RESORCINOL DERIVATIVES FOR THEIR COSMETIC USE

专利摘要:
The present invention relates to a compound of formula (I) for its use for depigmenting, lightening and / or whitening the skin in which R1, R2 independently denote H, an alkyl radical, an S * radical denoting a monosaccharide sugar radical or a radical sugar polysaccharide, a COR6 radical; R3 denotes a C1-C20 alkyl radical; R4, R5 independently denote H, a C2-C20 saturated or unsaturated C3-C20, or cyclic C3-C8 alkyl radical, optionally interrupted and / or optionally substituted; R7, R8 same or different, being selected from H, a linear saturated C1-C10 alkyl group, a linear unsaturated C 2 -C 10 alkyl group, a saturated or unsaturated branched C 3 -C 10 alkyl group, or a C 3 cycloalkyl group -C8; a C6 (C1-C4) alkyl (hetero) aryl group optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical and their salts, their solvates and their optical and / or geometric isomers, their racemates, alone or as a mixture. The present invention also relates to novel compounds (II) as well as to a process for their preparation and to a cosmetic process for the depigmentation of the skin using such compounds (I) or (II).
公开号:FR3045039A1
申请号:FR1562427
申请日:2015-12-15
公开日:2017-06-16
发明作者:Xavier Marat；Chunyu Ma
申请人:LOreal SA；
IPC主号:

专利说明:

The present invention relates to the cosmetic use of compounds derived from resorcinol for depigmenting and / or bleaching the skin, as well as certain novel resorcinol compounds. At different periods of their life, some people see appear on the skin and especially on the hands and face, darker spots and / or more colorful, giving the skin a heterogeneity. These spots are due in particular to a high concentration of melanin in the keratinocytes located on the surface of the skin. The use of harmless topical depigmenting substances having a good efficacy is particularly sought for treating pigmented spots.
The mechanism of formation of the pigmentation of the skin, that is to say the formation of melanin is particularly complex and schematically involves the following main steps:
Tyrosine - »Dopa -» Dopaquinone - »Dopachrome -» Melanin
Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxido-reductase EC 1.14.18.1) is the essential enzyme involved in this series of reactions. In particular, it catalyzes the conversion reaction of tyrosine to Dopa (dihydroxyphenylalanine) thanks to its hydroxylase activity and the conversion reaction of Dopa to dopaquinone by virtue of its oxidase activity. This tyrosinase only acts when it is maturing under the influence of certain biological factors.
A substance is recognized as depigmenting if it acts directly on the vitality of the epidermal melanocytes where the melanogenesis takes place, and / or if it interferes with one of the stages of melanin biosynthesis either by inhibiting one of the enzymes involved in melanogenesis, or by interposing itself as a structural analogue of one of the chemical compounds of the melanin synthesis chain, which chain can then be blocked and thus ensure depigmentation. Arbutin and kojic acid are known as depigmenting agents of the skin.
We have looked for substances that have an effective depigmenting action, especially greater than that of arbutin and kojic acid.
There remains the need for a new whitening agent for human skin with action as effective as those known, but not having their disadvantages, that is to say which is non-irritating, non-toxic and / or non-allergenic to the skin, while being stable in a composition, or alternatively which has a reinforced action so that it can be used in a smaller quantity, which considerably reduces the observed side effects. In this regard the Applicant has surprisingly and unexpectedly discovered that certain resorcinol compounds have good depigmenting activity, even at low concentration, without exhibiting cytotoxicity. In this respect, the Applicant has surprisingly and unexpectedly discovered that certain compounds derived from resorcinol have a good depigmenting activity, even at low concentration.
Certain compounds derived from resorcinol are already known in the prior art for their depigmenting activity. In this respect, mention may in particular be made of the documents WO 2005/085169 and WO 2004/017936. The subject of the invention is compounds of formula (I) as defined below for their dermatological use for depigmenting the skin. The invention also relates to novel compounds of formula (II) as defined below. The subject of the invention is also a non-therapeutic cosmetic treatment method for depigmenting, lightening and / or bleaching keratinous substances, in particular the skin, comprising applying to the skin at least one compound of formula ( I) as defined below. The subject of the invention is also a composition comprising, in a physiologically acceptable medium, at least one compound of formula (II) as defined below. The subject of the invention is also a non-therapeutic cosmetic method for depigmenting, lightening and / or bleaching keratinous substances, in particular the skin, comprising the application of the composition described above.
More preferably, it is the process for depigmenting, lightening and / or whitening the skin. The invention also relates to the non-therapeutic cosmetic use of at least one compound of formula (I) as defined below as a whitening, lightening and / or depigmenting agent for keratinous substances, in particular the skin.
The compounds according to the invention, namely in particular of formula (I) or of formula (II) as defined below, make it possible to depigment and / or lighten effectively, or even to whiten, the skin of beings. humans. They are particularly intended to be applied to the skin of individuals with brownish pigmentation spots, senescence spots, or on the skin of individuals wishing to combat the appearance of a brownish color from melanogenesis.
They can also help depigment and / or brighten hair, eyelashes, hair, as well as lips and / or nails. The subject of the invention is therefore compounds of formula (I) as follows, for their use for depigmenting, lightening and / or whitening the skin:
in which R1, R2 independently denote: a) H, b) a saturated or unsaturated C2-C20 alkyl radical, linear or branched C3-C20, or cyclic C3-C8, c) a radical S * denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 unit (s) saccharide (s), preferably from 2 to 3 unit (s) saccharide (s), preferentially a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said mono or polysaccharide radical S * being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this link being anomeric a or β, d) a COR6 radical in which R6 denotes a linear saturated C1-C20 alkyl radical, a linear unsaturated C2-C20 alkyl radical, a saturated or unsaturated branched C3-C20 radical or a C3 cycloalkyl radical; -C8, R3 denotes a saturated or unsaturated C1-C20 alkyl radical C2-C20, linear or branched C3-C20 or cyclic C3-C8, R4, R5 independently denote a) H, b) a C1-C20 alkyl radical saturated or unsaturated C2-C20 or branched C3-C20 , or cyclic C3-C8, optionally interrupted by one or more heteroatoms or non-adjacent groups, in particular one to three, chosen from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from: i) -OR7 ii) -SR7 iii) -NR7R8 iv) -CONHR7 v) -CONR7R8 vi) -COOR7 vii) -NHCONHR7 viii) -C (O) (C 1 -C 4) alkyl (ix) a nonhydrous saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls, in particular one to three, and / or by one or more C 1 -C 5 alkoxy and / or C 1 -C 6 alkyl radicals, especially one to three; one of the members of the (hetero) ring group possibly being a carbonyl group x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more radicals C1-C8 alkoxy and / or C1-C6 alkyl, especially one to three xi) -NH-C = NH (NH2) (guanidine group) R7, R8, which may be identical or different, chosen from H, an alkyl group C1-C10 linear saturated, linear unsaturated C2-C10 alkyl, saturated or unsaturated branched C3-C10 alkyl group, or C3-C8 cycloalkyl group; (C1-C4) alkyl (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; c) NR9R10 with R9 and R10 designating a radical chosen from
i) -H ii) a saturated linear C 1 -C 10 or unsaturated C 2 -C 10 or branched C 3 -C 10 or cyclic C 3 -C 8 alkyl group optionally interrupted by one or more heteroatoms or groups selected from N, O; CO or combinations thereof such as -NHCO-, -NHCONH-, and / or optionally substituted with one or more C 1 -C 6 alkyl groups, identical or different, in particular one to three iii) a C 5 -C 12 (hetero) aryl group , optionally containing one or more heteroatoms selected from O, N, S, especially one to three, optionally substituted by one or more hydroxyls and / or by one or more C 1 -C 5 alkoxy radicals, especially one to three; R9 and R10 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain optionally containing one or more radicals chosen from hydroxyl or C1-C4 alkoxy, especially one to three; d) OR 11 with R 11 denoting a radical chosen from:
i) -H ii) a linear C 1 -C 10 or C 3 -C 10 branched or C 3 -C 8 cyclic saturated alkyl group, R 4, R 5 being capable of forming, with the nitrogen which carries them, a 5- to 8-membered heterocyclic ring, contain one or more heteroatoms or groups selected from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; as well as their salts, their solvates and their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemates, alone or as a mixture.
In the context of the present invention, it is understood that when the radical S * represents a monosaccharide radical it may be in pyranose form (the sugar heterocycle which constitutes it is 6-membered) or furanose (Γheterocycle sugar which constitutes it is 5-membered); and when said radical S * represents a polysaccharide radical, it comprises a sequence of 2 to 5 saccharide units identical to or different from each other which may be in furanose or pyranose form.
These definitions of the radical S * apply to the compounds of formula (I) as well as to the compounds of formula (II) as defined below.
Preferably the polysaccharide is a disaccharide which results from the sequencing of a saccharide unit in furanose form and a unit in pyranose form or the sequence of a saccharide unit in pyranose form and a unit in furanose form; whether for the monosaccharide or polysaccharide radical, each saccharide unit may be in L-form levogyre or D dextrorotatory, and anomeric form a or β.
Preferably, the monosaccharide is chosen from glucose, galactose, mannose, xylose, lyxose, fucose, arabinose, rhamnose, quinovose, fructose, sorbose, talose, N-acetylglucosamine, N-acetylgalactosamine, and preferably glucose, galactose, mannose, xylose, lyxose, fucose, arabinose, rhamnose and fructose.
According to another embodiment, the polysaccharide radical may consist of from 2 to 5 saccharide units, in particular from 2 to 3, and preferably from 2 saccharide units, connected to each other via an oxygen (oxy) atom in 1 - > 4 (Cl of one saccharide unit -> C4 of the other saccharide unit) or 1 -> 3 (Cl of one saccharide unit -> C3 of the other saccharide unit) or 1 -> 6 (Cl d ' a saccharide unit -> C6 of the other saccharide unit), each saccharide unit of which consists of a heterocycle comprising 4 or 5 carbon atoms.
When the polysaccharide radical is a disaccharide, it may be chosen from: lactose, maltulose, palatinose, lactulose, tonsillosis, turanose, cellobiose, isomaltose, rutinose and maltose; and preferably it can be maltose.
Still within the scope of the present invention, the salts of the compounds of formula (I) and of formula (II) as defined hereinafter comprise the conventional non-toxic salts of said compounds such as those formed from acid or base .
As salts of the compound of formula (I) or of formula (II) (when it comprises a quaternizable nitrogen atom), mention may be made of: a) the salts obtained by addition of the compound of formula (I) or (II) with a mineral acid, in particular chosen from hydrochloric, boric, hydrobromic, hydroiodic, sulfuric, nitric, carbonic, phosphoric and tetrafluoroboric acids; b) or the salts obtained by adding the compound of formula (I) or (II) with an organic acid, in particular chosen from acetic, propionic, succinic, fumaric, lactic, glycolic, citric, gluconic, salicylic, tartaric and terephthalic acids; , methylsulfonic, ethylsulfonic, benzenesulphonic, toluenesulphonic, triflic.
Mention may also be made of the salts obtained by adding the compound of formula (I) or (II) (when it comprises an acid group) with a mineral base, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide, and carbonates or hydrogen carbonates of sodium, potassium or calcium for example; or with an organic base such as a primary, secondary or tertiary alkylamine, for example triethylamine or butylamine. This primary, secondary or tertiary alkylamine may comprise one or more nitrogen and / or oxygen atoms and may therefore comprise, for example, one or more alcohol functions; mention may in particular be made of 2-amino-2-methyl-propanol, ethanolamine, triethanolamine, 2-dimethylamino propanol, 2-amino-2- (hydroxymethyl) -1,3-propanediol, 3- (dimethylamino) ) propylamine.
Mention may also be made of amino acid salts such as, for example, lysine, arginine, guanidine, glutamic acid and aspartic acid. Advantageously, the salts of the compounds of formula (I) or (II) (when it comprises an acid group) may be chosen from alkali or alkaline earth salts such as sodium, potassium, calcium, magnesium; ammonium salts.
Advantageously, the salts of the compounds of formula (I) or (II) (when it comprises a quaternizable nitrogen atom) may be chosen from halides such as chloride, bromide; citrate, acetate, succinate, phosphate, lactate, tartrate.
The acceptable solvates of the compounds described in the present invention include conventional solvates such as those formed during the preparation of said compounds due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water or of linear or branched alcohols, such as ethanol or isopropanol.
Optical isomers include enantiomers and diastereoisomers.
Still within the scope of the present invention: a "(C 1 -C 4) alkyl group" denotes an alkyl group comprising from x to y carbon atoms. Such an alkyl group can be linear and saturated and typically contain 1 to 20 carbon atoms or 1 to 10 carbon atoms. It can also be linear and unsaturated and typically contain from 2 to 20 carbon atoms or from 2 to 10 carbon atoms. It can also be branched and typically contain from 3 to 20 carbon atoms or from 3 to 10 carbon atoms. An alkyl group can also be cyclic, it is then a cycloalkyl group which can typically contain from 3 to 8 carbon atoms.
Unless otherwise indicated, a "(C 1 -C 4) alkyl group" refers to a linear and saturated alkyl group having from about 1 to about 4 carbon atoms.
Preferably, the linear saturated or branched alkyl groups may be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
More preferably, the linear saturated or branched alkyl groups may be chosen from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, 2-ethylhexyl and octyl.
The cycloalkyl group may be chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. a "(C 1 -C 6) alkoxy" group denotes a linear and optionally branched group of formula -O (C 1 -C 4) alkyl which can typically contain from 1 to 8 carbon atoms or from 1 to 4 carbon atoms.
The alkoxy group may be chosen from methoxy, ethoxy, propoxy and butoxy and more particularly be a methoxy group. - A "non-aromatic saturated or unsaturated (hetero) ring group" refers to a monocyclic or bicyclic carbocyclic group having from 5 to 12 members, in particular from 5 to 8 members, which may contain one to three heteroatoms or groups selected from N, O , S and -C (O) -.
Such a (hetero) ring group may be selected from cyclohexyl, piperidyl, morpholinyl, piperazinyl, imidazolyl, and pyrrolidinyl. Preferably, it is the piperidyl or morpholinyl ring. "(Hetero) aryl" means an unsaturated or partially unsaturated carbocyclic group, monocyclic or bicyclic, containing from 5 to 12 carbon atoms and capable of containing one to three heteroatoms chosen from N, O and S.
The aryl radicals may be chosen from phenyl, naphthyl, indenyl, fluorenyl and anthracenyl. Preferentially it is the phenyl group. - A "heteroaryl group" denotes a mono or polycyclic group, condensed or not, comprising from 5 to 22 members, from 1 to 6 heteroatoms chosen from nitrogen, oxygen, sulfur, and at least one of which cycle is aromatic.
The heteroaryl radicals may be selected from furyl, acridinyl, benzimidazolyl, benzobistriazolyl, benzopyrazolyl, benzopyridazinyle, benzoquinolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, pyridinyl, tetrazolyl, dihydrothiazolyl, imidazopyridinyl, imidazolyl, indolyl, isoquinolyl, naphthoimidazolyle, naphthooxazolyle, naphthopyrazolyle, oxadiazolyl, oxazolyl , oxazolopyridyl, phenazinyl, phenoxazolyl, pyrazinyl, pyrazolyl, pyrilyl, pyrazoyltriazyl, pyridyl, pyridinoimidazolyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolopyridinyl, thiazoylimidazolyl, thiopyrylyl, triazolyl, xanthyl and its ammonium salt.
According to a first variant, the compounds of formula (I) are such that R4 denotes a hydrogen atom, R1, R2, R3 and R5 having the definitions given previously or subsequently, in the preferences. As examples of compounds of formula (I) according to this variant, there may be mentioned compounds 1 to 11, 14 to 25, 28 to 37, 39 to 57 described below.
According to a second variant, the compounds of formula (I) are such that R4 and R5 are identical, R1, R2, and R3 having the definitions given previously or subsequently, in the preferences.
According to this variant, R4 and R5 are preferably identical and represent a C1-C20 alkyl radical, preferably a C1-C10 alkyl radical, optionally substituted by an OR7 radical as defined above. As examples of compounds of formula (I) according to this second variant, there may be mentioned compounds 12, 13, 26 described below.
According to a third variant, the compounds of formula (I) are such that R4 and R5 are different and R4 denotes a radical chosen from methyl, ethyl or hydroxyethyl radicals, R1, R2, R3 and R5 having the definitions given previously or by the next, in the preferences. As examples of compounds of formula (I) according to this third variant, there may be mentioned compounds 27, 38 and 58 described below.
According to a fourth variant, the compounds of formula (I) are such that R4 and R5 form a saturated or unsaturated non-aromatic heterocycle having from 5 to 8 members, which may contain one or more heteroatoms or groups chosen from N, O, -CO- , in particular one to three, and / or optionally substituted by a C 1 -C 10 hydrocarbon-based chain, such a heterocycle possibly being chosen from pyrrolidine, piperidine, morpholine or piperazine, R 1, R 2, R 3 having the definitions given previously or subsequently, in preferences. As examples of compounds of formula (I) according to this third variant, mention may be made of compound 59 described below.
Among the compounds of formula (I), some are new and constitute another subject of the invention, as well as the compositions, in particular the cosmetic compositions, which contain them; they are the compounds of formula (II) below:
in which R'I, R'2 independently denote a) H, b) a linear or branched C3-C20 saturated or C3-C20 saturated or unsaturated alkyl, or a C3-C8 cyclic radical, c) a radical S * denoting a radical monosaccharide sugar or a polysaccharide sugar radical comprising from 2 to 5 unit (s) saccharide (s), preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar group comprising 1 or 2 unit (s) saccharide (s) ( s) (monosaccharide or disaccharide), said mono or polysaccharide radical S * being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono- or polysaccharide radical, this bond possibly being anomeric to β, d) a COR'6 radical in which R'6 denotes a linear saturated C1-C20 alkyl radical, a linear unsaturated C2-C20 alkyl radical, a saturated or unsaturated branched C3-C20 radical or a cycloalkyl radical; C3-C8, it being understood that R'I and R'2 can not designate simu at the present time, a methyl radical, R '3 denotes a C 2 -C 20 saturated or unsaturated C 2 -C 20 alkyl radical, linear or C 3 -C 20 branched or C 3 -C 8 cyclic R' 4, R '5 independently denote a) -H ; b) a saturated or unsaturated C2-C20 or branched C3-C20 or C3-C8 cyclic C1-C20 alkyl radical, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO- or their combinations such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from: i) -OR'7 ii) -SR'7 iii) -NR'7R'8 iv) -CONHR'7 v) -CONR'7R'8 vi) -COOR'7 vii) -NHCONHR'7 viii) -C (O) (C 1 -C 4) alkyl ix) a non aromatic saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls, especially one to three, and / or by one or more C 1 -C 6 alkoxy or alkyl radicals in C | -Cs, especially one to three; one of the chain members may be a carbonyl group; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C 5 alkyl radicals, in particular one to three xi) -NH-C = NH (NH2) (guanidine group) R'7, R'8, which may be identical or different, chosen from H, a linear saturated C1-C10 alkyl group, a C2-alkyl group; Linear or branched unsaturated C10, saturated or unsaturated branched C3-C10 alkyl group or C3-C8 cycloalkyl group; (C1-C4) alkyl (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and or optionally substituted with a C1-C10 hydrocarbon chain; c) NR'9R'10 R'9 and R'10 designating a radical chosen from
i) -H ii) a saturated linear C 1 -C 10 or unsaturated C 2 -C 10 or branched C 3 -C 10 or cyclic C 3 -C 8 alkyl group, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O , -CO or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more C 1 -C 6 alkyl groups, identical or different, in particular one to three; iii) a C5-C12 (hetero) aryl group, optionally containing one or more non-adjacent heteroatoms chosen from O, N, S, in particular one to three, optionally substituted by one or more hydroxyls and / or by one or more alkoxy radicals; in Ci-Cs, especially one to three; R9 and R10 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain optionally containing one or more radicals chosen from hydroxyl or C1-C4 alkoxy, especially one to three; d) OR '11 with R' 11 designating a radical chosen from:
i) -H ii) a linear saturated C 1 -C 10 or branched C 3 -C 10 or cyclic C 3 -C 8 alkyl group,
R'4, R'5 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and or optionally substituted with a C1-C10 hydrocarbon chain, and their salts, solvates, optical and / or geometric isomers, including enantiomers and diastereoisomers, and racemates, and with the exception of the following 3 compounds:
The four variants described above for the compounds of formula (I) can be applied to the compounds of formula (II) and also form part of the invention.
It is understood in the context of the present invention that when a first radical is substituted by one or more second radicals, the term "several" may mean two or three.
Likewise, when a first cyclic radical optionally contains one or more heteroatoms or groups, the term "several" may mean two or three.
Preferably, the compounds of formula (I) are such that: R 1, R 2 independently denote a) H, b) a C 1 -C 10 saturated or unsaturated C 2 -C 10 alkyl radical, linear or branched C 3 -C 10, or cyclic C3-C6 c) a radical S * as defined above and in particular a radical glucosyl, xylosyl, mannosyl, fucosyl or maltosyl d) a radical COR6 in which R6 denotes a linear saturated C1-C15 alkyl radical, an alkyl radical C2-C15 linear unsaturated or saturated or unsaturated C3-C15 alkyl radical, R3 denotes a linear saturated C1-C10 alkyl radical, a linear unsaturated C2-C10 alkyl radical, a saturated branched C3-C10 alkyl radical, or unsaturated or a C3-C6 cycloalkyl radical R4, R5 independently denote a) -H; b) a linear saturated C 1 -C 15 alkyl radical, a linear unsaturated C 2 -C 15 alkyl radical, a saturated or unsaturated C 3 -C 15 saturated alkyl radical or a C 3 -C 8 cycloalkyl radical, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one or two, chosen (s) of: i) -OR7 -OR7 such as a methyl or ethyl or isopropyl radical ii) -SR7 iii) -NR7R8 iv) -CONHR7 v) -CONR7R8 vi) -COOR7 vii) -NHCONHR7 viii) -C ( 0) (C 1 -C 4) alkyl (ix) a non-aromatic saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls and / or by one or more C 1 -C 5 alkoxy radicals or C 1 -C 12 alkyl, especially one to three; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C x alkyl radicals, in particular one to three xi) -NH-C = NH (NH 2) (guanidine group) R 7, R 8, which may be identical or different, being chosen from H, a linear saturated C 1 -C 10 alkyl group, a linear unsaturated C 2 -C 10 alkyl group, a saturated or unsaturated branched C3-C10 alkyl group or a C3-C8 cycloalkyl group; (C 1 -C 4) C 6 (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO- and / or optionally substituted with a C1-C6 hydrocarbon chain; C10, especially one to three; R4, R5 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO- and / or optionally substituted with a C1-C6 hydrocarbon chain; C10 such as pyrrolidine, piperidine, morpholine, piperazine.
Preferably, the compounds of formula (II) are such that: R'I, R'2 independently denote a) H, b) a linear saturated C 1 -C 10 alkyl radical, a linear or branched unsaturated C 2 -C 10 alkyl radical an unsaturated or saturated branched C3-C10 alkyl group or a C3-C6 cycloalkyl group; c) a radical S * denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 saccharide unit (s), preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said radical S * mono or polysaccharide being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this bond possibly being anomeric to a or β; and in particular a glucosyl, xylosyl, mannosyl, fucosyl or maltosyl radical d) a COR'6 group in which R'6 denotes a linear saturated C1-C15 alkyl group or a linear unsaturated C2-C15 alkyl group provided that R 1 and R'2 can not denote simultaneously a methyl radical R'3 denotes a linear saturated C1-C10 alkyl radical, a linear unsaturated C2-C10 alkyl radical, a saturated or unsaturated branched C3-C10 alkyl radical, or C3-C6 cycloalkyl radical R'4, R'5 independently denote a) -H; b) a linear C1-C15 alkyl radical, a linear unsaturated C2-C15 alkyl radical, a saturated or unsaturated C3-C15 branched radical or a C3-Cs cycloalkyl radical, optionally interrupted by one or more heteroatoms or chosen groups from N, O, -CO- or their combination such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from : i) -OR'7 such as a methyl or ethyl or isopropyl radical ii) -SR'7 iii) -NR'7R'8 iv) -CONHR'7 v) -CONR'7R'8 vi) -COOR ' Vii) -NHCONHR'7 viii) -C (O) (C 1 -C 4) alkyl ix) a non-aromatic saturated or unsaturated heterocycle group, said (hetero) ring group being optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or one or more C 1 -C 5 alkoxy or C 1 -C 5 alkyl radicals, especially one to three; one of the chain members may be a carbonyl group; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C x alkyl radicals, in particular one to three xi) -NH-C = NH (NH 2) (guanidine group) R '7, R' 8 being identical or different, being chosen from H, a linear saturated C 1 -C 10 alkyl group, a C2-alkyl radical; Linear unsaturated C10, a saturated or unsaturated branched C3-C10 alkyl radical, or a C3-C8 cycloalkyl radical; a (C 1 -C 4) alkyl (hetero) aryl group at G, optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and or optionally substituted with a C1-C10 hydrocarbon chain; R'4, R'5 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one or two, and / or optionally substituted with a C1-C10 hydrocarbon chain such as pyrrolidine, piperidine, morpholine, piperazine, and with the exception of the following compound:
More preferably still, the compounds of formula (I) are such that: R 1, R 2 independently denote a) H, b) a linear saturated C 1 -C 6 alkyl radical, a linear unsaturated C 2 -C 6 alkyl radical or an alkyl radical C3-C6 branched saturated or unsaturated, such as ethyl, isopropyl and n-propyl radicals; c) an S * radical denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 saccharide units, of preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said radical S * mono or polysaccharide being connected to the rest of the molecule by a bond between the carbon atom Ci of one of the sugars of said mono or polysaccharide radical, this bond possibly being anomeric to a or β; S * denoting in particular a glucose radical d) a COR6 radical in which R6 denotes a linear saturated C1-C15 alkyl radical, such as a methyl or hexyl radical R3 denotes a linear saturated C1-C6 alkyl radical, an alkyl radical saturated or unsaturated branched C3-Ce or a C3-C6 cycloalkyl radical, such as a methyl, ethyl or isopropyl radical R4, R5 independently denote a) -H; b) a linear C1-C15 alkyl group, a saturated or unsaturated branched C3-C15 alkyl group or a C3-C8 cycloalkyl group, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO or their combinations such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one to three, chosen from: i) -OR7 such that a methyl or ethyl or isopropyl radical ii) -SR7 such as SH or SMe iii) -NR7R8 such that NH2 iv) -C0NHR7 such that CONH2 v) -C00R7 such as CO2Me, CO2Et and CO2iPr vi) a (hetero) ring group saturated or unsaturated non-aromatic such as cyclohexyl, optionally substituted by one or more hydroxyl radicals, especially one to three, and / or by one or more C 1 -C 4 alkoxy or C 1 -C 4 alkyl radicals, especially one to three; one of the chain members possibly being a carbonyl group vii) a C5-C12 (hetero) aryl group, such as a phenyl, imidazolyl and indolyl radical, optionally substituted with one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 5 alkoxy and / or C 1 -C 1 alkyl radicals, especially one to three R 7, R 8 radicals, which may be identical or different, being chosen from H, a linear saturated C 1 -C 6 alkyl group or an alkyl group Saturated or unsaturated branched C3-C6; (C 1 -C 4) (hetero) aryl (C 6) alkyl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; R4, R5 being able to form, with the nitrogen which carries them, a heterocycle chosen from pyrrolidine, piperidine, morpholine and piperazine. Examples of radicals R4 include, for example, radicals, H, methyl, ethyl, n-butyl, - (CH2) xOMe with x denoting an integer ranging from 1 to 4 inclusive, in particular - (CH2) 2OMe. Examples of radicals R 5 include, for example, a hydrogen atom, n-butyl radicals; - (CH2) xOT with x denoting an integer ranging from 1 to 4 inclusive and T denoting a methyl or ethyl radical, in particular - (CH2) 3OMe, - (CH2) 3OEt, - (CH2) 2OMe, - ( CH2) 2OMe; ethyl; n-propyl; n-pentyl; n-hexyl; isopropyl; isobutyl; - (CH2) x-iPr, x having the same definition as above; cyclohexyl; -CH2-cyclohexyl; a radical of formula (III)
in which W1 denotes a linear or branched Ci-Cr saturated alkyl radical optionally substituted with a phenyl radical and W2 denotes H or a linear or branched C1-C4 saturated alkyl radical, such as the radicals of formulas (a) to (i) following:
or a radical of formula (IV)
with y denoting an integer between 1 and 4 inclusive terminals, p being equal to 0, 1, 2 or 3, q being equal to 0.1, 2 or 3, and p + q <6 Z denoting a linear alkyl radical C1-C4 saturates such as methyl, such as the following radicals (j) and (k):
Even more preferably, the compounds of formula (I) denote compounds 1 to 59 as listed in Table I below, as well as their salts and / or solvates.
More particularly, the compounds of formula (II) denote compounds for which: R'I, R'2 independently denote a) H, b) a linear saturated C 1 -C 6 alkyl group or an unsaturated branched C 3 -C 6 alkyl group or unsaturated such as ethyl, isopropyl and n-propyl radicals; c) an S * radical denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 saccharide units, preferably from 2 to 3 units; (S) saccharide (s), preferably a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said mono or polysaccharide S * radical being connected to the rest of the molecule by a bond between the a carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this bond possibly being anomeric to a or β; S * denoting in particular a glucose radical d) a COR'6 group with R'6 denoting a linear saturated C1-C15 alkyl radical or a linear unsaturated C2-C15 group, preferably a linear saturated C1-C15 alkyl radical , such as a methyl or hexyl radical, it being understood that R'1 and R'2 can not simultaneously designate a methyl radical R'3 denotes a linear saturated C1-C6 alkyl radical, a linear unsaturated C2-C10 alkyl radical, a saturated or unsaturated branched C 3 -C 6 alkyl radical or a C 3 -C 6 cycloalkyl radical such as a methyl, ethyl or isopropyl radical R '4, R' 5 independently denote a) -H; b) a linear saturated C1-C15 alkyl radical, a linear unsaturated C2-C15 alkyl radical, a saturated or unsaturated C3-C15 branched radical or a C3-C8 cycloalkyl radical, optionally interrupted by one or more heteroatoms or groups non-adjacent selected from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one to three, chosen ( s) from: i) -OR7 such as a methyl or ethyl or isopropyl radical ii) -SR7 such as SH or SMe iii) -NR7R8 such that NH2 iv) -CONHR7 such as CONH2 v) -COOR7 such that CO2Me, CO2E and C02iPr vi) a nonhydrous saturated or unsaturated (hetero) ring group such as cyclohexyl, optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C1-C4 alkoxy or C1-alkyl radicals; -C4, especially one to three; vii) a C 5 -C 12 (hetero) aryl group, such as a phenyl, imidazolyl and indolyl radical, optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 4 alkoxy radicals; Cs and / or C 1 -C x alkyl, in particular one to three viii) -NH-C = NH (NH 2) (guanidine group) R '7, R' 8 being identical or different, being chosen from H, an alkyl group Linear saturated C1-C10, linear unsaturated C2-C10 alkyl group, saturated or unsaturated branched C3-C10 alkyl group or C3-C8 cycloalkyl group; (C1-C4) alkyl (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups, in particular one or two, chosen from N, O, -CO- and / or or optionally substituted with a C1-C10 hydrocarbon chain; R'4, R'5 being able to form with the nitrogen which carries them a heterocycle chosen from pyrrolidine, piperidine, morpholine, piperazine. Examples of radicals R'4 include, for example, radicals, H, methyl , ethyl, n-butyl, - (CH2) xOMe with x denoting an integer from 1 to 4, inclusive, in particular - (CH2) 2OMe. Examples of R '5 radicals include, for example, n-butyl radicals; - (CH2) xOT with x denoting an integer ranging from 1 to 4 inclusive and T denoting a methyl or ethyl radical, in particular - (CH2) 3OMe, - (CH2) 3OEt, - (CH2) 2OMe, - ( CH2) 2OMe; ethyl; n-propyl; n-pentyl; n-hexyl; isopropyl; isobutyl; - (CH2) x-iPr, x having the same definition as above; cyclohexyl; -CH2-cyclohexyl; a radical of formula (III)
in which W1 denotes a linear or branched C1-C6 saturated alkyl radical optionally substituted by a phenyl radical and W2 denotes H or a linear or branched C1-C4 saturated alkyl radical, such as the radicals of formulas (a) to (i) below :
or a radical of formula (IV)
(IV) with y denoting an integer between 1 and 4 inclusive, p being 0, 1, 2 or 3, q being equal to 0.1, 2 or 3, and p + q <6 Z designating a C1-C4 saturated linear alkyl radical such as methyl, such as the following radicals (j) and (k):
Even more preferably, the novel compounds of formula (II) denote compounds 1 to 59 as listed in Table I below, as well as their salts and / or solvates.
Examples of compounds of formula (I) and (II) of the invention are summarized in Table 1 below.
Table 1
The numbers in the table correspond to the numbers used in the examples below.
The compounds of the invention can be prepared according to the following scheme 1.
Diagram 1
According to this scheme 1, the synthesis of compounds (I) and (II) passes through the key intermediate of dihydrocoumarin type D, the synthesis of which is described, inter alia, in WO2005 / 085169. Those skilled in the art can adapt the strategy according to the groups R3.
Resorcin A can react in the presence of a beta-keto ester B to lead to coumarin C. The latter is reduced by catalytic hydrogenation according to the conditions known to those skilled in the art to lead to D. D can also be obtained from resorcinol A in the presence of an alpha beta unsaturated ester E. The lactonic function of D is then opened in the presence of amine NHR4R5 with or without prior modifications of phenolic functions by known strategies of the skilled in the art in terms of reaction and protection / deprotection (formation of esters, ethers or glycosylations). The C and D derivatives can be obtained via the reaction between A and B or A and E, in particular in the presence of an organic solvent which can be chosen from toluene, tetrahydrofuran, heptane, isooctane and methyl. tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dioxane, ethyl acetate, isopropyl acetate, isododecane and mixtures thereof, in particular at a temperature of between 15 and 200 ° C., optionally in the presence of of a catalyst (acidic or basic) as described in the publications: Synthesis of 7-hydroxycoumarins by Pechmann reaction using Nafion resin / silica nanocomposites as catalysts: Laufer MC, Hausmann H, Holderich WF, J of catalysis, 2003, 218, 315-320; Synthesis of 7-hydroxycoumarins catalysed by solid acid catalysts Hoefnagel A, Gunnewegh E, Downing R, van Bekkum H, J Chem Common Soc Chem, 1995, 225-226; especially in the presence of an acid catalyst such as sulfuric acid, methanesulfonic acid, triflic acid, para-toluenesulphonic acid, sulfonic resins such as Dowex® or Amberlyst® (sold by Aldrich) ).
The compounds of formula (I) and (II) for which R 1 and R 2 (R '1 and R' 2) denote a COR 6 group (COR '6) can be obtained by acetylation / esterification. The acetylation / esterification reaction can be carried out with acetic anhydride (or R6COOCOR6 anhydride) or acetyl chloride (or R6COCl), especially in the presence of aprotic solvent such as toluene, pyridine, tetrahydrofuran. The acetylation reaction can be selective by employing protecting groups on the functions not to be acetylated and carrying out a deprotection reaction after acetylation, according to the known techniques of organic synthesis.
The opening reaction of the lactone D with amines NHR4R5 can be carried out optionally in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, 2-methyltetrahydrofuran or dichloromethane; toluene, methanol or ethanol; optionally in the presence of a catalyst selected from acidic Lewis or Bronsted catalysts or basic catalysts, such as potassium carbonate, triethylamine, diisopropylethylamine; optionally by heating at a temperature between 15 ° C and 200 ° C, especially between 20 ° C and 150 ° C.
In addition, when the final compounds (I) and (II) have on the radicals R4 and / or R5 (R'4 and / or R'5) a free carboxylic acid, the latter can be obtained by saponification using inorganic bases. such as, for example, NaOH or LiOH in the presence of protic or aprotic solvents such as for example ethanol or tetrahydrofuran or water at temperatures ranging between 0 and 100 ° C. The salts obtained are then re-acidified in the presence of conventional inorganic or organic acids such as, for example: hydrochloric acid, citric acid. All of these steps may also involve protection / deprotection strategies usually used in organic chemistry and compiled in the book "Protecting Groups in Organic Synthesis" Greene, Wuts, Wiley Interscience, depending on the nature of the radicals.
The selective glycosylation strategies are known to those skilled in the art and can be found in particular in the book "Handbook of Chemical Glycosylation" A. V. Demchenko Wiley VCH.
Thus the present application also relates to a process for preparing a compound of formula (II) as defined above consisting of
(i) reacting a compound of formula D
in which R 3 'is as defined above, by hydrogenation for a ring opening in the presence of a catalyst such as Pd / C, said compound of formula D having previously been protected on the hydroxyl group by a protecting group such as the benzyl group, and then (ii) reacting the compound obtained in step (i) with a compound of formula HNR4R5, in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, dichloromethane; toluene, methanol or ethanol; optionally in the presence of a catalyst selected from acidic Lewis or Bronsted catalysts or basic catalysts, such as potassium carbonate, triethylamine, diisopropylethylamine; optionally by heating at a temperature of between 15 ° C and 200 ° C, in particular
between 20 ° C and 150 ° C, to give the compound of formula G
wherein R3 ', R4' and R5 'are as defined above, said compound of formula G being able to give rise subsequently to a modification of the hydroxy groups to obtain said compound of formula (I).
The various schemes below describe different synthetic routes for obtaining the compounds of formula (I) and (II).
In these schemes "t.a. "Means ambient temperature.
Figure 2
According to this scheme 2, the compound of formula (I) or (II) in which R1 = R2 = H and R3 = CH3 and R4 and R5 have the definitions reported above, can be obtained via a succession of five steps with a satisfactory overall yield. Referring to the literature, A. Gharde and B. Ghiya Journal of the Indian Chemistry Society, 1992, 69 (7), 397, a suitable procedure was used to access compound 4 with concentrated sulfuric acid as well as a solvent and a catalyst. The subsequent decarboxylation at reflux in the presence of H 2 SO 4 makes it possible to obtain compound 3. Hydrogenation in HOAc in the presence of the Pd / C catalyst makes it possible to obtain lactone 2, which can easily be reacted by nucleophilic substitution with amines. primary or secondary to obtain the compound of formula (I) or (II) wherein R1 = R2 = H and R3 = CH3 and R4 and R5 have the definitions reported above.
Figure 3
Alternatively, the compound of formula (I) or (II) in which R1 = R2 = H and R3 = CH3 and R4 and R5 have the definitions reported above, can also be obtained with an optimized channel represented by this scheme 3. Compound 3 is indeed commercially available (7-hydroxy-4-methylcoumarin). Therefore, the same method can then be applied directly from this compound in the image of what has already been described in scheme 2 above to obtain compound 2 and then the compound of formula (I) or (II) wherein R1 = R2 = H and R3 = CH3 and R4 and R5 have the definitions reported above.
Figure 4
According to Scheme 4, the reagents ethyl propionylacetate and resorcinol react in the same manner as in Scheme 2 above to give compound 6, which can be converted to the final product in accordance with the same steps as mentioned above. -above. A description of this chemistry can be found in the following document Asian Journal of Chemistry, 2010, 22 (7), 5694-5698
Figure 5
According to scheme 5, resorcinol is reacted with methyl crotonic ester in the presence of excess MSOH to give 7-hydroxy-4-methyl-3,4-dihydrocoumarin 2. A yield of 24% can thus be obtained . The last step is identical to that already described above.
Figure 6
According to Scheme 6, the glycoside of formula (I) or (II) can be obtained by carrying out the Schmidt glycosylation reaction in the presence of the glycosylated trichloroacetimidate donor 9, which is reacted with compound 2 to give Tanomer 10 followed by nucleophilic substitution followed by removal of the benzyl groups.
Figure 7
According to Scheme 7, the glycoside of formula (I) or (II) can be obtained by carrying out the Schmidt glycosylation reaction. The beta anomer is obtained. An anomeric effect is observed due to the similar position of the acetyl group in compound 13. The subsequent deprotection is advantageously carried out under very moderate conditions.
Figure 8
According to Scheme 8, the glycoside beta anomer 18 was synthesized by the Mitsunobu reaction from the glucopyranose protected alpha-anomer 8 and the mono-benzyl resorcinol compound 17.
Figure 9
As illustrated by this scheme 9, the resorcinol derivatives according to the present invention can be obtained by different methods.
Figure 10
Scheme 10 illustrates a synthetic route in which the compound according to the invention has yet another example of significance for the radical R5.
The compounds of formula (I) or (II) according to the invention find a very particular application in the cosmetics field.
The composition according to the invention comprises, in a physiologically acceptable medium, a compound of formula (I) or (II) as described above.
By physiologically acceptable medium, an environment compatible with the keratin materials of human beings such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and / or the hair is understood.
The compound (I) or (II) may be present in the composition according to the invention in an amount which may be between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight, especially of 0.5 to 3% by weight, relative to the total weight of the composition.
The composition according to the invention is advantageously a cosmetic composition: it may comprise adjuvants usually used in the cosmetics field. cosmetics, UV filters, polymers, thickeners, preservatives, perfumes, bactericides, ceramides, odor absorbers, antioxidants.
These optional cosmetic adjuvants may be present in the composition in a proportion of 0.001 to 80% by weight, especially 0.1 to 40% by weight, relative to the total weight of the composition. In any case, these adjuvants, as well as their proportions, will be chosen by those skilled in the art in such a way that the advantageous properties of the compounds according to the invention are not, or not substantially, impaired by the addition envisaged.
As active agents, it will be advantageous to introduce into the composition according to the invention at least one compound chosen from: desquamating agents; soothing agents, organic or inorganic photoprotective agents, moisturizing agents; depigmenting agents; anti-glycation agents; NO-synthase inhibitors; agents stimulating the synthesis of dermal or epidermal macromolecules and / or preventing their degradation; agents stimulating the proliferation of fibroblasts and / or keratinocytes or stimulating the differentiation of keratinocytes; muscle relaxants and / or dermo-decontracting agents; tensors; anti-pollution and / or anti-radical agents; agents acting on microcirculation; agents acting on the energetic metabolism of cells; and their mixtures.
The composition according to the invention may be in any galenical form normally used in the cosmetics field, and in particular in the form of an aqueous or aqueous-alcoholic solution, optionally gelled, of a dispersion of the lotion type possibly two-phase, of an emulsion oil-in-water or water-in-oil or multiple (for example, (E / H / E or H / E / H), an aqueous gel, an oil dispersion in an aqueous phase at using spherules, these spherules may be polymeric nanoparticles such as nanospheres and nanocapsules or, better, lipid vesicles of ionic and / or nonionic type, aqueous or oily gel These compositions are prepared according to the usual methods. According to this invention, it is preferred to use a composition in the form of an emulsion, especially oil-in-water emulsion.
The composition according to the invention may constitute a skin care composition, and in particular a cream for cleaning, protecting, treating or caring for the face, for the hands, for the feet, for the large anatomical folds or for the body (eg day creams, night creams, make-up removers, foundation creams, sunscreen creams); a fluid foundation, a make-up removal milk, a body care or protection milk, an anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion.] The invention is further illustrated by the following non-limiting examples.
Example 1 Synthesis of compound No. 1 / N-butyl-3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (600 mg, 3.4 mmol) in 10 ml of THF, n-butylamine (990 mg, 13.5 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 200 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 960 mg of compound no. 1 as a white solid in 97% yield.
The MS and NMR spectra are consistent with the desired product.
Example 2 Synthesis of compound No. 2 / 3- (2,4-dihydroxyphenyl) -N- (3-methoxypropyl) butanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (600 mg, 3 mg) 4 mmol) in 10 ml THF was added 3-methoxypropylamine (630 mg, 6.7 mmol). The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 200 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 1: 1 to give 800 mg of compound no. 2 as a colorless oil in 90% yield.
The MS and NMR spectra are consistent with the desired product.
Example 3 Synthesis of compound No. 3 / N- (4-hydroxyphenethyl) -3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (600 mg, 3 mg) 4 mmol) in 20 ml of THF and 4.0 ml of DMF (1.0 g, 7.3 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 200 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 1.0 g of Compound No. 3 as a white solid in 94% yield.
The MS and NMR spectra are consistent with the desired product.
Example 4 Synthesis of compound No. 4 / 3- (2,4-dihydroxyphenyl) -N-ethylbutanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (700 mg, 3.9 mmol) in 10 ml of THF was added 65% aqueous ethylamine solution (1.0 ml, 14.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 200 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product was further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 1: 1 to give 550 mg of compound No. 4 as a white solid in 63% yield.
Melting point = 130 ° C
The MS and NMR spectra are consistent with the desired product.
Example 5 Synthesis of Compound No. 9 / N-Butyl-3- (2,4-dihydroxyphenyl) -4-methylpentanamide
The synthesis route shown in Scheme 4 described in the description was used.
Resorcinol (1.1 g, 10 mmol) was added to the mixture of isobutyryl ethyl acetate (2.37 g, 15 mmol) and concentrated H2SO4 (9.8 g, 100 mmol) at 0 ° C. The mixture was stirred at 0 for 1 h, then stirred at room temperature for 3 h. After that, the mixture was poured into ice water and extracted with ethyl acetate three times. The organic layer was concentrated and dried under vacuum. The resulting residue was purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 4/1) to give 1.21 g of 7-hydroxy-4-isopropyl coumarin as a white solid with a yield of 60%.
A mixture of 7-hydroxy-4-isopropyl coumarin (1.2 g, 5.9 mol) and 10% Pd / C (180 mg, 15% by weight) in 20 ml of HOAc was stirred under hydrogen at room temperature. room temperature for 36 hours. The mixture was filtered through a pad of celite to remove Pd / C. The filtrate was concentrated and dried under vacuum. The resulting residue was purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 4/1) to give 987 mg of 7-hydroxy-4-isopropyl-3,4-dihydrocoumarin form of a white solid with a yield of 82%. To a solution of 7-hydroxy-4-isopropyl-3,4-dihydrocoumarin (412 mg, 2.0 mmol) in 15 mL of THF was added n-butylamine (165 mg, 2.26 mmol). The reaction mixture was stirred at room temperature for 24 hours. Then, the mixture was concentrated and dried under vacuum. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2/1) to give 500 mg of N-butyl-3- (2,4-dihydroxyphenyl) -4-methylpentanamide. form of a pink solid with a yield of 91%.
The MS and NMR spectra are consistent with the desired product.
Example 6 Synthesis of compound No. 10 / N-butyl-3- (2,4-dihydroxyphenyl) pentanamide
The synthesis route shown in Scheme 4 described in the description was used. 1,3-dihydroxybenzene (1.1 g, 10 mmol) was added to the mixture of ethyl propionyl acetate (2.16 g, 15 mmol) and concentrated H2SO4 (9.8 g, 100 mmol) at 0 ° C. . The mixture was stirred at 0 for 1 h, then stirred at room temperature for 3 h. After that, the mixture was poured into ice water and stirred at 0 ° C for 30 minutes to result in the precipitation of a white solid. The solid was collected by filtration and dried under vacuum. Then, the solid was washed twice with dichloromethane to give 1.58 g of 7-hydroxy-4-ethyl-coumarin as a white solid with a yield of 83%.
A mixture of 7-hydroxy-4-ethyl-coumarin (1.5 g, 7.9 mol) and 10% Pd / C (225 mg, 15% by weight) in 30 ml of HOAc was stirred under hydrogen at room temperature. room temperature for 17 hours. The mixture was filtered through a pad of celite to remove Pd / C. The filtrate was concentrated and dried under vacuum. The resulting residue was purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 4/1) to give 1.3 g of 7-hydroxy-4-ethyl-3,4-dihydrocoumarin in the form of a white solid with a yield of 85%. To a solution of 7-hydroxy-4-ethyl-3,4-dihydrocoumarin (360 mg, 1.88 mmol) in 10 mL of THF was added n-butylamine (165 mg, 2.26 mmol). The reaction mixture was stirred at room temperature for 17 hours. Then, the mixture was concentrated and dried under vacuum. The resulting residue was purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 2/1) to give 374 mg of N-butyl-3- (2,4-dihydroxyphenyl) pentanamide as a solid pink with a yield of 75%.
The MS and NMR spectra are consistent with the desired product.
Example 7 Synthesis of Ethyl Compound No. 11 / 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate
A mixture of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (562 mg, 3.16 mmol) and DL-phenylalanine ethyl ester (610 mg, 3.16 mmol) was heated to 120 ° C. for 5 hours. The mixture was cooled to room temperature and extracted with EtOAc. The organic layer was concentrated and dried under vacuum. The crude product was further purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH = 500: 3 to afford 850 mg of compound no. 11 as a yellow solid with 73% yield.
The MS and NMR spectra are consistent with the desired product.
Example 8 Synthesis of compound 12 / 3- (2,4-dihydroxyphenyl) -N, N-diethylbutanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (500 mg, 2.8 mmol ) in 20 ml of THF was added diethylamine (408 mg, 5.6 mmol) and the DMAP catalyst. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 360 mg of Compound No. 12 as a white solid with a yield of 51%.
The MS and NMR spectra are consistent with the desired product.
Example 9 Synthesis of compound 13 / N, N-dibutyl-3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (500 mg, 2.8 mmol) in 20 ml of THF was added dibuthylamine (544 mg, 4.2 mmol). The reaction mixture was refluxed for 15 hours. After cooling to room temperature, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 730 mg of compound No. 13 as a pink oil at 84.6% yield. .
The MS and NMR spectra are consistent with the desired product.
Example 10: Synthesis of compound No. 14 / 3- (2,4-dihydroxyphenyl) -N-propylbutanamide to a solution of 7-hydroxy of 4-methyl-3,4-dihydrocoumarin (900 mg, 5.0 mmol) in To 20 ml of THF, n-propylamine (590 mg, 10.0 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 600 mg of compound 14 as a purple syrup in 50% yield, 6%.
The MS and NMR spectra are consistent with the desired product.
Example 11: Synthesis of compound No. 15 / 3- (2,4-dihydroxyphenyl) -N-pentylbutanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (900 mg, 5.0 mmol) in 20 ml. ml of THF was added amylamine (870 mg, 10.0 mmol). The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 900 mg of compound no. 15 as purple syrup in 68% yield.
The MS and NMR spectra are consistent with the desired product.
Example 12: Synthesis of compound No. 16 / 3- (2,4-dihydroxyphenyl) -N-hexylbutanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g, 5.6 mmol ) in hexylamine, 20 ml of THF (1.13 g, 11.2 mmol) is added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 1.2 g of compound no. 16 as a white solid with a yield of 77%.
The MS and NMR spectra are consistent with the desired product.
EXAMPLE 13 Synthesis of compound No. 17 / 3- (2,4-dihydroxyphenyl) -N- (3-ethoxypropyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g 5.6 mmol) in 20 ml of THF, 3-ethoxy-1-propylamine (1.15 g, 11.2 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 100 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 0.95 g of compound no. 17 as a violet syrup with a yield of 60%.
The MS and NMR spectra are consistent with the desired product.
EXAMPLE 14 Synthesis of compound No. 18 / 3- (2,4-dihydroxyphenyl) -N-isopropylbutanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (0.8 g, 0.45 mmol ) in 3 ml of THF was added isopropylamine (0.47 ml, 0.54 mmol). After stirring at room temperature for 5 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 50: 1) to give 0.85 g of compound no. 18 as a pink solid with a yield of 80%.
The MS and NMR spectra are consistent with the desired product.
Example 15: Synthesis of compound No. 19 / 3- (2,4-dihydroxyphenyl) -N-isobutylbutanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g, 0.56 mmol ) in 3 ml of THF was added isobutylamine (0.62 ml, 0.62 mmol). After stirring at room temperature for 5 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 50: 1) to give 1.2 g of compound no. 19 as a violet solid in 85% yield.
The MS and NMR spectra are consistent with the desired product.
Example 16: Synthesis of compound No. 20 / 3- (2,4-dihydroxyphenyl) -N-isopentylbutanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g, 0.56 mmol ) in 5 ml of THF was added isoamylamine (0.72 ml, 0.62 mmol). After stirring at room temperature for 5 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 60: 1) to give 1.29 g of compound no. 20 as a violet solid in 81% yield.
The MS and NMR spectra are consistent with the desired product.
Example 17: Synthesis of Compound 21 / 3- (2,4-dihydroxyphenyl) -N- (4-methylpentyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g 0.56 mmol) in 10 ml THF was added 4-methylpentylamine (0.85 g, 0.62 mmol) and DIPEA (1.08 ml, 0.62 mmol). After stirring at room temperature for 20 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (petroleum ether acetate / ethyl acetate = 2: 1) to give 0.7 g of compound no. 21 as a pink solid in 45% yield. .
The MS and NMR spectra are consistent with the desired product.
Example 18: Synthesis of compound No. 22 / N-cyclohexyl-3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (356 mg, 2.0 mmol) in 10 ml of THF was added cyclohexylamine (238 mg, 2.4 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol = 50/1) to give 430 mg of compound no. 22 as a pink solid in 87% yield.
The MS and NMR spectra are consistent with the desired product.
EXAMPLE 19 Synthesis of compound No. 23 / N- (cyclohexylmethyl) -3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (356 mg, 2.0 mmol) in 10 ml of THF was added cyclohexanemethylamine (271 mg, 2.4 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol = 50/1) to give 560 mg of compound no. 23 as a pink solid in 96% yield.
The MS and NMR spectra are consistent with the desired product.
Example 20: Synthesis of Compound No. 24 / N- (4-hydroxy-3-methoxyphenethyl) -3- (2,4-dihydroxyphenyl) butanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin ( 900 mg, 5.0 mmol) in 20 ml of THF and 20 ml of DMF, 4-hydroxy-3-methoxyphenethylamine hydrochloride (1.1 g, 5.4 mmol) and DMAP (660 mg) were added. 5.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. Then, 200 ml of water was poured into the mixture and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with a mixture of petroleum ether: EtOAc = 1: 1 to give 1.1 g of compound no. 24 as a purple solid with a yield of 63%.
The MS and NMR spectra are consistent with the desired product.
Example 21: Synthesis of ethyl compound No. 25 / 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (356 mg, 2 0 mmol) in 15 ml of DMF was added ethyl 2-aminopropanoate hydrochloride (370 mg, 2.4 mmol) and triethylamine (263 mg, 2.6 mmol). The mixture was heated to 120 ° C and reacted for 5 hours. After cooling the mixture, 30 ml of water was added to the mixture and extracted with ethyl acetate. The organic layers were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 50/1) to give 324 mg of compound no. 25 as a pink syrup with a yield of 55%.
The MS and NMR spectra are consistent with the desired product.
Example 22 Synthesis of Methyl Compound No. 5 / 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoate
A mixture of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.42 g, 8 mmol) and methyl 2-amino-4-methylpentanoate (1.39 g, 9.6 mmol) was heated to 120 ° C for 4 hours. After cooling to room temperature, the mixture was purified by chromatography on silica gel (dichloromethane / methanol = 40: 1) to give 2.0 g of compound No. 5 in the form of a brown syrup with a yield of 77%. .
The MS and NMR spectra are consistent with the desired product.
Example 23 Synthesis of Compound No. 26 / 3- (2,4-dihydroxyphenyl) -N, N-bis (2-methoxyethyl) butanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1 42 g, 8 mmol) in 10 ml THF was added bis (2-methoxyethyl) amine (1.6 g, 12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 50: 1) to give 1.9 g of compound no. 26 as a pink syrup with a yield of 75%.
The MS and NMR spectra are consistent with the desired product.
Example 24: Synthesis of compound No. 27 / 2- (3- (2,4-dihydroxyphenyl) -N-methylbutanamido) ethyl acetate to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (890 mg, 5 mmol) and TEA (657 mg, 6.5 mmol) in 10 ml of DMF, 2- (methylamino) acetate hydrochloride (924 mg, 6 mmol) was added at room temperature. The reaction mixture was heated at 120 ° C for 4 hours. After cooling to room temperature, the mixture was poured into 50 ml of water and extracted with EtOAc. The organic layer was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 30: 1) to give 964 mg of compound no. 27 as a purple syrup with 65% yield.
The MS and NMR spectra are consistent with the desired product.
EXAMPLE 25 Synthesis of compound No. 28 / 3- (2,4-dihydroxyphenyl) -N- (heptan-3-yl) butanamide To a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (534 mg 3.0 mmol) in 25 ml of THF, heptan-3-amine hydrochloride (547 mg, 3.6 mmol) and triethylamine (394 mg, 1.3 mmol) were added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and washed with ethylfactate three times. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol = 50/1) to give 550 mg of compound no. 28 in the form of a pink syrup with a yield of 65%.
The MS and NMR spectra are consistent with the desired product.
Example 26: Synthesis of compound No. 30 / 3- (2,4-dihydroxyphenyl) -N- (2-hydroxyethyl) butanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (1.0 g 5.6 mmol) in 30 ml of THF, 2-aminoethanol (410 mg, 6.7 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was poured into 200 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with a mixture of petroleum ether: EtOAc = 2: 1 to give 400 mg of compound no. 30 as a white solid with a yield of 40%.
The MS and NMR spectra are consistent with the desired product.
Example 27: Synthesis of compound No. 31 / 2- (3- (2,4-dihydroxyphenyl) butanamido) ethyl acetate to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin (810 mg, 4 5 mmol) in 15 ml of DMF was added glycine ethyl ester hydrochloride (945 mg, 6.8 mmol) and DMAP (830 mg, 6.8 mmol). The reaction mixture was heated at 120 ° C for 4 hours. Then, the mixture was cooled to room temperature and 100 ml of 1N HCl was poured into EtOAc and extracted three times. The combined organic layers were washed with water three times and concentrated and dried under vacuum. The crude product is further purified by silica gel column chromatography eluting with petroleum ether: EtOAc = 3: 1 to give 800 mg of compound No. 31 as a white solid in 63% yield.
The MS and NMR spectra are consistent with the desired product.
Example 28: Synthesis of compound 32 / 2- (3- (2,4-dihydroxyphenyl) butanamido) acetic acid To a solution of compound 24 (735 mg, 2.6 mmol) in 10 ml of THF, LiOH (129 mg, 3.1 mmol) was added to 1.2 ml of water. The reaction mixture was stirred at room temperature for 15 hours. Then, the mixture was acidified with concentrated HCl. The mixture was concentrated and dried under vacuum, and the resulting residue was purified by column chromatography on silica gel eluting with CH 2 Cl 2: MeOH = 30: 1 to give 275 mg of compound no. white solid with a yield of 42%.
The MS and NMR spectra are consistent with the desired product.
Example 29: Synthesis of compound No. 29 / N-ethyl-3- (2-hydroxy-4 - ((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) - tetrahydro-2H-pyran-2-yloxy) phenyl) butanamide
The synthetic route shown in Scheme 7 described in the description was used. To a solution of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranose compound 12 (according to scheme 7) (1 g, 2.87 mmol) in 15 ml of dry CH 2 Cl 2 was added 60% NaH (57 mg, 1.44 mmol, 0.5 equiv) and trichloroacetonitrile (1.44 mL, 14.4 mmol) under nitrogen at 0 ° C. After stirring at room temperature for 4 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 15: 1 to 6: 1) to give 1.05 g of compound 13 (according to scheme 7) as a colorless oil. with a yield of 74%. To a solution of compound 13 (according to scheme 7) (1.02 g, 2.1 mmol) and MS 4A in 10 ml of THF was added 7-hydroxy-4-methyl-3,4-dihydrocoumarin ( 0.37 g, 2.1 mmol) under nitrogen. After cooling to -78 ° C, 1 M boron-ether trifluoride in THF was added dropwise to the mixture. Then, the mixture was stirred at this temperature for 3 hours and poured into water and extracted with dichloromethane twice. The combined extracts were washed with saturated aqueous sodium bicarbonate solution once, water once and brine once, in that order, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / petroleum ether = 1: 1 to 1: 4) to give 1 g of compound 14 (according to scheme 7) as a white solid in 94% yield . To a solution of compound 14 (according to Scheme 7) (0.98 g, 1.9 mmol) in 8 ml of THF, a solution of 65% aqueous ethylamine (0.2 g, 2.9 g) was added. mmol). After stirring at room temperature for 5 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 300: 1) to give 0.7 g of compound 15 (according to scheme 7) as a white solid in 67% yield. To a solution of compound 15 (according to scheme 7) (0.64 g, 1.16 mmol) in 15 ml of methanol was added potassium carbonate (0.32 g, 2.3 mmol). After stirring at room temperature for 30 minutes, the mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel chromatography (dichloromethane / methanol = 6: 1 to 2: 1) to give 0.39 g of compound no. 29 as a white solid in 87% yield.
The MS and NMR spectra are consistent with the desired product.
Example 30: Synthesis of Compound No. 33 / N-ethyl-3- (4-hydroxy-2 - ((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) - tetrahydro-2H-pyran-2-yloxy) phenyl) butanamide
The synthetic route shown in Scheme 8 described in the description was used. To a solution of Compound 2 (according to Scheme 8) (2.0 g, 11.2 mmol) in 20 ml of MeCN, K2CO3 (2.0 g, 14.6 mmol) and BnBr (1 g) were added. 5 ml, 12.4 mmol). After stirring at reflux for 5 hours, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (ether / ethyl acetate = petroleum 15: 1) to give 2.6 g of compound 16 (according to scheme 7) as a white solid with yield 87%. To a solution of compound 16 (according to scheme 8) (2.6 g, 9.7 mmol) in 15 ml of THF, a solution of 65% aqueous ethylamine (0.87 g, 12.6 g) was added. mmol). After stirring at room temperature for 2 hours, the solvent was removed in vacuo. The residue was washed with ether to give 2.76 g of compound 17 (according to scheme 8) as a white solid with a yield of 91%. To a solution of compound 17 (according to scheme 8) (0.54 g, 1.0 mmol) and 2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranose (0.31 g, 1.0 mmol) in 15 ml of CH 2 Cl 2 was added tributylphosphane (0.37 ml, 1.5 mmol) and ADDP (Ι, Γ- (azobiscarbonyl) dipiperidine) (0.38 g, 1.5 mmol) at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature for 16 hours, the mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3: 1) to give 0.45 g of compound 18 (according to scheme 8) as a white oil with a yield of 99%. To a solution of compound 18 (according to scheme 8) (0.78 g, 0.93 mmol) in 20 ml of methanol, 0.78 g of Pd / C was added. After stirring at room temperature under hydrogen for 20 hours, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10: 1 to 6: 1) to give 0.27 g of compound no. 33 as a white solid in 75% yield.
The MS and NMR spectra are consistent with the desired product.
Example 31: Synthesis of Compound No. 34 / N-ethyl-3- (2-hydroxy-4 - ((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro) 2H-pyran-2-yloxy) phenyl) butanamide
The synthesis route shown in Scheme 6 described in the description was used. To a solution of 2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranose compound 8 (according to scheme 6) (2 g, 3.7 mmol) in 40 ml of dry CH 2 Cl 2 was added K2CO3 (0.66 g, 4.8 mmol, 1.3 equiv) and trichloroacetonitrile (1.48 mL, 14.8 mmol) under nitrogen at 0 ° C. After stirring at room temperature for 20 hours, the mixture was filtered. The solvent was removed in vacuo. The residue was purified by silica gel chromatography (ether / ethyl acetate = petroleum 10: 1) to give 0.77 g of compound 9 as a colorless oil in 31% yield. To a solution of Compound 9 (according to Scheme 6) (0.77 g, 1.1 mmol) and MS 4A in 10 ml of CH 2 Cl 2 was added 7-hydroxy-4-methyl-3,4-dihydrocoumarin ( 0.2 g, 1.1 mmol) under nitrogen. After cooling to 0 ° C, 1 M boron trifluoride etherate (0.18 mL, 1.5 mmol) in THF was added dropwise to the mixture. Then, the mixture was stirred at room temperature for 20 hours and poured into water and extracted with dichloromethane twice. The combined extracts were washed with saturated aqueous sodium bicarbonate solution once, water once and brine once, in that order, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / petroleum ether = 1: 1 to 3: 1) to give 0.66 g of compound 10 (according to scheme 6) as a yellow oil in a yield. 86%. To a solution of the compound 10 (according to scheme 6) (0.66 g, 0.94 mmol) in 10 ml of THF was added a solution of 65% aqueous ethylamine (0.13 g, 1.88 g). mmol). After stirring at room temperature for 2 hours, the solvent was removed in vacuo. The residue was washed with ether to give 0.59 g of compound 11 (according to scheme 6) as a colorless oil in 84% yield. To a solution of compound 11 (according to scheme 6) (0.58 g, 0.78 mmol) in 15 ml of methanol was added 0.58 g of 10% Pd / C. After stirring at room temperature under nitrogen for 20 hours, the mixture was filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 5: 1) to give 0.22 g of compound no. 34 as a white solid in 73% yield.
The MS and NMR spectra are consistent with the desired product.
Example 32 Synthesis of Compound No. 35 / 4- (4- (Ethylamino) -4-oxobutan-2-yl) -1,3-phenylene Diacetate
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 3- (2,4-dihydroxyphenyl) -N-butanamide (1.338 g, 6.0 mmol) in 40 ml of THF was added TEA (1.8 g, 18 mmol), after which Acetyl (1.4 g, 18 mmol) was slowly added to the mixture at 0 ° C in an ice bath. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 1: 1) to give 1.62 g of compound no. 35 as a white powder in 88% yield.
Melting point: 83 ° C
The MS and NMR spectra are consistent with the desired product.
Example 33 Synthesis of 4- (4- (ethylamino) -4-oxobutan-2-yl) -1,3-phenylene Compound No. 36 / Diheptanoate
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 3- (2,4-dihydroxyphenyl) -N-butanamide (1.115 g, 5.0 mmol) in 30 ml of THF was added TEA (1.515 g, 15 mmol), followed by heptanoyl chloride (2.255 g). g, 15 mmol) was slowly added dropwise to the mixture at 0 ° C in an ice bath. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 2: 1) to give 1.2 g of compound no. 36 as a white powder with a yield of 54%.
Melting point: 51 ° C
The MS and NMR spectra are consistent with the desired product.
Example 34: Synthesis of compound 37 / 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of methyl 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoate (2.57 g, 8.0 mmol) in 60 ml of MeCN was added K2CO3 (3.3 g). 23.9 mmol) and BnBr (4.1 g, 24.0 mmol). The reaction mixture was refluxed for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated and dried. The resulting residue was purified by column chromatography on silica gel using dichloromethane to obtain 2.7 g of methyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -4-methylpentanoate under form of a white powder with a yield of 67%. To a solution of methyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -4-methylpentanoate (2.66 g, 5.3 mmol) in 25 ml of THF was added LiOH ( 290 mg, 6.9 mmol) in 6.0 ml of water. The reaction mixture was stirred for 15 hours. 100 ml of water were poured into the mixture and acidified with ΓΗΟ 6 N at pH = 2, extracted twice with EtOAc. The combined organic layer was washed with water three times and concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 2) to give 2.2 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido acid. -methylpentanoic in the form of a white powder with a yield of 85%.
A mixture of Compound 24 (according to Scheme 10) (2.2 g, 4.5 mmol) and 200 mg of 10% Pd / C in 50 ml MeOH was stirred under a hydrogen atmosphere at room temperature for 15 minutes. hours. The reaction mixture was filtered and the filtrate was concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 20) to give 1.15 g of 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoic acid. in the form of a white powder with a yield of 83% yield.
Melting point: 115.6 ° C
The MS and NMR spectra are consistent with the desired product.
Example 35: Synthesis of compound No. 38 / 2- (3- (2,4-dihydroxyphenyl) -N-methylbutanamido) acetic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of ethyl 2- (3- (2,4-dihydroxyphenyl) -N-methylbutanamido) acetate (2.7 g, 9.15 mmol) in 60 ml of MeCN was added K2CO3 (3.3 g, 23.9 mmol) and BnBr (3.9 g, 22.8 mmol). The reaction mixture was refluxed for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated and dried. The resulting residue was purified by silica column chromatography using dichloromethane gel to give 4.3 g of ethyl 2- (3- (2,4-bis (benzyloxy) phenyl) -N-methylbutanamido) acetate. in the form of a white powder with a yield of 99%. To a solution of 2- (3- (2,4-bis (benzyloxy) phenyl) -N-methylbutanamido) ethyl acetate (4.3 g, 9.1 mmol) in 50 ml of THF was added LiOH. (465 mg, 11.1 mmol) in 8.0 ml of water. The reaction mixture was stirred for 15 hours. 200 ml of water were poured into the mixture and acidified with 6N HCl at pH = 2, then extracted twice with EtOAc. The combined organic layer was washed with water three times and concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 2) to give 3.5 g of 2- (3- (2,4-bis (benzyloxy) phenyl) -N-methylbutanamido acid. ) acetic form of white powder with a yield of 85%.
A mixture of 2- (3- (2,4-bis (benzyloxy) phenyl) -N-methylbutanamido) acetic acid (3.5 g, 7.8 mmol) and 400 mg of 10% Pd / C in 80 ml of MeOH was stirred under hydrogen at room temperature for 15 hours. The reaction mixture was filtered and the filtrate was concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 20) to give 1.5 g of 2- (3- (2,4-dihydroxyphenyl) -N-methylbutanamido) acetic powder white with a yield of 72%.
Melting point: 143.7 ° C
The MS and NMR spectra are consistent with the desired product.
Example 36: Synthesis of compound No. 39 / 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of 7-hydroxy-4-methyl-chroman-2-one (1 g, 5.6 mmol) in 20 ml of DMF was added ethyl 2-aminopropanoate hydrochloride (1.0 g, 6 g). 7 mmol) and triethylamine (0.97 ml, 6.7 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give 1.1 g of ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate in the form of yellow syrup. in a yield of 67%.
Synthesis of ethyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate: To a solution of methyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate (1.0 g, 3.4 mmol) in acetonitrile, K2CO3 (1.17 g, 8.5 mmol) and benzyl bromide (0.89 mL, 7.5 mmol) were added. After stirring at 80 ° C for 20 hours, the mixture was filtered, filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane ether / petroleum ether = 1: 2) to give 0.94 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate of ethyl in the form of a white solid with a yield of 58%. To a solution of methyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate (0.85 g, 1.8 mmol) in 10 ml of methanol, a solution of LiOH (98 mg, 2.3 mmol) in 2 ml of water at 0 ° C. The mixture was stirred at room temperature for 20 hours. Then the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (10: 1 dichloromethane / methanol = 10: 1) to give 0.77 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido acid) propanoic in the form of a white solid with a yield of 96%. To a solution of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoic acid (0.77 g, 1.72 mmol) in 20 ml of methanol, Pd / C was added. The mixture was stirred at room temperature under hydrogen for 20 hours. The mixture was filtered through Celite® 545 (Sigma). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 8: 1) to give 0.25 g of 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid as a white solid with a yield of 54%.
Melting point: 55 ° C.
The MS and NMR spectra are consistent with the desired product. been used. To a solution of 7-hydroxy-4-methyl-chrysan-2-one (0.94 g, 5.3 mmol) in 25 ml of DMF was added ethyl L-phenylalaninate hydrochloride (1.45 g). 6.3 mmol) and triethylamine (0.91 ml, 6.3 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give 1 g of ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate in the form of a yellow syrup with a yield of 51%.
To a solution of ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate (1.0 g, 2.7 mmol) in 25 ml of acetonitrile was added K2CO3 (0.93). g, 6.7 mmol) and benzyl bromide (0.71 ml, 5.9 mmol). After stirring at 80 ° C for 20 hours, the mixture is filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane ether / petroleum ether = 4: 1) to give 0.82 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido. Ethyl 3-phenylpropanoate in the form of a white solid with a yield of 55%.
A solution of ethyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -3-phenylpropanoate (0.81 g, 1.5 mmol) in 8 ml of methanol is added a solution of LiOH (80 mg, 1.9 mmol) in 1.9 ml of water at 0 ° C. The mixture was stirred at room temperature for 20 hours. Then the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 25: 1 to 8: 1) to give 0.76 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido acid. ) -3-phenylpropanoic form of a white solid with a yield of 99%. To a solution of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -3-phenylpropanoic acid (0.76 g, 1.45 mmol) in 20 ml of methanol was added Pd /VS. The mixture was stirred at room temperature under hydrogen for 20 hours. The mixture was filtered through Celite® 545 (Sigma). The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 10: 1) to give 0.26 g of 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoic acid in the form. of white solid with a yield of 52%.
Melting point: 95.4 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 38: Synthesis of compound 41 / 3- (2,4-dihydroxyphenyl) butanamide To a solution of 7-hydroxy-4-methyl-chroman-2-one (1.2 g, 6.7 mmol) in 50 ml of THF was added ammonia (5 ml). After stirring at room temperature for 2 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (EtOAc / petroleum ether = 1: 1) to give 1.04 g of compound no. 41 as a pink solid in 79% yield.
Melting point: 144-145 ° C
The MS and NMR spectra are consistent with the desired product.
Example 39 Synthesis of (S) -ethyl compound 42 / 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate To a solution of 7-hydroxy-4-methyl-chroman-2-one (3) 56 g, 20 mmol) in 80 ml of DMF was added L-alanine ethyl ester hydrochloride (CAS: 1115-59-9) (3.7 g, 24 mmol) and triethylamine (3 g). 5 ml, 24 mmol). The mixture was heated to 80 ° C and reacted for 15 hours. After cooling the mixture, 150 ml of water are added to the mixture and extracted with ethyl acetate three times. The organic layers were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane / methanol = 50/1) to give 2.9 g of compound No. 42 in the form of a white powder with a yield of 49%.
Melting point: 68-69 ° C
The MS and NMR spectra are consistent with the desired product.
Example 40: Synthesis of the Compound No. 43 / 2- (3- (2,4-Dihydroxyphenyl) butanamido) propanoate of (R) -ethyl to a solution of 7-hydroxy-4-methyl-chroman-2-one (2) 85 g, 16.0 mmol) in 40 ml of DMF was added D-ethyl 2-aminopropanoate hydrochloride (2.95 g, 19.2 mmol) and triethylamine (2.77 ml, 19.2%). mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give 2.2 g of ethyl (R) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate as a white solid with a yield of 47%.
Melting point: 55 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 41: Synthesis of compound No. 44 / (S) -2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of (S) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate (2.95 g, 10.0 mmol) in 50 ml of acetonitrile was added K 2 CO 3 (2%). 76 g, 20.0 mmol) and benzyl bromide (2.4 mL, 20.0 mmol). After stirring at 80 ° C. for 20 hours, the mixture is filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane ether / petroleum ether = 1: 2) to give 3.36 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate (S) -ethyl as a white solid with a yield of 70%. To a solution of (S) -ethyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate (3.33 g, 7.0 mmol) in 35 ml of methanol was added LiOH solution (385 mg, 9.1 mmol) in 7 ml of water. The mixture was stirred at room temperature for 20 hours. Then, the solvent was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 30: 1 to 10: 1) to give 0.87 g of (S) -2- (3- (2,4-bis (benzyloxy) acid). ) phenyl) butanamido) propanoic acid as a white solid with a yield of 28%. To a solution of (S) -2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoic acid (0.87 g, 1.95 mmol) in 20 ml of methanol was added 10% Pd / C (87 mg). The mixture was stirred at room temperature under hydrogen for 20 hours. The mixture was filtered. The filtrate was concentrated in vacuo to give 495 mg of Compound No. 44 as a white solid in 95% yield.
Melting point: 87-88 ° C
Example 42: Synthesis of compound 45 / (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of 7-hydroxy-4-methyl-chrysan-2-one (2.85 g, 16.0 mmol) in 40 ml of DMF was added D-ethyl 2-aminopropanoate hydrochloride (2.95 g). g, 19.2 mmol) and triethylamine (2.77 ml, 19.2 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give 2.2 g of ethyl (R) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate as a white solid with a yield of 47%. To a solution of (R) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate (1.66 g, 5.6 mmol) in 30 ml of acetonitrile, K2CO3 (1 94 g, 14 mmol) and benzyl bromide (1.48 ml, 12.4 mmol). After stirring at 80 ° C. for 20 hours, the mixture is filtered and evaporated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 1) to give 2.42 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate of (R) ethyl in the form of a white solid with a yield of 91%. To a solution of (R) -ethyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoate (2.42 g, 5.1 mmol) in 45 ml of methanol, a solution is added. LiOH (0.28 g, 6.6 mmol) in 6 ml of water at 0 ° C. The mixture was stirred at room temperature for 20 hours. Then the solvent was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give 2.1 g of (R) -2- (3- (2,4-bis (benzyloxy) phenyl) butanamido acid. ) propanoic as a white solid with a yield of 92%. To a solution of (R) -2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) propanoic acid (2 g, 4.5 mmol) in 10 ml of methanol and 10 ml of THF was added Pd / C. The mixture was stirred at room temperature under hydrogen for 20 hours.
The mixture was filtered through Celite® 545 (Sigma). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 15: 1) to give 0.95 g of compound no. 45 as a white solid in 79% yield.
Melting point: 130.5 ° C
The MS and NMR spectra are consistent with the desired product.
Example 43 Synthesis of Methyl Compound No. 46 / 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoate
A mixture of 7-hydroxy-4-methyl-chroman-2-one (1.78 g, 10.0 mmol) and D-leucine methyl ester hydrochloride (5845-53-4) (1.82 g) 10.0 mmol) and TEA (1.1 g, 10.9 mmol) in 40 ml of DMF was heated at 120 ° C for 4 hours. After cooling to room temperature, 100 ml of water was poured into EtOAc and extracted twice. The combined organic layer was washed with water three times and then concentrated and dried. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 40: 1) to give 1.3 g of compound no. 46 as a pink powder with a yield of 40%.
Melting point: 55-58 ° C
The MS and NMR spectra are consistent with the desired product.
Example 44: Synthesis of Compound No. 47 / (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoic acid
The synthesis route shown in Scheme 10 described in the description was used. To a solution of (R) -methyl 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoate (2.5 g, 7.7 mmol) in 60 ml of MeCN was added K 2 CO 3 ( 3.0 g, 21.7 mmol) and BnBr (3.42 g, 20.0 mmol). The reaction mixture was refluxed for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel using dichloromethane to give 3.48 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -4-methylpentanoate (R). ) -methyl in the form of a white powder with a yield of 89%. To a solution of (R) -methyl 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -4-methylpentanoate (3.48 g, 6.9 mmol) in 60 ml of THF was added LiOH (580 mg, 13.8 mmol) in 10.0 ml of water. The reaction mixture was stirred for 15 hours. 100 ml of water were poured into the mixture and acidified with 6N HCl to pH = 2, then extracted twice with EtOAc. The combined organic layer was washed with water three times and concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 2) to give 3.0 g of (R) -2- (3- (2,4-bis (benzyloxy) phenyl) acid. butanamido) -4-methylpentanoic in the form of a white powder with a yield of 91%. To a mixture of (R) -2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -4-methylpentanoic acid (2.9 g, 6.1 mmol) and 300 mg of Pd 10% C in 80 ml MeOH was stirred under hydrogen at room temperature for 15 hours. The reaction mixture was filtered and the filtrate was concentrated and dried. The resulting residue was purified by chromatography on silica gel (dichloromethane / methanol = 500: 20) to give 1.15 g of (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) -4 acid. -methylpentanoic in the form of a white powder with a yield of 89%.
Melting point: 78-82 ° C
The MS and NMR spectra are consistent with the desired product.
Example 45: Synthesis of the Compound No. 48 / 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate (R) -ethyl
To a solution of 7-hydroxy-4-methyl-chrysan-2-one (1.3 g, 7.3 mmol) in 30 ml of DMF was added ethyl D-phenylalaninate hydrochloride (2 g, 8.7 mmol) and triethylamine (1.26 ml, 8.7 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3: 1 to 1: 1) to give 1 g of compound no. 48 as a yellow syrup with a yield of 44. %.
Melting point: 100 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 46: Synthesis of compound No. 6 / 3- (2,4-diethoxyphenyl) -N-ethylbutanamide
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 3- (2,4-dihydroxyphenyl) -N-butanamide (0.447 g, 2.0 mmol) in iodoethane, 40 ml of MeCN (0.686 g, 4.4 mmol) and K2CO3 (0.608 g, 4.4 mmol). The mixture was refluxed for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 1: 1) to give 0.30 g of compound no. 6 in the form of a white powder with a yield of 54%. .
Melting point: 100 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 47: Synthesis of compound No. 49 / 3- (2-ethoxy-4-hydroxyphenyl) -N-ethylbutanamide
The synthetic route shown in Scheme 9 described in the description was used.
To a solution of 7-hydroxy-4-methyl-chroman-2-one (5 g, 28.1 mmol) in 100 ml of potassium acetonitrile carbonate (4.65 g, 33.7 mmol) was added and bromomethylbenzene (5.76 g, 33.7 mmol) at room temperature. The mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to give 6.87 g of 7- (benzyloxy) -4-methyl-chroman-2-one in the form of a colorless oil with a yield of 91%. To a solution of 7- (benzyloxy) -4-methyl-chrysan-2-one (2.68 g, 10 mmol) in 20 ml of THF was added dropwise 5 ml of 65% ethylamine solution. After stirring at room temperature for 2 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (petroleum ether acetate / ethyl acetate = 1: 1) to give 3 g of 3- (4- (benzyloxy) -2-hydroxyphenyl) -N-butanamide as a white solid with a yield of 96%. To a solution of 3- (4- (benzyloxy) -2-hydroxyphenyl) -N-butanamide (1 g, 3.2 mmol) in 50 was added THF iodomethane (0.593 g, 3.8 mmol). ) and potassium carbonate (0.525 g, 3.8 mmol). The mixture was stirred at reflux for 4 hours. After cooling to room temperature, the mixture was filtered and washed with THF. The filtrate was evaporated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to give 0.966 g of 3- (4- (benzyloxy) -2-ethoxy-phenyl) N-butanamide as a white solid with a yield of 88%. To a solution of 3- (4- (benzyloxy) -2-ethoxy-phenyl) -N-butanamide (600 mg, 1.76 mmol) in 30 ml of acetic acid the acid was added 100 mg Pd / C . The mixture was stirred under hydrogen and heated at 100 ° C for 6 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 80: 1 to 60: 1) to give 0.67 g of compound no. 49 as a white solid in 78% yield.
The MS and NMR spectra are consistent with the desired product.
Example 48 Synthesis of Compound No. 50 / 3- (4-ethoxy-2-hydroxyphenyl) -N-ethylbutanamide
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 7-hydroxy-4-methyl-chrysan-2-one (0.784 g, 4.4 mmol) in 15 ml of acetone is added iodomethane (0.967 g, 6.2 mmol) and sodium carbonate. potassium (1.546 g, 11.2 mmol) in the order. The mixture was stirred under reflux for 20 hours. After cooling to room temperature, the mixture was filtered and washed with acetone. The filtrate was evaporated in vacuo. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to give 0.65 g of 7-ethoxy-4-methyl-chroman-2-one in the form of a colorless oil with a yield of 72%. To a solution of 7-ethoxy-4-methyl-chroman-2-one (0.61 g, 2.96 mmol) in 15 ml of THF was added dropwise 65% ethylamine solution (0.41 g). 5.92 mmol). After stirring at room temperature for 20 hours, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 80: 1 to 60: 1) to give 0.67 g of compound No. 50 as a white with a yield of 90%.
Melting point: 150 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 49: Synthesis of Compound No. 51 / (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoic acid
The synthesis route shown in Scheme 11 below was used.
Figure 11
To a solution of 7-hydroxy-4-methyl-chroman-2-one (1.3 g, 7.3 mmol) in 30 ml of DMF was added ethyl D-phenylalaninate hydrochloride (2 g, 8%). 7 mmol) and triethylamine (1.26 ml, 8.7 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3: 1 to 1: 1) to give 1 g of 2- (3- (2,4-dihydroxyphenyl) butanamido) -3 (R) -ethyl phenylpropanoate in the form of a yellow syrup with a yield of 44%.
To a solution of (R) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate (1.21 g, 3.26 mmol) in 30 ml of acetonitrile, K2CO3 was added. (1.13 g, 8.15 mmol) and benzyl bromide (0.86 mL, 7.18 mmol). After stirring at 80 ° C for 20 hours, the mixture was filtered, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (dichloromethane ether / petroleum ether = 4: 1) to give 1.05 g of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido. 3- (R) -ethyl phenylpropanoate forms a white solid with a yield of 59%. To a solution of 2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -3-phenylpropanoate (R) -ethyl (1.05 g, 1.9 mmol) in 15 ml of methanol is added a solution of LiOH (104 mg, 2.4 mmol) in 2.4 ml of water at 0 ° C. The mixture was stirred at room temperature for 20 hours. Then the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 25: 1 to 8: 1) to give 0.95 g of (R) -2- (3- (2,4-bis ( benzyloxy) phenyl) butanamido) -3-phenylpropanoic acid as a white solid with a yield of 96%. To a solution of (R) -2- (3- (2,4-bis (benzyloxy) phenyl) butanamido) -3-phenylpropanoic acid (1.4 g, 2.7 mmol) in 10 ml of methanol and 15 ml of THF was added Pd / C. The mixture was stirred at room temperature under hydrogen for 20 hours. The mixture was filtered through Celite® 545 (Sigma). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10: 1) to give 0.7 g of compound no. 51 as a white solid with a yield of 76%.
Melting point: 114.2 ° C
The MS and NMR spectra are consistent with the desired product.
Example 50: Synthesis of compound No. 52 / 3- (2,4-diisopropoxyphenyl) -N-ethylbutanamide
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 3- (2,4-dihydroxyphenyl) -N-butanamide (0.893 g, 4.0 mmol) in 60 ml MeCN was added 2-iodopropane (3.4 g, 20.0 mmol). and K2CO3 (2.76 g, 20.0 mmol). The mixture was refluxed for 18 hours. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 2: 1) to give 0.928 g of 3- (2,4-diisopropoxyphenyl) -N-butanamide as a white powder with 75% yield.
Melting point: 111 ° C
The MS and NMR spectra are consistent with the desired product.
Example 51: Synthesis of compound No. 53 / 3- (2,4-dipropoxyphenyl) -N-ethylbutanamide to a solution of 3- (2,4-dihydroxyphenyl) -N-butanamide (0.447 g, 2.0 mmol) in 30 ml of MeCN was added 1-iodopropane (1.36 g, 8.0 mmol) and K2CO3 (1.104 g, 8.0 mmol). The mixture was refluxed for 18 hours. After cooling, the mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 2: 1) to give 0.4 g of compound No. 53 as a white powder in 65% yield.
Melting point: 82 ° C.
The MS and NMR spectra are consistent with the desired product.
Example 52: Synthesis of compound No. 54 / N-ethyl-3- (4-hydroxy-2-isopropoxyphenyl) butanamide
The synthetic route shown in Scheme 9 described in the description was used. To a solution of 3- (4- (benzyloxy) -2-isopropoxyphenyl) -N-butanamide (940 mg, 2.64 mmol) in 30 ml of acetic acid was added 100 mg Pd / C. The mixture was stirred under hydrogen and heated at 100 ° C for 6 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 80: 1 to 60: 1) to give 458 mg of compound no. 54 as a white solid in 65% yield.
The MS and NMR spectra are consistent with the desired product. been used. To a solution of 3- (4- (benzyloxy) -2-propoxyphenyl) -N-butanamide (1.12 g, 3.16 mmol) in 30 ml of acetic acid was added 200 mg Pd / C. The mixture was stirred under hydrogen and heated at 100 ° C for 6 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 80: 1 to 60: 1) to give 689 mg of compound no. 55 as a white solid with a yield of 82%.
The MS and NMR spectra are consistent with the desired product.
Example 54: Synthesis of Compound No. 56 / N-ethyl-3- (2-hydroxy-4-isopropoxyphenyl) butanamide To a solution of N-ethyl-3- (2- (benzyloxy) -4-isopropoxyphenyl) butanamide (0 41 g, 1.86 mmol) in 10 ml of THF was added dropwise a solution of 65% ethylamine (0.17 g, 3.72 mmol). After the reaction was complete, 10 ml of petroleum ether was added to the mixture. The mixture was stirred at room temperature for 30 minutes. Then the precipitate was filtered and washed with petroleum ether. The residue was dried under vacuum to give 0.41 g of Compound No. 56 as a white solid in 83% yield.
Melting point: 221.6 ° C
The MS and NMR spectra are consistent with the desired product.
Example 55: Synthesis of compound 57 / N-ethyl-3- (2-hydroxy-4-propoxyphenyl) butanamide To a solution of N-ethyl-3- (2- (benzyloxy) -4-propoxyphenyl) butanamide (0 3 g, 1.36 mmol) in 10 ml of THF was added dropwise a solution of 65% ethylamine (0.19 g, 2.72 mmol). After the reaction was complete, 10 ml of petroleum ether was added to the mixture. The mixture was stirred at room temperature for 30 minutes. Then the precipitate was filtered and washed with petroleum ether. The residue was dried under vacuum to give 0.23 g of Compound No. 57 as a white solid in 68% yield.
Melting point: 238.3 ° C
The MS and NMR spectra are consistent with the desired product.
Example 56: Synthesis of compound No. 58 / 3- (2,4-dihydroxyphenyl) -N-ethyl-N- (2-hydroxyethyl) butanamide to a solution of 7-hydroxy-4-methyl-3,4-dihydrocoumarin ( 1, g, 5.6 mmol) in 10 ml THF was added 2- (ethylamino) ethanol (0.75 g, 11.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 9: 1) to give 1.2 g of compound no. 58 as a gum in 79% yield.
The MS and NMR spectra are consistent with the desired product.
Example 57: Synthesis of Compound No. 59 / 3- (2,4-dihydroxyphenyl) -1- (morpholin-4-yl) butan-1-one to a solution of 7-hydroxy-4-methyl-3,4-diol Dihydrocoumarin (1. g, 5.6 mmol) in 10 ml THF was added 2- (ethylamino) ethanol (0.73 g, 11.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane / methanol = 9: 1) to give 1.2 g of compound no. 58 as an off-white solid in 80% yield.
The MS and NMR spectra are consistent with the desired product.
Example 58: Demonstration of depigmenting activity Efficacy was demonstrated on the basis of the following test:
Assessments of the effect of preventing or diminishing skin pigmentation and / or skin lightening of skin are exemplified in the following manner.
The measurement of the depigmenting activity (reduction of melanin production) of compounds of formula (I) was carried out by assaying normal human melanocytes in vitro as follows.
First, normal human melanocytes are grown and distributed in 384 plates. After 24 hours, the culture medium was replaced by a medium containing compounds of formula (I) to be evaluated. The cells were incubated for 72 hours before measuring the final optical density which measures the amount of melanin produced by the melanocytes. A dose effect is implemented using a wide range of concentration of the compounds evaluated. Thus, by matching concentrations and melanin measurements, it is possible to determine an IC50 in μΜ: concentration at which 50% decrease in melanin synthesis is achieved.
The compounds of formula (I) and / or (II) showed a strong depigmenting effect. Different test campaigns were conducted and collated in the following Tables 2, 3, 4 and 5.
Table 2
These results were compared from compounds described in the prior art, and more particularly - in the application WO2004 / 017936: TIC50 value is 0.241 μΜ.
(B). For this compound (B), the value of the IC50 is 0.26 μΜ, and - in the application W02005 / 085169:
(VS). For this compound (B), the IC50 value is 3 μΜ.
Table 3
These results were compared from compounds described in the prior art, and more particularly - in application WO2004 / 017936:
(AT). For this compound (A), the PIC50 value is 19.1 μΜ.
(B). For this compound (B), the value of riC50 is 24 μΜ, and - in the application W02005 / 085169:
(VS). For this compound (B), the PIC50 value is 108 μΜ.
Table 4
Table 5
Example 59: Cosmetic composition
A depigmenting composition for the skin comprising (in gram):
Compound No. 25 2 g PEG400 68 g
Ethanol 30 g
The composition applied to the skin helps to fade brown spots. Example 60: Gel
A depigmenting gel for the skin is prepared comprising (% by weight): Compound No. 4 0.25%
Carbomer (Carbopol 981 from Lubrizol) 1% preservative qs water qsp 100%
The composition applied to the skin helps to fade brown spots.

权利要求:
Claims (15)
[1]
A compound of formula (I) for use in depigmenting, lightening and / or whitening skin

in which R1, R2 independently denote: a) H, b) a saturated or unsaturated C2-C20 alkyl radical, linear or branched C3-C20, or cyclic C3-C8, c) a radical S * denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 unit (s) saccharide (s), preferably from 2 to 3 unit (s) saccharide (s), preferentially a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said mono or polysaccharide radical S * being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this link being anomeric a or β, d) a COR6 radical in which R6 denotes a linear saturated C1-C20 alkyl radical, a linear unsaturated C2-C20 alkyl radical, a saturated or unsaturated branched C3-C20 radical or a C3 cycloalkyl radical; -C8, R3 denotes a saturated or unsaturated C1-C20 alkyl radical C2-C20, linear or branched C3-C20 or cyclic C3-C8, R4, R5 independently denote a) H, b) a C1-C20 alkyl radical saturated or unsaturated C2-C20 or branched C3-C20 , or cyclic C3-C8, optionally interrupted by one or more heteroatoms or non-adjacent groups, in particular one to three, chosen from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from: i) -OR7 ii) -SR7 iii) -NR7R8 iv) -CONHR7 v) -CONR7R8 vi) -COOR7 vii) -NHCONHR7 viii) -C (O) (C 1 -C 4) alkyl (ix) a nonhydrous saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls, in particular one to three, and / or by one or more C 1 -C 5 alkoxy and / or C 1 -C 1 alkyl radicals, especially one to three; one of the members of the (hetero) ring group possibly being a carbonyl group x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more radicals C1-C8 alkoxy and / or C1-C4 alkyl, especially one to three xi) -NH-C = NH (NH2) (guanidine group) R7, R8, which may be identical or different, chosen from H, an alkyl group Linear saturated C1-C10, linear unsaturated C2-C10 alkyl, saturated or unsaturated branched C3-C10 alkyl group, or C3-C8 cycloalkyl group; a (C 1 -C 4) alkyl (hetero) aryl group at G, optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; c) NR9R10 with R9 and R10 denoting a radical chosen from i) -H ii) a saturated linear C 1 -C 10 or unsaturated C2-C10 or branched C3-C10 or cyclic C3-C8 alkyl group, optionally interrupted by a or more heteroatoms or groups selected from N, O, -CO or combinations thereof such as -NHCO-, -NHCONH-, and / or optionally substituted with one or more C 1 -C 6 alkyl groups, which are identical or different, in particular one to three iii) a C5-C12 (hetero) aryl group, optionally containing one or more heteroatoms chosen from O, N, S, especially one to three, optionally substituted with one or more hydroxyls and / or with one or more C1-alkoxy radicals; -Cs, especially one to three; R9 and R10 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain optionally containing one or more radicals chosen from hydroxyl or C1-C4 alkoxy, especially one to three; d) OR 11 with R 11 denoting a radical chosen from: i) -H ii) a saturated linear C 1 -C 10 or branched C 3 -C 10 or cyclic C 3 -C 8 alkyl group, R 4, R 5 being able to form with the nitrogen which forms them carries a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups selected from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; as well as their salts, their solvates and their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemates, alone or as a mixture.
[2]
2. Compound of formula (I) for use in depigmenting, lightening and / or whitening the skin according to claim 1, characterized in that R1, R2 independently denote a) H, b) a saturated C1-C10 alkyl radical or unsaturated C2-C10 linear or branched C3-C10, or cyclic C3-C6 c) a radical S * as defined above and in particular a radical glucosyl, xylosyl, mannosyl, fucosyl or maltosyl d) a radical COR6 in which R6 denotes a linear saturated C1-C15 alkyl radical, a linear unsaturated C2-C15 alkyl radical or a saturated or unsaturated branched C3-C15 alkyl radical, R3 denotes a linear saturated C1-C10 alkyl radical, an alkyl radical containing Linear unsaturated C2-C10, saturated or unsaturated C3-C10 alkyl radical or C3-C6 cycloalkyl radical R4, R5 independently denote a) -H; b) a linear saturated C 1 -C 15 alkyl radical, a linear unsaturated C 2 -C 15 alkyl radical, a saturated or unsaturated C 3 -C 15 saturated alkyl radical or a C 3 -C 8 cycloalkyl radical, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one or two, chosen (s) of: i) -OR7 -OR7 such as a methyl or ethyl or isopropyl radical ii) -SR7 iii) -NR7R8 iv) -CONHR7 v) -CONR7R8 vi) -COOR7 vii) -NHCONHR7 viii) -C ( 0) (C 1 -C 4) alkyl (ix) a non-aromatic saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls and / or by one or more C 1 -C 5 alkoxy radicals or C 1 -C 12 alkyl, especially one to three; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C x alkyl radicals, in particular one to three xi) -NH-C = NH (NH 2) (guanidine group) R 7, R 8, which may be identical or different, chosen from H, a linear saturated C 1 -C 10 alkyl group and a linear unsaturated C 2 -C 10 alkyl group; a saturated or unsaturated branched C3-C10 alkyl group or a C3-C8 cycloalkyl group; (C 1 -C 4) C 6 (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO- and / or optionally substituted with a C1-C6 hydrocarbon chain; C10, especially one to three; R4, R5 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO- and / or optionally substituted with a C1-C6 hydrocarbon chain; C10 such as pyrrolidine, piperidine, morpholine, piperazine; as well as their salts, their solvates and their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemates, alone or as a mixture.
[3]
3. Compound of formula (I) for use in depigmenting, lightening and / or whitening the skin according to claim 1 or 2, characterized in that R 1, R 2 independently denote a) H, b) a C 1 -C 6 alkyl radical linear saturated radical, a linear unsaturated C 2 -C 6 alkyl radical or a saturated or unsaturated branched C 3 -C 6 alkyl radical, such as the ethyl, isopropyl and n-propyl radicals; c) an S * radical denoting a monosaccharide sugar radical or a radical; polysaccharide sugar comprising from 2 to 5 unit (s) saccharide (s), preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar group comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said mono or polysaccharide radical S * being connected to the rest of the molecule by a bond between the carbon atom C 1 of one of the sugars of said mono or polysaccharide radical, this bond possibly being anomeric a or β; S * denoting in particular a glucose radical d) a radical C0R6 in which R6 denotes a linear saturated C1-C15 alkyl radical, such as a methyl or hexyl radical R3 denotes a linear saturated C1-C6 alkyl radical, an alkyl radical saturated or unsaturated branched C3-Ce or a C3-C6 cycloalkyl radical, such as a methyl, ethyl or isopropyl radical R4, R5 independently denote a) -H; b) a linear C1-C15 alkyl group, a saturated or unsaturated branched C3-C15 alkyl group or a C3-C8 cycloalkyl group, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO or their combinations such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one to three, chosen from: i) -OR7 such that a methyl or ethyl or isopropyl radical ii) -SR7 such as SH or SMe iii) -NR7R8 such that NH2 iv) -CONHR7 such as CONH2 v) -COOR7 such that CO2Me, CO2Et and CO2iPr vi) a (hetero) ring group saturated or unsaturated non-aromatic such as cyclohexyl, optionally substituted by one or more hydroxyl radicals, especially one to three, and / or by one or more C 1 -C 4 alkoxy or C 1 -C 4 alkyl radicals, especially one to three; one of the chain members possibly being a carbonyl group vii) a C5-C12 (hetero) aryl group, such as a phenyl, imidazolyl and indolyl radical, optionally substituted with one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 5 alkoxy and / or C 1 -C 1 alkyl radicals, especially one to three R 7, R 8 radicals, which may be identical or different, being chosen from H, a linear saturated C 1 -C 6 alkyl group or an alkyl group Saturated or unsaturated branched C3-C6; (C 1 -C 4) (hetero) aryl (C 6) alkyl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R7, R8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one to three, and / or optionally substituted by a C1-C10 hydrocarbon chain; R4, R5 being able to form with the nitrogen which carries them a heterocycle chosen from pyrrolidine, piperidine, morpholine and piperazine and their salts, their solvates and their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemic, alone or in mixture.
[4]
4. Compound of formula (I) for use in depigmenting, lightening and / or whitening the skin according to the preceding claim, characterized in that the radical R4 is chosen from radicals, H, methyl, ethyl, n-butyl, (CH2) xOMe with x denoting an integer ranging from 1 to 4 inclusive, in particular - (CH2) 2OMe.
[5]
5. A compound of formula (I) for its use for depigmenting, lightening and / or whitening the skin according to one of claims 3 or 4, characterized in that the radical R5 is chosen from a hydrogen atom and the radicals n- butyl; - (CH2) xOT with x denoting an integer ranging from 1 to 4 inclusive and T denoting a methyl or ethyl radical, in particular - (CH2) 3OMe, - (CH2) 3OEt, - (CH2) 2OMe, - ( CH2) 2OMe; ethyl; n-propyl; n-pentyl; n-hexyl; isopropyl; isobutyl; - (CH2) x-iPr, where x denotes an integer ranging from 1 to 4 inclusive, in particular - (CH2) 2OMe; cyclohexyl; -CH2-cyclohexyl; a radical of formula (III)

(III) wherein W1 denotes a linear or branched C1-C6 saturated alkyl radical optionally substituted by a phenyl radical and W2 denotes H or a linear or branched C1-C4 saturated alkyl radical, such as the radicals of formulas (a) to ( i) following:

or a radical of formula (IV)

(IV) with y denoting an integer between 1 and 4 inclusive, p being 0, 1, 2 or 3, q being equal to 0.1, 2 or 3, and p + q <6 Z designating a C1-C4 saturated linear alkyl radical such as methyl, such as the following radicals (j) and (k):


[6]
6. Compounds of formula (II) below:

in which R'I, R'2 independently denote a) H, b) a linear or branched C3-C20 saturated or C3-C20 saturated or unsaturated alkyl, or a C3-C8 cyclic radical, c) a radical S * denoting a radical monosaccharide sugar or a polysaccharide sugar radical comprising from 2 to 5 unit (s) saccharide (s), preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar group comprising 1 or 2 unit (s) saccharide (s) ( s) (monosaccharide or disaccharide), said mono or polysaccharide radical S * being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono- or polysaccharide radical, this bond possibly being anomeric to β, d) a COR'6 radical in which R'6 denotes a linear saturated C1-C20 alkyl radical, a linear unsaturated C2-C20 alkyl radical, a saturated or unsaturated branched C3-C20 radical or a cycloalkyl radical; C3-C8, it being understood that R'1 and R'2 can not designate simu at the present time, a methyl radical, R '3 denotes a C 2 -C 20 saturated or unsaturated C 2 -C 20 alkyl radical, linear or C 3 -C 20 branched or C 3 -C 8 cyclic R' 4, R '5 independently denote a) -H ; b) a saturated or unsaturated C2-C20 or branched C3-C20 or C3-C8 cyclic C1-C20 alkyl radical, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO- or their combinations such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from: i) -OR'7 ii) -SR'7 iii) -NR'7R'8 iv) -CONHR'7 v) -CONR'7R'8 vi) -COOR'7 vii) -NHCONHR'7 viii) -C (O) (C 1 -C 4) alkyl ix) a non aromatic saturated or unsaturated (hetero) ring group, said (hetero) ring group being optionally substituted by one or more hydroxyls, especially one to three, and / or by one or more C 1 -C 6 alkoxy or alkyl radicals in C | -Cx, especially one to three; one of the chain members may be a carbonyl group; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C x alkyl radicals, in particular one to three xi) -NH-C = NH (NH2) (guanidine group) R'7, R'8, which may be identical or different, being chosen from H, a linear saturated C1-C10 alkyl group, a C2-alkyl group; Linear or branched unsaturated C10, saturated or unsaturated branched C3-C10 alkyl group or C3-C8 cycloalkyl group; a (C 1 -C 4) alkyl (hetero) aryl group at G, optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and or optionally substituted with a C1-C10 hydrocarbon chain; c) NR'9R'10 R'9 and R'10 denoting a radical chosen from i) -H ii) a linear saturated alkyl group C1-C10 or unsaturated C2-C10 or branched C3-C10 or cyclic C3 -C8, optionally interrupted by one or more heteroatoms or non-adjacent groups chosen from N, O, -CO or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more groups C 1 -C 5 alkyl, identical or different, especially one to three; iii) a C5-C12 (hetero) aryl group, optionally containing one or more non-adjacent heteroatoms chosen from O, N, S, in particular one to three, optionally substituted by one or more hydroxyls and / or by one or more alkoxy radicals; in C | -Cs, especially one to three; R9 and R10 being able to form with the nitrogen which carries them a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and / or optionally substituted by a C1-C10 hydrocarbon-based chain optionally containing one or more radicals chosen from hydroxyl or C1-C4 alkoxy, especially one to three; d) OR'11 with R '11 denoting a radical chosen from: i) -H ii) a saturated linear C -C, branched C 3 -C 10 or cyclic C 3 -C 8, R'4, R'5 capable of forming, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and / or optionally substituted by a hydrocarbon-based chain C1-C10, as well as their salts, their solvates, their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemates, and with the exception of the following 3 compounds:


[7]
7. Compound of formula (II) according to the preceding claim, characterized in that R'I, R'2 independently denote a) H, b) a linear saturated C 1 -C 10 alkyl radical, an unsaturated C 2 -C 10 alkyl radical. linear or branched, an unsaturated or saturated branched C3-C10 alkyl group or a C3-C6 cycloalkyl group; c) a radical S * denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 unit (s) saccharide ( s), preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said radical S * mono or polysaccharide being connected to the the remainder of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this bond possibly being anomeric to a or β; and in particular a glucosyl, xylosyl, mannosyl, fucosyl or maltosyl radical d) a COR'6 group in which R'6 denotes a linear saturated C1-C15 alkyl group or a linear unsaturated C2-C15 alkyl group provided that R 1 and R'2 can not denote simultaneously a methyl radical R'3 denotes a linear saturated C1-C10 alkyl radical, a linear unsaturated C2-C10 alkyl radical, a saturated or unsaturated branched C3-C10 alkyl radical, or C3-C6 cycloalkyl radical R'4, R'5 independently denote a) -H; b) a linear C1-C15 alkyl radical, a linear unsaturated C2-C15 alkyl radical, a saturated or unsaturated C3-C15 branched radical or a C3-Cs cycloalkyl radical, optionally interrupted by one or more heteroatoms or chosen groups from N, O, -CO- or their combination such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted by one or more identical or different groups, in particular one to three, chosen from : i) -OR'7 such as a methyl or ethyl or isopropyl radical ii) -SR'7 iii) -NR'7R'8 iv) -CONHR'7 v) -CONR'7R'8 vi) -COOR ' Vii) -NHCONHR'7 viii) -C (O) (C 1 -C 4) alkyl ix) a non-aromatic saturated or unsaturated heterocycle group, said (hetero) ring group being optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or one or more C 1 -C 5 alkoxy or C 1 -C 5 alkyl radicals, especially one to three; one of the chain members may be a carbonyl group; x) a C 5 -C 12 (hetero) aryl group optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 6 alkoxy and / or C 1 -C x alkyl radicals, in particular one to three xi) -NH-C = NH (NH 2) (guanidine group) R '7, R' 8 being identical or different, being chosen from H, a linear saturated C 1 -C 10 alkyl group, a C2-alkyl radical; Linear unsaturated C10, a saturated or unsaturated branched C3-C10 alkyl radical, or a C3-C8 cycloalkyl radical; a (C 1 -C 4) alkyl (hetero) aryl group at G, optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, especially one to three, and or optionally substituted with a C1-C10 hydrocarbon chain; R'4, R'5 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle which may contain one or more heteroatoms or groups chosen from N, O, -CO-, in particular one or two, and / or optionally substituted with a C1-C10 hydrocarbon chain such as pyrrolidine, piperidine, morpholine, piperazine, as well as their salts, their solvates, their optical and / or geometric isomers, including enantiomers and diastereoisomers, their racemates, and except for the following compound:


[8]
8. Compound of formula (II) according to one of claims 6 or 7, characterized in that R'I, R'2 independently denote a) H, b) a linear saturated C 1 -C 6 alkyl group or an alkyl group unsaturated or unsaturated branched C3-C6 radicals such as ethyl, isopropyl and n-propyl radicals; c) an S * radical denoting a monosaccharide sugar radical or a polysaccharide sugar radical comprising from 2 to 5 saccharide units; preferably from 2 to 3 unit (s) saccharide (s), preferably a sugar radical comprising 1 or 2 unit (s) saccharide (s) (monosaccharide or disaccharide), said radical S * mono or polysaccharide being connected to the rest of the molecule by a bond between the carbon atom C1 of one of the sugars of said mono or polysaccharide radical, this bond being anomeric to a or β; S * denoting in particular a glucose radical d) a COR'6 group with R'6 denoting a linear saturated C1-C15 alkyl radical or a linear unsaturated C2-C15 group, preferably a linear saturated C1-C15 alkyl radical , such as a methyl or hexyl radical, it being understood that R'1 and R'2 can not simultaneously designate a methyl radical R'3 denotes a linear saturated C1-C6 alkyl radical, a linear unsaturated C2-C10 alkyl radical, a saturated or unsaturated branched C 3 -C 6 alkyl radical or a C 3 -C 6 cycloalkyl radical such as a methyl, ethyl or isopropyl radical R '4, R' 5 independently denote a) -H; b) a linear saturated C1-C15 alkyl radical, a linear unsaturated C2-C15 alkyl radical, a saturated or unsaturated C3-C15 branched radical or a C3-C8 cycloalkyl radical, optionally interrupted by one or more heteroatoms or groups non-adjacent selected from N, O, -CO- or combinations thereof such as -NHCO-, -NHCONH-, especially one to three, and / or optionally substituted with one or more identical or different groups, in particular one to three, chosen ( s) from: i) -OR7 such as a methyl or ethyl or isopropyl radical ii) -SR7 such as SH or SMe iii) -NR7R8 such that NH2 iv) -CONHR7 such as CONH2 v) -COOR7 such that CO2Me, CO2E and C02iPr vi) a nonhydrous saturated or unsaturated (hetero) ring group such as cyclohexyl, optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C1-C4 alkoxy or C1-alkyl radicals; -C4, especially one to three; vii) a C 5 -C 12 (hetero) aryl group, such as a phenyl, imidazolyl and indolyl radical, optionally substituted by one or more hydroxyl radicals, in particular one to three, and / or by one or more C 1 -C 4 alkoxy radicals; Cs and / or C1-C4 alkyl, especially one to three viii) -NH-C = NH (NH2) (guanidine group) R'7, R'8 identical or different, being chosen from H, a C1-alkyl group; -C10 linear saturated, linear unsaturated C 2 -C 10 alkyl, saturated or unsaturated branched C 3 -C 10 alkyl group or C 3 -C 8 cycloalkyl group; (C1-C4) alkyl (hetero) aryl optionally containing a nitrogen atom, especially a benzyl group; an acetyl radical; R'7, R'8 being able to form, with the nitrogen which carries them, a 5- to 8-membered heterocycle, which may contain one or more heteroatoms or groups, in particular one or two, chosen from N, O, -CO- and / or or optionally substituted with a C1-C10 hydrocarbon chain; R'4, R'5 being able to form with the nitrogen which carries them a heterocycle selected from pyrrolidine, piperidine, morpholine, piperazine, as well as their salts, their solvates, their optical and / or geometric isomers, including enantiomers and diastereoisomers; , their racemics.
[9]
9. Compound of formula (II) according to the preceding claim, characterized in that R'4 is chosen from radicals, H, methyl, ethyl, n-butyl, - (CH2) xOMe with x denoting an integer ranging from 1 at 4 inclusive, in particular - (CH ^ OMe.
[10]
10. Compound of formula (II) according to one of claims 8 or 9, characterized in that R'5 is selected from n-butyl radicals; - (CH2) xOT with x denoting an integer ranging from 1 to 4, inclusive limits and T denoting a methyl or ethyl radical, in particular - (EEC) OMe, - (CEE ^ OEt, - (CEEEOMe, - (CEEEOMe; ethyl, n-propyl, n-pentyl, n-hexyl, isopropyl, isobutyl, - (CH2) x-iPr, where x denotes an integer ranging from 1 to 4, inclusive, in particular - (CH 2 O) n, cyclohexyl; -CH2-cyclohexyl; a radical of formula (III)

(III) wherein W1 denotes a linear or branched Ci-Cr saturated alkyl radical optionally substituted by a phenyl radical and W2 denotes H or a linear or branched C1-C4 saturated alkyl radical, such as the radicals of formulas (a) to (i) following:

or a radical of formula (IV)

(IV) with y denoting an integer between 1 and 4 inclusive, p being 0, 1, 2 or 3, q being equal to 0.1, 2 or 3, and p + q <6 Z designating a C1-C4 saturated linear alkyl radical such as methyl, such as the following radicals (j) and (k):


[11]
11. Compound of formula (II) selected from the following compounds - N-butyl-3- (2,4-dihydroxyphenyl) butanamide - 3- (2,4-dihydroxyphenyl) -N- (3-methoxypropyl) butanamide - N- (4-Hydroxyphenethyl) -3- (2,4-dihydroxyphenyl) butanamide - 3- (2,4-dihydroxyphenyl) -N-ethylbutanamide - 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoate Methyl-3- (2,4-diethoxyphenyl) -N-ethylbutanamide-N-butyl-3- (2,4-dihydroxyphenyl) -4-methylpentanamide-N-butyl-3- (2,4-dihydroxyphenyl) pentanamide-2 Ethyl 3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoate - 3- (2,4-dihydroxyphenyl) -N, N-diethylbutanamide - N, N-dibutyl-3- (2,4-dihydroxyphenyl) -N, N-diethylbutanamide dihydroxyphenyl) butanamide - 3- (2,4-dihydroxyphenyl) -N-propylbutanamide - 3- (2,4-dihydroxyphenyl) -N-pentylbutanamide - 3- (2,4-dihydroxyphenyl) -N-hexylbutanamide - 3- (2-dihydroxyphenyl) butanamide 4-dihydroxyphenyl) -N- (3-ethoxypropyl) butanamide-3- (2,4-dihydroxyphenyl) -N-isopropylbutanamide-3- (2,4-dihydroxyphenyl) -N-isobutylbutanamide-3- (2,4-dihydroxyphenyl) -N- (3-ethoxypropyl) butanamide dihydroxyphenyl) -N-isopentylbu tanamide - 3- (2,4-dihydroxyphenyl) -N- (4-methylpentyl) butanamide - N-cyclohexyl-3- (2,4-dihydroxyphenyl) butanamide - N- (cyclohexylmethyl) -3- (2,4-dihydroxyphenyl) butanamide - N- (4-hydroxy-3-methoxyphenethyl) -3- (2,4-dihydroxyphenyl) butanamide - 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate, ethyl-3- (2, 4-Dihydroxyphenyl) -N, N-bis (2-methoxyethyl) butanamide - 2- (3- (2,4-dihydroxyphenyl) -N-methylbutanamido) ethyl acetate - 3- (2,4-dihydroxyphenyl) -N - (heptan-3-yl) butanamide - N-ethyl-3- (2-hydroxy-4 - ((2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) - tetrahydro-2H-pyran-2-yloxy) phenyl) butanamide - 3- (2,4-dihydroxyphenyl) -N- (2-hydroxyethyl) butanamide - 2- (3- (2,4-dihydroxyphenyl) butanamido) acetate Ethyl - 2- (3- (2,4-dihydroxyphenyl) butanamido) acetic acid - N-ethyl-3- (4-hydroxy-2 - ((2S, 3R, 4S, 5S, 6R) -3,4,5 trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yloxy) phenyl) butanamide-N-ethyl-3- (2-hydroxy-4 - ((3R, 4S, 5S, 6R) -3,4 , 5-trihydroxy-6- (hydroxymethyl ) 4- (4- (Ethylamino) -4-oxobutan-2-yl) -1,3-phenylene-diheptanoate 4- (4- (4- (4- (4- (4- (4- (4- (4-ethylamino) -4-oxobutan-2-yl) -1-tetrahydro-2H-pyran-2-yloxy) phenyl) butanamide diacetate; ethylamino) -4-oxobutan-2-yl) -1,3-phenylene - 2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoic acid - 2- (3- (2,4-dihydroxyphenyl) - ) -N-methylbutanamido) acetic acid - 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid - 2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoic acid - 3- (2, 4-Dihydroxyphenyl) butanamide - (R) -ethyl 2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate - ((S) -ethyl-2- (3- (2,4-dihydroxyphenyl) butanamido) propanoate (S) -2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid - (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) propanoic acid - 2- (3- (2, Methyl 4-dihydroxyphenyl) butanamido) -4-methylpentanoate - (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) -4-methylpentanoic acid - 2- (3- (2,4-dihydroxyphenyl) butanamido) ) -3-phenylpropanoate ethyl - 3- (2-ethoxy-4-hydroxyphenyl) -N- thylbutanamide - 3- (4-ethoxy-2-hydroxyphenyl) -N-ethylbutanamide - (R) -2- (3- (2,4-dihydroxyphenyl) butanamido) -3-phenylpropanoic acid - 3- (2,4-diisopropoxyphenyl) ) -N-Ethylbutanamide - 3- (2,4-dipropoxyphenyl) -N-ethylbutanamide-N-ethyl-3- (4-hydroxy-2-isopropoxyphenyl) butanamide-N-ethyl-3- (4-hydroxy-2-) -N-ethylbutanamide propoxyphenyl) butanamide - N-ethyl-3- (2-hydroxy-4-isopropoxyphenyl) butanamide - N-ethyl-3- (2-hydroxy-4-propoxyphenyl) butanamide - 3- (2,4-dihydroxyphenyl) -N- ethyl-N- (2-hydroxyethyl) butanamide-3- (2,4-dihydroxyphenyl) -1- (morpholin-4-yl) butan-1-one and their salts, solvates, optical isomers and / or geometric, including enantiomers and diastereoisomers, their racemates.
[12]
12. A composition comprising, in a physiologically acceptable medium, at least one compound of formula (II) according to any one of claims 6 to 11.
[13]
13. Composition according to the preceding claim, characterized in that said compound of formula (II) is present in an amount of between 0.01 and 10% by weight, preferably between 0.1 to 5% by weight, especially of 0. , 5 to 3% by weight, relative to the total weight of the composition.
[14]
14. Non-therapeutic cosmetic process for depigmentation, lightening and / or bleaching of keratinous substances, especially the skin, comprising the application of the composition according to claim 12 or 13 or of a composition comprising a compound of formula ( I) according to any one of claims 1 to 5.
[16]
15. Non-therapeutic cosmetic use of at least one compound of formula (I) or (II) according to any one of claims 1 to 11 as whitening agent, lightening and / or depigmenting keratin materials, including skin. A process for preparing a compound of formula (II) as defined in claim 6 comprising (i) reacting a compound of formula D

wherein R3 'is as defined in claim 6, by hydrogenation to a ring opening in the presence of a catalyst such as Pd / C, said compound of formula D having previously been protected on the hydroxy group by a protecting group such as the benzyl group, and then (ii) reacting the compound obtained in step (i) with a compound of formula HNR4R5, in the presence of an organic solvent, in particular tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, dichloromethane; toluene, methanol or ethanol; optionally in the presence of a catalyst selected from acidic Lewis or Bronsted catalysts or basic catalysts, such as potassium carbonate, triethylamine, diisopropylethylamine; optionally by heating at a temperature between 15 ° C and 200 ° C, especially between 20 ° C and 150 ° C, to result in the compound of formula G

wherein R3 ', R4' and R5 'are as defined in claim 6, said compound of formula G being able to give rise to a modification of the hydroxy groups to obtain said compound of formula (II).

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同族专利:

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公开号 | 公开日

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FR3045039B1|2017-12-22|

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WO2017102802A1|2017-06-22|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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WO2004017936A1|2002-08-23|2004-03-04|Unilever Plc|Skin lightening agents comprising coumarin derived from resorcinol derivatives|

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WO2005085169A1|2004-02-27|2005-09-15|Unilever Plc|Skin lightening agents, compositions and methods|

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FR2991985A1|2012-06-19|2013-12-20|Oreal|PROCESS FOR DEPIGMENTING KERATINIC MATERIALS USING NOVEL RESORCINOL DERIVED COMPOUNDS|FR3073145A1|2017-11-06|2019-05-10|L'oreal|PROCESS FOR TREATING KERATINIC MATERIALS FROM DERIVATIVES OF ACIDIC ESTERS OR AMIDES C-GLYCOSIDES AND THE COSMETIC COMPOSITION CONTAINING THEM|

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FR3085375A1|2018-08-28|2020-03-06|Greentech|NOVEL ALKYLRESORCINOL DERIVATIVES AND THEIR USE IN COSMETICS|

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CN111153947B|2019-08-21|2021-03-09|云南巅青生物科技有限公司|Aromatic ring compound|

法律状态:
2016-11-11| PLFP| Fee payment|Year of fee payment: 2 |

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2017-06-16| PLSC| Publication of the preliminary search report|Effective date: 20170616 |

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2017-11-13| PLFP| Fee payment|Year of fee payment: 3 |

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2019-11-15| PLFP| Fee payment|Year of fee payment: 5 |

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2020-11-12| PLFP| Fee payment|Year of fee payment: 6 |

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2021-11-09| PLFP| Fee payment|Year of fee payment: 7 |

优先权:

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申请号 | 申请日 | 专利标题

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FR1562427A|FR3045039B1|2015-12-15|2015-12-15|RESORCINOL DERIVATIVES FOR THEIR COSMETIC USE|FR1562427A| FR3045039B1|2015-12-15|2015-12-15|RESORCINOL DERIVATIVES FOR THEIR COSMETIC USE|

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PCT/EP2016/080911| WO2017102802A1|2015-12-15|2016-12-14|Resorcinol derivatives for their cosmetic use|