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US20120070395A1 - Novel amide derivative and whitening agent - Google Patents

Novel amide derivative and whitening agent Download PDF

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Publication number
US20120070395A1
US20120070395A1 US13/240,358 US201113240358A US2012070395A1 US 20120070395 A1 US20120070395 A1 US 20120070395A1 US 201113240358 A US201113240358 A US 201113240358A US 2012070395 A1 US2012070395 A1 US 2012070395A1
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group
compound
hydrogen atom
skin
carbon number
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Inventor
Yusuke Amino
Yoshinobu Takino
Satoru Ohashi
Fumie OKURA
Megumi Kaneko
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Assigned to AJINOMOTO CO., INC. reassignment AJINOMOTO CO., INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMINO, YUSUKE, KANEKO, MEGUMI, OHASHI, SATORU, OKURA, FUMIE, TAKINO, YOSHINOBU
Publication of US20120070395A1 publication Critical patent/US20120070395A1/en
Priority to US14/287,899 priority Critical patent/US9295624B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compound having a melanin production suppressive activity.
  • the present invention also relates to the use of such a compound in the field of cosmetics.
  • Hydroquinone glycoside (arbutin) is known to have various effects such as a whitening effect, tyrosinase inhibitory activity, suppression of active oxygen, and the like (see Funayama, M., Arakawa, H., Yamamoto, R., Nishino, T., Shin, T. and Murao, S., “Effect of ⁇ - and ⁇ -arubutin on activity of tyrosinases from mushroom, and mouse melanoma,” Biosci. Biotech. Biochem ., vol. p. 59, 143-144 (1995)), and is used as an ingredient for whitening cosmetics.
  • kojic acid or a derivative thereof and 4-n-butylresorcinol are also known as whitening components (see Kouji Miyazaki, Yumiko Nishida, Minoru Itioka, “Inhibitory Effects of Melanogenic Inhibitors on Dendricity of Cultured B16 Mouse Melanoma Cells,” Journal of Japanese Cosmetic Science Society , vol. 22, No. 3, pp. 182-186 (1998); Kiyoharu Sugiyama, “Evaluation of novel whitening agent—Rucinol (Shinki bihakuzai no hyouka—Rucinol ni tsuite),” The Journal of Japan Hair Science Association , vol. 30, No. 3, pp.
  • the present invention provides the following:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group;
  • X is a covalent bond, a methylene group, an ethylene group or a vinylene group;
  • Y is a covalent bond or a divalent group represented by the formula:
  • Z is a hydrogen atom, a hydroxycarbonyl group or an alkoxycarbonyl group having a carbon number of 1 to 3, and when Z is other than a hydrogen atom and a carbon atom bonded to Z contains an asymmetric center, the stereochemistry thereof may be any of (S), (R) and (SR); Ar is a substituent represented by the following formula (II):
  • R 6 and R 7 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, and * is a moiety bonded to Y, or the following formula (III):
  • R 8 and R 9 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 8 and R 9 in combination optionally form a methylenedioxy group, and * is a moiety bonded to Y; provided that the following compounds are excluded:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group;
  • X is a methylene group, an ethylene group or a vinylene group;
  • Z is a hydrogen atom, a hydroxycarbonyl group or an alkoxycarbonyl group having a carbon number of 1 to 3; and when Z is other than a hydrogen atom, the stereochemistry of a carbon atom bonded to Z may be any of (S), (R) and (SR); provided that the following compounds are excluded:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group;
  • Z is a hydrogen atom, a hydroxycarbonyl group or an alkoxycarbonyl group having a carbon number of 1 to 3, and when Z is other than a hydrogen atom, the stereochemistry of a carbon atom bonded to Z may be any of (S), (R) and (SR), provided that the following compound is excluded: a compound wherein, when Z is a hydrogen atom, R 1 , R 2 , R 5 and R 7 are hydrogen atoms, and R 6 is a hydroxyl group, then R 3 and R 4 are hydroxyl groups, or R 3 is a hydroxyl group and R 4 is a me
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group;
  • X is a covalent bond, a methylene group, an ethylene group or a vinylene group;
  • Y is a covalent bond or a divalent group represented by the formula:
  • Z is a hydrogen atom, a hydroxycarbonyl group or an alkoxycarbonyl group having a carbon number of 1 to 3, and when Z is other than a hydrogen atom and a carbon atom bonded to Z contains an asymmetric center, the stereochemistry thereof may be any of (S), (R) and (SR); R 8 and R 9 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 8 and R 9 in combination optionally form a methylenedioxy group, provided that the following compound is excluded: a compound wherein Y is an ethylene group, and one or both of R 8 and R 9 is/are a hydrogen atom(s); or a salt thereof.
  • a whitening agent comprising a compound represented by the following formula (I′):
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group;
  • X is a covalent bond, a methylene group, an ethylene group or a vinylene group;
  • Y is a covalent bond or a divalent group represented by the formula:
  • Z is a hydrogen atom, a hydroxycarbonyl group or an alkoxycarbonyl group having a carbon number of 1 to 3, and when Z is other than a hydrogen atom and a carbon atom bonded to Z contains an asymmetric center, the stereochemistry thereof may be any of (S), (R) and (SR); Ar is a substituent represented by the following formula (II):
  • R 6 and R 7 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, and * is a moiety bonded to Y, or the following formula (III):
  • R 8 and R 9 are each independently a hydrogen atom, an alkyl group having a carbon number of 1 to 3, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 8 and R 9 in combination optionally form a methylenedioxy group, and * is a moiety bonded to Y; provided that the following compounds are excluded:
  • a whitening agent comprising the compound of any of the aforementioned (1) to (4) or a salt thereof.
  • the compounds of the present invention are expected to exhibit a whitening action through a melanin production suppressive activity, and can be utilized as a whitening agent by itself or in combination with other whitening components.
  • FIG. 1 is a graph showing the results of Experimental example 1.
  • the unit of the values on the horizontal axis is ⁇ M.
  • FIG. 2 is a graph showing the results of Experimental example 1.
  • the unit of the values on the horizontal axis is ⁇ M.
  • FIG. 3 is a graph showing the results of Experimental example 1.
  • the unit of the values on the horizontal axis is ⁇ M.
  • FIG. 4 is a graph showing the results of Experimental example 1.
  • the unit of the values on the horizontal axis is ⁇ M.
  • FIG. 5 is a graph showing the results of Experimental example 1.
  • the unit of the values on the horizontal axis is ⁇ M.
  • Examples of the alkyl group having a carbon number of 1 to 3 for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 include a methyl group, an ethyl group, a propyl group and an isopropyl group. Of these, a methyl group is preferable.
  • Examples of the alkoxy group having a carbon number of 1 to 3 for R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 7 , R 8 or R 9 include a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group. Of these, a methoxy group or an ethoxy group is preferable, and a methoxy group is more preferable.
  • the alkoxycarbonyl group having a carbon number of 1 to 3 means those compounds in which the alkoxy moiety has a carbon number of 1 to 3.
  • Examples of the alkoxycarbonyl group having a carbon number of 1 to 3 for Z include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonyl group. Of these, a methoxycarbonyl group is preferable.
  • stereochemistry may be any of (S), (R) and (SR)” means it may be any of (S) form, (R) form, and a racemate which is a mixture of equivalent amounts of (S) form and (R) form.
  • X is preferably a covalent bond, an ethylene group or a vinylene group.
  • Y is preferably a divalent group represented by the formula
  • Z is as described above, and still more preferably an ethylene group.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R 1 and R 2 , or R 2 and R 3 in combination optionally form a methylenedioxy group.
  • At least one (preferably 1 to 3, more preferably 1 or 2) of R 1 , R 2 , R 3 , R 4 and R 5 is preferably a hydroxyl group, and R 3 is more preferably a hydroxyl group.
  • R 1 and R 5 are preferably hydroxyl groups.
  • R 6 and R 7 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3. More preferably, R 6 is a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, and R 7 is a hydrogen atom. Still more preferably, R 6 is a hydroxyl group and R 7 is a hydrogen atom.
  • R 8 and R 9 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3. More preferably, R 8 and R 9 are each independently a hydroxyl group or an alkoxy group having a carbon number of 1 to 3.
  • Preferable examples of the compound represented by the formula (I′) include the compounds of Examples 1 to 36 to be mentioned below.
  • preferable examples of the compound represented by the formula (I) include the compounds of Examples 1, 4, 5, 6 to 10, 14 to 23, and 25 to 36 to be mentioned below.
  • Examples of the salt of the compound represented by the formula (I), (I′), (IV), (V) or (VI) include salts with inorganic acids (e.g., hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like); salts with organic acids (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like); salts with acidic or basic amino acids (e.g., aspartic acid, glutamic acid, arginine, lysine, ornithine, and the like); salts with inorganic bases [for example, salts with metal (alkaline metal such as potassium, sodium, and the like; alkaline earth metal such as calcium, magnesium, and the like; aluminum), ammonium salt and the like]; and salts with organic bases (
  • the compound of the present invention represented by the following formula (I) is obtained by reacting an amine component with a carboxylic acid component or an acid chloride thereof.
  • a production method of a compound represented by the formula (I) (hereinafter to be also referred to as compound (I)) is explained.
  • R 1 -R 5 , Ar, X and Y are as described above.
  • a compound represented by the formula (I) can be produced by (i) subjecting amine component (VII) and carboxylic acid component (VIII) to a condensation reaction using a dehydrating-condensing agent, or (ii) once converting carboxylic acid component (VIII) to acid chloride (IX), and subjecting the compound and amine component (VII) to a condensation reaction in the presence of a base.
  • compound (I) can be obtained by protecting a hydroxyl group and the like with a protecting group, and removing the protecting group after the condensation reaction, where necessary.
  • Amine component (VII) may be a salt such as hydrochloride, p-toluenesulfonate and the like, and carboxylic acid component (VIII) may be a salt such as dicyclohexylamine salt and the like.
  • amine component (VII) is a salt
  • the reaction can be carried out by adding a base such as triethylamine and the like during the condensation reaction. While the ratio of amine component (VII) and carboxylic acid component (VIII) to be used is not limited, 0.8 to 1.2 equivalents of carboxylic acid component (VIII) may be used relative to 1 equivalent of amine component (VII) to achieve a reaction in a good yield.
  • the solvent to be used is not particularly limited as long as it does not react with amine component (VII) and carboxylic acid component (VIII) and, for example, dichloromethane (DCM), N,N-dimethylformamide (DMF), chloroform, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and a mixed solvent thereof can be used. Of these, dichloromethane and N,N-dimethylformamide are preferable.
  • the amount of the solvent is 10- to 500-fold weight, preferably 15- to 100-fold weight, relative to amine component (VII).
  • a dehydrating-condensing agent a general condensing agent used for peptide synthesis and the like may be used and, for example, N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and the like can be used.
  • DCC N,N′-dicyclohexylcarbodiimide
  • EDCI.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • a condensation accelerator such as 1-hydroxybenzo
  • the amount of the dehydrating-condensing agent to be used is 1.0 to 2.0 equivalents, preferably 1.05 to 1.20 equivalents, relative to amine component (VII).
  • the amount of the condensation accelerator to be used is 0.5 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to amine component (VII).
  • the reaction time is preferably about 3 to 24 hr, depending on the reaction temperature, which is preferably 5 to 35° C.
  • the obtained compound (I) can be isolated and purified according to a conventional method.
  • ethyl acetate, ethanol, methanol, diethyl ether, chloroform, dichloromethane, n-hexane and a mixed solvent thereof can be used as a solvent.
  • a purification method by chromatography preparative thin-layer chromatography (PTLC) or silica gel column chromatography can be used.
  • PTLC thin-layer chromatography
  • silica gel column chromatography silica gel column chromatography
  • Acid chloride (IX) to be used in the production method of (ii) can be obtained by reacting carboxylic acid component (VIII) with oxalyl chloride or thionyl chloride according to a conventional method. Acid chloride (IX) can be reacted with amine component (VII) in the presence of a base such as triethylamine, sodium hydroxide, and the like. While the ratio of amine component (VII) and acid chloride (IX) is not limited, 0.8 to 1.2 equivalents of acid chloride (IX) may be used relative to 1 equivalent of amine component (VII) to achieve a reaction in a good yield.
  • the amount of the base to be used is 0.8 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to amine component (VII).
  • the solvent to be used those recited as the solvents to be used in the aforementioned production method of (i) can be used.
  • the reaction time and the reaction temperature are the same as those in the production method of (i).
  • the thus-obtained compound of the present invention or a salt thereof can be provided as a whitening agent.
  • the whitening agent of the present invention contains the compound of the present invention or a salt thereof, and can be added to whitening cosmetics singly or in combination with other whitening components.
  • Other whitening components permitting combination with the whitening agent of the present invention are not particularly limited, and those having at least any of the tyrosinase activity inhibitory action, anti-inflammatory action, antioxidant action (including superoxide dismutase-like action), and excitometabolic action, which are said to be related to a whitening action, can be mentioned.
  • the whitening agent of the present invention When the whitening agent of the present invention is added to whitening cosmetics, it can be used in combination with components generally used as starting materials for cosmetics, for example, flavor, preservative, chelate compound, polyol, plant extract (herbal medicine extract) and the like.
  • components generally used as starting materials for cosmetics for example, flavor, preservative, chelate compound, polyol, plant extract (herbal medicine extract) and the like.
  • Serotonin hydrochloride 300 mg, 1.41 mmol
  • trans-cinnamic acid 208 mg, 1.41 mmol
  • a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml)
  • the solution was maintained at 0° C.
  • the ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate.
  • Serotonin hydrochloride 300 mg, 1.41 mmol
  • trans-2,4-dihydroxycinnamic acid 253 mg, 1.41 mmol
  • the ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate.
  • Serotonin hydrochloride (300 mg, 1.41 mmol) and 3-methyl-4-hydroxycinnamic acid (251 mg, 1.41 mmol) obtained above were dissolved in a mixed solvent of dichloromethane (10 ml) and N,N-dimethylformamide (5 ml), and the solution was maintained at 0° C.
  • the ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol-chloroform to give N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-(3-methyl-4-hydroxyphenyl)-2-propenamide (307 mg, yield 65.0%) as crystals.
  • 5-hydroxy-L-tryptophan methyl ester hydrochloride 350 mg, 1.29 mmol
  • ferulic acid 251 mg, 1.29 mmol
  • the ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate.
  • Serotonin hydrochloride (430 mg, 2 mmol) and 2,6-dihydroxybenzoic acid (312 mg, 2 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the solution temperature was maintained at 0° C.
  • To this solution were added triethylamine (310 ⁇ l, 2.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt H 2 O, 346 mg, 2.1 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI HCl, 429 mg, 2.1 mmol), the solution temperature was gradually warmed from 0° C. to room temperature, and the mixture was stirred at room temperature for 16 hours.
  • B16 melanom (purchased from Dainippon Sumitomo Pharma Co., Ltd.) was cultured in DMEM (Dulbecco's Modified Eagle Medium, high glucose, containing 10% serum). After confluent, the cells were trypsinized and seeded in a 96-well plate. On the following day, after adhesion of the cells to the plate, the medium was replaced with DMEM containing each evaluation sample (control (no sample addition), sample of each Production Example) at a given evaluation concentration (diluted from 100 ⁇ m according to sample), and the cells were incubated for 3 days.
  • DMEM Dulbecco's Modified Eagle Medium, high glucose, containing 10% serum
  • the 96-well plate was shaken in a plateshaker for 5 minutes, the absorbance at 450 nm was measured by a microplatereader (Benchmark microplatereader, manufactured by BIORAD), and the amount of melanin in the medium in each well was compared.
  • the absorbance at 3 days after addition of a given concentration of each sample was shown in relative percentage based on the measurement value (absorbance) of control (no sample addition) as 100%.
  • IC 50 50% melanin production-suppressive concentration
  • Kojic acid (KoA) used was purchased from Sigma-Aldrich Japan K. K., 4-n-hexylresorcinol used was purchased from TOKYO CHEMICAL INDUSTRY CO., LTD., and CS and FS used were synthesized by Ajinomoto Co., Inc.
  • NR extract acetic acid-ethanol, 200 ⁇ l/well
  • NR uptake by viable cells was examined by measuring the absorbance of the NR extract at 540 nm by a microplatereader (Benchmark microplatereader, manufactured by BIORAD).
  • the cytotoxicity of each sample was calculated as a relative percentage of the absorbance of NR extract of the cells added with a given concentration of each sample to the measurement value (absorbance) of a control NR extract (no sample) as 100%.
  • Example 32 and Example 33 showed cytotoxicity; however, the compounds of other Examples did not show cytotoxicity. Therefore, it has been demonstrated that the compound of the present invention is promising as a starting material for whitening cosmetics.
  • the present invention provides a compound having a melanin production suppressive activity, which is useful as a starting material for whitening cosmetics.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150031740A1 (en) * 2011-12-16 2015-01-29 Syntivia Cosmetic composition for stimulating the cellular anti-aging functions of the skin
CN105209435A (zh) * 2013-05-14 2015-12-30 3M创新有限公司 包含吡啶或吡嗪的化合物
US9284271B2 (en) 2010-12-13 2016-03-15 Katholieke Universiteit Leuven, K.U. Leuven R&D Compounds for the treatment of neurodegenerative diseases
CN110339079A (zh) * 2019-07-03 2019-10-18 温州婧爵医疗科技有限公司 包含酰胺衍生物的组合物及其在化妆品中的应用

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2012042621A1 (ja) * 2010-09-29 2014-02-03 味の素株式会社 塩味増強剤
CA2823647C (en) * 2011-01-07 2016-07-19 Allergan, Inc. Compositions comprising substituted benzaldehydes and use thereof for lightening skin or treating hyperpigmenation and hypermelanosis disorders
KR101604053B1 (ko) * 2011-08-05 2016-03-16 (주)아모레퍼시픽 신규 벤조산아미드 화합물
JP5916348B2 (ja) * 2011-11-02 2016-05-11 学校法人近畿大学 新規セロトニン化合物及びチロシナーゼ阻害剤、及び変色防止剤
CN102584672A (zh) * 2012-01-11 2012-07-18 合肥工业大学 一种5-甲氧基色胺衍生物、其制备方法及其用途
JP2014080406A (ja) * 2012-10-18 2014-05-08 Yukijirushi Shubyo Kk 植物成長調整剤
WO2016107720A1 (en) * 2014-12-30 2016-07-07 Unilever N.V. A skin lightening composition comprising niacinamide and ilomastat
US10166412B2 (en) 2014-12-30 2019-01-01 Conopco, Inc. Skin lightening composition comprising 4-hexylresorcinol and ilomastat
KR102209441B1 (ko) 2015-09-04 2021-01-29 신풍제약주식회사 혈소판 응집 저해 효과를 갖는 화합물 및 그 염, 그리고 이를 포함하는 혈전성 질환 예방 또는 치료용 조성물
WO2018046243A1 (en) * 2016-09-06 2018-03-15 Unilever N.V. Compounds for reducing cellular melanin content

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007032551A1 (ja) * 2005-09-14 2007-03-22 Ajinomoto Co., Inc. 血行動態改善剤

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0853332A (ja) * 1994-08-11 1996-02-27 Kao Corp 美白化粧料
JPH08175959A (ja) * 1994-12-27 1996-07-09 Kao Corp 皮膚化粧料
JP4341501B2 (ja) * 2004-08-10 2009-10-07 東亞合成株式会社 チロシナーゼ活性阻害剤
FR2892923B1 (fr) 2005-11-08 2009-01-16 Engelhard Lyon Sa Utilisatiion des derives de l'acide para-coumarique ou para- hydroxycinnamique dans des compositions cosmetiques ou dermatologiques.
JP2009040688A (ja) 2007-08-06 2009-02-26 Tsuchida Yuzo メラニン生成抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007032551A1 (ja) * 2005-09-14 2007-03-22 Ajinomoto Co., Inc. 血行動態改善剤
US20080171781A1 (en) * 2005-09-14 2008-07-17 Ajinomoto Co., Inc. Hemodynamics improving agent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Cannon, "Analog Design" in Burger's Medicinal Chemistry and Drug Discovery, 6th ed. 2003, Wiley, pages 687-714 *
Sakamura et al. (CAPLUS Abstract of: Agricultural and Biological Chemistry (1978), 42(9), 1805-6). *
Wermuth, The Practice of Medicinal Chemistry, 2nd ed. 2003, Elsevier, 768 pages. Chs. 12-13 provided. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9284271B2 (en) 2010-12-13 2016-03-15 Katholieke Universiteit Leuven, K.U. Leuven R&D Compounds for the treatment of neurodegenerative diseases
US20150031740A1 (en) * 2011-12-16 2015-01-29 Syntivia Cosmetic composition for stimulating the cellular anti-aging functions of the skin
CN105209435A (zh) * 2013-05-14 2015-12-30 3M创新有限公司 包含吡啶或吡嗪的化合物
CN110339079A (zh) * 2019-07-03 2019-10-18 温州婧爵医疗科技有限公司 包含酰胺衍生物的组合物及其在化妆品中的应用

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