US20120070395A1 - Novel amide derivative and whitening agent - Google Patents
Novel amide derivative and whitening agent Download PDFInfo
- 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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- compound
- hydrogen atom
- skin
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- KEUMZWGWXSZGHR-UHFFFAOYSA-N O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=C(O)C=CC=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC(O)=CC(O)=C1.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC(O)=CC=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC=C(O)C=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC=CC(O)=C1O Chemical compound O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=C(O)C=CC=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC(O)=CC(O)=C1.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC(O)=CC=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC=C(O)C=C1O.O=C(CCCC1=CNC2=C1C=C(O)C=C2)C1=CC=CC(O)=C1O KEUMZWGWXSZGHR-UHFFFAOYSA-N 0.000 description 1
- OEHWAJQCMQPDGB-UHFFFAOYSA-N O=C(CCCC1=CNC2=C1C=C(O)C=C2)CCC1=CC=C(O)C=C1 Chemical compound O=C(CCCC1=CNC2=C1C=C(O)C=C2)CCC1=CC=C(O)C=C1 OEHWAJQCMQPDGB-UHFFFAOYSA-N 0.000 description 1
- YXKFALZVRFVXFA-QHHAFSJGSA-N Oc(cc1)cc2c1[nH]cc2CCNC(/C=C/c(cc1O)ccc1O)=O Chemical compound Oc(cc1)cc2c1[nH]cc2CCNC(/C=C/c(cc1O)ccc1O)=O YXKFALZVRFVXFA-QHHAFSJGSA-N 0.000 description 1
- QENFZZPIMBWNGY-LZCJLJQNSA-N Oc1ccc2[nH]cc(CCNC(/C=C/c(cc(cc3)O)c3O)=O)c2c1 Chemical compound Oc1ccc2[nH]cc(CCNC(/C=C/c(cc(cc3)O)c3O)=O)c2c1 QENFZZPIMBWNGY-LZCJLJQNSA-N 0.000 description 1
- UMUWGEXTOUMFQQ-QHHAFSJGSA-N Oc1ccc2[nH]cc(CCNC(/C=C/c(ccc(O)c3O)c3O)=O)c2c1 Chemical compound Oc1ccc2[nH]cc(CCNC(/C=C/c(ccc(O)c3O)c3O)=O)c2c1 UMUWGEXTOUMFQQ-QHHAFSJGSA-N 0.000 description 1
- LKITWWLMBLPTAT-UHFFFAOYSA-N Oc1ccc2[nH]cc(CCNC(c3cc(O)cc(O)c3)=O)c2c1 Chemical compound Oc1ccc2[nH]cc(CCNC(c3cc(O)cc(O)c3)=O)c2c1 LKITWWLMBLPTAT-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
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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
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- 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
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- 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
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- 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
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- 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
Abstract
Description
- This application is a continuation of International Patent Application No. PCT/JP2010/055162, filed on Mar. 25, 2010, and claims priority to Japanese Patent Application No. 2009-075006, filed on Mar. 25, 2009, both of which are incorporated herein by reference in their entireties.
- 1. Field of the Invention
- The present invention relates to novels compound having a melanin production suppressive activity. The present invention also relates to the use of such a compound in the field of cosmetics.
- 2. Discussion of the Background
- 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 α- and β-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. In addition, kojic acid or a derivative thereof and 4-n-butylresorcinol (Rucinol (registered trade mark)) 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. 2-6 (1998); and Dong-Seok KIM, So-Young KIM, Seo-Hyoung PARK, Yeong-Gon CHOI, Sun-Bang KWON, Myo-Kyoung KIM, Jung-Im Na, Sang-Woong YOUN, and Kyoung-Chan PARK, “Inhibitory Effects of 4-n-Butylresorcinol on Tyrosinase Activity and Melanin Synthesis,” Biol. Pharm. Bull., vol. 28 (12), pp. 2216-2219 (2005)), and whitening cosmetics containing such components are commercially available. In recent years, prevention of sunburn due to ultraviolet rays to keep the skin white and beautiful is receiving increasing attention, and the development of a further whitening component is desired.
- Accordingly, it is one object of the present invention to provide novel compound having a melanin production suppressive activity, and the like.
- It is another object of the present invention to provide novel cosmetics which contain such a compound.
- These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery of novel compounds which have a melanin production suppressive activity, and the like.
- Thus, the present invention provides the following:
- (1) A compound represented by the following formula (I):
- wherein R1, R2, R3, R4 and R5 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 R1 and R2, or R2 and R3 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): - wherein R6 and R7 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): - wherein R8 and R9 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 R8 and R9 in combination optionally form a methylenedioxy group, and * is a moiety bonded to Y;
provided that the following compounds are excluded: - (1) a compound wherein, when Ar is a substituent represented by the formula (II), X is a vinylene group, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydroxyl groups, or R3 is a methoxy group and R4 is a hydroxyl group, or R3 is a methoxy group and R4 is a hydrogen atom;
- (2) a compound wherein, when Ar is a substituent represented by the formula (II), X is a vinylene group, Y is an ethylene group, and R1, R2, R5, R6 and R7 are hydrogen atoms, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a methoxy group and R4 is a hydrogen atom, or R3 and R4 are hydroxyl groups, or R3 is a hydroxyl group and R4 is a methoxy group;
- (3) a compound wherein, when Ar is a substituent represented by the formula (II), X is a vinylene group, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a methoxy group, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a methoxy group and R4 is a hydrogen atom, or R3 and R4 are hydrogen atoms;
- (4) a compound wherein, when Ar is a substituent represented by the formula (II), X is a covalent bond, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 and R4 are hydroxyl groups, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydrogen atoms, or R3 is a methoxy group and R4 is a hydrogen atom; and
- (5) a compound wherein Ar is a substituent represented by the formula (III), Y is an ethylene group, and one or both of R8 and R9 is/are a hydrogen atom(s);
- or a salt thereof.
- (2) A compound represented by the following formula (IV):
- wherein R1, R2, R3, R4, R5, R6 and R7 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 R1 and R2, or R2 and R3 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: - (1) a compound wherein, when X is a vinylene group, Z is a hydrogen atom, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydroxyl groups, or R3 is a methoxy group and R4 is a hydroxyl group, or R3 is a methoxy group and R4 is a hydrogen atom;
- (2) a compound wherein, when X is a vinylene group, Z is a hydrogen atom, and R1, R2, R5, R6 and R7 are hydrogen atoms, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a methoxy group and R4 is a hydrogen atom, or R3 and R4 are hydroxyl groups, or R3 is a hydroxyl group and R4 is a methoxy group; and
- (3) a compound wherein, when X is a vinylene group, Z is a hydrogen atom, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a methoxy group, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a methoxy group and R4 is a hydrogen atom, or R3 and R4 are hydrogen atoms;
- or a salt thereof.
- (3) A compound represented by the following formula (V):
- wherein R1, R2, R3, R4, R5, R6 and R7 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 R1 and R2, or R2 and R3 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, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 and R4 are hydroxyl groups, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydrogen atoms, or R3 is a methoxy group and R4 is a hydrogen atom; or a salt thereof. - (4) A compound represented by the following formula (VI):
- wherein R1, R2, R3, R4 and R5 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 R1 and R2, or R2 and R3 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);
R8 and R9 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 R8 and R9 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 R8 and R9 is/are a hydrogen atom(s); or a salt thereof. - (5) A whitening agent, comprising a compound represented by the following formula (I′):
- wherein R1, R2, R3, R4 and R5 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 R1 and R2, or R2 and R3 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): - wherein R6 and R7 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): - wherein R8 and R9 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 R8 and R9 in combination optionally form a methylenedioxy group, and * is a moiety bonded to Y;
provided that the following compounds are excluded: - (1) a compound wherein, when Ar is a substituent represented by the formula (II), X is a vinylene group, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 is a hydroxyl group and R4 is a hydrogen atom, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydroxyl groups;
- (2) a compound wherein, when Ar is a substituent represented by the formula (II), X is a vinylene group, Y is an ethylene group, and R1, R2, R5, R6 and R7 are hydrogen atoms, then R3 and R4 are hydroxyl groups;
- (3) a compound wherein, when Ar is a substituent represented by the formula (II), X is a covalent bond, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then R3 and R4 are hydroxyl groups, or R3 is a hydroxyl group and R4 is a methoxy group, or R3 and R4 are hydrogen atoms; and
- (4) a compound wherein Ar is a substituent represented by the formula (III), Y is an ethylene group, R1, R2, R5 and R8 are hydrogen atoms, and R3, R4 and R9 are hydroxyl groups;
- or a salt thereof.
- (6) 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.
- A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same become better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
-
FIG. 1 is a graph showing the results of Experimental example 1. In the graph, the unit of the values on the horizontal axis is μM. -
FIG. 2 is a graph showing the results of Experimental example 1. In the graph, the unit of the values on the horizontal axis is μM. -
FIG. 3 is a graph showing the results of Experimental example 1. In the graph, the unit of the values on the horizontal axis is μM. -
FIG. 4 is a graph showing the results of Experimental example 1. In the graph, the unit of the values on the horizontal axis is μM. -
FIG. 5 is a graph showing the results of Experimental example 1. In the graph, the unit of the values on the horizontal axis is μM. - The definitions of the symbols in each formula used in the present specification are explained.
- Examples of the alkyl group having a carbon number of 1 to 3 for R1, R2, R3, R4, R5, R6, R7, R8 or R9 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 R1, R2, R3, R4, R5, R8, R7, R8 or R9 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.
- That the “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
- wherein Z is as described above, more preferably a divalent group represented by the formula
- wherein Z is as described above, and still more preferably an ethylene group.
- Preferably, R1, R2, R3, R4 and R5 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, or R1 and R2, or R2 and R3 in combination optionally form a methylenedioxy group.
- At least one (preferably 1 to 3, more preferably 1 or 2) of R1, R2, R3, R4 and R5 is preferably a hydroxyl group, and R3 is more preferably a hydroxyl group. On the other hand, when X is a covalent bond, R1 and R5 are preferably hydroxyl groups.
- Preferably, R6 and R7 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3. More preferably, R6 is a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3, and R7 is a hydrogen atom. Still more preferably, R6 is a hydroxyl group and R7 is a hydrogen atom.
- Preferably, R8 and R9 are each independently a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of 1 to 3. More preferably, R8 and R9 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. In addition, 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 (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, and the like). As the above-mentioned salt, pharmacologically acceptable salts are preferably used.
- 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. In the following, a production method of a compound represented by the formula (I) (hereinafter to be also referred to as compound (I)) is explained.
- wherein R1-R5, 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. In this case, 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.
- wherein Ar and Y are as described above.
- wherein R1-R5 and X are as described above.
- wherein R1-R5 and X are as described above.
- While a production method of (i) is explained in detail in the following, the method is not limited thereto.
- 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. When 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).
- As 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. In this case, a condensation accelerator such as 1-hydroxybenzotriazole (HOBt) and the like may be used. 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. For example, when compound (I) is purified by crystallization, ethyl acetate, ethanol, methanol, diethyl ether, chloroform, dichloromethane, n-hexane and a mixed solvent thereof can be used as a solvent. As a purification method by chromatography, preparative thin-layer chromatography (PTLC) or silica gel column chromatography can be used. As an eluent therefor, the solvents recited earlier as the crystallization solvent can be used.
- 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). As 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.
- 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.
- Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
- In the following Production Examples, the structures of the synthesized compounds were identified by nuclear magnetic resonance spectrum (Bruker AVANCE 400).
- Serotonin hydrochloride (300 mg, 1.41 mmol) and trans-cinnamic acid (208 mg, 1.41 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (216 μl, 1.55 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 237 mg, 1.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl, 297 mg, 1.55 mmol), and the mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (10 ml). 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, and purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate) to give N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-phenyl-2-propenamide (217 mg, yield 50.0%) as a viscous oil.
- Serotonin hydrochloride (300 mg, 1.41 mmol) and trans-2,4-dihydroxycinnamic acid (253 mg, 1.41 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (216 μl, 1.55 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 237 mg, 1.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl, 297 mg, 1.55 mmol), and the mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (10 ml). 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, and purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate-n-hexane=2:1, 0.01% formic acid) to give N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-(2,4-dihydroxyphenyl)-2-propenamide (243 mg, yield 51.0%) as a viscous oil.
- 3-Methyl-4-hydroxybenzaldehyde (794 mg, 5.83 mmol), malonic acid (911 mg, 8.75 mmol) and piperidine (144 μl) were added to pyridine (5 ml), and the mixture was stirred at 60° C. for 22 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and water (20 ml) was added. 6N Hydrochloric acid was added to allow precipitation of a solid. The precipitated solid was collected by filtration, and the filtrate was washed with water and dried under reduced pressure. The obtained solid was recrystallized from diethylether-n-hexane to give 3-methyl-4-hydroxycinnamic acid (872 mg, yield 84.0%) as crystals.
- 1H NMR (DMSO, 400 MHz) δ 9.95 (OH), 7.45 (d, J=15.9 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.26 (d, J=15.9 Hz, 1H), 2.13 (s, 3H).
- 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. To this solution were added triethylamine (216 μl, 1.55 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 237 mg, 1.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl, 297 mg, 1.55 mmol), and the mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (10 ml). 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.
- Methanol (5 ml) was maintained at 0° C., and thionyl chloride (2.4 ml) was added dropwise under an argon atmosphere. To this solution was added 5-hydroxy-L-tryptophan (2.0 g), and the mixture was gradually warmed from 0° C. to room temperature, and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethanol and ether to give 5-hydroxy-L-tryptophan methyl ester hydrochloride (1.8 g, yield 74%) as crystals.
- As mentioned above, 5-hydroxy-L-tryptophan methyl ester hydrochloride (350 mg, 1.29 mmol) and ferulic acid (251 mg, 1.29 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (198 μl, 1.4 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 217 mg, 1.4 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI HCl, 217 mg, 1.4 mmol), the solution temperature was gradually raised from 0° C., and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (20 ml). 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, and purified by silica gel column chromatography (eluent: chloroform:methanol=3:1) to give 3-(3-methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-methoxycarbonylethyl]-2-propenamide (413 mg, yield 78.0%) as a powder.
- 3-(3-Methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-methoxycarbonylethyl]-2-propenamide synthesized from 5-hydroxy-L-tryptophan methyl ester hydrochloride (704 mg, 2.6 mmol) in the same manner as in Example 18 was dissolved in a mixed solvent of water (11.8 ml), 2.5N NaOH aqueous solution (11.8 ml), and N,N-dimethylformamide (23.6 ml) without purification, and the mixture was stirred at room temperature overnight. The reaction solvent was concentrated under reduced pressure, cooled to 0° C., and adjusted with 6N aqueous HCl solution to
pH 1 to 2. The solution was extracted three times with ethyl acetate (30 ml), and the organic layer was washed with 3N HCl (20 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (PTLC, eluent: chloroform:methanol=3:1) to give 3-(3-methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-hydroxycarbonylethyl]-2-propenamide (147 mg, yield 15.4%) as a powder. - 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 μl, 2.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 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. The solvent was removed under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (20 ml). 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, purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate:hexane=3:1) to give 2,6-dihydroxy-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-benzamide (93 mg, yield 14.9%) as a powder.
- The compounds of other Examples, which are shown in the following Table 1, were also synthesized in the same manner as in Examples 1, 4, 17, 18, 20 and 35. In addition, compounds having a carboxyl group were obtained by alkaline hydrolysis of the ester bond of the corresponding methoxycarbonyl group. The compounds of Reference Examples 1 and 2, which are shown in the following Table 1, were also synthesized in the same manner as in Examples 1, 4, 17, 18, 20 and 35.
-
TABLE 1 Prod. Ex. structural formula property, yield Ex. 1 1H NMR (DMSO, 400 MHz) δ 10.49 (NH), 8.59 (OH), 8.20 (NH), 7.56 (d, J = 6.9, 2H), 7.4 (m, 4H), 7.12 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.59 (dd, J = 8.6, 2.2 Hz, 1H), 3.44 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H). ESI-MS: [M − H]− = 305.0. yield: 50.0%. Ex. 2 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 8.11 (NH), 7.50 (d, J = 8.8 Hz, 2H) 7.36 (d, J = 15.7 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 2.3, 8.8 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 3.79 (s, 3H), 3.43 (m, 2H), 2.79 (t, J = 7.6 Hz, 2H). ESI-MS: [M − H]− = 335.3. yield: 88.0%. Ex. 3 1H NMR (DMSO, 400 MHz) δ 10.50 (NH), 8.12 (NH), 7.24 (d, J = 15.6 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 6.85 (s, 1H), 6.83 (d, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz, 1H), 6.59 (dd, J = 2.3, 8.8 Hz, 1H), 6.33 (d, J = 15.6 Hz, 1H), 3.30 (s, 3H), 3.25 (m, 2H), 2.78 (t, J = 7.6 Hz, 2H). ESI-MS: [M − H]− = 351.2. yield: 27.0%. Ex. 4 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 9.88 (OH), 9.65 (OH), 8.58 (OH), 8.00 (NH), 7.54 (d, J = 15.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 2.3, 8.6 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 2.3, 6.8 Hz, 1H), 3.43 (m, 2H), 2.78 (t, J = 7.4 Hz, 2H). ESI-MS: [M − H]− = 351.2. yield: 51.0%. Ex. 5 1H NMR (DMSO, 400 MHz) δ 10.48 (d, J = 2.1 Hz, 1H, NH), 8.59 (OH), 8.07 (NH), 7.34 (d, J = 15.7 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.07 (m, 2H) [7.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.05 (s, 1H)], 6.94 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 8.6, 2.3 Hz, 1H), 6.47 (d, J = 15.7 Hz, 1H), 6.07 (s, 2H), 3.43 (m, 2H), 2.77 (t, J = 7.4 Hz, 2H). ESI MS: [M − H]− = 337.3. (methylene moiety was dissociated, observed as 3.4- OH.) yield: 68.0%. Ref. Ex. 1 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 8.07 (NH, amide), 7.24 (d, J = 15.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.59 (dd, J = 8.6, 2.3 Hz, 1H), 6.33 (d, J = 15.6 Hz, 1H), 3.44 (m, 2H), 2.78 (m, 2H). ESI-MS: [M + H]+ = 339.1, [M + Na]+ = 361.0, [M − H]− = 337.2, [2M − H]− = 675.2. yield: 54.0%. Ex. 6 1H NMR (DMSO, 400 MHz) δ 10.46 (NH), 9.00 (OH), 8.61 (OH), 7.88 (t, J = 5.6 Hz, 1H, NH), 7.11 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.98 (m, 2H), 6.82 (d, J = 2.3 Hz, 1H), 6.65 (m, 1H), 6.58 (dd, J = 8.6, 2.3 Hz, 1H), 3.25 (m, 2H), 2.69 (m, 4H), 2.32 (m, 2H). ESI-MS: [M + H]+ = 325.1, [M + Na]+ = 347.2, [M − H]− = 323.2. yield: 63.0%. Ex. 7 1H NMR (DMSO, 400 MHz) δ 10.46 (NH), 8.59 (OH, 2H), 7.89 (NH), 7.11 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 1.9 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 8.6, 2.3 Hz, 1H), 6.57 (dd, J = 8.0, 2.3 Hz, 1H), 3.74 (s, 3H), 3.28 (m, 2H), 2.32 (m, 2H), 2.69 (m, 4H). ESI-MS: [M + Na]+ = 377.1, [M − H]− = 353.3. yield: 80.0%. Ex. 8 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 8.76 (OH), 8.59 (OH), 8.02 (NH), 7.34 (d, J = 15.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.85 (s, 3H), 6.59 (dd, J = 8.6, 2.3 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 3.80 (s, 3H), 3.43 (td, J = 7.4, 7.4 Hz, 2H), 3.32 (s, 3H), 2.78 (t, J = 7.4 Hz, 2H). ESI-MS: [M + Na]+ = 405.1, [M − H]− = 381.2. yield: 77.0%. Ex. 9 1H NMR (DMSO, 400 MHz) δ 10.47 (NH), 8.74 (OH), 8.57 (OH), 7.97 (NH), 7.11 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.82 (m, 2H), 6.68 (d, J = 8 Hz, 1H), 6.62 (dd, J = 8, 1.8 Hz, 1H), 6.58 (dd, J = 8.6, 2.2 Hz, 1H), 3.73 (s, 3H), 3.28 (m, 4H), 2.71 (t, J = 7.4 Hz, 2H). ESI-MS: [M + H]+ = 341.2, [M + Na]+ = 363.1, [2M − H]− = 339.2, [2M − H]− = 679.3. yield: 56.0%. Ex. 10 1H NMR (DMSO, 400 MHz) δ 10.64 (NH), 9.41 (OH), 8.05 (NH), 7.34 (d, J = 15.7 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.13 (m, 2H), 7.05 (d, J = 2.3 Hz, 1H), 7.00 (dd, J = 1.8, 2.3 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.71 (dd, J = 2.4, 8.2 Hz, 1H), 6.46 (d, J = 15.7 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.46 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H). ESI-MS: [M + Na]+ = 389.2, [M − H]− = 365.2. yield: 80.0%. Ex. 11 1H NMR (DMSO, 400 MHz) δ 10.46 (1H), 8.07 (1H), 7.38 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 15.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 6.71 (dd, J = 8.7, 2.4 Hz, 2H), 6.40 (d, J = 15.7 Hz, 2H), 3.75 (s, 3H), 3.43 (m, 2H), 2.84 (t J = 7.3 Hz, 2H). ESI-MS: [M + Na]+ = 359.2, [M − H]− = 335.3, [2M − H]− = 671.4. yield: 90.0%. Ex. 12 1H NMR (DMSO, 400 MHz) δ 10.81 (1H), 8.05 (1H), 7.55 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.08 (m, 1H), 7.00 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 15.7 Hz, 1H), 3.82 (s, 3H), 3.45 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H). ESI-MS: [M + Na]+ = 359.2, [M − H]− = 335.3. yield: 64.0%. Ex. 13 1H NMR (DMSO, 400 MHz) δ 10.81 (NH), 9.82 (OH), 8.01 (NH), 7.55 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 15.7 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H), 6.98 (t, J = 7.1 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.41 (d, J = 15.7 Hz, 1H), 3.45 (m, 2H), 2.88 (t, J = 7.3 Hz, 2H). ESI-MS: [M + Na]+ = 329.2, [M − H]− = 305.2, [2M − H]− = 611.3. yield: 73.0%. Ex. 14 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 9.32 (NH), 8.58 (OH), 8.02 (OH), 7.30 (d, J = 15.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 1.8, 8.2 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.59 (dd, J = 8.6, 2.2 Hz, 1H), 6.43 (d, J = 15.7 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.43 (m, 1H), 2.78 (m, 1H), 1.35 (t, J = 7.0 Hz, 3H). ESI-MS: [M + Na]+ = 389.2, [M − H]− = 365.2. yield: 79.0%. Ex. 15 1H NMR (DMSO, 400 MHz) δ 10.5 (NH), 8.08 (NH), 7.15 (d, J = 15.6 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.05 (s, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.59 (dd, J = 2.3, 8.5 Hz, 1H), 6.48 (s, 2H), 6.28 (d, J = 15.6 Hz, 1H), 3.35 (m, 2H), 2.77 (m, 2H). ESI-MS: [M − H]− = 353.3. yield: 43.0%. Ex. 16 1H NMR (DMSO, 400 MHz) δ 10.49 (NH), 9.39 (OH, 2H), 8.65 (OH), 8.19 (NH), 7.21 (d, J = 15.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 2.3, 8.7 Hz, 1H), 6.45 (d, J = 15.7 Hz, 1H), 6.38 (d, J = 2.1 Hz, 2H), 6.23 (t, J = 2.12 Hz, 1H), 3.43 (m, 2H), 2.78 (t, J = 7.5 Hz, 2H). ESI-MS: [M − H]− = 337.2. yield: 72.0%. Ex. 17 1H NMR (DMSO, 400 MHz) δ 10.48 (NH), 8.61 (OH), 8.02 (NH), 7.29 (d, J = 15.7 Hz, 1H), 7.27 (s, 1H), 7.20 (dd, J = 2.0, 8.3 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.59 (dd, J = 2.3, 8.6 Hz, 1H), 6.40 (d, J = 15.7 Hz, 1H), 3.43 (m, 2H), 2.75 (t, J = 7.6 Hz, 2H). ESI-MS: [M − H]− = 335.0. yield: 65.0%. Ex. 18 1H NMR (DMSO, 400 MHz) δ 10.54, 9.48, 8.62, 8.30 (NH, OH, 4H), 7.29 (d, J = 15.6 Hz, 1H), 7.12 (d, J = 8.12, 1H), 7.11 (s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.16 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 8.12 Hz, 1H), 6.58 (dd, J = 2.2, 8.16 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 4.16 (m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.05 (m, 1H). ESI-MS: [M + Na]+ = 433.3, [M − H]− = 409.2. yield: 78.0%. Ex. 19 1H NMR (DMSO, 400 MHz) δ 10.54 (s, NH), 9.8 (brs, OH), 8.62 (brs, OH), 8.34 (d, J = 7.5 Hz, NH), 7.38 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 15.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 6.59 (dd, J = 2.3, 8.6 Hz, 1H), 6.48 (d, J = 15.7 Hz, 1H), 4.60 (m, 1H), 3.62 (s, 3H), 3.00 (m, 2H). ESI-MS: [M − H]− = 379.2. yield: 74.0%. Ex. 20 1H NMR (DMSO, 400 MHz) δ 10.51 (NH), 9.44 (OH), 8.63 (OH), 8.17 (NH), 7.29 (d, J = 15.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.2, 1.9 Hz, 2H), 6.87 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.59 (dd, J = 8.6, 2.3 Hz, 1H), 6.55 (d, J = 15.7 Hz, 1H), 4.58 (m, 1H), 3.00 (m, 2H). ESI-MS: [M + H]+ = 397.0, [M − H]− = 395.0. yield: 15.0%. Ex. 21 1H NMR (DMSO, 400 MHz) δ 10.50 (NH), 9.83 (OH), 8.60 (OH), 8.17 (NH), 7.37 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 15.7 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 6.58 (dd, J = 8.7, 2.2 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 4.55 (m, 1H), 2.99 (m, 2H). ESI-MS: [M − H]− = 365.0. yield: 22.0%. Ex. 22 1H NMR (DMSO, 400 MHz) δ 7.91, 7.87 (d, 1H), 7.79, 7.76 (d, 1H), 7.19-6.36 (m, 6H), 3.60, 3.58, 3.56 (t, 2H), 2.96, 2.94, 2.92 (t, 2H). ESI-MS: [M − H]− = 353.0. yield: 8.7%. Ex. 23 1H NMR (MeOH-d, 400 MHz) δ 7.84, 7.80 (d, J = 16 Hz, 1H), 7.19, 7.17 (d, J = 9 Hz 1H), 7.05 (s, 1H), 6.98 (s, 1H), 6.91 (s, 1H), 6.69 (s, 2H), 6.65, 6.61 (d, J = 16 Hz, 1H), 3.59 (t, 1H), 2.95 (t, 1H). ESI-MS: [M + H]+ = 339.2, [M − H]− = 337.8. yield: 18.3%. Ex. 24 1H NMR (DMSO, 400 MHz) δ 9.83 (s, 1H), 8.04, 8.02, 8.01 (t, 1H), 7.39, 7.37 (d, 2H), 7.33, 7.29 (d, 1H), 7.15, 7.13 (d, 2H), 6.87, 6.85 (d, 2H), 6.80, 6.78 (d, 2H), 6.41, 6.37 (d, 1H), 3.72 (s, 3H), 2.72, 2.70, 2.68 (2H, t). ESI-MS [M + H]+ = 298.2, [M − H]− = 296.0. yield: 82.4%. Ex. 25 1H NMR (DMSO, 400 MHz) δ 9.83 (s, 1H), 8.03, 8.01, 8.00 (t, 1H), 7.39, 7.37 (d, 2H), 7.34, 7.30 (d, 1H), 6.87, 6.85 (d, 1H), 6.83, 6.82 (d, 1H), 6.80, 6.78 (d, 2H), 6.74, 6.72 (d, 1H), 6.42, 6.39 (d, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 2.72, 2.70, 2.68 (t, 2H). ESI-MS: [M + H]+ = 328.2, [M − H]− = 325.9. yield: 82.1%. Ex. 26 1H NMR (DMSO, 400 MHz) δ 9.82 (s, 1H), 8.70 (s, 1H), 8.01, 8.00, 7.98 (t, 1H), 7.39, 7.37 (d, 2H), 7.33, 7.29 (d, 1H), 6.80, 6.78 (d, 3H), 6.69, 6.67 (d, 1H), 6.61, 6.59 (d, 1H), 6.43, 6.39 (d, 1H), 3.75 (s, 3H), 2.68, 2.66, 2.64 (t, 2H). ESI-MS: [M + H]+ = 314.0, [M − H]− = 312.0. yield: 85.9%. Ex. 27 1H NMR (DMSO, 400 MHz) δ 9.81 (s, 1H), 9.17 (s, 1H), 8.02, 8.00, 7.99 (t, 1H), 7.39, 7.37 (d, 2H), 7.33, 7.29 (d, 1H), 7.02, 7.00 (d, 2H), 6.80, 6.76 (d, 2H), 6.69, 6.67 (d, 2H), 6.41, 6.37 (d, 1H), 2.66, 2.64, 2.62 (t, 2H). ESI-MS: [M + H]+ = 284.0, [M − H]− = 282.1. yield: 83.1%. Ex. 28 1H NMR (DMSO, 400 MHz) δ 9.82 (s, 1H), 8.84 (s, 1H), 8.35, 8.34, 8.33 (t, 1H), 7.40, 7.38 (d, 2H), 6.86 (s, 1H), 6.80, 6.78 (d, 2H), 6.71 (s, 1H), 6.69 (s, 1H), 6.48, 6.44 (d, 1H), 4.28, 4.26 (d, 2H), 3.75 (s, 3H). ESI-MS: [M + H]+ = 300.0, [M − H]− = 298.0. yield: 61.7%. Ex. 29 1H NMR (DMSO, 400 MHz) δ 9.83 (s, 1H), 8.92 (s, 1H), 8.37, 8.36, 8.34 (t, 1H), 7.40, 7.38 (d, 2H), 6.86, 6.84 (d, 1H), 6.80, 6.78 (d, 2H), 6.72 (s, 1H), 6.67, 6.65 (d, 1H), 6.48, 6.44 (d, 1H), 4.24, 4.23 (d, 2H), 3.73 (s, 3H). ESI-MS: [M + H]+ = 300.0, [M − H]− = 298.3. yield: 81.8%. Ex. 30 1H NMR (DMSO, 400 MHz) δ 10.80 (s, 1H), 9.88 (s, 1H), 9.65 (s, 1H), 8.03, 8.02, 8.00 (t, 1H), 7.57 (s, 1H), 7.55, 7.53 (d, 1H), 7.35, 7.33 (d, 1H), 7.24, 7.22 (d, 1H), 7.16, 7.15 (d, 1H), 7.09-7.05 (m, 1H), 7.00-6.96 (m, 1H), 6.47, 6.43 (d, 1H), 6.35 (s, 1H), 6.27, 6.25 (d, 1H), 3.47, 3.46, 3.44, 3.42 (q, 2H), 2.89, 2.87, 2.85 (t, 2H). ESI-MS: [M + H]+ = 323.2, [M − H]− = 320.9. yield: 12.7%. Ex. 31 1H NMR (DMSO, 400 MHz) δ 10.81 (s, 1H), 9.73 (s, 1H), 8.06, 8.05, 8.04 (t, 1H), 7.57, 7.55 (d, 1H), 7.33, 7.32 (d, 2H), 7.28 (s, 1H), 7.21, 7.19 (d, 1H), 7.17, 7.16 (d, 1H), 7.09, 7.07, 7.05 (t, 1H), 7.00, 6.98, 6.96 (t, 1H), 6.92, 6.88 (d, 1H), 6.42, 6.38 (d, 1H), 3.48, 3.47, 3.45, 3.43 (q, 2H), 2.89, 2.88, 2.86 (t, 2H). ESI-MS: [M + H]+ = 321.2, [M − H]− = 319.0 yield: 47.5%. Ex. 32 1H NMR (DMSO, 400 MHz) δ 10.51 (s, 1H), 9.14 (s, 1H), 8.94, 8.93, 8.92 (t, 1H), 8.61 (s, 1H), 7.30, 7.28 (d, 1H), 7.14, 7.12 (d, 1H), 7.08 (s, 1H), 6.92 (s, 1H), 6.90, 6.89 (d, 1H), 6.71, 6.69, 6.68 (t, 1H), 6.61, 6.59 (d, 1H), 3.55, 3.54, 3.52, 3.50 (q, 2H), 2.89, 2.87, 2.85 (t, 2H). ESI-MS: [M + H]+ = 313.1, [M − H]− = 310.9. yield: 23.0%. Ex. 33 1H NMR (DMSO, 400 MHz) δ 10.50 (s, 1H), 10.06 (s, 1H), 8.69, 8.68, 8.66 (t, 1H), 8.62 (s, 1H), 7.69, 7.67 (d, 1H), 7.14, 7.12 (d, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 6.61, 6.59 (d, 1H), 6.30, 6.27 (d, 1H), 6.23 (d, 1H), 3.53, 3.51, 3.49, 3.47 (q, 2H), 2.87, 2.85, 2.83 (t, 2H). ESI-MS: [M + H]+ = 313.1. [M − H]− = 310.9. yield: 34.3%. Ex. 34 1H NMR (DMSO, 400 MHz) δ 10.51 (s, 1H), 9.00 (s, 1H), 8.82 (s, 1H), 8.62 (s, 1H), 7.24, 7.23 (d, 1H), 7.13, 7.12 (d, 1H), 7.08, 7.07 (d, 1H), 6.86, 6.84 (d, 1H), 6.74, 6.71 (d, 1H), 6.61, 6.59 (d, 1H), 3.55, 3.53, 3.51, 3.50 (q, 2H), 2.87, 2.86, 2.84 (t, 2H). ESI-MS: [M + H]+ = 313.1, [M − H]− = 310.8. yield: 30.1%. Ex. 35 1H NMR (DMSO, 400 MHz) δ 10.54 (s, 1H), 9.01 (s, 1H), 8.62 (s, 1H), 7.16 (s, 1H), 7.14, 7.12 (d, 1H), 7.10, 7.09 (d, 1H), 6.90 (s, 1H), 6.62, 6.59 (d, 1H), 6.35, 6.33 (d, 2H), 3.64, 3.62, 3.61, 3.59 (q, 2H), 2.90, 2.88, 2.87 (t, 2H). ESI-MS: [M + H]+ = 313.1, [M − H]− = 310.9. yield: 14.9%. Ref. Ex. 2 1H NMR (DMSO, 400 MHz) δ 10.47 (s, 1H), 9.43 (s, 1H), 9.09 (s, 1H), 8.61 (s, 1H), 8.27, 8.25, 8.24 (t, 1H), 7.29 (s, 1H), 7.20, 7.18 (d, 1H), 7.13, 7.11 (s, 1H), 7.05 (s, 1H), 6.88 (s, 1H), 6.76, 6.74 (d, 1H), 6.60, 6.58 (d, 1H), 3.48, 3.46, 3.44, 3.42 (q, 2H), 2.83, 2.81, 2.79 (t, 2H). ESI-MS: [M + H]+ = 313.1, [M − H]− = 310.9. yield: 32.6%. Ex. 36 1H NMR (DMSO, 400 MHz) δ 10.48 (s, 1H), 9.44, 9.43 (s, 1H), 8.60 (s, 1H), 8.36, 8.35, 3.34 (t, 1H), 7.13, 7.11 (d, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 6.68 (s, 2H), 6.60, 6.58 (d, 1H), 6.35 (s, 1H), 3.47, 3.45, 3.43, 3.42 (q, 2H), 2.82, 2.81, 2.79 (t, 2H). ESI-MS: [M + H]+ = 313.1, [M − H]− = 310.8. yield: 60.5%. - 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 μm according to sample), and the cells were incubated for 3 days. 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%. As Comparative Example, a similar test was performed using kojic acid (KoA), 4-hexylresorcinol, CS(N-(p-coumaroyl)serotonin or N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-(4-hydroxyphenyl)-2-propenamide) and FS(N-feruloylcoumaroylserotonin or N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-(4-hydroxy-3-methoxyphenyl-2-propenamide). The results are shown in
FIGS. 1 to 5 . The concentration necessary for suppressing production of melanin in each sample by 50%, based on the amount of melanin in the control as 100%, was calculated as 50% melanin production-suppressive concentration IC50 (μM). The results are shown in Table 2. As a result, all the compounds of the present invention showed a tendency toward suppression of the amount of melanin. Hence, the compounds of the present invention were shown to be useful as a whitening agent. - 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.
-
TABLE 2 sample IC50 (μM) kojic acid 315.0 CS 28.5 FS 42.4 4-hexylresorcinol 23.5 compound of Example 4 10.7 compound of Example 13 21.5 compound of Example 17 14.6 compound of Example 24 33.3 compound of Example 30 17.1 compound of Reference Example 2 1.9 compound of Example 36 22.4 - After measurement of the absorbance in the melanin production suppression test of Experimental Example 1, the evaluation sample solution was removed from the plate, and each well was rinsed with DMEM (200 μl, high glucose, containing 10% serum). A medium containing NR (neutral red) was added to each well at 200 μl/well, and the plate was left standing for 2 hours at 37° C., 5% CO2 under a saturated vapor. The medium was removed, and a washing fixative solution (mixture of equal amounts of 2 wt % calcium chloride solution and 2 wt % formalin solution) was added at 200 μl/well. After 1 minute, the washing fixative solution was removed. An NR extract (acetic acid-ethanol, 200 μl/well) was added, and the mixture was shaken in a plateshaker for 15 minutes. 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%.
- As a result, the compounds of 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.
- Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and subranges within a numerical limit or range are specifically included as if explicitly written out.
- Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
- All patents and other references mentioned above are incorporated in full herein by this reference, the same as if set forth at length.
Claims (22)
1. A compound represented by formula (V):
wherein:
R1, R2, R3, R4, and R5 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 R1 and R2, or R2 and R3 in combination optionally form a methylenedioxy group, and at least one of R1, R2, R3, R4 and R5 is a hydroxyl group;
R6 is a hydroxyl group and R7 is a hydrogen atom;
Z is a hydrogen atom;
or a salt thereof,
provided that the following compound and salts thereof are excluded:
a compound wherein, when R1, R2, and R5 are hydrogen atoms, then:
R3 and R4 are hydroxyl groups, or
R3 is a hydroxyl group and R4 is a methoxy group,
or R3 and R4 are hydrogen atoms, or
R3 is a methoxy group and R4 is a hydrogen atom.
3. A whitening agent, comprising a compound according to claim 1 , or a salt thereof.
4. A whitening agent, comprising a compound according to claim 2 , or a salt thereof.
5. A method of whitening skin, comprising applying a whitening agent according to claim 3 to the skin.
6. A method of whitening skin, comprising applying a whitening agent according to claim 4 to the skin.
7. A method of whitening skin, comprising applying to the skin a whitening agent comprising a compound represented by formula (V):
wherein:
R1, R2, R3, R4, R5, R6 and R7 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 R1 and R2, or R2 and R3 in combination optionally form a methylenedioxy group, provided that at least one of R1, R2, R3, R4 and R5 is a hydroxyl group;
Z is a hydrogen atom;
or a salt thereof,
provided that the following compound and salts thereof are excluded:
a compound wherein, when R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then:
R3 and R4 are hydroxyl groups, or
R3 is a hydroxyl group and R4 is a methoxy group, or
R3 and R4 are hydrogen atoms, or
R3 is a methoxy group and R4 is a hydrogen atom.
8. A compound represented by formula (IV):
wherein:
R1, R2, R4, and R5 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 R1 and R2 in combination optionally form a methylenedioxy group;
R3 is a hydroxyl group;
R6 is a hydroxyl group;
R7 is a hydrogen atom;
X is a methylene group, an ethylene group, or a vinylene group;
Z is a hydrogen atom;
or a salt thereof,
provided that the following compound and salts thereof are excluded:
a compound wherein, when X is a vinylene group, and R1, R2, and R5 are hydrogen atoms, then
R4 is a hydrogen atom, a methoxy group, or a hydroxyl group.
11. A whitening agent, comprising a compound according to claim 8 , or a salt thereof.
12. A whitening agent, comprising a compound according to claim 9 , or a salt thereof.
13. A whitening agent, comprising a compound according to claim 10 , or a salt thereof.
14. A method of whitening skin, comprising applying a whitening agent of claim 11 to the skin.
15. A method of whitening skin, comprising applying a whitening agent of claim 12 to the skin.
16. A method of whitening skin, comprising applying a whitening agent of claim 13 to the skin.
17. A method of whitening skin, comprising applying to the skin a whitening agent, comprising a compound represented by formula (I′):
wherein:
R1, R2, R3, R4 and R5 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 R1 and R2, or R2 and R3 in combination optionally form a methylenedioxy group, and at least one of R1, R2, R3, R4 and R5 is a hydroxyl group;
X is a methylene group, an ethylene group, or a vinylene group;
Y is a divalent group represented by 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 formula (II):
wherein:
R6 and R7 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;
provided that the following compounds and salts thereof are excluded:
(1) a compound wherein, when X is a vinylene group, Y is an ethylene group, R1, R2, R5 and R7 are hydrogen atoms, and R6 is a hydroxyl group, then
R3 is a hydroxyl group and R4 is a hydrogen atom, or
R3 is a hydroxyl group and R4 is a methoxy group, or
R3 and R4 are hydroxyl groups; and
(2) a compound wherein, when X is a vinylene group, Y is an ethylene group, and R1, R2, R5, R6 and R7 are hydrogen atoms, then
R3 and R4 are hydroxyl groups.
20. A whitening agent, comprising a compound according to claim 19 , or a salt thereof.
21. A method of whitening skin, comprising applying a whitening agent according to claim 20 to the skin.
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US14/287,899 US9295624B2 (en) | 2009-03-25 | 2014-05-27 | Amide derivative and whitening agent |
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PCT/JP2010/055162 WO2010110353A1 (en) | 2009-03-25 | 2010-03-25 | Novel amide derivative and skin whitening agent |
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US14/287,899 Division US9295624B2 (en) | 2009-03-25 | 2014-05-27 | Amide derivative and whitening agent |
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US20120070395A1 true US20120070395A1 (en) | 2012-03-22 |
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US13/240,358 Abandoned US20120070395A1 (en) | 2009-03-25 | 2011-09-22 | Novel amide derivative and whitening agent |
US14/287,899 Expired - Fee Related US9295624B2 (en) | 2009-03-25 | 2014-05-27 | Amide derivative and whitening agent |
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US14/287,899 Expired - Fee Related US9295624B2 (en) | 2009-03-25 | 2014-05-27 | Amide derivative and whitening agent |
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US (2) | US20120070395A1 (en) |
EP (1) | EP2412701B1 (en) |
JP (1) | JP5737176B2 (en) |
WO (1) | WO2010110353A1 (en) |
Cited By (4)
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 (en) * | 2013-05-14 | 2015-12-30 | 3M创新有限公司 | Pyridine- or pyrazine-containing compounds |
US9284271B2 (en) | 2010-12-13 | 2016-03-15 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Compounds for the treatment of neurodegenerative diseases |
CN110339079A (en) * | 2019-07-03 | 2019-10-18 | 温州婧爵医疗科技有限公司 | Composition comprising amide derivatives and its application in cosmetics |
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EP2622970A4 (en) * | 2010-09-29 | 2014-04-16 | Ajinomoto Kk | Salty taste enhancer |
SG10202009963PA (en) * | 2011-01-07 | 2020-11-27 | Allergan Inc | Melanin modification compositions and methods of use |
KR101604053B1 (en) * | 2011-08-05 | 2016-03-16 | (주)아모레퍼시픽 | Novel benzoic acid amide compound |
JP5916348B2 (en) * | 2011-11-02 | 2016-05-11 | 学校法人近畿大学 | Novel serotonin compound, tyrosinase inhibitor, and discoloration inhibitor |
CN102584672A (en) * | 2012-01-11 | 2012-07-18 | 合肥工业大学 | 5-methoxytryptamine derivative, and preparation method and application thereof |
JP2014080406A (en) * | 2012-10-18 | 2014-05-08 | Yukijirushi Shubyo Kk | Plant growth regulator |
EP3240524B1 (en) * | 2014-12-30 | 2020-01-01 | Unilever N.V. | A skin lightening composition comprising 4-hexylresorcinol and ilomastat |
CN107106453B (en) * | 2014-12-30 | 2023-04-04 | 联合利华知识产权控股有限公司 | Skin lightening composition comprising niacinamide and ilomastat |
AU2016317968B2 (en) * | 2015-09-04 | 2021-03-25 | Shin Poong Pharmaceutical Co., Ltd. | Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same |
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Citations (1)
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WO2007032551A1 (en) * | 2005-09-14 | 2007-03-22 | Ajinomoto Co., Inc. | Hemodynamics improving agent |
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JPH0853332A (en) * | 1994-08-11 | 1996-02-27 | Kao Corp | Whitening cosmetic |
JPH08175959A (en) * | 1994-12-27 | 1996-07-09 | Kao Corp | Skin cosmetic |
JP4341501B2 (en) * | 2004-08-10 | 2009-10-07 | 東亞合成株式会社 | Tyrosinase activity inhibitor |
FR2892923B1 (en) * | 2005-11-08 | 2009-01-16 | Engelhard Lyon Sa | USE OF PARA-COUMARIC OR PARA-HYDROXYCINNAMIC ACID DERIVATIVES IN COSMETIC OR DERMATOLOGICAL COMPOSITIONS. |
JP2009040688A (en) | 2007-08-06 | 2009-02-26 | Tsuchida Yuzo | Melanogenesis inhibitor |
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2010
- 2010-03-25 JP JP2011506106A patent/JP5737176B2/en not_active Expired - Fee Related
- 2010-03-25 WO PCT/JP2010/055162 patent/WO2010110353A1/en active Application Filing
- 2010-03-25 EP EP10756149.0A patent/EP2412701B1/en not_active Not-in-force
-
2011
- 2011-09-22 US US13/240,358 patent/US20120070395A1/en not_active Abandoned
-
2014
- 2014-05-27 US US14/287,899 patent/US9295624B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007032551A1 (en) * | 2005-09-14 | 2007-03-22 | Ajinomoto Co., Inc. | Hemodynamics improving agent |
US20080171781A1 (en) * | 2005-09-14 | 2008-07-17 | Ajinomoto Co., Inc. | Hemodynamics improving agent |
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Cited By (4)
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 (en) * | 2013-05-14 | 2015-12-30 | 3M创新有限公司 | Pyridine- or pyrazine-containing compounds |
CN110339079A (en) * | 2019-07-03 | 2019-10-18 | 温州婧爵医疗科技有限公司 | Composition comprising amide derivatives and its application in cosmetics |
Also Published As
Publication number | Publication date |
---|---|
EP2412701A4 (en) | 2013-02-13 |
JP5737176B2 (en) | 2015-06-17 |
JPWO2010110353A1 (en) | 2012-10-04 |
EP2412701B1 (en) | 2015-08-12 |
US20140255327A1 (en) | 2014-09-11 |
US9295624B2 (en) | 2016-03-29 |
EP2412701A1 (en) | 2012-02-01 |
WO2010110353A1 (en) | 2010-09-30 |
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