Method for the treatment of keratin materials using amide C-glycoside derivatives, and cosmetic composition containing same

Abstract

The present invention relates to a method for the cosmetic treatment of keratin materials, comprising the application of a composition to the keratin materials, such as the skin, said composition comprising a compound (I), wherein R1, R2 and R3 are as defined in the description and S* is a mono or polysaccharide.

Claims

1. A cosmetic non-therapeutic process for the depigmentation, lightening and/or bleaching of human skin, comprising the application of a compound of formula (I) or of a composition comprising one or more compounds of formula (I): ##STR00126## in which: S* denotes a monosaccharide sugar radical chosen from glucose and xylose comprising one or more hydroxyl groups optionally substituted with a radical R′ chosen from: i) (C.sub.1-C.sub.6)alkyl; or ii) (C.sub.2-C.sub.6)alkenyl; or iii) an acetyl radical; or iv) a protective group (PG) for hydroxyl function(s); said monosaccharide radical optionally comprising one or more amino groups NR.sub.bR.sub.c with R.sub.b and R.sub.c, which may be identical or different, representing a hydrogen atom, an acetyl group, or a protective group for the amino function; said monosaccharide radical being connected to the rest of the molecule by a bond between the C.sub.1 carbon atom of one of the sugars of said monosaccharide radical, this bond possibly being α or β anomeric; R.sub.3 represents i) a hydrogen atom; or ii) a (C.sub.1-C.sub.18)alkyl group; or iii) a (C.sub.2-C.sub.18)alkenyl group; or iv) a hydroxyl-function-protective group (PG); R.sub.1 represents: i) a hydrogen atom; or ii) a (C.sub.1-C.sub.18)alkyl group; or iii) a (C.sub.2-C.sub.18)alkenyl group; R.sub.2 represents i) an optionally substituted aryl or heteroaryl radical; or (ii) a radical of formula (B1): ##STR00127## in which: R.sub.h and R.sub.k, independently of one another, denote a hydrogen atom or a methyl radical, it being understood that R.sub.h and R.sub.k cannot simultaneously denote a methyl radical; y=1 to 10; or iii) a radical of formula (B2): ##STR00128## in which: i=0 or 1; R.sub.4 represents i) a hydrogen atom, or ii) a radical chosen from the radicals (a1) to (a32) described below: ##STR00129## ##STR00130## ##STR00131## or iii) R.sub.4 can also form, with R.sub.1 and the nitrogen atom which bears R.sub.1, a saturated heterocycle of formula A1, or A2 or A3: ##STR00132## R.sub.6 denotes i) a hydroxyl radical OH; or ii) an alkoxide —O.sup.−, M.sup.= with M.sup.= representing a cation; or iii) a saturated or unsaturated (C.sub.1-C.sub.6)alkoxy radical; or iv) a radical —NR.sub.fR.sub.g with R.sub.f and R.sub.g, which may be identical or different, representing a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group.

2. The process according to claim 1, in which the compound(s) of formula (I) comprise(s) a radical R.sub.3 which represents a hydrogen atom, R.sub.1 which represents a hydrogen atom or a (C.sub.1-C.sub.18)alkyl group and R.sub.2 which represents an aryl or heteroaryl radical, which is optionally substituted.

3. The process according to claim 1, in which the compound(s) of formula (I) comprise(s) a radical R.sub.2 which represents a radical (B1) below: ##STR00133## in which: R.sub.h and R.sub.k, independently of one another, denote a hydrogen atom or a methyl radical, it being understood that R.sub.h and R.sub.k cannot simultaneously denote a methyl radical; y =1 to 10.

4. The process according to claim 1, in which the compound(s) of formula (I) comprise(s) a radical R.sub.2 which represents the radical (B2) below: ##STR00134## in which: i=0 or 1; R.sub.4 represents i) a hydrogen atom, or ii) is chosen from the radicals (a1) to (a32) described below: ##STR00135## ##STR00136## ##STR00137## or iii) R.sub.4 can also form, with R.sub.1 and the nitrogen atom which bears R.sub.1, a saturated heterocycle of formula A1, A2 or A3: ##STR00138## R.sub.6 denotes i) a hydroxyl radical —OH; or ii) an alkoxide —O.sup.−, M.sup.= with M.sup.= representing a cation; or iii) a saturated or unsaturated (C.sub.1-C.sub.6)alkoxy radical; or iv) a radical —NR.sub.fR.sub.g with R.sub.f and R.sub.g, which may be identical or different, representing a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group.

5. The process according to claim 1, in which the compound(s) of formula (I) is (are) chosen from the compounds of formulae (I′) below: ##STR00139## ##STR00140## and also the solvates thereof, the optical and geometric isomers and tautomers thereof and the organic or mineral base or acid salts thereof in which formulae (I′): R.sub.1′ has the same definition as that of R.sub.1 for the compounds of formula (I) R.sub.2′ has the same definition as that of R.sub.2 for the compounds of formula (I) R.sub.3′ has the same definition as that of R.sub.3 for the compounds of formula (I) R” represents i) (C.sub.1-C.sub.6)alkyl; or ii) (C.sub.2-C.sub.6)alkenyl; or iii) an acetyl radical; or iv) a protective group (PG) for hydroxyl function(s); or v) a hydrogen atom optionally substituted with a radical R′ chosen from: i) (C.sub.1-C.sub.6)alkyl; or ii) (C.sub.2-C.sub.6)alkenyl; or iii) an acetyl radical; or iv) a protective group (PG) for hydroxyl function(s), R′″ represents a hydrogen atom optionally substituted with a radical R′ chosen from: i) (C.sub.1-C.sub.6)alkyl; or ii) (C.sub.2-C.sub.6)alkenyl; or iii) an acetyl radical; or iv) a protective group (PG) for hydroxyl function(s).

6. The process according to claim 1, in which the compound(s) of formula (I) is (are) chosen from the following compounds: TABLE-US-00009 S* compound structure D-glucose  1 D-glucose  2 D-glucose  3 D-glucosee  4 D-glucose  5 D-glucose  6 D-glucose  7 D-glucose  9 D-xylose 10 D-xylose 11-dia1 D-xylose 11-dia2 D-xylose 12 D-xylose 13 D-glucose 14 D-glucose 15 D-glucose 16 D-glucose 17 D-glucose 18 D-xylose 19 D-xylose 20-dial D-xylose 20-dia2 D-xylose 21

7. The process according to claim 1, wherein S* denotes a sugar chosen from D-glucose and D-xylose.

8. The process according to claim 1, wherein R.sub.3 represents a hydrogen atom or an acetyl group, R.sub.1 represents a hydrogen radical, and R.sub.2 represents an aryl radical optionally substituted with a phenyl radical substituted with one or more groups chosen from methoxy, hydroxyl, carboxy, acetyloxy and/or benzyloxycarbonyl.

9. The process according to claim 1, wherein S* denotes a monosaccharide sugar radical chosen D-glucose and D-xylose; R.sub.3 represents a hydrogen atom; R.sub.1 represents a hydrogen atom or methyl; and R.sub.2 denotes a radical of formula (B2): ##STR00163## in which i=0 or 1, R.sub.6 represents an ethoxy, hydroxyl or NH.sub.2 radical, R.sub.4 represents a hydrogen atom, and when i=0, R.sub.4 represents a hydroxymethyl radical of formula (a5) ##STR00164## or else R.sub.4 can form, with R.sub.1 and the nitrogen atom which bears R.sub.1, a saturated heterocycle of formula A2: ##STR00165##

10. The process according to claim 9, wherein S* denotes a monosaccharide sugar radical chosen from glucose and xylose, having C3, and C4 and where appropriate C6 hydroxyl groups substituted with an acetyl group.

Description

EXAMPLES

Example 1

(1) Synthesis of Compounds 1, 2 and 3

(2) ##STR00120## ##STR00121##

(3) D-glucose (5 g), dissolved in water (56 ml), is introduced into a 250 ml single-necked round-bottomed flask. 1,3-Dimethylbarbituric acid (4.33 g) is added with stirring, then NaHCO.sub.3 is added up to pH 7. After neutralization, the round-bottomed flask is equipped with a condenser and the mixture is heated at 80° C. for 5 h. The reaction is monitored by TLC in 1:1 dichloromethane (DCM)/MeOH. The reaction mixture is concentrated under vacuum. The residue obtained is taken up in water, then precipitated from acetone and filtered and the solid I1 obtained is dried under vacuum. It is isolated in the form of an orange powder (9.3 g, yield 98%). The .sup.1H NMR spectra and the mass spectrometry are in accordance with the expected structure.

(4) 5 g of product I1 are dissolved in 10 ml of water at ambient temperature, then 30% H.sub.2O.sub.2 (3 ml) is added. The reaction mixture is stirred at ambient temperature for 2 hours. 0.21 equiv. of an aqueous 20% sodium metabisulfite solution is then added, and stirring is continued for 1 h at ambient temperature. The absence of peroxide is verified, then the reaction mixture is poured into 300 ml of ethanol. The precipitate formed is filtered off, and the filtrate is concentrated to a minimum volume. A further precipitate forms, and is collected and dried under vacuum at 30° C. (first product fraction, 1.6 g). The filtrate is again taken up in ethanol, the precipitate formed is filtered off, and the filtrate is concentrated to dryness to give another product fraction (0.8 g). Two batches of product I2 are thus recovered in the form of a white solid (2.4 g, yield 65%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(5) Compound I2 (2.56 g, 10 mmol) was added to a solution of NaOH (4 g, 100 mmol) in 50 ml of water. After stirring at 100° C. for 5 h, the reaction mixture is cooled to ambient temperature and then adjusted to pH 4 by adding an ion exchange resin. The resin is then removed by filtration. The filtrate is concentrated to give 2.3 g of the acid salt I3 in the form of a grey solid (quantitative yield). The .sup.1H NMR spectra and the mass spectrometry are in accordance with the expected structure.

(6) A mixture of the salt I3 (3.3 g, 12.6 mmol), benzyl bromide (2.6 g, 15.2 mmol), 12.6 ml of n-Bu.sub.4NF in 1 M solution in THF, and 20 ml of DMF, is stirred at ambient temperature for 16 h. The mixture is then concentrated to dryness. The residue is purified by silica column chromatography (dichloromethane/methanol=10/1) to give 2.4 g of the benzyl ester I4 in the form of a white solid (yield 58%). The .sup.1H NMR spectra and the mass spectrometry are in accordance with the expected structure.

(7) Acetic anhydride (19.6 g, 192 mmol) and pyridine (7.6 g, 96 mmol) are added to a solution of compound I4 (6.3 g, 19.2 mmol) in dichloromethane (30 ml). The reaction mixture is stirred for 16 h at ambient temperature, then the acetic anhydride is evaporated off and 50 ml of water are added. The mixture is extracted 3 times with dichloromethane. The organic phases are combined, washed with a saturated aqueous NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue is purified by silica gel chromatography (ethyl acetate/petroleum ether 1:2) to give compound I5 (white viscous solid, 2 g, yield=21% over the 5 steps at the start of the D-glucose).

(8) Pd/C 10% (0.2 g) is added to a solution of compound I5 (2 g, 3.7 mmol) in a 1:1 methanol/ethyl acetate mixture (20 ml). The mixture is hydrogenated under a hydrogen atmosphere for 16 h at ambient temperature. After filtration, the filtrate is evaporated to dryness to give compound I6 (white solid, 1.5 g, yield=90%).

(9) Oxalyl chloride (0.68 g, 5.4 mmol) and a drop of DMF are added to a solution of compound I6 (2 g, 4.5 mmol) in dichloromethane (10 ml). The reaction mixture is stirred for 2 h at ambient temperature and then evaporated to dryness. The residue I7 obtained is used directly in the next step.

(10) Triethylamine (0.9 g, 8.9 mmol) was added to a solution of compound I8 ([1444836-72-9], 1.27 g, 4.5 mmol) in dichloromethane (10 ml), then a solution of the crude residue I7 (2.08 g, 4.5 mmol) in dichloromethane (10 ml) was added dropwise. At the end of the addition, the reaction mixture was stirred for 16 h at ambient temperature, and then evaporated to dryness. The residue obtained was purified by silica gel chromatography (ethyl acetate/petroleum ether 1:2) to give compound 3 (white solid, 2 g, yield=65% over 2 steps).

(11) Pd/C 10% (0.2 g) is added to a solution of compound 3 (2 g, 2.8 mmol) in a 2:1 methanol/ethyl acetate mixture (15 ml). The mixture is hydrogenated under a hydrogen atmosphere for 16 h at ambient temperature. After filtration, the filtrate is evaporated to dryness to give compound 2 (white solid, 1.66 g, yield=95%).

(12) K.sub.2CO.sub.3 (0.733 g, 5.3 mmol) is added to a solution of compound 2 (1.66 g, 2.7 mmol) in methanol (10 ml). The reaction mixture is stirred for 24 h at ambient temperature, then Amberlite IR-120 resin is added. The suspension is stirred for 1 hour at ambient temperature. After filtration, the filtrate is evaporated to dryness. A precipitate forms after addition of 10 ml of ethyl acetate. The solid is filtered off, washed with ethyl acetate and dried under vacuum to give compound 1 (white solid, 0.69 g, yield=70%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(13) The MS and NMR spectra are in accordance with the desired product.

(14) Synthesis of Compounds 4 to 21

(15) Synthesis of Compounds 14 and 4

(16) ##STR00122##

(17) A mixture of the acid salt I3 (2.5 g, 10 mmol), NaOAc (2 g, 10 mmol), and 20 ml of Ac.sub.2O is stirred at 110° C. for 16 h, then the mixture is concentrated to dryness. The residue is taken up in 200 ml of sat. aq. NaHCO.sub.3 and extracted 3 times with ethyl acetate. The organic phases are combined and concentrated under vacuum, and the residue obtained is purified by silica chromatography (petroleum ether/ethyl acetate=2/1) to give 1.9 g of the lactone intermediate L1 in the form of a white solid, yield 50%. The .sup.1H NMR spectra and the mass spectrometry are in accordance with the expected structure.

(18) A solution of lactone L1 (1.50 g, 3.86 mmol), L-glycine ethyl ester hydrochloride (0.54 g, 3.86 mmol) and DIEA (1.50 g, 11.59 mmol) in THF (50 ml) is stirred for 14 h at 80° C. After the solvent has been evaporated off, 5 ml of ethyl acetate are added in order to dissolve the residue. The organic phase is washed twice with 0.1 M aq. HCl. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over MgSO.sub.4, filtered and evaporated. The residue is purified by silica gel chromatography (ethyl acetate/n-heptane 2:1) to give 14 (beige solid, 1.15 g, yield=61%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(19) The product 14 (569 mg, 1.16 mmol) is dissolved in a 7 M solution of aqueous ammonia in methanol (15 ml). The reaction mixture is stirred for 17 hours at ambient temperature. After the solvent has been evaporated off, 5 ml of methyl are added in order to dissolve the residue. A precipitate forms after the addition of 50 ml of ethyl acetate. The solid is filtered off, washed with ethyl acetate and n-heptane, and dried under vacuum to give compound 4 (white solid, 333 mg, yield=98%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(20) Synthesis of Compounds 15 and 5

(21) Compound 15 is obtained according to the procedure described for compound 14, from lactone L1 (1.80 g, 4.64 mmol), L-serine ethyl ester hydrochloride (0.79 g, 4.64 mmol) and DIEA (1.80 g, 13.91 mmol). Compound 15 is in the form of a beige solid (1.47 g, yield=61%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(22) Compound 5 is obtained according to the procedure described for compound 4, from 15 (1.47 g, 2.82 mmol). Compound 5 is in the form of a beige solid (857 mg, 94%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(23) Synthesis of Compounds 16 and 6

(24) Compound 16 is obtained according to the procedure described for compound 14, from lactone L1 (1.0 g, 2.58 mmol), L-proline ethyl ester (0.37 g, 2.58 mmol) and DIEA (3.33 g, 25.75 mmol). It is in the form of a yellow solid (640 mg, yield=49%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(25) Compound 6 is obtained according to the procedure described for compound 4, from 16 (640 mg, 1.20 mmol). Compound 6 is in the form of a beige solid (291 mg, yield=72%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(26) Synthesis of Compounds 17 and 7

(27) Compound 17 is obtained according to the procedure described for compound 14, from lactone L1 (1.50 g, 3.86 mmol), 1-alanine ethyl ester hydrochloride (0.68 g, 3.86 mmol) and DIEA (1.50 g, 11.59 mmol). It is in the form of a yellow solid (794 mg, yield=35%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(28) Compound 7 is obtained according to the procedure described for compound 4, from 17 (794 mg, 1.57 mmol). It is in the form of a beige solid (243 mg, yield=50%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(29) Synthesis of compound 18

(30) Compound 18 is obtained according to the procedure described for compound 14, from lactone L1 (1.0 g, 2.58 mmol), L-sarcosine ethyl ester (0.39 g, 2.58 mmol) and DIEA (3.33 g, 25.75 mmol). Yellow solid (650 mg, 50%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(31) Synthesis of Compound 9

(32) ##STR00123##

(33) 10 drops of conc. HCl are added to a solution of compound 14 (50 mg, 0.10 mmol) in ethanol (5 ml). After stirring for 17 h at ambient temperature, the mixture is evaporated to dryness to give compound 9 (colourless solid, 45 mg, quantitative yield). The .sup.1H NMR spectra and the mass spectrometry are in accordance with the expected structure.

(34) Synthesis of Compounds 19 and 10

(35) ##STR00124## ##STR00125##

(36) In a 5 l jacketed reactor equipped with a condenser, with a nitrogen inlet and with a bubbler, D-xylose (225 g, 1.50 mol) is dissolved in 3 l under an inert atmosphere. 1,3-Dimethylbarbituric acid (1.2 equiv., 281 g, 1.80 mol) is added with stirring, portionwise, followed by the addition of sodium bicarbonate (2.1 equiv., 264 g, 3.15 mol) up to pH=7. The solution is then heated at 90° C. for 5 h and then partially concentrated under vacuum. Acetone is then added to the concentrated aqueous solution in order to precipitate the compound which is then filtered off, washed with an approximately 4/1 acetone/water mixture, then dried under vacuum. 593.5 g of crude compound I9 (61% purity, NMR) are thus isolated in the form of a beige powder.

(37) In a 5 l jacketed reactor, compound I9 (286 g crude, 61% pure, i.e. 0.56 mol), under an inert atmosphere, is dissolved in 1.5 l of water, with stirring at ambient temperature. Hydrogen peroxide at 30% in water (n.sub.th=2 equiv., 188 ml, 1.84 mol) is added dropwise via a dropping funnel. The reaction medium is then heated at 70° C. for 5 h, then concentrated to dryness (after having verified the absence of residual peroxides) to give a pale yellow powder which is then used in the next step without purification (I10, 249 g crude, 43% purity, NMR).

(38) In a 5 l jacketed reactor, compound I10 (159.5 g crude, 43% pure, i.e. 0.32 mol), under an inert atmosphere, is dissolved in 2.5 l of water, with mechanical stirring at 20° C. 1 M sodium hydroxide (225 ml, 2.26 mol) is added via a dropping funnel. The reaction medium is then heated at 90° C. for 5 h. The reaction medium (2.7 l) containing the carboxylate of I11 (285 g, 26% purity, NMR) is then purified.

(39) The previous reaction medium (26% purity, NMR, corresponding to 49.0 g of product in acid form I11) is acidified. Compound I11 is then bound to a basic resin and the impurities are eliminated by aqueous washing. Compound I11 is then freed from the basic resin using 0.5 M hydrochloric acid. After lyophilization, a beige powder was obtained (21.45 g, compound I11 at 84% purity, NMR, 38% yield).

(40) A mixture of the acid I11 (8.5 g, 38 mmol), NaOAc (3.2 g, 38 mmol) and 73 ml of Ac.sub.2O is stirred at 55° C. for 20 h, then the mixture is treated with diisopropyl ether so as to recover a white solid after filtration. This solid is treated by fractional precipitation from ethyl acetate so as to obtain various fractions of a single diastereoisomer of the lactone L2, denoted dia1. The filtrates are concentrated and purified by silica chromatography (n-heptane/ethyl acetate 8:2) to give 2 other fractions of lactone L2 in the form of mixtures enriched with dia1 or with dia2 (2nd diastereoisomer). In total, 6.11 g of lactone are obtained (white powder, 56% yield). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(41) Compound 19 is obtained according to the procedure described for compound 14, from lactone L2 (1.5 g, 4.7 mmol), L-glycine ethyl ester hydrochloride (662 mg, 4.7 mmol) and DIEA (2.5 ml, 14 mmol): Yellow oil, 1.07 g, Yield=56%. The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure. Compound 10 is obtained according to the procedure described for compound 4, from 19 (800 mg, 1.9 mmol). The ethyl acetate is replaced with acetone for the precipitation. It is isolated in the form of a white powder, 435 mg, yield=86%.

(42) Synthesis of Compounds 20-Dia1 and 11-Dia1

(43) Compound 20-dia1 is obtained according to the procedure described for compound 19, from lactone L2-dia1 (1.34 g, 4.2 mmol), L-serine ethyl ester hydrochloride (719 mg, 4.24 mmol) and DIEA (3.7 ml, 21 mmol). Yellow oil (1 g, 45%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure. Compound 11-dia1 is obtained according to the procedure described for compound 10, from 20-dia1 (550 mg, 1.23 mmol). Yellow oil (160 mg, 44%). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(44) Synthesis of Compounds 20-Dia2 and 11-Dia2

(45) Compound 20-dia2 is obtained according to the procedure described for compound 19, from lactone L2-dia2 (1.5 g, 4.7 mmol), L-serine ethyl ester hydrochloride (804 mg, 4.7 mmol) and DIEA (4.1 ml, 24 mmol). Sticky white powder (860 mg). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(46) Compound 11-dia2 is obtained according to the procedure described for compound 10, from 20-dia2 (810 mg, 1.8 mmol). Yellow oil (380 mg, 72%, 2 steps). The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

(47) Synthesis of Compound 21

(48) Compound 21 is obtained according to the procedure described for compound 19, from lactone L2 (1.07 g, 3.4 mmol), L-sarcosine ethyl ester (520 mg, 3.4 mmol) and DIEA (7.1 ml, 41 mmol). Hard orange wax. The .sup.1H/.sup.13C NMR spectra and the mass spectrometry are in accordance with the expected structure.

Example 2: Demonstration of the Depigmenting Activity

(49) 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.

(50) First, normal human melanocytes are cultured and distributed in wells. After 24 hours, the culture medium was replaced with a medium containing the 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. The compounds are tested at 100 μM after calibration.

(51) Various test runs were performed and the results are collated in the following table.

(52) TABLE-US-00005 % Depigmentation at % depigmentation at Compound No. 100 μM (run 1) 100 μM (run 2)  1 13%  4 19%  5 31%  6 29%  7 34% 10 20% 11-dia1 28% 11-dia2 32% 12 20% (28% at the max dose tested 200 μM) 19 15% (43% at the max dose tested 200 μM) 20-dia1 23%

(53) The compounds of formula (I) showed a depigmenting effect.

Example 3: Cosmetic Composition

(54) A skin depigmenting composition is prepared, comprising (in grams):

(55) TABLE-US-00006 Compound NO. 10  2 g PEG400 68 g Ethanol 30 g

(56) The composition applied to the skin makes it possible to fade out brown spots.

(57) A similar composition is prepared with compound I1 (trans- or cis isomers or a mixture of the two).

Example 5: Gel

(58) A skin depigmenting composition is prepared, comprising (% by weight):

(59) TABLE-US-00007 Compound NO. 10 0.25% Carbomer (carbopol 981 from Lubrizol)   1% Preserving agent qs Water qs 100%

(60) The composition applied to the skin makes it possible to fade out brown spots.

(61) A similar composition is prepared with compound 11 (trans or cis isomers or a mixture of the two).

Example 6

(62) An anti-ageing gel for the skin is prepared, comprising (% by weight):

(63) TABLE-US-00008 compound 10 2% Hydroxypropylcellulose (Klucel H from Hercules) 1% fragrance, preservative qs isopropanol 40%  water qs 100%

(64) A similar composition is prepared with compound 11 (trans or cis isomers or mixture of the two).