CN108929271A - 酪氨酸酶抑制剂及其制备方法与用途 - Google Patents
酪氨酸酶抑制剂及其制备方法与用途 Download PDFInfo
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- CN108929271A CN108929271A CN201810693660.0A CN201810693660A CN108929271A CN 108929271 A CN108929271 A CN 108929271A CN 201810693660 A CN201810693660 A CN 201810693660A CN 108929271 A CN108929271 A CN 108929271A
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- Prior art keywords
- pyrazoles
- formamide
- phenyl
- dihydroxy phenyl
- compound
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- 101710147108 Tyrosinase inhibitor Proteins 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 3
- -1 sulfonic group Chemical group 0.000 claims description 115
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 97
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical class [H]C([H])([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical class [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical class BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Chemical class 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000001153 fluoro group Chemical class F* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- WKGHUAZJNBXABN-UHFFFAOYSA-N 3-bromo-2-chloro-6-methyl-5-nitropyridine Chemical compound CC1=NC(Cl)=C(Br)C=C1[N+]([O-])=O WKGHUAZJNBXABN-UHFFFAOYSA-N 0.000 claims description 4
- 229940095102 methyl benzoate Drugs 0.000 claims description 4
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 3
- JCBDYEGJWIDAKO-UHFFFAOYSA-N 4-(1H-pyrazol-5-yl)benzene-1,3-diol Chemical class OC1=CC(O)=CC=C1C1=NNC=C1 JCBDYEGJWIDAKO-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- FZKRWFHWHQCBPM-UHFFFAOYSA-N OC1=C(C=CC(=C1)O)C1=NN(C=C1)C1=CC(=CC=C1)F Chemical class OC1=C(C=CC(=C1)O)C1=NN(C=C1)C1=CC(=CC=C1)F FZKRWFHWHQCBPM-UHFFFAOYSA-N 0.000 claims description 3
- ZJTVMRVJWXMKCS-UHFFFAOYSA-N OC1=C(C=CC(=C1)O)C1=NN(C=C1)C1=CC=C(C=C1)Br Chemical class OC1=C(C=CC(=C1)O)C1=NN(C=C1)C1=CC=C(C=C1)Br ZJTVMRVJWXMKCS-UHFFFAOYSA-N 0.000 claims description 3
- UVHOIDDXHSRUPB-UHFFFAOYSA-N 4-(1-phenylpyrazol-3-yl)benzene-1,3-diol Chemical class OC1=C(C=CC(=C1)O)C1=NN(C=C1)C1=CC=CC=C1 UVHOIDDXHSRUPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical class FC(F)(F)* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 102000003425 Tyrosinase Human genes 0.000 abstract description 19
- 108060008724 Tyrosinase Proteins 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 25
- 238000010189 synthetic method Methods 0.000 description 25
- 239000002585 base Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- SULYEHHGGXARJS-UHFFFAOYSA-N 2',4'-dihydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1O SULYEHHGGXARJS-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
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- 230000002018 overexpression Effects 0.000 description 3
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 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 2
- AHMIDUVKSGCHAU-UHFFFAOYSA-N Dopaquinone Natural products OC(=O)C(N)CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- AHMIDUVKSGCHAU-LURJTMIESA-N L-dopaquinone Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1=CC(=O)C(=O)C=C1 AHMIDUVKSGCHAU-LURJTMIESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 208000003351 Melanosis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical group CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008099 melanin synthesis Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
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- KLAKIAVEMQMVBT-UHFFFAOYSA-N p-hydroxy-phenacyl alcohol Natural products OCC(=O)C1=CC=C(O)C=C1 KLAKIAVEMQMVBT-UHFFFAOYSA-N 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RESHZVQZWMQUMB-UHFFFAOYSA-N 1,3-bis(phenylmethoxy)benzene Chemical compound C=1C=CC=CC=1COC(C=1)=CC=CC=1OCC1=CC=CC=C1 RESHZVQZWMQUMB-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- TWSIYGATPWEKBK-UHFFFAOYSA-N 4h-1,3-benzodioxine Chemical compound C1=CC=C2OCOCC2=C1 TWSIYGATPWEKBK-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 241001656831 Arctous alpina Species 0.000 description 1
- 102000030523 Catechol oxidase Human genes 0.000 description 1
- 108010031396 Catechol oxidase Proteins 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 238000010521 absorption reaction Methods 0.000 description 1
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- 150000001336 alkenes 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
- 239000012267 brine Substances 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
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- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229960002852 ellagic acid Drugs 0.000 description 1
- 235000004132 ellagic acid Nutrition 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- LAPFGEZREMPMTB-UHFFFAOYSA-N ethyl 4-[2,4-bis(phenylmethoxy)phenyl]-2,4-dioxobutanoate Chemical compound C1=C(OCC=2C=CC=CC=2)C(C(=O)CC(=O)C(=O)OCC)=CC=C1OCC1=CC=CC=C1 LAPFGEZREMPMTB-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 150000002576 ketones Chemical class 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
- 229960004502 levodopa Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 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
- 239000000203 mixture Substances 0.000 description 1
- 108010058393 monophenolase Proteins 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明属于医药领域，涉及一类酪氨酸酶抑制剂(I)及其制备方法，具体涉及2,4‑二羟基苯酚‑吡唑‑苯胺结构类化合物，药效学试验证明，本发明的化合物通过抑制酪氨酸酶活性而具有抗黑色素生成的作用，可用于预防或治疗黑色素过表达疾病的药物。
Description
技术领域
本发明属于医药领域，涉及一类酪氨酸酶抑制剂及其制备方法，具体涉及2,4-二羟基苯酚-吡唑-苯胺结构类化合物，通过抑制酪氨酸酶活性而具有抗黑色素生成作用。
背景技术
酪氨酸酶(Tyrosinase，EC.1.14.18.1)是一种含酮的金属酶，同时兼有单酚酶和二酚酶生物活性，广泛分布于动、植物和微生物中。在动物、微生物中多被称为酪氨酸酶，在植物中多被称为多酚氧化酶。酪氨酸酶是黑色素生成过程中的关键酶，直接抑制酪氨酸酶的催化活性可以阻止黑色素的合成，因此抑制酪氨酸酶有希望作为治疗与黑色素过度表达相关的疾病，如雀斑、老年斑、黄褐斑、炎症后黑皮病、日光性着色斑，同时与治疗癌症疾病相关。酪氨酸酶也参与神经黑色素的生成，氧化多巴成为多巴醌，而多巴醌过表达可以造成神经细胞损伤和死亡，这表明酪氨酸酶也与神经退行性疾病有关，如帕金森病和亨延顿病等。酪氨酸酶也参与农产品蔬菜水果的褐变反应，酪氨酸酶抑制剂也可以用作食品保鲜剂。同时也可以作为生物杀虫剂应用农业抗虫领域。综上所述，酪氨酸酶抑制剂在美容保健、疾病治疗、虫害防治、食品保鲜等领域有着广泛的应用前景。
对酪氨酸酶及抑制剂的研究涉及生物、医学、农学、化学、药学等多个学科和领域，寻求新的酪氨酸酶抑制剂是药物化学家和食品科学家高度关注的研究课题之一。目前酪氨酸酶抑制剂被主要用于美白化妆品中。有许多广为人知的酪氨酸酶抑制剂，例如曲酸、熊果苷、氢醌、维生素C、鞣花酸及壬二酸等。由于这些酪氨酸酶抑制剂具有一些安全性问题，限制了它们的使用。因此，研究安全、高效、价格低廉、具有我国自主知识产权的酪氨酸酶抑制剂是迫切需要的。
发明内容
本发明公开了一类通式(I)的化合物，药效学试验证明本发明的化合物具有酪氨酸酶抑制活性，可用于预防或治疗黑色素过度表达相关疾病。
本发明化合物结构式如下：
其中R代表其中R1代表任意取代的羟基、卤素、C1～C4烷基、卤素取代的C1～C4烷基、C1～C4烷氧基、氰基、磺酸基、硝基或-NR2R3，R2、R3各自独立地代表氢或C1～C3烷基；其中R4代表任意取代的卤素、C1～C4烷基、C1～C4烷氧基、硝基，氰基或羟基；R5代表任意取代的卤素、C1～C4烷基、C1～C4烷氧基、硝基、氰基或羟基。
其中R1优选代表任意取代的氟、氯、溴、甲基、三氟甲基、甲氧基、氰基、硝基或-NR2R3；R2、R3独立的选自氢、甲基或乙基。
R4优选代表任意取代的氟、氯、溴、甲基、甲氧基、氰基或羟基。
R5优选代表任意取代的氟、氯、溴、甲基、甲氧基、氰基或羟基。
本发明更优选下列任一结构的化合物：
3-(2,4-二羟基苯基)-N-苯基-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(邻-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(间-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(对-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-异丙基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3-氟苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-氟苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-氯苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-溴苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2,4-二甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2,6-二甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3,4,5-三甲氧基苯基)-1H-吡唑-5-甲酰胺；
N-(苯并[d][1,3]二氧杂环戊烯-5-基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺；
4-(3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰氨基)苯甲酸甲酯；
3-(2,4-二羟基苯基)-N-(4-(三氟甲基)苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(吡啶-3-基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(6-甲基吡啶-2-基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(萘-1-基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(萘-2-基)-1H-吡唑-5-甲酰胺；
N-(4-(二乙基氨基)苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-(二甲基氨基)苯基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(4-硝基苯基)-1H-吡唑-5-甲酰胺；
N-(4-氰基苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺。
本发明的化合物制备方法包括：以2,4-二羟基苯乙酮为原料，经溴苄保护羟基后与草酸二乙脂反应得到4-(2,4-双(苄氧基)苯基)-2,4-二氧代丁酸乙酯，与盐酸肼反应得到3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸乙酯，然后氢氧化钠水解得到3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸；再与苯胺衍生物反应，得中间体，最后和甲酸铵、钯碳反应制备得到如式(Ⅰ)所示的抗酪氨酸酶活性作用化合物，反应式如下：
本发明化合物可以和药学上常用的盐成盐，比如：盐酸盐、马来酸盐、枸橼酸盐等。本发明化合物药学上可接受的盐具有与化合物同样的药效活性。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
下面是本发明部分化合物药效学试验及结果：
酪氨酸酶抑制活性的测定：
将0.005mL不同浓度的化合物溶液与0.05mL酪氨酸或L-DOPA溶液(1.25mM)，以及0.08mL磷酸盐缓冲溶液(0.05M，pH 6.8)在25℃预温10分钟。然后向混合物中加入0.015mL的酪氨酸酶水溶液(333U/mL)。分别在25℃下保温30分钟、5分钟后，在475nm下测定含有L-酪氨酸或L-DOPA的反应混合物的吸收(Abs)线性。
将0.005mL不含有化合物的纯溶剂作为空白对照，实验平行测定三次并求平均值，根据量效关系内插法计算IC50值。结果如下表1所示：
表1化合物对Tyrosinase和Dopa的测试结果
由表1可知，本发明化合物具有对酪氨酸酶的良好的抑制活性。因此，对于黑色素过度表达的相关疾病的治疗尤为重要。综上所述，酪氨酸酶抑制剂在美容保健、疾病治疗、虫害防治、食品保鲜等领域有着广泛的应用前景。
具体实施方式
实施例1
(1)1-(2,4-双(苄氧基)苯基)乙酮的合成
取2,4-二羟基苯乙酮(5g,32.8mmol)与溴化苄(14.1g,82.2mmol)，加入到茄形瓶中，加入乙腈，油浴加热85℃，反应液回流3～5小时，反应结束后，旋掉乙腈后加入水，用乙酸乙酯萃取，卤水洗，有机层干燥，重结晶，抽滤，滤饼红外下烘干，得白色固体，产率为95％。
(2)4-(2,4-双(苄氧基)苯基)-2,4-二氧代丁酸乙酯的合成
取1-(2,4-双(苄氧基)苯基)乙酮(8g，24.1mmol)、草酸二乙脂(4.22g，28.9mmol)及乙醇钠(3.28g，48.1mmol)，加入到茄形瓶中，加入乙醇，油浴加热80℃，反应液回流5～8小时，冷却至室温；析出黄色固体，抽滤，滤饼红外下烘干，产率为85％。
(3)3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸乙酯的合成
取4-(2,4-双(苄氧基)苯基)-2,4-二氧代丁酸乙酯(5g,11.6mmol)与盐酸肼(0.95g,13.9mmol)，加入乙醇，油浴加热85℃，回流反应4～8小时，反应结束后，冷却至室温，析出黄色固体，抽滤，滤饼红外下烘干，产率为92％。
(4)3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸的合成
取3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸乙酯，加入到茄形瓶中，再加入氢氧化钠水溶液(2mol/L)，油浴加热100℃，回流反应8小时，反应结束后，冷却至室温，调节pH至2析出白色固体，抽滤，滤饼红外下烘干，产率为86％。
(5)中间体1的合成
取3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酸，加入到茄形瓶中，加入二氯甲烷，滴加氯化亚砜，油浴加热75℃，反应4小时，制备成3-(2,4-双(苄氧基)苯基)-1氢-吡唑-5-甲酰氯，冰浴下滴加到苯胺衍生物里，碳酸钾为碱。滴加完毕后室温搅拌6小时，用水淬灭反应，二氯甲烷萃取分离有机层，干燥，旋干，柱层析分离得到中间体1，黄色固体，中间体结构通式为
其中R代表苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-异丁基苯基、3-氟苯基、4-氟苯基、4-氯苯基、4-溴苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2,4-二甲氧基苯基、2,6-二甲氧基苯基、3,4,5-三甲氧基苯基、3,4-亚甲二氧基苯基、4-甲氧羰基苯基、4-三氟甲基苯基、3-吡啶基、6-甲基吡啶基、1-萘基、2-萘基、4-N,N-二乙氨基苯基、4-N,N二甲氨基苯基、4-硝基、4-腈基。
(6)化合物(2)的合成
将中间体1(0.5g，1.05mmol)加入反应瓶中，将中间体1，甲酸铵、10％的钯碳溶于甲醇中，油浴加热65℃，反应回流2小时，抽滤，旋干，重结晶，抽滤，滤饼红外下烘干，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。
1H NMR(300MHz,DMSO-d6)δ10.03(s,1H),7.82(d,J＝7.6Hz,2H),7.49(d,J＝8.5Hz,1H),7.35(t,J＝7.9Hz,2H),7.16–7.05(m,2H),6.45(d,J＝2.2Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H).ESI-MS m/z 296.1052[M+H]+.
实施例2
3-(2,4-二羟基苯基)-N-(邻-甲苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(邻甲苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。
1H NMR(300MHz,DMSO-d6)δ13.16(s,1H),10.18(s,1H),9.61(s,1H),9.39(s,1H),7.71(s,1H),7.48(d,J＝8.3Hz,1H),7.24(m,2H),7.11(s,1H),7.01(s,1H),6.45(s,1H),6.34(d,J＝8.3Hz,1H),2.28(s,3H).ESI-MS m/z 310.1211[M+H]+.
实施例3
3-(2,4-二羟基苯基)-N-(间-甲苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(间甲苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。
1H NMR(300MHz,DMSO-d6)δ9.92(s,2H),7.69–7.55(m,2H),7.49(d,J＝8.5Hz,1H),7.23(t,J＝7.7Hz,1H),7.14(s,1H),6.91(d,J＝7.2Hz,1H),6.45(d,J＝2.2Hz,1H),6.35(dd,J＝8.5,2.3Hz,1H),2.31(s,3H).ESI-MS m/z 310.1203[M+H]+.
实施例4
3-(2,4-二羟基苯基)-N-(对-甲苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(对甲苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ10.10(s,1H),8.56(d,J＝4.5Hz,2H),7.82(d,J＝8.3Hz,2H),7.61(d,J＝8.5Hz,1H),7.32–7.16(m,2H),6.57(d,J＝1.8Hz,1H),6.46(dd,J＝8.4,2.4Hz,1H),2.41(s,3H).ESI-MS m/z 310.1211[M+H]+.
实施例5
3-(2,4-二羟基苯基)-N-(4-异丙基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(4-异丙基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ10.02(s,1H),8.48(d,J＝1.4Hz,1H),7.72(d,J＝6.9Hz,2H),7.49(d,J＝8.6Hz,1H),7.28–7.16(m,3H),6.47(s,1H),6.34(d,J＝8.7Hz,1H),2.86(d,J＝6.4Hz,1H),1.21(d,J＝6.8Hz,6H).ESI-MS m/z 338.1524[M+H]+.
实施例6
3-(2,4-二羟基苯基)-N-(3-氟苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(3-氟苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.16(s,1H),10.14(s,2H),9.62(s,1H),7.84(d,J＝8.8Hz,2H),7.53(s,1H),7.50(s,1H),7.25(d,J＝4.1Hz,1H),7.04(d,J＝1.6Hz,1H),6.47(d,J＝2.0Hz,1H),6.35(dd,J＝8.4,2.0Hz,1H).ESI-MS m/z 314.0954[M+H]+.
实施例7
3-(2,4-二羟基苯基)-N-(4-氟苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-氟苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.16(s,1H),10.14(d,J＝3.6Hz,2H),9.62(s,1H),7.91(s,1H),7.88(s,1H),7.40(s,1H),7.37(s,1H),7.24(s,1H),7.04(d,J＝1.5Hz,1H),6.47(d,J＝2.0Hz,1H),6.35(dd,J＝8.4,2.0Hz,1H).ESI-MS m/z 314.0844[M+H]+.
实施例8
3-(2,4-二羟基苯基)-N-(4-氯苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-氯苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.14(s,1H),10.13(s,1H),10.07(s,1H),9.61(s,1H),7.90–7.80(m,2H),7.49(d,J＝8.4Hz,1H),7.18(t,J＝8.7Hz,2H),7.03(s,1H),6.47(d,J＝2.0Hz,1H),6.35(dd,J＝8.4,2.0Hz,1H).ESI-MS m/z 330.0853[M+H]+.
实施例9
3-(2,4-二羟基苯基)-N-(4-溴苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-溴苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.14(s,1H),10.13(s,1H),10.07(s,1H),9.61(s,1H),7.90–7.80(m,2H),7.49(d,J＝8.4Hz,1H),7.18(t,J＝8.7Hz,2H),7.03(s,1H),6.47(d,J＝2.0Hz,1H),6.35(dd,J＝8.4,2.0Hz,1H).ESI-MS m/z 374.0102[M+H]+.
实施例10
3-(2,4-二羟基苯基)-N-(2-甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(2-甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.21(s,1H),10.26(s,1H),9.64(s,1H),9.44(s,1H),8.49–8.29(m,1H),7.48(d,J＝8.5Hz,1H),7.09(m,2H),7.00(m,2H),6.46(d,J＝2.3Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H),3.92(s,3H).ESI-MS m/z 326.1125[M+H]+.
实施例11
3-(2,4-二羟基苯基)-N-(3-甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(3-甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.14(s,1H),10.14(s,1H),9.91(s,1H),9.60(s,1H),7.58–7.46(m,2H),7.43(d,J＝8.5Hz,1H),7.23(t,J＝7.9Hz,1H),7.02(s,1H),6.66(d,J＝7.8Hz,1H),6.46(s,1H),6.38–6.28(m,1H),3.76(s,3H).ESI-MS m/z326.1123[M+H]+.
实施例12
3-(2,4-二羟基苯基)-N-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ9.84(s,1H),7.72–7.67(m,2H),7.48(d,J＝8.5Hz,1H),7.13(s,1H),6.98–6.86(m,2H),6.45(d,J＝2.3Hz,1H),6.36(dd,J＝8.5,2.4Hz,1H),3.76(s,3H).ESI-MS m/z 326.1137[M+H]+.
实施例13
3-(2,4-二羟基苯基)-N-(2,4-二甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(2,4-二甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.15(s,1H),10.22(s,1H),9.63(s,1H),9.23(s,1H),8.20(s,1H),7.47(d,J＝8.5Hz,1H),7.01(s,1H),6.70(d,J＝2.6Hz,1H),6.56(dd,J＝8.8,2.6Hz,1H),6.45(d,J＝2.1Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H),3.90(s,3H),3.77(s,3H).ESI-MS m/z 356.1232[M+H]+.
实施例14
3-(2,4-二羟基苯基)-N-(2,6-二甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(2,6-二甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),8.44(s,1H),7.45(d,J＝8.5Hz,1H),7.25(t,J＝8.4Hz,1H),7.10(s,1H),6.72(d,J＝8.5Hz,2H),6.44(d,J＝2.3Hz,1H),6.33(dd,J＝8.5,2.3Hz,1H),3.75(s,3H).ESI-MS m/z 356.1212[M+H]+.
实施例15
3-(2,4-二羟基苯基)-N-(3,4,5-三甲氧基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(3,4,5-三甲氧基苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ9.96(s,1H),8.47(s,1H),7.48(d,J＝8.5Hz,1H),7.30(s,2H),7.11(s,1H),6.46(d,J＝2.3Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H),3.78(s,6H),3.64(s,3H).ESI-MS m/z 386.1373[M+H]+.
实施例16
N-(苯并[d][1,3]二氧杂环戊烯-5-基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为N-(苯并[d][1,3]二氧杂环戊烯-5-基)-3-(2,4-双(苄氧基)苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.09(s,1H),9.96(s,1H),9.60(s,1H),7.49(m,2H),7.31–7.21(m,1H),7.09(s,1H),6.89(d,J＝8.4Hz,2H),6.44(d,J＝2.0Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H),6.01(s,2H).ESI-MS m/z340.0917[M+H]+.
实施例17
4-(3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰氨基)苯甲酸甲酯的制备：
参照实施例1的合成方法，实施例1的中间体1替换为4-(3-(2,4-双(苄氧基)苯基)-1H-吡唑-5-甲酰氨基)苯甲酸甲酯，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.22(s,1H),10.34(s,1H),10.15(s,1H),9.62(s,1H),7.98(q,J＝8.7Hz,4H),7.49(d,J＝8.5Hz,1H),7.06(s,1H),6.47(s,1H),6.35(d,J＝8.4Hz,1H),3.84(s,3H)..ESI-MS m/z 354.3308[M+H]+.
实施例18
3-(2,4-二羟基苯基)-N-(4-(三氟甲基)苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-双(苄氧基)苯基)-N-(4-(三氟甲基)苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),8.07(d,J＝8.4Hz,2H),7.70(d,J＝8.7Hz,2H),7.50(d,J＝8.5Hz,1H),7.15(s,1H),6.46(d,J＝2.3Hz,1H),6.36(dd,J＝8.5,2.4Hz,1H).ESI-MS m/z364.0856[M+H]+.
实施例19
3-(2,4-二羟基苯基)-N-(吡啶-3-基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(吡啶-3-基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.20(s,1H),10.26(s,1H),10.15(s,1H),9.62(s,1H),9.00(s,1H),8.27(m,2H),7.49(d,J＝8.4Hz,1H),7.37(m,1H),7.05(s,1H),6.46(s,1H),6.35(d,J＝8.5Hz,1H).ESI-MS m/z 297.0974[M+H]+.
实施例20
3-(2,4-二羟基苯基)-N-(6-甲基吡啶-2-基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(6-甲基吡啶-2-基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ9.62(s,2H),8.02(d,J＝8.1Hz,1H),7.79–7.66(m,1H),7.49(d,J＝8.5Hz,1H),7.17(s,1H),7.03(d,J＝7.5Hz,1H),6.45(d,J＝2.1Hz,1H),6.34(dd,J＝8.5,2.3Hz,1H),2.44(s,3H).ESI-MS m/z 311.1127[M+H]+.
实施例21
3-(2,4-二羟基苯基)-N-(萘-1-基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(萘-1-基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.23(s,1H),10.11(s,2H),9.62(s,1H),8.03–7.96(m,2H),7.84(d,J＝7.9Hz,1H),7.62–7.45(m,5H),7.08(s,1H),6.47(s,1H),6.36(d,J＝8.1Hz,1H).ESI-MS m/z 346.1195[M+H]+.
实施例22
3-(2,4-二羟基苯基)-N-(萘-2-基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(萘-2-基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.18(s,1H),10.15(s,2H),9.61(s,1H),8.50(s,1H),7.92–7.79(m,4H),7.55–7.37(m,3H),7.08(s,1H),6.48(d,J＝2.2Hz,1H),6.35(d,J＝8.5Hz,1H).ESI-MS m/z 346.1184[M+H]+.
实施例23
N-(4-(二乙基氨基)苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-(二乙基氨基)苯基)-1H-吡唑-5-甲酰胺，得白色固体化合物，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.02(s,1H),9.59(s,2H),7.55(d,J＝9.0Hz,2H),7.48(d,J＝8.5Hz,2H),7.01(s,1H),6.65(d,J＝9.1Hz,2H),6.43(s,1H),6.35(dd,J＝8.5,2.2Hz,1H),3.31(d,J＝7.0Hz,4H),1.08(t,J＝7.0Hz,6H).ESI-MSm/z 365.1768[M+H]+.
实施例24
3-(2,4-二羟基苯基)-N-(4-(二甲基氨基)苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-(二甲基氨基)苯基)-1H-吡唑-5-甲酰胺，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ13.05(s,1H),10.10(s,1H),9.61(d,J＝17.2Hz,2H),7.60(d,J＝8.4Hz,2H),7.48(d,J＝8.3Hz,1H),6.99(s,1H),6.73(d,J＝8.8Hz,2H),6.45(s,1H),6.35(d,J＝8.4Hz,1H),2.87(s,6H).ESI-MS m/z 339.1453[M+H]+.
实施例25
3-(2,4-二羟基苯基)-N-(4-硝基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-硝基苯基)-1H-吡唑-5-甲酰胺，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ10.69(s,1H),8.26(d,J＝9.3Hz,2H),8.14(d,J＝9.3Hz,2H),7.51(d,J＝8.5Hz,1H),7.14(s,1H),6.46(d,J＝2.2Hz,1H),6.35(dd,J＝8.5,2.3Hz,1H).ESI-MS m/z 341.0882[M+H]+.
实施例26
N-(4-氰基苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺的制备：
参照实施例1的合成方法，实施例1的中间体1替换为3-(2,4-二(苄氧基)苯基)-N-(4-氰基苯基)-1H-吡唑-5-甲酰胺，TLC检测为一点，紫外灯254nm下有荧光，365nm下无荧光。1H NMR(300MHz,DMSO-d6)δ10.50(s,1H),8.07(d,J＝8.5Hz,2H),7.81(d,J＝8.6Hz,2H),7.50(d,J＝8.4Hz,1H),7.11(s,1H),6.45(s,1H),6.34(dd,J＝8.5,2.2Hz,1H).ESI-MSm/z321.0983[M+H]+。
Claims (8)
1.通式(I)的化合物或其药学上可接受的盐：
其中R代表其中R1代表任意取代的羟基、卤素、C1～C4烷基、卤素取代的C1～C4烷基、C1～C4烷氧基、氰基、磺酸基、硝基或-NR2R3，R2、R3各自独立地代表氢或C1～C3烷基；其中R4代表任意取代的卤素、C1～C4烷基、C1～C4烷氧基、硝基，氰基或羟基；R5代表任意取代的卤素、C1～C4烷基、C1～C4烷氧基、硝基、氰基或羟基。
2.权利要求1的化合物或其药学上可接受的盐，其中R1代表任意取代的氟、氯、溴、甲基、三氟甲基、甲氧基、氰基、硝基或-NR2R3；R2、R3独立的选自氢、甲基或乙基。
3.权利要求1的化合物或其药学上可接受的盐，其中R4代表任意取代的氟、氯、溴、甲基、甲氧基、氰基或羟基。
4.权利要求1的化合物或其药学上可接受的盐，其中R5代表任意取代的氟、氯、溴、甲基、甲氧基、氰基或羟基。
5.权利要求1的化合物或其药学上可接受的盐，为下列任一结构的化合物：
3-(2,4-二羟基苯基)-N-苯基-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(邻-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(间-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(对-甲苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-异丙基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3-氟苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-氟苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-氯苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-溴苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2,4-二甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(2,6-二甲氧基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(3,4,5-三甲氧基苯基)-1H-吡唑-5-甲酰胺；
N-(苯并[d][1,3]二氧杂环戊烯-5-基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺；
4-(3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰氨基)苯甲酸甲酯；
3-(2,4-二羟基苯基)-N-(4-(三氟甲基)苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(吡啶-3-基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(6-甲基吡啶-2-基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(萘-1-基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(萘-2-基)-1H-吡唑-5-甲酰胺；
N-(4-(二乙基氨基)苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺；
3-(2,4-二羟基苯基)-N-(4-(二甲基氨基)苯基)-1H-吡唑-5-甲酰胺；
4-(2,4-二羟基苯基)-N-(4-硝基苯基)-1H-吡唑-5-甲酰胺；
N-(4-氰基苯基)-3-(2,4-二羟基苯基)-1H-吡唑-5-甲酰胺。
6.一种药物组合物，其中含有权利要求1至5中任一项的化合物或其药学上可接受的盐及药学上可接受的载体。
7.权利要求1至5中任一项的化合物或其药学上可接受的盐用于制备酪氨酸酶抑制剂的用途。
8.权利要求7的用途，其中酪氨酸酶抑制剂是预防或治疗黑色素过表达疾病的药物。
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