Resorcinol derivatives for their cosmetic use

Abstract

The invention relates to resorcinol-based compounds of formula (I), to the salts, solvates, optical and/or geometrical isomers thereof, to the use thereof as active agents for depigmenting, lightening and/or bleaching keratin materials, and/or for preventing, reducing and/or treating impairment of the skin complexion or of the colour of the semi-mucous membranes. The invention also relates to a non-therapeutic cosmetic treatment process for depigmenting, lightening and/or bleaching keratin materials, and/or for preventing, reducing and/or treating impairment of the skin complexion or the colour of the semi-mucous membranes. ##STR00001##

Claims

1. A compound of formula (I): ##STR00022## wherein: X denotes an oxygen atom O, a sulfur atom S or a radical NR.sub.a; R.sub.1 and R.sub.2 independently denote: a hydrogen atom H, a linear or branched, saturated C.sub.1-C.sub.6 hydrocarbon-based radical, optionally substituted with one or more hydroxyl radicals, a linear or branched, unsaturated C.sub.2-C.sub.6 hydrocarbon-based radical, optionally substituted with one or more hydroxyl radicals, or R.sub.1 and R.sub.2 form, together with each carbon atom that bears them, a phenyl group optionally substituted with one or more radicals —OR.sub.b, R.sub.a and R.sub.h independently denote: a hydrogen atom H, a linear or branched saturated C.sub.1-C.sub.6 hydrocarbon-based radical, or an acetyl radical; and also the salts thereof, the solvates thereof and the optical and/or geometrical isomers thereof, including enantiomers and diastereoisomers, and the racemic mixtures thereof, alone or as a mixture, with the proviso that the compound is not 4-[1-(1H-imidazol-2-yl)propan-2-yl]benzene-1,3-diol: ##STR00023##

2. The compound according to claim 1, wherein: X denotes an oxygen atom O, a sulfur atom S or a radical NR.sub.a; R.sub.1 and R.sub.2 independently denote: a hydrogen atom H, a linear saturated C.sub.1-C.sub.6 hydrocarbon-based radical, or R.sub.1 and R.sub.2 form, together with each carbon atom that bears them, a phenyl group optionally substituted with one or more radicals —OR.sub.b, R.sub.a and R.sub.h independently denote: a hydrogen atom H, a linear saturated C.sub.1-C.sub.2 hydrocarbon-based radical, or an acetyl radical.

3. The compound according to claim 1, wherein: X denotes an oxygen atom O, a sulfur atom S or a radical NR.sub.a; R.sub.1 and R.sub.2 independently denote: a hydrogen atom H, a linear saturated C.sub.1-C.sub.2 hydrocarbon-based radical, or R.sub.1 and R.sub.2 form, together with each carbon atom that bears them, a phenyl group optionally substituted with one or more radicals —OR.sub.b, R.sub.a and R.sub.b independently denote: a hydrogen atom H, a methyl radical, or an acetyl radical.

4. The compound according to claim 1, wherein: X denotes an oxygen atom O, a sulfur atom S or a radical NR.sub.a; R.sub.1 and R.sub.2 independently denote: a hydrogen atom H, or R.sub.1 and R.sub.2 form, together with each carbon atom that bears them, a phenyl group, R.sub.a denotes a hydrogen atom H.

5. The compound according to claim 1, selected from the group consisting of: ##STR00024## 4-[1-(1,3-thiazol-2-yl)propan-2-yl]benzene-1,3-diol; ##STR00025## 4-[1-(1,3-benzoxazol-2-yl)propan-2-yl]benzene-1,3 ##STR00026## 4-[1-(1,3-oxazol-2-yl)propan-2-yl]benzene-1,3-diol; ##STR00027## 4-[1-(1H-benzimidazol-2-yl)propan-2-yl]benzene-1,3-diol; ##STR00028## 4-[1-(1H-benzimidazol-2-yl)propan-2-yl]benzene-1,3-diol, and also the salts thereof, the solvates thereof and/or the optical isomers thereof, including enantiomers and diastereoisomers, and the racemic mixtures thereof, alone or as a mixture.

6. A composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) according to claim 1.

7. The composition according to claim 6, wherein compound of formula (I) is present in a content of between 0.01% and 10% by weight relative to the total weight of the composition.

8. The composition according to claim 6, further comprising: at least one adjuvant selected from the group consisting of organic solvents, oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers; cosmetic active agents, organic or mineral photoprotective agents, polymers, thickeners, preserving agents, fragrances, bactericides, ceramides, odour absorbers and antioxidants.

9. The composition according to claim 6 further comprising at least one active agent selected from the group consisting of desquamating agents; calmatives, organic or mineral photoprotective agents, moisturizers; depigmenting agents other than the compounds of the invention; 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; tensioning agents; anti-pollution agents and/or free-radical scavengers; agents acting on microcirculation; agents acting on energy metabolism of cells; and mixtures thereof.

10. A non-therapeutic cosmetic process for depigmenting, lightening and/or bleaching keratin materials, and/or for reducing and/or treating impairment of skin complexion or of colour of semi-mucous membranes, comprising: applying, to the skin of a face and/or body, at least one composition comprising at least one compound of formula (I) as defined according to claim 1.

11. The process according to claim 10 for depigmenting, lightening and/or bleaching the skin.

12. A method for depigmenting, lightening and/or bleaching keratin materials, and/or for reducing and/or treating impairment of skin complexion or of colour of semi-mucous membranes comprising applying the composition of claim 6 to the keratin material, skin or semi-mucous membrane.

13. The method according to claim 12, for making the complexion homogeneous and/or reviving the radiance of the complexion.

Description

EXAMPLE 1: SYNTHESIS OF COMPOUND A

(1) ##STR00011##
Procedure:

(2) Synthesis of Compound 3: To a solution of compound 2 (5.34 g, 30 mmol) in 80 ml of EtOH is added 1.0 ml of conc. H.sub.2SO.sub.4. The mixture is stirred at room temperature for 15 hours. The mixture is then poured into 500 ml of water and extracted three times with EtOAc. The combined organic phases are washed three times with water and concentrated to dryness under vacuum. The crude product is purified by chromatography on a column of silica gel, eluting with 1/1 PE/EtOAc to give 6.65 g of compound 3 in the form of a colourless oil in a yield of 99%.

(3) Synthesis of Compound 4: To a solution of compound 3 (6.4 g, 28.6 mmol) in 80 ml of MeCN are added K.sub.2CO.sub.3 (9.8 g, 71.0 mmol) and BnBr (12.14 g, 71.0 mmol). The reaction mixture is refluxed for 15 hours. The mixture is then filtered to remove the salt. The filtrate is concentrated to dryness. The crude product is then purified by chromatography on a column of silica gel, eluting with 5/1 PE/EtOAc to give 11.55 g of compound 4 in the form of a colourless oil in a yield of 100%.

(4) Synthesis of Compound 5: To a suspension of LiAlH.sub.4 (3.3 g, 54 mmol) in 80 ml of THF is added compound 4 (11.0 g, 27.2 mmol) in 20 ml of THF. The mixture is stirred at room temperature for 12 hours. 4.0 ml of saturated aqueous Na2SO4 are then added dropwise to the mixture. The mixture is filtered to remove the solids. The filtrate is concentrated to dryness under vacuum. The crude product is then purified by chromatography on a column of silica gel, eluting with 4/1 PE/EtOAc to give 8.96 g of compound 5 in the form of a colourless oil in a yield of 91%.

(5) Synthesis of Compound 6: To a solution of compound 5 (12.5 g, 34.6 mmol) in 120 ml dichloromethane is added PCC (9.7 g, 45 mmol). The mixture is stirred at room temperature for 15 hours and 120 ml of water are added to the mixture, which is extracted with dichloromethane. The organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/10 EtOAc/PE) to give 8.9 g of compound 6 in the form of a white solid in a yield of 71%.

(6) Synthesis of Compound 7: To a solution of compound 6 (360 mg, 1 mmol) in 2 ml of ethanol are added 40% oxaldehyde (2 ml) and a 25% solution of NH.sub.4OH (2 ml). The mixture is stirred at room temperature for 18 hours. 30 ml of 2N HCl are then added dropwise and the medium is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/5 EtOAc/PE) to give 163 mg of compound 7 in the form of a white solid in a yield of 41%.

(7) Synthesis of Compound A: To a solution of compound 7 (163 mg, 0.41 mmol) in 5 ml methanol is added Pd/C (20 mg). The mixture is stirred at room temperature for 16 hours under H.sub.2. The mixture is then filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/1 EtOAc/PE) to give 60 mg of compound A in the form of a red solid in a yield of 67%.

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

EXAMPLE 2: SYNTHESIS OF COMPOUND B

(9) ##STR00012##

(10) Synthesis of Compound 2: To a solution of compound 1 (3.0 g, 20.0 mmol) in 120 ml of MeCN are added K.sub.2CO.sub.3 (13.8 g, 100.0 mmol) and BnBr (15.05 g, 88.0 mmol). The reaction mixture is refluxed for 15 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated to dryness. The resulting residue is purified by chromatography on a column of silica gel using dichloromethane, to give 12.1 g of compound 2 in the form of a white powder in a yield of 95%.

(11) Synthesis of Compound 4: To a solution of compound 3 (1.98 g, 20.0 mmol) in 60 ml of THF are added 10.0 ml of 2.0 M LDA in THF at −78° C. After stirring for 30 minutes, a solution of compound 2 (6.36 g, 20.0 mmol) in 30 ml of THF is added. The reaction mixture is gradually warmed to room temperature and stirred for 2 hours. The reaction is quenched by adding 400 ml of saturated NH.sub.4Cl and extracted three times with EtOAc. The combined organic phases are washed with water and then concentrated to dryness under vacuum. The crude product is then purified by chromatography on a column of silica gel, eluting with 5/1 PE/EtOAc to give 5.5 g of compound 4 in the form of a white solid in a yield of 66%.

(12) Synthesis of Compound 5: To a solution of compound 4 (4.17 g, 10.0 mmol) in 80 ml CH.sub.2Cl.sub.2 is added PCC (2.6 g, 12.1 mmol). The reaction medium is stirred at room temperature for 15 hours and then concentrated to dryness under vacuum. The crude product is then purified by chromatography on a column of silica gel, eluting with 5/1 PE/EtOAc to give 3.7 g of compound 5 in the form of a white solid in a yield of 90%.

(13) Synthesis of Compound 6: To a solution of compound 5 (1.15 g, 2.77 mmol) and methyltriphenylphosphonium bromide (1.3 g, 3.6 mmol) in 40 ml THF is added NaH (250 mg, 4.2 mmol). The reaction medium is stirred at room temperature for 18 hours. 200 ml of saturated aqueous NH.sub.4Cl are poured into the mixture and the medium is extracted twice with EtOAc. The combined organic phases are washed with water three times and concentrated to dryness. The resulting residue is purified by chromatography on silica gel (5/1 PE/EtOAc) to give 0.78 g of compound 6 in the form of a yellow oil in a yield of 68%.

(14) Synthesis of Compound B: A mixture of compound 6 (0.78 g, 1.88 mmol) and Ni—R in 30 ml of MeOH is stirred under a hydrogen atmosphere at room temperature for 15 hours. The reaction medium is filtered cautiously and the filtrate is concentrated to dryness. The resulting residue is purified by chromatography on silica gel (250/1 dichloromethane/methanol) to give 54 mg of compound B in the form of a pink powder in a yield of 12%. m.p.: 105-107° C.

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

EXAMPLE 3: SYNTHESIS OF COMPOUND C

(16) ##STR00013##

(17) Synthesis of Compound 2: To a solution of compound 1 (3.0 g, 20.0 mmol) in 120 ml of MeCN are added K.sub.2CO.sub.3 (13.8 g, 100.0 mmol) and BnBr (8.55 g, 50.0 mmol). The reaction mixture is refluxed for 15 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated to dryness. The resulting residue is purified by chromatography on a column of silica gel using dichloromethane, to give 6.0 g of compound 2 in the form of a white powder in a yield of 90%.

(18) Synthesis of Compound 4: To a solution of compound 3 (0.83 g, 10.0 mmol) in 50 ml of THF are added 5.0 ml of 2.0 M LDA in THF at −78° C. After stirring for 30 minutes, a solution of compound 2 (3.0 g, 10.0 mmol) in 30 ml of THF is added. The reaction medium is gradually warmed to room temperature and stirred for 2 hours. The reaction is quenched by adding 400 ml of saturated NH.sub.4Cl and the medium is extracted three times with EtOAc. The combined organic phases are washed with water and then concentrated to dryness under vacuum. The crude product is then purified by chromatography on a column of silica gel, eluting with 5/1 PE/EtOAc to give 1.37 g of compound 4 in the form of a white solid in a yield of 33%.

(19) Synthesis of Compound C: A mixture of compound 4 (1.34 g, 3.2 mmol) and 10% Pd/C in 40 ml of AcOH is stirred under a hydrogen atmosphere at room temperature for 15 hours. The reaction medium is filtered and the filtrate is concentrated to dryness. The resulting residue is purified by chromatography on silica gel (500/5 dichloromethane/methanol) to give 500 mg of compound C in the form of a white powder in a yield of 72%. m.p.: 100-102° C.

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

EXAMPLE 4: SYNTHESIS OF COMPOUND D

(21) ##STR00014##

(22) The synthesis of compound 4 is described in the synthesis of Example 1.

(23) Synthesis of Compound 5: To a solution of compound 4 (2.43 g, 6.0 mmol) in 50 ml of ethanol is added a solution of KOH (673 mg, 12 mmol) in 5 ml of water. The mixture is refluxed for 5 hours. After cooling the mixture, 30 ml of 2N HCl are added and the medium is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to give 2.07 g of compound 5 in the form of a white solid in a yield of 92%.

(24) Synthesis of Compound 7: To a solution of compound 5 (350 mg, 0.93 mmol) in 10 ml of DMF are added benzene-1,2-diamine (119 mg, 1.1 mmol), EDCI (210 mg, 1.1 mmol), HOBT (149 mg, 1.1 mmol) and triethylamine (111 mg, 1.1 mmol). The mixture is stirred at room temperature for 4 hours and then poured into 50 ml of water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/2 EtOAc/PE) to give 320 mg of compound 7 in the form of a white solid in a yield of 74%.

(25) Synthesis of Compound 8: Compound 7 (93 mg, 0.2 mmol) in 10 ml of acetic acid is refluxed for 5 hours. After cooling the mixture, the solvent is removed under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/2 EtOAc/PE) to give 82 mg of compound 8 in the form of a white solid in a yield of 91%.

(26) Synthesis of Compound D: To a solution of compound 8 (82 mg, 0.18 mmol) in 20 ml methanol is added Pd/C (25 mg). The mixture is stirred at room temperature for 16 hours under H.sub.2. The mixture is then filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/1 EtOAc/PE) to give 39 mg of compound D in the form of a white solid in a yield of 80%.

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

EXAMPLE 5: SYNTHESIS OF COMPOUND E

(28) ##STR00015##

(29) The synthesis of 2 is described above in Example 4.

(30) Synthesis of Compound E: A mixture of compound 2 (534 mg, 3.0 mmol) and of compound 3 (563 mg, 4.5 mmol) in 25 ml of AcOH is refluxed for 8 hours. The reaction medium is cooled to room temperature and then poured into 200 ml of water and extracted three times with EtOAc. The combined organic phases are washed three times with water and concentrated to dryness under vacuum. The crude product is then purified by chromatography on a column of silica gel, eluting with 50/1 CH.sub.2Cl.sub.2/MeOH to give 684 mg of compound E in the form of a white solid in a yield of 80%. m.p.: 98-100° C.

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

EXAMPLE 6: SYNTHESIS OF COMPOUND F

(32) ##STR00016##

(33) The synthesis of compound 5 is described in the synthesis of compound D described in Example 4.

(34) Synthesis of Compound 2: To a solution of compound 5 (753 mg, 2 mmol) in 10 ml of DMF are added 2-aminophenol 1 (262 mg, 2.4 mmol), EDCI (458 mg, 2.4 mmol), HOBT (324 mg, 2.4 mmol) and triethylamine (242 mg, 2.4 mmol). The mixture is stirred at room temperature for 4 hours and then poured into 50 ml of water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/2 EtOAc/PE) to give 505 mg of compound 2 in the form of a white solid in a yield of 54%.

(35) Synthesis of compound 3: Compound 2 (504 mg, 1.08 mmol) in 10 ml of acetic acid is refluxed for 5 hours. After cooling the mixture, the solvent is removed under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/2 EtOAc/PE) to give 168 mg of compound 3 in the form of a white solid in a yield of 34%.

(36) Synthesis of compound F: To a solution of compound 3 (166 mg, 0.37 mmol) in 20 ml methanol is added Pd/C (20 mg). The mixture is stirred at room temperature for 16 hours under H.sub.2. The mixture is then filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (eluent: 1/1 EtOAc/PE) to give 460 mg of compound F in the form of a white solid in a yield of 53%.

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

EXAMPLE 7: DEMONSTRATION OF THE DEPIGMENTING ACTIVITY

(38) 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.

(39) First, normal human melanocytes are cultured and distributed in a multiwell plate. After 24 hours, the culture medium was replaced with a medium containing the 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 was performed using a wide concentration range of the compounds evaluated. Thus, by making the concentrations and the melanin measurements correspond, it was possible to determine an IC50 in μM: concentration at which a 50% decrease in melanin synthesis is achieved.

(40) Various test campaigns were conducted and the test results are collated in the tables below.

(41) These results were compared with those obtained with compounds described in the prior art, and more particularly the compound 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol described in patent application JP01038009A.

(42) TABLE-US-00002 Maximum Compound concentration No. Structure IC50 (μM) tested (μM) Compound B 5.9 200 Compound D 3.7 200 Compound of Reference 5-[(E)-2-(4- 8.18 200 the prior art hydroxyyphenyl)ethenyl]benzene- 1,3-diol Compound B 1.07* 200 Compound A 0 3.7* 200 Compound D 6.7* 200 *Different campaigns each time

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

(44) Coculture Experiment:

(45) A biological test demonstrated the depigmenting activity of compound D.

(46) The melanogenesis-modulating effect of compound D was measured according to the method described in patent FR-A-2734825, and also in the article by R. Schmidt, P. Krien and M. Régnier, Anal. Biochem., 235(2), 113-18, 1996. This test is performed on a coculture of keratinocytes and melanocytes.

(47) For the test compounds, the following were determined: the cytotoxicity, the inhibitory activity on melanin synthesis, by estimating the melanin optical density.

(48) The IC50 values (concentration for which 50% of the melanin synthesis is inhibited) were determined.

(49) 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol described in patent application JP01038009 A

(50) The test was also performed with the compound 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol described in the prior art patent application JP01038009,

(51) Prior art compound 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol: Non-cytotoxic, IC 50=2.77 μM

(52) Compound D: non-cytotoxic, IC50=1.38 μM

EXAMPLE 8: COSMETIC COMPOSITION

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

(54) TABLE-US-00003 Compound D  2 g PEG400 68 g Ethanol 30 g

(55) The composition applied to the skin makes it possible to homogenize the complexion and especially to attenuate brown spots.

EXAMPLE 9: GEL

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

(57) TABLE-US-00004 Compound D  .sup. 0.5% Carbomer (Carbopol 981 from Lubrizol)   .sup. 1% Preserving agent qs Water qs 100%

(58) The composition applied to the skin makes it possible to attenuate and homogenize the complexion and brown spots.