Resorcinol derivatives for their cosmetic use
11401236 · 2022-08-02
Assignee
Inventors
Cpc classification
C07C235/34
CHEMISTRY; METALLURGY
A61K8/498
HUMAN NECESSITIES
C07C235/36
CHEMISTRY; METALLURGY
International classification
C07C235/34
CHEMISTRY; METALLURGY
C07C235/36
CHEMISTRY; METALLURGY
Abstract
The invention relates to resorcinol-derived compounds of formula (I) and also the salts thereof, the solvates thereof and the optical and/or geometrical isomers thereof, including enantiomers and diastereoisomers, the racemic mixtures thereof, alone or as a mixture. The invention also relates to a cosmetic process for depigmenting, lightening and/or bleaching keratin materials, in particular the skin, using these compounds (I).
Claims
1. A compound chosen from: TABLE-US-00007 Compound No. Structure Chemical name 2
2. The compound according to claim 1, chosen from: TABLE-US-00008 Compound No. Structure Chemical name 2
3. A cosmetic composition comprising, in a physiologically acceptable medium, a compound according to claim 1.
4. The composition according to claim 3, wherein the compound (I) is present in a content of between 0.01% and 10% by weight relative to the total weight of the composition.
5. The composition according to claim 3, which comprises at least one adjuvant chosen from the group of organic solvents; waxes, pigments, fillers, dyes, surfactants, emulsifiers; cosmetic active agents, organic or inorganic photoprotective agents, polymers, thickeners, preserving agents, fragrances, bactericides, ceramides, odour absorbers, and antioxidants.
6. The composition according to claim 3, which comprises at least one active agent chosen from: desquamating agents; calmatives, organic or inorganic photo protective agents, moisturizers; depigmenting 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; tensioning agents; anti-pollution agents and/or free-radical scavengers; agents acting on the capillary circulation; agents acting on the energy metabolism of cells; and mixtures thereof.
7. The compound according to claim 1, chosen from 4-(2,4-dihydroxyphenyl)-N-ethylpentanamide, represented by the formula: ##STR00138## the non-toxic salts thereof, solvates thereof, optical and/or geometrical isomers thereof, racemic mixtures thereof, alone or mixtures thereof.
8. The compound according to claim 1, chosen from 4-(2,4-dihydroxyphenyl)-N-[2-(4-hydroxyphenyl)ethyl]pentanamide, represented by the formula: ##STR00139## the non-toxic salts thereof, solvates thereof, optical and/or geometrical isomers thereof, racemic mixtures thereof, alone or mixtures thereof.
Description
EXAMPLE
(1) The invention is illustrated in greater detail by the following non-limiting examples.
Example 1: Synthesis of Compound No. 1: 4-(2,4-dihydroxyphenyl)pentanoic Acid
(2) ##STR00040##
This compound is described in the article R Gopal; P Gupta Synthesis of succin-as-eins; Bulletin of the Chemical Society of Japan, 47, 7, 1789-1790.
The MS and NMR spectra are in accordance with the desired product and the compound is stable.
Example 2: Synthesis of Compound No. 2: 4-(2,4-dihydroxyphenyl)-N-ethylpentanamide
(3) ##STR00041##
(4) Synthesis of compound 2: To a solution of compound 1 (3.45 g, 16.4 mmol) and of ethylamine hydrochloride (2.0 g, 24.5 mmol) in 50 ml of DMF were added DMAP (3.6 g, 29.5 mmol) and EDCI (3.8 g, 19.8 mmol). The reaction mixture was stirred at ambient temperature for 15 h. The mixture was then poured into 300 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water three times and concentrated to dryness. The crude product was purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=10:1 to give 1.99 g of compound 2 in the form of a yellow solid with a yield of 51%. The MS and NMR spectra are in accordance with the desired product.
Example 3: Synthesis of Compound No. 3/4-(2,4-dihydroxyphenyl)-N-(propan-2-yl)pentanamide
(5) ##STR00042##
(6) Synthesis of compound 3: To a solution of compound 1 (1.05 g, 5.0 mmol) in 20 ml of DMF were added EDCI (1.24 g, 6.5 mmol), DMAP (0.12 g, 1.0 mmol) and isopropylamine (0.52 ml, 6.0 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.3 g of compound. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.3 g of compound 3 in the form of a pale yellow solid with a yield of 24%. Mp: 60-65° C.
(7) The MS and NMR spectra are in accordance with the desired product.
Example 4: Synthesis of Compound No. 4/N-butyl-4-(2,4-dihydroxyphenyl)pentanamide
(8) ##STR00043##
(9) To a solution of compound 1 (1.0 g, 4.76 mmol) and of butylamine hydrochloride (427 mg, 5.7 mmol) in 20 ml of DMF were added DMAP (cat.) and EDCI (1.1 g, 5.7 mmol). The reaction mixture was stirred at ambient temperature for 15 h. The mixture was then poured into 300 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water three times and concentrated to dryness. The crude product was purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=10:1 to give 605 mg of compound 4 in the form of a yellow solid with a yield of 48%. m.p.: 76□.
(10) The MS and NMR spectra are in accordance with the desired product.
Example 5: Synthesis of Compound No. 5/N-(butan-2-yl)-4-(2,4-dihydroxyphenyl)pentanamide
(11) ##STR00044##
To a solution of compound 1 (692 mg, 3.6 mmol) in 10 ml of THF was added butan-2-amine (293 mg, 4 mmol). The mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: EtOAc/PE=1/2) to give 470 mg of compound 5 in the form of a white solid with a yield of 49%.
(12) The MS and NMR spectra are in accordance with the desired product.
Example 6: Synthesis of Compound No. 6/N-cyclohexyl-4-(2,4-dihydroxyphenyl)pentanamide
(13) ##STR00045##
Synthesis of the compound F′:
(14) ##STR00046##
To a solution of compound 1 (3.2 g, 15.2 mmol) in 40 ml of DMF were added EDCI (3.78 g, 19.8 mmol) and DMAP (0.46 g, 3.8 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate.
The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (PE/EA=5:1) to give 2.5 g of compound F′ in the form of a white solid with a yield of 86%. Melting point: 63-67° C.
Synthesis of compound 6: To a solution of compound F′ (650 mg, 3.38 mmol) in 20 ml of THF was added cyclohexylamine (396 mg, 4.0 mmol). The reaction mixture was heated at 50° C. for 8 h. The mixture was cooled to ambient temperature. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water three times and concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50:1 to give 800 mg of compound 6 in the form of a white solid with a yield of 80%. Mp. 75-78□.
(15) The MS and NMR spectra are in accordance with the desired product.
Example 7: Synthesis of Compound No. 7/N-(cyclohexylmethyl)-4-(2,4-dihydroxyphenyl)pentanamide
(16) ##STR00047##
(17) To a solution of compound F′ (692 mg, 3.6 mmol) (0.5 g, 2.6 mmol) in 15 ml of THF was added aminomethylcyclohexane (0.4 ml, 3.1 mmol). After stirring at ambient temperature for 20 h, the solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.4 g of compound 7 in the form of a white solid with a yield of 50%.
(18) The MS and NMR spectra are in accordance with the desired product.
Example 8: Synthesis of Compound No. 8/4-(2,4-dihydroxyphenyl)-N-[2-(4-hydroxyphenyl)ethyl]pentanamide
(19) ##STR00048##
To a solution of compound 1 (690 mg, 3.2 mmol) and of 4-(2-aminoethyl)phenol (527 mg, 3.8 mmol) in 20 ml of DMF were added DMAP (cat.) and EDCI (730 mg, 3.8 mmol). The reaction mixture was stirred at ambient temperature for 15 h. The mixture was then poured into 300 ml of water and extracted three times with EtOAc. The organic phase was washed with water three times and concentrated to dryness. The crude product was purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=10:1 to give 700 mg of compound 8 in the form of a yellow solid with a yield of 67%. m.p.: 135□.
(20) The MS and NMR spectra are in accordance with the desired product.
Example 9: Synthesis of Compound No. 9/4-(2,4-dihydroxyphenyl)-N-(2-hydroxyethyl)pentanamide
(21) ##STR00049##
(22) To a solution of compound F′ (0.5 g, 2.6 mmol) in 15 ml of THF was added ethanolamine (0.19 ml, 3.1 mmol). After having stirred at 80° C. for 20 h, the mixture was poured into water and extracted two times with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated under vacuum. The residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1 to 15:1) to give 0.5 g of compound 9 in the form of a pale pink oil with a yield of 76%.
(23) The MS and NMR spectra are in accordance with the desired product.
Example 10: Synthesis of Compound No. 10/4-(2,4-dihydroxyphenyl)pentanamide
(24) ##STR00050##
To a solution of compound F′ (800 mg, 4.16 mmol) in 20 ml of THF was added NH.sub.3H.sub.2O (350 mg, 10.0 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water three times and concentrated to dryness under vacuum. The crude product was further purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50:1 to give 650 mg of compound 10 in the form of a white solid with a yield of 75%. MP. 54-56□
(25) The MS and NMR spectra are in accordance with the desired product.
Example 11: Synthesis of Compound No. 11/4-[5-(ethylamino)-5-oxopentan-2-yl]benzene-1,3-diyl diacetate
(26) ##STR00051##
To a solution of compound 2 (0.57 g, 2.4 mmol) in 40 ml of THF was added TEA (0.72 g, 7.2 mmol), followed by slow deposit of acetyl chloride (0.56 g, 7.2 mmol) into the mixture at 0° C. in an ice bath. The mixture was stirred at ambient temperature for 16 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: 3/1 petroleum ether/ethyl acetate) to give 0.48 g of compound 11 in the form of a white powder with a yield of 62%.
(27) The MS and NMR spectra are in accordance with the desired product.
Example 12: Synthesis of Compound No. 12/4-(2,4-dihydroxyphenyl)-N-(3-methoxypropyl)pentanamide
(28) ##STR00052##
To a solution of compound 1 (1.1 g, 5.2 mmol) in 20 ml of DMF were added EDCI (1.3 g, 6.8 mmol), DMAP (0.13 g, 1.05 mmol) and 3-methoxypropylamine (0.64 ml, 6.3 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.4 g of compound 12 in the form of a pale pink oil with a yield of 27%.
(29) The MS and NMR spectra are in accordance with the desired product.
Example 13: Synthesis of Compound No. 13/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]glycinate
(30) ##STR00053##
To a solution of compound F′ (2.1 g, 10.9 mmol) in 40 ml of DMF were added glycine ethyl ester hydrochloride (1.8 g, 13.1 mmol) and triethylamine (2.1 mg, 14.2 mmol). After stirring at 90° C. for 20 h, the mixture was filtered. The filtrate was poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=60:1) to give 1.3 g of compound 3 in the form of a yellow solid with a yield of 41%. Mp: 56° C.
(31) The MS and NMR spectra are in accordance with the desired product.
Example 14: Synthesis of Compound No. 14/N-[4-(2,4-dihydroxyphenyl)pentanoyl]glycine
(32) ##STR00054##
To a solution of compound 13 (1.22 g, 4.1 mmol) in 30 ml of acetonitrile were added K.sub.2CO.sub.3 (1.3 g, 9.5 mmol) and benzyl bromide (1.1 ml, 9.1 mmol). After stirring at reflux for 20 h, the mixture was filtered and evaporated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=6:1) to give 1.83 g of an intermediate benzylated ethyl ester in the form of a white solid with a yield of 95%.
A solution of this benzylated intermediate (1.83 g, 3.85 mmol) in 30 ml of methanol was added to a solution of LiOH.H.sub.2O (0.22 g, 5.4 mmol) in 2 ml of water at 0° C. The mixture was stirred at ambient temperature for 20 h. The mixture was then adjusted to pH=6 using HCl and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=40:1) to give 1.2 g of benzylated acid intermediate in the form of a yellow solid with a yield of 65%.
To a solution of benzylated acid intermediate (1.6 g, 3.6 mmol) in 20 ml of methanol was added 0.3 g of Pd/C. The mixture was stirred at ambient temperature under hydrogen for 20 h. The mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=40:1) to give 0.45 g of compound 14 in the form of a white solid with a yield of 47%. Mp: 59-65° C.
(33) The MS and NMR spectra are in accordance with the desired product.
Example 15: Synthesis of Compound No. 15/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]-L-alaninate
(34) ##STR00055##
To a solution of compound F′ (768 mg, 4.0 mmol) and L-alanine ethyl ester hydrochloride (L-alanine: (S)-2-aminopropionic acid; CAS: 1115 to 59-9) (675 mg, 4.4 mmol) in 20 ml of DMF was added TEA (253 mg, 2.5 mmol). The reaction mixture was heated at 80° C. for 15 h. The mixture was cooled to ambient temperature. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic layers were washed with water three times and concentrated to dryness under vacuum. The crude product was further purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50:1 to give 742 mg of compound 15 in the form of a yellow solid with a yield of 60%. Mp: 48-50° C.
(35) The MS and NMR spectra are in accordance with the desired product.
Example 16: Synthesis of Compound No. 16/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]-D-alaninate
(36) ##STR00056##
To a solution of compound F′ (768 mg, 4.0 mmol) and D-alanine ethyl ester hydrochloride (D-alanine: (R)-2-aminopropionic acid; CAS: 6331-09-5) (675 mg, 4.4 mmol) in 20 ml of DMF was added TEA (253 mg, 2.5 mmol). The reaction mixture was heated at 80° C. for 15 h. The mixture was cooled to ambient temperature. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic layers were washed with water three times and concentrated to dryness under vacuum. The crude product was further purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50:1 to give 650 mg of compound 16 in the form of a yellow solid with a yield of 60%.
(37) The MS and NMR spectra are in accordance with the desired product.
Example 17: Synthesis of Compound No. 17/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]-DL-alaninate
(38) ##STR00057##
To a solution of compound F′ (430 mg, 2.2 mmol) and alanine hydrochloride (384 mg, 2.5 mmol) in 20 ml of DMF was added TEA (253 mg, 2.5 mmol). The reaction mixture was heated at 80° C. for 15 h. The mixture was cooled to ambient temperature. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic layers were washed with water three times and concentrated to dryness under vacuum. The crude product was further purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50:1 to give 544 mg of compound 17 in the form of a yellow solid with a yield of 80%. P.p.45-48° C.
(39) The MS and NMR spectra are in accordance with the desired product.
Example 18: Synthesis of Compound No. 18/N-[4-(2,4-dihydroxyphenyl)pentanoyl]-D-alanine
(40) ##STR00058##
To a solution of compound 15 (1.55 g, 5.0 mmol) in 60 ml of MeCN were added K.sub.2CO.sub.3 (1.73 g, 12.5 mmol) and BnBr (1.88 g, 11.0 mmol). The reaction mixture was refluxed for 15 h. After cooling to ambient temperature, the mixture was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by silica gel column chromatography using dichloromethane, to give 2.3 g of intermediate benzylated ester in the form of a white powder with a yield of 93%.
To a solution of the benzylated ester intermediate (2.3 g, 4.7 mmol) in 50 ml of THF was added LiOH (236 mg, 5.6 mmol) in 8.0 ml of water. The reaction mixture was stirred for 15 h. 200 ml of water were poured into the mixture and said mixture was acidified with 6N HCl at pH=2, and the resulting mixture was extracted twice with EtOAc. The combined organic layer was washed with water three times and concentrated to dryness. The resulting residue was purified by silica gel chromatography (dichloromethane/methanol=500:2) to give 1.7 g of benzylated acid intermediate in the form of a white powder with a yield of 77%.
A mixture of benzylated acid intermediate (1.5 g, 3.3 mmol) and 400 mg of 10% of Pd/C in 60 ml of MeOH was stirred under hydrogen at ambient temperature for 15 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by silica gel chromatography (dichloromethane/methanol=250:1) to give 795 mg of compound 18 in the form of a white powder with a yield of 87%. Mp: 65 to 68□.
(41) The MS and NMR spectra are in accordance with the desired product.
Example 19: Synthesis of Compound No. 19/N-[4-(2,4-dihydroxyphenyl)pentanoyl]-L-alanine
(42) ##STR00059##
To a solution of compound 16 (1.55 g, 5.0 mmol) in 60 ml of MeCN were added K.sub.2CO.sub.3 (1.73 g, 12.5 mmol) and BnBr (1.88 g, 11.0 mmol). The reaction mixture was refluxed for 15 h. After cooling to ambient temperature, the mixture was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by silica gel column chromatography using dichloromethane, to give 2.35 g of intermediate benzylated ester in the form of white powder with a yield of 96%.
To a solution of the benzylated ester intermediate (2.3 g, 4.7 mmol) in 50 ml of THF was added LiOH (236 mg, 5.6 mmol) in 8.0 ml of water. The reaction mixture was stirred for 15 h. 200 ml of water were poured into the mixture and said mixture was acidified with 6N HCl at pH=2, and the resulting mixture was extracted twice with EtOAc. The combined organic layer was washed with water three times and concentrated to dryness. The resulting residue was purified by silica gel chromatography (dichloromethane/methanol=500:2) to give 1.4 g of benzylated acid intermediate in the form of a white powder with a yield of 62%.
A mixture of benzylated acid intermediate (1.3 g, 2.8 mmol) and 400 mg of 10% Pd/C in 60 ml of MeOH was stirred under hydrogen at ambient temperature for 15 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by silica gel chromatography, (dichloromethane/methanol=250:1) to give 578 mg of compound 19 in the form of a white powder with a yield of 73%.
The MS and NMR spectra are in accordance with the desired product.
Example 20: Synthesis of Compound No. 20/methyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]leucinate
(43) ##STR00060##
To a solution of compound 1 (3.15 g, 15 mmol) in 80 ml of DMF were added D-leucine methacrylate hydrochloride (CAS: 5845-53-4) (3.27 g, 18 mmol), EDCI (3.46 g, 18 mmol), HOBt (2.43 g, 18 mmol) and TEA (5.25 ml, 36 mmol). The mixture was stirred at ambient temperature for 15 h. 200 ml of water were then added to the mixture and extracted three times with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: 50/1 dichloromethane/methanol) to give 3.6 g of compound 20 in the form of a white powder with a yield of 71%.
Mp: 63° C.
The MS and NMR spectra are in accordance with the desired product.
Example 21: Synthesis of Compound No. 21/N-[4-(2,4-dihydroxyphenyl)pentanoyl]leucine
(44) ##STR00061##
To a solution of compound 20 (4.2 g, 12.4 mmol) in 80 ml of acetonitrile were added K.sub.2CO.sub.3 (3.94 g, 28.5 mmol) and benzyl bromide (4.88 g, 28.5 mmol). After refluxing for 20 hours, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified by silica gel chromatography (PE/EA=6:1) to give 4.18 g of benzylated ester intermediate as a pale yellow oil with a yield of 65%.
To a solution of it (4.18 g, 8.07 mmol) in 60 ml of THF was added a solution of LiOH.H.sub.2O (0.68 g, 16.14 mmol) in 10 ml of water at 0° C. The mixture was stirred at ambient temperature for 20 h. The mixture was then adjusted to pH=6 using HCl and concentrated under vacuum. The residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 2.2 g of benzylated acid intermediate as a pale yellow oil with a yield of 54%. Mp: 56-57° C.
To a solution of it (2.2 g, 4.37 mmol) in 60 ml of methanol was added 0.38 g of Pd/C. The mixture was stirred at ambient temperature under hydrogen for 20 h. The mixture was filtered using a diatomite. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=25:1) to give 0.97 g of compound 21 in the form of a white solid with a yield of 69%.
The MS and NMR spectra are in accordance with the desired product.
Example 22: Synthesis of Compound No. 22/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]phenylalaninate
(45) ##STR00062##
To a solution of compound 1 (0.6 g, 2.86 mmol) in 15 ml of DMF were added EDCI (0.71 g, 3.71 mmol), DMAP (0.52 g, 4.29 mmol) and ethylphenyl alaninate hydrochloride (0.79 g, 3.43 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=50:1) to give 0.4 g of compound 22 in the form of a white solid with a yield of 36%. Mp: 51-59□.
The MS and NMR spectra are in accordance with the desired product.
Example 23: Synthesis of Compound No. 23/N-[4-(2,4-dihydroxyphenyl)pentanoyl]phenylalanine
(46) ##STR00063##
To a solution of compound 22 (1 g, 2.6 mmol) in 30 ml of acetonitrile were added K.sub.2CO.sub.3 (0.82 g, 6.0 mmol) and benzyl bromide (0.65 ml, 5.5 mmol). After stirring at reflux for 20 h, the mixture was filtered and the filtrated was evaporated under vacuum. The residue was purified by silica gel chromatography (PE/EA=6:1) to give 1.22 g of a pale yellow oil with a yield of 83%. Mp: 74-80° C. A solution of the latter (1.1 g, 1.95 mmol) in 15 ml of methanol was added to a solution of LiOH.H.sub.2O (0.11 g, 2.73 mmol) in 2 ml of water at 0° C. The mixture was stirred at ambient temperature for 20 h. The mixture was then adjusted to pH=6 using HCl and concentrated under vacuum. The residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.97 g of a pale yellow oil with a yield of 94%. To a solution of this benzylated carboxylic acid (0.97 g, 1.8 mmol) in 20 ml of methanol was added 0.2 g of Pd/C. The mixture was stirred at ambient temperature under hydrogen for 15 h. The mixture was filtered using a diatomite. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=25:1) to give 0.32 g of compound 23 in the form of a white solid with a yield of 50%.
The MS and NMR spectra are in accordance with the desired product.
Example 24: Synthesis of Compound No. 24/4-(2,4-dihydroxyphenyl)-N,N-diethylpentanamide
(47) ##STR00064##
To a solution of compound F′ (0.577 g, 3 mmol) in 40 ml of DMF was added diethylamine (0.342 g, 4.5 mmol). The mixture was heated to 90° C. and was reacted for 6 h. After cooling of the mixture, 100 ml of water were added to the mixture and the latter was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: 50/1 dichloromethane/methanol) to give 423 mg of compound 24 in the form of a pale yellow oil with a yield of 51%.
(48) The MS and NMR spectra are in accordance with the desired product.
Example 25: Synthesis of Compound No. 25/4-(2,4-dihydroxyphenyl)-N,N-bis(2-methoxyethyl)pentanamide
(49) ##STR00065##
To a solution of compound F′ (810 mg, 4.2 mmol) in 20 ml of DMF was added bis(2-methoxyethyl)amine (670 mg, 5.0 mmol). The reaction mixture was heated at 90° C. for 15 h. The mixture was cooled to ambient temperature. The mixture was then poured into 200 ml of water and extracted three times with EtOAc. The combined organic layers were washed with water three times and concentrated to dryness under vacuum. The crude product was further purified by silica gel column chromatography, eluting with CH.sub.2Cl.sub.2:MeOH=50/1 to give 330 mg of compound 25 in the form of a white solid with a yield of 23%. Mp: 78-81° C.
The MS and NMR spectra are in accordance with the desired product.
Example 26: Synthesis of Compound No. 26/4-(2,4-dihydroxyphenyl)-N-ethyl-N-(2-hydroxyethyl)pentanamide
(50) ##STR00066##
Synthesis of compound 26: To a solution of compound F′ (1.92 g, 10 mmol) in 80 ml of DMF was added 2-(ethylamino)ethanol (1.34 g, 15 mmol). The mixture was heated to 120° C. and was reacted for 5 h. After cooling of the mixture, 150 ml of water were added to the mixture and the latter was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: 50/1 dichloromethane/methanol) to give 890 mg of compound 26 in the form of a white powder with a yield of 32%.
The MS and NMR spectra are in accordance with the desired product.
Example 27: Synthesis of Compound No. 27/ethyl N-[4-(2,4-dihydroxyphenyl)pentanoyl]-N-methylglycinate
(51) ##STR00067##
To a solution of compound F′ (3.2 g, 15.2 mmol) in 40 ml of DMF were added EDCI (3.78 g, 19.8 mmol) and DMAP (0.46 g, 3.8 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (PE/EA=5:1) to give 2.5 g of compound 27 in the form of white solid with a yield of 86%.
The MS and NMR spectra are in accordance with the desired product.
Example 28: Synthesis of Compound No. 28/N-[4-(2,4-dihydroxyphenyl)pentanoyl]-N-methylglycine
(52) ##STR00068##
To a solution of compound 27 (1 g, 2.6 mmol) in 30 ml of acetonitrile were added K.sub.2CO.sub.3 (0.82 g, 6.0 mmol) and benzyl bromide (0.65 ml, 5.5 mmol). After stirring at reflux for 20 h, the mixture was filtered and the filtrated was evaporated under vacuum. The residue was purified by silica gel chromatography (PE/EA=6:1) to give 1.22 g of a pale yellow oil with a yield of 83%. A solution of the latter (1.1 g, 1.95 mmol) in 15 ml of methanol was added to a solution of LiOH.H.sub.2O (0.11 g, 2.73 mmol) in 2 ml of water at 0° C. The mixture was stirred at ambient temperature for 20 h. The mixture was then adjusted to pH=6 using HCl and concentrated under vacuum. The residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=40:1) to give 0.97 g of a pale yellow oil with a yield of 94%. To a solution of the latter (0.97 g, 1.8 mmol) in 20 ml of methanol was added 0.2 g of Pd/C. The mixture was stirred at ambient temperature under hydrogen for 15 h. The mixture was filtered using a diatomite. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane/methanol=25:1) to give 0.32 g of compound 28 in the form of a white solid with a yield of 50%.
The MS and NMR spectra are in accordance with the desired product.
Example 29: Synthesis of Compound No. 29/4-(2,4-dihydroxyphenyl)-1-(morpholin-4-yl)pentan-1-one
(53) ##STR00069##
To a solution of compound F′ (846 mg, 4.4 mmol) in 10 ml of THF was added morpholine (401 mg, 4.6 mmol). The mixture was stirred at a.t. for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: EtOAc/PE=1/2) to give 700 mg of compound 29 in the form of a white solid with a yield of 57%.
The MS and NMR spectra are in accordance with the desired product.
Example 30: Synthesis of Compound No. 30/ethyl 4-(2,4-dihydroxyphenyl)pentanoate
(54) ##STR00070##
To a solution of compound 1 (500 mg, 2.3 mmol) in 20 ml of ethanol were added drops of sulfuric acid. The mixture was stirred at a.t. for 18 h. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: EtOAc/PE=1/2) to give 437 mg of compound 30 in the form of an oil with a yield of 88%.
The MS and NMR spectra are in accordance with the desired product.
Example 31: Synthesis of Compound No. 31/propan-2-yl 4-(2,4-dihydroxyphenyl)pentanoate
(55) ##STR00071##
The same procedure as for compound 30 using isopropanol at 80° C. gives compound 31 in the form of an oil with a yield of 95%
The MS and NMR spectra are in accordance with the desired product.
Example 32: Synthesis of Compound No. 32/5-O-[4-(2,4-dihydroxyphenyl)pentanoyl]-D-xylitol
(56) ##STR00072##
To a solution of compound 1 (1 g, 4.8 mmol) in 50 ml of acetonitrile were added benzyl bromide (5 eq) and potassium carbonate (5 eq). The mixture was refluxed for 20 h and, after filtration and removal of the solvent under vacuum, was subjected to silica gel chromatography (eluent: EtOAc/PE=1/2) to give a perbenzylated intermediate with a yield of 83% in the form of an oil (1.9 g). This intermediate was saponified with potassium hydroxide in aqueous methanol at 70° C. for 20 h, to give dibenzylated resorcinol carboxylic acid (after acid treatment), which was used in the next step. To 0.33 g of the latter (0.84 mmol) in 15 ml of DMF were added EDCI (0.242 g, 1.26 mmol), DMAP (0.4 g) and 2,3:4,5-di-O-isopropylidene-D-xylitol (0.588 g, 2.5 mmol) in sequence at 0° C. After stirring at ambient temperature for 20 h, the mixture was adjusted to pH=7 using 3N HCl. The solution was then poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (CH.sub.2Cl.sub.2/MeOH=50:1) to give 0.28 g (55%) of protected alcohol as oil. This oil was subjected to a deprotection of the acetonides and subsequent hydrogenolysis, to give compound 33 (yield 27% two steps) in the form of a hydroscopic oil.
(57) ##STR00073##
The MS and NMR spectra are in accordance with the desired product.
Example 33: Synthesis of Compound No. 33/3,7-dimethyloct-6-en-1-yl 4-(2,4-dihydroxyphenyl)pentanoate
(58) ##STR00074##
The same procedure as for compound 30 using (S) (−) citronellol at a.t. gives compound 33 in the form of an oil with a yield of 45%
The MS and NMR spectra are in accordance with the desired product.
Example 34: Synthesis of Compound No. 34/3-{[(2,2,5,5-tetramethyl-1,3-dioxan-4-yl)carbonyl]amino}propyl 4-(2,4-dihydroxyphenyl)pentanoate
(59) ##STR00075##
Panthenol acetonide (or (4R)—N-(3-hydroxypropyl)-2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide, commercially available) was condensed with benzylated carboxylic acid with EDCI and DMAP in dichloromethane to give 3.4 g of the benzylated intermediate. The hydrogenolysis was carried out, to give compound 34 in the form of a yellow oil.
(60) ##STR00076##
The MS and NMR spectra are in accordance with the desired product.
Example 35: Demonstration of the Depigmenting Activity
(61) The effectiveness was demonstrated on the basis of the following test:
(62) For the evaluations of the effect of prevention or of decrease of pigmentation of the skin and/or of lightening of this skin, the examples are carried out in the following way.
(63) 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.
(64) First of all, normal human melanocytes were cultured and dispensed into 384 wells. After 24 hours, the culture medium was replaced with a medium containing compounds of formula (I) to be evaluated. The cells were incubated for 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 measurements of melanin correspond, it is possible to determine an IC50 in μM: concentration at which 50% decrease in melanin synthesis is achieved.
(65) The compounds of formula (I) showed a strong depigmenting effect.
(66) Various test campaigns were conducted and collated in the tables below.
(67) TABLE-US-00002 TABLE 2 Maximum concentration Compound No. IC50 (μM) tested (μM) 8 0.391 200 7 0.401 200 5 0.447 200 6 0.557 200 3 0.617 200 9 0.636 200 4 0.692 200 2 0.824 200 11 0.94 200 30 1.01 200 24 1.02 200 10 1.07 200 15 1.08 200 20 1.58 200 18 1.63 200 26 1.96 200 29 2.94 200 34 2.95 200 32 3.03 200 1 4.8 200
(68) These results were compared with compounds described in the prior art, and more particularly in patent application WO 2004/017 936:
(69) ##STR00077##
For this compound (A), the IC50 value is 3.86 μM. in patent application WO 2005/085 169:
(70) ##STR00078##
For this compound (B), the IC50 value is 4.97 μM. in patent application EP623339/JP11255638:
(71) ##STR00079##
For this compound (C), the IC50 value is 63.1 μM.
(72) TABLE-US-00003 TABLE 3 Maximum concentration Compound No. IC50 (μM) tested (μM) 17 0.391 200 6 0.391 200 5 0.391 200 20 1.2 200 29 1.82 200 25 5.27 200 22 8.33 200 14 18.5 200 28 31.1 200 27 51.3 200
Example 36: Demonstration of the Depigmenting Activity
(73) Two other tests were carried out:
(74) The modulatory effect on melanogenesis of each compound was measured according to the method described in the 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 carried out on a coculture of keratinocytes and melanocytes.
For the compounds tested, the following were determined: the cytotoxicity, the inhibitory activity on melanin synthesis, by estimating the melanin optical density, the IC50 values (concentration for which 50% of the melanin synthesis is inhibited).
Compound 17: non-cytotoxic IC50=0.12 μM,
Compound 26: non-cytotoxic IC50=0.45 μM,
Compound 6: non-cytotoxic IC50=0.14 μM,
4-n-butyl resorcinol (reference) IC50=0.79 μM.
Example 37: Demonstration of the Depigmenting Activity
(75) Experiment on pigmented reconstructed epidermis
(76) TABLE-US-00004 Comparison of melanin with respect Effective to the solvent Compound concentration (DMSO) Lucinol (4-n-butyl 500 μM −25% resorcinol) Compound 2 50 μM −26%
(77) Compound 2 has a depigmenting efficiency which is greater than lucinol on pigmented reconstructed epidermis.
Example 38: Cosmetic Composition
(78) A skin depigmenting composition is prepared, comprising (in grams):
(79) TABLE-US-00005 Compound No. 2 2 g PEG400 68 g Ethanol 30 g
The composition applied to the skin makes it possible to attenuate brown spots.
Example 39: Gel
(80) A skin depigmenting gel is prepared, comprising (% by weight):
(81) TABLE-US-00006 Compound No. 2 0.25% Carbomer (Carbopol 981 from Lubrizol) 1% preserving agent qs water qs 100%
The composition applied to the skin makes it possible to attenuate brown spots.