CN105408306A - Resorcinol derivatives and cosmetic application thereof - Google Patents

Resorcinol derivatives and cosmetic application thereof Download PDF

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CN105408306A
CN105408306A CN201380032421.6A CN201380032421A CN105408306A CN 105408306 A CN105408306 A CN 105408306A CN 201380032421 A CN201380032421 A CN 201380032421A CN 105408306 A CN105408306 A CN 105408306A
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acrinyl
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CN105408306B (en
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泽维尔·马拉
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LOreal SA
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LOreal SA
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    • A—HUMAN NECESSITIES
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    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
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    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
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    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract

The present invention relates to a compound of formula (I): in which: Rdenotes a hydrogen atom or an acetyl group; and Ydenotes a radical chosen from OR' or NAR''; and their salts, their solvates and their optical isomers, their racemates, alone or as mixtures. It also relates to their cosmetic use, in particular as depigmenting agent, and to the associated cosmetic method.

Description

Resorcinol derivatives and cosmetic applications thereof
The present invention relates to the new compound from resorcinol derived and cosmetic treatment method, especially use the method that this compound makes skin depigmentation and/or bleaches.
Some find at its life different steps its skin, and especially hand and face skin darkening and/or have more coloured speckle, make skin appearance be heterogeneous.Specifically these spots are because caused by the keratinocyte high density melanochrome being positioned at skin surface.
The present invention seeks the use of efficient harmless local decoloring substances uniquely from the angle for the treatment of pigment spot.
Skin pigment Forming Mechanism i.e. melanic formation complicated especially, be broadly directed to following key step:
Tyrosine--> DOPA--> DOPA quinone--> dopachrome--> melanochrome
Tyrosine oxidase (single phenol dopa: Sauerstoffatom oxydo-reductase EC1.14.18.1) participates in these a series of indispensable enzymes of answering.Specifically, it utilizes the active catalytic tyrosine of self hydroxylase to generate the conversion reaction of DOPA (dopa), utilizes the active catalytic DOPA of autoxidation enzyme to generate the conversion reaction of DOPA quinone.This tyrosine oxidase is only in maturity state and just works under certain biotic factor effect.
If a kind of material has following effect can think to have depigmentation: directly act on the vigor place that melanochrome generates the epidermal melanophore of part, and/or by the analog suppressing one of enzyme participating in melanochrome generation or insert as one of compound in B16 cell order, thus one of stage of interference melanin biosynthesis, make B16 cell order be obstructed and decolour.
Arbutin and kojic acid are the discoloring agents becoming known for skin.
Now having sought effectively to decolour especially is better than the material of arbutin and kojic acid.
Even if applicant company surprisingly finds that some compounds derived from Resorcinol also show good decolouring activity at low concentrations in this respect.
One of present subject matter is hereinafter described new compound shown in molecular formula (I).
The present invention another theme as physiology can in accepting medium, comprise the composition of at least one hereinafter described compound shown in molecular formula (I).
The present invention another theme as and make keratinization material especially skin depigmentation, the non-therapeutic cosmetic method that brightens and/or bleach, it comprises uses above-mentioned composition.
The method more preferably making skin depigmentation, brighten and/or bleach.
The present invention also relates to compound shown in molecular formula (I) as the non-therapeutic cosmetic use of the reagent bleaching, brighten and/or decolour for keratinization material especially skin.
Compound of the present invention may make human skin decolouring and/or brighten even to bleach effectively.Specifically they are applied to brown color spot or occur that because of old and feeble the individual of spot stops skin, or want to be applied to the individual's skin prevented because of the caused brown of melanochrome generation.
They also may make non-hair of scalp, eyelashes or hair and lip and/or nail decolouring and/or brighten.
Therefore one of present subject matter is the new compound shown in following molecular formula (I):
Wherein:
R is hydrogen atom or ethanoyl,
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group may be selected from following groups by three alternatively replaces:
i)-OR5，
ii)-SR5，
iii)-NR6R7，
iv)-C(O)NHR6，
v)-C(O)NR6R7，
vi)-C(O)OR6，
vii)-NHC(O)NHR6，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) group of alkyl replaces;
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) group of alkyl replaces;
R5 is selected from:
H, and
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl,
R6 and R7 can be the same or different, and it is selected from:
·H，
Acetyl free radical, and
Saturated straight chain (C 1-C 10) alkyl or unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl is as benzyl or pyridyl (C 1-C 4) alkyl;
R6 and R7 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is optional by (C 1-C 10) alkyl replaces;
A is selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three alternatively replaces:
i)-OR15，
ii)-SR15，
iii)-NR16R17，
iv)-C(O)NHR16，
v)-C(O)NR16R17，
vi)-C(O)OR16，
vii)-NHC(O)NHR16，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) group of alkyl replaces;
Xi)-NH-C=NH (NH2) (guanidine radicals);
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) group of alkyl replaces;
d)-NR12R13；
e)-OR14；
F)-C (O) NHR14; And
G)-C (O) (C 1-C 10) alkyl;
R12 and R13 can be the same or different, and is selected from following free radical:
·-H，
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, described group also may be replaced by one to three identical or different-OR15 group, and
Aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces,
R12 and R13 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is optional by (C 1-C 10) alkyl replaces; Should (C 1-C 10) alkyl can be selected from hydroxyl and (C by one to three alternatively 1-C 4) group of alkoxyl group replaces;
R14 is selected from following free radical:
·-H，
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may be replaced by the identical or different group that to three is selected from following groups alternatively:
Vi)-C (O) OR16, and
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and
Aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces;
R15 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl;
R16 and R17 can be the same or different, and it is selected from H, acetyl free radical, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is alternatively by (C 1-C 10) alkyl replaces;
R " refer to be selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group may be selected from following groups by three replaces:
i)-OR25，
ii)-SR25，
iii)-NR26R27，
iv)-C(O)NHR26，
v)-C(O)NR26R27，
vi)-C(O)OR26，
vii)-NHC(O)NHR26，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) group of alkyl replaces;
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) group of alkyl replaces;
R25 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl;
R26 and R27 can be the same or different, and it is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R26 and R27 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle may alternatively by (C 1-C 10) alkyl replaces;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 10) alkyl, hydroxyl (C 1-C 10) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) group of alkyl;
And their salt, their solvate and their optical isomer, their racemize salt, independent or as mixture.
Shown in molecular formula (I), the salt of compound comprises the conventional non-toxic salts of described compound, as the salt formed by acid or alkali.
The salt of compound shown in molecular formula (I) (when its contain can quatemised nitrogen atoms time) comprising of can mentioning:
A) compound (I) is added the salt obtained in mineral acid, specifically mineral acid is selected from hydrochloric acid, boric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid or Tetrafluoroboric acid;
B) or by compound (I) add the salt obtained in organic acid, specifically organic acid is selected from acetic acid, propionic acid, succsinic acid, fumaric acid, lactic acid, hydroxyethanoic acid, citric acid, gluconic acid, Whitfield's ointment, tartrate, terephthalic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids or trifluoromethanesulfonic acid.
Can also mention salt to comprise compound molecular formula (I) Suo Shi (when it contains acid group) is added mineral alkali and obtains, described inorganic basis is the carbonate of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, magnesium hydroxide, lithium hydroxide and sodium, potassium or calcium or supercarbonate in this way;
Or add organic bases, and as primary, secondary or tertiary alkylammonium, such as triethylamine or butylamine and obtain.This primary, secondary or tertiary alkylammonium can comprise one or more nitrogen-atoms and/or Sauerstoffatom, thus can comprise such as one or more carbinol-functional group; That can mention especially comprises 2-ammonia-2-methylpropanol, thanomin, trolamine, 2-(dimethylamino) propyl alcohol, 2-amino-2-(methylol)-1,3-PD or 3-(dimethylamino) propylamine.
That also can mention comprises amino acid whose salt, as the salt of Methionin, arginine, guanidine, L-glutamic acid or aspartic acid.Advantageously the salt of compound (when it contains acid group) shown in molecular formula (I) can be selected from basic metal or alkaline earth salt as sodium salt, sylvite, calcium salt or magnesium salts or ammonium salt.
Advantageously compound shown in molecular formula (I) (when its contain can quatemised nitrogen atoms time) salt can be selected from halogenide as muriate or bromide, Citrate trianion, acetate, succinate, phosphoric acid salt, lactic acid salt or tartrate.
The acceptable solvate of compound of the present invention comprises Conventional solvents compound, as described in the solvate that formed because there is solvent in preparation of compounds.For example described solvate can be the solvate because water or straight or branched alcohols exist as ethanol or Virahol and formed.
Optical isomer is enantiomorph and diastereomer specifically.
In the context of the invention:
-" (C x-C y) alkyl " refer to the alkyl comprising x ~ y carbon atom.This alkyl can be that straight chain is saturated, typically can contain 1 ~ 20 carbon atom or 1 ~ 10 carbon atom.This alkyl also can be that straight chain is unsaturated, typically can contain 2 ~ 20 carbon atoms or 2 ~ 10 carbon atoms.It also can be branched-chain alkyl, typically can contain 3 ~ 20 carbon atoms or 3 ~ 10 carbon atoms.Alkyl also in the form of a ring, can be cycloalkyl, generally includes 3 ~ 8 carbon atoms.
If no special instructions, " (C x-C y) alkyl " refer to the straight chain saturated alkyl comprising x ~ y carbon atom.
Side chain or straight chain saturated alkyl can preferably from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, 2-ethylhexyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyls.
More preferably side chain or straight chain saturated alkyl are selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, 2-ethylhexyl and octyl group.
Cycloalkyl can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
-" (C x-C y) alkoxyl group " refer to that molecular formula is-O (C x-C y) straight chain of alkyl and suitable branched group, generally include 1 ~ 8 carbon atom and also comprise 1 ~ 4 carbon atom.
Alkoxyl group can be selected from methoxyl group, oxyethyl group, propoxy-and butoxy, especially methoxyl group.
-" saturated or unsaturated non aromatic heterocyclyl " refers to containing the monocycle of 5 ~ 8 ring member nitrogen atoms or bicyclic carbocyclic group, also comprise one to three be selected from N, O, S and-C (O)-heteroatoms or group.
Heterocyclic radical can be selected from piperidines, morpholine, piperazine and pyrrolidyl.Be preferably piperidine ring or morpholine ring.
-" aromatic base " refers to the unsaturated monocycle of unsaturated or part or the bicyclic carbocyclic group that contain 5 ~ 12 carbon atoms.
Aryl biradical can be selected from phenyl, naphthyl, indenyl, fluorenyl and anthryl.Preferably it is phenyl.
What-" heteroaryl " referred to be selected from N, O or S atom containing 5 ~ 22 ring member nitrogen atoms and 1 ~ 6 heteroatomicly condenses or the many rings of non-condensed or monocyclic groups, and wherein at least one ring is aromatic nucleus.
Assorted fragrant free radical can be selected from furyl, acridyl, benzimidazolyl-, the two triazolyl of benzo, benzopyrazoles base, benzo pyridazinyl, benzoquinoline base, benzoquinolizine base, benzothiazolyl, benzotriazole base, benzoxazolyl, pyridyl, tetrazyl, dihydro-thiazolyl, imidazopyridyl, imidazolyl, indyl, isoquinolyl, naphtho-imidazolyl, Nai Bing oxazolyl, naphtho-pyrazolyl, oxazole pyridazinyl, oxazolyl, oxazole pyridyl, phenazinyl, Fen oxazolyl, pyrazinyl, pyrazolyl, pyrazoles triazinyl (pyrazoyltriazyl), pyridyl, pyridine imidazolyl, pyrryl, quinolyl, tetrazyl, thiadiazolyl group (thiadiazolyl), thiazolyl, thiazole pyridyl, Tiabendazole base, sulphur pyranyl (thiopyrylyl), triazolyl, xanthyl and ammonium salt thereof.
Compound shown in molecular formula (I) is preferably containing following meanings:
R is hydrogen atom or ethanoyl;
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, described group also may be replaced by one to three identical or different-OR5 group, and
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
R5 is selected from H and saturated straight chain (C 1-C 4) alkyl;
A is selected from free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three replaces:
i)-OR15，
ii)-SR15，
iii)-NR16R17，
iv)-C(O)NHR16，
vi)-C(O)OR16，
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace;
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) group of alkyl replaces;
D)-NR12R13, and
e)-OR14；
R12 and R13 can be the same or different, and refers to be selected from following free radical:
·-H，
Saturated straight chain (C 1-C 4) alkyl, and
Phenyl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace; With
R12 and R13 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is optional by (C 1-C 10) alkyl replacement; Should (C 1-C 10) alkyl can be selected from hydroxyl and (C by one to three alternatively 1-C 4) alkoxyl group group replace;
R14 is selected from free radical:
-H, and
Saturated straight chain (C 1-C 10) alkyl, it is selected from saturated straight chain (C by one to three alternatively 1-C 10) the identical or different group of alkyl replaces, replaced by one or more benzene radical alternatively, described phenyl is selected from hydroxyl and (C by one to three alternatively 1-C 8) the identical or different group of alkoxyl group replaces;
R15 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl and (C3-C 8) cycloalkyl;
R16 and R17 can be the same or different, and is selected from:
·H，
Acetyl free radical, and
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl,
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is alternatively by (C 1-C 10) alkyl replaces;
R " be selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 10) alkyl, described group may be replaced by one to three identical or different-OR25 group alternatively;
R25 is selected from H or straight chain (C 1-C 10) alkyl;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 4) alkyl, hydroxyl (C 1-C 4) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 6) alkyl and side chain (C 3-C 6) group of alkyl;
And their salt, their solvate and their optical isomer, their racemize salt, independent or as mixture.
More preferably molecular formula (I) compound possesses following meanings:
R is hydrogen atom;
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively interrupt by one to three Sauerstoffatom, described group also may be replaced by one to three identical or different group being selected from hydroxyl, methoxyl group and oxyethyl group alternatively;
A is selected from free radical:
a)-H；
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively interrupt by one to three Sauerstoffatom, the identical or different group that described group also may be selected from following groups by three alternatively replaces:
i)-OR15，
Ii)-SR15, preferred SMe,
iii)-NR16R17，
iv)-C(O)NHR16，
vi)-C(O)OR16，
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and is preferably selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group replace imidazolyl, indyl or phenyl, particularly preferably imidazolyl, indyl or phenyl, and
X) saturated or unsaturated, preferably saturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace;
C) phenyl, its group that can be selected from hydroxyl, methoxyl group and oxyethyl group by one to three alternatively replaces;
D)-NR12R13, and
e)-OR14；
R12 and R13 can be the same or different, and is selected from:
·-H，
Saturated straight chain (C 1-C 4) alkyl, and
Phenyl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace; R12 and R13 is preferably hydrogen atom or (C 1-C 4) alkyl;
R14 is selected from free radical:
-H, and
Saturated straight chain (C 1-C 4) alkyl, its alternatively by phenyl as benzyl replaces;
R15 is selected from H, saturated straight chain (C 1-C 4) alkyl and side chain (C 3-C 4) alkyl;
R16 and R17 can be the same or different, and is selected from H, ethanoyl, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl,
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle comprise one to three be selected from N, O and-C (O)-heteroatoms or group, there is (C alternatively in this heterocycle 1-C 10) alkyl replacement;
R " be selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may be replaced by one to three identical or different-OR25 group alternatively;
R25 is selected from H and saturated straight chain (C 1-C 10) alkyl;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 4) alkyl, hydroxyl (C 1-C 4) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 6) alkyl and side chain (C 3-C 6) group of alkyl, the preferred piperidyl of described heterocycle or morpholinyl;
And their salt, their solvate and their chemical isomer, their racemize salt, independent or as mixture.
Preferably R=H in molecular formula (I) compound.
Shown in molecular formula (I), the several embodiments of compound is as follows:
A) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is alternatively by i) hydroxyl replacement;
Be compound 1,10,12,13,17,19,20,24,26 and 27 by the particularly preferred compound of the present embodiment.
B) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, interrupted by Sauerstoffatom and replaced by i) hydroxyl alternatively;
Be compound 44,45 and 46 by the particularly preferred compound of the present embodiment.
C) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is by vi) replacement of one or two identical C (O) OR16 group, and replaced by the group being selected from following groups alternatively;
ii)-SR15,
Ix) phenyl, it is replaced by a hydroxyl alternatively, and
Ix) heteroaryl,
R16 is selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) alkyl, and
R15 is saturated straight chain (C 1-C 10) alkyl;
Be compound 5,6,7,15,16,22,38,40,41,42 and 47 by the particularly preferred compound of the present embodiment.
D) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is replaced by the group being selected from following groups alternatively;
iii)-NR16R17,
Ix) phenyl, it is alternatively by a hydroxyl and/or (C 1-C 8) alkoxyl group replaces, and
Ix) heteroaryl, its ring member nitrogen atoms number is 5 ~ 12, containing Sauerstoffatom,
X) saturated heterocyclic, ring member nitrogen atoms number is 5 ~ 8, containing one or two Sauerstoffatom, alternatively by one or two (C 1-C 4) alkyl replacement,
Xii) (C 3-C 8) cycloalkyl,
R16 and R17 can be the same or different, and is selected from H, saturated straight chain (C 1-C 10) alkyl and ethanoyl;
Be compound 21,25,28,34,35,48,49 and 51 by the particularly preferred compound of the present embodiment.E) R=H, Y=-NAR ", R "=H, A=side chain (C 3-C 10) alkyl, it is replaced by the group being selected from following groups alternatively;
I)-hydroxyl,
Vi) COOR16 group, R16 is selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) alkyl;
Be compound 2,3,4,8,9,14,18 and 23 by the particularly preferred compound of the present embodiment.
F) R=H, Y=-NAR ", R "=H, simultaneously
A=ring-type (C 3-C 8) alkyl, or
A=phenyl, there is hydroxyl alternatively and replace in it;
Be compound 11,36 and 37 by the particularly preferred compound of the present embodiment.
G) R=H, Y=-NAR ", simultaneously
A and R " form with the nitrogen-atoms carrying them heterocycle that annular atoms number is 5 ~ 8, comprise Sauerstoffatom alternatively, replaced by C (O) OT group alternatively, T is saturated straight chain (C simultaneously 1-C 10) alkyl; Be compound 29,32 and 39 by the particularly preferred compound of the present embodiment.
H) R=H, Y=-NAR ", simultaneously
A is saturated straight chain (C 1-C 10) alkyl, interrupted by one or two Sauerstoffatom alternatively, and replaced by one or two groups being selected from following groups alternatively:
I)-hydroxyl,
vi)-COOR16，
R16 is saturated straight chain (C 1-C 10) alkyl, and
R " be saturated straight chain (C 1-C 10) alkyl, it is interrupted by one or two Sauerstoffatom alternatively, and is replaced by one or two groups being selected from following groups alternatively:
I)-hydroxyl,
Vi)-COOR26, R26 are saturated straight chain (C 1-C 10) alkyl;
Be compound 30,31,33 and 50 by the particularly preferred compound of the present embodiment.
J) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl;
Be compound 43 by the particularly preferred compound of the present embodiment.
K) R=H, Y=-NAR ", R "=H, simultaneously
A=-NR12R13 or
A＝-OR14,
R12 and R13 can be the same or different, and it is selected from free radical:
A)-H, and
B) saturated straight chain (C 1-C 10) alkyl;
R14 is selected from free radical:
a)-H，
B) there is the saturated straight chain (C that phenyl replaces 1-C 10) alkyl;
Be compound 52,53,54 and 55 by the particularly preferred compound of the present embodiment.
l)R＝H，Y＝-OR’，
R '=saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 10) alkyl, its alternatively interrupt by Sauerstoffatom, and alternatively by one or two i) hydroxyl replace.
Be compound 56 and 61 by the particularly preferred compound of the present embodiment.
Shown in molecular formula of the present invention (I), the embodiment of compound is organized in Table I below.
Table 1
Numeral in table corresponds to numeral used in Examples below.
Their salt, they solvate, their isomer and their racemize salt separately or also form part of the present invention as mixture.
Particularly preferably be most compound 1 ~ 37,39,44 and 56 under background of the present invention in these compounds, and their salt, their solvate, their isomer and their racemize salt, individually or as mixture.
The compounds of this invention can be prepared according to following scheme 1:
Scheme 1:
Shown in scheme 1, process comprises following phases:
A) one of ester shown in Resorcinol (A1) and methylene-succinic acid (B) or its acid anhydride (B ') or its molecular formula (B1) reacts,
Wherein R1 is H, straight chain (C 1-C 6) alkyl or side chain (C 3-C 6) alkyl, thus generate Compound C,
B) make this Compound C reduce, thus generate intermediate (III), then
C) then intermediate (III) and derivative YH react, and wherein Y is as defined above, thus can use compound (I).
A kind of alternative is that (III) is generated compound (IV) with alcohol roh process, then react with YH and generates the shown compound of molecular formula (I).
The last stage is for carrying out acetylization reaction (shown in the molecular formula (I) of R=ethanoyl compound) alternatively.
The present invention another theme as compound shown in compound shown in molecular formula (III) and molecular formula (IV).
Wherein R is H or straight chain (C 1-C 6) alkyl or side chain (C 3-C 6) alkyl.
According to aforementioned schemes, preferably ROH is ethanol, the R free radical of compound shown in molecular formula (IV) is ethyl.
One of ester shown in Resorcinol mentioned above (A1) and methylene-succinic acid (B) or its acid anhydride (B ') or its molecular formula (B1) carries out reacting thus the reaction generating Compound C is deposited at organic solvent and carried out in case specifically, organic solvent can be selected from toluene, tetrahydrofuran (THF), heptane, octane-iso, methyltetrahydrofuran, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), diox, ethyl acetate, isopropyl acetate, Permethyl 99A. and composition thereof, concrete temperature of reaction is between 15 and 200 DEG C, catalyzer (acid or basic catalyst) alternatively described in following publication is deposited and is translated in case: use perfluorinated sulfonic acid ester resin/silica mixture as catalyzer, the synthesis of the umbelliferone reacted by Pechmann, the LauferMC of katalysis, HausmannH and wF, J., 2003,218,315-320, synthesis by the umbelliferone of solid acid catalyst: HoefnagelA, GunneweghE, DowningR and vanBekkumH, J.Chem.Soc., Chem.Commun., 1995,225-226, deposit in case at an acidic catalyst specifically, as methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid or sulfonic acid, as or Amberlyst product (being sold by Aldrich).
Compound (B1) can carry out selective esterification with one or more alcohol shown in molecular formula ROH by currently known methods and obtain in the acidic medium of methylene-succinic acid, and the method is shown in and (deposits the selective esterification of non-conjugated carboxylic acid in case in conjugation or aromatic carboxylic acid relative to the methylsulfonic acid that gac supports described in document; Feng, ZeWang, Zhao, XinQi and Bi, Hua, Chinese science, B series: chemistry (2008), the effective and regiospecific esterification of the bisgallic acid of 1 (10), 990-992/ use PTSA; Devi, A.Rama and Rajaram, S., India's chemical periodical, part B: comprise pharmaceutical chemical organic chemistry (2000), 39B (4), 294-296/ deposit in case by the selective esterification of non-conjugated carboxyl, for the simple method of the preparation of the monomethyl ester of dicarboxylic acid at the carboxyl of aromatic series or conjugation; Ram, RamN. and Meher, NabinKumar; Chemical research periodical, summary (2000), (6), 282-283).
According to a specific embodiments of building-up process, when the R group of Compound C is H, compound shown in molecular formula (I) makes sour C activate by the method for known activated acids and obtains, activation method to specifically describe in R.Larock, WileyVCHEd. show chapters and sections " the mutual conversion of nitrile, carboxylic acid and derivative " in comprehensive organic transformation (ComprehensiveOrganicTransformations).
Described acid activation method is as follows:
-generate sour chloride intermediates (such as can utilize thionyl or oxalyl chloride compound, or chloro-N, N, the 2-trimethylammonium of 1--1-allylamine),
-generate mixed anhydride intermediate (such as at alkali as under triethylamine or diisopropylethylamine existent condition, C to be used 2-C 6alkyl chloride formate, as isobutyl chloride formate),
The intermediate of-generation isourea vitriol (carbamimidate) or acylphosphate salt (such as can utilize carbodiimide or diethyl cyanogen phosphoric acid salt; Phosphorus in organic synthesis-XI, amino acid and peptide-XXI, the reaction of diethyl cyanophosphonate and carboxylic acid. the new synthesis of carboxylicesters and acid amides, tetrahedron, 32,1976,2211-2217).
The Compound C existed with sour form can according to being reduced with muriate shown in scheme 2 thus obtain compound shown in molecular formula (III) after acid treatment.
Scheme 2
This reduction reaction can between-30 DEG C and+60 DEG C in protonic solvent or aprotic solvent (tetrahydrofuran (THF), diox, ethanol, methyl alcohol) and metal hydride donor such as sodium borohydride, triacetyl oxygen sodium borohydride or diisobutyl aluminium hydride react.
Shown in molecular formula (III), shown in compound and molecular formula YH, the reaction of compound can be implemented by scheme 3.
Scheme 3
This reaction is implemented alternatively under organic solvent especially tetrahydrofuran (THF), diox, dimethyl formamide, methyl-sulphoxide, 2-methyltetrahydrofuran, methylene dichloride, toluene, methyl alcohol or ethanol existent condition,
Reaction is implemented alternatively under catalyzer existence condition, and catalyzer can be selected from Louis (Lewis) type an acidic catalyst or cloth youth Si Taide (Bronsted) type basic catalyst, as salt of wormwood, triethylamine or diisopropylethylamine,
Temperature of reaction can be heated between 15 DEG C and 200 DEG C especially between 30 DEG C and 150 DEG C alternatively.
It should be noted that lactone (III) can be formed with ethyl ester form (III ') when there being ethanol to exist to balance.This non-ring type ester can react with YH compound and obtain compound (I).
R is that the shown compound acetyl of molecular formula (I) that the shown compound of molecular formula (I) of ethanoyl can be H by R obtains.
Acetylization reaction especially can be implemented with diacetyl oxide or Acetyl Chloride 98Min. under aprotic solvent is as the existence of toluene, pyridine or tetrahydrofuran (THF).
According to the known technology of organic synthesis, by acetylizad functional group utilizing blocking group and then by protective reaction, acetylization reaction can be optionally.
As R ', A and R " characteristic of free radical; all these stages also can adopt protection conventional in organic chemistry/remove Preservation tactics; in " in organic synthesis blocking group " (Greene and Wuts, WileyInterscience) works, edited and recorded these strategies.
In addition when finalization compound (I) is at A or R " when free radical having a free carboxy acid; these compounds can use mineral alkali; if NaOH or LiOH is at protonic solvent or aprotic solvent; as obtained through saponification reaction under ethanol or tetrahydrofuran (THF) or water existence condition, and temperature can fluctuate between 0 DEG C and 100 DEG C.Gained salt at general inorganic or organic acid, acidifying again under example hydrochloric acid or citric acid existent condition.
To have in cosmetic field according to compound molecular formula of the present invention (I) Suo Shi and apply very especially.
According to composition of the present invention be included in physiology can in accepting medium, compound shown in described molecular formula (I) above.
Term " physiology can accepting medium " is interpreted as the medium with human keratinocyte's substances compatible, as the skin of health or face, lip, mucous membrane, eyelashes, nail, scalp and/or hair.
Compound (I) content in the compositions of the present invention accounts for composition total weight calculating by weight and can account between 0.01% ~ 10%, preferably accounts between 0.1% ~ 5%, especially between 0.5% ~ 3%.
The present composition is cosmetic composition with being conducive to: it can comprise adjuvant conventional in cosmetic field.
The adjuvant can mentioned especially comprises water, organic solvent, especially C 2-C 6alcohol, oils is hydrocarbon ils or silicone oil, wax, pigment, weighting agent, tinting material, tensio-active agent, emulsifying agent, active cosmetic agent, UV separant, polymkeric substance, thickening material, sanitas, perfume compound, sterilant, ceramide, odour absorbents or antioxidant especially.
These optional cosmetic adjuvants ratio in the composition calculates in the ratio that its weight accounts for composition gross weight can account for 0.001% ~ 80% especially 0.1% ~ 40%.In any case, these adjuvants and ratio thereof will be selected by those skilled in the art, thus the advantageous feature of the compounds of this invention can not be subject to or substantially can not be subject to these contemplated disadvantageous effects of adding.
It is favourable that at least one compound adds the present composition as promoting agent, and this at least one compound is selected from: decorticating agent, soothing agent, organic or inorganic light protective agent, wetting Agent for Printing Inks, discoloring agent, anti-saccharifying agent, NO synthase inhibitor, the reagent stimulating corium or epidermal macromolecules synthesis and/or the reagent suppressing it to decompose, stimulate inoblast and/or keratinocyte proliferation or stimulation Keratinocyte differentiation; The reagent of muscle relaxant and/or cutis laxa agent, tensioning agent, antipollution and/or free radical, the reagent acting on microcirculatory reagent, act on cellular energy metabolism, and their mixture.
This type of adds examples of compounds and comprises: Vogan-Neu and derivative thereof, as retinyl palmitate, xitix and derivative thereof, as anti-hematic acid phosphoric acid ester magnesium salts and ascorbic acid glucoside, tocopherol and derivative thereof, as Vitamin E-acetate, nicotinic acid and precursor thereof, as niacinamide, ubiquinone, gsh and precursor thereof, as L-2-oxothiazoiium quinoline-4-carboxylic acid; Plant milk extract, especially vegetable-protein and hydrolysate thereof and plant hormone; Marine extracts, as Algae Extract; Bacterial extract; Saponin, as diosgenin and wild yam extract, ceramide containing same substance; Hydroxy acid, as Whitfield's ointment and 5-(n-capryloyl) Whitfield's ointment; Trans-resveratrol; Oligopeptides and plan dipeptides and acylated derivatives thereof, manganese salt and magnesium salts, especially gluconate, and composition thereof.
Term " decorticating agent " is interpreted as any compound with effect as described below:
-peeled off by promotion and directly peel, as β-hydroxy acid, especially Whitfield's ointment and derivative (comprising 5-(n-capryloyl) Whitfield's ointment) thereof; Alpha-hydroxy acid, as hydroxyethanoic acid, citric acid, lactic acid, tartrate, oxysuccinic acid or mandelic acid; Urea; Gentisinic acid; Few Fucose; Styracin; Chinese scholartree (Saphorajaponica) extract, or trans-resveratrol.
-or act on the enzyme participating in decortication or corneodesmosome decomposition, as Glycosylase, stratum corneum Chymotrypsin (SCCE) or other proteolytic enzyme (trypsinase of Chymotrypsin sample).The reagent that can mention comprises: the inorganic salt of chelating: EDTA; N-acyl group-N, N ', N '-ethylene diamine tetraacetic acid; Sulfamic acid compound, especially N-(2-hydroxyethyl) piperazine-N '-2-ethanesulfonic acid (HEPES); 2-oxo tetrahydro-thiazoles-4-carboxylic acid (the third halfcystine) derivative; The derivative of glycine type a-amino acid (as described in EP0852949 material, and the MDGA sodium sold with trade(brand)name TrilonM by BASF); Honey; Or carbohydrate derivative is as O-capryloyl-6-D-maltose and N-Acetyl-D-glucosamine.
Decorticating agent ratio in the compositions of the present invention calculates in the ratio that it accounts for composition total weight and usually accounts for 0.01% ~ 15% weight range, preferable range 0.1% ~ 10% weight range.
Soothing agent available in the present composition comprises pentacyclic triterpene and the plant milk extract (as glycyrrhiza glabra (Glycyrrhizaglabra)) containing same substance, as β-glycyrrhetinic acid and salt thereof and/or its derivative (glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetate, 3-(stearoyl-oxy) glycyrrhetinic acid), ursolic acid and salt thereof, oleanolic acid and salt thereof, betulinic acid and salt thereof, the extract of tree peony (Paeoniasuffruticosa) and/or Chinese herbaceous peony (Paeonialactijlora), salicylate is zinc salicylate especially, from the algae sugar (phycosaccharides) of Codif, a kind of sugared sea-tangle (Laminariasaccharina) extract, mustard caul-fat, bisabolol, Flos Chrysanthemi extract, wallantoin, from the SepivitalEPC (the phosphorus diester of vitamin-E and C) of Seppic, Ω-3 unsaturated oil, as musk rose oil, Ribes nigrum L. oil, blueweed oil or fish oil, plankton extractions, decoyl glycine, from the SeppicalmVG (palmityl Sodium proline and water lily (Nymphaeaalba)) of Seppic, pygeumafricaum (Pygeum) extract, boswellia serrata tree (Boswelliaserrata) extract, Myriogyne minuta (Centipedacunninghamii) extract, Sunflower Receptacle (Helianthusannuus) extract, flax (Linumusitatissimum) extract, tocotrienols, light kola nut (Colanitida) extract, piperonylaldehyde, Flos Caryophylli extract, willow herb (Epilobiumangustifolium) extract, aloe (aloevera) extract, Herba Bacopae monnieri (Bacopamoniera) extract, plant sterol, Scheroson, hydrocortisone, INDOMETHACIN and Betamethasone Valerate.
Soothing agent ratio in the compositions of the present invention calculates in the ratio that it accounts for composition total weight and usually accounts for scope 0.01% ~ 15% weight, preferably 0.1% ~ 10% weight.
Organic light protective agent is selected from anthranilic acid especially; Cinnamon derivative; DBM derives; Salicyclic acid derivatives; Camphor derivatives; Pyrrolotriazine derivatives, those as described in patent application US4367390, EP863145, EP517104, EP570838, EP796851, EP775698, EP878469, EP933376, EP507691, EP507692, EP790243 and EP944624; Benzophenone derivates; β, β-Diphenylacrylate derivative; Benzotriazole derivatives; α-tolylene malonate derivative; Benzimidizole derivatives; Tetrahydroglyoxaline; Dibenzoxazine (bis-benzazolyl) derivative, as described in patent EP669323 and US2463264, para-amino benzoic acid (PABA) derivative, methylene-bis (hydroxy-phenyl benzotriazole) derivative, as described in the applications such as US5237071, US5166355, GB2303549, DE19726184 and EP893119; Isolation polymer and isolation polysiloxane, such as, described in WO-93/04665 application; And derive from the dipolymer of alpha-alkyl phenylethylene, those such as described in patent application DE19855649; And Merocyanine derivatives, as WO2011/113719 and FR2957251 application described in those.
Inorganic light protective agent can be selected from specifically bag by or the metal oxide pigment of non-packet quilt or nanometer pigment (mean size of Dominant particle is generally between 5nm ~ 100nm, preferably between 10nm ~ 50nm), such as titanium oxide (rutile-type of amorphous or crystallization and/or Detitanium-ore-type), the known UV light protective agent such as ferric oxide, zinc oxide, zirconium white or cerium oxide nano pigment.Conventional bag is aluminum oxide and/or aluminum stearate by reagent.Concrete visible EP518772 and the EP518773 patent application of metal oxide nano pigment of these bag quilts or non-packet quilt describes.
Photo-protection reagent ratio in the compositions of the present invention calculates in the ratio that it accounts for composition total weight and usually accounts for scope 0.1% ~ 20% weight, preferably 0.2% ~ 15% weight.
The present composition can provide with all formulations that cosmetic field is conventional, especially the gelatinous aqueous solution or water/alcoholic solution alternatively, alternatively containing the lotion type dispersion liquid of two-phase, oil-in-water or water-in-oil or heterogeneous (such as W/O/W or O/W/O) emulsion, oil dispersion liquid in the aqueous phase of aqueous gel, use bead, these beads may be the nano particles of polymerization, such as nanosphere body and nanometer wafer or be still the vesicles of ionic and/or non-ionic type fat better, or be aqueous gel or contain oleogel.Prepared by these composition ordinary methods.According to the present invention, composition preferably uses emulsion especially oil-in-water emulsion.
The present composition can form the composition for nursing skin, especially clean, to protect, treat or nurse face, hand, foot, major anatomical gauffer or health frost (such as day cream, late frost, makeup removing frost, foundation cream or sunscreen); Foundation emulsion; Makeup removing breast, protectiveness or nursing body lotion or sunscreen, or the washing lotion of nursing skin, gel or mousse, such as clean washing lotion.
Hereafter with non-limiting example, more specific description is carried out to the present invention.
Embodiment 1: obtain intermediate
1.1. the lactone C of the C1 of acid form is obtained
In the round-bottomed flask that Dean and Stark (DeanandStark) device be housed have Aldrich sell the condition of Amberlyst15 resin under, Resorcinol 10g and methylene-succinic acid 11.8g is dissolved in 150ml toluene/diox mixture (volume ratio 1/1).Reaction medium was in 100 DEG C of heating 3 hours.After cooling, reacting coarse product filters, and filter vacuum concentrates.Crude product under heat condition from re-crystallizing in ethyl acetate.The 10g white powder (yield is 50%) of expection product must be corresponded to.
Fusing point: 174 ~ 175 DEG C. 1hNMR and mass spectrum consistent with the structure of expection product.
1.2. 4-(2,4-dihydroxy benzyl) dihydrofuran-2 (3H)-one shown in synthetic molecules formula (III)
Sodium borohydride 6.8g (2 equivalent) joins in the solution of 20g intermediate C1 in 100ml tetrahydrofuran (THF).Mixture was in stirring at room temperature 5 days.Add water, by ethyl acetate, organic phase is extracted 3 times.Spend the night in the moisture eliminator after vacuum concentration, crude product being placed in heating.Second day crude product 50ml dichloromethane trituration.Pink precipitate forms rear sintered glass filter and filters, and obtain compound shown in molecular formula (III), yield is 77%.
1hNMR and mass spectrum consistent with the structure of compound molecular formula (III) Suo Shi.
Compound shown in molecular formula (III) is subsequently by reacting with compound YH described in scheme 3 above; When YH be liquid as when YH is amine (3 equivalent) respectively as reactant and solvent, then reaction medium was in 60 DEG C of reactions 2 hours.
When YH is solid, enough methyltetrahydrofurans can be added and carry out solubilizing reaction medium.
At the end of reaction, reaction medium vacuum concentration.Crude product is dissolved in methyltetrahydrofuran, then washes with water with the hydrochloric acid soln washing of 0.1N.Collect organic phase, by dried over sodium sulfate, then vacuum-drying.On crude product, chromatography obtains expecting product.
Embodiment hereafter illustrates the stage below.
Embodiment 2: synthetic compound 2
The leucinethylester (before neutralization hydrochloride form 49g) of compound and 3.5 equivalents shown in 15g molecular formula (III) is added in round-bottomed flask.Reaction medium was in 145 DEG C of heating 5 hours.The rear diluted ethyl acetate of reaction medium cooling, gets organic phase priority 1N hydrochloric acid soln and saturated nacl aqueous solution washing.The dry final vacuum of organic phase with sodium sulfate concentrates, and obtains orange wax (18g).Used silicon post (eluant is methylene dichloride: methyl alcohol 9:1) purifying.Collect target components to be concentrated, obtain 12.8g faint yellow solid, 1hNMR measure and show that itself and compound 2 two kinds of diastereomer ratios are the mixture consistent (48%) of 53/47.
1hNMR and mass spectrum consistent with the structure of expection non-enantiomer mixture.
Embodiment 3: synthetic compound 6:
Compound and 9.6g tyrosine ethyl ester shown in 1.6g molecular formula (IV) is added in round-bottomed flask.Reaction medium was in 130 DEG C of heating 4 hours.Filter with after 100ml methanol dilution after reaction medium cooling.Filter vacuum concentrates, and on products therefrom, silicon post (eluant is methylene chloride/methanol 30/1) purifying, obtains 1.5g white solid, with 1hNMR measure and show that itself and compound 6 (yield 47%) two kinds of diastereomer ratios are the mixture consistent (48%) of 55/45.
1hNMR and mass spectrum consistent with the structure of expection non-enantiomer mixture.
Embodiment 4: synthetic compound 5 (compound 6 saponification)
Having under 480mg lithium hydroxide existent condition, getting 1g compound 6 and be placed in 5ml ethanol.Stir after 14 hours, solvent in vacuo concentrates, and reaction medium uses 1N hcl acidifying to pH2 under ethyl acetate existent condition.By ethyl acetate extracted twice aqueous phase, dried over mgso, the organic phase vacuum concentration of merging.Silicon column purification (eluant is methylene chloride/methanol 20/1) on gained crude product, obtains the yellow solid (yield 27%) that 260mg corresponds to compound 5.
1hNMR and mass spectrum consistent with the structure of expection product.
Embodiment 5 ~ 33: compou nd synthesis
Operate equally as described in foregoing embodiments with different amine listed in Table:
Embodiment 34: the embodiment of diastereomeric separation and qualification
Use the performance of preparation HPLC chromatographic column separating compound 2
Equipment: SFC-80 (Thar, Waters)
Post: (R, R) WHELK-O150*250mm5 μm (Regis)
Column temperature: 40 DEG C
Moving phase: CO 2/ Virahol=70/30
Flow velocity: 150g/ minute
Counterpressure: 100 bar
Injection cycle: 4.4 minutes
Per injection amount: 116mg
First diastereomer retention time (2-a): 3.87min
Second diastereomer retention time (2-b): 4.55min
1with two kinds, HNMR and mass spectrum expect that the structure of product is consistent.
Embodiment 35: the proof of the activity that constitutive character melanochrome generates
Biological test confirms that the decolouring of compound shown in molecular formula (I) is active.
According to patent FR-A-2734825 and R.Schmidt, P.Krien and M.R é gnier, Anal.Biochem., 235 (2), 113-18, the method described in 1996 articles measures the regulating and controlling effect that compound 2 pairs of melanochrome generate.This test keratinocyte and melanophore co-cultivation are implemented.
Following mensuration is carried out to test-compound:
Leucicly mix or use ALMA indigo plant (AlamarBlue) to evaluate cytotoxicity by estimating;
Mix the ratio that leucine is mixed evaluate its inhibitory activity to B16 cell by estimating deracil relative to 100% (contrasting the test corresponding to not having test-compound to carry out) of contrast.Measure IC 50value (making B16 cell 50% be suppressed required concentration).
Also test with the arbutin and kojic acid that are known as decolouring compound simultaneously.
Comparative result sees the following form:
Compound To the cytotoxicity of co-cultivation thing IC 50
Arbutin No cytotoxicity Do not reach (or > 500 μM)
Kojic acid 100μM Do not reach (or > 500 μM)
2 No cytotoxicity 1.1μM
Therefore the compounds of this invention show effective check melanin generate, and than arbutin and kojic acid more effective.
Embodiment 36: the use of cosmetic
Prepare skin destaining gel, containing (by weight %):
Compound 2 (embodiment 1) 2%
Carbomer (Carbopol981 of Lubrizol) 1%
Preservative qs
Water in right amount to 100%
Brown macules may be made after said composition is applied to skin to soften.
Another compound 1 prepares similar composition.

Claims (15)

1. compound shown in molecular formula (I):
Wherein:
R is hydrogen atom or ethanoyl,
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cyclic group, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three alternatively replaces:
i)-OR5，
ii)-SR5，
iii)-NR6R7，
iv)-C(O)NHR6，
v)-C(O)NR6R7，
vi)-C(O)OR6，
vii)-NHC(O)NHR6，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace;
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
R5 is selected from:
H, and
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl,
R6 and R7 can be the same or different, and it is selected from:
·H，
Ethanoyl, and
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, and phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl,
R6 and R7 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is optional by (C 1-C 10) alkyl replacement;
A is selected from following free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three alternatively replaces:
i)-OR15，
ii)-SR15，
iii)-NR16R17，
iv)-C(O)NHR16，
v)-C(O)NR16R17，
vi)-C(O)OR16，
vii)-NHC(O)NHR16，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace,
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace, and
Xi)-NH-C=NH (NH 2) (guanidine radicals);
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
d)-NR12R13；
e)-OR14；
f)-C(O)NHR14；
G)-C (O) (C 1-C 10) alkyl;
R12 and R13 can be the same or different, and is selected from following free radical:
·-H，
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, described group also may be replaced by one to three identical or different-OR15 group alternatively, and
Aromatic base or heteroaryl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace,
R12 and R13 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is alternatively by (C 1-C 10) alkyl replacement, should (C 1-C 10) alkyl is selected from hydroxyl and (C by one to three alternatively 1-C 4) alkoxyl group group replace;
R14 is selected from following free radical:
·-H，
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may be replaced by the identical or different group that to three is selected from following groups alternatively:
Vi)-C (O) OR16, and
Ix) aromatic base or heteroaryl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace, and
Aromatic base or heteroaryl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace;
R15 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl;
R16 with R17 can be identical, also can be different, and it is selected from H; Ethanoyl; Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl; And phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is alternatively by (C 1-C 10) alkyl replacement;
R " be selected from free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three alternatively replaces:
i)-OR25，
ii)-SR25，
iii)-NR26R27，
iv)-C(O)NHR26，
v)-C(O)NR26R27，
vi)-C(O)OR26，
vii)-NHC(O)NHR26，
Viii)-C (O) (C 1-C 4) alkyl,
Ix) aromatic base or heteroaryl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace; And
C) aromatic base or heteroaryl, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
R25 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl;
R26 and R27 can be the same or different, and it is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl; Phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R26 and R27 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle may alternatively by (C 1-C 10) alkyl replacement;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 10) alkyl, hydroxyl (C 1-C 10) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) group of alkyl;
And their salt, their solvate and their optical isomer, their racemize salt, individually or as mixture.
2. the compound according to aforementioned claim, wherein:
R is hydrogen atom or ethanoyl;
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from free radical:
a)-H；
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, described group also may be replaced by one to three identical or different-OR5 group alternatively, and
C) aromatic base or heteroaryl, it can be selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
R5 is selected from H and saturated straight chain (C 1-C 4) alkyl;
A is selected from free radical:
a)-H；
B) saturated straight chain (C 1-C 20) alkyl, unsaturated (C 2-C 20) alkyl, side chain (C 3-C 20) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively by one to three be selected from N, O ,-C (O)-, the heteroatoms of-NHC (O)-and-NHC (O) NH-or group interrupt, the identical or different group that described group also may be selected from following groups by three replaces:
i)-OR15，
ii)-SR15，
iii)-NR16R17，
iv)-C(O)NHR16，
vi)-C(O)OR16，
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace, and
X) saturated or unsaturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace;
C) aromatic base or heteroaryl, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 8) alkyl group replace;
D)-NR12R13, and
e)-OR14；
R12 and R13 can be the same or different, and is selected from free radical:
·-H，
Saturated straight chain (C 1-C 4) alkyl, and
Phenyl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace;
R12 and R13 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them simultaneously, and described heterocycle is alternatively by (C 1-C 10) alkyl replacement; Should (C 1-C 10) alkyl is selected from hydroxyl and (C by one to three alternatively 1-C 4) alkoxyl group group replace;
R14 is selected from free radical:
-H, and
Saturated straight chain (C 1-C 10) alkyl, it is selected from straight chain (C by one to three alternatively 1-C 10) the identical or different group of alkyl replaces, replaced by one or more phenyl alternatively, described phenyl is selected from hydroxyl and (C by one to three alternatively 1-C 8) the identical or different group of alkoxyl group replaces;
R15 is selected from H, saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl and (C3-C 8) cycloalkyl;
R16 and R17 can be the same or different, and is selected from:
·H，
Ethanoyl, and
Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl; And phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle is optional by (C 1-C 10) alkyl replacement;
R " be selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 20) alkyl, described group may be optional
Ground is replaced by one to three identical or different-OR25 group;
R25 is selected from H and saturated straight chain (C 1-C 10) alkyl;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 4) alkyl, hydroxyl (C 1-C 4) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 6) alkyl and side chain (C 3-C 6) group of alkyl;
And their salt, their solvate and their optical isomer, their racemize salt, individually
Or as mixture.
3. the compound according to aforementioned any one claim, wherein:
R is hydrogen atom;
Y is for being selected from OR ' or NAR " free radical;
R ' is selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively interrupt by one to three Sauerstoffatom, described group also may be replaced by one to three identical or different group being selected from hydroxyl, methoxyl group and oxyethyl group alternatively;
A is selected from:
a)-H；
B) saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl, described group may alternatively interrupt by one to three Sauerstoffatom, the identical or different group that described group also may be selected from following groups by three replaces:
i)-OR15，
Ii)-SR15, preferred SMe,
iii)-NR16R17，
vi)-C(O)OR16，
Ix) aromatic base or heteroaryl, it can be selected from hydroxyl and (C by one to three alternatively 1-C 8) group of alkoxyl group replaces, and preferably, is selected from hydroxyl and (C alternatively by one to three 1-C 8) alkoxyl group replace imidazolyl, indyl or phenyl, particularly preferably imidazolyl, indyl or phenyl, and
X) saturated or unsaturated, preferably saturated non-aromatic (C 3-C 8) cycloalkyl or heterocyclic radical, it is selected from hydroxyl, (C by one to three alternatively 1-C 8) alkoxyl group and (C 1-C 4) alkyl group replace;
C) phenyl, its group being selected from hydroxyl, methoxyl group and oxyethyl group by one to three alternatively replaces;
D)-NR12R13, and
e)-OR14；
R12 and R13 can be the same or different, and is selected from:
·-H，
Saturated straight chain (C 1-C 4) alkyl, and
Phenyl, it is selected from hydroxyl and (C by one to three alternatively 1-C 8) alkoxyl group group replace; R12 and R13 is preferably hydrogen atom or (C 1-C 4) alkyl;
R14 is selected from free radical:
-H, and
Saturated straight chain (C 1-C 4) alkyl, it is alternatively by phenyl, as benzyl replaces;
R15 is selected from H, saturated straight chain (C 1-C 4) alkyl and side chain (C 3-C 4) alkyl;
R16 and R17 can be the same or different, and is selected from H; Ethanoyl; Saturated straight chain (C 1-C 10) alkyl, unsaturated (C 2-C 10) alkyl, side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl; And phenyl (C 1-C 4) alkyl, as benzyl or pyridyl (C 1-C 4) alkyl;
R16 and R17 can form saturated or unsaturated non-aromatic heterocyclic with the nitrogen carrying them, described heterocycle comprise one to three be selected from N, O and-C (O)-heteroatoms or group, this heterocycle is alternatively by (C 1-C 10) alkyl replacement;
R " be selected from free radical:
A)-H; With
B) saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 10) alkyl or (C 3-C 8) cycloalkyl,
Described group may be replaced by one to three identical or different-OR25 group alternatively;
R25 is selected from H and saturated straight chain (C 1-C 10) alkyl;
Be appreciated that A and R " saturated or unsaturated non-aromatic heterocyclic can be formed with the nitrogen carrying them, described heterocycle may alternatively by being selected from (C 1-C 4) alkyl, hydroxyl (C 1-C 4) group of alkyl and C (O) OT replaces, wherein T is for being selected from H, saturated straight chain (C 1-C 6) alkyl and side chain (C 3-C 6) group of alkyl, the preferred piperidyl of described heterocycle or morpholinyl;
And their salt, their solvate and their optical isomer, their racemize salt, individually or as mixture.
4. the compound according to aforementioned any one claim, wherein R=H.
5. the compound according to aforementioned any one claim, wherein said compound has following meanings:
A) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is alternatively by i) hydroxyl replacement;
B) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, by Sauerstoffatom interruption with alternatively by i) hydroxyl replacement;
C) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is by vi) replacement of one or two identical COOR16 group, and replaced by the group being selected from following groups alternatively;
ii)-SR15,
Ix) phenyl, it is replaced by hydroxyl alternatively, and
Ix) heteroaryl, its ring member nitrogen atoms number is 5 ~ 12, is selected from the heteroatoms of O, N or S containing one or two,
R16 is selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) alkyl,
R15 is saturated straight chain (C 1-C 10) alkyl;
D) R=H, Y=-NAR ", R "=H, A=saturated straight chain (C 1-C 10) alkyl, it is replaced by the group being selected from following groups alternatively;
iii)-NR16R17,
Ix) phenyl, it is alternatively by hydroxyl and/or (C 1-C 8) alkoxyl group replacement, and
Ix) heteroaryl, its ring member nitrogen atoms number is 5 ~ 12, containing Sauerstoffatom,
X) saturated heterocyclic, ring member nitrogen atoms number is 5 ~ 8, containing one or two Sauerstoffatom, alternatively by one or two (C 1-C 4) alkyl replacement,
Xii) (C 3-C 8) cycloalkyl,
R16 and R17 can be the same or different, and is selected from H, saturated straight chain (C 1-C 10) alkyl and ethanoyl;
E) R=H, Y=-NAR ", R " saturated (C of=H, A= 3-C 10) alkyl, it is replaced by the group being selected from following groups alternatively;
I) hydroxyl,
Vi) COOR16 group, R16 is selected from H, saturated straight chain (C 1-C 10) alkyl and side chain (C 3-C 10) alkyl;
F) R=H, Y=-NAR ", R "=H, and
A=ring (C 3-C 8) alkyl, or
A=phenyl, it is optionally substituted by a hydroxyl group alternatively;
G) R=H, Y=-NAR ", and
A and R " form with the nitrogen-atoms carrying them saturated heterocyclic that annular atoms number is 5 ~ 8, comprise Sauerstoffatom alternatively, and replaced by C (O) OT group alternatively, T is saturated straight chain (C 1-C 10) alkyl;
H) R=H, Y=-NAR ", and
A is saturated straight chain (C 1-C 10) alkyl, its alternatively interrupt by one or two Sauerstoffatom, with alternatively by being selected from one of following groups or two groups replace:
Ii)-hydroxyl,
vi)－COOR16，
R16 is saturated straight chain (C 1-C 10) alkyl; With
R " be saturated straight chain (C 1-C 10) alkyl, its alternatively interrupt by one or two Sauerstoffatom, with alternatively by being selected from one of following groups or two groups replace:
I) hydroxyl,
vi)-COOR26，
R26 is saturated straight chain (C 1-C 10) alkyl;
J) R=ethanoyl, Y=-NAR ", R " and=H, A=saturated straight chain (C 1-C 10) alkyl;
K) R=H, Y=-NAR ", R "=H, and
A=-NR12R13 or
A＝-OR14,
R12 and R13, they are identical, and it is selected from free radical:
A)-H, and
B) saturated straight chain (C 1-C 10) alkyl;
R14 is selected from free radical:
a)-H，
B) saturated straight chain (C replaced by phenyl 1-C 10) alkyl;
l)R＝H，Y＝-OR’，
R '=saturated straight chain (C 1-C 10) alkyl or side chain (C 3-C 10) alkyl, its alternatively interrupt by Sauerstoffatom, and alternatively by one or two i) hydroxyl replace.
6. the compound according to claim arbitrary in claims 1 to 3, it is selected from following compounds:
N-butyl-3-(2,4-bis-acrinyl)-4-maloyl group amine,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] leucine salt,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] α-amino-isovaleric acid salt,
N-[3-(2,4-bis-acrinyl)-4-maloyl group] α-amino-isovaleric acid,
N-[3-(2,4-bis-acrinyl)-4-maloyl group] tyrosine,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] tyrosine salt,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] glycinate,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(1-hydroxyl-3-first butyl-2-base-) butyramide,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(1-hydroxyl-4-first amyl group-2-base-) butyramide,
3-(2,4-bis-acrinyl)-4-hydroxy-n-the third butyramide,
N-cyclopentyl-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(2-hydroxyethyl) butyramide,
3-(2,4-bis-acrinyl)-N-ethyl-4-maloyl group amine,
N-[3-(2,4-bis-acrinyl)-4-maloyl group] leucine,
N-[3-(2,4-bis-acrinyl)-4-maloyl group] glycine,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] phenylalanine salt,
3-(2,4-bis-acrinyl)-4-hydroxy-n-Xin butyramide,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(6-first heptyl) butyramide,
3-(2,4-bis-acrinyl)-4-hydroxy-n-penta butyramide,
3-(2,4-bis-acrinyl)-4-hydroxy-n-ninth of the ten Heavenly Stems butyramide,
N-(cyclohexyl methyl)-3-(2,4-bis-acrinyl)-4-maloyl group amine,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group]-D-trp salt,
3-(2,4-bis-acrinyl)-N-(2-ethylhexyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-N-hexyl-4-maloyl group amine,
N-(hexamethylene ethyl)-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-N-heptyl-4-maloyl group amine,
3-(2,4-bis-acrinyl)-N-(2,3-dihydroxypropyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-N-[(2,2-dimethyl-DOX-4-base) methyl]-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxyl-1-(morpholine-4-base) butane-1-ketone,
3-(2,4-bis-acrinyl)-4-hydroxy-n, two (2-hydroxyethyl) butyramide of N-,
3-(2,4-bis-acrinyl)-N, N-diethyl-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxyl-1-(piperidin-1-yl) butane-1-ketone,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group]-sarcosine salt,
N-benzyl-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxy-n-[2-(4-hydroxyl-3-methoxyphenyl) ethyl] butyramide,
N-phenyl-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(4-hydroxyphenyl) butyramide,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] glutaminate,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] proline salt,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] Histidine salt,
Ethyl n-[3-(2,4-bis-acrinyl)-4-maloyl group] methionine(Met) salt,
Propane-2-base N-[3-(2,4-bis-acrinyl)-4-maloyl group] glycinate,
4-{2-[(acetyl oxygen) methyl]-4-(fourth is amino)-4-oxygen-butyl } benzene-1,3-bis-base diacetate,
3-(2,4-bis-acrinyl)-4-hydroxy-n-(3-methoxycarbonyl propyl) butyramide,
3-(2,4-bis-acrinyl)-N-(2-ethoxyethyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxy-n-[2-(2-hydroxyl-oxethyl) ethyl] butyramide,
Ethyl 4-{ [3-(2,4-bis-acrinyl)-4-maloyl group] is amino } butyrates,
3-(2,4-bis-acrinyl)-N-[2-(dimethylamino) ethyl]-4-maloyl group amine,
N-[2-(acetylamino) ethyl]-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-hydroxy-n, two (2-methoxy ethyl) butyramide of N-,
3-(2,4-bis-acrinyl)-N-(furans-2-ylmethyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-N, 4-dihydroxyl butyramide,
N-(benzyloxy)-3-(2,4-bis-acrinyl)-4-maloyl group amine,
3-(2,4-bis-acrinyl)-4-maloyl group hydrazine,
3-(2,4-bis-acrinyl)-4-hydroxy-n ', N '-dimethyl daminozide,
Ethyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
Sec.-propyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
Butyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
Hexyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
2,3-dihydroxypropyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
2-methoxy-propyl 3-(2,4-bis-acrinyl)-4 hydroxybutyric acid salt,
And their salt, their solvate and their optical isomer, their racemize salt, individually or as mixture.
7. be stored in physiology can in accepting medium, comprise the composition of compound shown in molecular formula (I) described in aforementioned any one claim.
8. the composition according to aforementioned claim, it is characterized in that: shown in molecular formula (I), compound accounts for the content of composition total weight is by weight between 0.01% ~ 10%, preferably between 0.1% ~ 5%, especially between 0.5% ~ 3%.
9. the composition according to claim 7 and 8, it is characterized in that: it comprises at least one adjuvant, this adjuvant is selected from water, organic solvent, hydrocarbon ils, silicone oil, wax, pigment, weighting agent, tinting material, tensio-active agent, emulsifying agent, active cosmetic ingredients, UV separant, polymkeric substance, thickening material, sanitas, perfume compound, sterilant, ceramide, odour absorbents and antioxidant.
10. the composition according to claim arbitrary in claim 7 to 9, is characterized in that: it comprises at least one promoting agent, and this promoting agent is selected from: decorticating agent; Soothing agent; Organic or inorganic light protective agent; Wetting Agent for Printing Inks; Discoloring agent; Anti-saccharifying agent; NO synthase inhibitor; Stimulate the reagent that corium or epidermal macromolecules synthesize and/or suppress it to decompose; Stimulate the reagent of inoblast and/or keratinocyte proliferation or stimulation Keratinocyte differentiation; Muscle relaxant and/or cutis laxa agent; Tensioning agent; The reagent of antipollution and/or free radical; Act on microcirculatory reagent; Act on the reagent of cellular energy metabolism, and their mixture.
11. make keratose, especially skin depigmentation, the non-therapeutic cosmetic method that brightens and/or bleach, and it comprises the composition used in claim 7 to 10 described in arbitrary claim.
12. methods according to aforementioned claim, for making skin depigmentation, brightening and/or bleach.
13. as claim arbitrary in claim 1 to 6 compound shown in the molecular formula (I) that limits as keratose, the especially non-therapeutic cosmetic use of the reagent that bleaches, brightens and/or decolour of skin.
14., according to the preparation method of compound shown in the molecular formula (I) of a claim in claim 1 to 6, comprise following phases:
A) one of ester shown in Resorcinol (A1) and methylene-succinic acid (B) or its acid anhydride (B ') or its molecular formula (B1) reacts,
Wherein R1 is H or straight chain (C 1-C 6) alkyl or side chain (C 3-C 6) alkyl, thus generate Compound C shown in following molecular formula,
B) make this Compound C reduce, thus generate intermediate (III),
C) intermediate (III) and derivative YH react, wherein Y as claim arbitrary in claim 1 to 5 define, thus compound (I) can be obtained.
15. molecular formula (III) and (IV) shown intermediate compound:
Wherein R is H or straight chain (C 1-C 6) alkyl or side chain (C 3-C 6) alkyl.
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