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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- independently
- 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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- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000009916 joint effect Effects 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000005980 lung dysfunction Effects 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- ISWZBNSYRICPDB-UHFFFAOYSA-N methyl 1,2-dihydroquinoline-3-carboxylate Chemical compound C1=CC=C2NCC(C(=O)OC)=CC2=C1 ISWZBNSYRICPDB-UHFFFAOYSA-N 0.000 description 1
- LDDDAZYOHDSDOI-UHFFFAOYSA-N methyl 1-(2-cyclopropylethyl)-4-hydroxy-2-oxo-7-phenoxyquinoline-3-carboxylate Chemical compound C1(CC1)CCN1C(C(=C(C2=CC=C(C=C12)OC1=CC=CC=C1)O)C(=O)OC)=O LDDDAZYOHDSDOI-UHFFFAOYSA-N 0.000 description 1
- OVHIPEYONTVANB-UHFFFAOYSA-N methyl 2-amino-4-bromo-5-fluorobenzoate Chemical compound COC(=O)C1=CC(F)=C(Br)C=C1N OVHIPEYONTVANB-UHFFFAOYSA-N 0.000 description 1
- BUMOYDRCZQHASC-UHFFFAOYSA-N methyl 6-benzamido-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound C(C1=CC=CC=C1)(=O)NC=1C=C2C(=C(C(N(C2=CC=1)C)=O)C(=O)OC)O BUMOYDRCZQHASC-UHFFFAOYSA-N 0.000 description 1
- FTZJYRUUMBGBGL-UHFFFAOYSA-N methyl 6-chlorosulfonyl-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound ClS(=O)(=O)C=1C=C2C(=C(C(N(C2=CC=1)C)=O)C(=O)OC)O FTZJYRUUMBGBGL-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 201000002652 newborn respiratory distress syndrome Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 208000012307 pale mucous membrane Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003214 pyranose derivatives Chemical class 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 229940029258 sodium glycinate Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 125000000626 sulfinic acid group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 229940082632 vitamin b12 and folic acid Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
R1はH又はC1〜4アルキル基であり、R1のうち、前記C1〜4アルキル基は、オキソ(=O)、ハロゲン、アミノ基、ヒドロキシ基、メルカプト基、シアノ基、C1〜4アルキル基、C2〜4アルケニル基、ハロ置換C1〜4アルキル基、C1〜4アルコキシ基、アシル基、スルホニル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基又はC1〜5ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R2、R3、R4及びR5は、それぞれ独立してH又は−L−R10であり、且つR2、R3、R4及びR5は同時にHではなく、
ただし、Lは、それぞれ独立して−(CR11R12)m−、−(CR11R12)p−O−、−(CR11R12)p−S(=O)n−、−(CR11R12)p−N(R13)−、−(CR11R12)p−C(=X)−、−(CR11R12)p−C(=X)N(R13)−(CR11R12)q−、−(CR11R12)p−C(=X)O−(CR11R12)q−、−(CR11R12)p−OC(=X)N(R13)−(CR11R12)q−、−(CR11R12)p−N(R13)C(=X)N(R13)−(CR11R12)q−、−(CR11R12)p−S(=O)2N(R13)−(CR11R12)q−、−(CR11R12)p−S(=O)2O−(CR11R12)q−、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基又はC1〜9ヘテロアリール基であり、Lのうち、前記C3〜10シクロアルキル基、C2〜9ヘテロシクリル基及びC1〜9ヘテロアリール基は独立して、オキソ(=O)、ヒドロキシ基、メルカプト基、アミノ基、ニトロ基、シアノ基、ハロゲン、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、アシル基、スルホニル基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
ただし、Xは、それぞれ独立してO又はSであり、
R11及びR12は、それぞれ独立してH、ハロゲン、シアノ基、ヒドロキシ基、メルカプト基、アミノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基であり、R11とR12のうち、前記ヒドロキシ基、メルカプト基、アミノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基及びC1〜9ヘテロアリール基は独立して、オキソ(=O)、ハロゲン、ヒドロキシ基、アミノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、アシル基、スルホニル基、C3〜8シクロアルキル基、C2〜7ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH、C1〜6アルキル基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基であり、R13のうち、前記C1〜6アルキル基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基及びC1〜9ヘテロアリール基は独立して、オキソ(=O)、シアノ基、ニトロ基、ハロゲン、ヒドロキシ基、アミノ基、メルカプト基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、アシル基、スルホニル基、C3〜8シクロアルキル基、C2〜7ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R10は、それぞれ独立して−OR14、−NR15R16、−C(=O)NR15R16、−N(R15)C(=O)R17、−C(=O)R17、−S(=O)nR18、−S(=O)2NR15R16、−N(R15)S(=O)2R18、C3〜10シクロアルキル基、C3〜10シクロアルキルC1〜6アルキル基、C2〜9ヘテロシクリル基、C2〜9ヘテロシクリルC1〜6アルキル基、C6〜10アリール基、C6〜10アリールC1〜6アルキル基、C1〜9ヘテロアリール基又はC1〜9ヘテロアリールC1〜6アルキル基であり、R10のうち、前記C3〜10シクロアルキル基、C3〜10シクロアルキルC1〜6アルキル基、C2〜9ヘテロシクリル基、C2〜9ヘテロシクリルC1〜6アルキル基、C6〜10アリール基、C6〜10アリールC1〜6アルキル基、C1〜9ヘテロアリール基及びC1〜9ヘテロアリールC1〜6アルキル基は独立して、オキソ(=O)、ハロゲン、ヒドロキシ基、メルカプト基、アミノ基、ニトロ基、シアノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、アシル基、スルホニル基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R14、R16、R17及びR18は、それぞれ独立してC3〜10シクロアルキル基、C3〜10シクロアルキルC1〜6アルキル基、C2〜9ヘテロシクリル基、C2〜9ヘテロシクリルC1〜6アルキル基、C6〜10アリール基、C6〜10アリールC1〜6アルキル基、C1〜9ヘテロアリール基又はC1〜9ヘテロアリールC1〜6アルキル基であり、R14、R16、R17及びR18のうち、前記C3〜10シクロアルキル基、C3〜10シクロアルキルC1〜6アルキル基、C2〜9ヘテロシクリル基、C2〜9ヘテロシクリルC1〜6アルキル基、C6〜10アリール基、C6〜10アリールC1〜6アルキル基、C1〜9ヘテロアリール基及びC1〜9ヘテロアリールC1〜6アルキル基は独立して、オキソ(=O)、ハロゲン、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1〜4アルキル基、ハロ置換C1〜4アルキル基、C1〜4アルコキシ基、ハロ置換C1〜4アルコキシ基、アシル基又はスルホニル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R15は、それぞれ独立してH又はC1〜6アルキル基であり、R15のうち、前記C1〜6アルキル基は独立して、オキソ(=O)、ハロゲン、C1〜4アルキル基、ハロ置換C1〜4アルキル基、アミノ基、C1〜4アルコキシ基、ハロ置換C1〜4アルコキシ基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R6はH、ヒドロキシ基、メルカプト基、アミノ基又はC1〜4アルキル基であり、
R7は水素又はC1〜4アルキル基であり、R7のうち、前記C1〜4アルキル基は独立して、ハロゲン、アミノ基、ヒドロキシ基、C1〜4アルキル基、C1〜4アルコキシ基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R8とR9は、それぞれ独立してH又はC1〜4アルキル基であり、R8とR9のうち、前記C1〜4アルキル基は独立して、ハロゲン、アミノ基、ヒドロキシ基、C1〜4アルキル基、C1〜4アルコキシ基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
kは1、2、3又は4であり、
mは、それぞれ独立して1、2、3又は4であり、
nは、それぞれ独立して0、1又は2であり、
pとqは、それぞれ独立して0、1、2、3又は4である。)
ただし、R11とR12は、それぞれ独立してH、フッ素、塩素、臭素、C1〜4アルキル基、ハロ置換C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基であり、R11とR12のうち、前記C1〜4アルキル基、ハロ置換C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜5ヘテロアリール基は独立して、オキソ(=O)、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基、ナフチル基、ピロリル基、チエニル基又はピリジル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH、C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基であり、R13のうち、前記C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜5ヘテロアリール基は独立して、オキソ(=O)、シアノ基、ニトロ基、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基、アセチル基、メチルスルホニル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基又はピリジル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
ただし、R11とR12は、それぞれ独立してH、C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基であり、R11とR12のうち、前記C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜5ヘテロアリール基は独立して、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基、ピロリル基又はピリジル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13はそれぞれ独立してH又はC1〜4アルキル基であり、R13のうち、前記C1〜4アルキル基は独立して、シアノ基、ニトロ基、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基、アセチル基、メチルスルホニル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基又はピリジル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
ただし、R11とR12は、それぞれ独立してH、メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基又はピリジル基であり、R11とR12のうち、前記メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基及びピリジル基は独立して、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、トリフルオロメチル基、メトキシ基又はトリフルオロメトキシ基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13はそれぞれ独立してH、メチル基、エチル基、プロピル基又はブチル基である。
以下、本発明のいくつかの実施形態を詳細に説明し、その例を添付した構造式及び化学式により説明する。本発明は、全ての代替、変更及び同等技術案を含むことを意図し、それらはすべて特許請求の範囲に定義された本発明の範囲内に含まれる。当業者にとっては、本明細書の内容に類似又は同等する多数の方法及び材料は全て本発明の実施に適用でき、本発明は本明細書の前記方法及び材料に制限されないことが明らかである。参照される文献、特許や類似資料の1つ又は複数は本願と異なる又は矛盾する場合(定義される用語、用語使用、説明した技術等を含むが、それらに制限されない)、本願を基準にする。
アルキル基の例は、メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、i−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、2−ペンチル基、3−ペンチル基、2−メチル−2−ブチル基、3−メチル−2−ブチル基、3−メチル−1−ブチル基、2−メチル−1−ブチル基、n−ヘキシル基、2−ヘキシル基、3−ヘキシル基、2−メチル−2−ペンチル基、3−メチル−2−ペンチル基、4−メチル−2−ペンチル基、3−メチル−3−ペンチル基、2−メチル−3−ペンチル基、2,3−ジメチル−2−ブチル基、3,3−ジメチル−2−ブチル基、n−ヘプチル基、n−オクチル基等を含むが、それらに制限される。
用語「アルケニル基」は2〜12個の炭素原子を有する直鎖又は分岐状一価炭化水素基を示し、その中、少なくとも1個の不飽和部位、すなわち1個の炭素−炭素sp2二重結合を有し、前記アルケニル基は、1個又は複数の本発明に記載の置換基により置換されてもよく、「cis」と「tans」の位置決め、又は「E」と「Z」の位置決めを含む。いくつかの実施形態において、アルケニル基は2〜8個の炭素原子を含み、別の実施形態において、アルケニル基は2〜6個の炭素原子を含み、更なる実施形態において、アルケニル基は2〜4個の炭素原子を含む。アルケニル基の例は、エチレン基(−CH=CH2)、アリル基(−CH2CH=CH2)等を含むが、それらに制限されない。
「エリスロポエチン(EPO)に関連する疾患」とは、内因性エリスロポエチンの正常値未満、異常又は不適な調節によるあらゆる病状である。EPO関連病状は、EPOの含有量を向上させることが治療によい任意の病状を含む。EPO関連疾患は、貧血(糖尿病、潰瘍、腎不全、癌、感染、透析、手術や化学療法に関連する貧血)、虚血及び低酸素の病状(例えば、動脈閉塞性疾患、狭心症、腸梗塞、肺塞栓症、脳虚血や心筋梗塞等を含む)を含むが、これらに制限されない。
HIF及び/又はEPOに関連する疾患は、貧血、虚血、血管疾患、狭心症、心筋虚血、心筋梗塞、代謝障害又は傷口癒合等を含むが、これらに制限されない。
本発明は、HIF−PHD抑制剤として使用可能な新規なキノリノン系化合物及びその薬物組成物、並びに前記化合物又は前記薬物組成物の製薬における用途を提供し、前記薬物は、HIF及び/又はEPOに関連する疾患を予防、処置、治療又は軽減させるために用いられる。
LとR10は本発明で説明した定義を有する。
ただし、Xは、それぞれ独立してO又はSである。
R11、R12、R13、m、n、p及びqは本発明で説明した定義を有する。
R14、R15、R16、R17及びR18は本発明で説明した定義を有する。
R15は、それぞれ独立してH又はアルキル基であり、R15のうち、前記アルキル基は独立して、オキソ(=O)、ハロゲン、アルキル基、ハロアルキル基、アミノ基、アルコキシ基、ハロ置換アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基又はヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
R7は水素又はアルキル基であり、R7のうち、前記アルキル基は独立して、ハロゲン、アミノ基、ヒドロキシ基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基又はヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
R8とR9は、それぞれ独立してH又はアルキル基であり、R8とR9のうち、前記アルキル基は独立して、ハロゲン、アミノ基、ヒドロキシ基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基又はヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
ただし、Xは、それぞれ独立してO又はSであり、R11、R12、R13、m、n、p及びqは本発明で説明した定義を有する。
ただし、R11、R12、R13、m、n、p及びqは本発明で説明した定義を有する。
ただし、R14、R15、R16、R17及びR18は、本発明で説明した定義を有する。
R15は、それぞれ独立してH又はC1〜6アルキル基であり、R15のうち、前記C1〜6アルキル基は独立して、オキソ(=O)、ハロゲン、C1〜4アルキル基、ハロ置換C1〜4アルキル基、アミノ基、C1〜4アルコキシ基、ハロ置換C1〜4アルコキシ基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい。
R6はH又はヒドロキシ基であり、
R7は水素、メチル基、エチル基、プロピル基又はブチル基であり、
R8とR9は、それぞれ独立してH、メチル基、エチル基、プロピル基又はブチル基である。
ただし、R11、R12及びR13は本発明で説明した定義を有する。
又はその立体異性体、幾何異性体、互変異性体、窒素酸化物、水和物、溶媒和物、代謝産物、エステル、薬学的に許容可能な塩又はプロドラッグを含む。
一局面によれば、本発明の薬物組成物は、式(I)又は式(II)に示されるキノリノン系化合物、本発明で挙げられた化合物、又は実施例1〜52の化合物、及び薬学的に許容可能な担体、アジュバント、又は賦形剤を含むことを特徴とする。本発明の組成物における化合物の量は、患者のHIF及び/又はEPOに関連する疾患を効果的に治療又は軽減できる。
表1 低分解能マススペクトル移動相の勾配溶離条件
CDC13 重水素化クロロホルム
DMF−d7 重水素化N,N−ジメチルホルムアミド
DMSO−d6 重水素化ジメチルスルホキシド
Acetone−d6 重水素化アセトン
EA、 EtOAc 酢酸エチル
DMF N,N−ジメチルホルムアミド
g グラム
mg ミリグラム
mol モル
mmol ミリモル
h 時間
min 分間
mL ミリリットル
μL マイクロリットル
EPO エリスロポエチン
ATCC アメリカン・タイプ・カルチャー・コレクション
1H NMR(400 MHz,DMSO−d6)δ(ppm): 11.94(s,1H),7.81(d,J =8.0 Hz,1H),7.48 − 7.26(m,2H).
1H NMR(400MHz,Acetone−d6)δ(ppm): 8.14(s,1H),7.51(s,2H),7.21(t,J=35.4 Hz,4H),6.94(s,1H),4.26(s,2H),3.61(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.91(s,1H),10.45(t,J=5.2 Hz,1H),8.16 - 8.04(m,J=8.6,5.8 Hz,1H),7.50(t,J=7.7 Hz,2H),7.29(t,J=7.3 Hz,1H),7.21(d,J=8.3 Hz,3H),7.02 - 6.88(m,1H),4.20 - 4.01(m,J=6.2 Hz,4H),1.18 - 1.02(m,1H),0.44(d,J=7.8 Hz,2H),0.36(d,J=4.3 Hz,2H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 11.86(s,1H),8.05 - 7.83(m,2H),7.11(d,J=8.7 Hz,1H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 8.10 - 7.96(m,2H),7.41(d,J=8.8 Hz,1H),3.45(s,3H).
1H NMR(400MHz,DMF−d7)δ(ppm): 10.99(s,1H),10.68(s,1H),8.76(d,J=2.1 Hz,1H),8.26(d,J=9.3 Hz,1H),7.81(d,J=9.1 Hz,1H),7.62(d,J=7.3 Hz,2H),7.54(t,J=7.5 Hz,2H),7.45(t,J=7.2 Hz,1H),4.47(d,J=5.5 Hz,2H),3.96(s,2H),3.87(s,3H).
1H NMR(400MHz,DMF−d7)δ(ppm): 10.68(s,1H),8.18(d,J=8.8 Hz,1H),7.60(d,J=8.1 Hz,2H),7.29(M,3H),7.02(d,J=8.3 Hz,1H),4.31(d,J=5.2 Hz,2H),4.28(s,2H),4.13 - 4.06(m,2H),3.91 - 3.84(m,2H),3.67(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.92(s,1H),10.59(s,1H),7.69(d,J=9.1 Hz,1H),7.60 - 7.48(m,2H),7.44(t,J=7.7 Hz,2H),7.20(t,J=7.3 Hz,1H),7.09(d,J=7.9 Hz,2H),4.13(d,J=5.4 Hz,2H),3.65(s,3H).
1H NMR(400MHz,DMF−d7)δ(ppm): 10.84(s,1H),10.59(s,1H),8.80(d,J=1.2 Hz,1H),8.36(d,J=8.2 Hz,1H),8.14(d,J=7.3 Hz,2H),7.65(ddd,J=23.9,19.3,8.1 Hz,4H),4.32(d,J=4.9 Hz,2H),3.75(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.31(t,J=5.1 Hz,1H),8.51(d,J=1.8 Hz,1H),8.23(dd,J=9.1,2.3 Hz,1H),7.98(d,J=8.3 Hz,1H),7.89(d,J=3.7 Hz,1H),7.72(d,J=9.2 Hz,1H),7.60(d,J=7.8 Hz,1H),7.37(t,J=7.8 Hz,1H),7.25(t,J=7.5 Hz,1H),6.87(d,J=3.2 Hz,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H)。
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.47(s,1H),8.07(dd,J=15.9,8.8 Hz,2H),7.98(d,J=7.7 Hz,1H),7.91(d,J=7.6 Hz,1H),7.67(s,1H),7.53(t,J=7.8 Hz,2H),7.40(d,J=8.8 Hz,1H),7.27(s,1H),6.97(d,J=8.8 Hz,1H),4.13(d,J=2.9 Hz,2H),3.55(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.59(t,J=5.4 Hz,1H),8.01(d,J=8.9 Hz,1H),7.94(d,J=7.9 Hz,1H),7.84(d,J=7.9 Hz,1H),7.72(d,J=9.2 Hz,1H),7.65(dd,J=9.2,2.7 Hz,1H),7.60(d,J=2.6 Hz,1H),7.54 - 7.43(m,3H),7.36(dd,J=8.9,2.4 Hz,1H),4.13(d,J=5.5 Hz,2H),3.67(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 9.03(d,J=8.8 Hz,1H),8.37(d,J=2.1 Hz,1H),7.87(dd,J=8.8,2.1 Hz,1H),7.34(d,J=4.3 Hz,8H),7.29 - 7.23(m,2H),7.07(s,2H),6.80(d,J=8.8 Hz,1H),6.39(d,J=8.7 Hz,1H),3.82(s,3H).
2−アミノ−5−(ジベンジルアミノホルミル)安息香酸(1.16g、3.35mmol)をテトラヒドロフラン(40mL)に溶解して、トリホスゲン(0.497g、1.67mmol)を加え、次に70℃に加熱して24時間撹拌した。室温まで冷却させて、水(40mL)を加えて反応をクエンチし、酢酸エチル(20mL×2)で抽出した。有機相を混合し、順に水(30mL)、飽和食塩水(20mL)で洗浄して、無水硫酸ナトリウムで乾燥させた。濾過し、減圧蒸留により溶剤を除去し、黄色固体(1.19g、95.4%)を得た。
1H NMR(600MHz,DMSO−d6)δ(ppm): 9.09(d,J=8.8 Hz,1H),8.46(d,J=2.1 Hz,1H),8.05(dd,J=8.9,2.0 Hz,1H),7.90(d,J=4.9 Hz,1H),7.35(d,J=4.3 Hz,8H),7.27(dd,J=8.3,4.5 Hz,2H),6.77(d,J=9.0 Hz,1H),6.41(d,J=8.8 Hz,1H),3.83(s,3H),2.91(d,J=5.0 Hz,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.50(d,J=5.4 Hz,1H),9.58(d,J=8.7 Hz,1H),8.73(d,J=1.7 Hz,1H),8.34(dd,J=8.9,1.9 Hz,1H),7.71(d,J=9.0 Hz,1H),7.42 - 7.33(m,8H),7.28(t,J=6.4 Hz,2H),6.46(d,J=8.6 Hz,1H),4.15(d,J=5.5 Hz,2H),3.67(s,3H).
1H NMR(600MHz,DMSO−d6)δ(ppm): 10.49(s,1H),8.08(s,1H),7.87(s,1H),7.69(d,J=8.8 Hz,1H),7.40(dt,J=38.7,7.4 Hz,6H),7.21(s,5H),4.14(d,J=5.4 Hz,2H),3.65(s,3H),2.76(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.47(s,1H),8.09(d,J=8.8 Hz,1H),7.49(t,J=8.1 Hz,1H),7.32(d,J=8.0 Hz,1H),7.29(d,J=2.0 Hz,1H),7.25(d,J=1.9 Hz,1H),7.15(dd,J=8.2,2.0 Hz,1H),6.94(dd,J=8.9,2.0 Hz,1H),4.03(d,J=5.3 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.48(s,1H),8.08(d,J=8.8 Hz,1H),7.52(d,J=8.6 Hz,2H),7.31 - 7.07(m,3H),6.91(d,J=8.8 Hz,1H),3.89(d,J=4.6 Hz,2H),3.54(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.47(s,1H),8.10(d,J=8.9 Hz,1H),7.46 - 7.25(m,3H),7.19(t,J=7.7Hz,1H),6.97(dd,J=8.9,2.0 Hz,1H),4.12(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.91(s,1H),10.45(t,J=5.5 Hz,1H),8.06(d,J=8.9 Hz,1H),7.61 - 7.53(m,1H),7.48(td,J=9.2,5.7 Hz,1H),7.22(t,J=8.2 Hz,1H),7.17(d,J=2.0 Hz,1H),6.86(dd,J=8.9,1.9 Hz,1H),4.13(d,J=5.5 Hz,2H),3.55(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.4 Hz,1H),8.08(d,J=8.9 Hz,1H),7.52 - 7.33(m,3H),7.24(d,J=2.0 Hz,1H),6.86(dd,J=8.9,1.8 Hz,1H),4.13(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(s,1H),8.08(d,J=8.9 Hz,1H),7.54(dd,J=19.3,9.4 Hz,1H),7.47 - 7.38(m,1H),7.19(s,1H),7.07(d,J=8.3 Hz,1H),6.95(dd,J=8.8,1.6 Hz,1H),4.12(d,J=5.4 Hz,2H),3.55(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.48(t,J=5.2 Hz,1H),8.13(d,J=8.8 Hz,1H),7.32(d,J=2.0 Hz,1H),7.13(tt,J=9.3,2.2 Hz,1H),7.05(dd,J=8.8,2.1 Hz,1H),6.97(dd,J=8.2,2.0 Hz,2H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.47(s,1H),8.10(d,J=8.9 Hz,1H),7.60 - 7.48(m,J=9.8,5.2 Hz,1H),7.41 - 7.31(m,1H),7.27 - 7.15(m,2H),6.95(d,J=8.8 Hz,1H),4.12(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.92(s,1H),10.47(t,J=5.5 Hz,1H),8.09(d,J=8.9 Hz,1H),7.58 - 7.49(m,1H),7.40 - 7.26(m,3H),6.94(dd,J=8.9,1.9 Hz,1H),4.13(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.90(s,1H),10.46(t,J=5.5 Hz,1H),8.07(d,J=8.9 Hz,1H),7.76 - 7.69(m,1H),7.47 - 7.35(m,2H),7.22(d,J=2.1 Hz,1H),6.94 - 6.85(m,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.96(s,1H),10.47(t,J=5.5 Hz,1H),8.10(d,J=8.9 Hz,1H),7.60 - 7.48(m,2H),7.47 - 7.38(m,1H),7.27(d,J=1.9 Hz,1H),6.94(dd,J=8.9,1.9 Hz,1H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.92(s,1H),10.46(t,J=5.5 Hz,1H),8.08(d,J=8.9 Hz,1H),7.63 - 7.41(m,3H),7.23(d,J=2.1 Hz,1H),6.76(dd,J=8.9,2.0 Hz,1H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.4 Hz,1H),8.09(d,J=8.9 Hz,1H),7.54 - 7.43(m,1H),7.38(t,J=8.2 Hz,1H),7.27(d,J=2.0 Hz,1H),7.17(d,J=8.3 Hz,1H),6.93 - 6.80(m,1H),4.13(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.93(s,1H),10.47(s,1H),8.10(d,J=8.8 Hz,1H),7.67(t,J=8.7 Hz,1H),7.37(d,J=8.7 Hz,1H),7.28(s,1H),7.04(dd,J=21.6,8.5 Hz,2H),4.13(d,J=5.4 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.48(s,1H),8.12(d,J=8.9 Hz,1H),7.39 - 7.25(m,2H),7.20 - 7.08(m,2H),7.04(dd,J=8.8,2.0 Hz,1H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.91(s,1H),10.46(t,J=5.5 Hz,1H),8.07(d,J=8.9 Hz,1H),7.72(dd,J=8.4,2.9 Hz,1H),7.44(dd,J=9.0,5.3 Hz,1H),7.36(td,J=8.6,3.0 Hz,1H),7.18(d,J=2.1 Hz,1H),6.80(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.6 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.90(s,1H),10.47(d,J=5.0 Hz,1H),8.09(d,J=8.8 Hz,1H),7.58 - 7.48(m,2H),7.30 - 7.19(m,2H),6.95(d,J=8.8 Hz,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(d,J=5.4 Hz,1H),8.09(d,J=8.9 Hz,1H),7.60(d,J=7.3 Hz,1H),7.47(t,J=8.2 Hz,1H),7.29(dd,J=12.7,5.0 Hz,2H),6.86(dd,J=8.9,1.9 Hz,1H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.92(s,1H),10.44(s,1H),7.94(d,J=83.7 Hz,2H),7.62 - 7.08(m,3H),6.83(s,1H),4.12(s,2H),3.54(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.3 Hz,1H),8.07(d,J=8.9 Hz,1H),7.71(d,J=8.2 Hz,2H),7.45(t,J=8.2 Hz,1H),7.21(d,J=1.9 Hz,1H),6.66(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.48(s,1H),8.12(d,J=8.5 Hz,1H),7.71(d,J=8.6 Hz,1H),7.53(s,1H),7.29(s,1H),7.21(d,J=8.9 Hz,1H),7.01(d,J=9.3 Hz,1H),4.07(d,J=4.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.93(s,1H),10.47(t,J=5.3 Hz,1H),8.12(d,J=8.8 Hz,1H),7.49(s,1H),7.37 - 7.25(m,3H),7.03(dd,J=8.8,1.7 Hz,1H),4.14(d,J=5.5 Hz,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.93(s,1H),10.47(s,1H),8.10(d,J=8.8 Hz,1H),7.72(d,J=8.6 Hz,1H),7.50 - 7.37(m,2H),7.27(s,1H),6.93 - 6.82(m,1H),4.12(s,2H),3.58(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.5 Hz,1H),8.04(d,J=8.9 Hz,1H),7.16(d,J=9.0 Hz,2H),7.06(dd,J=17.4,5.5 Hz,3H),6.82(dd,J=8.9,2.1 Hz,1H),4.12(d,J=5.5 Hz,2H),3.79(s,3H),3.53(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.88(s,1H),10.46(t,J=5.3 Hz,1H),8.05(d,J=8.9 Hz,1H),7.38(t,J=8.2 Hz,1H),7.17(s,1H),6.94 - 6.80(m,2H),6.80 - 6.68(m,2H),4.13(d,J=5.4 Hz,2H),3.77(s,3H),3.54(s,3H).
1H NMR(600MHz,DMSO−d6)δ(ppm): 10.48(t,J=5.5 Hz,1H),8.03(d,J=8.9 Hz,1H),7.37 - 7.29(m,1H),7.28 - 7.18(m,2H),7.10 - 7.02(m,2H),6.74 - 6.67(m,1H),4.13(d,J=5.6 Hz,2H),3.75(s,3H),3.54(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.48(s,1H),7.95(d,J=10.8 Hz,1H),7.46(t,J=7.8 Hz,2H),7.33 - 7.20(m,2H),7.16(d,J=8.1 Hz,2H),4.14(d,J=5.4 Hz,2H),3.49(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.95(s,1H),10.47(t,J=5.4 Hz,1H),8.11(d,J=8.9 Hz,1H),7.62(d,J=8.0 Hz,1H),7.51(td,J=7.9,1.4 Hz,1H),7.46 - 7.33(m,2H),7.24(d,J=2.0 Hz,1H),6.88(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 12.89(s,1H),10.47(t,J=5.5 Hz,1H),9.76(s,1H),8.08(d,J=8.9 Hz,1H),7.25(t,J=8.1 Hz,1H),7.19(d,J=2.0 Hz,1H),6.90(dd,J=8.9,2.1 Hz,1H),6.66(dd,J=8.2,1.5 Hz,1H),6.58(dd,J=7.8,1.8 Hz,1H),6.53(t,J=2.2 Hz,1H),4.13(d,J=5.6 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.60(t,J=5.2 Hz,1H),8.23(d,J=8.9 Hz,1H),7.65(t,J=7.9 Hz,2H),7.45(t,J=7.4 Hz,1H),7.36(d,J=7.7 Hz,2H),7.17(s,1H),7.10(dd,J=8.9,1.9 Hz,1H),4.31(t,2H),4.25(d,J=5.5 Hz,2H),1.58(dd,J=14.9,7.2 Hz,2H),0.87 - 0.74(m,1H),0.52 - 0.43(m,2H),0.07 - 0.00(m,J=5.0 Hz,2H).
1H NMR(400MHz,D2O)δ(ppm): 7.70(d,J=41.5 Hz,3H),6.81(s,2H),6.37(s,2H),3.54(s,2H),3.06(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.4 Hz,1H),9.11(s,1H),8.80(s,1H),8.12(d,J=8.9 Hz,2H),7.35(d,J=2.0 Hz,1H),7.09(dd,J=8.9,2.1 Hz,1H),4.14(d,J=5.5 Hz,2H),3.57(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.5 Hz,1H),8.08(d,J=8.9 Hz,1H),7.54 - 7.44(m,1H),7.43 - 7.29(m,3H),7.20(d,J=2.0 Hz,1H),6.85(dd,J=8.9,2.0 Hz,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.47(t,J=5.4 Hz,1H),8.10(d,J=8.8 Hz,1H),7.51(dd,J=15.6,8.5 Hz,1H),7.25(d,J=2.0 Hz,1H),7.15 - 7.08(m,2H),7.05 - 7.00(m,1H),6.97(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.5 Hz,1H),8.06(d,J=8.9 Hz,1H),7.36 - 7.29(m,J=11.8,5.7 Hz,2H),7.29 - 7.22(m,2H),7.14(d,J=2.0 Hz,1H),6.87(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.5 Hz,2H),3.54(s,3H).
1H NMR(400MHz,DMSO−d6)δ(ppm): 10.46(t,J=5.4 Hz,1H),8.08(d,J=8.9 Hz,1H),7.68(d,J=7.9 Hz,1H),7.52 - 7.43(m,1H),7.35(t,J=7.5 Hz,2H),7.20(d,J=1.9 Hz,1H),6.78(dd,J=8.9,2.1 Hz,1H),4.13(d,J=5.5 Hz,2H),3.56(s,3H).
表2のデータから明らかなように、本発明の化合物は優れたEPO誘導活性を有する。
表3のデータから明らかなように、本発明の化合物は、優れたインビボ薬物動態学性質、良好な吸収や暴露量を有し、生物学的利用能が高い。
Claims (17)
- 式(I)に示される化合物又は式(I)に示される化合物の水和物、溶媒和物若しくは薬学的に許容可能な塩である化合物。
(I)
(式中、
R1はC 1〜4 アルキル基であり、前記C1〜4アルキル基は独立して選ばれる1、2、3又は4個のC 3〜6 シクロアルキル基により置換されてもよく、
R 2 及びR 5 はそれぞれHであり、
R 3 及びR 4 はそれぞれ独立してH又は−L−R10であり、且つR2、R3、R4及びR5は同時にHではなく、
各Lは独立して−(CR11R12)m−、−(CR11R12)p−O−、−(CR11R12)p−S(=O)n−、−(CR11R12)p−N(R13)−又は−(CR11R12)p−C(=X)N(R13)−(CR11R12)q −であり、
Xは、それぞれ独立してO又はSであり、
R11とR12は、それぞれ独立してH、ハロゲン、C 1〜6アルキル基、ハロ置換C1〜6アルキル基、C 3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基であり、R11とR12のうち、前記C 1〜6アルキル基、ハロ置換C1〜6アルキル基、C 3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基及びC1〜9ヘテロアリール基はそれぞれ、オキソ(=O)、ハロゲン、ヒドロキシ基、アミノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基又はハロ置換C1〜6アルコキシ基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH又はC1〜6アルキル基であり、
R10は、それぞれ独立してC 3〜10シクロアルキル基、C 2〜9ヘテロシクリル基、C 6〜10アリール基又はC1〜9ヘテロアリール基であり、R10のうち、前記C3〜10シクロアルキル基、C 2〜9ヘテロシクリル基、C 6〜10アリール基及びC1〜9ヘテロアリール基はそれぞれ、オキソ(=O)、ハロゲン、ヒドロキシ基、メルカプト基、アミノ基、ニトロ基、シアノ基、C1〜6アルキル基、ハロ置換C1〜6アルキル基、C1〜6アルコキシ基、ハロ置換C1〜6アルコキシ基、アシル基、スルホニル基、C3〜10シクロアルキル基、C2〜9ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R 6はヒドロキシ基又はメルカプト基であり、
R7は水素又はC1〜4アルキル基であり、
R 8とR9は、それぞれ独立してH又はC1〜4アルキル基であり、
kは1、2、3又は4であり、
mは、それぞれ独立して1、2、3又は4であり、
nは、それぞれ独立して0、1又は2であり、
pは、それぞれ独立して0であり、
qは、それぞれ独立して0、1、2、3又は4である。) - Lは、それぞれ独立して−(CR11R12)m−、−(CR11R12)p−O−、−(CR11R12)p−S(=O)n−、−(CR11R12)p−N(R13)−又は−(CR11R12)p−C(=O)N(R13)−(CR11R12)q −であり、
R11とR12は、それぞれ独立してH、フッ素、塩素、臭素、C1〜4アルキル基、ハロ置換C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基であり、R11とR12のうち、前記C1〜4アルキル基、ハロ置換C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜5ヘテロアリール基はそれぞれ、オキソ(=O)、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基又はトリフルオロメトキシ基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH又はC1〜4アルキル基である、請求項1に記載の化合物。 - Lは、それぞれ独立して−(CR11R12)m−、−O−、−S(O)n−、−N(R13)−又は−(CR11R12)p−C(=O)N(R13)−(CR11R12)q −であり、
R 11とR12は、それぞれ独立してH、C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜5ヘテロアリール基であり、R11とR12のうち、前記C1〜4アルキル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜5ヘテロアリール基は独立して、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基又はトリフルオロメトキシ基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH又はC1〜4アルキル基である、請求項2に記載の化合物。 - R10は、それぞれ独立してC3〜8シクロアルキル基、C 2〜7ヘテロシクリル基、C 6〜10アリール基又はC1〜9ヘテロアリール基であり、R10のうち、前記C3〜8シクロアルキル基、C 2〜7ヘテロシクリル基、C 6〜10アリール基及びC1〜9ヘテロアリール基は独立して、オキソ(=O)、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、ニトロ基、シアノ基、C1〜4アルキル基、ハロ置換C1〜4アルキル基、C1〜4アルコキシ基、ハロ置換C1〜4アルコキシ基、アシル基、スルホニル基、C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい、請求項1に記載の化合物。
- R10は、それぞれ独立してC3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基又はC1〜9ヘテロアリール基であり、R10のうち、前記C3〜6シクロアルキル基、C2〜5ヘテロシクリル基、C6〜10アリール基及びC1〜9ヘテロアリール基はそれぞれ、オキソ(=O)、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、ニトロ基、シアノ基、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基、エトキシ基、トリフルオロメトキシ基、アセチル基、−C(=O)OCH 3 、−C(=O)NH 2 、メチルスルホニル基、アミノスルホニル基、メトキシスルホニル基、シクロプロピル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、オキソモルホリニル基、フェニル基、ナフチル基、ピロリル基、チエニル基、ピリジル基、ピリミジニル基又はキノリル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい、請求項4に記載の化合物。
- Lは、それぞれ独立して−(CR11R12)−、−(CR11R12)2−、−O−、−S(=O)2−、−C(=O)N(R13)−又は−C(=O)N(R13)−(CR11R12)−であり、
R 11とR12は、それぞれ独立してH、メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基又はピリジル基であり、R11とR12のうち、前記メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、フェニル基及びピリジル基はそれぞれ、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、メチル基、エチル基、トリフルオロメチル基、メトキシ基又はトリフルオロメトキシ基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよく、
R13は、それぞれ独立してH、メチル基、エチル基、プロピル基又はブチル基である、請求項1又は請求項6に記載の化合物。 - R10は、それぞれ独立してシクロプロピル基、シクロペンチル基、シクロヘキシル基、オキシラニル基、ピロリジニル基、ピラゾリジニル基、オキサゾリジニル基、ピペリジニル基、モルホリニル基、テトラヒドロピリミジニル基、ピペラジニル基、オキサジナニル基、フェニル基、2,3−ジヒドロ−1H−インデニル基、ナフチル基、ピロリル基、ピラゾリル基、フラニル基、イミダゾリル基、オキサゾリル基、チエニル基、チアゾリル基、ピリジル基、ピリミジニル基、インドリル基、ジヒドロインドリル基、キノリル基、イソキノリル基、キナゾリニル基、イミダゾピリジル基、ベンゾイミダゾリル基、ベンゾフラニル基又はベンゾチエニル基であり、R10のうち、前記シクロプロピル基、シクロペンチル基、シクロヘキシル基、オキシラニル基、ピロリジニル基、ピラゾリジニル基、オキサゾリジニル基、ピペリジニル基、モルホリニル基、テトラヒドロピリミジニル基、ピペラジニル基、オキサジナニル基、フェニル基、2,3−ジヒドロ−1H−インデニル基、ナフチル基、ピロリル基、ピラゾリル基、フラニル基、イミダゾリル基、オキサゾリル基、チエニル基、チアゾリル基、ピリジル基、ピリミジニル基、インドリル基、ジヒドロインドリル基、キノリル基、イソキノリル基、キナゾリニル基、イミダゾピリジル基、ベンゾイミダゾリル基、ベンゾフラニル基又はベンゾチエニル基はそれぞれ、オキソ(=O)、フッ素、塩素、臭素、ヒドロキシ基、−NH2、メチルアミノ基、ジメチルアミノ基、ニトロ基、シアノ基、メチル基、エチル基、プロピル基、n−ブチル基、t−ブチル基、トリフルオロメチル基、メトキシ基、エトキシ基、トリフルオロメトキシ基、アセチル基、−C(=O)OCH 3 、−C(=O)NH 2 、メチルスルホニル基、アミノスルホニル基、メトキシスルホニル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基、ピロリジニル基、ピペリジニル基、モルホリニル基、オキソモルホリニル基、フェニル基、ピロリル基、チエニル基又はピリジル基から独立して選ばれる1、2、3又は4個の置換基により置換されてもよい、請求項1又は請求項6に記載の化合物。
- 請求項1〜9のいずれか1項に記載の化合物を含む薬物組成物。
- 薬学的に許容可能な担体、賦形剤、希釈剤、アジュバント及び媒質の少なくとも1種を更に含む、請求項10に記載の薬物組成物。
- 低酸素誘導因子及び/又はエリスロポエチンに関連する疾患の予防、処置、治療又は軽減のための、請求項10又は11に記載の薬物組成物。
- 少なくとも一部の低酸素誘導因子プロリルヒドロキシラーゼを介した疾患を予防、処置、治療又は軽減させるための、請求項12に記載の薬物組成物。
- 前記疾患は貧血、虚血、血管疾患、狭心症、心筋虚血、心筋梗塞、代謝障害又は傷口癒合である、請求項12に記載の薬物組成物。
- 低酸素誘導因子及び/又はエリスロポエチンに関連する疾患を予防、処置、治療又は軽減させるための薬物の製造に用いるための、請求項1〜9のいずれか1項に記載の化合物又は請求項10〜14のいずれか1項に記載の薬物組成物の使用。
- 前記薬物は少なくとも一部の低酸素誘導因子プロリルヒドロキシラーゼを介した疾患を予防、処置、治療又は軽減させるために用いられる、請求項15に記載の使用。
- 前記疾患は貧血、虚血、血管疾患、狭心症、心筋虚血、心筋梗塞、代謝障害又は傷口癒合である、請求項15に記載の使用。
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