CN103204825B - 作为蛋白激酶抑制剂的苯并噻唑化合物及其制备方法和用途 - Google Patents
作为蛋白激酶抑制剂的苯并噻唑化合物及其制备方法和用途 Download PDFInfo
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- CN103204825B CN103204825B CN201210190520.4A CN201210190520A CN103204825B CN 103204825 B CN103204825 B CN 103204825B CN 201210190520 A CN201210190520 A CN 201210190520A CN 103204825 B CN103204825 B CN 103204825B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title abstract description 6
- 239000003909 protein kinase inhibitor Substances 0.000 title abstract 3
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- -1 benzothiazole compound Chemical class 0.000 claims abstract description 60
- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 109
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 239000007822 coupling agent Substances 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
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- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
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- 208000022371 chronic pain syndrome Diseases 0.000 claims 1
- 230000002596 correlated effect Effects 0.000 claims 1
- 208000030533 eye disease Diseases 0.000 claims 1
- 230000000250 revascularization Effects 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 16
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- 239000012453 solvate Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 6
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 5
- 241000124008 Mammalia Species 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract 2
- 230000004054 inflammatory process Effects 0.000 abstract 2
- 229940043355 kinase inhibitor Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000012074 organic phase Substances 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 239000002904 solvent Substances 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- 239000012043 crude product Substances 0.000 description 30
- 125000000217 alkyl group Chemical group 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 125000000753 cycloalkyl group Chemical group 0.000 description 20
- 239000001963 growth medium Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 11
- 235000008504 concentrate Nutrition 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 10
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 239000012737 fresh medium Substances 0.000 description 9
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 8
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 102000001253 Protein Kinase Human genes 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 108060006633 protein kinase Proteins 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 7
- SEHOKTMUKIIIGY-UHFFFAOYSA-N 4-fluoro-5-(2-fluoro-4-iodoanilino)-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(I)C=C1F SEHOKTMUKIIIGY-UHFFFAOYSA-N 0.000 description 7
- GSJSSMQHDLIDNO-UHFFFAOYSA-N 5-(4-bromo-2-chloroanilino)-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=2SC=NC=2C(F)=C1NC1=CC=C(Br)C=C1Cl GSJSSMQHDLIDNO-UHFFFAOYSA-N 0.000 description 7
- 102000004388 Interleukin-4 Human genes 0.000 description 7
- 108090000978 Interleukin-4 Proteins 0.000 description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 229940028885 interleukin-4 Drugs 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 206010009944 Colon cancer Diseases 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
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- 208000029742 colonic neoplasm Diseases 0.000 description 6
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical group C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
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- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- 0 *c1nc(c(*)c(c(C(O)=O)c2*)NC(C3=*)=CC=C(*)C3=C)c2[s]1 Chemical compound *c1nc(c(*)c(c(C(O)=O)c2*)NC(C3=*)=CC=C(*)C3=C)c2[s]1 0.000 description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
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- 235000011181 potassium carbonates Nutrition 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XQIATTAAVBLNAN-UHFFFAOYSA-N 5-bromo-2,3,4-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=C(F)C(F)=C1F XQIATTAAVBLNAN-UHFFFAOYSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 239000007864 aqueous solution Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
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- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- 150000004820 halides Chemical class 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
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| EP13738359.2A EP2804855B1 (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
| HK15103824.9A HK1203486B (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
| US14/372,731 US9290468B2 (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
| JP2014551508A JP6077006B2 (ja) | 2012-01-17 | 2013-01-16 | ベンゾ複素環式化合物およびその使用 |
| CA2897259A CA2897259C (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
| PCT/CN2013/000037 WO2013107283A1 (en) | 2012-01-17 | 2013-01-16 | Benzoheterocyclic compounds and use thereof |
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| US15/050,045 US9937158B2 (en) | 2012-01-17 | 2016-02-22 | Benzoheterocyclic compounds and use thereof |
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| CN201210189086.8A Active CN103204822B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噁唑化合物及其制备方法和用途 |
| CN201210189087.2A Active CN103204827B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噻二唑化合物及其制备方法和用途 |
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| CN201210189087.2A Active CN103204827B (zh) | 2012-01-17 | 2012-06-08 | 作为蛋白激酶抑制剂的苯并噻二唑化合物及其制备方法和用途 |
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| CN104710417B (zh) * | 2013-12-11 | 2020-09-08 | 上海科州药物研发有限公司 | 氮杂吲哚类衍生物及其合成方法 |
| CN105384738B (zh) * | 2014-08-21 | 2017-08-29 | 上海科州药物研发有限公司 | 作为蛋白激酶抑制剂的杂环类化合物及其制备方法和用途 |
| CN105859543A (zh) * | 2016-05-06 | 2016-08-17 | 蚌埠中实化学技术有限公司 | 一种2,6-二氟-4-溴苯甲酰氯的制备方法 |
| CN111205244B (zh) * | 2018-11-22 | 2023-08-18 | 上海科技大学 | 噻唑并环类化合物、其制备方法、中间体和应用 |
| EA202192575A1 (ru) | 2019-03-21 | 2022-01-14 | Онксео | Соединения dbait в сочетании с ингибиторами киназ для лечения рака |
| CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| CN113440616A (zh) * | 2020-03-25 | 2021-09-28 | 上海科州药物研发有限公司 | Ras或raf突变型癌症的联合疗法 |
| CN120112519A (zh) * | 2023-02-10 | 2025-06-06 | 上海科州药物股份有限公司 | 作为蛋白激酶Mek抑制剂的多晶型物、及其制备方法和用途 |
| WO2025073765A1 (en) | 2023-10-03 | 2025-04-10 | Institut National de la Santé et de la Recherche Médicale | Methods of prognosis and treatment of patients suffering from melanoma |
| WO2025242163A1 (zh) * | 2024-05-23 | 2025-11-27 | 上海科州药物股份有限公司 | 蛋白激酶mek抑制剂的盐及其用途 |
| WO2025261499A1 (zh) * | 2024-06-20 | 2025-12-26 | 上海科州药物股份有限公司 | 蛋白激酶Mek抑制剂苯并噻唑的颗粒药物组合物 |
| CN120463660A (zh) * | 2024-09-30 | 2025-08-12 | 上海科州药物股份有限公司 | 大规模制备妥拉美替尼及其中间体的方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007121154A2 (en) * | 2006-04-11 | 2007-10-25 | Janssen Pharmaceutica, N.V. | Substituted benzothiazole kinase inhibitors |
| CN101213196A (zh) * | 2005-07-01 | 2008-07-02 | 赛诺菲-安万特 | 吡啶并[2,3-d]嘧啶衍生物，它们的制备，在治疗中的用途 |
Family Cites Families (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA73073C2 (uk) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція |
| BR9810385A (pt) | 1997-07-01 | 2000-09-05 | Warner Lambert Co | Derivados de ácido benzóico 2-(4-bromo ou 4-iodo fenilamino) e sua utilização como inibidores de mek |
| NZ501276A (en) | 1997-07-01 | 2000-10-27 | Warner Lambert Co | 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors in treating proliferative disorders |
| US6120451A (en) | 1998-12-31 | 2000-09-19 | General Electric Company | Ultrasound color flow display optimization by adjustment of threshold |
| ATE311363T1 (de) | 1999-01-13 | 2005-12-15 | Warner Lambert Co | Sulfohydroxamsäure and sulfohydroxamate und ihre verwendung als mek-inhibitoren |
| CA2349180A1 (en) | 1999-01-13 | 2000-07-20 | Stephen Douglas Barrett | Anthranilic acid derivatives |
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| DE69926914T2 (de) | 1999-01-13 | 2006-06-29 | Warner-Lambert Co. Llc | 1-heterozyklus-substituierte diarylaminen |
| JP2000204079A (ja) * | 1999-01-13 | 2000-07-25 | Warner Lambert Co | ジアリ―ルアミン |
| GB9910577D0 (en) | 1999-05-08 | 1999-07-07 | Zeneca Ltd | Chemical compounds |
| PL352835A1 (en) | 1999-07-16 | 2003-09-08 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
| MXPA02008103A (es) | 2000-03-15 | 2002-11-29 | Warner Lambert Co | Diarilaminas sustituidas con 5-amida como inhibidores mek. |
| JP3811775B2 (ja) | 2000-07-19 | 2006-08-23 | ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー | ４−ヨードフェニルアミノベンズヒドロキサム酸の酸素化エステル |
| EP1482944A4 (en) | 2002-03-13 | 2006-04-19 | Array Biopharma Inc | NZ ALKYL BENZIMIDAZOLE DERIVATIVES AS MEK INHIBITORS |
| KR100984595B1 (ko) * | 2002-03-13 | 2010-09-30 | 어레이 바이오파마 인크. | Ｍｅｋ 억제제로서의 ｎ3 알킬화 벤즈이미다졸 유도체 |
| US7235537B2 (en) * | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| US20050004186A1 (en) * | 2002-12-20 | 2005-01-06 | Pfizer Inc | MEK inhibiting compounds |
| WO2005000818A1 (en) | 2003-06-27 | 2005-01-06 | Warner-Lambert Company Llc | 5-substituted-4-`(substituted phenyl)!amino!-2-pyridone deviatives for use as mek inhibitors |
| WO2005007616A1 (en) | 2003-07-23 | 2005-01-27 | Warner-Lambert Company Llc | Diphenylamino ketone derivatives as mek inhibitors |
| ES2331246T3 (es) | 2003-07-24 | 2009-12-28 | Warner-Lambert Company Llc | Derivados de benzamidazol como inhibidores del mek. |
| US7144907B2 (en) | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| WO2005046665A1 (en) | 2003-11-13 | 2005-05-26 | Warner-Lambert Company Llc | Combination chemotherapy comprising a mek inhibitor and a erbb1/2 receptor inhibitor |
| CN1905873A (zh) | 2003-11-19 | 2007-01-31 | 阵列生物制药公司 | Mek的杂环抑制剂及其使用方法 |
| ES2405785T3 (es) | 2005-05-18 | 2013-06-03 | Array Biopharma Inc. | Inhibidores heterocíclicos de MEK y métodos de uso de los mismos |
| WO2006134469A1 (en) | 2005-06-14 | 2006-12-21 | Warner-Lambert Company Llc | Methods of preparing mek inhibitor |
| CA2618218C (en) | 2005-07-21 | 2015-06-30 | Ardea Biosciences, Inc. | N-(arylamino)-sulfonamide inhibitors of mek |
| US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
| SI1934174T1 (sl) | 2005-10-07 | 2011-08-31 | Exelixis Inc | Inhibitorji MEK in postopki za njihovo uporabo |
| WO2007071951A1 (en) | 2005-12-21 | 2007-06-28 | Astrazeneca Ab | Tosylate salt of 6- (4-br0m0-2-chl0r0phenylamin0) -7-fluoro-n- (2-hydroxyethoxy) -3-methyl-3h-benzimi dazole- 5 - carboxamide , mek inhibitor useful in the treatment of cancer |
| US7842836B2 (en) | 2006-04-11 | 2010-11-30 | Ardea Biosciences | N-aryl-N'alkyl sulfamides as MEK inhibitors |
| JP5269762B2 (ja) | 2006-04-18 | 2013-08-21 | アーディア・バイオサイエンシーズ・インコーポレイテッド | Ｍｅｋ阻害剤としてのピリドンスルホンアミドおよびピリドンスルファミド |
| CN101528231A (zh) | 2006-08-16 | 2009-09-09 | 埃克塞利希斯股份有限公司 | 在癌症的治疗中使用pi3k和mek调控剂 |
| PL2101759T3 (pl) | 2006-12-14 | 2019-05-31 | Exelixis Inc | Sposoby stosowania inhibitorów MEK |
| GB0625691D0 (en) | 2006-12-22 | 2007-01-31 | Astrazeneca Ab | Combination product |
| FR2911138B1 (fr) * | 2007-01-05 | 2009-02-20 | Sanofi Aventis Sa | Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk |
| KR20090111847A (ko) | 2007-01-19 | 2009-10-27 | 아디아 바이오사이언스즈 인크. | Ｍｅｋ 억제제 |
| WO2008120004A1 (en) | 2007-04-02 | 2008-10-09 | Astrazeneca Ab | Combination of a mek- inhibitor and a b-raf inhibitor for the treatment of cancer |
| WO2008124085A2 (en) | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
| US20100130519A1 (en) | 2007-04-13 | 2010-05-27 | Stephen Robert Wedge | Combination therapy comprising azd2171 and azd6244 or mek-inhibitor ii |
| US7960567B2 (en) | 2007-05-02 | 2011-06-14 | Amgen Inc. | Compounds and methods useful for treating asthma and allergic inflammation |
| EP2162132A4 (en) * | 2007-05-21 | 2013-01-16 | Sgx Pharmaceuticals Inc | Heterocyclic kinase modulators |
| FR2918785B1 (fr) | 2007-07-13 | 2009-11-13 | Lemer Prot Anti X Par Abrevati | Materiau radioattenuateur, et procede pour l'obtention d'un tel materiau |
| CA2924436A1 (en) | 2007-07-30 | 2009-02-05 | Ardea Biosciences, Inc. | Pharmaceutical combinations of n-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide as inhibitors of mek and methods of use |
| CN101896227A (zh) | 2007-12-12 | 2010-11-24 | 阿斯利康(瑞典)有限公司 | 包含mek抑制剂和极光激酶抑制剂的组合 |
| EP2240494B1 (en) | 2008-01-21 | 2016-03-30 | UCB Biopharma SPRL | Thieno-pyridine derivatives as mek inhibitors |
| GB0801080D0 (en) | 2008-01-21 | 2008-02-27 | Ucb Pharma Sa | Therapeutic agents |
| GB0801081D0 (en) | 2008-01-21 | 2008-02-27 | Ucb Pharma Sa | Therapeutic agents |
| GB0811304D0 (en) | 2008-06-19 | 2008-07-30 | Ucb Pharma Sa | Therapeutic agents |
| EA201200823A1 (ru) | 2009-12-08 | 2013-02-28 | Новартис Аг | Гетероциклические производные сульфонамидов |
| CN102020651B (zh) | 2010-11-02 | 2012-07-18 | 北京赛林泰医药技术有限公司 | 6-芳基氨基吡啶酮甲酰胺mek抑制剂 |
| FR2967672B1 (fr) | 2010-11-22 | 2012-12-28 | Sanofi Aventis | Derives de nitrobenzothiazoles, leur preparation et leurs applications therapeutiques |
| UA111841C2 (uk) | 2011-04-21 | 2016-06-24 | Гіліад Сайєнсіз, Інк. | Сполуки бензотіазолу та їх фармацевтичне застосування |
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- 2013-01-16 US US14/372,731 patent/US9290468B2/en active Active
- 2013-01-16 NZ NZ627631A patent/NZ627631A/en unknown
- 2013-01-16 CA CA2897259A patent/CA2897259C/en active Active
- 2013-01-16 EP EP13738359.2A patent/EP2804855B1/en active Active
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2016
- 2016-02-22 US US15/050,045 patent/US9937158B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101213196A (zh) * | 2005-07-01 | 2008-07-02 | 赛诺菲-安万特 | 吡啶并[2,3-d]嘧啶衍生物，它们的制备，在治疗中的用途 |
| WO2007121154A2 (en) * | 2006-04-11 | 2007-10-25 | Janssen Pharmaceutica, N.V. | Substituted benzothiazole kinase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103204827B (zh) | 2014-12-03 |
| JP6077006B2 (ja) | 2017-02-08 |
| CA2897259C (en) | 2019-05-07 |
| CN103204822A (zh) | 2013-07-17 |
| CN103204827A (zh) | 2013-07-17 |
| US20160235721A1 (en) | 2016-08-18 |
| NZ627631A (en) | 2016-10-28 |
| EP2804855A1 (en) | 2014-11-26 |
| US9937158B2 (en) | 2018-04-10 |
| CA2897259A1 (en) | 2013-07-25 |
| AU2013201455A8 (en) | 2016-04-14 |
| US9290468B2 (en) | 2016-03-22 |
| CN103204825A (zh) | 2013-07-17 |
| AU2013201455A1 (en) | 2013-08-01 |
| AU2013201455C1 (en) | 2016-01-21 |
| HK1203486A1 (en) | 2015-10-30 |
| EP2804855B1 (en) | 2017-09-20 |
| JP2015503597A (ja) | 2015-02-02 |
| CN103204822B (zh) | 2014-12-03 |
| EP2804855A4 (en) | 2015-07-29 |
| WO2013107283A1 (en) | 2013-07-25 |
| US20140371278A1 (en) | 2014-12-18 |
| AU2013201455B2 (en) | 2015-07-23 |
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