ES2654434T3 - Derivado de pirazina - Google Patents
Derivado de pirazina Download PDFInfo
- Publication number
- ES2654434T3 ES2654434T3 ES15792266.7T ES15792266T ES2654434T3 ES 2654434 T3 ES2654434 T3 ES 2654434T3 ES 15792266 T ES15792266 T ES 15792266T ES 2654434 T3 ES2654434 T3 ES 2654434T3
- Authority
- ES
- Spain
- Prior art keywords
- group
- methyl
- pharmaceutically acceptable
- solvates
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003216 pyrazines Chemical class 0.000 title claims abstract description 42
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 50
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 239000012453 solvate Substances 0.000 claims abstract description 31
- 125000005843 halogen group Chemical group 0.000 claims abstract description 29
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 17
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000003277 amino group Chemical group 0.000 claims abstract description 11
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 5
- 125000006773 (C2-C7) alkylcarbonyl group Chemical group 0.000 claims abstract description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 142
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 201000001431 Hyperuricemia Diseases 0.000 claims description 13
- 201000005569 Gout Diseases 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 208000009625 Lesch-Nyhan syndrome Diseases 0.000 claims description 6
- 208000035317 Total hypoxanthine-guanine phosphoribosyl transferase deficiency Diseases 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 230000003449 preventive effect Effects 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- OTQIKKBNIWNDHC-UHFFFAOYSA-N 1-[(2,5-dichlorophenyl)methyl]-5-pyrazin-2-ylpyrrole-2-carboxylic acid Chemical compound ClC1=C(CN2C(=CC=C2C(=O)O)C2=NC=CN=C2)C=C(C=C1)Cl OTQIKKBNIWNDHC-UHFFFAOYSA-N 0.000 claims description 3
- DCYTULXIJQTPEW-UHFFFAOYSA-N 2-(6-cyanopyrazin-2-yl)-3-[(2,5-dichlorophenyl)methyl]-5-methylimidazole-4-carboxylic acid Chemical compound C(#N)C1=CN=CC(=N1)C=1N(C(=C(N=1)C)C(=O)O)CC1=C(C=CC(=C1)Cl)Cl DCYTULXIJQTPEW-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- UFAXIQXKXNRNKK-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-2-(6-ethoxypyrazin-2-yl)-5-methylimidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)OCC)C=C(C=C1)Cl UFAXIQXKXNRNKK-UHFFFAOYSA-N 0.000 claims description 3
- TZATXNVJILUVCE-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-2-(6-ethylpyrazin-2-yl)-5-methylimidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)CC)C=C(C=C1)Cl TZATXNVJILUVCE-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 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 description 3
- 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 description 3
- 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 description 3
- SOCRBZIALSDUNY-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-5-methyl-2-(6-propan-2-ylpyrazin-2-yl)imidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC(=CN=C2)C(C)C)C=C(C=C1)Cl SOCRBZIALSDUNY-UHFFFAOYSA-N 0.000 claims description 3
- FVWVMNATKMYAFH-UHFFFAOYSA-N 3-[(2,5-dichlorophenyl)methyl]-5-methyl-2-pyrazin-2-ylimidazole-4-carboxylic acid Chemical compound ClC1=C(CN2C(=NC(=C2C(=O)O)C)C2=NC=CN=C2)C=C(C=C1)Cl FVWVMNATKMYAFH-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 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 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 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
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- CUFJEDGLCSGVEN-UHFFFAOYSA-N 3-benzyl-2-[6-(2-fluoro-6-methoxyphenoxy)pyrazin-2-yl]-5-methylimidazole-4-carboxylic acid Chemical compound C(C1=CC=CC=C1)N1C(=NC(=C1C(=O)O)C)C1=NC(=CN=C1)OC1=C(C=CC=C1OC)F CUFJEDGLCSGVEN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- -1 2-buten-1-yl group Chemical group 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- 239000002904 solvent Substances 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- 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
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 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 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 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 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000007126 N-alkylation reaction Methods 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 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 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000006751 Mitsunobu reaction Methods 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229940109239 creatinine Drugs 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 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 description 5
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
- 239000012981 Hank's balanced salt solution Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 229940083914 URAT1 inhibitor Drugs 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- 150000002170 ethers Chemical class 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
- 230000029142 excretion Effects 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 102000056457 human SLC22A12 Human genes 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- 229910002666 PdCl2 Inorganic materials 0.000 description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 238000006619 Stille reaction Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 201000006334 interstitial nephritis Diseases 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- 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
- C07D403/02—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
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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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- Plural Heterocyclic Compounds (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014099677 | 2014-05-13 | ||
| JP2014099677 | 2014-05-13 | ||
| PCT/JP2015/063654 WO2015174417A1 (ja) | 2014-05-13 | 2015-05-12 | ピラジン誘導体 |
Publications (1)
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| ES2654434T3 true ES2654434T3 (es) | 2018-02-13 |
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| ES15792266.7T Active ES2654434T3 (es) | 2014-05-13 | 2015-05-12 | Derivado de pirazina |
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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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| WO1998034922A1 (en) * | 1997-02-05 | 1998-08-13 | Sankyo Company, Limited | Prophylactic or therapeutic agent for diabetic complication |
| JP4397875B2 (ja) * | 1997-02-05 | 2010-01-13 | 第一三共株式会社 | 糖尿病合併症予防薬又は治療薬 |
| CN101012193A (zh) * | 2003-01-02 | 2007-08-08 | 霍夫曼-拉罗奇有限公司 | 新cb 1受体反激动剂 |
| JP2007145786A (ja) * | 2005-11-30 | 2007-06-14 | Toray Ind Inc | ピラジン誘導体及びそれを有効成分とする腎炎治療薬 |
| JP5378988B2 (ja) | 2007-04-11 | 2013-12-25 | キッセイ薬品工業株式会社 | ５員環へテロ環誘導体及びその医薬用途 |
| AR081930A1 (es) | 2010-06-16 | 2012-10-31 | Ardea Biosciences Inc | Compuestos de tioacetato |
| KR20150082194A (ko) | 2012-11-14 | 2015-07-15 | 데이진 화-마 가부시키가이샤 | 피리딘 유도체 |
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| EP3144306B1 (en) | 2017-11-15 |
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| PT3144306T (pt) | 2018-01-08 |
| HUE035728T2 (en) | 2018-05-28 |
| JP6173576B2 (ja) | 2017-08-02 |
| JPWO2015174417A1 (ja) | 2017-04-20 |
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| US9856237B2 (en) | 2018-01-02 |
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| SMT201800155T1 (it) | 2018-05-02 |
| US20170152242A1 (en) | 2017-06-01 |
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