a makeup product.

This composition may constitute a cream for cleaning, protecting, treating or caring for the face, for the hands, for the feet, for large anatomical folds or for the body (for example, day creams, night creams, creams). make-up removers, foundation creams, sunscreen creams); a fluid foundation, a make-up removal milk, a body care or protection milk, an anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion.

In an advantageous aspect of the invention, the compositions used may further comprise at least one desquamating agent, and / or at least one soothing agent, and / or at least one organic photoprotective agent and / or at least one inorganic photoprotective agent. By "desquamating agent" is meant any compound capable of acting:

or directly on desquamation by promoting exfoliation, such as 13-hydroxy acids, in particular salicylic acid and its derivatives (including n-octanoyl-5-salicylic acid); α-hydroxy acids, such as glycolic, citric, lactic, tartaric, malic or mandelic acids; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; resveratrol;

or on the enzymes involved in desquamation or degradation of corneodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE) or even other proteases (trypsin, chymotrypsin-like). Mention may be made of the chelating agents for mineral salts: EDTA; N-acyl-N, N ', N', ethylene diaminetriacetic acid; aminosulfonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane) sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid derivatives (procysteine); glycine-type alpha amino acid derivatives (as described in EP-0 852 949, as well as the sodium methyl glycine diacetate marketed by BASF under the trade name TRILON M); honey ; sugar derivatives such as O-octanoyl-6-D-maltose and N-acetyl glucosamine. As calming agents that may be used in the composition according to the invention, mention may be made of: pentacyclic triterpenes and plant extracts (eg Glycyrrhiza glabra) containing them, such as 3-glycyrrhetinic acid and its salts and / or derivatives thereof glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, 3-stearoyloxy glycyrrhetic acid), ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts, an extract of Paeonia suffruticosa and or lactiflora, salts of salicylic acid and in particular zinc salicylate, phycosaccharides from Codif, an extract of Laminaria saccharina, canola oil, bisabolol and chamomile extracts, allantoin, SEPIC SEPIVITAL EPC (diesterphosphoric vitamin E and C), omega 3 unsaturated oils such as rosehip musca, black currant, ecchium, fish, plankton extract, capryloyl glycine, Seppicalm V G (sodium palmitoylproline and nymphea alba) of Seppic, an extract of Pygeum, an extract of Boswellia serrata, an extract of Centipeda cunnighami, an extract of Helianthus annuus, an extract of Linum usitatissimum, tocotrienols, extracts of Cola nitida , piperonal, clove extract, Epilobium Angustifolium extract, aloe vera, Bacopa moniera extract, phytosterols, cortisone, hydrocortisone, indomethacin and beta methasone.5 Agents organic photoprotective agents are especially chosen from anthranilates; cinnamic derivatives; dibenzoylmethane derivatives; salicylic derivatives, camphor derivatives; triazine derivatives such as those described in US Patent Application Nos. 4367390, EP863145, EP517104, EP570838, EP796851, EP775698, EP878469, EP933376, EP507691, EP507692, EP790243, EP944624; benzophenone derivatives; 13,13-diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzoazolyl derivatives as described in patents EP669323 and US 2,463,264; paminobenzoic acid derivatives (PABA); methylene bis (hydroxyphenyl benzotriazole) derivatives as described in US5,237,071, US5,166,355, GB2303549, DE 197 26 184 and EP893119; and filter polymers and silicone filters such as those described in particular in the application WO-93/04665; α-alkylstyrene derived dimers such as those described in patent application DE19855649.

The inorganic photoprotective agents are chosen from pigments or even nanopigments (average size of the primary particles: generally between 5 nm and 100 nm, preferably between 10 nm and 50 nm) of coated or uncoated metal oxides, for example nanopigments of titanium oxide (amorphous or crystallized in rutile and / or anatase form), iron, zinc, zirconium or cerium which are all UV photoprotective agents well known per se. Conventional coating agents are, moreover, alumina and / or aluminum stearate. Such nanopigments of metal oxides, coated or uncoated, are in particular described in patent applications EP518772 and EP518773.

The photoprotective agents are generally present in the composition according to the invention in proportions ranging from 0.1 to 20% by weight relative to the total weight of the composition, and preferably ranging from 0.2 to 15% by weight relative to to the total weight of the composition.

The examples which follow illustrate the invention without limiting its scope. The compounds are, as the case may be, cited in chemical names or CTFA names (International Cosmetic Ingredient Dictionary and Handbook).

Example 1: Demonstration of the activity on melanogenesis.

A bioassay demonstrated the depigmenting activity of the tetrasodium salt of hydroquinone 1,6-O-diphosphate (compound 1). The modulatory effect on the melanogenesis of compound 1 was measured according to the method described in patent FR-A-2734825, as well as in the article by R. Schmidt, P. Krien and M. Régnier, Anal. Bichem., 235 (2), 113-18,1996. This test is performed on coculture of keratinocytes and melanocytes.

For the test compound, it was determined: the cytotoxicity, by estimating the incorporation of leucine, the inhibitory activity on melanin synthesis, by estimating the ratio of the incorporation of thiouracil to the incorporation of leucine, reported at 100% of the control (the control corresponds to the test carried out without test compound). The IC50 values (concentration for which 50% of the synthesis of melanin is inhibited) have been determined.

The test was also performed with arbutin which is a known depigmenting compound.

The results are summarized in the following table: Cytotoxicity IC 50 (M) Compound 1 No 50 Arbutin No 100 The compound of Example 1 is therefore effective in inhibiting melanogenesis; it is also more effective than arbutin. In addition, for hydroquinone, cytotoxicity appears rapidly at higher concentrations (50% CI: 30% at 3 M).

Example 2: A whitening facial cream of the type emulsion oil-in-water, comprising (% by weight):

tetrasodium salt of hydroquinone 1,6-0-diphosphate (compound 1) 0.005% glycerol stearate 2% polysorbate 60 (ICI Tween 60) 1 1.4% 0.7% 0.4% 12% 12% 0 , 05% 35 stearic acid triethanolamine carbomer liquid fraction shea butter perhydrosqualene antioxidant perfume, preservative qs water gsp100%

The composition applied to the skin with pigmentation spots makes it possible to reduce these tasks. Example 3 A skin depigmenting gel comprising (% by weight) is prepared: tetrasodium salt of hydroquinone 1,6-0-diphosphate (compound 1) 2% hydroxypropylcellulose (Klucel H from Hercules) 1

Antioxidant 0.05% isopropanol 40% perfume, preservative qs water gsp100% 205

Claims (13)

1. A composition comprising, in a physiologically acceptable medium, at least one compound of formula (I): ## STR2 ## in which: R and R 'denote a phosphate group; R1 and R2 denote, independently of one another, a hydrogen atom or a C1-C6 or branched C3-C6 linear alkyl group, optionally substituted with a group -COOR 'or -CONR'R ", R and R "denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group; as well as their cosmetically acceptable salts, their solvates such as hydrates and their optical and geometrical isomers. 20 2. Composition according to the preceding claim, characterized in that the R1 group of the compound of formula (I) is in position ortho relative to the group - OR. 3. Composition according to any one of the preceding claims, characterized in that for the compound of formula (I): R1 = R2 = H, or -R1 = H and R2 denotes a linear C1-alkyl group C6-C6 or branched C3-C6, optionally substituted with a group -COOR 'or -CONR'R ", R' and R" denoting, independently of one another, a hydrogen atom or a C 1 -C 6 alkyl group; -C4. 4. Composition according to any one of the preceding claims, characterized in that for the compound of formula (I): R1 = R2 = H, or -R1 = H and R2 denotes a C1-C6 linear alkyl group substituted with a group -COO CH2CH3. 5. Composition according to any one of the preceding claims, characterized in that the compound of formula (I) is chosen from: - 1,6-O-diphosphate of hydroquinone; ethyl homogentisate diphosphate; - and their salts. 6. Composition according to any one of the preceding claims, characterized in that the compound of formula (I) is present in an amount ranging from 0.001% to 10% by weight, relative to the total weight of the composition, of preference. from 0.01% to 5% by weight. A cosmetic process for depigmenting and / or bleaching human skin, hair, or hair comprising applying to the skin, hair, or hair a composition according to any one of the preceding claims. 8. Cosmetic use of a compound of formula (I) as defined according to any one of claims 1 to 5, as whitening agent and / or depigmenting skin. 9. Use of a compound of formula (I) as defined in any one of claims 1 to 5, for the manufacture of a dermatological composition for depigmenting and / or whitening the skin. 25 10. Compounds of formula (I '): wherein R 1 and R' denote a phosphate group; R 1 and R 2 denote, independently of each other, a hydrogen atom or a linear C 1 -C 6 or branched C 3 -C 6 alkyl group, optionally substituted with a group -COOR 'or -CONR'R ", R and R "denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group; with the proviso that R1 and R2 do not simultaneously designate a hydrogen atom, as well as their cosmetically acceptable salts, their solvates such as hydrates and their optical and geometrical isomers. 11. Compounds according to the preceding claim, characterized in that R1 = H and R2 denotes a C1-C6 or branched C3-C6 linear alkyl group, optionally substituted by a group -COOR 'or -CONR'R ", R' and R "denoting, independently of one another, a hydrogen atom or a C1-C4 alkyl group. 12. Compounds according to claim 10 or 11, characterized in that. R1 = H and R2 denotes a linear C1-C6 alkyl group substituted with a group --COOCH2CH3. 13. Compounds according to any one of claims 10 to 12, characterized in that it is ethyl homogentisate diphosphate or its salts.