Xyloside derivatives of resveratrol for use thereof in cosmetics
11654096 · 2023-05-23
Assignee
Inventors
Cpc classification
A61K8/97
HUMAN NECESSITIES
C07H15/203
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to the use of a compound of formula (I): in which R1, R2 and R3 independently denote: —a group of formula (II), or —a hydrogen atom H, it being understood that at least one of the radicals R1, R2, R3 denotes a group of formula (II); and also the salts thereof, the solvates thereof, and/or the isomers thereof, for preventing and/or cosmetically treating the signs of skin aging. ##STR00001##
Claims
1. A process for reducing and/or treating the signs of the aging of keratin material, which comprises applying to the keratin material at least one compound of formula (I): ##STR00033## in which R1, R2 and R3 independently denote: a group of formula (II), ##STR00034## in which the asterisk “*” denotes the point of attachment of the radical to the rest of the compound, or a hydrogen atom H, wherein at least one of the radicals R1, R2, R3 denotes a group of formula (II); the salts thereof, the solvates thereof, and/or the isomers thereof.
2. The process as claimed in claim 1, wherein: R1 denotes a group of formula (II) ##STR00035## and R2 and R3 each denote a hydrogen atom H.
3. The process as claimed in claim 1, wherein: R2 denotes a group of formula (II) ##STR00036## and R1 and R3 each denote a hydrogen atom H.
4. The process as claimed in claim 1, wherein the compound is chosen from the following compounds: TABLE-US-00014 Compound Structure Chemical name 1
5. The process as claimed in claim 1, wherein the compound is chosen from the following compounds: TABLE-US-00015 Compound Structure Chemical name 1a
6. A process for the non-therapeutic cosmetic treatment of the skin, comprising the application to the skin of at least one compound of formula (I) as defined in claim 1 or of a composition comprising said at least one compound.
7. The process as claimed in claim 6, wherein the composition is applied to mature and/or wrinkled skin.
8. A process for the non-therapeutic treatment for improving the firmness of the skin, comprising applying to the skin at least one compound of formula (I) as defined in claim 1 or of a composition comprising said at least one compound.
9. A process for the non-therapeutic treatment of signs of photoinduced or hormonal aging of the skin, comprising applying to the skin at least one compound of formula (I) as defined in claim 1 or of a composition comprising said at least one compound.
Description
(1) The invention is illustrated in greater detail by the following non-limiting examples.
EXAMPLE 1: SYNTHESIS OF THE COMPOUND 1A CAS: 195989-55-0
(2) ##STR00029##
(3) The syntheses of the intermediates A and C are known to those skilled in the art and the synthesis is described in Zhongguo Yaowu Huaxue Zazhi (2010), 20(1), 19-24.
Synthesis of Compound B
(4) Potassium carbonate (0.3 g 2.16 mmol) is added to a solution of compound A (0.5 g 1.08 mmol) and of trifluoro-N-phenylacetimidoyl chloride (CAS 61881-19-4) in 10 ml of acetone. The reaction mixture is stirred at ambient temperature for 1 h, then the heterogeneous mixture is subsequently filtered on diatomite and the filtrate is concentrated under vacuum. The residue is used without purification in the next step.
Synthesis of Compound D
(5) Trimethylsilyltriflate (TMSOTf 5.4 mg 0.025 mmol) is added dropwise to a solution of crude compound B (0.21 g 0.34 mmol) and of compound C (0.15 g 0.24 mmol) in dichloromethane, and the reaction mixture is stirred at ambient temperature for 1 hour. The mixture is then concentrated under vacuum and the residue is purified on a silica chromatography column (eluent 8/1 petroleum ether/ethyl acetate) to give 0.12 g of compound D in the form of a white foam (54% yield).
Synthesis of the Compound 1a
(6) 3 ml of 2 M sodium hydroxide are added to a solution of compound D (0.12 g 0.13 mmol) in 6 ml of methanol/acetone (1/1 v/v). The reaction medium is stirred at ambient temperature for 5 h, then concentrated under vacuum and purified by MPLC preparative chromatography to give 30 mg of the compound 1a in the form of a white foam (62% yield).
(7) The .sup.1H NMR and mass spectra are in accordance with the structure of the expected product.
EXAMPLE 2: SYNTHESIS OF THE COMPOUND 2A CAS: 1245637-91-5
(8) ##STR00030##
(9) The syntheses of the intermediates A and C′ are known to those skilled in the art and the synthesis is described in Zhongguo Yaowu Huaxue Zazhi (2010), 20(1), 19-24.
Synthesis of Compound D′
(10) Trimethylsilyltriflate (TMSOTf 5.4 mg 0.025 mmol) is added dropwise to a solution of crude compound B (0.21 g 0.34 mmol) and of compound C′ (0.2 g 0.24 mmol) in dichloromethane, and the reaction mixture is stirred at ambient temperature for 1 hour. The mixture is then concentrated under vacuum and the residue is purified on a silica chromatography column (eluent 8/1 petroleum ether/ethyl acetate) to give 0.10 g of compound D′ in the form of a white powder.
Synthesis of the Compound 2a
(11) 3 ml of 2 M sodium hydroxide are added to a solution of compound D′ (0.10 g 0.10 mmol) in 6 ml of methanol/acetone (1/1 v/v). The reaction medium is stirred at ambient temperature for 5 h, then concentrated under vacuum and purified by preparative chromatography to give 25 mg of the compound 2a in the form of a white foam (53% yield).
(12) The .sup.1H NMR and mass spectra are in accordance with the structure of the expected product.
EXAMPLE 3: SYNTHESIS OF THE COMPOUND 2B (NOVEL COMPOUND)
(13) ##STR00031##
Synthesis of Compound E
(14) To a stirred solution of D-xylose (7 g, 46.7 mmol) in 45 ml of pyridine at 0 C was added acetic anhydride (26 g, 255 mmol). The resulting mixture was stirred at rt for 16 h. After the solvent was removed, water and ethyl acetate were added. The organic layer was collected and washed with diluted HCl, aq. NaHCO3, and brine in sequence. Then, the extracts were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give the compound E as a colorless oil. Yield: 14.7 g (99%)
Synthesis of Compound F
(15) To a stirred solution of compound E (14.7 g, 46.3 mmol) and 4-iodophenol (11.2 g, 50.9 mmol) in 100 ml of dry dichloromethane was added 5 g of 4A molecular sieves under nitrogen. After the mixture was cooled to 0 C, TMSOTf (1 g, 4.6 mmol) was added via syringe. The reaction was stirred at rt for 24 h. Then, the mixture was cooled again to 0 C and another batch of TMSOTf (1 g, 4.6 mmol) was added via syringe. The reaction was continued to stir at rt for another 24 h and then quenched with aq. NaHCO3 solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The resulting residue was subjected to silica gel chromatography (petroleum ether/ethyl acetate=5/1) to give the compound F as a pale yellow solid. Yield: 7.19 g (32%)
Synthesis of Compound G
(16) To a stirred solution of 3,5-dihydroxybenzaldehyde (5 g, 36.2 mmol) and imidazole (7.4 g, 108.7 mmol) in 30 ml of dry DMF at 0 C was added dropwise TBDMSCl (16.4 g, 108.7 mmol) under nitrogen. After the addition was complete, the mixture was stirred at 0 C for 1 h and then warmed to rt for another 16 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with water twice, aq. NaHCO3 once, and brine once. The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The resulting residue was subjected to silica gel chromatography (petroleum ether/ethyl acetate=100/1 to 20/1) to give the compound G as a colorless oil. Yield: 13.1 g (98%)
Synthesis of Compound H
(17) To a stirred suspension of MePPh3Br (15.2 g, 42.6 mmol) in 100 ml of dry THF at 0 C was added dropwise 17 ml of 2.5 M n-BuLi-hexane solution under nitrogen. After the addition was complete, the mixture was stirred at 0 C for 1 h. Then, a solution of compound G (13 g, 35.5 mmol) in 20 ml of dry THF was added slowly to the above-mentioned mixture. The reaction was stirred at rt for 16 h and quenched with water. The organic layer was extracted with ethyl acetate twice. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The resulting residue was subjected to silica gel chromatography by using petroleum ether as an eluent to give the compound H as a colorless oil. Yield: 11.6 g (90%)
Synthesis of Compound K
(18) To a stirred solution of compound F (7.19 g, 15.0 mmol) and compound H (6.57 g, 18.1 mmol) in 135 ml of DMF and 15 ml of water were added Pd(OAc)2 (1 g, 4.5 mmol), t-Bu4NBr (9.7 g, 30.0 mmol), and triethylamine (15 ml) under nitrogen. The reaction mixture was stirred at rt for 16 h. After filtration, the filtrate was diluted with water and then extracted with ethyl acetate twice. The combined organic extracts were washed with water three times and brine once, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The resulting residue was subjected to silica gel chromatography (petroleum ether/ethyl acetate=3/1) to give the compound K as a yellow solid. Yield: 5.38 g (60%)
Synthesis of 2b
(19) To a stirred methanol (100 ml) was added a grain of sodium (0.825 g, 36 mmol). After the sodium disappeared completely, a solution of compound K (5.38 g, 8.97 mmol) in 10 ml of dichloromethane was added. The mixture was stirred at rt for 16 h and then adjusted to pH˜4 by addition of Amberlite IR-120(H) ion exchange resin. After filtration, the filtrate was evaporated to dryness. The resulting residue was subjected to silica gel chromatography (dichloromethane/methanol=10/1) to give the desired target 2b as a white solid. Yield: 1 g (31%)
(20) The .sup.1H NMR and mass spectra are in accordance with the structure of the expected product.
EXAMPLE 4: SYNTHESIS OF THE COMPOUND 1B (NOVEL COMPOUND)
(21) ##STR00032##
(22) In the same manner than compound 2b, we could obtain compound 1b from coupling between F′ and H′. H′ could be prepared in the same way than H, starting from 4-hydroxybenzaldehyde. F′ could be prepared from coupling between N and E in the same process than F. N is synthesized in 3 steps starting from phloroglucinol. Phloroglucinol is treated with ammonia aqueous solution to give compound L. Then, diazotization of compound L with sodium nitrite followed by iodization with KI is carried out. After work-up, the desired compound M is isolated in 88% yield. Then, treatment of M with 1 equiv. of acetyl chloride gives compound N.
EXAMPLE 5: STUDY OF THE EFFECT OF COMPOUNDS ACCORDING TO THE INVENTION ON TOTAL AND SULFATED GLYCOSAMINOGLYCAN SYNTHESIS ON FIBROBLASTS AND ON KERATINOCYTES
(23) The effects of the compounds on the neosynthesis of total and sulfated glycosaminoglycans (GAGs) were studied on two cell models, normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs). The effects of these compounds were evaluated by measuring: the incorporation of [3H]-glucosamine into the total GAGs neosynthesized by NHEKs and by NHDFs, the incorporation of [35S]-sulfate into the sulfated GAGs neosynthesized by NHEKs and by NHDFs.
(24) The keratinocytes were seeded into wells and cultured in culture medium for 24 hours. The medium was then replaced with culture medium containing or not containing (control) the compounds to be tested or the reference (4-nitrophenyl β-D-xylopyranoside at 300 μM), then the cells were incubated for 72 hours with the addition of the [3H]-glucosamine radioactive label (total GAGs) or of the [35S]-sulfate radioactive label (sulfated GAGs) for the final 24 hours of incubation.
(25) The fibroblasts were seeded into wells and cultured in culture medium for 24 hours. The medium was then replaced with culture medium containing or not containing (controt) the compounds to be tested or the reference (TGF-β at 10 ng/ml), then the cells were incubated for 72 hours with the addition of the [35S]-sulfate radioactive label (sulfated GAGs) or of the [3H]-glucosamine radioactive label (total GAGs) for the final 24 hours of incubation.
(26) At the end of the incubation, the glycosaminoglycans were extracted from the cells with a chaotropic buffer. The GAGs were then purified by ion exchange chromatography: adsorption of the anionic molecules on Q-Sepharose beads and desorption of the molecules of low or medium anionic nature, with a suitable solution.
(27) The radioactivity incorporated into the molecules left on the support (GAGs, predominantly) was measured by liquid scintillation.
(28) All the experimental conditions were performed in n=3.
(29) The radioactivity incorporated into the molecules left on the support (GAGs, predominantly) was measured by liquid scintillation.
(30) The inter-group comparisons were performed using Student's non-paired two-sided t-test. The statistical analyses can be interpreted if n≥5; however, for n<5, the data calculated are provided only by way of indication.
(31) Standard error of the mean:
sem=standard deviation (Sd)/√n
The standard error of the mean (sem) represents the deviation of the sample mean relative to the true population mean. The sem is calculated by dividing the Sd by the square root of the sample size.
(32) Cpm: counts per minute
(33) Sd: standard deviation
(34) TABLE-US-00008 TABLE 1 Effect of the compounds on the synthesis of total glycoaminoglycans by NHEKs (campaign 1) [.sup.3H]-gluco- Comounds samine Mean sem % sem tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 13641 12928 474 100 4 — 12030 13112 4-Nitrophenyl 300 μM 26835 26611 117 206 1 *** β-D-xylopyra- 26438 noside 26560 Compound 1a 10 μM 14440 15165 413 117 3 * 15184 15871 100 μM 30079 30380 811 235 6 *** 29149 31911 Resveratrol 10 μM 7566 8328 393 64 3 ** 8537 8880 100 μM 1509 1743 132 13 1 *** 1754 1967 Polydatin 10 μM 13405 13202 114 102 1 ns (resveratrol 4 13192 glucoside) 13010 100 μM 12222 11660 291 90 2 ns 11510 11248 Threshold for statistical significance ns: >0.05, Not significant *: 0.01 to 0.05, Significant **: 0.001 to 0.01, Very significant ***: <0.001, Extremely significant
(35) Threshold for Statistical Significance
(36) ns: >0.05, Not significant
(37) *: 0.01 to 0.05, Significant
(38) **: 0.001 to 0.01, Very significant
(39) ***: <0.001, Extremely significant
(40) TABLE-US-00009 TABLE 2 Effect of the compounds on the synthesis of sulfated glycosaminoglycans by NHEKs (campaign 1) [.sup.35S]-Sul- Compounds fate Mean sem % sem tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 6093 6784 355 100 5 — 6988 7271 4-Nitrophenyl 300 μM 60267 62566 1164 922 17 *** β-D-xylopyra- 63396 noside 64036 Compound 1a 10 μM 9304 9319 113 137 2 ** 9522 9131 100 μM 53801 56923 1861 839 27 *** 56728 60239 Resveratrol 10 μM 5238 5254 141 77 2 * 5506 5018 100 μM 1836 1802 39 27 1 *** 1725 1845 Polydatin 10 μM 6316 6760 246 100 4 ns 6800 7164 100 μM 7007 8043 530 119 8 ns 8365 8756
(41) In another series of assays, compound 2a was tested as well.
(42) TABLE-US-00010 TABLE 3 Effect of the compounds on the synthesis of total and sulfated glycosamino- glycans by NHEKs (campaign 2) [.sup.3H]-glucosa- Compound mine Mean esm % esm tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 7024 8513 747 100 9 — 9373 9142 4-Nitrophenyl 300 μM 22239 20694 975 243 11 *** β-D-xylopyra- 20953 noside 18891 Resveratrol 1 μM 10734 9628 774 113 9 ns 10012 8137 10 μM 6772 7347 404 86 5 ns 7143 8126 Compound 1a 10 μM 10145 11405 638 134 7 * 11857 12213 100 μM 16745 16980 324 199 4 *** 16574 17621 Compound 2a 1 μM 9472 10215 455 120 5 ns 10133 11041 10 μM 11913 12844 680 151 8 * 12452 14167 [.sup.35S]-Sul- Compound fate Mean esm % esm tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 5021 5309 195 100 4 — 5680 5227 4-Nitrophenyl 300 μM 54440 54615 1078 1029 20 *** B-D-xylopyra- 52841 noside 56564 Resveratrol 1 μM 6885 6530 322 123 6 * 6817 5888 10 μM 5137 4973 97 94 2 ns 4981 4802 Compound 1a 10 μM 10206 11501 684 217 13 *** 12532 11765 100 μM 46568 51673 2553 973 48 *** 54125 54327 Compound 2a 1 μM 5974 6073 149 114 3 * 6365 5879 10 μM 11209 12748 777 240 15 *** 13332 13703
(43) The treatment of the normal human epidermal keratinocytes (NHEKs) with the 4-nitrophenyl β-D-xylopyranoside reference, tested at 300 μM, stimulated the neosynthesis of the total GAGs and that of the sulfated GAGs (respectively 206%/243% and 922%/1029% of the control, tables 1, 2 and 3).
(44) The polydatin compound, tested at 10 and 100 μM, did not modulate the neosynthesis of the sulfated and total GAGs by the NHEKs (tables 1 and 2).
(45) The resveratrol compound, tested at 10 and 100 μM, inhibited, in a concentration-dependent manner, the neosynthesis of the total and sulfated GAGs by the NHEKs (tables 1 and 2).
(46) Surprisingly, the compound 1a tested at 10 and 100 μM, stimulated, in a concentration-dependent manner, the neosynthesis of the total GAGs (117% and 235%, respectively, table 1; 134% and 199%, respectively, table 3) and strongly stimulated in a concentration-dependent manner the neosynthesis of the sulfated GAGs by the NHEKs (137% and 839%, respectively, table 2; 217% and 973%, respectively, table 3).
(47) In the same manner, surprisingly the compound 2a tested at 1 and 10 μM, stimulated in a concentration-dependent manner, the neosynthesis of the total GAGs as well as the neosynthesis of the sulfated GAGs by the NHEKs (table 3).
(48) TABLE-US-00011 TABLE 4 Effect of the compounds on the synthesis of sulfated glycosaminoglycans by NHDFs (campaign 1) [.sup.35S]-Sul- Compound fate Mean sem % sem tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 1678 1647 16 100 1 — 1639 1624 TGF-β 10 ng/ml 3397 3433 30 208 2 *** 3492 3411 Compound 10 μM 3286 3472 93 211 6 *** 1a 3573 3557 100 μM 8753 8844 210 537 13 *** 8534 9244 Resveratrol 10 μM 1506 1527 15 93 1 ** 1556 1519 100 μM 967 1019 26 62 2 *** 1045 1046 Polydatin 10 μM 1523 1573 73 96 4 ns 1479 1718 100 μM 1290 1287 18 78 1 *** 1317 1255
(49) In another series of assays, compound 2a was tested as well.
(50) TABLE-US-00012 TABLE 5 Effect of the compounds on the synthesis of total and sulfated glycosamino- glycans by NHDFs (campaign 2) [.sup.3H]-gluco- Compound samine Mean esm % esm tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 1515 1562 58 100 4 — 1493 1677 TGF-β 10 ng/ml 5999 5167 533 331 34 ** 4173 5328 Resveratrol 10 μM 1439 1534 55 98 4 ns 1533 1630 100 μM 1253 1339 45 86 3 * 1360 1404 Compound 10 μM 1622 1684 37 108 2 ns 1a 1750 1680 100 μM 1422 1408 41 90 3 ns 1331 1470 Compound 10 μM 1758 1624 81 104 5 ns 2a 1479 1636 100 μM 1958 1973 15 126 1 ** 1959 2003 [.sup.35S]- Compound Sulfate Mean esm % esm tested Concentration (cpm) (cpm) (cpm) Control (%) p.sup.(1) Control — 564 566 31 100 6 — 513 621 TGF-β 10 ng/ml 1471 1452 25 257 4 *** 1482 1403 Resveratrol 10 μM 613 571 30 101 5 ns 513 586 100 μM 355 305 25 54 4 ** 283 276 Compound 10 μM 1274 1254 38 221 7 *** 1a 1307 1180 100 μM 2237 2328 46 411 8 *** 2369 2379 Compound 10 μM 765 795 21 141 4 ** 2a 835 786 100 μM 2858 3015 111 533 20 *** 3230 2958
(51) The treatment of the normal human dermal fibroblasts (NHDFs) with the TGF-β reference, tested at 10 ng/ml, stimulated the neosynthesis of total and sulfated GAGs (respectively 331% and 208%/257% of the control, tables 4 and 5).
(52) The resveratrol and polydatin compounds, tested at 10 and 100 μM, overall inhibited the neosynthesis of the total and sulfated GAGs by the NHDFs in a concentration-dependent manner (tables 4 and 5).
(53) Surprisingly, the compound 1a, tested at 10 and 100 μM, strongly stimulated, in a concentration-dependent manner, the neosynthesis of the sulfated GAGs by the NHDFs (211% and 537%, respectively, table 4; 221% and 411%, respectively, table 5).
(54) In addition, surprisingly the compound 2a tested at 10 and 100 μM, stimulated in a concentration-dependent manner, the neosynthesis of the total GAGs (table 5), and strongly stimulated in a concentration-dependent manner, the neosynthesis of the sulfated GAGs by the NHDFs (141% and 533%, respectively, table 5).
(55) The effect of compound 2a and compound 2b on the neosynthesis of total and sulfated glycosaminoglycans (GAGs) were studied on two cell models, normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs) is evaluated.
EXAMPLE 6
(56) An anti-aging gel for the skin is prepared, comprising (% by weight):
(57) TABLE-US-00013 compound 1a of example 1 2% hydroxypropylcellulose (Klucel H from Hercules) 1% antioxidant qs fragrance, preservative qs isopropanol 40% water qs 100%
(58) A similar composition is prepared with the compound of example 2.
(59) A similar composition is prepared with the compound of example 3 or with the compound of example 4.
(60) The composition applied to the face makes it possible to reinforce the firmness of the skin and thus to soften the signs of skin aging.