WO2013190483A1

WO2013190483A1 - Novel resorcinol derivatives and their cosmetic applications

Info

Publication number: WO2013190483A1
Application number: PCT/IB2013/055028
Authority: WO
Inventors: Xavier Marat
Original assignee: L'oreal
Priority date: 2012-06-19
Filing date: 2013-06-19
Publication date: 2013-12-27
Also published as: FR2991986B1; IN2014KN02723A; FR2991986A1

Abstract

The present invention relates to novel compounds which are resorcinol derivatives of general formula (I): in which: R denotes a hydrogen atom or an acetyl group; A denotes an optionally interrupted and/or substituted alkyl group; an optionally substituted aryl or heteroaryl group; -NR2R3; -OR4; -C(0)NHR4; and - C(0)alkyl; R2 and R3, which are identical or different, denoting a radical chosen from: -H; an optionally interrupted and/or substituted alkyl group; and an optionally substituted aryl or heteroaryl group; it being possible for R2 and R3 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic and optionally substituted heterocycle; R4 denoting a radical chosen from: -H; an optionally substituted alkyl group; and an optionally substituted aryl or heteroaryl group; and to a cosmetic treatment method, in particular for depigmenting and/or whitening the skin, employing such a compound.

Description

"Novel resorcinol derivatives and their cosmetic applications"

The present invention relates to novel compounds derived from resorcinol and to a cosmetic treatment method, in particular for depigmenting and/or whitening the skin, employing such a compound.

At different periods in their lives, some people witness the appearance on the skin and more especially on the hands and face of darker and/or more highly coloured blemishes which give the skin a heterogeneous appearance. These blemishes are due in particular to a high concentration of melanin in the keratinocytes situated at the surface of the skin.

The use of inoffensive topical depigmenting substances which are highly effective is very particularly sought after with a view to treating pigment blemishes.

The mechanism of formation of the pigmentation of the skin, that is to say of the formation of melanin, is particularly complex and involves, schematically, the fo Ho wing main stages :

Tyrosine— > Dopa— > Dopaquinone— > Dopachrome— > Melanin

Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this sequence of reactions. In particular, it catalyses the conversion reaction of tyrosine to give Dopa (dihydroxyphenylalanine), by virtue of its hydroxylase activity, and the conversion reaction of Dopa to give dopaquinone, by virtue of its oxidase activity. This tyrosinase only acts when it is in the maturation state under the effect of certain biological factors.

A substance is recognised as depigmenting if it acts directly on the vitality of the epidermal melanocytes where melanogenesis takes place and/or if it interferes with one of the stages of the biosynthesis of melanin, either by inhibiting one of the enzymes involved in melanogenesis or by being inserted as structural analogue of one of the chemical compounds in the sequence for the synthesis of melanin, which sequence can then be blocked and thus ensure depigmentation.

Thus, for exemple document Young Mi Ha et al. Med. Chem. Commun., 2011, 2, discloses 542 hydroxybenzylidenyl pyrrolidine-2,5-diones as depigmenting agents for the skin.

Arbutin and kojic acid are known as depigmenting agents for the skin. Substances have been sought which exhibit an effective depigmenting action, in particular superior to that of arbutin and kojic acid.

In this regard, the Applicant Company has discovered, surprisingly and unexpectedly, that some compounds derived from resorcinol exhibit a good depigmenting activity, even at low concentration.

A subject-matter of the invention is thus novel compounds of formula (I) as defined below.

Another subject-matter of the invention is a composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined below.

Another subject-matter of the invention is a non-therapeutic cosmetic method for depigmenting, lightening and/or whitening keratinous substances, in particular the skin, comprising the application of the composition described above.

More preferably, it is the method for depigmenting, lightening and/or whitening the skin.

The invention also relates to the non-therapeutic cosmetic use of a compound of formula (I) as whitening, lightening and/or depigmenting agent for keratinous substances, in particular the skin.

The compounds according to the invention make it possible to effectively depigment and/or lighten, indeed even to whiten, the skin of human beings. They are in particular intended to be applied to the skin of individuals exhibiting brownish pigmentation blemishes or blemishes due to ageing or to the skin of individuals desiring to combat the appearance of a brownish colour originating from melanogenesis.

The can also make it possible to depigment and/or lighten non-scalp hair, the eyelashes or the hair, and also the lips and/or the nails.

A subject-matter of the invention is thus novel compounds of formula (I) as follows:

in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) -H;

b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C₂-C₂o)alkyl group, a branched (C₃-C₂o)alkyl group or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5,

ii) -SR5,

iii) -NR6R7,

iv) -C(0)NHR6,

v) -C(0)NR6R7,

vi) -C(0)OR6,

vii) -NHC(0)NHR6,

viii) -C(0)(Ci-C₄)alkyl,

ix) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group,

x) a saturated or unsaturated nonaromatic heterocycle, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C₄)alkyl group; and

xi) -NH-C=NH(NH₂) (guanidine group);

c) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci- C₈)alkyl group;

d) -NR2R3;

e) -OR4;

f) -C(0)NHR4;

and g) -C(0)(Ci-Cio)alkyl;

R2 and R3, which are identical or different, denoting a radical chosen from:

• -H,

• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different -OR5 groups, and

• an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;

it being possible for R2 and R3 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci- C₄)alkoxy group;

R4 denoting a radical chosen from:

• -H,

• a saturated linear (Ci-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

vi) -C(0)OR6, and

ix) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and

· an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;

R5 being chosen from

• -H, and

• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group;

R6 and R7, which are identical or different, being chosen from

• -H, • a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group,

• a phenyl(Ci-C₄)alkyl group, such as a benzyl group, or a pyridyl(Ci- C₄)alkyl group, and

· an acetyl radical;

it being possible for R6 and R7 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group;

and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.

In a specific embodiment, A is not a hydrogen atom.

In one embodiment, the invention relates to the compounds of formula (I) as defined above, with the exception of the compound 4-(pyrrolidin-3-ylmethyl)benzene-l ,3- diol.

The salts of the compounds of formula (I) comprise conventional non-toxic salts of the said compounds, such as those formed from acid or base.

Mention may be made, as salts of the compound of formula (I) (when it comprises a quaternizable nitrogen atom), of:

a) the salts obtained by addition of the compound (I) to an inorganic acid, chosen in particular from hydrochloric, boric, hydrobromic, hydriodic, sulfuric, nitric, carbonic, phosphoric or tetrafluoroboric acid;

b) or the salts obtained by addition of the compound (I) to an organic acid, chosen in particular from acetic, propionic, succinic, fumaric, lactic, gly colic, citric, gluconic, salicylic, tartaric, terephthalic, methylsulfonic, ethylsulfonic, benzenesulfonic, toluenesulfonic or triflic acid.

Mention may also be made of the salts obtained by addition of the compound of formula (I) (when it comprises an acid group) to an inorganic base, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and the carbonates or hydrogencarbonates of sodium, of potassium or of calcium, for example, or to an organic base, such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. This primary, secondary or tertiary alkylamine can comprise one or more nitrogen and/or oxygen atoms and can thus comprise, for example, one or more alcohol functional groups; mention may in particular be made of 2-amino-2-methylpropanol, ethanolamine, triethanolamine, 2- (dimethylamino)propanol, 2-amino-2-(hydroxymethyl)- 1 ,3 -propanediol or 3- (dimethy lamino)propy lamine .

Mention may also be made of the salts of amino acids, such as, for example, lysine, arginine, guanidine, glutamic acid or aspartic acid. Advantageously, the salts of the compound of formula (I) (when it comprises an acid group) can be chosen from alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium; or ammonium salts.

Advantageously, the salts of the compound of formula (I) (when it comprises a quaternizable nitrogen atom) can be chosen from halides, such as chloride or bromide, citrate, acetate, succinate, phosphate, lactate or tartrate.

The acceptable solvates of the compounds described in the present invention comprise conventional solvates, such as those formed during the preparation of the said compounds due to the presence of solvents. Mention may be made, by way of example, of the solvates due to the presence of water or of linear or branched alcohols, such as ethanol or isopropanol.

The optical isomers are in particular enantiomers and diastereoisomers.

In the context of the present invention:

a "(C_x-C_y)alkyl group" denotes an alkyl group comprising from x to y carbon atoms. Such an alkyl group can be linear and saturated and can typically include from 1 to 20 carbon atoms or also from 1 to 10 carbon atoms. It can also be linear and unsaturated and can typically include from 2 to 20 carbon atoms or also from 2 to 10 carbon atoms. It can also be branched and can typically include from 3 to 20 carbon atoms or also from 3 to 10 carbon atoms. An alkyl group can also be cyclic; it is then a cycloalkyl group, which can typically include from 3 to 8 carbon atoms.

Unless otherwise indicated, a "(C_x-C_y)alkyl group" denotes a saturated and linear alkyl group comprising from x to y carbon atoms. Preferably, the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.

More preferably, the branched or saturated linear alkyl groups can be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2- ethylhexyl and octyl.

The cycloalkyl group can be chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

- A "(C_x-C_y)alkoxy group" denotes a linear and if appropriate branched group of formula -0(C_x-C_y)alkyl which can typically include from 1 to 8 carbon atoms or also from 1 to 4 carbon atoms.

The alkoxy group can be chosen from methoxy, ethoxy, propoxy and butoxy and can more particularly be a methoxy group.

- A "saturated or unsaturated nonaromatic heterocycle group" denotes a monocyclic or bicyclic carbocyclic group having from 5 to 8 ring members and comprising from one to three heteroatoms or groups chosen from N, O, S and -C(O)-.

A heterocycle group can be chosen from dihydrothiazolyl, piperidyl, morpholinyl, piperazinyl and pyrrolidinyl. Preferably, it is the piperidyl or morpholinyl ring.

- An "aryl group" denotes an unsaturated or partially unsaturated monocyclic or bicyclic carbocyclic group including from 5 to 12 carbon atoms.

The aryl radicals can be chosen from phenyl, naphthyl, indenyl, fluorenyl and anthracenyl. Preferably, it is the phenyl group.

- A "heteroaryl group" denotes a fused or nonfused poly- or monocyclic group comprising from 5 to 22 ring members and from 1 to 6 heteroatoms chosen from a nitrogen, oxygen or sulfur atom, at least one ring of which is aromatic.

The heteroaryl radicals can be chosen from furyl, acridinyl, benzimidazolyl, benzobistriazolyl, benzopyrazolyl, benzopyridazinyl, benzoquinolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, pyridinyl, imidazopyridinyl, imidazolyl, indolyl, isoquinolyl, naphtho imidazolyl, naphthooxazolyl, naphthopyrazolyl, oxadiazolyl, oxazolyl, oxazolopyridyl, phenazinyl, phenooxazolyl, pyrazinyl, pyrazolyl, pyrazoyltriazyl, pyridyl, pyridinoimidazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolopyridinyl, thiazoylimidazolyl, thiopyrylyl, triazolyl, xanthyl and its ammonium salt.

The invention preferably relates to the compounds of formula (I) having the following meanings:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) -H;

b) a saturated linear (Ci-C₂o)alkyl group, in particular a saturated linear (Ci- Cio)alkyl group, an unsaturated (C₂-C₂o)alkyl group, in particular an unsaturated (C₂-

Cio)alkyl group, a branched (C₃-C₂o)alkyl group, in particular a branched (C₃-Cio)alkyl group, or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5, and

ix) an aryl group, preferably a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;

and

c) an aryl group, preferably a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C₈)alkoxy group and a (Ci-C₈)alkyl group;

R5 being chosen from

• -H, and

· a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group and a (C3-C₈)cycloalkyl group;

The invention more preferably relates to the compounds of formula (I) having the following meanings:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from: a) -H;

b) a saturated linear (Ci-Cio)alkyl group or a branched (C3-Cio)alkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5, and

ix) a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and preferably by one to three hydroxyl groups;

and

c) a phenyl group optionally substituted by one to three groups chosen from a hydroxyl group, a methoxy group and an ethoxy group, preferably an unsubstituted phenyl group;

R5 being chosen from

· H, and

• a saturated linear (Ci-C4)alkyl group and a branched (C3-C4)alkyl group, R5 preferably being H;

Preferably, R = H for the compounds of formula (I).

In a specific embodiment, as above mentioned, A is not a hydrogen atom.

Several embodiments of compounds of formula (I) are described below:

a) R = H, A = saturated linear (Ci-Cio)alkyl;

According to this embodiment, the particularly preferred compounds are the compounds 1 , 3, 6 and 7;

b) R = acetyl, A = saturated linear (Ci-Cio)alkyl;

According to this embodiment, the particularly preferred compound is the compound 9. c) R = H, A = saturated branched (C3-Cio)alkyl, substituted by a hydroxyl and/or a phenyl group;

According to this embodiment, the particularly preferred compounds are the compounds 4, 5 and 1 1 ;

d) R = H, A = saturated linear (Ci-Cio)alkyl, substituted by a hydroxyl and/or a phenyl group, the phenyl group optionally being substituted by a hydroxyl;

According to this embodiment, the particularly preferred compounds are the compounds 8, 10 and 12;

and

e) R = H, A = phenyl;

According to this embodiment, the particularly preferred compound is the compound 13.

Examples of compounds of formula (I) of the invention are collated in Table I below.

Table I

The numbers of the table correspond to the numbers used in the examples below.

Their salts, their solvates, their isomers and their racemates, taken alone or as mixtures, also form part of the invention. Among these compounds, the most particularly preferred compounds in the context of the present invention are the following: compounds 1 to 8, 10, 11 and 13, and their salts, their solvates, their isomers and their racemates, taken alone or as mixtures. The compounds of the invention can be prepared according to the following

Scheme 1 :

Scheme 1

The process according to this Scheme 1 comprises the following stages:

a) Reaction of resorcinol (Al) with itaconic acid (B) or with its anhydride (Β') or with one of its esters of formula (Bl)

B1

in which Ri denotes H or a linear (Ci-C6)alkyl group or a branched (C₃-

C₆)alkyl group, in order to form a compound C;

b) Reaction of the compound C with an amine of formula A-NH₂, in order to result in an imide intermediate of formula (III), A having the same meanings described above for the compounds of formula (I);

c) Reduction of the carbonyls of the imide of the compounds (III), in order to result in the compounds (I) for which R = H;

and optionally a stage:

d) Acetylation of the compounds resulting from stage c), in order to access the compounds of formula (I) for which R = acetyl.

In order to obtain a compound in which A = H, a compound of formula (I) in which A≠ H can be subjected to a hydrogenation reaction, according to the conditions known to a person skilled in the art. The reaction according to stage a) of resorcinol (Al) in the presence of itaconic acid (B) or of its anhydride (Β') or one of its esters of formula (Bl) described above, in order to form the compound C, is carried out in particular in the presence of an organic solvent which can be chosen from toluene, tetrahydrofuran, heptane, isooctane, methyltetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane and their mixtures, in particular at a temperature of between 15 and 200°C, optionally in the presence of a catalyst (acidic or basic) as described in the publications: Synthesis of 7-hydroxycoumarins by Pechmann reaction using Nafion resin/silica nanocomposites as catalysts: Laufer MC, Hausmann H and Holderich WF, J. of Catalysis, 2003, 218, 315-320; Synthesis of 7-hydroxycoumarins catalysed by solid acid catalysts: Hoefnagel A, Gunnewegh E, Downing R and van Bekkum H, J. Chem. Soc, Chem. Commun., 1995, 225-226; in particular in the presence of an acid catalyst, such as methanesulfonic acid, triflic acid, para-toluenesulfonic acid or sulfonic resins, such as the Dowex® products or the Amberlyst® products (sold by Aldrich).

The compounds (Bl) can be obtained in a known way by selective esterification in an acidic medium of itaconic acid with one or more alcohols of formula RiOH, as described in the literature ("Selective esterification of non-conjugated carboxylic acids in the presence of conjugated or aromatic carboxylic acids over active carbon supported methanesulfonic acid"; Feng, Ze Wang, Zhao, Xin Qi and Bi, Hua, Science in China, Series B: Chemistry (2008), 1(10), 990-992 / "An efficient and regiospecific esterification of dioic acids using PTSA"; Devi, A. Rama and Rajaram, S., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2000), 39B(4), 294-296 / "A simple method for the preparation of monomethyl esters of dicarboxylic acids by selective esterification of the nonconjugated carboxyl group in the presence of an aromatic or conjugated carboxyl group"; Ram, Ram N. and Meher, Nabin Kumar; Journal of Chemical Research, Synopses (2000), (6), 282-283).

According to a specific embodiment of the process of synthesis, when the Ri group of the compound C denotes H, the compound of formula (I) can be obtained by activation of the acid C according to the known methods for the activation of acids, in particular described in "Comprehensive Organic Transformation" by R. Larock, Wiley VCH Ed., in the chapter Interconversion of nitriles, carboxylic acids and derivatives. Mention may be made, as acid activation method, of:

- the intermediate formation of acid chloride (for example by using thionyl or oxalyl chloride, or l-chloro-N,N,2-trimethyl-l-propenamine),

- the intermediate formation of mixed anhydride (for example by using a C₂-C₆ alkyl chloroformate, such as isobutyl chloroformate, in the presence of a base, such as, for example, triethylamine or diisopropylethylamine,

- the intermediate formation of carbamimidate or of acylphosphonate (for example by using carbodiimides or diethyl cyanophosphate; Phosphorus in organic synthesis-XI, Amino acids and peptides-XXI, Reaction of diethyl phosphorocyanidate with carboxylic acids. A new synthesis of carboxylic esters and amides, Tetrahedron, 32, 1976, 2211-2217).

The reaction according to stage b) of the compound of formula C with an amine of formula A-NH₂, in order to result in the compounds of formula (III), can be carried out according to the following Scheme 2:

Scheme 2

c (in)

The reaction can optionally be carried out in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2- methyltetrahydrofuran, dichloromethane, toluene, methanol or ethanol;

optionally in the presence of a catalyst chosen from acid catalysts of Lewis or Bronsted type or basic catalysts, such as potassium carbonate, triethylamine or diisopropylethylamine ;

optionally by heating to a temperature of between 15°C and 200°C, in particular between 30°C and 150°C.

The compound (III) is subsequently subjected according to stage c) to a reduction using hydride in order to result in the compound of formula (I) for which R = H after acid treatment, according to Scheme 3. Scheme 3

(III)

The reduction according to this Scheme 3 can be carried out between -30 and + 70°C in protic or aprotic solvents (tetrahydrofuran, dioxane, ethanol, methanol) with metal hydride donors, such as sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminium hydride and lithium aluminium hydride.

The compounds of formula (I) for which R denotes an acetyl group can be obtained by acetylation according to optional stage d) of compounds of formula (I) for which R = H.

The acetylation reaction can be carried out with acetic anhydride or acetyl chloride, in particular in the presence of an aprotic solvent, such as toluene, pyridine or tetrahydrofuran.

The acetylation reaction can be selective by employing protective groups on the functional groups which must not be acetylated and by carrying out, after acetylation, a deprotection reaction, according to the known techniques of organic synthesis.

All of these stages can also resort to protection/deprotection strategies normally used in organic chemistry and compiled in the work "Protecting Groups in Organic Synthesis", Greene and Wuts, Wiley Interscience, as a function of the nature of the A radicals.

The compounds of formula (I) according to the invention have a very particular application in the cosmetics field.

The composition according to the invention comprises, in a physiologically acceptable medium, a compound of formula (I) as described above.

The term "physiologically acceptable medium" is understood to mean a medium compatible with human keratinous substances, such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and/or the hair.

The compound (I) can be present in the composition according to the invention in an amount which can be between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight, in particular from 0.5% to 3% by weight, with respect to the total weight of the composition.

The composition according to the invention is advantageously a cosmetic composition: it can comprise adjuvants normally employed in the cosmetics field.

Mention may in particular be made of water; organic solvents, in particular C₂-

C₆ alcohols; oils, in particular hydrocarbon oils or silicone oils; waxes, pigments, fillers, dyes, surfactants, emulsifiers; cosmetic active agents, UV screening agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers, antioxidants.

These optional cosmetic adjuvants can be present in the composition in a proportion of 0.001% to 80%> by weight, in particular of 0.1 % to 40%> by weight, with respect to the total weight of the composition. In any case, these adjuvants, and their proportions, will be chosen by a person skilled in the art so that the advantageous properties of the compounds according to the invention are not, or not substantially, detrimentally affected by the envisaged addition.

As active agents, it will be advantageous to introduce, into the composition according to the invention, at least one compound chosen from: desquamating agents; soothing agents; organic or inorganic photoprotective agents; moisturizing agents; depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents which stimulate the synthesis of dermal or epidermal macromolecules and/or which prevent their decomposition; agents which stimulate the proliferation of fibroblasts and/or keratinocytes or which stimulate the differentiation of keratinocytes; muscle-relaxing agents and/or dermo-decontracting agents; tightening agents; agents for combating pollution and/or free radicals; agents which act on the microcirculation; agents which act on the energy metabolism of cells; and their mixtures.

Examples of such additional compounds are: retinol and its derivatives, such as retinyl palmitate; ascorbic acid and its derivatives, such as magnesium ascorbyl phosphate and ascorbyl glucoside; tocopherol and its derivatives, such as tocopheryl acetate; nicotinic acid and its precursors, such as nicotinamide; ubiquinone; glutathione and its precursors, such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in particular plant proteins and their hydro lysates, and also phyto hormones; marine extracts, such as algal extracts; bacterial extracts; sapogenins, such as diosgenin, and wild yam extracts comprising same; ceramides; hydroxy acids, such as salicylic acid and 5-(n- octanoyl)salicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acylated derivatives; manganese salts and magnesium salts, in particular gluconates; and their mixtures.

The term "desquamating agent" is understood to mean any compound capable of having an effect:

- 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); a-hydroxy acids, such as gly colic, citric, lactic, tartaric, malic or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; or resveratrol;

- or on the enzymes involved in desquamation or decomposition of the corneodesmosomes, such as glycosidases, stratum corneum chymotryptic enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like). Mention may be made of agents which chelate inorganic salts: EDTA; N-acyl-N,N',N'-ethylenediaminetriacetic acid; amino sulfonic compounds, in particular N-(2-hydroxyethyl)piperazine-N'-2- ethanesulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (procysteine) derivatives; derivatives of alpha-amino acids of glycine type (such as described in EP 0 852 949, and also sodium methyl glycine diacetate, sold by BASF under the trade name Trilon M); honey; or sugar derivatives, such as O-octanoyl-6-D-maltose and N- acetylglucosamine.

The desquamating agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1% to 10% by weight, with respect to the total weight of the composition.

Mention may be made, as soothing agents which can be used in the composition according to the invention, of pentacyclic triterpenes and extracts of plants (for example Glycyrrhiza glabra) comprising the same, such as β-glycyrrhetinic acid and its salts and/or its derivatives (glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, 3-(stearoyloxy)glycyrrhetic acid), ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts, a Paeonia suffruticosa and/or lactiflora extract, salicylic acid salts and in particular zinc salicylate, phycosaccharides from Codif, a Laminaria saccharina extract, canola oil, bisabolol, camomile extracts, allantoin, Sepivital EPC (phosphoric diester of vitamins E and C) from Seppic, omega-3 unsaturated oils, such as musk rose oil, blackcurrant oil, echium oil or fish oil, plankton extracts, capryloyl glycine, Seppicalm VG (sodium palmitoylproline and Nymphaea alba) from Seppic, a Pygeum extract, a Boswellia serrata extract, a Centipeda cunninghamii extract, a Helianthus annuus extract, a Linum usitatissimum extract, tocotrienols, Cola nitida extracts, piperonal, a clove extract, an Epilobium angustifolium extract, aloe vera, a Bacopa moniera extract, phytosterols, cortisone, hydrocortisone, indomethacin and betamethasone.

The soothing agents are generally present in the composition according to the invention in proportions ranging from 0.01% to 15% by weight, preferably ranging from 0.1 %> to 10%) by weight, with respect to the total weight of the composition.

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 4 367 390, EP 863 145, EP 517 104, EP 570 838, EP 796 851, EP 775 698, EP 878 469, EP 933 376, EP 507 691, EP 507 692, EP 790 243 and EP 944 624; benzophenone derivatives; β,β- diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzoazolyl derivatives, such as described in Patents EP 669 323 and US 2 463 264; p-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives, such as described in Applications US 5 237 071, US 5 166 355, GB 2 303 549, DE19726184 and EP 893 119; screening polymers and screening silicones, such as those described in particular in Application WO- 93/04665; dimers derived from a-alkylstyrene, such as those described in Patent Application DE19855649; and merocyanine derivatives, such as those described in Applications WO 2011/113719 and FR 2 957 251. The inorganic photoprotective agents can be chosen in particular from coated or non-coated metal oxide pigments or nanopigments (mean size of the primary particles generally of between 5 nm and 100 nm, preferably between 10 nm and 50 nm), such as, for example, titanium oxide (amorphous or crystallized in rutile and/or anatase form), iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments, which are all well- known UV photoprotective agents. Conventional coating agents are furthermore alumina and/or aluminium stearate. Such coated or non-coated metal oxide nanopigments are described in particular in Patent Applications EP 518 772 and EP 518 773. The photoprotective agents are generally present in the composition according to the invention in proportions ranging from 0.1% to 20% by weight, preferably ranging from 0.2% to 15% by weight, with respect to the total weight of the composition.

The composition according to the invention can be provided in all the formulation forms normally used in the cosmetics field and in particular in the form of an aqueous or aqueous/alcoholic solution, which is optionally gelled, of a dispersion of the lotion type, optionally comprising two phases, of an oil-in-water or water-in-oil or multiple (W/O/W or 0/W/O, for example) emulsion, of an aqueous gel, of a dispersion of oil in an aqueous phase using spherules, it being possible for these spherules to be polymeric nanoparticles such as nanospheres and nanocapsules or better still lipid vesicles of ionic and/or non-ionic type, or of an aqueous or oily gel. These compositions are prepared according to the usual methods. Use is preferably made, according to this invention, of a composition in the form of an emulsion, in particular an oil-in-water emulsion.

The composition according to the invention can constitute a composition for caring for the skin and in particular a cleansing, protecting, treating or care cream for the face, for the hands, for the feet, for the major anatomical folds or for the body (for example, day creams, night creams, make-up-removing creams, foundation creams or anti- sun creams); a fluid foundation; a make-up-removing milk, a protective or care body milk or an anti-sun milk; or a lotion, gel or mousse for caring for the skin, such as a cleansing lotion.

The invention is illustrated in more detail by the following non- limiting examples. Example 1: attainment of the intermediates C

1.1. Attainment of the lactone C in the acid form (compound CI)

10 g of resorcinol and 11.8 g of itaconic acid were dissolved in 150 ml of a toluene/dioxane mixture (1/1 ratio by volume) in the presence of Amberlyst 15 resin from Aldrich in a round-bottomed flask equipped with a Dean and Stark apparatus. The reaction medium was heated at 100°C for 3 hours. After cooling, the crude reaction product was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized under hot conditions from ethyl acetate. 10 g of a white powder corresponding to the expected product were obtained (yield of 50%).

Melting point: 174-175°C. The 1H NMR and mass spectra are in accordance with the structure of the expected product.

1.2. Synthesis of ethyl (7-hydroxy-2-oxo-3,4-dihydro-2H-chromen-3-yl)acetate C2

4.4 g (0.04 mol) ofresorcinol and 6.32 g (0.04 mol) of itaconic acid ethyl half- ester, and also 8.8 g of Amberlyst 15 resin from Aldrich, were added to 100 ml of toluene. The reaction mixture was stirred at reflux for 2 hours and then filtered, after cooling. The filtrate was concentrated and purified by flash chromatography on a silica column (eluent CH₂CI₂: MeOH = 50: 1), in order to result, after recrystallisation from a hexane/ethyl acetate 3/1 mixture, in 4.6 g (46% yield) of the expected lactone C2 in the form of a white solid.

Melting point: 102-103 °C. The 1H NMR and mass spectra are in accordance with the structure of the expected product.

The compounds CI or C2 obtained above are reacted with the ANH₂ derivatives according to Scheme 2 described above, with or without solvent, at a temperature of between 15 and 150°C, in the presence or absence of acidic or basic catalyst (for example K₂C0₃), in order to result in the compounds of formula (III).

The compound of formula (III) thus obtained is reacted with lithium aluminium hydride in tetrahydrofuran at a temperature of between 0 and 70°C, according to Scheme 3 described above, and results in the compounds of corresponding formula (I).

The examples below illustrate these subsequent stages.

Example 2: synthesis of compound 1

2.1. 1.6 g (22 mmol) of butylamine (amine ANH₂ with A = C₄H₉) and 3 g (22 mmol) of potassium carbonate were added to a solution of 5.5 g (22 mmol) of ethyl (7-hydroxy-2- oxo-3,4-dihydro-2H-chromen-3-yl)acetate (compound C2) in 50 ml of THF. The mixture was stirred at 40°C for 12 hours. After filtering and concentrating the filtrate, the crude product was purified by chromatography on a silica column, in order to thus obtain 5 g (82% yield) of the corresponding imide compound ((III) with A = nBu).

Melting point: 122-123°C. The 1H NMR and mass spectra are in accordance with the structure of the expected product.

2.2. 3 g of L1AIH₄ are added at ambient temperature, little by little, to a solution of 5 g of the above imide in 150 ml oftetrahydrofuran. The mixture is heated at reflux for 16 hours. After cooling, the reaction is halted by addition of water at 0°C. The reaction medium is filtered and the precipitate is washed with THF and methanol. The filtrate is concentrated under vacuum and the residue is purified on a silica column (eluent dichloromethane/methanol 20/1), in order to result in 1.9 g of the desired compound in the form of a brown solid identified as compound 1 (37% yield). The 1H NMR and mass spectra are in accordance with the structure of the expected product.

Example 3: synthesis of compound 10

The procedure described above is applied to benzylamine. The benzylated imide is obtained with a yield of 45% starting from the ethyl ester form C2. The reduction makes it possible to obtain compound 10 with a yield of 55%. The 1H NMR and mass spectra are in accordance with the expected structure.

Example 4: synthesis of compound 2

10 mol% of palladium-on-charcoal are added to a mixture of 200 mg of compound 10 of Example 3 in 10 ml of methanol. The reaction medium is subjected to hydrogenation at atmospheric pressure and at ambient temperature. Once the reaction is complete, the reaction mixture is filtered and the cake is washed with methanol. The filtrate is concentrated under vacuum and the residue is purified on a silica column (eluent dichloromethane/methanol 20/1), in order to result in compound 2 with a yield of 65% in the form of a colourless oil. The 1H NMR and mass spectra are in accordance with the expected structure.

Examples 5 to 10: Synthesis of the compounds The same procedure was carried out as in the examples described above, different amine specified in the table below:

Example 11: Demonstration of the activity with regard to constitutive melanogenesis

A biological test demonstrated the depigmenting activity of the compounds of formula (I).

The modulating effect on melanogenesis of compound 1 was measured according to the method described in Patent FR-A-2 734 825, and in the paper by R. Schmidt, P. Krien and M. Regnier, Anal. Biochem., 235(2), 113-18, 1996. This test is carried out on a coculture of keratinocytes and melanocytes. For the test compound, the following were determined:

- the cytotoxicity, by estimating the incorporation of leucine, or by the use of Alamar Blue,

- the inhibitory activity on melanin synthesis, by estimating the ratio of the incorporation of thiouracil to the incorporation of leucine, relative to 100% for the control (the control corresponds to the test carried out without test compound). The IC₅₀ (concentration for which 50% of the synthesis of the melanin is inhibited) values were determined.

The test was also carried out with arbutin and kojic acid, which are known depigmenting compounds.

The results are collated in the following Table 2:

Table 2

The compounds according to the invention are thus shown to be effective in inhibiting melanogenesis and are furthermore more effective than arbutin and kojic acid.

Example 12: Use of a cosmetic formulation

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

Compound 2 (Example 4) 2%

Carbomer (Carbopol 981 from Lubrizol) 1%

Preservative q.s. Water q.s. for 100%

The composition, applied to the skin, makes it possible to soften brown blemishes.

A similar composition is prepared with compound 1.

Claims

1. Compound of formula (I)

in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

saturated linear (Ci-C2o)alkyl group, an unsaturated (C₂-C₂o)alkyl group, branched (C3-C₂o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5,

ii) -SR5,

iii) -NR6R7,

iv) -C(0)NHR6,

v) -C(0)NR6R7,

vi) -C(0)OR6,

vii) -NHC(0)NHR6,

viii) -C(0)(Ci-C₄)alkyl,

x) a saturated or unsaturated nonaromatic heterocycle, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-Cs)alkoxy group and a (Ci-C4)alkyl group; and

xi) -NH-C=NH(NH₂) (guanidine group); b) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci- C₈)alkyl group;

c) -NR2R3;

d) -OR4;

e) -C(0)NHR4;

and

f) -C(0)(Ci-Cio)alkyl;

R2 and R3, which are identical or different, denoting a radical chosen from: · -H,

R4 denoting a radical chosen from:

• -H,

· a saturated linear (Ci-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a

(C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

vi) -C(0)OR6, and

ix) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-C8)alkoxy group, and • an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group;

R5 being chosen from

• -H, and

· a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group;

R6 and R7, which are identical or different, being chosen from

• -H,

• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group,

• a phenyl(Ci-C4)alkyl group, such as a benzyl group, or a pyridyl(Ci- C4)alkyl group, and

• an acetyl radical;

2. Compound according to Claim 1 , in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) a saturated linear (Ci-C₂o)alkyl group, in particular a saturated linear (Ci- Cio)alkyl group, an unsaturated (C₂-C₂o)alkyl group, in particular an unsaturated (C₂- Cio)alkyl group, a branched (C₃-C₂o)alkyl group, in particular a branched (C₃-Cio)alkyl group, or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5, and

ix) an aryl group, preferably a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group; and

b) an aryl group, preferably a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group, a (Ci-C₈)alkoxy group and a (Ci-C₈)alkyl group;

R5 being chosen from

• -H, and

• a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group and a (C₃-C₈)cycloalkyl group;

3. Compound according to either one of the preceding claims, in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) a saturated linear (Ci-Cio)alkyl group or a branched (C₃-Cio)alkyl group, it being possible for the said groups to be optionally interrupted by one to three oxygen atoms, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5, and

ix) a phenyl group, optionally substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group, and preferably by one to three hydroxyl groups;

and

b) a phenyl group optionally substituted by one to three groups chosen from a hydroxyl group, a methoxy group and an ethoxy group, preferably an unsubstituted phenyl group;

R5 being chosen from

• H, and

• a saturated linear (Ci-C₄)alkyl group and a branched (C₃-C₄)alkyl group, R5 preferably being H; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures.

4. Compound according to any one of the preceding claims, in which R = H.

5. Compound according to any one of Claims 1 to 3, in which the compounds have one of the following meanings:

a) R = H, A = saturated linear (Ci-Cio)alkyl;

b) R = acetyl, A = saturated linear (Ci-Cio)alkyl;

c) R = H, A = saturated branched (C3-Cio)alkyl, substituted by a hydroxyl and/or a phenyl group;

d) R = H, A = saturated linear (Ci-Cio)alkyl, substituted by a hydroxyl and/or a phenyl group, the phenyl group optionally being substituted by a hydroxyl; and

e) R = H, A = phenyl.

6. Compound according to any one of Claims 1 to 3, chosen from the following compounds:

4- [( 1 -butylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

4- [( 1 -propylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

4- { [ 1 -( 1 -hydroxypropan-2-yl)pyrrolidin-3 -yl]methyl} benzene- 1 ,3 -diol,

4- { [ 1 -( 1 -hydroxy-3 -methylbutan-2-yl)pyrrolidin-3 -yl]methyl} benzene- 1 ,3 -diol,

4- [( 1 -ethylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

4- [( 1 -methylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

4- { [ 1 -(2-hydroxyethyl)pyrrolidin-3 -yl]methyl} benzene- 1 ,3 -diol,

4- [( 1 -butylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diyl diacetate,

4- [( 1 -benzylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

4- {[ 1 -( 1 -hydroxy-3 -phenylpropan-2-yl)pyrrolidin-3 -yl]methyl} benzene- 1 ,3 -diol, 4-( { 1 -[2-(4-hydroxyphenyl)ethyl]pyrrolidin-3-yl}methyl)benzene-l ,3-diol, 4- [( 1 -phenylpyrrolidin-3 -yl)methyl]benzene- 1 ,3 -diol,

and their salts, their solvates, their optical isomers, their racemates, taken alone or as mixtures.

7. Composition comprising, in a physiologically acceptable medium, a compound of formula (I):

in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) -H;

b) a saturated linear (Ci-C₂o)alkyl group, an unsaturated (C₂-C₂o)alkyl group, a branched (C₃-C₂o)alkyl group or a (C₃-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5,

ii) -SR5,

iii) -NR6R7,

iv) -C(0)NHR6,

v) -C(0)NR6R7,

vi) -C(0)OR6,

vii) -NHC(0)NHR6,

viii) -C(0)(Ci-C₄)alkyl,

xi) -NH-C=NH(NH₂) (guanidine group); c) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci- C₈)alkyl group;

d) -NR2R3;

e) -OR4;

f) -C(0)NHR4;

and

g) -C(0)(Ci-Cio)alkyl;

R2 and R3, which are identical or different, denoting a radical chosen from:

• -H,

R4 denoting a radical chosen from:

• -H,

vi) -C(0)OR6, and

R5 being chosen from

• -H, and

R6 and R7, which are identical or different, being chosen from

• -H,

• an acetyl radical;

8. Composition according to the preceding claim, characterized in that the compound of formula (I) is chosen from a compound according to any one of Claims 1 to 6.

9. Composition according to either of Claims 7 and 8, characterized in that the compound of formula (I) is present in a content of between 0.01% and 10%> by weight, preferably between 0.1% and 5% by weight, in particular from 0.5%> to 3% by weight, with respect to the total weight of the composition.

10. Composition according to one of Claims 7 to 9, characterized in that it comprises at least one adjuvant chosen from the group formed by: water, organic solvents, hydrocarbon oils, silicone oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers; cosmetic active agents, UV screening agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odour absorbers and antioxidants.

1 1. Composition according to any one of Claims 7 to 10, characterized in that it comprises at least one active agent chosen from: desquamating agents; soothing agents; organic or inorganic photoprotective agents; moisturizing agents; depigmenting agents; antiglycation agents; NO-synthase inhibitors; agents which stimulate the synthesis of dermal or epidermal macromolecules and/or which prevent their decomposition; agents which stimulate the proliferation of fibroblasts and/or keratinocytes or which stimulate the differentiation of keratinocytes; muscle-relaxing agents and/or dermo-decontracting agents; tightening agents; agents for combating pollution and/or free radicals; agents which act on the microcirculation; agents which act on the energy metabolism of cells; and their mixtures.

12. Non-therapeutic cosmetic method for depigmenting, lightening and/or whitening keratinous substances, in particular the skin, comprising the application of a composition according to any one of Claims 7 to 1 1.

13. Method according to the preceding claim, for depigmenting, lightening and/or whitening the skin.

14. Non-thera eutic cosmetic use of a compound of formula (I):

in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) -H;

i) -OR5,

ii) -SR5,

iii) -NR6R7, iv) -C(0)NHR6,

v) -C(0)NR6R7,

vi) -C(0)OR6,

vii) -NHC(0)NHR6,

viii) -C(0)(Ci-C₄)alkyl,

xi) -NH-C=NH(NH₂) (guanidine group);

c) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group, a (Ci-C8)alkoxy group and a (Ci- Cs)alkyl group;

d) -NR2R3;

e) -OR4;

f) -C(0)NHR4;

and

g) -C(0)(Ci-Cio)alkyl;

R2 and R3, which are identical or different, denoting a radical chosen from:

• -H,

it being possible for R2 and R3 to form, with the nitrogen which carries them, a saturated or unsaturated nonaromatic heterocycle, it being possible for the said heterocycle to be optionally substituted by a (Ci-Cio)alkyl group, the said (Ci-Cio)alkyl optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci- C4)alkoxy group;

R4 denoting a radical chosen from:

• -H,

vi) -C(0)OR6, and

ix) an aryl or heteroaryl group, the said group optionally being substituted by one to three groups chosen from a hydroxyl group and a (Ci-Cs)alkoxy group, and

R5 being chosen from

· -H, and

R6 and R7, which are identical or different, being chosen from

• -H,

· a saturated linear (Ci-Cio)alkyl group, an unsaturated (C₂-Cio)alkyl group, a branched (C₃-Cio)alkyl group or a (C₃-Cs)cycloalkyl group,

• an acetyl radical;

and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures;

or of a compound of formula (I) as defined according to any one of Claims 1 to

6, as whitening, lightening and/or depigmenting agent for keratinous substances, in particular the skin.

15. Process for the preparation of the compounds of formula (I):

in which:

R denotes a hydrogen atom or an acetyl group;

A denotes a radical chosen from:

a) -H;

b) a saturated linear (Ci-C2o)alkyl group, an unsaturated (C₂-C₂o)alkyl group, a branched (C3-C₂o)alkyl group or a (C3-Cs)cycloalkyl group, it being possible for the said groups to be optionally interrupted by one to three heteroatoms or groups chosen from N, O, -C(O)-, -NHC(O)- and -NHC(0)NH-, it being possible for the said groups to be optionally substituted by one to three identical or different groups chosen from:

i) -OR5,

ii) -SR5,

iii) -NR6R7,

iv) -C(0)NHR6,

v) -C(0)NR6R7,

vi) -C(0)OR6,

vii) -NHC(0)NHR6,

viii) -C(0)(Ci-C₄)alkyl,

d) -NR2R3;

e) -OR4;

f) -C(0)NHR4;

and

g) -C(0)(Ci-Cio)alkyl;

R4 denoting a radical chosen from:

• -H,

vi) -C(0)OR6, and

R5 being chosen from

• -H, and

R6 and R7, which are identical or different, being chosen from

• -H,

• an acetyl radical;

or of the compounds of formula (I) according to any one of Claims 1 to 6, comprising the following stages:

B1

in which Ri denotes H or a linear (Ci-C6)alkyl group or a branched (C₃- C₆)alkyl group, in order to form a compound of formula C:

C b) Reaction of the compound C with an amine of formula A-NH₂, in order to result in an imide intermediate of formula (III),

(III)

A having the same meanings as those provided in Claims 1 to 3;

and optionally a stage:

d) Acetylation of the compounds resulting from stage c), in order to access the compounds of formula (I) for which R = acetyl;

and optionally again a stage of hydrogenation of a compound of formula (I) in which A≠ H, in order to obtain a compound of formula (I) in which A = H.