JP6506390B2 - キノリノン系化合物及びその薬物への使用 - Google Patents
キノリノン系化合物及びその薬物への使用 Download PDFInfo
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- JP6506390B2 JP6506390B2 JP2017512046A JP2017512046A JP6506390B2 JP 6506390 B2 JP6506390 B2 JP 6506390B2 JP 2017512046 A JP2017512046 A JP 2017512046A JP 2017512046 A JP2017512046 A JP 2017512046A JP 6506390 B2 JP6506390 B2 JP 6506390B2
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- methyl
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- hydroxy
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- 239000003814 drug Substances 0.000 title claims description 67
- 229940079593 drug Drugs 0.000 title claims description 60
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 236
- -1 methoxysulfonyl group Chemical group 0.000 claims description 156
- 125000001072 heteroaryl group Chemical group 0.000 claims description 143
- 125000000623 heterocyclic group Chemical group 0.000 claims description 142
- 239000000203 mixture Substances 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 117
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 125000001424 substituent group Chemical group 0.000 claims description 99
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 75
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 67
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 57
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 201000010099 disease Diseases 0.000 claims description 52
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 50
- 208000007502 anemia Diseases 0.000 claims description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 239000000460 chlorine Substances 0.000 claims description 41
- 125000003277 amino group Chemical group 0.000 claims description 40
- 102000003951 Erythropoietin Human genes 0.000 claims description 39
- 108090000394 Erythropoietin Proteins 0.000 claims description 39
- 229910052801 chlorine Inorganic materials 0.000 claims description 39
- 229910052794 bromium Inorganic materials 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 229940105423 erythropoietin Drugs 0.000 claims description 38
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 38
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 37
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 36
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical group 0.000 claims description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 35
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 34
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 33
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 33
- 239000011737 fluorine Substances 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 33
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 32
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 32
- 125000003386 piperidinyl group Chemical group 0.000 claims description 32
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 30
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 29
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 29
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 29
- 125000002252 acyl group Chemical group 0.000 claims description 28
- 125000002757 morpholinyl group Chemical group 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 24
- 206010021143 Hypoxia Diseases 0.000 claims description 23
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 23
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 23
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 23
- 125000001544 thienyl group Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 230000007954 hypoxia Effects 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 18
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 17
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 208000028867 ischemia Diseases 0.000 claims description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 230000001939 inductive effect Effects 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 11
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000005493 quinolyl group Chemical group 0.000 claims description 11
- 206010002383 Angina Pectoris Diseases 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 9
- 208000030159 metabolic disease Diseases 0.000 claims description 9
- 208000031225 myocardial ischemia Diseases 0.000 claims description 9
- 208000019553 vascular disease Diseases 0.000 claims description 9
- 230000029663 wound healing Effects 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000000466 oxiranyl group Chemical group 0.000 claims description 7
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 7
- 101710138860 Hypoxia-inducible factor prolyl hydroxylase Proteins 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 381
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 147
- 235000019439 ethyl acetate Nutrition 0.000 description 127
- 239000007787 solid Substances 0.000 description 125
- 239000002904 solvent Substances 0.000 description 123
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 108
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 107
- 150000002500 ions Chemical class 0.000 description 106
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 103
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 70
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 68
- 238000005292 vacuum distillation Methods 0.000 description 68
- 229910001873 dinitrogen Inorganic materials 0.000 description 66
- 239000012074 organic phase Substances 0.000 description 65
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 64
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 64
- 239000012065 filter cake Substances 0.000 description 58
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 56
- 238000005481 NMR spectroscopy Methods 0.000 description 53
- 238000000034 method Methods 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000003208 petroleum Substances 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- 238000004440 column chromatography Methods 0.000 description 44
- 239000012043 crude product Substances 0.000 description 44
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 42
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 39
- 229910000024 caesium carbonate Inorganic materials 0.000 description 39
- 238000004821 distillation Methods 0.000 description 39
- 125000004043 oxo group Chemical group O=* 0.000 description 39
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 38
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 38
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 36
- 108700003601 dimethylglycine Proteins 0.000 description 32
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 32
- 238000003756 stirring Methods 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- XWKZJTBXSQLOTP-UHFFFAOYSA-N methyl 7-bromo-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound C1=C(Br)C=C2N(C)C(=O)C(C(=O)OC)=C(O)C2=C1 XWKZJTBXSQLOTP-UHFFFAOYSA-N 0.000 description 27
- 230000009471 action Effects 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 20
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 description 14
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 125000004438 haloalkoxy group Chemical group 0.000 description 11
- 125000001188 haloalkyl group Chemical group 0.000 description 11
- 238000001356 surgical procedure Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 9
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 9
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 7
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 7
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000002512 chemotherapy Methods 0.000 description 7
- 208000020832 chronic kidney disease Diseases 0.000 description 7
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- PUSGMBHWYLPROH-UHFFFAOYSA-N methyl 6-bromo-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound BrC=1C=C2C(=C(C(N(C2=CC=1)C)=O)C(=O)OC)O PUSGMBHWYLPROH-UHFFFAOYSA-N 0.000 description 7
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- 238000006467 substitution reaction Methods 0.000 description 7
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 6
- 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 6
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- 102000001554 Hemoglobins Human genes 0.000 description 6
- 108010054147 Hemoglobins Proteins 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
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- 239000002244 precipitate Substances 0.000 description 6
- 238000004237 preparative chromatography Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- TXJUTRJFNRYTHH-UHFFFAOYSA-N 1h-3,1-benzoxazine-2,4-dione Chemical compound C1=CC=C2C(=O)OC(=O)NC2=C1 TXJUTRJFNRYTHH-UHFFFAOYSA-N 0.000 description 5
- 208000030090 Acute Disease Diseases 0.000 description 5
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- SEEGOUYVLRUNQR-UHFFFAOYSA-N methyl 7-(2,4-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound ClC1=C(OC2=CC=C3C(=C(C(N(C3=C2)C)=O)C(=O)OC)O)C=CC(=C1)Cl SEEGOUYVLRUNQR-UHFFFAOYSA-N 0.000 description 2
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- XNRJPZROMRPQHC-UHFFFAOYSA-N methyl 7-(2,5-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound ClC1=C(OC2=CC=C3C(=C(C(N(C3=C2)C)=O)C(=O)OC)O)C=C(C=C1)Cl XNRJPZROMRPQHC-UHFFFAOYSA-N 0.000 description 2
- MACAHCYHVREBCG-UHFFFAOYSA-N methyl 7-(2,5-difluorophenoxy)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound FC1=C(OC2=CC=C3C(=C(C(N(C3=C2)C)=O)C(=O)OC)O)C=C(C=C1)F MACAHCYHVREBCG-UHFFFAOYSA-N 0.000 description 2
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- NPVDPJKGGJCVTA-UHFFFAOYSA-N methyl 7-(2-chloro-4-fluorophenoxy)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound ClC1=C(OC2=CC=C3C(=C(C(N(C3=C2)C)=O)C(=O)OC)O)C=CC(=C1)F NPVDPJKGGJCVTA-UHFFFAOYSA-N 0.000 description 2
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- FWAZRZKDTMJPLU-UHFFFAOYSA-N methyl 7-(3,4-dichlorophenoxy)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound ClC=1C=C(OC2=CC=C3C(=C(C(N(C3=C2)C)=O)C(=O)OC)O)C=CC=1Cl FWAZRZKDTMJPLU-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410442574.4 | 2014-09-02 | ||
| CN201410442574 | 2014-09-02 | ||
| PCT/CN2015/088799 WO2016034108A1 (zh) | 2014-09-02 | 2015-09-01 | 喹啉酮类化合物及其应用 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017525737A JP2017525737A (ja) | 2017-09-07 |
| JP2017525737A5 JP2017525737A5 (en:Method) | 2018-06-14 |
| JP6506390B2 true JP6506390B2 (ja) | 2019-04-24 |
Family
ID=55417512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017512046A Active JP6506390B2 (ja) | 2014-09-02 | 2015-09-01 | キノリノン系化合物及びその薬物への使用 |
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| CA (1) | CA2959688C (en:Method) |
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| CN106146414A (zh) * | 2016-07-07 | 2016-11-23 | 浙江大学 | 喹唑啉二酮类衍生物及其制备方法和用途 |
| CN108069952B (zh) * | 2016-11-08 | 2022-09-27 | 广东东阳光药业有限公司 | 喹啉酮类化合物及其在药物中应用 |
| CN108069957B (zh) * | 2016-11-09 | 2022-11-04 | 广东东阳光药业有限公司 | 脯氨酰羟化酶抑制剂及其用途 |
| CN108285460A (zh) * | 2017-01-09 | 2018-07-17 | 南京圣和药业股份有限公司 | 一种egfr激酶抑制剂的药用盐及其制备方法与用途 |
| JP6999469B2 (ja) * | 2018-03-28 | 2022-01-18 | 東京応化工業株式会社 | 水素バリア剤、水素バリア膜形成用組成物、水素バリア膜、水素バリア膜の製造方法、及び電子素子 |
| CN111269178A (zh) * | 2019-11-28 | 2020-06-12 | 南北兄弟药业投资有限公司 | 喹啉酮类化合物的晶型 |
| CN111269176A (zh) * | 2019-11-28 | 2020-06-12 | 南北兄弟药业投资有限公司 | 喹啉酮类化合物的晶型 |
| CN111269177B (zh) * | 2019-11-28 | 2023-05-09 | 广东东阳光药业有限公司 | 喹啉酮类化合物的晶型 |
| US20230002325A1 (en) * | 2019-11-28 | 2023-01-05 | Sunshine Lake Pharma Co., Ltd. | Crystal form of quinolinone compound and use thereof |
| CN115010664A (zh) * | 2021-03-05 | 2022-09-06 | 广东东阳光药业有限公司 | 喹啉酮类化合物的晶型及其用途 |
| CN115010662B (zh) * | 2021-03-05 | 2023-12-08 | 广东东阳光药业股份有限公司 | 喹啉酮类化合物的晶型及其用途 |
| CN115010663A (zh) * | 2021-03-05 | 2022-09-06 | 广东东阳光药业有限公司 | 喹啉酮类化合物的晶型及其用途 |
| CN114989085B (zh) * | 2022-05-23 | 2023-11-24 | 安徽医科大学 | 一种芳基内酰胺环类化合物、药物组合物及其应用 |
| CN117159549B (zh) * | 2023-10-11 | 2025-02-14 | 中国药科大学 | 一种酯类化合物的应用 |
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| US10065928B2 (en) | 2018-09-04 |
| US20170247332A1 (en) | 2017-08-31 |
| CN105384687B (zh) | 2018-05-01 |
| CA2959688A1 (en) | 2016-03-10 |
| EP3190104B1 (en) | 2021-10-27 |
| EP3190104A4 (en) | 2018-04-11 |
| AU2015311333B2 (en) | 2017-11-16 |
| AU2015311333A1 (en) | 2017-02-16 |
| WO2016034108A1 (zh) | 2016-03-10 |
| JP2017525737A (ja) | 2017-09-07 |
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