TW201609702A - 吡嗪衍生物 - Google Patents
吡嗪衍生物 Download PDFInfo
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- TW201609702A TW201609702A TW104115028A TW104115028A TW201609702A TW 201609702 A TW201609702 A TW 201609702A TW 104115028 A TW104115028 A TW 104115028A TW 104115028 A TW104115028 A TW 104115028A TW 201609702 A TW201609702 A TW 201609702A
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- Prior art keywords
- group
- methyl
- pharmaceutically acceptable
- acceptable salt
- solvent mixture
- Prior art date
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- 150000003216 pyrazines Chemical class 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 201000005569 Gout Diseases 0.000 claims abstract description 12
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 208000017169 kidney disease Diseases 0.000 claims abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 6
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 111
- -1 carbenyl Chemical group 0.000 claims description 67
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 239000011877 solvent mixture Substances 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 230000000069 prophylactic effect Effects 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 125000006773 (C2-C7) alkylcarbonyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229940083914 URAT1 inhibitor Drugs 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- ASUMVAPLXCRBMA-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydro-1,4-benzoxazin-4-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2OCC1 ASUMVAPLXCRBMA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- YQIRMNZWWRIXHU-UHFFFAOYSA-N 2-(6-cyclopropylpyrazin-2-yl)-3-[(2,5-dichlorophenyl)methyl]-5-methylimidazole-4-carboxylic acid Chemical compound C1(CC1)C1=CN=CC(=N1)C=1N(C(=C(N=1)C)C(=O)O)CC1=C(C=CC(=C1)Cl)Cl YQIRMNZWWRIXHU-UHFFFAOYSA-N 0.000 claims 2
- HMKGBOBTFIOBCI-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-5-methyl-2-(6-methylpyrazin-2-yl)imidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)C)C=C(C=C1)Cl HMKGBOBTFIOBCI-UHFFFAOYSA-N 0.000 claims 2
- KWPRUZXMSRFIMD-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-5-methyl-2-(6-phenylpyrazin-2-yl)imidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)C2=CC=CC=C2)C=C(C=C1)Cl KWPRUZXMSRFIMD-UHFFFAOYSA-N 0.000 claims 2
- DDBVXDKQUBUDMO-UHFFFAOYSA-N 3-[(2,5-dichlorothiophen-3-yl)methyl]-5-methyl-2-(6-methylpyrazin-2-yl)imidazole-4-carboxylic acid Chemical compound ClC=1SC(=CC=1CN1C(=NC(=C1C(=O)O)C)C1=NC(=CN=C1)C)Cl DDBVXDKQUBUDMO-UHFFFAOYSA-N 0.000 claims 2
- VFFJZSIWAWTRLZ-UHFFFAOYSA-N 3-[(2,5-dichlorothiophen-3-yl)methyl]-5-methyl-2-pyrazin-2-ylimidazole-4-carboxylic acid Chemical compound ClC=1SC(=CC=1CN1C(=NC(=C1C(=O)O)C)C1=NC=CN=C1)Cl VFFJZSIWAWTRLZ-UHFFFAOYSA-N 0.000 claims 2
- KRBUOYHOAMZQPB-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-2-(6-methoxypyrazin-2-yl)-5-methylimidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)OC)C=C(C=C1)Cl KRBUOYHOAMZQPB-UHFFFAOYSA-N 0.000 claims 1
- GQAGKBUYGPOSML-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-5-methyl-2-(6-phenoxypyrazin-2-yl)imidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)OC2=CC=CC=C2)C=C(C=C1)Cl GQAGKBUYGPOSML-UHFFFAOYSA-N 0.000 claims 1
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 abstract description 19
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 6
- 201000006334 interstitial nephritis Diseases 0.000 abstract description 5
- 229940124597 therapeutic agent Drugs 0.000 abstract description 5
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 208000009625 Lesch-Nyhan syndrome Diseases 0.000 abstract 1
- 208000035317 Total hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 229940116269 uric acid Drugs 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 26
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 26
- 239000002585 base Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
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- 238000004458 analytical method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 125000004432 carbon atom Chemical group C* 0.000 description 8
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
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- 238000001514 detection method Methods 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
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- 150000002170 ethers Chemical class 0.000 description 3
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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| CN111943957B (zh) * | 2019-05-17 | 2023-01-06 | 中国医学科学院药物研究所 | 喹啉甲酰胺类化合物及其制备方法和用途 |
| CN116496198A (zh) * | 2023-06-26 | 2023-07-28 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | 一种4-羟基-2'-(1-苄基-5-硝基吡咯甲叉)-苯甲酰肼衍生物及其制备方法和应用 |
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