CN103124735B - 4-烷基间苯二酚衍生物和含有该衍生物的皮肤外用剂 - Google Patents
4-烷基间苯二酚衍生物和含有该衍生物的皮肤外用剂 Download PDFInfo
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- CN103124735B CN103124735B CN201180035055.0A CN201180035055A CN103124735B CN 103124735 B CN103124735 B CN 103124735B CN 201180035055 A CN201180035055 A CN 201180035055A CN 103124735 B CN103124735 B CN 103124735B
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- alkyl
- compound
- resorcinol derivative
- alkyl resorcinol
- salt
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- 238000002360 preparation method Methods 0.000 title description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 230000002087 whitening effect Effects 0.000 claims description 11
- 239000000470 constituent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 7
- 206010040829 Skin discolouration Diseases 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- HVGQWHMSVYODLJ-GFCCVEGCSA-N melanochrome Natural products CC1(C)Oc2cc3OC(=CC(=O)c3c(O)c2C[C@H]1O)CO HVGQWHMSVYODLJ-GFCCVEGCSA-N 0.000 description 18
- 210000003491 skin Anatomy 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- -1 isobutyl- Chemical group 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- GHMLBKRAJCXXBS-UHFFFAOYSA-N Resorcinol Natural products OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- VGMJYYDKPUPTID-UHFFFAOYSA-N 4-ethylbenzene-1,3-diol Chemical compound CCC1=CC=C(O)C=C1O VGMJYYDKPUPTID-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
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- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- LSEHCENPUMUIKC-UHFFFAOYSA-N 4-cyclohexylbenzene-1,3-diol Chemical compound OC1=CC(O)=CC=C1C1CCCCC1 LSEHCENPUMUIKC-UHFFFAOYSA-N 0.000 description 2
- CSHZYWUPJWVTMQ-UHFFFAOYSA-N 4-n-Butylresorcinol Chemical compound CCCCC1=CC=C(O)C=C1O CSHZYWUPJWVTMQ-UHFFFAOYSA-N 0.000 description 2
- NBMRFDSIHFRAQQ-UHFFFAOYSA-M C(C1=CC=CC=C1)OP(=O)(OCC1=CC=CC=C1)[O-].[Cl+] Chemical compound C(C1=CC=CC=C1)OP(=O)(OCC1=CC=CC=C1)[O-].[Cl+] NBMRFDSIHFRAQQ-UHFFFAOYSA-M 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- CRPRCSYCZWFVED-UHFFFAOYSA-N (4-ethylphenyl)phosphonic acid Chemical compound CCC1=CC=C(P(O)(O)=O)C=C1 CRPRCSYCZWFVED-UHFFFAOYSA-N 0.000 description 1
- WTVNRJZKWMXPJC-UHFFFAOYSA-N (4-propan-2-ylphenyl)phosphonic acid Chemical compound CC(C)C1=CC=C(P(O)(O)=O)C=C1 WTVNRJZKWMXPJC-UHFFFAOYSA-N 0.000 description 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 1
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 1
- 229920002079 Ellagic acid Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229960000271 arbutin Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 210000003764 chromatophore Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- IGARGHRYKHJQSM-UHFFFAOYSA-N cyclohexylbenzene Chemical compound C1CCCCC1C1=CC=CC=C1 IGARGHRYKHJQSM-UHFFFAOYSA-N 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960002852 ellagic acid Drugs 0.000 description 1
- 235000004132 ellagic acid Nutrition 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- 229960004232 linoleic acid Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940078752 magnesium ascorbyl phosphate Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- HTJNEBVCZXHBNJ-XCTPRCOBSA-H trimagnesium;(2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;diphosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.OC[C@H](O)[C@H]1OC(=O)C(O)=C1O HTJNEBVCZXHBNJ-XCTPRCOBSA-H 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- 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
- A61K8/55—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
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Abstract
本发明提供具有高的美白效果、安全性或稳定性也优异的化合物、以及混合有该化合物的皮肤外用剂。本发明化合物为下述通式(1)所示的4-烷基间苯二酚衍生物或其盐。(式中,R1为支链或环状的碳原子数3~7的烷基、或者直链的碳原子数2~5的烷基;R2和R3各自独立为氢原子或-P(O)(OR4)(OR5)所示的基团,且R2和R3中的一方或两方为-P(O)(OR4)(OR5)所示的基团;R4和R5各自独立为氢原子、或者直链或支链的碳原子数2~5的烷基。)
Description
相关申请
本申请主张2010年7月16日提交的日本国专利申请2010-161274号的优先权,将其纳入本申请。
技术领域
本发明涉及间苯二酚衍生物、特别是美白效果好、安全性、稳定性也优异的4-烷基间苯二酚衍生物。
背景技术
皮肤的褐斑、雀斑等色素沉积是由于激素的异常或紫外线的刺激引起表皮色素细胞内的黑色素产生亢进、黑色素在表皮内过剩沉积而发生的。
为了防止、改善这样的黑色素的异常沉积,人们在皮肤外用剂中混合美白剂。作为美白剂,大多是以具有黑色素生成抑制作用的化合物作为有效成分。
关于具有美白效果的化合物,迄今为止人们进行了许多研究,例如专利文献1~5中记载着4-烷基间苯二酚具有美白效果。
但是,4-烷基间苯二酚的效果或安全性、稳定性尚不能满足要求。
现有技术文献
专利文献
专利文献1:日本特开平2-49715号公报;
专利文献2:日本特表2002-540095号公报;
专利文献3:日本特开平11-152203;
专利文献4:日本特开2006-124357号公报;
专利文献5:日本特开2006-124358号公报。
发明内容
发明所要解决的课题
本发明鉴于上述背景技术而设,其目的在于提供:具有高的美白效果、安全性或稳定性也优异的化合物。
解决课题的方法
本发明人等进行了深入研究,结果发现:特定的4-烷基间苯二酚衍生物具有优异的黑色素生成抑制作用,安全性、稳定性也高,从而完成了本发明。
即,本发明所涉及的4-烷基间苯二酚衍生物为下述通式(1)所示的4-烷基间苯二酚衍生物或其盐:
式中,R1为支链或环状的碳原子数3~7的烷基、或者直链的碳原子数2~5的烷基;
R2和R3各自独立为氢原子或-P(O)(OR4)(OR5)所示的基团,但R2和R3中的一方或两方为-P(O)(OR4)(OR5)所示的基团;
R4和R5各自独立为氢原子、或者直链或支链的碳原子数2~5的烷基。
本发明还提供4-烷基间苯二酚衍生物或其盐,其特征在于:在上述的衍生物中,R2和R3两方为-P(O)(OR4)(OR5)所示的基团。
本发明还提供4-烷基间苯二酚衍生物或其盐,其特征在于:在上述任一项所述的衍生物中,R4和R5两方为氢原子。
另外,本发明所涉及的皮肤外用剂,其特征在于:含有选自上述任一项所述的4-烷基间苯二酚衍生物及其药理学上可接受的盐中的一种以上。
另外,本发明所涉及的美白剂,其特征在于:以选自上述任一项所述的4-烷基间苯二酚衍生物及其药理学上可接受的盐中的一种以上作为有效成分。
发明效果
本发明的4-烷基间苯二酚衍生物具有优异的黑色素生成抑制作用,还没有细胞毒性,因此通过混合该衍生物,可以得到具有高的美白效果和安全性的皮肤外用剂。另外,本发明的4-烷基间苯二酚衍生物不会因光而变色,稳定性也优异。
具体实施方式
本发明的4-烷基间苯二酚衍生物以下述通式(1)表示:
式(1)中,R1为支链或环状的碳原子数3~7的烷基、或者直链的碳原子数2~5的烷基。
作为碳原子数3~7的支链烷基,例如可以列举:异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基、1-甲基丁基、1-乙基丙基、1-乙基-2-甲基丙基、1-异丙基-2-甲基丙基等,但并不限于这些。支链烷基的支链位置或支链数也是任意的,没有特别限定。
作为碳原子数3~7的环状烷基,只要是包含至少一个饱和烃环、且总碳原子数为3~7的饱和烃基即可,例如可以列举:环戊基、环己基、4-甲基环戊基、1,4-二甲基环戊基、2-环戊基乙基、4-甲基环己基、环己基甲基等。
作为碳原子数2~5的直链烷基,可以列举:乙基、丙基、丁基、戊基。
虽然R2和R3各自独立为氢原子或-P(O)(OR4)(OR5)所示的基团,但R2和R3的一方或两方为-P(O)(OR4)(OR5)所示的基团。
R4和R5各自独立为氢原子、或者直链或支链的碳原子数2~5的烷基。
如上所述,本发明的4-烷基间苯二酚衍生物为4-烷基间苯二酚的至少一个酚羟基的氢原子被基团-P(O)(OR4)(OR5)取代而得到的磷酸酯类化合物。
作为本发明的4-烷基间苯二酚衍生物的优选例之一,可以列举:R2和R3两者为-P(O)(OR4)(OR5)所示的基团的4-烷基间苯二酚衍生物。
作为其他优选例之一,可以列举:R4和R5两者为氢原子的4-烷基间苯二酚衍生物。
本发明的4-烷基间苯二酚衍生物可以利用公知的方法进行合成,代表性的方法有:可以通过对4-烷基间苯二酚进行磷酸酯化反应来进行合成。例如,使4-烷基间苯二酚在THF等溶剂中与氢化钠反应,之后与磷酸烷基卤化物反应,从而可以得到R2和R3中的至少一个为基团-P(O)(OR4)(OR5)[R4、R5定义同上,但至少有一个为烷基]的4-烷基间苯二酚衍生物(参照J. Org. Chem. 第43卷, No.25, 第4797-4799页(1978)等)。
另外,通过使用磷酸二苄基卤化物等代替磷酸烷基卤化物,将4-烷基间苯二酚磷酸酯化,之后在Pd-C存在下进行催化还原以除去苄基,也可以得到R2和R3中的至少一个为基团-P(O)(OR4)(OR5)[R4和R5为氢原子]的4-烷基间苯二酚衍生物。
此外,利用使用磷酰氯的方法[Biochimica et Biophysica Acta; 第13卷; (1954); 第260-267页,WO2008/103415]、使用五氧化二磷的方法[Bulletin of the Chemical Society of Japan; 第80卷; nb. 7; (2007); 第1429-1434页]等,也可以得到本发明所涉及的4-烷基间苯二酚衍生物。
4-烷基间苯二酚可以利用上述专利文献1~5或其他文献中记载的方法进行合成。
磷酸烷基卤化物或磷酸苄基卤化物可以使用市售品,此外还可以使用利用公知的方法合成的产品。例如,可以在甲苯、氯苯或二氯苯等非极性溶剂中,在三甲胺、三乙胺或N,N-二甲基苯胺等碱的存在下,通过使对应的醇与氯氧化磷在0~20℃下反应来合成。
当R4和/或R5为氢原子时等,根据需要,可以利用常规方法形成盐。例如,可以列举钠、钾、钙、镁等碱金属或碱土金属的盐等,优选的盐有钠盐、钾盐。
本发明的4-烷基间苯二酚衍生物具有优异的黑色素生成抑制效果,其效果高于对应的4-烷基间苯二酚(R2=R3=H)。另外,无细胞毒性,安全性也优异,因此还可以在皮肤外用剂中高浓度混合。而且,本发明的4-烷基间苯二酚衍生物在光稳定性方面也非常优异。
因此,本发明的4-烷基间苯二酚衍生物可用作美白剂,适于混合在皮肤外用剂、特别是以改善或预防褐斑、雀斑、脸色发暗等为目的的皮肤外用剂中。
在皮肤外用剂中混合本发明的4-烷基间苯二酚衍生物时,对其在皮肤外用剂中的混合量没有特别限定,但通常为0.01质量%以上、优选为0.1质量%以上。若混合量太少,则效果得不到充分发挥。对上限没有特别限定,但通常为10质量%以下、优选5质量%以下、进一步优选为1质量%以下。即使过剩混合,有时也得不到与总量相称的显著的效果的提高。
本发明所涉及的皮肤外用剂,除了混合4-烷基间苯二酚衍生物以外,还可以利用常规方法来制备。
另外,在本发明的皮肤外用剂中,除了混合4-烷基间苯二酚衍生物以外,在不损及本发明效果的范围内,根据需要还可以适当混合通常用于化妆品或药品等皮肤外用剂的其他成分、例如油分、润湿剂、防紫外线剂、抗氧化剂、金属离子封闭剂、表面活性剂、防腐剂、保湿剂、香料、水、醇、增稠剂、粉末、色材、生药、其他各种药效成分等。
而且,还可以适当混合维生素C、抗坏血酸磷酸镁、抗坏血酸葡糖苷、熊果苷、曲酸、噜忻喏(rucinol)、鞣花酸、氨甲环酸、亚油酸等其他美白剂。
本发明的皮肤外用剂可以在化妆品、药品、准药品领域广泛使用。对其剂型没有特别限定,只要可以应用于皮肤即可,例如可以使用溶液状、乳化状、固体状、半固体状、粉末状、粉末分散状、水-油两层分离状、水-油-粉末三层分离状、软膏状、凝胶状、气溶胶状、泡沫状(ムース状)、棒状等任意剂型。另外,其使用形式也是任意的,例如可以列举:化妆水、乳液、霜剂、面膜、精华素、凝胶等护肤化妆品;或粉底、化妆基底、遮瑕膏等美容化妆品等。
以下,列举具体例子以进一步说明本发明,但并不限于这些例子。
实施例
试验例1 黑色素生成抑制和细胞毒性试验
按照以下方法研究黑色素生成抑制效果以及细胞毒性。
(1) 细胞接种、试验物质的添加
将小鼠B16黑素瘤细胞以100,000细胞/孔接种在6孔板上。第二天,添加试验物质溶液(溶剂:二甲基亚砜),供给细胞增殖试验和黑色素生成抑制试验。
(2) 细胞增殖试验
添加试验物质溶液起3天后吸引除去培养基,之后添加1ml含有10%的Alamar Blue溶液的EMEM培养基,使之在37℃下反应。30分钟后将100μl移入96孔板上,在激发波长544nm、测定波长590nm下测定荧光。以该值作为细胞数的相对值,算出试验物质添加组与试验物质未添加组(只添加溶剂)的细胞数比率(%细胞数)。%细胞数越高则意味着细胞毒性越低。
(3) 黑色素生成抑制试验
添加试验物质溶液起3天后吸引除去培养基,用缓冲液(50mM的磷酸缓冲液、pH6.8)清洗,之后添加1M的NaOH溶解细胞,测定475nm的吸光度。以该值作为黑色素量的相对值,算出试验物质添加组与试验物质未添加组(只添加溶剂)的黑色素量比率(%)。黑色素量比率越低则意味着黑色素生成抑制效果越高。
表1显示作为本发明化合物的1,3-双膦酰氧基-4-乙基苯(化合物1)、1,3-双膦酰氧基-4-异丙基苯(化合物2)和1,3-双膦酰氧基-4-环己基苯(化合物3)的结果。
由黑色素量比率可知:本发明化合物具有优异的黑色素生成抑制效果,并且即使在高浓度下也没有细胞毒性。
[表1]
*各化合物的结构式:
。
表2显示4-乙基间苯二酚(比较化合物1)、4-异丙基间苯二酚(比较化合物2)和4-环己基间苯二酚(比较化合物3)的结果。
比较表1和表2时可知:本发明化合物即使在较比较化合物低的浓度下也显示出几乎相同程度的黑色素生成抑制效果。即,可以说本发明化合物具有较比较化合物高的黑色素生成抑制效果。
[表2]
*各化合物的结构式:
。
试验例2 光稳定性试验
将受检化合物溶液装入透明密闭的玻璃容器内,进行日光暴露(50MJ)或氙灯(Xe)照射(96小时),肉眼观察外观。作为对照,用铝箔包覆容器使其完全避光后进行日光暴露。
下述表3显示作为本发明化合物的1,3-双膦酰氧基-4-乙基苯(化合物1)和1,3-双(二乙基膦酰氧基)-4-乙基苯(化合物4)、以及作为比较例的4-乙基间苯二酚(比较化合物1)的结果。受检化合物溶液的浓度均为0.1质量%[溶剂:乙醇/水(20/80,v/v)]。
如表3所示,在比较化合物中通过光照射确认到着色,相对于此,在本发明化合物中外观上完全没有确认到变化。
如上所述,本发明所涉及的4-烷基间苯二酚衍生物的光稳定性非常优异。
[表3]
*化合物4:
。
以下显示本发明所涉及的4-烷基间苯二酚衍生物的代表性制备例。使用对应的原料,根据这些制备例进行反应,从而可以得到所期望的4-烷基间苯二酚衍生物。
制备例1 1,3-双膦酰氧基-4-乙基苯(化合物1)
向423mg 4-乙基间苯二酚的10ml四氢呋喃溶液中加入269mg氢化钠(60%、分散在液体石蜡中),在0℃下搅拌30分钟,之后滴加20ml氯磷酸二苄酯(10w/v%苯溶液)。在室温下搅拌3小时,之后加入10ml水,用30ml乙酸乙酯提取,之后用10ml饱和食盐水清洗,用无水硫酸钠干燥后浓缩。将2.16g残余物供给硅胶柱层析(60g硅胶、氯仿~氯仿:甲醇=50:1),得到1.65g为黄色液体的1,3-双(二苄基膦酰氧基)-4-乙基苯(收率为84%)。
1H-NMR (CDCl3)δ: 1.13 (3H, t, J=0.0 Hz), 2.57 (2H, q, J=0.0 Hz), 5.09 (8H, m), 6.96 (1H, d, J=0.0 Hz), 7.08 (1H, d, J=0.0 Hz), 7.18 (1H, s), 7.32 (20H, m)。
向1.09g 1,3-双(二苄基膦酰氧基)-4-乙基苯的10ml乙醇溶液中加入97.3mg 5%钯-碳(50%含水品),在氢气环境中、室温下搅拌7小时。滤去催化剂后将滤液浓缩,得到463mg为淡黄色固体的标题化合物(收率为93%)。
1H-NMR (DMSO-d 6 )δ: 1.12 (3H, t, J=0.0 Hz), 2.57 (2H, q, J=0.0 Hz), 5.5 -6.7 (4H, brs), 6.90 (1H, d, J=0.0 Hz), 7.09 (1H, s), 7.16 (1H, d, J=0.0 Hz)。
制备例2 1,3-双膦酰氧基-4-异丙基苯(化合物2)
向466mg 4-异丙基间苯二酚的10ml四氢呋喃溶液中加入269mg氢化钠(60%、分散在液体石蜡中),在0℃下搅拌30分钟,之后滴加20ml氯磷酸二苄酯(10w/v%苯溶液)。在室温下搅拌3小时,之后加入30ml水,用30ml乙酸乙酯提取,之后用20ml饱和食盐水清洗,用无水硫酸钠干燥后浓缩。将2.23g残余物供给硅胶柱层析(76g硅胶、氯仿~氯仿:甲醇=70:1),得到1.71g为黄色液体的1,3-双(二苄基膦酰氧基)-4-异丙基苯(收率为83%)。
1H-NMR (CDCl3)δ: 1.13 (6H, d, J=6.8 Hz), 3.19 (1H, septet, J=6.8 Hz), 5.04 -5.13 (8H, m), 6.99 (1H, d, J=8.7 Hz), 7.14 (1H, d, J=8.7 Hz), 7.19 (1H, s), 7.30 (20H, m)。
向1.01g 1,3-双(二苄基膦酰氧基)-4-异丙基苯的10ml乙醇溶液中加入109mg 5%钯-碳(50%含水品),在氢气环境中、室温下搅拌14小时。滤去催化剂后将滤液浓缩,得到464mg为黄色糊状的标题化合物(收率为100%)。
1H-NMR (DMSO-d 6 )δ: 1.14 (6H, d, J=6.8 Hz), 3.25 (1H, septet, J=6.8 Hz), 4.5 -6.2 (4H, brs), 6.93 (1H, d, J=8.2 Hz), 7.09 (1H, s), 7.21 (1H, d, J=8.2 Hz)。
制备例3 1,3-双膦酰氧基-4-环己基苯(化合物3)
向926mg 4-环己基间苯二酚的10ml四氢呋喃溶液中加入404mg氢化钠(60%、分散在液体石蜡中),在0℃下搅拌30分钟,之后滴加30ml氯磷酸二苄基酯(10w/v%苯溶液)。在室温下搅拌3小时,之后加入30ml水,用30ml乙酸乙酯提取,之后用20ml饱和食盐水清洗,用无水硫酸钠干燥后浓缩。将4.12g残余物供给硅胶柱层析(90g硅胶、氯仿~氯仿:甲醇=100:1),得到2.19g为黄色液体的1,3-双(二苄基膦酰氧基)-4-环己基苯(收率为64%)。
1H-NMR (CDCl3)δ: 1.12 -1.38 (5H, m), 1.66 -1.82 (5H, m), 2.84 (1H, m), 5.09 (8H, m), 6.98 (1H, d, J=8.7 Hz), 7.13 (1H, d, J=8.7 Hz), 7.18 (1H, s), 7.30 (20H, m)。
向1.75g 1,3-双(二苄基膦酰氧基)-4-环己基苯的10ml乙醇溶液中加入256mg 5%钯-碳(50%含水品),在氢气环境中、室温下搅拌14小时。滤去催化剂后将滤液浓缩,得到805mg为淡黄色泡沫状的标题化合物(收率为93%)。
1H-NMR (DMSO-d 6 )δ: 1.13 -1.41 (5H, m), 1.60 -1.85 (5H, m), 2.88 (1H, m), 6.7 -8.2 (4H, brs), 6.92 (1H, d, J=8.2 Hz), 7.08 (1H, s), 7.18 (1H, d, J=8.2 Hz)。
制备例4 1,3-双(二乙基膦酰氧基)-4-乙基苯(化合物4)
向691mg 4-乙基间苯二酚的10ml四氢呋喃溶液中加入440mg氢化钠(60%、分散在液体石蜡中),在0℃下搅拌30分钟,之后滴加1.73ml氯磷酸二乙酯。在室温下搅拌3小时,之后加入10ml水,用30ml乙酸乙酯提取,之后用10ml饱和食盐水清洗,用无水硫酸钠干燥后浓缩。将2.43g残余物供给硅胶柱层析(40g硅胶、氯仿~氯仿:甲醇=10:1),得到2.05g淡黄色油状的标题化合物(收率为100%)。
1H-NMR (CDCl3)δ: 1.20 (3H, t, J=0.0 Hz), 1.36 (12H, m), 2.67 (2H, q, J=0.0 Hz),4.22 (8H, m), 7.02 (1H, d, J=0.0 Hz), 7.16 (1H, d, J=0.0 Hz), 7.22 (1H, s)。
以下,给出混合了本发明的4-烷基间苯二酚衍生物的皮肤外用剂的配方例。通过混合本发明的4-烷基间苯二酚衍生物,这些皮肤外用剂均发挥美白效果。
Claims (5)
1.通式(1)所示的4-烷基间苯二酚衍生物或其盐:
式中,R1为支链或环状的碳原子数3~7的烷基、或者直链的碳原子数2~5的烷基;
R2和R3各自独立为氢原子或-P(O)(OR4)(OR5)所示的基团,但R2或R3、或者R2和R3均为-P(O)(OR4)(OR5)所示的基团;
R4和R5各自独立为氢原子、或者直链或支链的碳原子数2~5的烷基。
2.权利要求1所述的4-烷基间苯二酚衍生物或其盐,其特征在于:R2和R3均为-P(O)(OR4)(OR5)所示的基团。
3.权利要求1或2所述的4-烷基间苯二酚衍生物或其盐,其特征在于:R4和R5均为氢原子。
4.皮肤外用剂,其特征在于:含有选自权利要求1~3中任一项所述的4-烷基间苯二酚衍生物或其盐中的一种以上。
5.美白剂,其特征在于:以选自权利要求1~3中任一项所述的4-烷基间苯二酚衍生物或其盐中的一种以上作为有效成分。
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