DITHIAZOCANE COMPOUNDS FOR THE COSMETIC USE THEREOF
20210000727 · 2021-01-07
Inventors
Cpc classification
C07D417/12
CHEMISTRY; METALLURGY
International classification
Abstract
The invention relates to the non-therapeutic cosmetic use of at least one compound of formula (I) as defined below, as an agent for bleaching, lightening and/or depigmenting keratin materials, especially the skin. The invention also relates to a non-therapeutic cosmetic process for depigmenting, lightening and/or bleaching keratin materials, especially the skin, using these compounds (I).
##STR00001##
Claims
1.-17. (canceled)
18. A method for bleaching, lightening, and/or depigmenting a keratin material, comprising applying to the keratin material a composition comprising at least one compound of formula (I), ##STR00071## salts thereof, solvates thereof, optical and/or geometrical isomers thereof, including enantiomers and diastereoisomers thereof, racemates thereof, or mixtures thereof: wherein in formula (I): R is chosen from a radical OR or NR.sub.aR.sub.b; R.sub.1 is chosen from a hydrogen atom or a (C.sub.1-C.sub.18)alkyl group; R is chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; (hetero)cycloalkyl, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the (hetero)cycloalkyl denoting a ketone (CO); or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; or iv) an optionally substituted aryl or heteroaryl radical; R.sub.a and R.sub.b are independently chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl; optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; iv) an aryl or heteroaryl radical, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, hydroxyl, or C.sub.1-C.sub.4 alkoxy; or v) a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the heterocycloalkyl radical denoting a ketone (CO); or R.sub.a and R.sub.b form, together with the nitrogen atom to which R.sub.a and R.sub.b are attached, an optionally substituted heterocycloalkyl.
19. The method of claim 18, wherein the at least one compound of formula (I) is of R configuration.
20. The method of claim 18, wherein in formula (I), R.sub.1 is chosen from a (C.sub.1-C.sub.6)alkyl group or a hydrogen atom.
21. The method of claim 18, wherein in formula (I), R is an OR radical, in which R is chosen from: A) a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group; B) a (C.sub.1-C.sub.6) alkyl group optionally substituted with at least one identical or different radical chosen from: hydroxyl; heterocycloalkyl substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, and/or one of the ring members of the heterocycloalkyl is a ketone (CO); or phenyl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; C) a (C.sub.1-C.sub.14)alkyl group, the (C.sub.1-C.sub.14) alkyl group being interrupted with at least one heteroatom; D) a radical of formula (B1): ##STR00072## wherein R.sub.h and R.sub.k are independently chosen from a hydrogen atom or a methyl radical; R.sub.l is H or OH; and y denotes an integer from 1 to 10; or E) a (C.sub.1-C.sub.6) alkenyl group, optionally substituted with at least one identical or different radical chosen from: hydroxyl; heterocycloalkyl substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy; and/or one of the ring members of the heterocycloalkyl is a ketone (CO); or phenyl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl.
22. The method of claim 18, wherein in formula (I), R is an NR.sub.aR.sub.b radical, wherein: A) R.sub.a and R.sub.b are independently chosen from a hydrogen atom or a (C.sub.1-C.sub.18)alkyl group; B) R.sub.a is a hydrogen atom and R.sub.b is chosen from a (C.sub.1-C.sub.4)alkyl group, the (C.sub.1-C.sub.4)alkyl group being optionally substituted with at least one identical or different radical chosen from: hydroxyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, or phenyl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; or C) R.sub.a is a hydrogen atom and R.sub.b represents a radical of the following formula B2: ##STR00073## wherein: i=0 or 1; R.sub.4 is chosen from a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group optionally substituted with at least one group chosen from: i) ZC(Z)ZR.sub.C, wherein Z, Z, and Z, which are identical or different, represent an oxygen atom, a sulfur atom, or N(R.sub.D), wherein R.sub.C and R.sub.D, which are identical or different, are chosen from a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group; ii) (hetero)aryl, optionally substituted with a hydroxyl group; iii) (di)(C.sub.1-C.sub.4)(alkyl)amino; iv) C(Z)ZR.sub.C, wherein Z, Z and R.sub.C are defined as above; or v) ZR.sub.C, wherein Z is chosen from an oxygen, a sulfur atom, a selenium atom, or an NH group, and R.sub.C is as defined previously; or, when i=0, R.sub.a and R.sub.4 form, together with the nitrogen atom which bears R.sub.a and with the carbon atom which bears R.sub.4, a saturated 5- or 6-membered heterocycle; R.sub.6 is chosen from: i) a hydroxyl radical OH; ii) a saturated or unsaturated (C.sub.1-C.sub.6)alkoxy radical; or iii) an NRfRg radical, wherein Rf and Rg, which are identical or different, are chosen from a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; D) R.sub.a is a hydrogen atom and R.sub.b represents a radical of formula (B2) as defined above, wherein in formula (B2), R.sub.6 is a hydroxyl radical or a saturated or unsaturated (C.sub.1-C.sub.6)alkoxy radical, and R.sub.4 is a hydrogen atom or is chosen from radicals (a1) to (a32): ##STR00074## ##STR00075## or, when i=0, R.sub.a and R.sub.4 form, together with the nitrogen atom which bears R.sub.a and with the carbon atom which bears R.sub.4, a saturated 5- or 6-membered heterocycle of formula A1, A2, or A3: ##STR00076## E) R.sub.a is a hydrogen atom and R.sub.b is a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of the ring members of the heterocycloalkyl radical is a ketone (CO); or F) R.sub.a is a hydrogen atom and R.sub.b represents a glucopyran radical of formula (V): ##STR00077## wherein in formula (V), R.sub.a, R.sup.b, R.sup.d, R.sup.e, and R.sup.f, which are identical or different, are chosen from: i) a hydroxyl group, ii) (C.sub.1-C.sub.4)alkoxy, the alkyl part of which is optionally substituted with at least one hydroxyl group, iii) carboxy, or iv) an NR.sub.1R.sub.2 group, wherein R.sub.1 and R.sub.2, which are identical or different, are chosen from a hydrogen atom, (C.sub.1-C.sub.4)alkyl, or acetyl; and wherein one of the radicals R.sub.a, R.sup.b, R.sup.d, R.sup.e, and R.sup.f represents a covalent bond with the nitrogen atom of the NR.sub.aR.sub.b radical; and the configuration of the glucopyran radical of formula (V) is D or Land of (alpha) or (beta) anomeric configuration.
23. The method of claim 18, wherein the at least of one compound of formula is chosen from compounds 1 to 15 and 18 to 20, salts thereof, solvates thereof, optical and/or geometrical isomers thereof, including enantiomers and diastereoisomers thereof, racemates thereof, or mixtures thereof: TABLE-US-00008 Structure Compound
24. The method of claim 23, wherein the at least one compound of formula (I) is chosen from the compounds 5 to 15 and 18 to 20, or compounds 1 to 4 below, salts thereof, solvates thereof, optical and/or geometrical isomers thereof, including enantiomers and diastereoisomers thereof, racemates thereof, or mixtures thereof: 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylic acid (compound 1 (R enantiomer)), methyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 2), 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxamide (compound 3), N,N,7,7-tetramethyl-6-oxo-1,2,5-dithiazocane-4-carboxamide (compound 4), TABLE-US-00009 Structure Compound
25. The method of claim 18, wherein in the at least one compound of formula (I) is chosen from 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-(R)-carboxylic acid (compound 1), methyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4 (R)-carboxylate (compound 2) below: TABLE-US-00010 Compound Structure 1
26. The method of claim 18, where the method comprises topically applying the composition to skin.
27. A compound of formula (I), a salt thereof, a solvate thereof, an optical isomer thereof, a geometrical isomer thereof, including an enantiomer or diastereoisomer thereof, or a racemate thereof, ##STR00106## wherein in formula (I): R is chosen from a radical OR or NR.sub.aR.sub.b; R.sub.1 is chosen from a hydrogen atom or a (C.sub.1-C.sub.18)alkyl group; R is chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; (hetero)cycloalkyl, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the (hetero)cycloalkyl denoting a ketone (CO); or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; or iv) an optionally substituted aryl or heteroaryl radical; R.sub.a and R.sub.b are independently chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl; optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; iv) an aryl or heteroaryl radical, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, hydroxyl, or C.sub.1-C.sub.4 alkoxy; or v) a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the heterocycloalkyl radical denoting a ketone (CO); or Ra and Rb form, together with the nitrogen atom to which R.sub.a and R.sub.b are attached, an optionally substituted heterocycloalkyl; wherein the compound is not chosen from compounds Cp1 to Cp5 below: 1,2,5-Dithiazocine-4-carboxamide, hexahydro-7,7-dimethyl-6-oxo-, (4R)-(Cp1), 1,2,5-Dithiazocine-4-carboxamide, hexahydro-N,N,7,7-tetramethyl-6-oxo-, (4R)-Rotation () (Cp2), 1,2,5-Dithiazocine-4-carboxylic acid, hexahydro-7,7-dimethyl-6-oxo-, methyl ester, (R)-(9Cl) (Cp3), 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylic acid (Cp4), TABLE-US-00011 Structure Compound
28. The compound of claim 27, wherein the compound is chosen from compounds of formula (F1), salts thereof, solvates thereof, optical isomers thereof, geometrical isomers thereof, including enantiomers and diastereoisomers thereof, racemates thereof, or mixtures thereof: ##STR00111## wherein in formula (F1): R is chosen from a radical OR or NR.sub.aR.sub.b; and Sub represents a (C.sub.1-C.sub.18)alkyl group.
29. The compound of claim 27, wherein the compound is chosen from compounds of formula (F2), salts thereof, solvates thereof, optical isomers thereof, geometrical isomers thereof, including enantiomers and diastereoisomers thereof, racemates thereof, or mixtures thereof: ##STR00112## wherein in formula (F2): Sub is a radical OT or NT.sub.aT.sub.b; T is chosen from: i) a (C.sub.2-C.sub.18)alkyl group, wherein: the (C.sub.2-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; (hetero)cycloalkyl, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of the ring members of the (hetero)cycloalkyl denoting a ketone (CO); aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or the (C.sub.2-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; ii) a (C.sub.2-C.sub.18)alkenyl group, wherein: the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl, aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; or iii) an optionally substituted aryl or heteroaryl radical; Ta represents a radical chosen from: i) a hydrogen atom; ii) a (C.sub.2-C.sub.18)alkyl group, the (C.sub.2-C.sub.18)alkyl group being optionally substituted with at least one identical or different radicals chosen from: hydroxyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or the (C.sub.2-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, the (C.sub.2-C.sub.18)alkenyl group being optionally substituted with at least one identical or different radicals chosen from: hydroxyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; iv) an aryl or heteroaryl radical, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, hydroxyl, or C.sub.1-C.sub.4 alkoxy; v) a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of the ring members of the heterocycloalkyl radical denoting a ketone (CO); T.sub.b represents a radical chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, the (C.sub.1-C.sub.18)alkyl group being optionally substituted with at least one identical or different radical chosen from: hydroxyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, aryl, optionally substituted with at least one identical or different radicals chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxyl, and/or the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, the (C.sub.2-C.sub.18)alkenyl group being optionally substituted with at least one identical or different radicals chosen from: hydroxyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; iv) an aryl or heteroaryl radical, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, hydroxyl, or C.sub.1-C.sub.4 alkoxy; v) a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of the ring members of the heterocycloalkyl radical denoting a ketone (CO); or Ta and T.sub.b form, together with the nitrogen atom to which Ta and T.sub.b are attached, an optionally substituted heterocycloalkyl.
30. The compound of claim 27, wherein the compound is chosen from compounds 5 to 15 and 18 to 20 below: ethyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 5); propan-2-yl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 6); N-(2-hydroxyethyl)-7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxamide (compound 7); ethyl N-[(7,7-dimethyl-6-oxo-1,2,5-dithiazocan-4-yl)carbonyl]glycinate (compound 8); ethyl N-[(7,7-dimethyl-6-oxo-1,2,5-dithiazocan-4-yl)carbonyl]phenylalaninate (compound 9); 2-(2-methoxyethoxy)ethyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 10); 1-({1-[(1-methoxypropan-2-yl)oxy]propan-2-yl}oxy)propan-2-yl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 11); N-[(7,7-dimethyl-6-oxo-1,2,5-dithiazocan-4-yl)carbonyl]glycine (compound 12); N-heptyl-7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxamide (compound 13); 2-deoxy-2-{[(7,7-dimethyl-6-oxo-1,2,5-dithiazocan-4-yl)carbonyl]amino}hexo-pyranose (compound 14); 2-(4-hydroxyphenyl)ethyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 15); 2,3-dihydroxypropyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 18); 4,8-anhydro-1,3-dideoxy-2-O-[(7,7-dimethyl-6-oxo-1,2,5-dithiazocan-4-yl)-carbonyl]octitol (compound 19); or 2-(3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-carboxylate (compound 20): TABLE-US-00012 Structure Compound
31. The compound of claim 27, wherein the compound is chosen from 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4-(R)-carboxylic acid (compound 1), methyl 7,7-dimethyl-6-oxo-1,2,5-dithiazocane-4 (R)-carboxylate (compound 2) below: TABLE-US-00013 Compound Structure 1
32. A composition comprising, in a physiologically acceptable medium, at least one compound of formula (I), ##STR00129## a salt thereof, a solvate thereof, an optical isomer thereof, a geometrical isomer thereof, including an enantiomer and a diastereoisomer thereof, a racemate thereof, or a mixture thereof; wherein in formula (I): R is chosen from a radical OR or NR.sub.aR.sub.b; R.sub.1 is chosen from a hydrogen atom or a (C.sub.1-C.sub.18)alkyl group; R is chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; (hetero)cycloalkyl, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the (hetero)cycloalkyl denoting a ketone (CO); or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; or iv) an optionally substituted aryl or heteroaryl radical; R.sub.a and R.sub.b are independently chosen from: i) a hydrogen atom; ii) a (C.sub.1-C.sub.18)alkyl group, wherein: a) the (C.sub.1-C.sub.18)alkyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.1-C.sub.18)alkyl group is optionally interrupted with at least one heteroatom; iii) a (C.sub.2-C.sub.18)alkenyl group, wherein: a) the (C.sub.2-C.sub.18)alkenyl group is optionally substituted with at least one identical or different radical chosen from: hydroxyl; carboxy; (C.sub.1-C.sub.6)alkyloxycarbonyl; or aryl; optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or hydroxyl; and/or b) the (C.sub.2-C.sub.18)alkenyl group is optionally interrupted with at least one heteroatom; iv) an aryl or heteroaryl radical, optionally substituted with at least one identical or different radical chosen from C.sub.1-C.sub.4 alkyl, hydroxyl, or C.sub.1-C.sub.4 alkoxy; or v) a heterocycloalkyl radical, optionally substituted with at least one identical or different radical chosen from hydroxyl, C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy, and/or at least one of ring members of the heterocycloalkyl radical denoting a ketone (CO); or R.sub.a and R.sub.b form, together with the nitrogen atom to which R.sub.a and R.sub.b are attached, an optionally substituted heterocycloalkyl.
33. The composition of claim 32, wherein the at least one compound of formula (I) is present in an amount of between 0.01% and 10% by weight, relative to the total weight of the composition.
34. The composition of claim 32, wherein the at least one compound of formula (I) is present in an amount of between 0.1% and 5% by weight, relative to the total weight of the composition.
35. The composition of claim 32, wherein the at least one compound of formula (I) is present in an amount of between 0.5% and 3% by weight, relative to the total weight of the composition.
36. The composition of claim 32, wherein the composition further comprises at least one adjuvant chosen from organic solvents, oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic active agents, organic or mineral photoprotective agents, polymers, thickeners, preservatives, fragrances, bactericides, ceramides, odor absorbers, or antioxidants.
Description
EXAMPLES 1 AND 2: SYNTHESIS OF COMPOUNDS 1 AND 2
[0244] By Ito, Susumu et al., from Chemical & Pharmaceutical Bulletin, 41(6), 1066-73; 1993 and in patent EP 356006A1 Procedure:
[0245] To a solution of N-(3-mercapto-2,2-dimethylpropionyl)-L-cysteine (31 g, 130 mmol) in 440 ml of ethyl acetate, the following are added: a solution of iodine (33 g, 130 mmol) in 440 ml of EtOAc, then dropwise, between 10 and +5 C., a solution of triethylamine (29 g, 290 mmol) in 430 ml of EtOAc over 3 h. The mixture is stirred at this temperature for 1 hour. The triethylammonium iodide precipitate formed is then filtered, and the filtrate is washed with 1 N hydrochloric acid, sodium bisulfite at 1% in water then a saturated sodium chloride solution. After concentrating the filtrate under vacuum, a precipitate forms which, after filtration, is recrystallized in a (1/5) ethanol/water mixture to give compound 1 (19.4 g, 63%).
[0246] The MS and NMR spectra are in accordance with the desired product.
[0247] Diazomethane dissolved in ether at 0 C. is added to a solution of compound 1 (11 g) acidified with hydrochloric acid (3.9 N in EtOAc) in methyl acetate (250 ml). At the end of the addition, the reaction mixture is stirred for 10 minutes before adding 8 ml of acetic acid thereto. After concentration under vacuum, the crude product is purified by silica column to give compound 2 with a yield of 88%.
[0248] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 3: SYNTHESIS OF COMPOUND 3
[0249] To a solution of compound 1 (1 eq, 500 mg) in anhydrous Tetrahydrofurane (THF) 5 ml at 0 C., we added oxalyle chloride (COCl).sub.2 (1.5 eq, 0.274 ml) and 2 drops of N,N-Dimethylformamide (DMF). The mixture was stirred for 4 hours and concentrated with toluene. The residue was solubilized in a mix of THF/dioxane/DMF (60 ml/30 ml/15 ml) and cool at 0 C. bubbling with ammonia during 1 hour and the stirring is continued for 16 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on inverse silica gel (H.sub.2O/Acetonitrile: 95/5 to 5/95) and lyophilized to give compound 3 with a yield of 42%.
[0250] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 4: SYNTHESIS OF COMPOUND 4
[0251] To a solution of compound 1 (1 eq; 200 mg) in anhydrous N,N-Dimethylformamide (DMF) 4 ml, we added Me.sub.2NH (2 eq, 2M/THF; 0.85 ml), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.1 eq; 355 mg) and N, N-diisopropylthylamine (DIEA) (3 eq, 0.421 ml). The mixture was stirred for 20 hours at room temperature. Water was added to the mixture and extracted with Dicloromethane (DCM) (1 time), ethyl acetate (AcOEt) (1 time) and dichloromethane (DCM) (1 time). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/MeOH: 97/3) to give compound 4, with a yield of 49%.
[0252] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 5: SYNTHESIS OF COMPOUND 5
[0253] To a solution of compound 1 (1 eq; 300 mg) in dichloromethane (DCM) 6 ml, we added successively N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 395 mg), Ethanol (5 eq, 0.37 ml) and 4-dimethylaminopyridine (DMAP) (0.1 eq, 15.6 mg). The mixture was stirred for 16 hours at room temperature. Brine was added to the mixture and extracted with ethyl acetate (AcOEt) (3 times). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/cyclohexane: 9/1) to give compound 5 with a yield of 71%.
[0254] The MS and NMR spectra are in accordance with the desired product
EXAMPLE 6: SYNTHESIS OF COMPOUND 6
[0255] To a solution of compound 1 (1 eq, 250 mg) in dichloromethane (DCM) 5 ml, we added successively N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 328 mg), Isopropanol (5 eq, 0.41 ml) and 4-dimethylaminopyridine (DMAP) (0.1 eq, 13 mg). The mixture was stirred for 16 hours at room temperature. Brine was added to the mixture and extracted with ethyl acetate (AcOEt) (3 times). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (cyclohexane/AcOEt: 8/2) to give compound 6, with a yield of 72%.
[0256] The MS and NMR spectra are in accordance with the desired product
EXAMPLE 7: SYNTHESIS OF COMPOUND 7
[0257] To a solution of compound 1 (1 eq, 400 mg) in anhydrous N,N-Dimethylformamide (DMF) 8 ml, we added (2-aminoethoxy)(tert-butyl)dimethylsilane (2 eq, 596 mg), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.1 eq, 732 mg) and N, N-diisopropylthylamine (DIEA) (3 eq, 0.843 ml). The mixture was stirred for 40 hours at room temperature. Water was added to the mixture and extracted with dichloromethane (DCM) (1 time), AcOEt (1 time) and dichloromethane (DCM) (1 time). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/acetone 99/1 to 95/5) to give intermediate compound with a yield of 55%.
[0258] The compound obtained (1 eq, 370 mg) previously was dissolved in anhydrous DCM 10 ml, HCl (4N/dioxane, 2 eq, 0.47 ml) was added at 0 C. The mixture was stirred for 20 hours at 0 C. after it was concentrated under reduced pressure. The residue is purified by chromatography on silica gel (3 times DCM/EtOH: 95/5 to 92/8 and 1 time AcOEt/MeOH: 97/3) to give compound 7 with a yield of 27%.
[0259] The MS and NMR spectra are in accordance with the desired product
EXAMPLE 8: SYNTHESIS OF COMPOUND 8
[0260] To a solution of compound 1 (1 eq, 400 mg) in anhydrous N,N-Dimethylformamide (DMF).sub.12 ml, we added at 0 C. under Argon, ethyl-2-(chloroamino)-acetate (2 eq, 303 mg), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.1 eq, 732 mg) and N, N-diisopropylthylamine (DIEA) (5 eq, 1.38 ml). The mixture was stirred for 40 hours at room temperature after it was concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/AcOEt: 85/15 to 75/15 (2 times)) to give compound 8 with a yield of 70%.
[0261] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 9: SYNTHESIS OF COMPOUND 9
[0262] To a solution of compound 1 (1 eq; 150 mg) in anhydrous N,N-Dimethylformamide (DMF) 5 ml, we added at 0 C. under Argon, ethyl-2-(chloroamino)-3-phenyl-propanoate (1.3 eq, 187 mg), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.1 eq, 286 mg) and DIEA (5 eq, 0.55 ml). The mixture was stirred for 40 hours at room temperature after it was concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/AcOEt: 85/15 to 8/2) to give compound 9 with a yield of 89%.
[0263] The MS and NMR spectra are in accordance with the desired product
EXAMPLE 10: SYNTHESIS OF COMPOUND 10
[0264] To a solution of compound 1 (1 eq, 250 mg) in dichloromethane (DCM) 5 ml, we added successively N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 328 mg), 2-(2-methoxyethoxy)ethanol (5 eq, 0.632 ml) and 4-dimethylaminopyridine (DMAP) (0.2 eq, 26 mg). The mixture was stirred for 16 hours at room temperature. Brine was added to the mixture and extracted with ethyl acetate (AcOEt) (3 times). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/AcOEt: 85/15 (6 times)) to give compound 10 with a yield of 52%.
[0265] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 11: SYNTHESIS OF COMPOUND 11
[0266] To a solution of compound 1 (1 eq, 250 mg) in dichloromethane (DCM) 5 ml, we added successively N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 328 mg), 1-({1-[(1-methoxypropan-2-yl}oxy]propan-2-yl)oxy)popan-2-ol (5 eq, 1.15 g) and 4-dimethylaminopyridine (DMAP) (0.2 eq, 26 mg). The mixture was stirred for 16 hours at room temperature. Brine was added to the mixture and extracted with ethyl acetate (AcOEt) (3 times). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/AcOEt: 85/15 (5 times)) to give compound 11 with a yield of 54%.
[0267] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 12: SYNTHESIS OF COMPOUND 12
[0268] To a solution of compound 1 (1 eq, 400 mg) with N-hydroxysuccinimide (1.5 eq, 293 mg) in N,N-Dimethylformamide (DMF) 4 ml at 0 C., we added slowly N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 526 mg) in solution in N,N-Dimethylformamide (DMF) 3 ml. The mixture was stirred for 2 hours at room temperature and a solution of glycine (1.1 eq, 140 mg) with KHCO.sub.3 (2 eq, 340 mg) in water (10 ml) was added. The mixture was stirred for 16 hours at room temperature and cool with ice bath. Water (5 ml) was added and slowly formic acid was added pH 3.
[0269] The mixture was lyophilized. The crude was purified by chromatography on inverse silica gel (H.sub.2O/Acetonitrile: 95/5 to 5/95) to give compound 12 with a yield of 36%.
[0270] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 13: SYNTHESIS OF COMPOUND 13
[0271] To a solution of compound 1 (1 eq; 300 mg) in anhydrous N,N-Dimethylformamide (DMF) 6 ml, we added reactant heptylamine (2 eq, 0.838 ml), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.1 eq; 549 mg) and N, N-diisopropylthylamine (DIEA) (3 eq, 0.632 ml). The mixture was stirred for 40 hours at room temperature. Water was added to the mixture and extracted with Dicloromethane (DCM) (1 time), ethyl acetate (AcOEt) (1 time) and dichloromethane (DCM) (1 time). The organic layer was mixed and dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (DCM/Acetone: 95/5 (2 times) and DCM/AcOEt: 8/2 (2 times)) to give compound 13 with a yield of 48%.
[0272] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 14: SYNTHESIS OF COMPOUND 14
[0273] To a suspension of D-(+)-glucosamine.HCl (1 eq, 400 mg) in pyridine (8 ml), we added successively hexamethyldisilazane (HMDS) (10 eq, 3.94 ml) and chlorotrimethylsilane (10 eq, 2.37 ml). The mixture was stirred for 20 hours at room temperature after it was concentrated under reduced pressure with toluene and purified by chromatography on silica gel (cyclohexane/AcOEt: 9/1). A colorless oil is obtained, yield 63%
[0274] To a solution of compound 1 (1 eq, 178 mg) in N,N-Dimethylformamide (DMF) 4.5 ml, we added successively the compound synthesized previously (1.1 eq, 390 mg), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.2 eq, 345 mg) and N, N-diisopropylthylamine (DIEA) (5 eq, 0.63 ml). The mixture was stirred for 20 hours at room temperature. Water (30 ml) was added and the solution was lyophilized. The crude was used for the next step.
[0275] The crude was solubilized in a mix of DCM/MeOH 8/2 (15 ml) after silicagel and a little of AcOH (0.1 ml) was added. The mixture was stirred for 2 days at room temperature before to be filtered and concentrated under reduced pressure. The crude was purified by chromatography on inverse silica gel (H.sub.2O/ACN: 98/2 to 95/5). We obtained a white powder with global yield of 77% for the three steps.
[0276] The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 15: SYNTHESIS OF COMPOUND 18
[0277] To a solution of compound 1 (1 eq, 400 mg) in dichloromethane (DCM)/N,N-Dimethylformamide (DMF) (6 ml/3 ml), we added N,N-dicyclohexylcarbodiimide (DCC) (1.5 eq, 526 mg). The mixture was stirred for 5 min at room temperature after solketal (5 eq, 1.09 ml) and 4-dimethylaminopyridine (DMAP) (0.1 eq, 20 mg) was added. The mixture was stirred for 16 hours at room temperature. Dicloromethane (DCM) was added and the mixture was filtered on Bchner. The solution obtained was concentrated under reduced pressure and purified by chromatography on silica gel (DCM/acetone: 95/5). A white powder is obtained, yield 23%.
[0278] A solution of the compound synthesized previously (1 eq, 258 mg) in AcOH (8 ml) with water (1.95 ml) was stirred for 2 days at room temperature and lyophilized. A white hygroscopic powder (quantitative yield) was obtained. The MS and NMR spectra are in accordance with the desired product.
EXAMPLE 16: SYNTHESIS OF COMPOUND 19
[0279] ##STR00056##
[0280] To suspension of compound (3) above (1 eq, 2 g) in pyridine (45.1 ml), we added successively hexamethyldisilazane (HMDS (1 eq 223 ml) and chlorotrimethylsilane (10 eq, 13.4 ml). The mixture was stirred for 16 hours at room temperature after it was concentrated under reduced pressure with toluene and purified by chromatography on silica gel (cyclohexane/AcOEt: 9/1). A pale yellow oil is obtained, yield 85%.
[0281] To a solution of previous compound (4) above (1 eq, 1 g) in EtOH (30 ml), we added NaBH.sub.4 (1 eq, 0.093 g). The mixture was stirred for 1 hour at room temperature. The mixture is then poured in saturated aqueous solution of NH.sub.4Cl, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/AcOEt: 8/2). We obtained a colorless oil compound (5) with yield 62%.
[0282] To a solution of compound 1 (1 eq, 200 mg) in anhydrous ttrahydrofurane (THF) 16 ml we added 1,1-Carbonyldiimidazole (CDI) (1.2 eq, 165 mg), and the mixture was stirred at room temperature for 3 h. Compound (5) below (1.2 eq, 416 mg) in solution in anhydrous THF (3 ml) was added and the mixture was heated at 60 C. during 2 days.
[0283] After cool, the mixture was diluted in a solution of DCM/MeOH 8/2 (20 ml), and a little of AcOH (1 ml) was added. The solution was stirred for 2 days and concentrated under reduced pressure with toluene. The oil obtained was purified by chromatography on inverse silica gel (H.sub.2O/ACN: 98/2 to 5/95). We obtained a white powder with yield 19%.
[0284] The MS and NMR spectra are in accordance with the desired product
EXAMPLE 17: DEMONSTRATION OF THE DEPIGMENTING ACTIVITY
[0285] The measurement of the depigmenting activity (reduction of melanin production) of compounds of formula (I) was performed by assaying normal human melanocytes in vitro as follows.
[0286] First of all, normal human melanocytes are cultured and dispensed into wells. After 24 hours, the culture medium was replaced with a medium containing compounds of formula (I) to be evaluated. The cells were incubated 72 hours before measurement of 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 a 50% decrease in melanin synthesis is achieved.
[0287] Various test campaigns were conducted and the results collated in the table below.
TABLE-US-00005 Maximum concentration Compound IC50 on tested No. Structure (M) (M) Compound 1
[0288] The compounds of formula (I) showed a strong depigmenting effect.
[0289] Coculture Experiment:
[0290] A biological test demonstrated the depigmenting activity of compound 1.
[0291] The melanogenesis-modulating effect of compound 1 was measured according to the method described in patent FR-A-2734825, and also in the article by R. Schmidt, P. Krien and M. Rgnier, Anal. Biochem., 235(2), 113-18, 1996. This test is performed on a coculture of keratinocytes and melanocytes.
[0292] The following were determined for the test compound: [0293] the cytotoxicity, [0294] the inhibitory activity on melanin synthesis, by estimating the melanin optical density.
[0295] The IC50 values (concentration for which 50% of the melanin synthesis is inhibited) were determined.
Compound 1: non-cytotoxic, IC50=9.6 M.
Compound 2: non-cytotoxic IC50=0.74 M.
Compound 5: non-cytotoxic IC50=0.79 M.
Compound 6: non-cytotoxic IC50=1.57 M.
Compound 7: non-cytotoxic IC50=1.04 M.
Compound 8: non-cytotoxic IC50=1.23 M.
Compound 10: non-cytotoxic IC50=7.62 M.
EXAMPLE 18: OTHER DEMONSTRATION OF THE DEPIGMENTING ACTIVITY
[0296] Compositions comprising 300 M of compound 1 in DMSO were applied to samples of pigmented reconstructed epidermis (cf. EP 1 878 790). The control is DMSO.
[0297] 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, see
[0298] The pigmented reconstructed epidermis standard study model was published by: 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.
[0299] Significant depigmenting activity was evaluated at 300 M for compound 1 (pValue<0.05: significant depigmenting activity).
EXAMPLE 19: COSMETIC COMPOSITION
[0300] A skin depigmenting composition is prepared, comprising (in grams):
TABLE-US-00006 Compound No. 1 2 g PEG400 68 g Ethanol 30 g
[0301] The composition applied to the skin makes it possible to lighten the skin of the face and especially to attenuate brown blemishes.
EXAMPLE 20: GEL
[0302] A skin depigmenting gel is prepared, comprising (% by weight):
TABLE-US-00007 Compound No. 1 0.25% Carbomer (Carbopol 981 from Lubrizol) 1% Preservative qs Water qs 100%
[0303] The composition applied to the skin makes it possible to attenuate brown blemishes.