EP2542237A1

EP2542237A1 - Paraconic acids as pigmentation activators

Info

Publication number: EP2542237A1
Application number: EP11712967A
Authority: EP
Inventors: Joël BOUSTIE; Marie-Dominique Galibert-Anne; Françoise LOHEZIC-LE-DEVEHAT; Marylène CHOLLET-KRUGLER; Sophie Tomasi
Original assignee: Centre National de la Recherche Scientifique CNRS; Universite de Rennes 1
Current assignee: Centre National de la Recherche Scientifique CNRS; Universite de Rennes 1
Priority date: 2010-03-05
Filing date: 2011-03-04
Publication date: 2013-01-09
Also published as: KR20130043098A; CN103096886A; JP2013521331A; WO2011107720A1; US8816101B2; US20120329868A1; FR2957078A1; FR2957078B1

Abstract

The invention relates to a mixture including: protolichesterinic acid or one of the salts, diastereoisomers or derivatives thereof; and lichesterinic acid or one of the salts, enantiomers or derivatives thereof, to be used for stimulating the pigmentation of the skin and/or the hair and nails. The invention also relates to lichesterinic acid derivatives of formula (A).

Description

Paraconic acids as pigmentation activators

The invention relates to a mixture comprising protolichesterinic acid or a salt thereof or one of its diastereoisomers or a derivative thereof, and lichesterinic acid or a salt thereof or one of its enantiomers or one of its derivatives, for its use to stimulate the pigmentation of the skin and / or integuments.

The invention also relates to compounds of formula (A), and their use for stimulating pigmentation of the skin and / or superficial body growths.

The color of the human skin and its integuments (hair, nails, hair ...) is a function of various factors including seasons of the year, race, sex and age. It is mainly determined by the concentration of melanin produced by melanocytes. Melanocytes are specialized cells that, via particular organelles, melanosomes, synthesize melanin. It is known that in most populations the brown coloration of the skin or the maintenance of a constant coloration of the hair are important aspirations. There are also diseases of pigmentation, such as vitiligo which is an autoimmune disease and is characterized by the appearance of white patches on the skin related to a lack of pigmentation.

There is therefore a real need for a product that facilitates and / or improves the pigmentation of the skin and / or its integuments.

In this regard, many solutions in the field of artificial coloring have been made. Indeed, exogenous dyes have been synthesized and are intended to give the skin and / or hair a coloration as close as possible to the natural color.

Excellent results are certainly obtained by the solutions proposed in the prior art, but the fact remains that the stimulation of pigmentation of the skin or its integuments by the natural way (melanogenesis) remains the ideal way of pigmentation. The discovery of substances having an effect on the pigmentation of the skin or its integuments remains a major objective of research in this area.

Surprisingly, the inventors have now discovered that certain compounds derived from lichen stimulate the natural pathway of melanogenesis and thus promote the pigmentation of the skin or its integuments. Thus, the subject of the invention is a mixture comprising (i) protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, and (ii) lichesterinic acid or one of its salts or one of its enantiomers or one of its derivatives (hereinafter "mixture"), the weight ratio (i): (ii) being between 1: 4 and 4: 1 , for its use as a medicine.

In particular, the subject of the invention is a mixture comprising (i) protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, and (ii) acid lichestérique or a salt thereof or one of its enantiomers or a derivative thereof (hereinafter "mixture"), the weight ratio (i): (ii) being between 1: 4 and 4: 1, for its use to stimulate the pigmentation of the skin and / or integuments. Preferably, the mixture in the indicated weight ratio is used to treat hypopigmentary disorders. The invention also relates to the use of said mixture for preparing a medicament for stimulating pigmentation of the skin and / or integuments, preferably for treating hypopigmentary disorders.

The mixture according to the invention may further comprise dihydrolichesterinic acid, especially roccellaric acid. By "dander" is meant hair, hair and nails.

In the present application, the term "protolichesterinic acid" means (+) - protolichesterinic acid, and "lichesterinic acid" (+) - lichestérinique acid. (+) - protolichesterinic acid and (+) - lichesterinic acid are paraconic acids (ie having a β-substituted-acid-substituted β-methylene-γ-lactone ring) of respective formula (I) and (II) ) next :

These compounds are extracted from lichens, and in particular lichen Cetraria islandica Ach. or lichen from Iceland.

The (+) - protolichesterinic acid (formula (I)) is of 4S, 5R configuration thanks to the two asymmetric carbons at the 4 and 5 ring positions.

The (+) - lichesterinic acid (formula (II)) is of 5R configuration thanks to the asymmetric carbon at the 5-position of the ring, the double bond is of the endo type.

The term "salts" of protolichesterinic acid or lichesterinic acid means the salts of these compounds with alkali metals such as sodium, potassium or lithium, but also the salts of these compounds with ammonium ions.

By "diastereoisomers" of protolichesterinic acid is meant in particular the 4R, 5S diastereoisomer of protolichesterinic acid. By "enantiomer" of lichesterinic acid is meant the 5S enantiomeric derivative of lichesterinic acid.

By "derivatives" of protolichesterinic acid or lichesterinic acid is meant the esters of these compounds with methanol or ethanol, but also the following compounds of formula (A), their salts and their enantiomers:

(A) wherein R ⁴ represents a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, an unsubstituted phenyl radical (Ph), a radical unsubstituted phenethyl (PhCH ₂ CH ₂ ) or the COOR group where R = Na, K, Li, NH ₄ , H, methyl or ethyl,

and R ⁵ is selected from hydrogen, C 1 -C 6 alkyl; ₃ linear or branched, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ , provided that when R ⁴ represents COOH, then R ⁵ is different from the linear alkyl radical C- | ₃ H ₂₇ .

In the present invention, unless otherwise stated, "alkyl radical having 1 to 6 carbon atoms" means methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl and i-butyl. Preferably, the alkyl radical having 1 to 6 carbon atoms is an n-butyl radical.

The term "linear or branched C1-C13 alkyl radical" means an alkyl radical having from 1 to 13 linear or branched carbon atoms, such as in particular the pentyl, nonyl or tridecyl radicals.

The mixture according to the invention is used to stimulate the pigmentation of the skin and / or superficial body growths. Preferably, the mixture according to the invention is used to treat hypopigmentary disorders.

Hypopigmentary disorders preferably include vitiligo, genetic hypopigmentary diseases, pityriasis versicolor, post-inflammatory hypopigmentations, hypopigmentations or depigmentations due to skin grafts, photoinduced hypopigmentations or depigmentations, hypopigmentations or depigmentations post -Treatment, hypopigmentations or depigmentation due to aging and hair depigmentation.

Vitiligo is characterized by the appearance of white spots on the skin. There are two main forms: the "generalized" form is characterized by plates approximately symmetrical about the median axis of the body and represents almost nine tenths of the cases. The segmental shape is a little more common in children, especially in the face, with a faster progression. In late stages, a depigmentation of hair or hair can be seen. This disease does not cause physical pain but can pose aesthetic contrarieties. Genetic hypopigmentary diseases include albinism, piebaldism (characterized by a frontal white lock) or the Xeroderma pigmentosum.

Albinism is a genetic disease characterized by an absence of pigmentation of the skin, hair, hair, eyes, due to the absence of melanin. This disease is known in several possible forms: partial albinism (ocular albinism) or total albinism (oculocutaneous albinism). Albinos have deficient vision and are prone to skin cancer if they are not protected from the sun.

Piebaldism is a rare autosomal dominant disease. It is characterized by a triangular or frontal rhombic achrome with a frontal white wick.

Xeroderma pigmentosum, or "Moon child" disease, is an autosomal rare genetic disease that affects approximately 3,000 to 4,000 people worldwide. This epitheliomatous pigmentary disease that develops during childhood increases the risk of multiple skin cancers by a factor of 1,000. Children with this condition are extremely sensitive to sunlight and can only survive at the cost of extreme caution.

Pityriasis versicolor is a benign and frequent condition caused by the overgrowth of a fungus that belongs to the yeast group of the genus Malassezia. Yeasts of the genus Malassezia reside on the surface of normal human skin and may, in some patients, cause pityriasis versicolor, which results in pigmented or depigmented spots on the trunk.

Post-inflammatory hypopigmentations follow certain inflammatory conditions (especially bullous dermatoses), burns and skin infections, and appear on scars and atrophic skin areas. Although the pigmentation is diminished, the skin is not necessarily ivory white and may end up repigulating spontaneously. Preferably, the hypopigmentary disorder is vitiligo. The mixture according to the invention comprises (i) protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, and (ii) lichesterinic acid or one of of its salts or one of its enantiomers or one of its derivatives, in a respective weight ratio (i): (ii) of between 1: 4 and 4: 1, preferably of between 2: 3 and 3: 1, more preferably between 1: 1 and 5: 2.

Preferably, the mixture according to the invention comprises from 20 to 80% by weight relative to the total weight of the mixture of protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, preferably from 40% to 60% by weight.

Preferably, the mixture according to the invention comprises from 20 to 80% by weight relative to the total weight of the mixture of lichesterinic acid or one of its salts or one of its enantiomers or one of its derivatives, preferably from 40% to 60% by weight.

The specific weight ratios of protolichesterinic acid, its salt, its diastereoisomer or its derivative and lichesterinic acid, its salt, its enantiomer or its derivative, as described above, have a synergistic effect stimulating the pigmentation of the skin and / or superficial body growths, as demonstrated in Example 1.

By "synergistic effect" or "synergy" is meant that the mixture of protolichesterinic acid, its salt, its diastereoisomer or its derivative and lichesterinic acid, its salt, its enantiomer or its derivative according to the invention, has an activity pigmenting greater than the sum of the pigmenting activity of each compound taken alone. Preferably, the mixture according to the invention comprises protolichesterinic acid and lichesterinic acid.

When the mixture comprises dihydrolichesterinic acid, it comprises this acid in an amount of between 1 and 15% by weight relative to the total weight of the mixture, preferably between 3 and 10% by weight, of preferably between 3 and 7% by weight relative to the total weight of the mixture.

Preferably, the mixture according to the invention comprises protolichesterinic acid, lichesterinic acid and dihydrolichesterinic acid.

Preferably, the mixture according to the invention consists of 50 to 70% of protolichesterinic acid, 20 to 40% of lichesteric acid, and 3 to 10% of dihydrolichesterinic acid, the percentages being expressed by weight by weight. relative to the total weight of the mixture.

The mixture according to the invention may be administered by means of a composition orally, systemically or topically by application to the skin and / or superficial body growths.

Depending on the mode of administration, the composition comprising the mixture according to the invention may be in any galenic form.

Preferably, the mixture according to the invention is included in a composition which is administered topically to the skin and / or the superficial body growths. The protolichesterinic acid, its salt, its diastereoisomer or its derivative according to the invention, and the lichesterinic acid, its salt, its enantiomer or its derivative according to the invention may be packaged together in the same composition, or separately in the form of a kit whose components will be mixed extemporaneously.

Orally, the compositions may be in the form of tablets, capsules, lozenges, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release.

For topical application to the skin, the composition may have the form in particular of aqueous or oily solution or of dispersion of the lotion or serum type; emulsion of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O); emulsion of soft consistency of the cream type; of gel aqueous or anhydrous; or else microcapsules or microparticles, or vesicular dispersions of ionic and / or nonionic type. These compositions are prepared according to the usual methods known to those skilled in the art. For topical application to the hair, the composition may be in the form of aqueous, alcoholic or hydroalcoholic solutions; gels; emulsions; mosses; or in the form of aerosol compositions also comprising a propellant under pressure. The composition according to the invention may also be a hair care composition, and especially a shampoo, a treatment lotion, a cream or a styling gel, or a lotion or a fall protection gel.

For systemic application, the composition may be in the form of an aqueous or oily solution or in the form of serum.

The composition comprising the mixture according to the invention may comprise in particular a fatty phase, an emulsifier, a solvent, a propenetrant or a gelling agent (lipophilic or hydrophilic). When the composition comprises a fatty phase, the latter comprises at least one oil or a wax.

As oils or waxes that can be used in the invention, mention may be made of mineral oils (vaseline oil), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils ( Purcellin oil), silicone oils or waxes (cyclomethicone), fluorinated oils (perfluoropolyethers), beeswax, carnauba or paraffin waxes, as well as fatty alcohols and fatty acids (stearic acid).

The composition may also comprise at least one emulsifier. This emulsifier may be anionic, cationic, nonionic or amphoteric.

Suitable solvents according to the invention include lower alcohols, especially ethanol and isopropanol, and propylene glycols. As propenetrants that can be used according to the invention, mention may be made of glycols, in particular 1,2-propanediol (or propylene glycol) and polyethylene glycols. As hydrophilic gelling agents that may be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, ethylcellulose or polyethylene.

According to the invention, the composition may associate the mixture with other active agents.

Among these active agents, there may be mentioned by way of example:

self-tanning agents such as dihydroxyacetone (DHA) or erythrulose;

agents which improve the activity on regrowth and / or on the braking of hair loss, and which have already been described for this activity, for example minoxidil, aminexil or nicotinic acid esters, in particular the tocopherol nicotinate, benzyl nicotinate and C1-C6 alkyl nicotinates such as methyl or hexyl nicotinates;

steroidal anti-inflammatory agents, such as hydrocortisone, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as, for example, ibuprofen and its salts, diclofenac and its salts, acid acetylsalicylic acid, acetaminophen or glycyrrhizic acid;

antifungal agents such as ketoconazole, selenium sulphide, itraconazole or fluconazole;

antipruritic agents such as thenaldine, trimeprazine or cyproheptadine.

The composition may also include conventional adjuvants, such as preservatives, antioxidants, fragrances, fillers, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used, and for example from 0.01% to 20% by weight relative to the total weight of the composition.

In addition to the above mixture and its applications, the invention also relates to an ormule (A), its salt or its enantiomer:

(A) wherein R ⁴ represents a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, an unsubstituted phenyl radical, an unsubstituted phenethyl radical or a COOR group where R = Na, K, Li or NH ₄ , H, methyl or ethyl,

Being heard that :

when R ⁴ represents a hydrogen atom, then R ⁵ is chosen from a linear or branched C ₁₀ or C ₁₂ alkyl radical, CH ₂ C≡CH and (CH ₂ ) i ₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, preferably an n-butyl radical, then R ⁵ is chosen from a C ₂ alkyl radical,

Linear or branched C ₃ or C ₅ to C ₁₃ , CH ₂ CCH, Ph, PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an unsubstituted phenethyl radical, then R ⁵ is chosen from H, a C 1 -C 6 alkyl radical; ₃ linear or branched, CH ₂ CCH, Ph, PhCH ₂ ,

PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an unsubstituted phenyl radical, then R ⁵ is chosen from a C ₃ to C ₆ alkyl radical; ₃ linear or branched, CH ₂ CCH, Ph, PhCH ₂ ,

when R ⁴ represents COONa, then R ⁵ is chosen from H, a linear or branched C ₁ to C ₁₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents COOH, then R ⁵ is chosen from a C ₂ alkyl radical

C ₄ or C _6, C _7, C _9, C-io or C ₂ linear or branched, CH ₂ CCH, Ph, PhCH _2,

PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ or OH; when R ⁴ represents COOCH ₃ , then R ⁵ is chosen from a linear or branched C ₂ -C ₄ or C ₆ -C 12 alkyl radical, CH ₂ CCH, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ or OH; and

when R ⁴ represents COOCH ₂ CH ₃ , then R ⁵ is chosen from a linear or branched C ₂ -C ₁₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ .

Such compounds may be incorporated into a pharmaceutical composition; also the subject of the invention is a pharmaceutical composition comprising, in a physiologically acceptable vehicle, at least one such compound.

By "physiologically acceptable vehicle" is meant a vehicle compatible with the skin, the mucous membranes and the integuments. Preferably, the compound of formula (A), its salt or its enantiomer has the following structure:

Being heard that :

when R ⁴ represents a hydrogen atom, then R ⁵ is chosen from a linear or branched C ₁₀ or C ₁₂ alkyl radical, CH ₂ C≡CH and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, preferably an n-butyl radical, then R ⁵ is chosen from a linear or branched C ₂ , C ₃ or C ₅ to C ₁₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ; when R ⁴ represents an unsubstituted phenethyl radical, then R ⁵ is chosen from H, a linear or branched C 1 to C ₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH _3, OH or CH _3;

when R ⁴ represents an unsubstituted phenyl, then R ⁵ is selected from linear alkyl, C ₃ d ₃ or branched, CH ₂ CCH, Ph, PhCH _2, PhCH ₂ CH ₂ and (CH ₂₎ ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents COONa, then R ⁵ is chosen from H, a linear or branched d-C13 alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents COOH, then R ⁵ is chosen from a linear or branched C ₂ -C ₄ or C ₆ , C _7, C ₉ , C ₁₂ or C ₁₂ alkyl radical, CH ₂ CCH, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ or OH, preferably R ⁵ is selected from CH ₂ CCH and (CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ or OH;

when R ⁴ represents COOCH ₃ , then R ⁵ is chosen from a linear or branched C ₂ -C ₄ or C ₆ -C ₁₂ alkyl radical, CH ₂ CCH, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ or OH, preferably R ⁵ is selected from CH ₂ CCH (CH ₂₎ ₁₃ COR ⁶ where R ⁶ = OCH ₃ or OH; and

The subject of the invention is also a compound of formula (A), its salt or its enantiomer, in which R ⁴ represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, in particular an n-butyl radical. an unsubstituted phenyl radical, an unsubstituted phenethyl radical or the COOR group where R = Na, K, Li, NH ₄ , H, methyl or ethyl,

and R ⁵ is chosen from a hydrogen atom, a linear or branched C 1 to C ₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ,

it being understood that when R ⁴ represents COOH, then R ⁵ is different from the linear alkyl radical d ₃ H ₂₇ , for its use as a medicine. Preferably, such a derivative is used to stimulate the pigmentation of the skin and / or superficial body growths.

Several processes will be envisaged depending on the nature of the radicals R ⁴ and R ⁵ of the compounds of formula (A). The process below describes both the enantioselective synthesis of the compounds of formula (A) but also the synthesis of the corresponding protolichesterin derivative with R ⁴ = COOR where R = Na, H, CH ₃ or C ₂ H ₅ and R ⁵ = linear or branched C -C alkyl radical: This is an enantioselective synthesis in 8 steps of which the first 6 (af steps) are described by S. Braukmuller and R. Bruckner, Eur. J. Org. Chem. 2006, 21 10-21 18. Enantiocontrol is imposed by steps b and d.

Condensation of the aldehyde on methyl hydrogenalalonate (step a) results in a trans-3, γ-unsaturated carboxylic ester. Asymmetric dihydroxylation of Sharpless makes it possible to obtain an β-hydroxy-γ-lactone enantiopure (step b). After dehydration (step c) and a selective frans-addition of tris (methylthio) methane (step d), the compound is converted to paraconic acid (step e). The a-activation in the presence of magnesium methyl carbonate followed by a decarboxylative methylenation leads to the derivative of (+) or (-) protolichesterinic acid (step f). Esterification (step g) followed by isomerization of the exo double bond endo in the presence of catalytic amount of rhodium chloride leads to certain derivatives of formula (A) (step h).

a) HOOCCH2CO2C2H5 (1 eq), NEt ₃ (1.0 eq), 90 ° C, 3 h; b) AD mix-α® or AD mix-β®, MeSO ₂ NH ₂ (1.0 eq), f-BuOH / H ₂ O (1: 1), 0 ° C, 40 h;

c) MsCl (1.1 eq), NEt ₃ (2.1 eq), CH ₂ Cl ₂ , 0 ° C, 15 min;

d) HC (SMe) ₃ (1.1 eq), THF, -78 ° C, nBuLi (1.1 eq), 2-2.5 h; addition of furanone, 1.5-2 h;

e) HgO (5.0 eq), THF / H ₂ O (4: 1), BF ₃ and ₂ (15 eq), TA 2.5 h;

f) (i) MeOMg [O (C = O) Ω] (38 eq) in DMF, 135-140 ° C, 70 h, crude isolation; (ii) crude, HOAc / NaOAc / formalin (= 35-40% aq., Solution of formaldehyde) / N-methylaniline (excess, 4: 0.03: 3: 1), TA. 2 h;

g) CH ₃ OH (1.0 eq) or C ₂ H ₅ OH (1.0 eq), H ₂ SO ₄ (1 eq), CH ₂ CI ₂ , 18 h;

h) if R = H: NEt ₃ , DMF, 18h, if R = CH ₃ , C ₂ H ₅ : RhCl ₃ , x H ₂ O (0.1 eq), EtOH / H ₂ O (10: 1), 65 ° C, 18h.

The subject of the invention is also the cosmetic use of a mixture comprising (i) protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, and (ii) lichesterinic acid or one of its salts or one of its enantiomers or a derivative thereof, in a weight ratio (i): (ii) of between 1: 4 and 4: 1, as agent to stimulate the pigmentation of the skin and / or integuments.

The invention finally relates to the cosmetic use of a compound of formula (A) as an agent for stimulating the pigmentation of the skin and / or integuments. Of course, those skilled in the art are careful not to introduce compounds into the composition used in the present invention in such a way that they contravene the desired technical effect of the present invention. Examples will now be given by way of illustration which can not in any way limit the scope of the invention.

EXAMPLE 1 In Vitro Pigmenting Activity of the Protolesterinic Acid (APL (+)) and Lichestheric Acid (AL (+)) Mixture Protocol: The melanin content of murine B16 cells is determined spectrophotometrically.

The cells are seeded in a 10 cm Petri dish at a density of 1 × 10 ⁶ per dish and are treated every 24 hours for 72 hours, with the defined dose of purified lichenic molecule solubilized in DMSO. After dilution, the final concentration of DMSO does not exceed 0.1%, which corresponds to the indicated control solution DMSO in FIG. After treatment, the cells are washed twice with PBS and recovered by treatment with trypsin. The number of cells recovered is estimated by counting using a hemocytometer. A fraction is used to determine the melanin content and a second for the protein concentration. The melanin content is determined by the absorbance at 405 nm (VersaMax Microplate Reader, Molecular Devices, USA) of the cell solution after solubilization of melanine with 1 M sodium hydroxide, for 15 min at 80 ° C. The protein concentration is determined according to the protocol of the "DC Protein Assay" kit developed by Bio-Rad Laboratories, USA. For each sample treated, the melanin content is related to the amount of protein and expressed as a percentage of the control situation (DMSO solution alone). Each measurement is performed in triplicate and each experiment is performed independently a minimum of 3 times.

Figure 1 summarizes the results. This FIG. 1 shows the melanin content of the B16 cells treated for 72 h in the presence of purified (APL (+) and AL (+)) or semi-purified lichenic molecules (precipitate = APL / AL / roccellaric acid mixture, hereinafter ADL : 65/30/5 by weight, therefore weight ratio of 13: 6: 1) and a positive control, glycyrrhizic acid

On the abscissa are the molecules tested with their concentrations expressed in μΜ.

On the ordinate, the melanin content is expressed as a percentage relative to the control (DMSO alone = concentration of 0.1%). The results show that:

- protolichesterinic acid alone at 0.5μΜ has a depigmenting effect (72% pigmentation compared to the control, ie 28% depigmentation);

- lichesterinic acid alone at 5μΜ has a moderate pro-pigmenting effect (26% pigmentation);

- the mixture of protolichesterinic acid and lichesterinic acid has a significant pro-pigmenting effect (85% pigmentation), which is opposite to that of protolichesterinic acid alone, and 3 to 4 times greater than that of the lichesterinic acid alone.

The results obtained thus demonstrate the synergistic activity of the mixture according to the invention.

EXAMPLE 2 In Vitro Evaluation of the Tyrosinase Activity Induced by the Mixture of Protolesteresteric Acid and Lichesterinic Acid

Protocol: The enzymatic activity of the endogenous tyrosinase enzyme is determined by the measurement at 450 nm of the amount of DOPA substrate oxidized to DOPAchrome. As before, the cells are inoculated in a 10 cm Petri dish at a density of 1 × 10 ⁶ per dish and are treated every 24 hours for 72 hours, with the defined dose of purified lichenic molecule solubilized in DMSO. After dilution, the final concentration of DMSO does not exceed 0.1%, which corresponds to the control solution where no product has been added. After treatment, the cells are washed twice with PBS and recovered by treatment with trypsin. The number of cells recovered is estimated by counting using a hemocytometer. Lysis of the cells is obtained by adding a solution of Triton X-100 (1% in 1 × PBS). One milliliter of a solution of L-DOPA (1 ml to 10 mM), prepared extemporaneously is added to each sample of cell lysate (400 μΙ) and incubated in the dark at 37 ° C on a time kinetics of 30 min to 8 h . The amount of DOPAchrome formed is measured spectrophotometrically at 450nm (Labsystems multiskan RC). The amount of DOPAchrome formed correlates with the enzymatic activity of the tyrosinase enzyme. Each measurement is carried out in tnplicata and each experiment is performed independently a minimum of 3 times.

Figure 2 summarizes the results. This FIG. 2 corresponds to the measurement of the enzymatic activity of the endogenous tyrosinase enzyme in the presence of lichesteric acid, of the APL / AL / ADL mixture: 65/30/5 - weight ratio of 13: 6: 1 - ( = mixture), glycyrrhizic acid (positive control) and with the dilution solvent alone (= control).

The abscissa shows the contact time of the products before the measurement of DOPAchrome formed for each of the tests.

On the ordinate, the percentage of DOPAchrome generated relative to the control (DMSO alone at 0.1%), reflects the enzymatic activity of tyrosinase.

For each time (30min, 1h, 4h and 8h), the first histograms correspond to the control, the second to the glycyrrhizic acid, the third to the mixture APL / AL / ADL (65/30/5), and the fourth to lichesterinic acid alone.

EXAMPLE 3 Formulation according to the invention

A mixture of protolichesterinic acid, lichesterinic acid and dihydrolichesterinic acid (or roccelaric acid) is prepared in a respective weight ratio of 13: 6: 1.

This mixture is incorporated in propylene glycol (or 1, 2-propanediol) at a final concentration of 50μΜ.

Claims

A mixture comprising (i) protolichesterinic acid or a salt thereof or a diastereoisomer thereof or a derivative thereof, and (ii) lichesterinic acid or a salt thereof, or one of its enantiomers or one of its derivatives, in a weight ratio (i): (ii) of between 1: 4 and 4: 1, for its use as a medicament.

Mixture according to claim 1, for its use to stimulate the pigmentation of the skin and / or superficial body growths.

Mixture according to claim 1 or 2, characterized in that the weight ratio (i): (ii) is between 2: 3 and 3: 1, more preferably between 1: 1 and 5: 2.

Mixture according to one of claims 1 to 3, characterized in that it comprises (i) protolichesterinic acid or its sodium salt, its potassium salt, its lithium salt, its ammonium salt, or its diastereoisomer 4R, 5S or a derivative thereof, and (ii) lichesterinic acid or its sodium salt, its potassium salt, its lithium salt, its ammonium salt, or its 5S enantiomer or the one of its derivatives.

Mixture according to one of claims 1 to 4, characterized in that it comprises protolichestérinique acid and lichestérinique acid.

Mixture according to one of claims 1 to 5, characterized in that it further comprises dihydrolichesterinic acid.

Mixture according to one of claims 1 to 6, for its use in the treatment of a disorder chosen from vitiligo, genetic hypopigmentary diseases, pityriasis versicolor, post-inflammatory hypopigmentations, hypopigmentations or depigmentations due to transplants. skin, photo-induced hypopigmentation or depigmentation, post-scarring hypopigmentations or depigmentations, hypopigmentations or depigmentation due to aging and hair depigmentation.

Cosmetic use of a mixture comprising (i) protolichesterinic acid or one of its salts or one of its diastereoisomers or one of its derivatives, and (ii) lichesterinic acid or one of its salts or one of its enantiomers or one of its derivatives, in a weight ratio of between 1: 4 and 4: 1, as agent for stimulating pigmentation of the skin and / or superficial body growths.

Compound chosen from the compounds of the following formula (A), their salts

in which R ⁴ represents a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, an unsubstituted phenyl radical, an unsubstituted phenethyl radical or a COOR group in which R = Na, K or Li or NH ₄ , H, methyl or ethyl,

Being heard that :

when R ⁴ represents a hydrogen atom, then R ⁵ is chosen from a linear or branched C ₁₂ or C ₁₂ alkyl radical, CH ₂ CCH and (CH ₂ ) i ₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, preferably an n-butyl radical, then R ⁵ is chosen from a linear or branched C ₂ , C ₃ or C ₅ to C ₁₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents an unsubstituted phenethyl radical, then R ⁵ is chosen from H, a linear or branched C 1 to C ₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH _3, OH or CH _3;

when R ⁴ represents an unsubstituted phenyl, then R ⁵ is selected from linear alkyl, C ₃ d ₃ or branched, CH ₂ CCH, Ph, PhCH _2, PhCH ₂ CH ₂ and (CH ₂₎ ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ ; when R ⁴ represents COONa, then R ⁵ is chosen from H, a linear or branched d-C13 alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and

(CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ , OH or CH ₃ ;

when R ⁴ represents COOH, then R ⁵ is chosen from a linear or branched C ₂ -C ₄ or C ₆ , C ₇ , C ₉ , C ₁₀ or C ₁₂ alkyl radical, CH ₂ CCH, PhCH ₂ ,

PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ or OH;

when R ⁴ represents COOCH ₃ , then R ⁵ is selected from an alkyl radical

C ₂ to C ₄ or C ₆ to C 12 linear or branched, CH ₂ CCH, PhCH ₂ , PhCH ₂ CH ₂ and

(CH ₂ ) ₁₃ COR ⁶ wherein R ⁶ = OCH ₃ or OH; and

when R ⁴ represents COOCH ₂ CH ₃ , then R ⁵ is chosen from a linear or branched C ₂ -C ₁₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and

(CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ .

10. Compound according to claim 9, characterized in that the alkyl radical having 1 to 6 carbon atoms is chosen from methyl, ethyl, isopropyl, n-propyl, n-butyl, i-butyl and t-butyl radicals, preferably an n-butyl radical.

1 1. A pharmaceutical composition comprising, in a physiologically acceptable vehicle, at least one compound according to claim 9 or 10.

12. Compound chosen from the derivatives of formula (A), their salts and their enantiomers:

(A) wherein R ⁴ represents a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, an unsubstituted phenyl radical, an unsubstituted phenethyl radical or the COOR group, where R = Na, K, Li , NH ₄ , H, methyl or ethyl,

and R ⁵ is chosen from a hydrogen atom, a linear or branched C 1 to C ₃ alkyl radical, CH ₂ CCH, Ph, PhCH ₂ , PhCH ₂ CH ₂ and (CH ₂ ) ₁₃ COR ⁶ where R ⁶ = OCH ₃ , OH or CH ₃ , it being understood that when R ⁴ represents COOH, then R ⁵ is different from the linear alkyl radical C-13H27,

for its use as a medicine. 13. Compound according to claim 12 for its use to stimulate the pigmentation of the skin and / or superficial body growths.

14. Cosmetic use of a compound according to one of claims 9 or 10 as an agent for stimulating the pigmentation of the skin and / or superficial body growths.