MXPA99003665A - Aminophenol derivatives and their use in cosmetics - Google Patents

Abstract

The invention concerns novel aminophenol derivatives, a composition containing them and their use in a composition as depigmenting and/or bleaching agent for human skin, hairs and/or hair. The invention also concerns a method for depigmenting and/or bleaching the skin, hairs and/or hair, which consists in applying on human skin, hairs and/or hair a composition containing said novel compounds (I).

Description

COMPOUNDS DERIVED FROM AMXNOPHENOL AND ITS USE IN COSMETICS DESCRIPTION OF THE INVENTION The present invention relates to the use of aminophenol derivatives, as depigmentation agent or bleaching agent in a cosmetic and / or dermatological composition, to a cosmetic and / or dermatological composition comprising said derivatives and to new derivatives of aminophenol. The color of human skin varies depending on different factors and especially the seasons, race and sex, and is determined mainly by the nature and concentration of melanin produced by elanocytes. Melanocytes are specialized cells that, through particular organelles, melanosomes, synthesize melanin. On the other hand, in different periods of life, some people see appearing on the skin and more precisely on the hands, darker and / or more colored spots, which give the skin a heterogeneous appearance. These spots are also due to a significant concentration of melanin in the keratinocytes that are found on the surface of the skin. REF .: 29830 In the same way, the color of the hairs and the hair is due to the melanin, when the hairs or the hair are dark, some people want them to look lighter. This is particularly interesting for those hairs that are less visible when they are clear, than when they are dark. The mechanism of formation of the pigmentation of the skin, of the hairs and hairs, that is to say of the formation of melanin, is particularly complex and intervenes in it schematically, the following main stages: Tyrosine - > Dopa - > Dopaquinone - Dopacrom - > Melanin Tyrosine (monophenol dihydroxylphenylalanine: oxygenated reductase EC 1.14.18.1) is the essential enzyme involved in this sequence of reactions. It catalyzes especially the reaction of transformation of tyrosine in Dopa (dihydroxyphenylamine) thanks to its hydroxylase activity and the reaction of Dopa transformation in dopaquinone, thanks to its oxidase activity. This tyrosinase only acts when it is in a state of maturation, under the action of some biological factors.

It is understood that a substance is depigmenting, if it acts directly on the vitality of the epidermal melanocytes where the elanogenesis develops and / or if one of the stages of the biosynthesis of melanin interferes, either by inhibiting one of the enzymes involved in melanogenesis , or interspersed as a structural analogue of one of the chemical compounds of the melanin synthesis chain, a chain that can then be blocked and thus ensure depigmentation. The substances most commonly used as depigmentation agents are more precisely hydroquinone and its derivatives, in particular its ethers, such as monomethyl ether and hydroquinone monoethyl ether. Although these compounds have a certain effectiveness, unfortunately, they are not exempt from side effects due to their toxicity, which makes their use delicate, and even dangerous. This toxicity is due to the fact that they intervene in fundamental mechanisms of melanogenesis, killing cells that can then disturb their biological environment and therefore force the skin, to evacuate them producing toxins. In this way, hydroquinone is a particularly irritating and cytotoxic compound for melanocytes, whose total or partial replacement has been addressed by numerous authors. For this reason, substances that do not intervene in the mechanism of melanogenesis have been sought, but they act earlier on tyrosinase, preventing their activation and that is why they are much less toxic. Kojic acid, which forms a heterocycle with the copper present in the active site of this enzyme. Unfortunately, this compound can cause allergic reactions ("Contact allergy to kojic acid in skin care products") Nakagawa M. et al., in Contact Dermatitis, Jan. 95, Vol 42 (1), pp. 9-13). That compound is also unstable in solution, which complicates the manufacture of the composition a little. The use of harmless topical depigmenting substances, which present an important efficacy, is being investigated, with a view to treating regional hyperpigmentation by melanocytic hyperpigmentation, such as idiopathic melasmas, resulting from pregnancy ("pregnancy mask" or chloasma) or of estroprogestogenic contraception, hyperpigmentations localized by hyperactivity and benign melanocytic proliferation, such as senile pigmentary spots called actinic lentigo, hyperpigmentation or accidental depigmentation, possibly due to photosensitization or scarring after an injury, as well as certain leukodermias , such as vitiligo. For the latter, (the scarring can end in a scar that gives the skin a whiter appearance and leucodermias), as it can not repigment the injured skin, the areas of normal residual skin are depigmented, to give the skin in its set, a homogeneous white hue. Also, there remains a need for a new bleaching agent for human skin, hair and / or hair action as effective as known, but does not present its drawbacks, ie it is non-irritating, non-toxic and / or non-allergic to the skin and stable in a composition. The applicant has unexpectedly found that the new aminophenol derivatives exhibit a depigmenting activity, even at low concentrations, without showing signs of toxicity. The subject of the present invention is therefore to provide the following aminophenol derivatives of formula (I): wherein: R represents a hydrogen atom or a radical -C0R, with R ', identical or different, representing a radical chosen from an alkyl or alkoxy radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 optionally hydroxylated carbon atoms, Ri is selected from a radical of formulas (a), (b) or (c) below: (a) -CO-NR3R4 (b) -CO-O-R5 (c) -SOc-Rs with R representing a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, linear or branched, saturated or unsaturated, optionally hydroxylated, with R 4 representing a hydrogen atom or a radical chosen from an alkyl, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms, optionally hydroxylated, with R 5 representing a hydrogen atom chosen from an alkyl, saturated or unsaturated, linear, cyclic or branched radical, with 1 to 30 carbon atoms , optionally hydroxylated, in a depigm cosmetic composition and / or bleach of human skin, hair or hair. These compounds have the advantage of being easy to obtain. They can be obtained in particular by reacting an aminophenol with an activated chemical entity, such as an imidazolide or an isocyanate, when R is a radical of formula (a), a chloroformate, when R is a radical of formula (b), or a chloride of sulfonyl, when Ri is a radical of formula (c). According to the present invention, linear or branched alkyl radicals having from 1 to 30 carbon atoms may advantageously be mentioned as methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, hexyl, octyl, nonyl, 2- radicals. ethylhexyl and dodecyl. Preferably, these radicals have from 1 to 12 carbon atoms. Even more preferably, the alkyl radical generally comprises from 1 to 6 carbon atoms. Mention may be made, as the lower alkyl radical, of methyl, ethyl, propyl, isopropyl, tertbutyl, hexyl radicals.

Among the linear alkyl radicals having from 1 to 30 carbon atoms, mention may be made especially of the methyl, ethyl, propyl, octyl, dodecyl, tridecyl, hexadecyl, behenyl, octadecyl, tetracosyl, hexacosyl, octacosyl and myristyl radicals. Among the branched alkyl radicals having from 1 to 30 carbon atoms, mention may be made especially of the 2-ethylhexyl, 2-butyloctyl, 2-hexyldecyl radicals. When unsaturated, a radical having one or more ethylenic unsaturations is preferred, such as, more precisely, the radical neryl, 2-nonyl-2-butenyl, 6 (1,3-pentadienyl) -2,4,7-dodecanetrien-9- inil and more particularly, the allyl radical. When the alkyl radical is cyclic, the cyclohexyl, cholesteryl or tert-butylcyclohexyl radical can be mentioned in particular. When it is hydroxylated, the radical preferably comprises 1 to 6 carbon atoms and 1 to 5 hydroxyl groups. Among the monohydroxyalkyl radicals, a radical containing preferably 1 or 3 carbon atoms, in particular the hydroxyethyl, 2-hydroxyethyl, 2 or 3-hydroxypropyl radicals, is preferred.

Among the polyhydroxyalkyl radicals, • prefers a radical having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2, 3-dihydroxypropyl, 2, 3, 4-trihydroxbutyl, 2, 3, 4, 5-tetrahydroxypentyl radicals and , 3,4,5,6-pentahydroxyhexyl. Alkoxylated radicals are alkyl radicals, such as in particular those described above, preceded by an oxygen atom. Preferably, the aminophenol derivatives of the present invention are those for which at least one and preferably all the following conditions are respected: - R represents a hydrogen atom, - the -OR function on the phenyl radical is in position ortho or advantageously in position for, Ri is chosen from a radical of formulas (a) or (b). The compounds of formula (I) are chosen more precisely, between N-ethyloxycarbonyl-4-aminophenol, N-ethyloxycarbonyl-O-ethyloxycarbonyl-4-aminophenol; he N-Chloesteryloxycarbonyl-4-aminophenol and the N-ethyl-aminocarbonyl-4-aminophenol. The present invention also relates to compositions comprising at least one aminophenol derivative of formula (I) and a cosmetically and / or dermatologically acceptable medium. This composition is intended more precisely for a topical use on the skin and / or its phallic areas (hair, hairs and nails). This cosmetic or dermatological composition is advantageously intended to depigment and / or bleach the human skin and / or remove the pigmented spots on the skin and / or depigment the hairs and / or the hairs. The subject of the present invention is also the use of these aminophenol derivatives in and / or for the manufacture of a cosmetic and / or dermatological composition, as an inhibitor of tyrosinase and / or of the synthesis of melanin and / or as an agent of depigmentation and / or bleaching of the skin, of the hairs or of the hair. Another subject of the present invention is new aminophenol derivatives of the following formula (I): wherein: R represents a hydrogen atom or a radical -COR2, with R2,. which represents a radical chosen from an alkyl or alkoxy radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms optionally hydroxylated, Ri is selected from the following radicals: (a) -CO-NR3R4 (b) a choleseryloxycarbonyl radical (c) -SO2-R5 with R3 representing a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, linear or branched, saturated or unsaturated, optionally hydroxylated, with R4 representing a hydrogen atom or a radical chosen from an alkyl radical, saturated or unsaturated, linear, cyclic or branched, with 13 to 30 carbon atoms, optionally hydroxylated, with R 5 representing a hydrogen atom chosen from an alkyl, saturated or unsaturated, linear, cyclic radical or branched, with 1 to 30 carbon atoms, optionally hydroxylated. The present invention also relates to a cosmetic depigmentation and / or bleaching process of human skin, hair or hair consisting of applying to the skin, hairs or hair a cosmetic composition according to the invention. The composition according to the invention is suitable for topical use and therefore contains a cosmetically or dermatologically acceptable medium, that is to say compatible with the skin, the hair or the hair. The aminophenol derivatives will be used in an effective amount to obtain the desired depigmentation or bleaching effect and this amount will be present depending on the nature of the aminophenol derivatives considered. Particularly, the aminophenol derivatives of formula (I) can be present in the composition, especially in an amount ranging from 0.001 to 10% and preferably from 0.005 to 5% of the total weight of the composition. The composition of the invention can be present in all galenic forms normally used for a topical application, especially in the form of an aqueous, hydroalcoholic or oily solution, of an oil-in-water or water-in-oil or multiple emulsion, of a gel aqueous or oily, from a liquid, pasty or solid anhydrous product, from a dispersion of oil in an aqueous phase with the help of spherules, these spherules being able to be polymeric nanoparticles such as nanospheres and nanocapsules or better still, lipid vesicles of the type ionic or non-ionic. This composition can 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 foam. It can eventually be applied on the skin or on the hair in the form of an aerosol. It can also be presented in solid form, and for example in the form of a bar. It can be used as a care product and / or as a makeup product. It can also be presented in the form of shampoo or after shampooing. In a known way, the composition of the invention can also contain the usual additives used in the fields of cosmetics and dermatology, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers, filters, pigments , odor absorbents and coloring matters. The amounts of these different additives are those conventionally used in the areas considered, and for example from 0.01 to 20% of the total weight of the composition. These additives, according to their nature, can be introduced in the fatty phase, in the aqueous phase, in the lipid vesicles and / or in the nanoparticles. 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 with respect to the total weight of the composition. The oils, emulsifiers and co-emulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field in question. 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 with respect to the total weight of the composition. As oils capable of being used in the invention, mineral oils (petroleum jelly), oils of vegetable origin (avocado oil, soybean oil), oils of animal origin can be mentioned. (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). It can also be used as fats of fatty alcohols (cetyl alcohol), fatty acids, waxes (carnauba wax, ozokerite).

As emulsifiers and co-emulsifiers which can be used in the invention, mention may be made, for example, of the fatty acid and polyethylene glycol esters such as PEG-20 stearate, and the fatty acid and glycerin esters such as glyceryl stearate. As hydrophilic gelling agents, mention may be made, in particular, of the carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, there may be mentioned modified clays such as benthones, metal salts of acids fatty acids, hydrophobic silica and polyethylenes. As active, polyols (glycerin, propylene glycol), vitamins, keratolytic and / or scavenging agents (salicylic acid and its derivatives, alpha-hydroxy acids, ascorbic acid and its derivatives), anti-inflammatory agents, soothing agents can be used or its mixtures. It is also possible to associate the aminophenol derivatives with other depigmentation agents, such as kojic acid or hydroquinone and its derivatives, which allows the latter to be used in doses less toxic to the skin. In case of incompatibility, these assets and / or the aminophenol derivatives can be incorporated into spherules, especially ionic or non-ionic vesicles and / or nanoparticles (nanocapsules and / or nanospheres), so as to isolate them from each other in the composition. Next, the invention will be illustrated with the help of the following examples. The concentrations are given in percentage of weight.

Examples of compounds EXAMPLE 1 N-Ethyloxycarbonyl-4-aminophenol 20 g of 4-aminophenol (Mw = 109.13, 0.18324 mol) are suspended in 200 cm 3 of anhydrous dichloromethane under an inert atmosphere. Cool to a temperature of 0 ° C in an ice bath, then add 16.4 cm3 of anhydrous pyridine (Mw = 79.10, d = 0.981, 0.2034 mol). Then, dropwise, so as to maintain at a temperature lower than 10 ° C, 17.6 cm 3 of ethyl chloroformate (Mw = 108.53, d = 1.13, 0.18324 mol) is added. The reaction mixture is kept under stirring for two hours. The mixture is poured into one liter of ice water, then extracted with ethyl acetate. The organic phase is washed with water, then dried, filtered and evaporated in vacuo. After recrystallization from a heptane-ethyl acetate mixture, a white powder of mass 21 g is obtained, which corresponds to a yield of 63%. The melting temperature of the product obtained is 127.2 ° C. The 1 H NMR spectrum and the elemental analysis are in accordance with the expected product.

EXAMPLE 2 N-Ethyloxycarbonyl-O-ethyloxycarbonyl-1-4-aminophenol 10 g of 4-aminophenol (Mw = 109.13, 0.0916 mol) in 100 cm 3 of anhydrous dichloromethane are suspended in an inert atmosphere. Cool to a temperature of 0 ° C in an ice bath, then add 8.2 cm3 of anhydrous pyridine (Mw = 79.10, d = 0.981, 0.102 mol). Then, dropwise, so as to maintain at a temperature lower than 10 ° C, 9.8 cm3 of ethyl chloroformate (Mw = 108.53, d = 1.13, 0.104 mol) is added. The reaction mixture is kept under stirring for two hours. The mixture is poured into one liter of ice water, then extracted with ethyl acetate. The organic phase is washed with water, then dried, filtered and evaporated in vacuo. After recrystallization from ethanol, a white powder of mass 18 g is obtained, which corresponds to a yield of 80%. The melting temperature of the product obtained is 110.8 ° C. The 1H 200MHz NMR spectrum and the elemental analysis are in accordance with the expected product.

Example 3 N-cholesteryloxycarbonyl-4-aminophenol 21.8 g of 4-aminophenol (Mw = 109.13) are suspended.; 0.2 mol) in 200 cm3 of anhydrous N, N-dimethylacetamide, under an inert atmosphere. Then, dropwise, so as to maintain at a temperature lower than 30 ° C, 44.9 cm3 of cholesteryl chloroformate (Mw = 449.11, 0.1 mol) is added. The mixture is kept reacting under stirring for two hours. The mixture is poured into five liters of water, then filtered and the precipitate is dried. After recrystallization from a water-ethanol mixture, a white powder with a mass of 46 g is obtained, which corresponds to a yield of 88%. The melting temperature of the product obtained is 186.9 ° C. The 13C lOOMHz NMR spectrum and the elemental analysis are in accordance with the expected product.

Example 4 N-Ethylaminocarbonyl-1-aminophenol 10 g of 4-aminophenol are suspended.

(Mw = 109.13; 0.0916 mol) in 100 cm3 of anhydrous N-methylpyrrolidone, under inert atmosphere. Then, 6.5 g of ethyl isocyanate (Mw = 71.08, 0.0914 mol) are added dropwise. The reaction mixture is brought to a temperature of 60 ° C under stirring for two hours. The mixture is poured into one liter of water, then filtered and the precipitate is dried. After recrystallization from ethanol, a white powder of mass 9 g is obtained, which corresponds to a yield of 55%. The melting temperature of the product obtained is 173. ° C. The 1H 200MHz NMR spectrum and the elemental analysis are in accordance with the expected product.

Tests: A biological test has demonstrated the depigmenting activity of the aminophenol derivatives of formula (I). This test corresponds to that described in patent FR 2734825 filed by the applicant, as well as in the article by R. Schmidt, P. Krine and M. Régnier, Anal. Bioche., 235 (2), 113-18, (1996). This test was carried out on a coculture of keratinocytes and melanocytes.

For each compound tested, the IC50 value corresponding to the micromolar concentration (μM) has been determined for which 50% inhibition of melanogenesis is observed. On the other hand, a class has been assigned to each of these compounds for its maximum depigmenting activity: Class 1: 10 to 30% inhibition of melanogenesis with respect to the control (same experience without the compound to be tested); Class 2: 30 to 60% inhibition of melanogenesis with respect to the control (same experience without the compound to be tested); Class 3: 60 to 100% inhibition of melanogenesis with respect to the control (same experience without compound to be tested). The results are gathered in the following table (1) • These compounds of formula (1) therefore have a greater depigmenting efficacy than kojic acid. In addition, they have the advantage of not presenting cytotoxicity against keratinocytes and melanocytes, which is the major defect of the existing depigmenting agents.

Examples of compositions Example 5: Treatment cream - Cetyl alcohol 1. 05% - PEG-20 stearate (Myrj 49 sold by the company ICI) 2% - Cyclomethicone 6% - Compound of example 1 0. 5% - Carbomer 0 6% - Glycerin 3% - Triethanolamine 1% - Preservatives 0.5% - Demineralized water qsp 100% The cream obtained used in daily application, allows to obtain a bleaching of the skin.

Example 6: Treatment Gel - Propylene Glycol 10% - Ethyl alcohol 40% - Glycerin 3% - Compound of example 2 0.5% - Preservatives 0.15% - Perfume 0.15% - Demineralised water qsp 100% The gel obtained can be used daily and is suitable for depigmenting the skin.

Example 7: Treatment bar - Carnauba wax 5% - Ozokerite 7% - Lanolin 6% - Titanium dioxide (pigments) 20% - Rice starch (charge) 7% - EDTA 0.1% - Compound of example 3 2% - Perhydrosqualene qsp 100% The obtained bar, used on the pigmented spots, allows to attenuate them even to make them disappear. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (10)

2. . Having described the invention as above, the content of the following claims is claimed as property: 1. Use of at least one aminophenol derivative of the following formula (I): characterized in that: R represents a hydrogen atom or a radical -COR2, with R¿, representing a radical chosen from an alkyl or alkoxyl radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms optionally hydroxylated Ri is selected from a radical of formulas (a), (b) or (c) below: (a) -CO-NR3R4 (b) -co-o-Rs (c) -S0.-Ro with R representing a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, linear or branched, saturated or unsaturated, optionally hydroxylated, with R 4 representing a hydrogen atom or a radical chosen from an alkyl radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms, optionally hydroxylated, with R 5 representing a hydrogen atom chosen from an alkyl, saturated or unsaturated, linear, cyclic or branched radical, with 1 to 30 carbon atoms, optionally hydroxylated, in a depigmenting cosmetic composition and / or bleaching of human skin, hair or hair. 2. Use according to claim 1, characterized in that said aminophenol derivative has at least one and preferably all of the following conditions: R represents a hydrogen atom, - The -OR function on the phenyl radical is ortho or advantageously in para position, Ri is chosen from a radical of formulas (a) or (b).
3. 3. Derivatives according to claim 1 6 2, characterized in that they are chosen from N-ethyloxycarbonyl-4-aminophenol; N-ethyloxycarbonyl-O-ethyloxycarbonyl-4-aminophenol; N-cholesteryloxycarbonyl-4-aminophenol and N-ethylaminocarbonyl-4-aminophenol.
4. 4. Use of at least one derivative having the formula (I), characterized in that it has been defined in any of claims 1 to 3, in and / or for the manufacture of a cosmetic and / or dermatological composition, as a tyrosinase inhibitor and / o of the synthesis of melanin.
5. 5. Cosmetic and / or dermatological composition characterized in that it comprises at least one aminophenol derivative of formula (I) as defined in any of claims 1 to 4 and a cosmetically and / or dermatologically acceptable medium. Composition according to the preceding claim, characterized in that it is intended to depigment and / or bleach the human skin and / or remove the pigmented spots on the skin and / or depigment the hairs and / or the hairs. Composition according to any one of claims 5 to 6, characterized in that the aminophenol derivative is present in an amount ranging from 0.001 to 10% and preferably from 0.005 to 5% of the total weight of the composition. 8. Composition according to any of claims 5 to 7, characterized in that the composition also comprises at least one active selected from the keratolytic and / or scavenging agents, anti-inflammatory, painkillers, other depigmenting agents and mixtures thereof. 9. Aminophenol derivatives of the following formula (I): characterized in that: R represents a hydrogen atom or a radical -COR2, with R2 / representing a radical chosen from an alkyl or alkoxyl radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms optionally hydroxylated, Ri is selected from the following radicals: (e) a choleseriloxycarbonyl radical (f) -S02-R5 with R3 representing a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, linear or branched, saturated or unsaturated, optionally hydroxylated, with R 4 representing a hydrogen atom or a radical chosen from an alkyl radical, saturated or unsaturated, linear, cyclic or branched, with 13 to 30 carbon atoms, optionally hydroxylated, with R 5 representing a hydrogen atom chosen from an alkyl radical, saturated or unsaturated, linear, cyclic or branched, with 1 to 30 carbon atoms, optionally hydroxylated. Cosmetic procedure for depigmenting and / or bleaching of human skin, hair or hair, characterized in that it consists in applying to the skin, hair or hair a composition described according to any of the preceding claims 5 a 8