WO2004084854A1

WO2004084854A1 - Cosmetic use of cinnamic acid derivatives as lightening agents

Info

Publication number: WO2004084854A1
Application number: PCT/EP2004/004018
Authority: WO
Inventors: Jean Maignan
Original assignee: L'oreal
Priority date: 2003-03-25
Filing date: 2004-03-24
Publication date: 2004-10-07
Also published as: WO2004084854A8

Abstract

The subject of the present invention is the cosmetic or dermatological use of at least one compound of formula (I ) in a composition, as agent for removing brownish pigmented spots, senescence spots, and/or as antibronzing agent for the skin. The subject of the invention is also a cosmetic method for removing brownish pigmented spots and/or senescence spots, and/or a cosmetic method for lightening bronzed skin, comprising the application to the skin, of a cosmetic composition containing a compound of formula (I) defined above.

Description

Cosmetic use of cinnamic acid derivatives as lightening agents

The present invention relates to the use of cinnamic acid derivatives in a composition, in particular a cosmetic composition, the said derivatives and/or the said composition being intended for lightening human skin, body hair or head hair.

The invention also relates to the use of cinnamic acid derivatives for the preparation of a composition, in particular a dermatological composition, intended for depigmenting human skin, body hair or head hair.

The colour of human skin depends on various factors, and in particular on the seasons of the year, on race and on gender; it is mainly determined by the nature and the concentration of melanin produced by the melanocytes. Melanocytes are specialized cells which, by means of specific organelles, the melanosomes, synthesize melanin. In addition, at various periods of their life, some people seem darker and/or more coloured spots appear on the skin and more especially on the hands, conferring heterogeneity on the skin. These spots are also due to a high concentration of melanin in the keratinocytes situated at the surface of the skin.

Likewise, the colour of body hair and of head visible when they are light than when they are dark.

The use of inoffensive topical depigmenting substances exhibiting good efficacy is most particularly sought in order to treat regional hyperpigmentations by melanocyte hyperactivity such as idiopathic melasm s , occurring during pregnancy ("mask of pregnancy" or chloasma) or oestro-progestational contraception, localized hyperpigmentations by benign melanocyte hyperactivity and proliferation, such as senile pigmented spots termed actinic lentigo, accidental hyperpigmentations, possibly due to photosensitization or to post-lesion cicatrization, and some leucodermas such as vitiligo. For the latter (cicatrizations which can result in a scar giving the skin a lighter appearance) , in the absence of being able to repigment the leεioned skin, the depigmenting of the areas of residual normal skin is completed in order to give the whole skin a homogeneous light complexion. The mechanism of formation of skin pigmentation, that is to say the formation of melanin, is particularly complex and schematically involves the following main stages :

Tyrosine >Dopa >Dopaquinone >Dopachrome >Melanin

Tyrosinase (monophenol dihydroxyl phenylalanine : oxygen oxidoreductase EC 1.14.18.1) is the main enzyme involved in this sequence of reactions. It catalyses in particular the reaction of conversion of tyrosine to Dopa (dihydroxyphenylalanine) by virtue of its hydroxylase activity and the reaction of conversion of Dopa to dopaquinone by virtue of its oxidase activity. This tyrosinase only acts when it is in the state of maturation under the action of certain biological factors. ^■ A substance is recognized as depigmenting if it acts directly on the vitality of the epidermal melanocytes where elanogenesis occurs, and/or if it interferes with one of the steps in the biosynthesis of melanin either by inhibiting one of the enzymes involved in melanogenesis, or by intervening as a structural analogue of one of the chemical compounds in the chain for synthesizing melanin, a chain which can then be blocked and thus bring about depigmentation. The substances most widely used as depigmenting agents are most particularly hydroquinone and its derivatives, in particular its ethers such as monomethyl ether and monoethyl ether of hydroquinone. These compounds, although they exhibit a certain degree of efficacy, are unfortunately not free of side effects because of their toxicity, which can make their use delicate, or even dangerous. This toxicity results from the fact that they act on fundamental mechanisms ^■ of melanogenesis by killing cells which then risk disrupting their biological environment and which consequently force the skin to discharge them by producing toxins . Thus, hydroquinone is a compound which is particularly irritating and cytotoxic for the melanocyte, whose complete or partial replacement has been envisaged by many authors .

Substances have thus been sought which are not involved in the mechanism of melanogenesis but which act upstream on tyrosinase by preventing its activation and are thereby a lot less toxic. There is commonly used as inhibitor of tyrosinase activition kojic acid which complexes copper at the active site of this enzyme. Unfortunately, this compound is unstable in solution, which somewhat complicates the manufacture of the composition.

The need remains for a novel agent for lightening human skin, body hair and/or head hair whose action is as effective as those known, but which does not have their disadvantages, that is to say which is nonirritating, nontoxic and/or nonallergenic for the skin, while being stable in a composition, or alternatively which possesses an enhanced action so as to be able to be used in a lower quantity, which considerably reduces the side effects observed. In this regard, the applicant has surprisingly and unexpectedly discovered that some α- (phenyl) cinnamic acid derivatives exhibit good depigmenting activity, even in low concentration, without being cytotoxic. Certain α-phenylcinnamic acid derivatives have been described in patent application JP-10 175 854 for their use in the treatment of skin pigmentation due to haemochromatosis . This genetic disease is characterized by the appearance of greyish spots in some areas of the skin, following accumulation of iron in the bloodstream, due to intestinal hyperabsorption of iron. The compounds described prevent this phenomenon by trapping iron.

However, to the knowledge of the applicant, the α-phenylcinnamic acid derivatives according to the invention have never been used for a cosmetic purpose for combating the excess of skin pigmentation resulting from melanogenesis, or from a disruption of this biosynthetic process. The invention therefore relates to the use of α-phenylcinnamic acid as lightening agents for removing pigmented spots, senescence spots and/or as anti- bronzing agents.

The compounds according to the invention are intended to be applied to the skin of individuals having brownish pigmentation spots, senescence spots, or to the skin of individuals wishing to combat the appearance of a brownish colour resulting from melanogenesis, for example following exposure to ultraviolet radiation. Nothing suggested to persons skilled in the art that compounds with a structure similar to those disclosed in the document JP-10 175 854 and trapping iron, could have melanogenesis-inhibiting properties, and could thus be used on the skin of different groups of individuals.

The subject of the present invention, is more particularly the cosmetic use of at least one compound of formula (I) :

in which, n and m independently represent an integer between 0 and 5,

R, Ri and R₂ independently^' represent a hydrogen atom, or a group chosen from a linear or branched C₁-C₁₂ alkyl group, a C3-C₈ cycloalkyl group, a linear or branched C₂-C₁₂ alkenyl group, a C₃-C₈ cycloalkenyl group, a linear or branched C₂-C₁₂ alkynyl group, a group R3-CO-, a group R₄O-CO- and a group R₄NH-CO-,

R₃ represents a linear or branched C₁-C₂₄ alkyl group, a C₃-C₈ cycloalkyl group, an aryl group optionally substituted with one or more -0R₄, -SR₄, -COOR₄, -NR₄R4/ aryl or heteroaryl groups, R₄ represents a hydrogen atom,- or a group chosen from a linear or branched C₁-C₁₂ alkyl group, a C₃-C₈ cycloalkyl group, a linear or branched -' heteroalkyl group, a heterocycloalkyl group and an arylalkyl group, it being possible for each of these groups to be optionally substituted with one or more halogen atoms or -OR₅, -COOR₅ or -NR₅R₅ groups , R₅ represents a hydrogen atom or a linear or branched C₁-C12 alkyl group or a C₃-C₈ cycloalkyl group, in a composition, as an agent for removing brownish pigmented spots, senescence spots, and/or as anti- bronzing agent for the skin,

it being understood that the term aryl denotes a phenyl or naphthyl group, the term heteroaryl denotes a mono- or bicyclic group containing at least one 5- to 11-membered aromatic ring, containing from 1 to 5 heteroatoms chosen from nitrogen, oxygen and sulphur, the term heteroalkyl denotes a C₁-C₁2 alkyl group in which a carbon atom has been replaced by a heteroatom chosen from nitrogen, oxygen and sulphur, the term heterocycloalkyl denotes a 5- to 8- membered saturated cyclic group containing from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulphur, and that in the groups -NR₄R₄ or -NR5R5, the radicals R or R₅ are identical or different.

An advantageous aspect of the invention relates to the compounds of formula (I) for which n and m are independently chosen from the integers 0 and 1, and cannot simultaneously represent 0.

Another advantageous aspect of the invention relates to the compounds of formula (I) for which the group RiO is in the para position of the aromatic ring and/or the group R₂O is in the meta position of the aromatic ring.

In the preferred compounds of formula (I) , the group R represents a hydrogen atom.

In the compounds of formula (I) , the group R₄ preferably represents a linear or branched Ci-Cε alkyl group .

Other preferred compounds of formula (I) are those for which the group R₅ represents a hydrogen atom or a linear or branched Ci-Cε alkyl group.

The compounds of formula (I) may be in the cis or trans form, or alternatively in the form of a mixture .

In the compounds of formula (I) , the alkyl groups are preferably linear or branched Ci-Cε alkyl groups. There may be mentioned for example methyl, ethyl, propyl, isopropyl or butyl groups.

The halogen atoms present in the compounds of formula (I) are advantageously chosen from fluorine, chlorine, bromine and iodine atoms.

The preferred cycloalkyl groups according to the invention are cyclopentyl, cyclohexyl or cyclo eptyl groups . Among the preferred heteroaryl groups for carrying out the present invention, there may be mentioned furyl, thienyl, pyrazolyl, imidazolyl, pyridyl and pyrimidyl groups .

A compound of formula (I) which is particularly suitable for carrying out the present invention is α- (m-hydroxyphenyl) -p-hydroxycinnamic acid of formula (A) :

Another compound of formula (I) which is particularly suitable for carrying out the present invention is α-phenyl-p-hydroxycinnamic acid of formula (B) :

The compounds of formula (I) may be obtained by persons skilled in the art by synthesis according to customary methods, in particular using the methods described in FR-2 829 760.

The subject of the invention is also a cosmetic method for removing brownish pigmented spots and/or senescence spots, and/or a cosmetic method for lightening bronzed skin, comprising the application to the skin, of a cosmetic composition containing a compound of formula (I) as defined above.

The quantity of derivatives which can be used in the context of the invention quite obviously depends on the desired effect. By way of example, this quantity 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 according to the invention is intended in particular for topical application. It comprises moreover a physiologically acceptable medium, that is to say which is compatible with the skin, including the scalp, the mucous membranes, head hair, body hair and/or the eyes and can constitute in particular a cosmetic or dermatological composition. The composition may then comprise all the constituents customarily used in the application envisaged. There may be mentioned in particular water, solvents, oils of mineral, animal and/or vegetable origin, waxes, pigments, fillers, surfactants, cosmetic or dermatological active agents, UV-screening agents, polymers, gelling agents and preservatives. Of course persons skilled in the art will be careful to choose this or these possible additional compound (s) and/or their quantity, such 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 provided in any galenic forms normally used in the cosmetics and dermatological fields; it may be in particular in the form of an aqueous, aqueous- alcoholic, optionally gelled, solution, a dispersion of the lotion type, optionally biphasic, an oil-in-water or water-in-oil or multiple emulsion, an aqueous gel, a dispersion of oil in an aqueous phase with the aid of spherules, it being possible for these spherules to be polymeric nanoparticles such as nanospheres and nanocapsules, or even better lipid vesicles of the ionic and/or nonionic type. When the composition of the invention is an emulsion, the proportion of the fatty phase may 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, the emulsifiers and the optional coemulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field considered. The emulsifier and the coemulsifier are present in the composition in a proportion which may range 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 may have the appearance of a white or coloured cream, an ointment, a milk, a lotion, a serum, a paste or a mousse. It may be optionally applied to the skin or to the hair in the form of an aerosol. It may also be provided in a solid form, and for example in the form of a stick. It may be used as a care product and/or as a makeup product. It may also be in the form of a shampoo or a conditioner.

This composition can constitute a cleansing, protective, treatment or care cream for the face, for the hands, for the feet, for large anatomical folds or for the body (for example day creams, night creams, makeup-removing creams, foundation creams, antisun creams) ; a fluid foundation, a makeup-removing milk, a protective or care body milk, an antisun' milk; a care lotion, gel or mousse for the skin, as a cleansing lotion.

In an advantageous aspect of the invention, the compositions used may further contain 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. The expression "desquamating agent" is understood to mean any compound capable of acting: either directly on desquamation by promoting . exfoliation, such as β-hydroxy acids, in particular salicylic acid and its derivatives (including 5- (n- octanoyl) salicylic acid); α-hydroxy acids such as glycolic, citric, lactic, tartaric, malic or mandelic acids; urea; gentisic acid; oligofucoses; cinnamic acid; extract of Saphora japonica; resveratrol; or on the enzymes involved in desquamation or the degradation of the corneodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE) or even other proteases (trypsin, chymotrypsin-like) . There may be mentioned chelating agents for inorganic salts : EDTA; N-acyl-N,N' ,N' -ethylenediaminetriacetic acid; aminoεulphonic compounds and in particular (N-2- hydroxyethylpiperazine-N-2-ethane) sulphonic acid (HEPES) ; 2-oxothiazolidine-4-carboxylic acid derivatives (procysteine) ; alpha-amino acid derivatives of the glycine type (as described in EP-0 852 949), and sodium methylglycine diacetate marketed by BASF under the trade name TRILON M) ; honey; sugar derivatives such as O-octanoyl-6-D-maltose and N-acetylglucosamine. As soothing agents which can be used in the composition according to the invention, there may be mentioned: pentacyclic triterpenes and plant extracts (e.g.: Glycyrrhiza glabra) containing them such as β-glycyrrhetinic acid and its salts and/or its derivatives (glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, 3-stearoyloxyglycyrrhetic 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 the company Codif, an extract of Laminaria saccharina, canola oil, bisabolol and camomile extracts, allantoin, Sepivital EPC (phosphoric diester of vitamin E and C) from Seppic, omega-3 unsaturated oils such as rose-musk oil, blackcurrant seed oil, echium oil, fish oil, plankton extracts, capryloylglycine, Seppicalm VG (sodium palmitoylproline and Nymphea alba) from 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, an extract of clove, an extract of Epilobium angustifolium, Aloe vera, an extract of Bacopa moniera, phytosterols, cortisone, hydrocortisone, indomethacin and beta-methasone .

The organic photoprotective agents are chosen in particular from anthranilates; cinnamic derivatives, dibenzoylmethane derivatives; salicylic derivatives, camphor derivatives; triazine derivatives such as those described in Patent Applications US 4367390, EP863145, EP517104, EP570838, EP796851, EP775698, EP878469, EP933376, EP507691, EP507692, EP790243, EP944624; benzophenone derivatives; β, β-diphenylacrylate derivatives; benzotriazole derivatives; benzal alonate derivatives; benzi idazole derivatives; imidazolines; bisbenzoxazolyl derivatives as described in Patents EP669323 and US 2,463,264; p-aminobenzoic acid (PABA) derivatives; methylenebis (hydroxyphenylbenzotriazole) derivatives as described in Applications US5,237,071, US5,166,355, GB2303549, DE 197 26 184 and EP893119; and screening polymers and screening silicones such as those described in particular in Application

WO-93/04665; dimers derived from α-alkylstyrene such as those described in Patent Application DE19855649.

The inorganic photoprotective agents are chosen from pigments or nanopigments (mean primary particle size: generally between 5 nm and 100 nm, preferably between 10 nm and 50 nm) of coated or uncoated metal oxides such as for example nanopigments of titanium oxide (amorphous or crystallized in rutile and/or anatase form) , iron oxide, zinc oxide, zirconium oxide or cerium oxide which are all UV photoprotective agents well known per se. Conventional coating agents are moreover alumina and/or aluminium stearate. Such nanopigments of metal oxides, coated or uncoated, >are described in particular 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 the total weight of the composition. The examples which follow illustrate the invention without limiting its scope. The compounds are, depending on the case, cited as chemical names or as CTFA names (International Cosmetic Ingredient Dictionary and Handbook) . Eκample 1; Demonstration of the activity on melanogenesis

A biological test demonstrated the depigmenting activity of the α-phenylcinnamic acid derivatives of formula (I) . The modulating effect on melanogenesis of the compounds of formula (I) was measured according to the method described in Application EP-0 993 -826 filed by the applicant, and in the article by R. Schmidt,

P. Krien and M. Regnier, Anal. Biochem. , 235(2), 113-

18, (1996).

For each compound tested, the following were determined: the cytotoxicity, by estimating the incorporation of leucine, - the inhibitory activity on the synthesis of melanin, by estimating the ratio of the incorporation of thiouracil to the incorporation of leucine, expressed relative to 100% of the control (the control corresponds to the test carried out without compound to be tested) . The IC50 (concentration for which 50% of the synthesis of melanin is inhibited) values were determined. The results are assembled in the following table :

Compounds A and B are described above . The compounds of formula (I) therefore prove very effective for inhibiting melanogenesis. Example 2

A lightening cream for facial care of the oil-in-water emulsion type is prepared, comprising (% by weight) :

α- (m-hydroxyphenyl) -p-hydroxycinnamic acid 0.005% glyceryl stearate 2% polysorbate 60 (Tween 60 from ICI) 1% stearic acid 1.4% triethanolamine 0.7% carbomer 0.4% liquid fraction of shea butter 12% perhydrosqualene 12% antioxidant 0.05% perfume, preservative qs water qs 100%

Example 3 A depigmenting gel for the skin is prepared, comprising (% by weight) :

α-phenyl-p-hydroxycinnamic acid 2% hydroxypropylcellulose (Klucel H from

Hercules) 1% antioxidant 0.05% isopropanol 40% perfume, preservative qs water qs 100%

Claims

1. Cosmetic use of at least one compound of formula (I) :

• 5 in which, n and m independently represent an integer between 0 and 5,

R, Ri and R₂ independently represent a hydrogen atom, or a group chosen from a linear or branched

10 C₁-C12 alkyl group, a C3-C8 cycloalkyl group, a linear or branched C2-C12 alkenyl group, a C₃-Cs cycloalkenyl group, a linear or branched C₂-C₁₂ alkynyl group, a group R3-CO-, a group R₄O-CO- and a> group RNH-CO-,

15 R₃ represents a linear or branched C₁-C₂₄ alkyl group, a C3-C₈ cycloalkyl group, an aryl group optionally substituted with one or more -0R₄, -SR₄, -COOR₄, -NR₄R₄, aryl or heteroaryl groups, R₄ represents a hydrogen atom, or a group chosen

20 from a linear or branched C₁-C₁₂ alkyl group, a C3-C8 cycloalkyl group, a linear or branched heteroalkyl group, a heterocycloalkyl group and an ^' arylalkyl group, it being possible for each of these groups to be optionally substituted with one

25 or more halogen atoms or -OR₅, -COOR₅ or -NR₅R₅ groups,-

R₅ represents a hydrogen atom or a linear or branched C1-C12 alkyl group or a C3-C₈ cycloalkyl group, in a composition, as an agent for removing brownish pigmented spots, senescence spots, ^' and/or as anti- bronzing agent for the skin,

it being understood that the term aryl denotes a phenyl or naphthyl group, the term heteroaryl denotes a mono- or bicyclic group containing at least one 5- to 11-membered aromatic ring, containing from 1 to 5 heteroato s chosen from nitrogen, oxygen and sulphur, the term heteroalkyl denotes a C1-C₁₂ alkyl group in which a carbon atom has been replaced by a heteroatom chosen from nitrogen, oxygen and sulphur, the term heterocycloalkyl denotes a 5- to 8- membered saturated cyclic group containing from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulphur, and that in the groups -NR₄R₄ or -NR5R5, the radicals R₄ or R5 are identical or different.

2. Use according to Claim 1, characterized in that n and are independently chosen from the integers 0 and 1, n and m cannot simultaneously represent 0.

3. Use according to either of Claims 1 and 2, characterized in that the group RiO is in the para position of the aromatic ring.

4. Use according to one of Claims 1 to 3 , characterized in that the group R0 is in the meta position of the aromatic ring.

5. Use according to one of Claims 1 to 4, characterized in that the group R represents a hydrogen atom.

6. Use according to one of Claims 1 to 5, characterized in that the group R₄ represents a linear or branched Ci-Cε alkyl group.

7. Use according to one of Claims 1 to 6, characterized in that the group R₅ represents a hydrogen atom or a linear or branched Ci-Cε alkyl group.

8. Use according to one of Claims 1 to 7 , characterized in that the compound of formula (I) is α- (m-hydroxyphenyl) -p-hydroxycinnamic acid.

9. Use according to one of Claims 1 to 8, characterized in that the compound of formula (I) is α-phenyl-p-hydroxycinnamic acid.

10. Cosmetic method for removing brownish pigmented spots and/or senescence spots from human skin, comprising the application to the skin, of a cosmetic composition containing at least one compound of formula (I) as defined in Claim 1.

11. Cosmetic method for lightening bronzed skin, comprising the application to the skin, of a cosmetic composition containing at least one compound of formula (I) as defined in Claim 1.