EA017112B1 - N-замещенные производные глицина: ингибиторы гидроксилаз - Google Patents

Info

Publication number

EA017112B1

EA017112B1 EA200970680A EA200970680A EA017112B1 EA 017112 B1 EA017112 B1 EA 017112B1 EA 200970680 A EA200970680 A EA 200970680A EA 200970680 A EA200970680 A EA 200970680A EA 017112 B1 EA017112 B1 EA 017112B1

Authority

EA

Eurasian Patent Office

Prior art keywords

hydroxy

oxo

glycine

dihydro

carbonyl

Prior art date

2007-01-12

Links

• Espacenet
• Global Dossier
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• 150000002332 glycine derivatives Chemical class 0.000 title abstract description 3
• 108010049175 N-substituted Glycines Proteins 0.000 title abstract 2
• 102000008109 Mixed Function Oxygenases Human genes 0.000 title description 3
• 108010074633 Mixed Function Oxygenases Proteins 0.000 title description 3
• 239000003112 inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 436
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 347
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 270
• -1 -C (O) OK 10 Chemical group 0.000 claims description 240
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 149
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 128
• 150000003839 salts Chemical class 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 19
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 16
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 13
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical group 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 3
• BMEBRCIDAGDITE-UHFFFAOYSA-N 2-[[6-(carboxymethylcarbamoyl)-2-[(2-chlorophenyl)methyl]-5-hydroxy-3-oxopyridazine-4-carbonyl]amino]acetic acid Chemical compound O=C1C(C(=O)NCC(O)=O)=C(O)C(C(=O)NCC(=O)O)=NN1CC1=CC=CC=C1Cl BMEBRCIDAGDITE-UHFFFAOYSA-N 0.000 claims description 3
• 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
• ZHIDTPLDXKHNAO-UHFFFAOYSA-N 4-[2-[[5-(carboxymethylcarbamoyl)-4-hydroxy-6-oxo-3-propan-2-ylpyridazin-1-yl]methyl]phenyl]benzoic acid Chemical compound O=C1C(C(=O)NCC(O)=O)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1C1=CC=C(C(O)=O)C=C1 ZHIDTPLDXKHNAO-UHFFFAOYSA-N 0.000 claims description 3
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
• MWYARROAFXFMBB-UHFFFAOYSA-N 4-[4-[[5-(carboxymethylcarbamoyl)-4-hydroxy-6-oxo-3-propan-2-ylpyridazin-1-yl]methyl]phenyl]benzoic acid Chemical compound O=C1C(C(=O)NCC(O)=O)=C(O)C(C(C)C)=NN1CC1=CC=C(C=2C=CC(=CC=2)C(O)=O)C=C1 MWYARROAFXFMBB-UHFFFAOYSA-N 0.000 claims description 2
• 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 2
• 125000001041 indolyl group Chemical group 0.000 claims description 2
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000001544 thienyl group Chemical group 0.000 claims description 2
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
• HOFQOZPOIRYDEZ-UHFFFAOYSA-N 2-[[2-[[2-fluoro-4-(2-methoxyphenyl)phenyl]methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carbonyl]amino]acetic acid Chemical compound COC1=CC=CC=C1C(C=C1F)=CC=C1CN1C(=O)C(C(=O)NCC(O)=O)=C(O)C(C(C)C)=N1 HOFQOZPOIRYDEZ-UHFFFAOYSA-N 0.000 claims 1
• SZKPZWMBMGCDDY-UHFFFAOYSA-N 2-[[2-[[2-fluoro-4-[4-(trifluoromethyl)phenyl]phenyl]methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carbonyl]amino]acetic acid Chemical compound O=C1C(C(=O)NCC(O)=O)=C(O)C(C(C)C)=NN1CC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1F SZKPZWMBMGCDDY-UHFFFAOYSA-N 0.000 claims 1
• NLEDBOJPZUGKKW-UHFFFAOYSA-N 2-[[5-hydroxy-2-[[4-(2-methoxypyridin-4-yl)phenyl]methyl]-3-oxo-6-propan-2-ylpyridazine-4-carbonyl]amino]acetic acid Chemical compound C1=NC(OC)=CC(C=2C=CC(CN3C(C(C(=O)NCC(O)=O)=C(O)C(C(C)C)=N3)=O)=CC=2)=C1 NLEDBOJPZUGKKW-UHFFFAOYSA-N 0.000 claims 1
• 125000005037 alkyl phenyl group Chemical group 0.000 claims 1
• 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 claims 1
• 230000008520 organization Effects 0.000 claims 1
• 208000007502 anemia Diseases 0.000 abstract description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
• 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 11
• 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 11
• 201000010099 disease Diseases 0.000 abstract description 8
• 102000004190 Enzymes Human genes 0.000 abstract description 7
• 108090000790 Enzymes Proteins 0.000 abstract description 7
• 230000005764 inhibitory process Effects 0.000 abstract description 7
• 239000005557 antagonist Substances 0.000 abstract description 2
• MYKHANQTTIRZJK-UHFFFAOYSA-N pyridazine-3,4-dione Chemical compound O=C1C=CN=NC1=O MYKHANQTTIRZJK-UHFFFAOYSA-N 0.000 abstract 1
• 239000011541 reaction mixture Substances 0.000 description 336
• 239000000243 solution Substances 0.000 description 334
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 323
• 239000004471 Glycine Substances 0.000 description 230
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 225
• 229910001868 water Inorganic materials 0.000 description 223
• 239000000203 mixture Substances 0.000 description 222
• 239000000047 product Substances 0.000 description 222
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 213
• 238000005481 NMR spectroscopy Methods 0.000 description 205
• 238000006243 chemical reaction Methods 0.000 description 136
• 239000007787 solid Substances 0.000 description 133
• 239000010410 layer Substances 0.000 description 127
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
• 238000010992 reflux Methods 0.000 description 95
• 239000012267 brine Substances 0.000 description 92
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 92
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 85
• 239000012044 organic layer Substances 0.000 description 83
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 80
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 77
• XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 76
• 238000004440 column chromatography Methods 0.000 description 72
• WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 72
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 70
• 239000012312 sodium hydride Substances 0.000 description 70
• 229910000104 sodium hydride Inorganic materials 0.000 description 70
• 230000002829 reductive effect Effects 0.000 description 67
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 57
• 239000002904 solvent Substances 0.000 description 57
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 56
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 53
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 52
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 52
• 238000009835 boiling Methods 0.000 description 51
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 49
• 239000000843 powder Substances 0.000 description 43
• 238000010438 heat treatment Methods 0.000 description 42
• 239000007864 aqueous solution Substances 0.000 description 36
• 238000004128 high performance liquid chromatography Methods 0.000 description 34
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
• 125000001072 heteroaryl group Chemical group 0.000 description 32
• 239000000377 silicon dioxide Substances 0.000 description 32
• 125000003118 aryl group Chemical group 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 30
• 229910002027 silica gel Inorganic materials 0.000 description 30
• 235000002639 sodium chloride Nutrition 0.000 description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
• 229910000027 potassium carbonate Inorganic materials 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 27
• 239000012299 nitrogen atmosphere Substances 0.000 description 27
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 22
• 239000012074 organic phase Substances 0.000 description 22
• 239000000284 extract Substances 0.000 description 21
• 238000000034 method Methods 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• 239000003921 oil Substances 0.000 description 20
• 235000019198 oils Nutrition 0.000 description 19
• 238000003756 stirring Methods 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 238000004587 chromatography analysis Methods 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 17
• 239000002244 precipitate Substances 0.000 description 17
• 239000008346 aqueous phase Substances 0.000 description 16
• 229910052757 nitrogen Inorganic materials 0.000 description 15
• 239000012258 stirred mixture Substances 0.000 description 15
• 125000000217 alkyl group Chemical group 0.000 description 14
• 239000010779 crude oil Substances 0.000 description 14
• GGIYCALCWUWLHT-UHFFFAOYSA-N n-(3-chloro-2-methylphenyl)-4,5-dihydro-1,3-thiazol-2-amine Chemical compound CC1=C(Cl)C=CC=C1NC1=NCCS1 GGIYCALCWUWLHT-UHFFFAOYSA-N 0.000 description 14
• PURSZYWBIQIANP-UHFFFAOYSA-N 1-(bromomethyl)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1CBr PURSZYWBIQIANP-UHFFFAOYSA-N 0.000 description 13
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 13
• 125000005865 C2-C10alkynyl group Chemical group 0.000 description 13
• 102000003951 Erythropoietin Human genes 0.000 description 13
• 108090000394 Erythropoietin Proteins 0.000 description 13
• 150000002431 hydrogen Chemical class 0.000 description 13
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
• 235000019341 magnesium sulphate Nutrition 0.000 description 13
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 12
• 239000008194 pharmaceutical composition Substances 0.000 description 12
• 238000001953 recrystallisation Methods 0.000 description 12
• 239000012453 solvate Substances 0.000 description 12
• 230000003197 catalytic effect Effects 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 239000011347 resin Substances 0.000 description 11
• 229920005989 resin Polymers 0.000 description 11
• 229960000583 acetic acid Drugs 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• 239000012053 oil suspension Substances 0.000 description 10
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 9
• GQHTUMJGOHRCHB-UHFFFAOYSA-N DBU Substances C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 229940105423 erythropoietin Drugs 0.000 description 9
• 238000003818 flash chromatography Methods 0.000 description 9
• 239000011777 magnesium Substances 0.000 description 9
• 238000004519 manufacturing process Methods 0.000 description 9
• 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 description 9
• 238000001556 precipitation Methods 0.000 description 9
• 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• UCQPLDQYPHTEMR-UHFFFAOYSA-N ethyl 4-hydroxy-6-oxo-3-propan-2-yl-1h-pyridazine-5-carboxylate Chemical compound CCOC(=O)C1=C(O)C(C(C)C)=NNC1=O UCQPLDQYPHTEMR-UHFFFAOYSA-N 0.000 description 8
• 150000007857 hydrazones Chemical class 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• 159000000000 sodium salts Chemical class 0.000 description 8
• 239000003826 tablet Substances 0.000 description 8
• 238000011282 treatment Methods 0.000 description 8
• 239000000543 intermediate Substances 0.000 description 7
• SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 6
• TXVVVEUSVBLDED-UHFFFAOYSA-N 1-(bromomethyl)-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1CBr TXVVVEUSVBLDED-UHFFFAOYSA-N 0.000 description 6
• QZNQSIHCDAGZIA-UHFFFAOYSA-N 1-(bromomethyl)-4-tert-butylbenzene Chemical compound CC(C)(C)C1=CC=C(CBr)C=C1 QZNQSIHCDAGZIA-UHFFFAOYSA-N 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• 239000012230 colorless oil Substances 0.000 description 6
• 230000003247 decreasing effect Effects 0.000 description 6
• 239000003085 diluting agent Substances 0.000 description 6
• 230000002401 inhibitory effect Effects 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• 239000000546 pharmaceutical excipient Substances 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• KVSVNRFSKRFPIL-UHFFFAOYSA-N 1-(bromomethyl)-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(CBr)=C1 KVSVNRFSKRFPIL-UHFFFAOYSA-N 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• 150000001768 cations Chemical class 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• GOQQIBZDTDSGQA-UHFFFAOYSA-N ethyl 3-cyclohexyl-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C2CCCCC2)=N1 GOQQIBZDTDSGQA-UHFFFAOYSA-N 0.000 description 5
• 238000011534 incubation Methods 0.000 description 5
• 239000000314 lubricant Substances 0.000 description 5
• 239000000651 prodrug Substances 0.000 description 5
• 229940002612 prodrug Drugs 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
• HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 description 4
• 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 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
• FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 4
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
• 150000001721 carbon Chemical group 0.000 description 4
• 238000004113 cell culture Methods 0.000 description 4
• 238000000576 coating method Methods 0.000 description 4
• 238000001816 cooling Methods 0.000 description 4
• 125000004093 cyano group Chemical group *C#N 0.000 description 4
• 239000002552 dosage form Substances 0.000 description 4
• 239000003814 drug Substances 0.000 description 4
• 230000000694 effects Effects 0.000 description 4
• 150000002148 esters Chemical class 0.000 description 4
• CKTYYUQUWFEUCO-UHFFFAOYSA-N ethyl 3-methyl-2-oxobutanoate Chemical compound CCOC(=O)C(=O)C(C)C CKTYYUQUWFEUCO-UHFFFAOYSA-N 0.000 description 4
• OHTMYMLQNPNRJD-UHFFFAOYSA-N ethyl 4-hydroxy-6-oxo-3-phenyl-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=CC=CC=2)=N1 OHTMYMLQNPNRJD-UHFFFAOYSA-N 0.000 description 4
• 238000001704 evaporation Methods 0.000 description 4
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• NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
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• 238000004090 dissolution Methods 0.000 description 1
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• POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
• 231100000673 dose–response relationship Toxicity 0.000 description 1
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• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
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• PQTGSSMVZPQHTN-UHFFFAOYSA-N ethyl 2-(1,3-benzothiazol-2-ylmethyl)-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=NC2=CC=CC=C2S1 PQTGSSMVZPQHTN-UHFFFAOYSA-N 0.000 description 1
• WTPMFFQBDYIARF-UHFFFAOYSA-N ethyl 2-(1h-indol-3-yl)-2-oxoacetate Chemical compound C1=CC=C2C(C(=O)C(=O)OCC)=CNC2=C1 WTPMFFQBDYIARF-UHFFFAOYSA-N 0.000 description 1
• KJZRFVYVKDZBHT-UHFFFAOYSA-N ethyl 2-(2-cyclohexylethyl)-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CCC1CCCCC1 KJZRFVYVKDZBHT-UHFFFAOYSA-N 0.000 description 1
• DNRUIQVIEDGXJH-UHFFFAOYSA-N ethyl 2-(2-cyclopropylethyl)-6-(4-fluorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC(F)=CC=2)=NN1CCC1CC1 DNRUIQVIEDGXJH-UHFFFAOYSA-N 0.000 description 1
• BXHARDVKQMJAEM-UHFFFAOYSA-N ethyl 2-(cyclohexylhydrazinylidene)-3,3-dimethylbutanoate Chemical compound CCOC(=O)C(C(C)(C)C)=NNC1CCCCC1 BXHARDVKQMJAEM-UHFFFAOYSA-N 0.000 description 1
• DJMKTEXQYZVXGI-UHFFFAOYSA-N ethyl 2-(cyclohexylhydrazinylidene)-3-methylbutanoate Chemical compound CCOC(=O)C(C(C)C)=NNC1CCCCC1 DJMKTEXQYZVXGI-UHFFFAOYSA-N 0.000 description 1
• RILAPGUOLBUFTK-UHFFFAOYSA-N ethyl 2-[(2,3-dichlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC(Cl)=C1Cl RILAPGUOLBUFTK-UHFFFAOYSA-N 0.000 description 1
• BIGUQIKFECWKQO-UHFFFAOYSA-N ethyl 2-[(2,4-dichlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(Cl)C=C1Cl BIGUQIKFECWKQO-UHFFFAOYSA-N 0.000 description 1
• IDBQEZDRIXAHIK-UHFFFAOYSA-N ethyl 2-[(2,4-difluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(F)C=C1F IDBQEZDRIXAHIK-UHFFFAOYSA-N 0.000 description 1
• AKSDIRUPAFAJOD-UHFFFAOYSA-N ethyl 2-[(2,5-dichlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC(Cl)=CC=C1Cl AKSDIRUPAFAJOD-UHFFFAOYSA-N 0.000 description 1
• NMUXZVIBAUYGBH-UHFFFAOYSA-N ethyl 2-[(2,5-difluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC(F)=CC=C1F NMUXZVIBAUYGBH-UHFFFAOYSA-N 0.000 description 1
• BEKIJTINZPSVME-UHFFFAOYSA-N ethyl 2-[(2,6-dichlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=C(Cl)C=CC=C1Cl BEKIJTINZPSVME-UHFFFAOYSA-N 0.000 description 1
• NWJVJYVPSJGWEY-UHFFFAOYSA-N ethyl 2-[(2-bromophenyl)methyl]-6-tert-butyl-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)(C)C)=NN1CC1=CC=CC=C1Br NWJVJYVPSJGWEY-UHFFFAOYSA-N 0.000 description 1
• SKNPLGQCOHFBLA-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1Cl SKNPLGQCOHFBLA-UHFFFAOYSA-N 0.000 description 1
• FOOBXZCSIKNPRJ-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-5-hydroxy-6-(2-methoxyphenyl)-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C(=CC=CC=2)OC)=NN1CC1=CC=CC=C1Cl FOOBXZCSIKNPRJ-UHFFFAOYSA-N 0.000 description 1
• LVVIHGFOFSQTBA-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-5-hydroxy-6-(3-methoxyphenyl)-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(OC)C=CC=2)=NN1CC1=CC=CC=C1Cl LVVIHGFOFSQTBA-UHFFFAOYSA-N 0.000 description 1
• WZUZYFJRHCMZPT-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-5-hydroxy-6-(4-methoxyphenyl)-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC(OC)=CC=2)=NN1CC1=CC=CC=C1Cl WZUZYFJRHCMZPT-UHFFFAOYSA-N 0.000 description 1
• MISMZBNWTCKWKN-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-6-(3,5-difluorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(F)C=C(F)C=2)=NN1CC1=CC=CC=C1Cl MISMZBNWTCKWKN-UHFFFAOYSA-N 0.000 description 1
• FAKJYTIJYVYXHC-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-6-(3-ethoxy-5-fluorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(OCC)C=C(F)C=2)=NN1CC1=CC=CC=C1Cl FAKJYTIJYVYXHC-UHFFFAOYSA-N 0.000 description 1
• RTOLSFNTBSHEPQ-UHFFFAOYSA-N ethyl 2-[(2-chlorophenyl)methyl]-6-(4-fluorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC(F)=CC=2)=NN1CC1=CC=CC=C1Cl RTOLSFNTBSHEPQ-UHFFFAOYSA-N 0.000 description 1
• FNUZXSFHLXICNL-UHFFFAOYSA-N ethyl 2-[(2-fluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1F FNUZXSFHLXICNL-UHFFFAOYSA-N 0.000 description 1
• OYVYWSQDTPNXEC-UHFFFAOYSA-N ethyl 2-[(3,4-dichlorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(Cl)C(Cl)=C1 OYVYWSQDTPNXEC-UHFFFAOYSA-N 0.000 description 1
• LEJBYZXKJRAFLQ-UHFFFAOYSA-N ethyl 2-[(3,5-difluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC(F)=CC(F)=C1 LEJBYZXKJRAFLQ-UHFFFAOYSA-N 0.000 description 1
• OXPCSLROEHKMBN-UHFFFAOYSA-N ethyl 2-[(3,5-difluorophenyl)methyl]-5-hydroxy-6-(4-methoxyphenyl)-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC(OC)=CC=2)=NN1CC1=CC(F)=CC(F)=C1 OXPCSLROEHKMBN-UHFFFAOYSA-N 0.000 description 1
• QLNVYZIIVPMQEL-UHFFFAOYSA-N ethyl 2-[(3,5-difluorophenyl)methyl]-6-(3-ethoxy-5-fluorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(OCC)C=C(F)C=2)=NN1CC1=CC(F)=CC(F)=C1 QLNVYZIIVPMQEL-UHFFFAOYSA-N 0.000 description 1
• GMGUMMRHVSGWLR-UHFFFAOYSA-N ethyl 2-[(3-cyanophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC(C#N)=C1 GMGUMMRHVSGWLR-UHFFFAOYSA-N 0.000 description 1
• SBEOSNPMUSUGTP-UHFFFAOYSA-N ethyl 2-[(4-chloro-2-fluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(Cl)C=C1F SBEOSNPMUSUGTP-UHFFFAOYSA-N 0.000 description 1
• XHDFJUVTCOOEJU-UHFFFAOYSA-N ethyl 2-[(4-fluorophenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(F)C=C1 XHDFJUVTCOOEJU-UHFFFAOYSA-N 0.000 description 1
• VYIAZTBMFYMKHQ-UHFFFAOYSA-N ethyl 2-[(4-tert-butylphenyl)methyl]-5-hydroxy-3-oxo-6-phenylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC=CC=2)=NN1CC1=CC=C(C(C)(C)C)C=C1 VYIAZTBMFYMKHQ-UHFFFAOYSA-N 0.000 description 1
• WUHIIDQYZURKDY-UHFFFAOYSA-N ethyl 2-[(4-tert-butylphenyl)methyl]-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=C(C(C)(C)C)C=C1 WUHIIDQYZURKDY-UHFFFAOYSA-N 0.000 description 1
• VGHLUOXKWDBQSY-UHFFFAOYSA-N ethyl 2-[(4-tert-butylphenyl)methyl]-6-(4-chlorophenyl)-5-hydroxy-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC(Cl)=CC=2)=NN1CC1=CC=C(C(C)(C)C)C=C1 VGHLUOXKWDBQSY-UHFFFAOYSA-N 0.000 description 1
• MWPSAODZTPWQHZ-UHFFFAOYSA-N ethyl 2-[cyclohexyl-(3-ethoxy-3-oxopropanoyl)hydrazinylidene]-3,3-dimethylbutanoate Chemical compound CCOC(=O)CC(=O)N(N=C(C(=O)OCC)C(C)(C)C)C1CCCCC1 MWPSAODZTPWQHZ-UHFFFAOYSA-N 0.000 description 1
• CYYDHMRTGWZCKX-UHFFFAOYSA-N ethyl 2-[cyclohexyl-(3-ethoxy-3-oxopropanoyl)hydrazinylidene]-3-methylbutanoate Chemical compound CCOC(=O)CC(=O)N(N=C(C(C)C)C(=O)OCC)C1CCCCC1 CYYDHMRTGWZCKX-UHFFFAOYSA-N 0.000 description 1
• RTHPVPCAPPLPFM-UHFFFAOYSA-N ethyl 2-benzyl-5-hydroxy-3-oxo-6-phenylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=CC=CC=2)=NN1CC1=CC=CC=C1 RTHPVPCAPPLPFM-UHFFFAOYSA-N 0.000 description 1
• GSBBJRDPZXPTIS-UHFFFAOYSA-N ethyl 2-benzyl-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1 GSBBJRDPZXPTIS-UHFFFAOYSA-N 0.000 description 1
• PNYREBFWYMKVQF-UHFFFAOYSA-N ethyl 2-benzyl-5-hydroxy-6-methyl-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C)=NN1CC1=CC=CC=C1 PNYREBFWYMKVQF-UHFFFAOYSA-N 0.000 description 1
• OVLJDDQVJUXGCG-UHFFFAOYSA-N ethyl 2-cyclohexyl-5-hydroxy-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1C1CCCCC1 OVLJDDQVJUXGCG-UHFFFAOYSA-N 0.000 description 1
• KJHQVUNUOIEYSV-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-oxopropanoate Chemical compound CCOC(=O)C(=O)C(F)(F)F KJHQVUNUOIEYSV-UHFFFAOYSA-N 0.000 description 1
• LPUVHKRZLUSGEQ-UHFFFAOYSA-N ethyl 3,3-dimethyl-2-oxobutanoate Chemical compound CCOC(=O)C(=O)C(C)(C)C LPUVHKRZLUSGEQ-UHFFFAOYSA-N 0.000 description 1
• BQZFXMNIQCQKIX-UHFFFAOYSA-N ethyl 3-(3,5-difluorophenyl)-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=C(F)C=C(F)C=2)=N1 BQZFXMNIQCQKIX-UHFFFAOYSA-N 0.000 description 1
• AVARYYXXTRTXRB-UHFFFAOYSA-N ethyl 3-(3-ethoxy-5-fluorophenyl)-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=C(OCC)C=C(F)C=2)=N1 AVARYYXXTRTXRB-UHFFFAOYSA-N 0.000 description 1
• YEOKDXHMOSZPCZ-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=CC(F)=CC=2)=N1 YEOKDXHMOSZPCZ-UHFFFAOYSA-N 0.000 description 1
• LFWGLDJNGIHCAJ-UHFFFAOYSA-N ethyl 3-(4-tert-butylphenyl)-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=CC(=CC=2)C(C)(C)C)=N1 LFWGLDJNGIHCAJ-UHFFFAOYSA-N 0.000 description 1
• NGMXLTSUYKPJKU-UHFFFAOYSA-N ethyl 3-[2-(2-ethoxy-2-oxo-1-phenylethylidene)hydrazinyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN=C(C(=O)OCC)C1=CC=CC=C1 NGMXLTSUYKPJKU-UHFFFAOYSA-N 0.000 description 1
• OOLBBCCSDMJLOD-UHFFFAOYSA-N ethyl 3-[2-[1-(3,5-difluorophenyl)-2-ethoxy-2-oxoethylidene]hydrazinyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN=C(C(=O)OCC)C1=CC(F)=CC(F)=C1 OOLBBCCSDMJLOD-UHFFFAOYSA-N 0.000 description 1
• RPIUKKGKWXYGNX-UHFFFAOYSA-N ethyl 3-[2-[1-(4-tert-butylphenyl)-2-ethoxy-2-oxoethylidene]hydrazinyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN=C(C(=O)OCC)C1=CC=C(C(C)(C)C)C=C1 RPIUKKGKWXYGNX-UHFFFAOYSA-N 0.000 description 1
• OMZDSZXALBFULY-UHFFFAOYSA-N ethyl 3-[2-[2-ethoxy-1-(2-methoxyphenyl)-2-oxoethylidene]hydrazinyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN=C(C(=O)OCC)C1=CC=CC=C1OC OMZDSZXALBFULY-UHFFFAOYSA-N 0.000 description 1
• GOHKBEDFBMDARV-UHFFFAOYSA-N ethyl 3-[2-[2-ethoxy-1-(3-methoxyphenyl)-2-oxoethylidene]hydrazinyl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN=C(C(=O)OCC)C1=CC=CC(OC)=C1 GOHKBEDFBMDARV-UHFFFAOYSA-N 0.000 description 1
• CMMVOTXBVRTMGS-UHFFFAOYSA-N ethyl 3-[amino(benzyl)amino]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)N(N)CC1=CC=CC=C1 CMMVOTXBVRTMGS-UHFFFAOYSA-N 0.000 description 1
• AVPVXFAGUUDDRI-UHFFFAOYSA-N ethyl 3-[benzyl-[(2-ethoxy-2-oxo-1-phenylethylidene)amino]amino]-3-oxopropanoate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)=NN(C(=O)CC(=O)OCC)CC1=CC=CC=C1 AVPVXFAGUUDDRI-UHFFFAOYSA-N 0.000 description 1
• RFNZDFBJGNNBJE-UHFFFAOYSA-N ethyl 3-tert-butyl-4-hydroxy-6-oxo-1h-pyridazine-5-carboxylate Chemical compound CCOC(=O)C1=C(O)C(C(C)(C)C)=NNC1=O RFNZDFBJGNNBJE-UHFFFAOYSA-N 0.000 description 1
• FEQFEJYLNDJIHD-UHFFFAOYSA-N ethyl 4-hydroxy-3-(2-methoxyphenyl)-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C(=CC=CC=2)OC)=N1 FEQFEJYLNDJIHD-UHFFFAOYSA-N 0.000 description 1
• VYSXDXSBJDMABJ-UHFFFAOYSA-N ethyl 4-hydroxy-3-(3-methoxyphenyl)-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=C(OC)C=CC=2)=N1 VYSXDXSBJDMABJ-UHFFFAOYSA-N 0.000 description 1
• QWMGBEFHRVZPBO-UHFFFAOYSA-N ethyl 4-hydroxy-3-(4-methoxyphenyl)-6-oxo-1h-pyridazine-5-carboxylate Chemical compound N1C(=O)C(C(=O)OCC)=C(O)C(C=2C=CC(OC)=CC=2)=N1 QWMGBEFHRVZPBO-UHFFFAOYSA-N 0.000 description 1
• PHNUTWFXHAUORG-UHFFFAOYSA-N ethyl 4-hydroxy-3-methyl-6-oxo-1h-pyridazine-5-carboxylate Chemical compound CCOC(=O)C1=C(O)C(C)=NNC1=O PHNUTWFXHAUORG-UHFFFAOYSA-N 0.000 description 1
• ZZLSPUMGEBANAF-UHFFFAOYSA-N ethyl 5-hydroxy-2-[(2-nitrophenyl)methyl]-3-oxo-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1[N+]([O-])=O ZZLSPUMGEBANAF-UHFFFAOYSA-N 0.000 description 1
• NDJSVYLEOSFDIJ-UHFFFAOYSA-N ethyl 5-hydroxy-3-oxo-2-[(3-phenylphenyl)methyl]-6-propan-2-ylpyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC(C=2C=CC=CC=2)=C1 NDJSVYLEOSFDIJ-UHFFFAOYSA-N 0.000 description 1
• DOOAVVBBRJIHKQ-UHFFFAOYSA-N ethyl 5-hydroxy-3-oxo-6-propan-2-yl-2-[[2-(trifluoromethyl)phenyl]methyl]pyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C(C)C)=NN1CC1=CC=CC=C1C(F)(F)F DOOAVVBBRJIHKQ-UHFFFAOYSA-N 0.000 description 1
• RJTVKMIDGBDJRY-UHFFFAOYSA-N ethyl 5-hydroxy-6-(3-methoxyphenyl)-3-oxo-2-[[2-(trifluoromethyl)phenyl]methyl]pyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(OC)C=CC=2)=NN1CC1=CC=CC=C1C(F)(F)F RJTVKMIDGBDJRY-UHFFFAOYSA-N 0.000 description 1
• LQBPJIJAGZTKBU-UHFFFAOYSA-N ethyl 5-hydroxy-6-methyl-2-[(2-nitrophenyl)methyl]-3-oxopyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C)=NN1CC1=CC=CC=C1[N+]([O-])=O LQBPJIJAGZTKBU-UHFFFAOYSA-N 0.000 description 1
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• KHXIWILCHUCWGL-UHFFFAOYSA-N ethyl 6-(3,5-difluorophenyl)-5-hydroxy-3-oxo-2-[[2-(trifluoromethyl)phenyl]methyl]pyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(F)C=C(F)C=2)=NN1CC1=CC=CC=C1C(F)(F)F KHXIWILCHUCWGL-UHFFFAOYSA-N 0.000 description 1
• OJBOSBJHUITZDT-UHFFFAOYSA-N ethyl 6-(3-ethoxy-5-fluorophenyl)-5-hydroxy-3-oxo-2-[[2-(trifluoromethyl)phenyl]methyl]pyridazine-4-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C(C=2C=C(OCC)C=C(F)C=2)=NN1CC1=CC=CC=C1C(F)(F)F OJBOSBJHUITZDT-UHFFFAOYSA-N 0.000 description 1
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