JP5248600B2 - トリアゾリルアミノピリミジン化合物 - Google Patents
トリアゾリルアミノピリミジン化合物 Download PDFInfo
- Publication number
- JP5248600B2 JP5248600B2 JP2010508500A JP2010508500A JP5248600B2 JP 5248600 B2 JP5248600 B2 JP 5248600B2 JP 2010508500 A JP2010508500 A JP 2010508500A JP 2010508500 A JP2010508500 A JP 2010508500A JP 5248600 B2 JP5248600 B2 JP 5248600B2
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- Japan
- Prior art keywords
- amino
- mmol
- ethyl
- alkyl
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims description 127
- -1 methoxy, hydroxy, amino, chloro, amino Chemical group 0.000 claims description 129
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004267 aziridin-2-yl group Chemical group [H]N1C([H])([H])C1([H])* 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 241001024304 Mino Species 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 192
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
- 239000000243 solution Substances 0.000 description 120
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 118
- 239000000203 mixture Substances 0.000 description 107
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 238000002360 preparation method Methods 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 47
- 229920006395 saturated elastomer Polymers 0.000 description 47
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 41
- 239000011780 sodium chloride Substances 0.000 description 41
- 229910052938 sodium sulfate Inorganic materials 0.000 description 41
- 235000011152 sodium sulphate Nutrition 0.000 description 41
- 239000007787 solid Substances 0.000 description 39
- 238000000034 method Methods 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 108010056274 polo-like kinase 1 Proteins 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 239000000377 silicon dioxide Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000908 ammonium hydroxide Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 239000005457 ice water Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 5
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 5
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 201000006958 oropharynx cancer Diseases 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 4
- OPZDXMCOWFPQPE-UHFFFAOYSA-N 2-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Br)=C1 OPZDXMCOWFPQPE-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 206010014733 Endometrial cancer Diseases 0.000 description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
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- 125000005605 benzo group Chemical group 0.000 description 4
- WGXZDYPGLJYBJW-UHFFFAOYSA-N chloroform;propan-2-ol Chemical compound CC(C)O.ClC(Cl)Cl WGXZDYPGLJYBJW-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000000394 mitotic effect Effects 0.000 description 4
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 4
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000001851 vibrational circular dichroism spectroscopy Methods 0.000 description 4
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- NKQYHZABKBYUMX-UHFFFAOYSA-N 2-[2-(4-methyltriazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound N1=NC(C)=CN1CCN1C(=O)C2=CC=CC=C2C1=O NKQYHZABKBYUMX-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- KFMCIPBFYIWCCS-HSZRJFAPSA-N 4-[7-[[2-[(1r)-1-amino-2,2,2-trifluoroethyl]-5-fluorophenyl]methyl]-1-benzothiophen-2-yl]-5-fluoro-n-[2-(triazol-1-yl)ethyl]pyrimidin-2-amine Chemical compound FC(F)(F)[C@H](N)C1=CC=C(F)C=C1CC1=CC=CC2=C1SC(C=1C(=CN=C(NCCN3N=NC=C3)N=1)F)=C2 KFMCIPBFYIWCCS-HSZRJFAPSA-N 0.000 description 2
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- 238000001704 evaporation Methods 0.000 description 1
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
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- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- JENBPOJAZCPSEW-UHFFFAOYSA-N methyl 2-bromo-4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1Br JENBPOJAZCPSEW-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000008600 mitotic progression Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PDSMKSHEQLUGGZ-UHFFFAOYSA-N n-[1-(2-bromo-4-fluorophenyl)ethyl]-2,2-difluoroethanamine Chemical compound FC(F)CNC(C)C1=CC=C(F)C=C1Br PDSMKSHEQLUGGZ-UHFFFAOYSA-N 0.000 description 1
- DPLPRQURUMMJQY-UHFFFAOYSA-N n-[1-(2-bromophenyl)ethylidene]hydroxylamine Chemical compound ON=C(C)C1=CC=CC=C1Br DPLPRQURUMMJQY-UHFFFAOYSA-N 0.000 description 1
- HWDCORJXLBHJMV-UHFFFAOYSA-N n-[2-(2-bromo-4-fluorophenyl)propan-2-yl]formamide Chemical compound O=CNC(C)(C)C1=CC=C(F)C=C1Br HWDCORJXLBHJMV-UHFFFAOYSA-N 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- HHOPPKOLHCBNJI-UHFFFAOYSA-N tert-butyl 2-(2-bromo-4-fluorophenyl)aziridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC1C1=CC=C(F)C=C1Br HHOPPKOLHCBNJI-UHFFFAOYSA-N 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- MNZCBGMOGKPXCU-UHFFFAOYSA-N tert-butyl n-[1-(2-bromo-4-fluorophenyl)cyclopropyl]carbamate Chemical compound C=1C=C(F)C=C(Br)C=1C1(NC(=O)OC(C)(C)C)CC1 MNZCBGMOGKPXCU-UHFFFAOYSA-N 0.000 description 1
- KHVYXBFMEJBYTM-UHFFFAOYSA-N tert-butyl n-[1-(2-bromo-4-fluorophenyl)ethyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C(C)C1=CC=C(F)C=C1Br KHVYXBFMEJBYTM-UHFFFAOYSA-N 0.000 description 1
- CCLKBQZVNSHZLO-UHFFFAOYSA-N tert-butyl n-[2-(2-bromophenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCC1=CC=CC=C1Br CCLKBQZVNSHZLO-UHFFFAOYSA-N 0.000 description 1
- DJFYXCGXQHJTJC-UHFFFAOYSA-N tert-butyl n-[[2-[2-[5-fluoro-2-[2-(triazol-1-yl)ethylamino]pyrimidin-4-yl]-1-benzothiophen-7-yl]phenyl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC=C1C1=CC=CC2=C1SC(C=1C(=CN=C(NCCN3N=NC=C3)N=1)F)=C2 DJFYXCGXQHJTJC-UHFFFAOYSA-N 0.000 description 1
- GMRIOAVKKGNMMV-UHFFFAOYSA-N tetrabutylazanium;azide Chemical compound [N-]=[N+]=[N-].CCCC[N+](CCCC)(CCCC)CCCC GMRIOAVKKGNMMV-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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|---|---|---|---|
| US93834707P | 2007-05-16 | 2007-05-16 | |
| US60/938,347 | 2007-05-16 | ||
| PCT/US2008/062808 WO2008144223A2 (en) | 2007-05-16 | 2008-05-07 | Triazolyl aminopyrimidine compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2010527365A JP2010527365A (ja) | 2010-08-12 |
| JP2010527365A5 JP2010527365A5 (enExample) | 2011-06-16 |
| JP5248600B2 true JP5248600B2 (ja) | 2013-07-31 |
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| JP2010508500A Expired - Fee Related JP5248600B2 (ja) | 2007-05-16 | 2008-05-07 | トリアゾリルアミノピリミジン化合物 |
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| US (1) | US8063035B2 (enExample) |
| EP (1) | EP2155734A2 (enExample) |
| JP (1) | JP5248600B2 (enExample) |
| KR (1) | KR101131261B1 (enExample) |
| CN (1) | CN101679395B (enExample) |
| AR (1) | AR066473A1 (enExample) |
| AU (1) | AU2008254319B2 (enExample) |
| BR (1) | BRPI0811433A2 (enExample) |
| CA (1) | CA2691997A1 (enExample) |
| CL (1) | CL2008001323A1 (enExample) |
| EA (1) | EA016781B1 (enExample) |
| MX (1) | MX2009012228A (enExample) |
| PE (1) | PE20090216A1 (enExample) |
| TW (1) | TW200908981A (enExample) |
| WO (1) | WO2008144223A2 (enExample) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7964729B2 (en) | 2006-08-28 | 2011-06-21 | Massachusetts Institute Of Technology | Sox-based kinase sensor |
| US8101628B2 (en) | 2006-12-21 | 2012-01-24 | Eli Lilly And Company | Imidazolidinonyl aminopyrimidine compounds for the treatment of cancer |
| SI2125794T1 (sl) | 2006-12-21 | 2011-02-28 | Lilly Co Eli | Spojine imidazolidinonil aminopirimidina za zdravljenje raka |
| US8440835B2 (en) | 2007-02-26 | 2013-05-14 | Massachusetts Institute Of Technology | Environmentally sensitive fluorophores |
| EA016781B1 (ru) | 2007-05-16 | 2012-07-30 | Эли Лилли Энд Компани | Триазолиламинопиримидиновые соединения |
| WO2008144222A2 (en) * | 2007-05-16 | 2008-11-27 | Eli Lilly And Company | Triazolyl aminopyrimidine compounds |
| KR101123178B1 (ko) * | 2009-04-09 | 2012-06-13 | (주)에스메디 | 2-아릴벤조싸이오펜 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 |
| EP2470652A1 (en) * | 2009-08-25 | 2012-07-04 | OncoTherapy Science, Inc. | Ercc6l as target genes for cancer therapy and diagnosis |
| WO2011025546A1 (en) * | 2009-08-31 | 2011-03-03 | Massachusetts Institute Of Technology | 1, 2, 3-triazole containing protein kinase sensors |
| UA119247C2 (uk) | 2013-09-06 | 2019-05-27 | РОЙВЕНТ САЙЕНСИЗ ҐмбГ | Спіроциклічні сполуки як інгібітори триптофангідроксилази |
| US9611201B2 (en) * | 2015-03-05 | 2017-04-04 | Karos Pharmaceuticals, Inc. | Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone |
| JP7090037B2 (ja) * | 2016-06-23 | 2022-06-23 | エフ．ホフマン－ラ ロシュ アーゲー | 新規な［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン誘導体 |
| US11084829B2 (en) | 2018-09-24 | 2021-08-10 | Rapt Therapeutics, Inc. | Ubiquitin-specific-processing protease 7 (USP7) modulators and uses thereof |
| KR20220059951A (ko) * | 2019-09-05 | 2022-05-10 | 더 유니버시티 오브 멜버른 | 질화 억제제 |
| CN112341428A (zh) * | 2020-11-04 | 2021-02-09 | 菏泽鸿特药业有限公司 | 一种噻吩-2-乙胺的生产方法 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4929726A (en) * | 1988-02-09 | 1990-05-29 | Georgia State University Foundation, Inc. | Novel diazines and their method of preparation |
| WO2004063192A1 (en) | 2003-01-10 | 2004-07-29 | Pharmacopeia Drug Discovery, Inc. | Imidazolyl pyrimidine derivatives useful as il-8 receptor modulators |
| GB0308466D0 (en) | 2003-04-11 | 2003-05-21 | Novartis Ag | Organic compounds |
| JP2007533602A (ja) * | 2003-07-31 | 2007-11-22 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | 置換ベンゾチオフェン化合物及びそれらの使用 |
| AU2005316312B2 (en) * | 2004-12-17 | 2009-10-22 | Amgen, Inc. | Aminopyrimidine compounds and methods of use |
| TW200800201A (en) | 2005-11-18 | 2008-01-01 | Lilly Co Eli | Pyrimidinyl benzothiophene compounds |
| US8008481B2 (en) | 2006-03-31 | 2011-08-30 | Ericsson Anna M | Indazole compounds |
| US8101628B2 (en) | 2006-12-21 | 2012-01-24 | Eli Lilly And Company | Imidazolidinonyl aminopyrimidine compounds for the treatment of cancer |
| SI2125794T1 (sl) * | 2006-12-21 | 2011-02-28 | Lilly Co Eli | Spojine imidazolidinonil aminopirimidina za zdravljenje raka |
| EA016781B1 (ru) | 2007-05-16 | 2012-07-30 | Эли Лилли Энд Компани | Триазолиламинопиримидиновые соединения |
| WO2008144222A2 (en) | 2007-05-16 | 2008-11-27 | Eli Lilly And Company | Triazolyl aminopyrimidine compounds |
-
2008
- 2008-05-07 EA EA200971068A patent/EA016781B1/ru not_active IP Right Cessation
- 2008-05-07 BR BRPI0811433A patent/BRPI0811433A2/pt not_active IP Right Cessation
- 2008-05-07 WO PCT/US2008/062808 patent/WO2008144223A2/en not_active Ceased
- 2008-05-07 MX MX2009012228A patent/MX2009012228A/es active IP Right Grant
- 2008-05-07 CN CN2008800157689A patent/CN101679395B/zh not_active Expired - Fee Related
- 2008-05-07 PE PE2008000798A patent/PE20090216A1/es not_active Application Discontinuation
- 2008-05-07 AR ARP080101932A patent/AR066473A1/es unknown
- 2008-05-07 EP EP08747731A patent/EP2155734A2/en not_active Withdrawn
- 2008-05-07 JP JP2010508500A patent/JP5248600B2/ja not_active Expired - Fee Related
- 2008-05-07 CA CA002691997A patent/CA2691997A1/en not_active Abandoned
- 2008-05-07 KR KR1020097023340A patent/KR101131261B1/ko not_active Expired - Fee Related
- 2008-05-07 CL CL2008001323A patent/CL2008001323A1/es unknown
- 2008-05-07 US US12/598,926 patent/US8063035B2/en not_active Expired - Fee Related
- 2008-05-07 AU AU2008254319A patent/AU2008254319B2/en not_active Ceased
- 2008-05-07 TW TW097116886A patent/TW200908981A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2155734A2 (en) | 2010-02-24 |
| AU2008254319A1 (en) | 2008-11-27 |
| US8063035B2 (en) | 2011-11-22 |
| WO2008144223A3 (en) | 2009-02-05 |
| EA016781B1 (ru) | 2012-07-30 |
| MX2009012228A (es) | 2009-12-01 |
| EA200971068A1 (ru) | 2010-04-30 |
| KR101131261B1 (ko) | 2012-04-24 |
| CL2008001323A1 (es) | 2009-05-29 |
| WO2008144223A2 (en) | 2008-11-27 |
| US20100087431A1 (en) | 2010-04-08 |
| JP2010527365A (ja) | 2010-08-12 |
| TW200908981A (en) | 2009-03-01 |
| CN101679395B (zh) | 2012-06-13 |
| AR066473A1 (es) | 2009-08-19 |
| KR20090130242A (ko) | 2009-12-21 |
| PE20090216A1 (es) | 2009-02-28 |
| CA2691997A1 (en) | 2008-11-27 |
| CN101679395A (zh) | 2010-03-24 |
| AU2008254319B2 (en) | 2012-04-19 |
| BRPI0811433A2 (pt) | 2016-03-22 |
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