PROCESS FOR DEPIGMENTING KERATIN MATERIALS USING THIOPYRIDINONE COMPOUNDS
20190380937 · 2019-12-19
Inventors
- Xavier Marat (Aulnay-sous-Bois, FR)
- Amélie GUEGUINIAT (Aulnay-sous-Bois, FR)
- Sébastien GREGOIRE (Aulnay-sous-Bois, FR)
- Jinzhu XU (Aulnay-sous-Bois, FR)
- Patricio GUERREIRO (Aulnay-sous-Bois, FR)
Cpc classification
A61K8/4933
HUMAN NECESSITIES
International classification
Abstract
The invention relates to a cosmetic process for depigmenting, lightening and/or bleaching keratin materials, in particular the skin, comprising the application of a cosmetic composition comprising a compound of formula (I): compound of formula (I): (I) The invention also relates to the novel compounds of formula (I), to the compositions containing same and also to the cosmetic use of a compound (I) as an agent for bleaching, lightening and/or depigmenting keratin materials.
##STR00001##
Claims
1.-16. (canceled)
17. A method for depigmenting, lightening, and/or bleaching keratin materials, comprising applying to the keratin materials, a cosmetic composition, the cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I): ##STR00024## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; and R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof.
18. The method of claim 17, wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.4 alkyl radical; and R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.6 alkyl group; or c) a saturated branched C.sub.3-C.sub.6 alkyl group.
19. The method of claim 17, wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a methyl radical; and R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.4 alkyl group; or c) a saturated branched C.sub.3-C.sub.4 alkyl group.
20. The method of claim 17, wherein the at least one compound of formula (I) is chosen from: TABLE-US-00006 Compound Structure No. Chemical name
21. The method of claim 17, wherein the at least one compound of formula (I) is chosen from: TABLE-US-00007 Compound Structure No. Chemical name
22. The method of claim 17, wherein the at least one compound of formula (I) is present in an amount ranging from about 0.01% to about 10% by weight, relative to the total weight of the composition.
23. The method of claim 17, wherein the at least one compound of formula (I) is present in an amount ranging from about 0.5% to about 3% by weight, relative to the total weight of the composition.
24. The method of claim 17, wherein the composition further comprises at least one adjuvant chosen from water; organic solvents; carbon-based or silicone oils of mineral, animal, 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; or mixtures thereof.
25. The method of claim 17, wherein the composition comprises at least one active agent chosen from desquamating agents; soothing agents; organic or inorganic photo protective agents; moisturizers; depigmenting or propigmenting 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 fibroblast and/or keratinocyte proliferation or for stimulating keratinocyte differentiation; muscle relaxants and/or dermo-decontracting agents; tensioning agents; anti-pollution agents and/or free-radical scavengers; agents acting on the capillary circulation; agents acting on the energy metabolism of cells; or mixtures thereof.
26. A compound of formula (II): ##STR00031## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof, with the exception of the following two compounds (a) and (b) and the tautomers thereof: ##STR00032##
27. The compound of claim 26, wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.4 alkyl radical; R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.6 alkyl group; or c) a saturated branched C.sub.3-C.sub.6 alkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof, with the exception of the following compound (a) and the tautomers thereof: ##STR00033##
28. The compound of claim 26, chosen from: TABLE-US-00008 Compound Structure No. Chemical name
29. A cosmetic composition comprising at least one compound of formula (II), wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof, with the exception of the following two compounds (a) and (b) and the tautomers thereof: ##STR00037##
30. The composition of claim 29, wherein the at least one compound of formula (II) is present in an amount ranging from about 0.01% to about and 10% by weight, relative to the total weight of the composition.
31. The composition of claim 29, wherein the at least one compound of formula (II) is present in an amount ranging from about 0.5% to about 3% by weight, relative to the total weight of the composition.
32. A method for preparing compounds of formulae (I) and (II) below: ##STR00038## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; and R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof; ##STR00039## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, or a tautomer thereof, a salt thereof, a solvate thereof, an optical isomer thereof, a racemate thereof, or mixtures thereof, with the exception of the following two compounds (a) and (b) and the tautomers thereof: ##STR00040## according to the following scheme: ##STR00041## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, and X forms an acid halide, a mixed anhydride, a carbamimidate, or an acylphosphonate by activation of the carboxylic group of the 2-chloronicotinic acid in the presence of an agent for activating carboxylic acids according to the conventional methods for activating acids.
33. The method of claim 32, comprising: (i) preparing a compound of formula (W): ##STR00042## wherein X forms an acid halide, a mixed anhydride, a carbamimidate, or an acylphosphonate by activation of the carboxylic group of the 2-chloronicotinic acid in the presence of an agent for activating carboxylic acids according to the conventional methods for activating acids; ii) reacting the compound (W) with an amine of formula (V): ##STR00043## wherein: R1 is a radical chosen from: a) a hydrogen atom; or b) a saturated linear C.sub.1-C.sub.6 alkyl group; and R2 is a radical chosen from: a) a hydrogen atom; b) a saturated linear C.sub.1-C.sub.10 alkyl group; c) a saturated branched C.sub.3-C.sub.10 alkyl group; or d) a C.sub.1-C.sub.6 phenylalkyl group, so as to form a compound of formula (Y); ##STR00044## and iii) exchanging between the chlorine and the sulfur by means of reagents so as to form the compounds of formulae (I) or (II), iv) optionally, for the compounds of formulae (I) and (II) wherein the R2 radical is a hydrogen atom, the compounds are obtained either directly or by means of an additional step of saponification of the corresponding esters using inorganic bases following acidification.
Description
EXAMPLE 1: SYNTHESIS OF COMPOUND 3ETHYL N-[(2-THIOXO-1,2-DIHYDROPYRIDIN-3-YL)CARBONYL]GLYCINATE
[0104] ##STR00014##
Route 1: Via 2-mercaptonicotinic Acid
[0105] ##STR00015##
[0106] In a round-bottomed flask, thionicotinic acid is introduced into acetonitrile, followed by carbonyldiimidazole (CDI). The mixture is refluxed for 1 hour. The mixture is returned to ambient temperature and ethyl glycinate hydrochloride is added and then the heating is recommenced at 60 C. for 3 hours and then overnight at ambient temperature.
[0107] After the overnight period, the reaction medium is evaporated. The residue is taken up in dichloromethane and washed twice with 2 N HCl. The organic phase is dried over anhydrous sodium sulfate and then evaporated and purified on silica, 97/3 dichloromethane/methanol.
[0108] The fractions are evaporated.
[0109] A light-yellow-coloured powder is obtained: Yield: 37%.
Route 2: Via 2-Chloronicotinic Acid
[0110] ##STR00016##
[0111] In a three-necked flask, 2-chloronicotinic acid (250.0 g, 1.587 mol) is introduced into ethyl acetate (500 ml) and SOCl.sub.2 (210.0 g, 1.761 mol), dropwise. The mixture is refluxed until complete conversion is obtained. The medium is cooled to ambient temperature and diluted with ethyl acetate (375 ml). A solution of ethyl glycinate hydrochloride (265.8 g, 1.904 mol) diluted in water (400 ml) and triethylamine (393.5 g, 3.88 mol) are then added. The mixture is stirred for 3 to 4 h and the ethyl acetate is removed under vacuum. The aqueous solution obtained is diluted with water (1250 ml) and acidified with 3 N HCl (25 ml). Sodium thiosulfate (1379 g, 5.555 mol) is charged to the resulting solution and the mixture is refluxed for 6 h. After cooling to 10 C., the yellow solid is filtered off and washed with water (3750 ml).
[0112] The crude product is taken up with carbon black in a 75/25 ethanol/water mixture. The carbon black is filtered off under hot conditions and the ethanol is evaporated off. The product is cooled to ambient temperature, filtered and dried under vacuum. A light-yellow-coloured powder is obtained: Yield: 88%.
[0113] The .sup.1H NMR and mass spectra are in accordance with the structure. Melting point: 151 C. (capillary tube)
EXAMPLE 2: SYNTHESIS OF COMPOUND 1
N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycine from Compound 3
[0114] ##STR00017##
[0115] Ethyl N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate (48 g, 0.317 mol), 95% EtOH (48 ml) are introduced into a three-necked flask and cooled to 10 C. A solution of NaOH (16 g) in 144 ml of water is added dropwise. The organic solvent is evaporated off and the pH is adjusted to 3-4. The resulting product is cooled to 0-10 C. and filtered. The product is washed with water and dried under vacuum.
[0116] A light-yellow-coloured powder is obtained: Yield: 96%.
[0117] The .sup.1H NMR and mass spectra are in accordance with the structure.
[0118] Melting point: 241.0-241.8 C. (capillary tube)
EXAMPLE 3: SYNTHESIS OF COMPOUND 4ETHYL N-METHYL-N-[(2-THIOXO-1,2-DIHYDROPYRIDIN-3-YL)CARBONYL]GLYCINATE
[0119] ##STR00018##
Route 1: Via 2-mercaptonicotinic Acid
[0120] ##STR00019##
[0121] In a round-bottomed flask, thionicotinic acid is introduced into acetonitrile, followed by carbonyldiimidazole (CDI). The mixture is refluxed for 1 hour. The mixture is returned to ambient temperature and ethyl sarcosinate hydrochloride is added and then the heating is recommenced at 60 C. for 3 hours and then overnight at ambient temperature.
[0122] After the overnight period, the reaction medium is evaporated. The residue is purified on silica, 20/80 ethyl acetate/heptane.
[0123] The fractions are evaporated and then the product is taken up in dichloromethane and precipitated from isopropyl ether.
[0124] A light-yellow-coloured powder is obtained: Yield: 22%.
Route 2: Via 2-chloronicotinic Acid
[0125] ##STR00020##
[0126] In a three-necked flask, 2-chloronicotinic acid (300.0 g, 1.904 mol) is introduced into ethyl acetate (600 ml) and SOCl.sub.2 (249.0 g, 2.095 mol), dropwise. The mixture is refluxed until complete conversion is obtained. The medium is cooled to ambient temperature and diluted with ethyl acetate (450 ml). A solution of ethyl sarcosinate hydrochloride (351 g, 2.285 mol) diluted in water (480 ml) and triethylamine (481.8 g, 4.76 mol) are then added. The mixture is stirred for 3 to 4 h and the ethyl acetate is removed under vacuum. The aqueous solution obtained is diluted with water (1500 ml) and acidified with 3 N HCl (30 ml). Sodium thiosulfate (1796 g, 7.24 mol) is charged to the resulting solution and the mixture is refluxed until complete conversion is obtained. After cooling to 10 C., the yellow solid is filtered off and washed with water (3900 ml). The crude product is taken up with carbon black in a 75/25 ethanol/water mixture. The carbon black is filtered off under hot conditions and the ethanol is evaporated off. The product is cooled to ambient temperature, filtered and dried under vacuum. A light-yellow-coloured powder is obtained: Yield: 69%.
[0127] The .sup.1H NMR and mass spectra are in accordance with the structure. Melting point: 175 C. (capillary tube)
EXAMPLE 4: SYNTHESIS OF COMPOUND 2 FROM COMPOUND 4 N-METHYL-N-[(2-THIOXO-1,2-DIHYDROPYRIDIN-3-YL)CARBONYL]GLYCINE
[0128] ##STR00021##
[0129] Ethyl N-methyl-N-[(2-thioxo-1,2-dihydropyridin-3-yl)carbonyl]glycinate (50 g, 0.317 mol), 95% EtOH (100 ml) and water (80 ml) are introduced into a three-necked flask. The mixture is cooled to 10 C. A solution of NaOH (23.6 g) in 70 ml of water is added dropwise. After complete conversion, the organic solvent is evaporated off and the pH is adjusted to 2-3. The resulting product is cooled to 0-10 C. and filtered. The product is washed with water and dried under vacuum. A light-yellow-coloured powder is obtained: Yield: 45%.
[0130] The .sup.1H NMR and mass spectra are in accordance with the structure.
[0131] Melting point: 210.9-221.8 C. (capillary tube)
EXAMPLE 5: DEMONSTRATION OF THE ACTIVITY ON CONSTITUTIVE MELANOGENESIS
[0132] For the evaluations of the effect of prevention or of decrease of pigmentation of the skin and/or of lightening of the skin, the examples are carried out in the following way.
[0133] The measurement of the depigmenting activity (reduction of melanin production) of compounds of formula (I) was carried out by assaying normal human melanocytes in vitro as follows.
[0134] First of all, normal human melanocytes are cultured and dispensed into 384 wells. After 24 hours, the culture medium was replaced with a medium containing compounds of formula (I) to be evaluated. The cells were incubated for 72 hours before measuring the final optical density, which measures the amount of melanin produced by the melanocytes. A dose-effect is performed using a wide concentration range of the compounds evaluated. Thus, by making the concentrations and the melanin measurements correspond, it is possible to determine an IC50 in M: concentration at which 50% decrease in melanin synthesis is achieved. The highest concentration used in the test is 200 M.
[0135] The compounds of formula (I) showed a strong depigmenting effect.
TABLE-US-00002 Compound No. IC50 (M) 1 11.4 2 5.27 3 36.8 4 67.6
[0136] In another campaign, compound 3 was compared with the closest compound of the prior art described in patent FR 2 968 661:
TABLE-US-00003 Compound No. IC50 (M)
[0137] The compounds of the invention have an activity on melanogenesis reduction that is greater than that of the compound (CAS 1379867-59-0) outside the invention.
EXAMPLE 6: COSMETIC COMPOSITION
[0138] A skin depigmenting composition is prepared, comprising (in grams):
TABLE-US-00004 Compound No. 4 2 g PEG 400 68 g Ethanol 30 g
[0139] The composition applied to the skin makes it possible to cause brown spots to become less marked.
EXAMPLE 7: GEL
[0140] A skin depigmenting gel is prepared, comprising (% by weight):
TABLE-US-00005 Compound No. 1 0.5% Carbomer 1% (Carbopol 981 from Lubrizol) preservative qs water qs 100%
[0141] The composition applied to the skin makes it possible to cause brown spots to become less marked.
EXAMPLE 8
Test on Pigmented Reconstructed Epidermis Samples
[0142] Compositions comprising 300 M of compound 1, 2, 3 or 4 in DMSO were applied to samples of pigmented reconstructed epidermis (cf. EP 1 878 790). The control is DMSO. The melanin was quantified by image analysis on histological slices after staining with Fontana Masson dye. Each sample of coloured epidermis is photographed over its entire length using a camera connected to a microscope. The melanin is thresholded and the number of melanin pixels is measured in each field using automated image analysis software. A non-parametric statistical test is performed in order to determine the significance of the measurements (Mann-Whitney test).
[0143] The pigmented reconstructed epidermis standard study model was published by:
[0144] Regnier M, Duval C, Galey J B, Philippe M, Lagrange A, Tuloup R, Schmidt R, Cellular and Molecular Biology, 1999, 45, 7, 969-980: Keratinocyte-Melanocyte co-cultures and pigmented reconstructed human epidermis: models to study modulation of melanogenesis.
[0145] Significant depigmenting activity was evaluated at 100 M for compounds 1 and 2. (pValue<0.05: significant depigmenting activity).
[0146] Significant depigmenting activity was evaluated at 300 M for compounds 3 and 4. (pValue<0.05: significant depigmenting activity).