Method for depigmenting keratinous materials using thiopyridone compounds

Abstract

The present application relates to a method for depigmenting keratin materials using thiopyridone compounds. The present invention relates to a cosmetic method for depigmenting, lightening and / or bleaching keratin materials, in particular the skin, which method comprises applying a cosmetic composition comprising a compound of formula (I): Compound of formula (I): #imgabs0# (I) The present invention also relates to novel compounds of formula (I), compositions containing them and also the cosmetic use of compound (I) as an agent for bleaching, lightening and / or depigmenting keratin materials.

Description

[0001] The present application is a divisional application of an invention patent application, the application date of the parent application is December 1, 2016, the application number is 201680074205.1 (PCT / EP2016 / 079394), and the name of the invention is "Method for decolorizing keratin materials using thiopyridone compounds".

[0002] The present invention relates to a cosmetic treatment method, in particular for depigmenting and / or bleaching the skin using at least one thiopyridone compound.

[0003] At different times in their lives, some people see on their skin, and more particularly on the hands, the appearance of darker and / or more colored spots, which give unevenness to the skin. These spots are caused in particular by a high concentration of melanin in the keratinocytes located at the surface of the skin.

[0004] For the purpose of treating pigmented spots, it is most particularly desirable to use harmless topical depigmenting substances with good efficacy.

[0005] The mechanism of skin pigmentation formation (i.e., melanin formation) is particularly complex and schematically involves the following major steps:

[0006] Tyrosine--->DOPA--->DOPAQ1N--->DOPACHINE--->MELANIN

[0007] Tyrosinase (monophenolic dihydroxyphenylalanine: oxygen oxidoreductase EC 1.14.18.1) is an essential enzyme involved in this sequence of reactions. It specifically catalyzes the conversion of tyrosine to DOPA (dihydroxyphenylalanine) through its hydroxylase activity and the conversion of DOPA to DOPAquinone through its oxidase activity. This tyrosinase is only active when it is in a mature form under the action of certain biological factors.

[0008] A substance is recognized as having depigmenting properties if it acts directly on the vitality of the epidermal melanocytes in which melanogenesis occurs and / or if it interferes with one of the steps of melanin biosynthesis by inhibiting one of the enzymes involved in melanogenesis or by inserting itself as a structural analogue of one of the chemical compounds of the melanin synthesis chain (which can then block this chain), thereby ensuring depigmentation.

[0009] Arbutin, niacinamide, and kojic acid are known as skin depigmenting agents.

[0010] Substances having an effective depigmenting effect, in particular greater than arbutin, niacinamide and kojic acid, have been sought.

[0011] In this regard, the applicants have surprisingly and unexpectedly found that certain thiopyridone compounds have good decolorizing activity even at low concentrations.

[0012] A subject of the present invention is therefore a non-therapeutic cosmetic method for depigmenting, lightening and / or bleaching keratin materials, in particular the skin, which method comprises applying a cosmetic composition comprising at least one compound of formula (I) as defined below in a physiologically acceptable medium.

[0013] The invention also relates to the non-therapeutic cosmetic use of the compounds of formula (I) as agents for bleaching, lightening and / or depigmenting keratin materials, in particular the skin.

[0014] The compounds used according to the invention can effectively depigment and / or lighten or even bleach human skin. They are particularly intended for application to the skin of individuals with brown pigmentation spots or aging spots, or to the skin of individuals who wish to counteract the brown appearance caused by melanin production.

[0015] They may also make it possible to depigment and / or lighten body hair, eyelashes, hair and also lips and / or nails.

[0016] A subject of the present invention is also the cosmetic use of the compounds of formula (I) as described above as agents for bleaching and / or depigmenting the skin, body hair, eyelashes or hair and also the lips and / or nails and preferably the skin, in particular for eliminating pigmented spots or aging spots, and / or as sunscreens.

[0017] The compounds used according to the invention therefore correspond to the following formula (I):

[0018]

[0019] in:

[0020] R1 represents a group selected from the following:

[0021] a) Hydrogen atom;

[0022] b) saturated straight chain C1-C6 alkyl;

[0023] R2 represents a group selected from the following:

[0024] a) Hydrogen atom;

[0025] b) Saturated straight chain C1-C 10 alkyl;

[0026] c) Saturated branched chain C3-C 10 alkyl;

[0027] d) C1-C6 phenylalkyl such as benzyl,

[0028] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, either individually or as a mixture.

[0029] Salts of the compounds of formula (I) include conventional non-toxic salts of the compounds, such as those formed from acids or bases.

[0030] As salts of the compounds of formula (I), mention may be made of:

[0031] Salts obtained by adding a compound of formula (I) (when it contains an acid group) to a mineral base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide and sodium, potassium or calcium carbonates or bicarbonates;

[0032] Or salts obtained by addition to an organic base such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. Such primary, secondary or tertiary alkylamines may contain one or more nitrogen and / or oxygen atoms and may therefore contain, for example, one or more alcohol functions; mention may be made in particular of 2-amino-2-methylpropanol, ethanolamine, triethanolamine, 2-dimethylaminopropanol, 2-amino-2-(hydroxymethyl)-1,3-propanediol and 3-(dimethylamino)propylamine.

[0033] Mention may also be made of the salts of amino acids such as lysine, arginine, guanidine, glutamic acid and aspartic acid. Advantageously, the salts of the compounds of formula (I) when they contain an acid group may be chosen from alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts; ammonium salts.

[0034] Acceptable solvates of the compounds described in the present invention include conventional solvates, such as those formed during the preparation of the compounds due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water or linear or branched alcohols such as ethanol or isopropanol.

[0035] Optical isomers are in particular enantiomers and diastereomers.

[0036] Preferably, the straight-chain or branched group may be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0037] More preferably, the saturated straight or branched alkyl group may be selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, pentyl, hexyl, heptyl and octyl.

[0038] Compound a) is disclosed in PubCHEM database (No. 47329290)

[0039] http: / / pubchem.ncbi.nlm.nih.gov / compound / 47329290.

[0040] Compound b) CAS>1240664-41-8 is described in the publication:

[0041] Synthesis of N-(2-mercaptopyridyl-3-formyl)-N-alkyl glycine and the corresponding disulfides

[0042] Luo, YL; Yang, ZX; Peng, SX

[0043] Div.Med.Chem.,China Pharm.Univ.,Nanjing,210009,Peop.Rep.China[Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing,210009,People's Republic of China]

[0044] Yaoxue Xuebao[Journal of Pharmacy](1990), 25(5), 374-8.

[0045] Preferably, the compounds of formula (I) have the following meanings:

[0046] R1 represents a group selected from the following:

[0047] a) Hydrogen atom;

[0048] b) a saturated straight chain C1-C4 alkyl group and preferably a methyl group;

[0049] R2 represents a group selected from the following:

[0050] a) Hydrogen atom;

[0051] b) saturated straight chain C1-C6 alkyl;

[0052] c) saturated branched C3-C6 alkyl;

[0053] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, either individually or as a mixture.

[0054] More preferably, the compounds of formula (I) have the following meanings:

[0055] R1 represents a group selected from the following:

[0056] a) Hydrogen atom;

[0057] b) methyl;

[0058] R2 represents a group selected from the following:

[0059] a) Hydrogen atom;

[0060] b) saturated straight chain C1-C4 alkyl, preferably ethyl;

[0061] c) saturated branched C3-C4 alkyl, preferably isopropyl and isobutyl,

[0062] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, either individually or as a mixture.

[0063] Novel compounds

[0064] Another subject of the present invention are novel compounds of formula (II):

[0065]

[0066] in:

[0067] R1 represents a group selected from the following:

[0068] a) Hydrogen atom;

[0069] b) saturated straight chain C1-C6 alkyl;

[0070] R2 represents a group selected from the following:

[0071] a) Hydrogen atom;

[0072] b) Saturated straight chain C1-C 10 alkyl;

[0073] c) Saturated branched chain C3-C 10 alkyl;

[0074] d) C1-C6 phenylalkyl such as benzyl,

[0075] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, alone or as a mixture,

[0076] The following two compounds (a) and (b) and their tautomers are excluded:

[0077]

[0078] Preferably, the compounds of formula (II) have the following meanings:

[0079] R1 represents a group selected from the following:

[0080] a) Hydrogen Atom:

[0081] b) a saturated straight chain C1-C4 alkyl group and preferably a methyl group;

[0082] R2 represents a group selected from the following:

[0083] a) Hydrogen atom;

[0084] b) saturated straight chain C1-C6 alkyl;

[0085] c) saturated branched C3-C6 alkyl;

[0086] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, alone or as a mixture,

[0087] The following compounds (a) and their tautomers are excluded:

[0088]

[0089] More preferably, the compounds of formula (II) have the following meanings:

[0090] R1 represents a group selected from the following:

[0091] a) Hydrogen atom;

[0092] b) methyl;

[0093] R2 represents a group selected from the following:

[0094] a) Hydrogen atom;

[0095] b) saturated straight chain C1-C4 alkyl, preferably ethyl;

[0096] c) saturated branched C3-C4 alkyl, preferably isopropyl and isobutyl,

[0097] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, alone or as a mixture,

[0098] The following compounds (a) and their tautomers are excluded:

[0099]

[0100] Among the compounds of formula (I) or (II), the following compounds are preferably used:

[0101]

[0102] and also their tautomers, their salts, their solvates and their optical isomers, and their racemates, either individually or as a mixture.

[0103] Of these compounds, Compound 1 and Compound 2 and also their salts, their solvates, their isomers and their racemates (taken individually or as a mixture) are more particularly preferred.

[0104] Compounds of formula (I) can be obtained in a known manner by reacting 2-mercaptonicotinic acid with an amine of formula (V), in particular in the presence of a coupling agent or a base such as carbonyldiimidazole:

[0105]

[0106] wherein R1 and R2 have the meanings described above.

[0107] Compounds of formula (I) and (II) can also be obtained in a known manner by reacting 2-mercaptonicotinic acid or 2-chloronicotinic acid, after activation of the carboxylic acid to the form of formula (W), with an amine of formula (V) (R1 and R2 have the meanings described above),

[0108]

[0109] wherein X is activated by conventional methods for activating acids in the presence of a reagent for activating carboxylic acids (activation of the carboxyl group of 2-chloronicotinic acid to form an acyl halide, mixed anhydride, carbamimidate or acylphosphonate is described, for example, in Comprehensive Organic Transformation by R. Larock, published by Wiley VCH, in the chapter Interconversion of nitriles, carboxylic acids and derivatives). Preference is given to using reagents for activating carboxylic acids which allow the formation of acid chlorides (for example by using thionyl chloride or oxalyl chloride, or 1-chloro-N,N,2-trimethyl-1-propenamine) or of mixed anhydrides (using alkyl or aryl chloroformates) or of isoureas or acylphosphonates (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).

[0110] When 2-chloronicotinic acid is used as starting reagent, the chloroamide of formula (Y) obtained is then used for an exchange reaction between chlorine and sulfur (in basic medium) by reagents such as NaSH, thiourea, Bunte salt, sodium thiosulfate or thioacetic acid.

[0111] According to the following general synthesis scheme:

[0112]

[0113] wherein R1, R2 and X have the same meanings as those defined previously.

[0114] In addition, when the final compounds (I) and (II) have a free carboxylic acid on the R2 group, the compounds can be obtained from the corresponding amino acids or by saponifying the corresponding esters using an inorganic base such as, for example, NaOH or LiOH in the presence of a protic or aprotic solvent such as, for example, ethanol or tetrahydrofuran or water at a temperature ranging between zero and 100° C. The salts obtained can then be acidified with mineral or organic acids such as, for example, hydrochloric acid or citric acid.

[0115] The compounds of the formula (I) and / or (II) according to the invention have quite particular application in the cosmetics sector.

[0116] The compositions used according to the invention comprise a compound of formula (I) and / or (II) as described above in a physiologically acceptable medium.

[0117] Compounds (I) and / or (II) may be present in the composition used according to the invention in an amount which may be between 0.01% and 10% by weight, preferably between 0.1% and 5% by weight and in particular from 0.5% to 3% by weight relative to the total weight of the composition.

[0118] The term "physiologically acceptable medium" is intended to mean a medium that is compatible with human keratin materials such as the skin of the body or face, the lips, mucous membranes, eyelashes, nails, scalp and / or hair.

[0119] The composition used according to the invention may then contain any adjuvants customary in the cosmetic field. Mention may be made in particular of water; organic solvents, in particular C1-C6 alcohols, more preferably C2-C6 alcohols and C2-C 10 Carboxylic acid esters; oils, in particular hydrocarbon-based oils of mineral, animal and / or vegetable origin and / or silicone oils; waxes, pigments, fillers, dyes, surfactants, emulsifiers; cosmetic or dermatological active agents, UV screening agents, polymers, hydrophilic or lipophilic gelling agents, thickeners, preservatives, fragrances, bactericides, ceramides, odor absorbers and antioxidants.

[0120] These optional cosmetic adjuvants may be present in the composition in a proportion of from 0.001% to 80% by weight and in particular from 0.1% to 40% by weight relative 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 substantially not adversely affected by the envisaged addition.

[0121] As active agent, it will be advantageous to introduce into the composition used according to the invention at least one compound chosen from the following: desquamating agents; soothing agents, organic or inorganic photoprotective agents, moisturizing agents; depigmenting or pigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents for stimulating the synthesis of dermal or epidermal macromolecules and / or for preventing their degradation; agents for stimulating the proliferation of fibroblasts and / or keratinocytes or for stimulating the differentiation of keratinocytes; muscle relaxants and / or dermo-decontracting agents; tensioning agents; anti-pollution agents and / or free radical scavengers; agents acting on capillary circulation; agents acting on cellular energy metabolism; and mixtures thereof.

[0122] 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; niacin and its precursors, such as niacinamide; ubiquinone; glutathione and its precursors, such as L-2-oxothiazolidine-4-carboxylic acid; plant extracts, and in particular plant proteins and their hydrolysates, and also plant hormones; marine extracts, such as algae extracts; bacterial extracts; sapogenins, such as diosgenin and extracts of wild yam containing it; ceramides; hydroxy acids, such as salicylic acid and 5-n-octanoylsalicylic acid; resveratrol; oligopeptides and pseudodipeptides and their acylated derivatives; manganese and magnesium salts, in particular gluconates; and mixtures thereof.

[0123] The term "dermative agent" is intended to mean an agent that:

[0124] - any compound that acts directly on desquamation (by promoting shedding), such as beta-hydroxy acids, in particular salicylic acid and its derivatives (including 5-n-octanoylsalicylic acid); alpha-hydroxy acids, such as glycolic acid, citric acid, lactic acid, tartaric acid, malic acid or mandelic acid; urea; gentisic acid; oligofucose; cinnamic acid; extracts of Saphora japonica; resveratrol;

[0125] - or any compound acting on the enzymes involved in the desquamation or degradation of corneodesmosomes, glycosidases, stratum corneum chymotrypsin (SCCE) or other proteases (trypsin, chymotrypsin-like). Mention may be made of mineral salt chelators: EDTA; N-acyl-N,N′,N′-ethylenediaminetriacetic acid; aminosulfonic acid compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane)sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid (alanine) derivatives; derivatives of α-amino acids of the glycine type (such as described in EP 0852949 and also sodium methylglycine diacetate sold under the trade name Trilon M by BASF); honey; sugar derivatives, such as O-octanoyl-6-D-maltose and N-acetylglucosamine.

[0126] These desquamation agents are generally present in the composition according to the invention in a proportion ranging from 0.01% to 15% by weight, preferably from 0.1% to 10% by weight relative to the total weight of the composition.

[0127] As soothing agents that can be used in the compositions according to the invention, mention may be made of pentacyclic triterpenes and extracts of plants containing them (for example Glycyrrhiza glabra), for example β-glycyrrhetinic acid and its salts and / or its derivatives (glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, 3-stearoyloxyglycyrrhetinic acid), ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts, extracts of Paeonia suffruticosa and / or Paeonia lactiflora, salicylates and in particular zinc salicylate, algae sugar from Codif, extracts of Laminaria saccharina, rapeseed oil, bisabolol and extracts of chamomile, allantoin, Sepivita from SEPPIC EPC (phosphodiester of vitamins E and C), omega-3 unsaturated oils such as rose oil, black currant oil, ecchium oil, fish oil, plankton extract, capryloyl glycine, Seppicalm VG (sodium palmitoyl proline and Nymphea alba) from SEPPIC, extract of Pygeum, extract of Boswellia serrata, extract of Centipeda cunninghami, extract of Helianthus annuus, extract of flax, tocotrienols, extract of Cola nitida, piperonal, extract of clove, Epilobium angustifolium, aloe vera, extract of Bacopamoniera, phytosterols, cortisone, hydrocortisone, indomethacin and betamethasone.

[0128] These soothing agents are generally present in the composition used according to the invention in a proportion ranging from 0.01% to 15% by weight, preferably from 0.1% to 10% by weight relative to the total weight of the composition.

[0129] The organic photoprotective agents are chosen in particular from anthranilates; cinnamic acid derivatives; dibenzoylmethane derivatives; salicylic acid derivatives, camphor derivatives; triazine derivatives, such as those described in patent applications US 4 367 390, EP 863 145, EP 517104, EP 570 838, EP 796 851, EP 775 698, EP 878 469, EP 933 376, EP 507 691, EP 507692, EP 790 243 and EP 944 624; benzophenone derivatives; β,β-diphenylacrylate derivatives; benzotriazole derivatives; benzylidenemalonate derivatives; benzimidazole derivatives; imidazoline; bis-benzoxazolyl derivatives, such as those described in patents EP 669323 and US 2463264; para-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives, as described in patent applications US 5237071, US 5166355, GB 2303549, DE19726184 and EP 893119; screen polymers and screen silicones, such as those described in particular in patent application WO 93 / 04665; dimers based on alpha-alkylstyrene, such as those described in patent application DE 19855649.

[0130] Inorganic light protection agents can be selected in particular from coated or uncoated metal oxide pigments or nanopigments (the average size of the primary particles is usually between 5 nm and 100 nm, preferably between 10 nm and 50 nm), such as titanium oxide (amorphous or crystallized in the form of rutile and / or anatase), iron oxide, zinc oxide, zirconium oxide or cerium oxide nanopigments, which are well-known UV-light protection agents. In addition, conventional coating agents are aluminum oxide and / or aluminum stearate. Such coated or uncoated metal oxide nanopigments are described in particular in patent applications EP-518 772 and EP-518 773.

[0131] These photoprotective agents are generally present in the composition used according to the invention in a proportion ranging from 0.1% to 20% by weight, preferably from 0.2% to 15% by weight relative to the total weight of the composition.

[0132] The composition used according to the invention may be in any galenical form commonly used in the cosmetic field, and in particular in the form of an aqueous or aqueous-alcoholic solution (optionally gelled), a lotion-type dispersion, optionally a two-phase dispersion, an oil-in-water or water-in-oil or composite (e.g. W / O / W or O / W / O) emulsion, a hydrogel, a dispersion of oil in an aqueous phase by means of globules, which may be polymer nanoparticles such as nanospheres and nanocapsules, or even better ionic and / or nonionic lipid vesicles; an aqueous or oily gel. These compositions can be prepared according to the general methods. According to the invention, preference is given to using compositions in the form of emulsions, in particular oil-in-water emulsions.

[0133] The composition used according to the invention may constitute a skin care composition and in particular a cleansing, protection, treatment or care cream (for example a day cream, night cream, make-up remover, foundation cream or sunscreen) for the face, hands, feet, the major anatomical folds or the body; a fluid foundation, a make-up remover, a protective or care body lotion or a sunscreen; a skin care lotion, gel or mousse, such as a cleansing lotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] Figure 1 The evaluated compounds 1 and 2 showed significant decolorization activity at 100 μM (p value < 0.05: significant decolorization activity);

[0135] Figure 2 The evaluated compounds 3 and 4 showed significant decolorization activity at 300 μM (p value < 0.05: significant decolorization activity).

[0136] The present invention is illustrated in more detail by the following non-limiting examples.

[0137] Example 1: Synthesis of compound 3-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine ethyl ester

[0138]

[0139] Route 1: via 2-mercaptonicotinic acid

[0140]

[0141] In a round bottom flask, thionicotinic acid was introduced into acetonitrile followed by carbonyldiimidazole (CDI). The mixture was refluxed for 1 hour. The mixture was returned to ambient temperature and glycine ethyl ester hydrochloride was added, and heating was then resumed at 60°C for 3 hours, and then overnight at ambient temperature.

[0142] After an overnight period, the reaction medium was evaporated. The residue was taken up in dichloromethane and washed twice with 2N HCl. The organic phase was dried over anhydrous sodium sulfate and then evaporated and purified on silica with 97 / 3 dichloromethane / methanol.

[0143] The fractions were evaporated.

[0144] A light yellow powder was obtained: Yield: 37%.

[0145] Route 2: via 2-chloronicotinic acid

[0146]

[0147] In a three-necked flask, 2-chloronicotinic acid (250.0g, 1.587 moles) was introduced dropwise into ethyl acetate (500ml) and SOCl2 (210.0g, 1.761 moles). The mixture was refluxed until complete conversion was obtained. The medium was cooled to ambient temperature and diluted with ethyl acetate (375ml). Then a solution of glycine ethyl ester hydrochloride (265.8g, 1.904 moles) and triethylamine (393.5g, 3.88 moles) diluted in water (400ml) were added. The mixture was stirred for 3 to 4 hours, and ethyl acetate was removed under vacuum. The obtained aqueous solution was diluted with water (1250ml) and acidified with 3N HCI (25ml). Sodium thiosulfate (1379g, 5.555 moles) was loaded into the resulting solution and the mixture was refluxed for 6 hours. After being cooled to 10°C, a yellow solid was filtered out and washed with water (3×750ml).

[0148] The crude product was absorbed with carbon black in a 75 / 25 ethanol / water mixture. The carbon black was filtered off under hot conditions and the ethanol was evaporated. The product was cooled to ambient temperature, filtered and dried under vacuum. A light yellow powder was obtained: Yield: 88%.

[0149] 1 H NMR and mass spectra were consistent with the structure.

[0150] Melting point: 151°C (capillary)

[0151] Example 2: Synthesis of Compound 1 from Compound 3

[0152] N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

[0153]

[0154] N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine ethyl ester (48 g, 0.317 mole), 95% EtOH (48 ml) were introduced into a three-necked flask and cooled to 10° C. A solution of NaOH (16 g) in 144 ml of water was added dropwise. The organic solvent was evaporated and the pH was adjusted to 3-4. The resulting product was cooled to 0° C.-10° C. and filtered off. The product was washed with water and dried under vacuum.

[0155] A light yellow powder was obtained: Yield: 96%.

[0156] 1 H NMR and mass spectra were consistent with the structure.

[0157] Melting point: 241.0℃-241.8℃(capillary)

[0158] Example 3: Synthesis of Compound 4 N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine ethyl ester

[0159]

[0160] Route 1: via 2-mercaptonicotinic acid

[0161]

[0162] In a round bottom flask, thionicotinic acid was introduced into acetonitrile followed by carbonyldiimidazole (CDI). The mixture was refluxed for 1 hour. The mixture was returned to ambient temperature and sarcosine ethyl ester hydrochloride was added, and heating was then resumed at 60°C for 3 hours, and then overnight at ambient temperature.

[0163] After an overnight period, the reaction medium is evaporated. The residue is purified on silica with 20 / 80 ethyl acetate / heptane.

[0164] The fractions were evaporated and the product was then taken up in dichloromethane and precipitated from isopropyl ether.

[0165] A light yellow powder was obtained: yield: 22%.

[0166] Route 2: via 2-chloronicotinic acid

[0167]

[0168] In a three-necked flask, 2-chloronicotinic acid (300.0 g, 1.904 moles) was introduced dropwise into ethyl acetate (600 ml) and SOCl2 (249.0 g, 2.095 moles). The mixture was refluxed until complete conversion was obtained. The medium was cooled to ambient temperature and diluted with ethyl acetate (450 ml). Then a solution of sarcosine ethyl ester hydrochloride (351 g, 2.285 moles) and triethylamine (481.8 g, 4.76 moles) diluted in water (480 ml) were added. The mixture was stirred for 3 to 4 hours, and ethyl acetate was removed under vacuum. The obtained aqueous solution was diluted with water (1500 ml) and acidified with 3N HCl (30 ml). Sodium thiosulfate (1796 g, 7.24 moles) was loaded into the resulting solution and the mixture was refluxed until complete conversion was obtained. After cooling to 10°C, the yellow solid was filtered out and washed with water (3×900 ml).

[0169] The crude product was absorbed with carbon black in a 75 / 25 ethanol / water mixture. The carbon black was filtered off under hot conditions and the ethanol was evaporated. The product was cooled to ambient temperature, filtered and dried under vacuum. A light yellow powder was obtained: Yield: 69%.

[0170] 1 H NMR and mass spectra were consistent with the structure.

[0171] Melting point: 175°C (capillary)

[0172] Example 4: Synthesis of Compound 2 from Compound 4

[0173] N-Methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine

[0174]

[0175] N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine ethyl ester (50 g, 0.317 mole), 95% EtOH (100 ml) and water (80 ml) were introduced into a three-necked flask. The mixture was cooled to 10° C. A solution of NaOH (23.6 g) in 70 ml of water was added dropwise. After the conversion was complete, the organic solvent was evaporated and the pH was adjusted to 2-3. The resulting product was cooled to 0° C.-10° C. and filtered off. The product was washed with water and dried under vacuum.

[0176] A pale yellow powder was obtained: Yield: 45%.

[0177] 1 H NMR and mass spectra were consistent with the structure.

[0178] Melting point: 210.9℃-221.8℃(capillary)

[0179] Example 5 : Evidence of activity that constitutes melanin production

[0180] In order to evaluate the effect of preventing or reducing skin pigmentation and / or lightening the skin, the examples were carried out in the following manner.

[0181] The depigmenting activity (reduction of melanin production) of the compounds of formula (I) was measured by assaying normal human melanocytes in vitro as follows.

[0182] First, normal human melanocytes were cultured and distributed into 384 wells. After 24 hours, the culture medium was replaced with a medium containing the compound of formula (I) to be evaluated. The cells were incubated for 72 hours, and the final optical density was then measured, which measured the amount of melanin produced by the melanocytes. The dose-effect was performed using the compounds evaluated over a wide concentration range. Therefore, by making the concentrations correspond to the melanin measurements, the IC50 (μM: concentration) when achieving a 50% reduction in melanin synthesis can be determined. The highest concentration used in the test was 200 μM.

[0183] The compounds of formula (I) exhibit a strong decolorizing effect.

[0184] Compound No. IC50(μM) 1 11.4 2 5.27 3 36.8 4 67.6

[0185] In another exercise, compound 3 was compared with the closest compound of the prior art described in patent FR 2968661:

[0186]

[0187] The compounds of the present invention have an activity on reducing melanin production which is greater than that of a compound outside the present invention (CAS 1379867-59-0).

[0188] Example 6: Cosmetic composition

[0189] A skin depigmenting composition was prepared, comprising (g):

[0190] Compound No. 4 2g

[0191] PEG 400 68g

[0192] Ethanol 30g

[0193] The composition applied to the skin causes brown spots that may be caused to become less noticeable.

[0194] Example 7: Gel

[0195] A skin depigmenting gel was prepared comprising (in % by weight):

[0196]

[0197] The composition applied to the skin causes brown spots that may be caused to become less noticeable.

[0198] Example 8:

[0199] Tested on pigmented reconstructed epidermal samples

[0200] The composition of the solution of compound 1, 2, 3 or 4 included in 300 μM in DMSO is applied to the epidermal sample of pigmentation reconstruction (referring to EP 1878790). The control is DMSO. After staining with Fontana Masson dye, quantitative melanin is carried out by image analysis to histological sections. Each colored epidermal sample is photographed over its entire length using a camera connected to a microscope. Melanin is thresholded and the number of melanin pixels is measured in each region using automatic image analysis software. Non-parametric statistical tests are carried out to determine the significance of measurement (Mann-Whitney test).

[0201] The standard research model for reconstructed epidermis with pigmentation is published by:

[0202] Regnier M, Duval C, Galey JB, Philippe M, Lagrange A, Tuloup R, Schmidt R, Cellular and Molecular Biology, 1999, 45, 7, 969-980: "Keratinocyte-Melanocyte co-cultutes and pigmented reconstructed human epidermis: models to study modulation of melanogenesis".

Claims

1. A non-therapeutic cosmetic method for depigmenting, lightening and / or bleaching keratin materials, which method comprises applying a cosmetic composition comprising at least one compound of formula (I) in a physiologically acceptable medium: in: R1 represents a group selected from the following: a) Hydrogen atom; R2 represents a group selected from the following: a) Saturated straight chain C1-C 10 alkyl; b) Saturated branched chain C3-C 10 alkyl; c) C1-C6 phenylalkyl, And also their tautomers and their salts, alone or as a mixture.

2. The method according to claim 1, wherein the C1-C6 phenylalkyl group is a benzyl group.

3. The method according to claim 1 or 2, wherein: R1 represents a group selected from the following: a) Hydrogen atom; R2 represents a group selected from the following: a) saturated straight chain C1-C6 alkyl; b) Saturated branched C3-C6 alkyl.

4. The method according to claim 1 or 2, wherein: R1 represents a group selected from the following: a) Hydrogen atom; R2 represents a group selected from the following: a) saturated straight chain C1-C4 alkyl; b) Saturated branched C3-C4 alkyl.

5. The method according to claim 4, wherein the saturated straight-chain C1-C4 alkyl group is ethyl; and / or the saturated branched-chain C3-C4 alkyl group is selected from isopropyl, isobutyl and combinations thereof.

6. The method according to claim 1 or 2, wherein the compounds of formula (I) are selected from: And also their tautomers and their salts, alone or as a mixture.

7. The process according to claim 1 or 2, wherein the compound of formula (I) is present in the composition alone or as a mixture in an amount between 0.01% and 10% by weight relative to the total weight of the composition.

8. The process according to claim 7, wherein the compound of formula (I) is present in the composition alone or as a mixture in an amount between 0.1% and 5% by weight relative to the total weight of the composition.

9. The process according to claim 8, wherein the compound of formula (I) is present in the composition alone or as a mixture in an amount between 0.5% and 3% by weight relative to the total weight of the composition.

10. The method according to claim 1 or 2, wherein the composition comprises at least one auxiliary agent selected from the group consisting of: water; organic solvents; carbon-based oils and / or silicone oils of mineral, animal and / or plant origin; waxes, pigments, fillers, dyes, surfactants, emulsifiers, co-emulsifiers; cosmetic or dermatological active agents, UV screening agents, polymers, hydrophilic or lipophilic gelling agents, thickeners, preservatives, fragrances, bactericides, ceramides, odor absorbers, antioxidants.

11. The method according to claim 10, wherein the organic solvent is selected from C1-C6 alcohol, C2-C 10 Carboxylates and combinations thereof.

12. The method according to claim 1 or 2, wherein the composition comprises at least one active agent selected from the group consisting of: desquamation agents; soothing agents, organic or inorganic photoprotectants, moisturizers; depigmenting agents or pigment enhancers; anti-glycation agents; NO-synthase inhibitors; agents for stimulating the synthesis of dermal or epidermal macromolecules and / or for preventing their degradation; agents for stimulating the proliferation of fibroblasts and / or keratinocytes or for stimulating the differentiation of keratinocytes; muscle relaxants and / or dermal relaxants; tightening agents; anti-pollution agents and / or free radical scavengers; agents acting on capillary circulation; agents acting on cellular energy metabolism; and mixtures thereof.

13. Non-therapeutic cosmetic use of a compound of formula (I) according to any one of claims 1 to 9 as an agent for bleaching, lightening and / or depigmenting keratin materials.

14. A compound of formula (II): in: R1 represents a group selected from the following: a) Hydrogen atom; R2 represents a group selected from the following: a) Saturated straight chain C1-C 10 alkyl; b) Saturated branched chain C3-C 10 alkyl; c) C1-C6 phenylalkyl, and also their tautomers and their salts, alone or as a mixture, The following two compounds (a) and (b) and their tautomers are excluded: 。 15. The compound of formula (II) according to claim 14, wherein the C1-C6 phenylalkyl group is benzyl.

16. A compound of formula (II) according to claim 14 or 15, wherein R1 represents a group selected from the following: a) Hydrogen atom; R2 represents a group selected from the following: a) saturated straight chain C1-C6 alkyl; b) saturated branched C3-C6 alkyl; and also their tautomers and their salts, alone or as a mixture, The following compounds (a) and their tautomers are excluded: 。 17. A composition comprising at least one compound of formula (II) according to any one of claims 14 to 16.

18. The composition according to claim 17, wherein the composition is a cosmetic composition.

19. The composition according to claim 17 or 18, characterized in that Said compound of formula (II) is present in an amount between 0.01% and 10% by weight relative to the total weight of the composition.

20. The composition according to claim 19, characterized in that Said compound of formula (II) is present in an amount between 0.1% and 5% by weight relative to the total weight of the composition.

21. The composition according to claim 20, characterized in that Said compound of formula (II) is present in an amount between 0.5% and 3% by weight relative to the total weight of the composition.

22. A method for preparing compounds of formula (I) and (II) as described in any one of claims 1 to 21 according to the following scheme:

23. The preparation method according to claim 22, comprising the following steps: (i) Steps for preparing the compound of formula (W) wherein X forms an acyl halide, a mixed anhydride, an isourea or an acylphosphonate by activating the carboxyl group of 2-chloronicotinic acid in the presence of a reagent for activating a carboxylic acid according to a conventional method for activating an acid; and then ii) a step of reacting the compound (W) with an amine of formula (V) wherein R1 and R2 have the same meanings as those described in claim 1 to form a compound of formula (Y); Then iii) a step of exchanging chlorine with sulfur by a reagent to form compounds of formula (I) and (II), and then optionally iv) For compounds of formula (I) and (II) in which the R2 group represents hydrogen, said compounds can be obtained directly or by an additional step of saponification of the corresponding ester using an inorganic base after acidification.

24. The preparation method according to claim 23, wherein the reagent is selected from the group consisting of sodium bisulfite, thiourea, sodium thiosulfate, thioacetic acid and combinations thereof.

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