NOVEL 1,2-DIPHENYLETHYLENE GLYCOL COMPOUNDS FOR COMBATING AGING OF THE SKIN, AND COSMETIC USE THEREOF

Abstract

The present invention relates to novel compounds of formula (I)

##STR00001##

to cosmetic compositions comprising same, and also to the use thereof for preventing and/or cosmetically treating the signs of aging of the skin.

Claims

1. A process for preventing and/or reducing the signs of aging of the skin which comprises applying to the skin one or more compounds of formula (I): ##STR00044## in which R1, R1′, R2, R2′, R3, R4, R4′, R5 and R5′ independently denote a hydrogen atom or a radical —OR, and R3′ denotes a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C1-6 acyl radical, an optical isomer, stereoisomer, diastereoisomer and/or salts thereof.

2. The process as claimed in claim 1, wherein, in the compound of formula (I), R1, R1′, R5 and R5′ denote a hydrogen atom, R2, R2′, R3, R4 and R4′ independently denote a hydrogen atom or a radical —OT1 in which T1 denotes a hydrogen atom or a linear C1-C4 alkyl radical, and preferably T1 denotes a hydrogen atom or a methyl radical, and R3′ denotes a radical —OT1 in which T1 denotes a hydrogen atom or a linear C1-C4 alkyl radical, and preferably T1 denotes a hydrogen atom or a methyl radical,

3. The process as claimed in claim 1 wherein the compound of formula (I) is a compound of formula (II): ##STR00045## in which R1, R2, R4 and R5 independently denote a hydrogen atom or a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C1-6 acyl radical, and R3 denotes a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C1-6 acyl radical.

4. The process as claimed in claim 3, in which R1 and R5 denote a hydrogen atom, R2 and R4 independently denote a hydrogen atom or a radical —OT2 with T2 denoting a hydrogen atom or a linear C1-C4 alkyl radical, and R3 denotes a radical —OT2 with T2 denoting a hydrogen atom or a linear C1-C4 alkyl radical.

5. The process as claimed in claim 1, wherein the compound of formula (I) or (II) is chosen from compounds 1 to 3 below, an optical isomer, stereoisomer, diastereoisomer and/or salts thereof: ##STR00046##

6. The process as claimed in claim 1, wherein the compound of formula (I) is a compound of formula (III): ##STR00047## in which: R2 and R4 independently denote —OR R1′, R2′, R4′ and R5′ independently denote a hydrogen atom or a radical —OR, R3′ denotes a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C1-6 acyl radical.

7. The use as claimed in claim 1, wherein the compound of formula (I) is chosen from compounds 4 to 10 below, an optical isomer, stereoisomer, diastereoisomer and/or salts thereof: TABLE-US-00007 Compound Structure 4 5 6 7 8 10

8. The process as claimed claim 1, wherein the compound of formula (I) is present, in a composition containing a physiologically acceptable medium, at a concentration of between 0.0001% and 40% relative to the total weight of the composition.

9. The process according to claim 1 which is a cosmetic treatment process for reducing or preventing the signs of aging of mature and/or wrinkled skin, wherein a compound of formula (I) or a composition containing it, as defined in claim 1, is applied to the mature and/or wrinkled skin.

10. The cosmetic treatment process as claimed in claim 9, which it is intended for promoting the renewal of the keratinocytes and for reducing or preventing signs chosen from thinning of the epidermis, surface wrinkles and impairment of the barrier function.

11. A compound of formula (IIIA): ##STR00054## in which: R2 and R4 independently denote a radical —OR R1′, R2′, R4′ and R5′ independently denote a hydrogen atom or a radical —OR, R3′ denotes a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C2-C6 acyl radical, with the exception of the following 3 compounds: ##STR00055##

12. The compound as claimed in claim 11, wherein the compounds of formula (IIIA) are compounds of formula (IVA): ##STR00056## in which R4′ independently denotes a hydrogen atom or a radical —OR in which R denotes a hydrogen atom or a linear C1-C4 alkyl radical, and R3′ denotes a radical —OR in which R denotes a hydrogen atom or a linear C1-C4 alkyl radical, with the exception of the following compound: ##STR00057##

13. The compound as claimed in claim 11, wherein the compounds of formula (IIIA), optical isomers, stereoisomers and diastereoisomers and/or geometrical isomers and/or salts are chosen from compounds 5 to 10 below: TABLE-US-00008 Compound Structure 5 6 7 8 10

14. A cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) ##STR00063## in which R1, R1′, R2, R2′, R3, R4, R4′, R5 and R5′ independently denote a hydrogen atom or a radical —OR, and R3′ denotes a radical —OR, R denotes a hydrogen atom or a linear C1-C6 or branched C3-C6 alkyl or linear C1-6 acyl radical, an optical isomer, stereoisomer, diastereoisomer and/or salts thereof.

15. The composition as claimed in claim 14, in which the compound of formula (I) is present, alone or as a mixture, in an amount of between 0.01% and 30% by weight relative to the total weight of the composition.

16. The composition as claimed in claim 14, comprising at least one cosmetic ingredient chosen from water; organic solvents; hydrocarbon-based oils, silicone oils, fluoro oils, waxes, pigments, fillers, dyes, surfactants, emulsifiers, cosmetic or dermatological active agents, UV-screening agents, film-forming polymers, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic thickeners, preserving agents, fragrances, odor absorbers and antioxidants.

17. The composition as claimed in claim 14, in which the physiologically acceptable medium comprises at least one cosmetic active agent other than the compounds of formula (I) chosen from: desquamating 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; dermo-decontracting agents; tensioning agents; agents acting on microcirculation; agents acting on the energy metabolism of cells; and mixtures thereof.

18. A composition comprising, in a physiologically acceptable medium, at least one compound of formula (IIIA) as claimed in claim 11 ##STR00064##

19. A non-therapeutic cosmetic process for treating the skin, comprising the application to the skin of a cosmetic composition as defined in claim 14.

20. The process as claimed in claim 19, in which the composition is applied to mature and/or wrinkled skin.

Description

EXAMPLE 1: PREPARATION OF COMPOUND 1

[0143] ##STR00041##

1st Step

[0144] The Zhan catalyst (commercially available from the supplier Sigma USA under the reference 762261) (44 mg, 0.061 mmol, 0.01 eq.) is added to a solution of commercial anethole (298 mg, 2.0 mmol) in anhydrous toluene. The reaction mixture is heated at 110° C. under an inert atmosphere (N.sub.2) for 2 hours. After cooling to room temperature, the toluene is evaporated off under reduced pressure and the residue is purified by column chromatography on silica gel (5/1 hexane/dichloromethane) to isolate the intermediate in the form of a white solid after evaporating off the solvents (433 mg, 90% yield).

[0145] The .sup.1H NMR spectra and mass spectra are in accordance with the expected structure.

[0146] 2nd Step

[0147] The intermediate derived from the first step and AD-mix-β (1.9 g) are dissolved in 8 mL of a t-BuOH/water two-phase mixture (1/1 proportions) and the medium is stirred at room temperature for 16 hours.

[0148] The product is extracted with ethyl acetate and the organic phase is washed with saturated aqueous Na.sub.2SO.sub.3 solution and then with aqueous 2N NaOH solution, dried over sodium sulfate and then concentrated to dryness. The residue is purified by column chromatography on silica gel (EtOAc/hexanes=1/3) to give compound 1 in the form of a white solid (105 mg, 72% yield).

[0149] The .sup.1H NMR spectra and mass spectra are in accordance with the expected structure.

EXAMPLE 2: PREPARATION OF COMPOUND 3

[0150] Compound 3 is obtained in 4 steps according to the sequence described below:

##STR00042##

1st Step

[0151] The Zhan catalyst (commercially available from the supplier Sigma USA under the reference 762261) (447 mg, 0.061 mmol, 0.01 eq.) is added to a solution of commercial isoeugenol (10 g, 61 mmol, 1 eq.) in anhydrous toluene (50 mL). The reaction mixture is heated at 110° C. under an inert atmosphere for 24 hours. After cooling to room temperature, the toluene is evaporated off under reduced pressure and the residue is recrystallized from acetonitrile to give the expected intermediate in the form of a gray solid (6.0 g, 75% yield).

[0152] 2nd Step

[0153] The intermediate derived from the first step (5.9 g, 21.8 mmol, 1 eq.), dissolved in DMF (100 mL), is treated with benzyl bromide (11.2 g, 65.4 mmol, 3 eq.) in the presence of potassium carbonate (12.0 g, 87.2 mmol, 4 eq.). The reaction mixture is stirred at room temperature for 12 hours and the product is then precipitated by adding a large volume of water (100 mL). After filtration, the solid is washed with water and then with hexane and dried under vacuum. The intermediate is obtained in the form of a pale yellow solid (9.8 g, 95% yield).

[0154] 3rd Step

[0155] AD-mix-β (9 g) is dissolved in 120 mL of a t-BuOH/water two-phase mixture (1/1 proportions) and the medium is stirred at room temperature until dissolution is complete. The following are then successively added: [0156] methanesulfonamide (1.3 g, 13.3 mmol, 2 eq.) [0157] intermediate derived from the second step (3.0 g, 6.6 mmol) [0158] dichloromethane (50 ml)

[0159] The reaction medium is maintained at 50° C. for 72 hours. After cooling to room temperature, it is stirred at room temperature in contact with sodium sulfite (10 g) to neutralize the peroxides. The product is extracted 3 times with dichloromethane and the organic phases are combined, dried over sodium sulfate and concentrated to dryness. The residue is purified by column chromatography on silica gel (EtOAc/hexanes=1/2) to give the expected intermediate (protected compound 3), after evaporating off the solvents, in the form of a white solid (1.0 g, 30% yield).

[0160] 4th Step

[0161] The catalyst 10% Pd/C (200 mg) is suspended in a solution of the intermediate derived from the third step in a 1/1 MeOH/EtOAc mixture (40 mL). The reaction medium is stirred at room temperature under an atmosphere of dihydrogen for 24 hours. After removal of the catalyst by filtration, the filtrate is concentrated and the residue is purified by column chromatography on silica gel (dichloromethane/EtOAc: 1/2) to give, after evaporating off the solvents, compound 3 in the form of a white solid (1.0 g, 85% yield).

[0162] The .sup.1H NMR spectra and mass spectra are in accordance with the expected structure.

EXAMPLE 3: PREPARATION OF COMPOUND 4

[0163] Compound 4 is obtained in 3 steps from commercial resveratrol, according to the protection-dihydroxylation-deprotection sequence described below:

##STR00043##

1st Step

[0164] The following are placed in a three-necked flask:

[0165] resveratrol (1.0 g, 4.4 mmol)

[0166] N,N-dimethylformamide (15 ml)

[0167] benzyl bromide (3.4 g, 19.7 mmol, 4.5 eq.)

[0168] potassium carbonate (3.6 g, 26.3 mmol, 6 eq.).

[0169] The reaction mixture is stirred at room temperature for 16 hours and then poured into 20 mL of water. The solid thus formed is filtered off and washed with water and then with petroleum ether. It is dried under vacuum to give a white powder corresponding to the protected resveratrol (m=2.1 g, 95% yield).

[0170] The intermediate thus obtained is used as obtained in the following step.

[0171] 2nd Step

[0172] AD-mix-β (26 g) is dissolved in 200 mL of a t-BuOH/water two-phase mixture (1/1 proportions) and the medium is stirred at room temperature until dissolution is complete. The following are then successively added: [0173] methanesulfonamide (3.5 g, 37.2 mmol) [0174] the intermediate derived from the first step (9.3 g, 18.6 mmol) [0175] dichloromethane (30 ml)

[0176] The reaction medium is maintained at 50° C. for 72 hours. After cooling to room temperature, it is stirred at room temperature in contact with sodium sulfite (10 g) to neutralize the peroxides. The product is extracted 3 times with dichloromethane and the organic phases are combined, dried over sodium sulfate and concentrated to dryness. The residue is purified by column chromatography on silica gel (EtOAc/hexanes=1/2) to give the expected intermediate (protected compound 4) in the form of a pale yellow solid after evaporating off the solvents (m=7.4 g, 70% yield).

[0177] 3rd Step

[0178] The following are placed in a round-bottomed flask: [0179] the intermediate derived from the second step (11 g, 20.7 mmol) [0180] ethyl acetate (50 mL) [0181] methanol (50 mL) [0182] 10% Pd/C (1.1 g)

[0183] The reaction medium is stirred at room temperature under an atmosphere of dihydrogen for 8 hours. The catalyst is then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (dichloromethane/EtOAc: 1/2) to give compound 4 in the form of a white solid after evaporating off the solvents (m=4.7 g, 87% yield).

[0184] The .sup.1H NMR spectra and mass spectra are in accordance with the expected structure.

EXAMPLE 4

[0185] Normal human epidermal keratinocytes are seeded at 180 000 cells per well and cultured in SFM culture medium (supplier Gibco) supplemented with 0.25 ng/ml EGF, 25 μg/ml of pituitary extract and 25 μg/ml gentamicin, up to confluence, and incubated in a humid oven at 37° C. and 5% CO2. The culture medium was then replaced with test medium (SFM (Gibco) supplemented with 25 μg/ml gentamicin) containing or not containing (control) the test compounds, the combinations or the reference (AICAR—(5-amino-4-imidazolecarboxamide riboside) at 500 μM). The cells were then incubated for 12 hours.

[0186] The level of expression of p-AMPK was analyzed by Western blotting.

[0187] At the end of the incubation, the proteins were extracted and quantified and then separated by electrophoresis on 10% polyacrylamide gel and then transferred onto a nitrocellulose membrane.

[0188] After saturation of the membranes in PBS/Tween/1% BSA solution, the phospho-AMPK proteins (Thr-172) (p-AMPK) and GAPDH were successively revealed using specific antibodies that were themselves revealed using an anti-immunoglobulin-peroxidase conjugate. After washing with PBS/Tween, the peroxidase activity and thus the proteins of interest was revealed via the ECL+ (enhanced chemiluminescence) method. Between each successive revelation, the antibodies were detached using a “stripping” buffer. The images were acquired with a Fuji LAS 3000 chemiluminescence scanner (Fujifilm) and the densitometric analyses were performed using the Multigauge software (Fujifilm).

[0189] An increase in the phosphorylated form of AMPK (active form of the enzyme) relative to the control is evaluated in this test.

Results

[0190] Expressed in the form of the p-AMPK/GAPDH ratio relative to the control (100%):

TABLE-US-00005 compound AICAR 500 μM 1 μM 10 μM 100 μM 1 290% 133% 171% 198% 2 283%  94% 134% 149% 3 357% 112% 147% 158% 4 290% 132% 140% 159%

EXAMPLE 5

[0191] The following anti-aging composition is prepared:

[0192] The percentages are indicated on a weight basis.

TABLE-US-00006 Compound of Example 3 2% Glycerol 12%  Polyacrylamide at 40% AM (Sepigel 305 from SEPPIC) 1% AM Mixture of polydimethylsiloxane containing α,ω-hydroxyl 2% and cyclopentadimethylsiloxane groups (15/85) Preserving agents qs Fragrance qs Water qs 100%
AM: active material
When applied to the skin, this cream reduces the signs of aging of the skin.