CN1313768A - 含氮杂环羧酰胺衍生物或其盐以及含有二者的抗病毒药 - Google Patents
含氮杂环羧酰胺衍生物或其盐以及含有二者的抗病毒药 Download PDFInfo
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- CN1313768A CN1313768A CN99809897A CN99809897A CN1313768A CN 1313768 A CN1313768 A CN 1313768A CN 99809897 A CN99809897 A CN 99809897A CN 99809897 A CN99809897 A CN 99809897A CN 1313768 A CN1313768 A CN 1313768A
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- ring
- virus
- pyrazine
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- 150000003839 salts Chemical class 0.000 title claims abstract description 36
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 title abstract description 3
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 11
- 125000005242 carbamoyl alkyl group Chemical group 0.000 claims abstract description 7
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 7
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 150000003216 pyrazines Chemical class 0.000 claims abstract description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims abstract description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims abstract description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 nitrogen heterocyclic ring carboxamide Chemical class 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 241000700605 Viruses Species 0.000 claims description 15
- 239000003443 antiviral agent Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 230000003612 virological effect Effects 0.000 claims description 5
- 241000709661 Enterovirus Species 0.000 claims description 4
- 235000010894 Artemisia argyi Nutrition 0.000 claims description 2
- 241000271566 Aves Species 0.000 claims description 2
- 241000709687 Coxsackievirus Species 0.000 claims description 2
- 241000991587 Enterovirus C Species 0.000 claims description 2
- 241000711549 Hepacivirus C Species 0.000 claims description 2
- 241000700721 Hepatitis B virus Species 0.000 claims description 2
- 241000709721 Hepatovirus A Species 0.000 claims description 2
- 241000701806 Human papillomavirus Species 0.000 claims description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 2
- 241000710842 Japanese encephalitis virus Species 0.000 claims description 2
- 241000711386 Mumps virus Species 0.000 claims description 2
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- 206010014599 encephalitis Diseases 0.000 claims description 2
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- 150000001875 compounds Chemical class 0.000 description 39
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 229910014033 C-OH Inorganic materials 0.000 description 15
- 229910014570 C—OH Inorganic materials 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 229910021529 ammonia Inorganic materials 0.000 description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
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- 229920006395 saturated elastomer Polymers 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000006414 CCl Chemical group ClC* 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
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- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 206010022000 influenza Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- SZPBAPFUXAADQV-UHFFFAOYSA-N 2-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC=CN=C1O SZPBAPFUXAADQV-UHFFFAOYSA-N 0.000 description 4
- 125000006416 CBr Chemical group BrC* 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 210000003501 vero cell Anatomy 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 241001597008 Nomeidae Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000001769 aryl amino group Chemical group 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
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- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 3
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- 150000002170 ethers Chemical class 0.000 description 3
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- 125000000623 heterocyclic group Chemical group 0.000 description 3
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- YVUBNSIFWJGXBQ-UHFFFAOYSA-N methyl 2-oxo-1h-pyrazine-3-carboxylate Chemical compound COC(=O)C1=NC=CNC1=O YVUBNSIFWJGXBQ-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- QPAYMYPTOQKVNY-UHFFFAOYSA-N ethyl 5-carbamoyl-2-hydroxy-6-oxo-1H-pyrazine-3-carboxylate Chemical class CCOC(=O)C1=NC(C(N)=O)=C(O)N=C1O QPAYMYPTOQKVNY-UHFFFAOYSA-N 0.000 description 2
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- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
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- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
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- JSLZUBLGGPEVQN-DIPNUNPCSA-N (2r)-4-methyl-2-propan-2-yl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazin-1-yl]butoxy]phenyl]-1,4-benzothiazin-3-one Chemical compound COC1=C(OC)C(OC)=CC(CCN2CCN(CCCCOC=3C(=CC=CC=3)[C@@]3(C(N(C)C4=CC=CC=C4S3)=O)C(C)C)CC2)=C1 JSLZUBLGGPEVQN-DIPNUNPCSA-N 0.000 description 1
- PDOSLLUCFBSMMD-BYPYZUCNSA-N (2s)-2-[(2-oxo-1h-pyrazine-3-carbonyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)C1=NC=CNC1=O PDOSLLUCFBSMMD-BYPYZUCNSA-N 0.000 description 1
- AAYHSAYVLVQUQZ-MMALYQPHSA-N (2s)-2-[[(2s)-2-aminopropanoyl]amino]propanoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C[C@H](N)C(=O)N[C@@H](C)C(O)=O AAYHSAYVLVQUQZ-MMALYQPHSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
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- RQDIQSVKEXAXQO-UHFFFAOYSA-N 2-(2-amino-2-oxoethyl)-3-oxo-1,4-dihydropyrazine-2-carboxamide Chemical class NC(CC1(NC=CN=C1O)C(=O)N)=O RQDIQSVKEXAXQO-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Abstract
通式(Ⅰ)所示的含氮杂环羧酰胺衍生物或其盐可以用作病毒感染,特别是流感病毒感染的预防和治疗药物。在所述通式中,A是任选取代的吡嗪、嘧啶、哒嗪或三嗪环;R1是O或OH;R2是氢、酰基或任选取代的氨基甲酰基烷基或羧基烷基;且虚线代表单键或双键。
Description
技术领域
本发明涉及包含含氮杂环羧酰胺衍生物或其盐的抗病毒药。
背景技术
当前,根据目标病毒选择和使用抗病毒药。例如,阿昔洛韦和阿糖腺苷用于疱疹病毒;更昔洛韦和膦甲酸用于巨细胞病毒;且干扰素用于肝炎病毒。
流感病毒是伤风综合征(cold syndrome)的主要病毒,其周期性地袭击人类而引起高达数千万人次的死亡。尽管死亡数字在近年由于卫生和营养条件的提高而呈下降趋势,但流感的流行每年都会重复,且应理解的是新的病毒可能引起更大范围的流行。
为了预防流感病毒,广泛使用牛痘苗,此外还使用低分子量物质如金刚烷胺和利巴韦林。
金刚烷胺用于预防和治疗流感。其作用机理据说在于抑制流感病毒和细胞膜之间的融合且其对A型流感病毒有效。然而,其问题在于对B型流感病毒无效,出现其耐药性病毒且引起副作用如神经紊乱。尽管为金刚烷胺的衍生物的金刚乙胺具有更为改进的抗病毒活性,但仍然未克服副作用的问题。为鸟苷衍生物的利巴韦林具有病毒RNA聚合酶抑制活性且对A和B型流感病毒有效。但其内部使用尚不能引起足够的临床效果。
本发明提供了一种抗病毒药,其对各种病毒,尤其是流感病毒具有预防作用和治疗作用。
发明公开
本发明的发明人研究并考察了对各种病毒,尤其是流感病毒显示抗病毒活性的化合物。结果发现吡嗪羧酰胺衍生物具有抗流感病毒活性。本发明的发明人进一步研究发现如下通式[1]所示的含氮杂环羧酰胺衍生物或其盐对A-、B-和C-型流感病毒和其他各种病毒显示优异的抗病毒活性:其中环A代表取代或未取代的吡嗪、嘧啶、哒嗪或三嗪环;R1代表O或OH;R2代表氢原子、酰基或取代或未取代的氨基甲酰基烷基或羧基烷基;且虚线代表单键或双键;这些化合物具有低细胞毒性且可用作具有高安全性的抗病毒药,而且由如下通式[1a]表示的新型含N杂环羧酰胺衍生物或其盐具有优异的抗病毒活性:其中环A’代表卤素原子、羟基或氧化物基团取代的吡嗪环;R1代表O或OH;R2代表氢原子、酰基或取代或未取代的氨基甲酰基烷基或羧基烷基;且虚线代表单键或双键。基于这些发现,本发明得以完成。
下面详细描述本发明。
除非另有所指,本说明书中所用的术语“卤素原子”意指氟原子、氯原子、溴原子或碘原子;术语“烷基”意指直链或支链C1-6烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基等;术语“链烯基”意指直链或支链C2-6链烯基,如乙烯基、烯丙基等;术语“环烷基”意指C3-6环烷基,如环丙基、环戊基、环己基等;术语“烷氧基”意指直链或支链C1-6烷基-O-基团,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基等;术语“环烷氧基”意指C3-6环烷基-O-基团,如环丙氧基、环戊氧基、环己氧基等;术语“烷硫基”意指直链或支链C1-6烷基-S-基团,如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、戊硫基等;术语“烷基氨基”意指被一个或多个直链或支链C1-6烷基取代的氨基,如甲氨基、乙氨基、丙氨基、丁氨基、戊氨基、己氨基、二甲基氨基、二乙基氨基、甲基乙基氨基、二丙基氨基、二丁基氨基、二戊基氨基等;术语“环烷基氨基”意指C3-6环烷基-NH-基团,如环丙氨基、环戊氨基、环己氨基等;术语“卤代烷基”意指卤素取代的C1-6烷基,如三氟甲基、三氯甲基、氯甲基等;术语“芳基”意指苯基、萘基等;术语“芳氧基”意指芳基-O-基团,如苯氧基、萘氧基等;术语“芳硫基”意指芳基-S-基团,如苯硫基、萘硫基等;术语“芳基氨基”意指芳基-NH-基团,如苯基氨基、萘基氨基等;术语“酰基”意指C2-5链烷酰基,如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基等和芳酰基如苯甲酰基、萘甲酰基等;术语“烷氧基羰基”意指直链或支链C1-6烷氧基羰基,如甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、正丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基等;术语“烷基氨基甲酰基”意指被一个或多个直链或支链C1-6烷基取代的氨基甲酰基,如甲基氨基甲酰基、二甲基氨基甲酰基等;术语“氨基甲酰基烷基”意指被氨基甲酰基取代的直链或支链C1-6烷基,如氨基甲酰基甲基、氨基甲酰基乙基、氨基甲酰基异丙基等;术语“羧基烷基”意指被羧基取代的直链或支链C1-6烷基,如羧基甲基、羧基乙基、羧基异丙基等;术语“杂环基”意指4-、5-或6-元环或其稠合环,其具有至少一个选自氧原子、氮原子和硫原子的杂原子作为构成所述环的杂原子,如氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、咪唑基、噻唑基、异噻唑基、吡咯烷基、苯并呋喃基、苯并噻唑基、吡啶基、喹啉基、嘧啶基和吗啉基;且术语“氧化物基团”意指与环中氮原子连接的氧原子。术语“低级”意指碳原子的数目为1-6。
羧基的保护基团包括通常可以用作羧基的保护基团的任何基团。其实例包括烷基如甲基、乙基、正丙基、异丙基、1,1-二甲基丙基、正丁基、叔丁基等;芳基如苯基、萘基等;芳烷基,如苄基、二苯基甲基、三苯甲基、对硝基苄基、对甲氧基苄基、双(对甲氧基苯基)甲基等;酰基烷基,如乙酰基甲基、苯甲酰基甲基、对硝基苯甲酰基甲基、对溴苯甲酰基甲基、对甲磺酰基苯甲酰基甲基等;含氧杂环基团如2-四氢吡喃基、2-四氢呋喃基等;卤代烷基如2,2,2-三氯乙基等;烷基甲硅烷基烷基如2-(三甲基甲硅烷基)乙基等;酰氧基烷基如乙酰氧基甲基、丙酰氧基甲基、新戊酰氧基甲基等;含氮杂环烷基如邻苯二甲酰亚氨基甲基、琥珀酰亚氨基甲基等;环烷基如环己基等;烷氧基烷基如甲氧基甲基、乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基等;芳烷氧基烷基如苄氧基甲基等;烷硫基烷基如甲硫基甲基、2-甲硫基乙基等;芳硫基烷基如苯硫基甲基等;链烯基如1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基等;取代的甲硅烷基如三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、二苯基甲基甲硅烷基、叔丁基甲氧基苯基甲硅烷基等。
R2所代表的氨基甲酰基烷基或羧基烷基可以被至少一个选自如下的取代基取代:卤素原子;未取代或被羟基、烷氧基、烷硫基、芳基、氨基或烷基氨基取代的烷基;卤代烷基;链烯基;环烷基;羟基;烷氧基;环烷氧基;烷氧基羰基;巯基;未取代或被一个或多个芳基取代的烷硫基;芳基;芳氧基;芳硫基;芳基氨基;氰基;硝基;未取代或被一个或多个酰基取代的氨基;烷基氨基;环烷基氨基;酰基;肼基;羧基;氨基甲酰基;硫代氨基甲酰基;烷基氨基甲酰基和杂环基。
在通式[1]所代表的环A中,优选的是吡嗪环、嘧啶环和三嗪环,更优选的是吡嗪环。环A上的取代基包括选自如下的基团:卤原子;未取代的或被一个或多个羟基、烷氧基、烷硫基、芳基、氨基或烷基氨基取代的烷基;卤代烷基;链烯基;环烷基;羟基;烷氧基;环烷氧基;烷氧基羰基;巯基;未取代的或被一个或多个芳基取代的烷硫基;芳基;芳氧基;芳硫基;芳基氨基;氰基;硝基;未取代的或被一个或多个酰基取代的氨基;烷基氨基;环烷基氨基;酰基;肼基;羧基;氨基甲酰基;硫代氨基甲酰基;烷基氨基甲酰基和杂环基。环A可以具有上述取代基中的一个或多个。此外,环A上的取代基优选连于该环的碳原子上。
通式[1]化合物的盐包括任何通常已知的在碱性基团如氨基位置形成的盐和在酸性基团如羟基和羧基位置形成的盐。在碱性基团位置形成的盐包括无机酸如盐酸、氢溴酸、硫酸等的盐;有机羧酸如酒石酸、甲酸、柠檬酸、三氯乙酸、三氟乙酸等的盐以及磺酸如甲磺酸、苯磺酸、对甲苯磺酸、均三甲苯磺酸、萘磺酸等的盐。在酸性基团位置形成的盐包括碱金属如钠、钾等的盐;碱土金属如钙、镁等的盐;铵盐;以及含氮有机碱如三甲胺、三乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己基胺、普鲁卡因、二苄基胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N,N’-二苄基乙二胺等的盐。在上述盐中,优选药理学上可接受的盐。
通式[1]所代表的典型化合物示于表1-4中。
在如下所示的表中,缩写具有下列含义:
Me: 甲基
Et: 乙基
iPr:异丙基
tBu:叔丁基
Ph: 苯基
Ac: 乙酰基
Bz: 苯甲酰基
R2a:-CH(COOH)CH2COOH
R2b:-CH(CH3)CONHCH(CH3)COOH表1No. G1 G2 G3 G4 R21 N CH CH N H2 N CH CH N→O H3 N CH CH N Ac4 N CH CH N Bz5 N CH CH H C(O)tBu6 N CH CH H CH2CONH27 N CH C-Cl N H8 N CH C-Br N H9 N CH C-OH N H10 N CH C-OMe N H11 N CH C-OEt N H12 N CH C-OiPr N H13 N CH C-O-环丙基 N H14 N CH C-NHMe N H15 N CH C-NMe2 N H16 N CH C-NH-环丙基N H17 N CH C-NHAc N H18 N CH C-NHBz N H19 N CH C-NHPh N H20 N CH C-SH N H21 N CH C-SMe N H22 N CH C-COOH N H23 N CH C-COOMe N H24 N CH C-COOEt N H25 N CH C-CONH2 N H26 N CH C-CSNH2 N H27 N CH C-CONHMe N H28 N CH C-CONMe2 N H29 N CH C-Et N H30 N CH C-iPr N H31 N CH C-CCl3 N H32 N CH C-CF3 N H33 N CH C-CH2Cl N H34 N CH C-CH2-SMe N H35 N CH C-CH2-OMe N H36 N CH C-CH2-Ph N H37 N CH C-CH2-NH2N H38 N CH C-CH2-OH N H39 N CH C-CH2-NHMeN H40 N CH C-CH=CH2 N H表2No. G1 G2 G3 G4 R241 N CH C-Ph N H42 N CH C-吡啶-3-基 N H43 N CH C-呋喃-2-基 N H44 N CH C-噻吩-2-基 N H45 N CH C-噻唑-2-基 N H46 N CH C-吡咯烷-1-基 N H47 N CH C-哌啶-1-基 N H48 N CH C-吗啉-4-基 N H49 N CH C-CN N H50 N CH C-NO2 N H51 N CH C-Bz N H52 N CH C-Ac N H53 N C-CONH2 C-NH2 N H54 N C-NH2 C-COOH N H55 N C-NH2 C-COOMe N H56 N C-Cl C-COOMe N H57 N C-OMe C-Me N H58 N C-COOH C-Me N H59 N C-COOH C-NHMe N H60 N C-COOMe C-Cl N H61 N C-COOMe C-哌啶-1-基 N H62 N C-OMe C-CN N H63 N C-Me C-Me N H64 N C-Ph C-Ph N H65 N C-F CH N H66 N C-Cl CH N H67 N C-Br CH N H68 N C-OH CH N H69 N C-OMe CH N H70 N C-OET CH N H71 N C-O-iPr CH N H72 N C-环丙基 CH N H73 N C-OPh CH N H74 N C-NH2 CH N H75 N C-NHMe CH N H76 N C-NMe2 CH N H77 N C-环丙基 CH N H78 N C-NHPh CH N H79 N C-NHAc CH N H80 N C-NHBz CH N H表3No. G1 G2 G3 G4 R281 N C-COOMe CH N H82 N C-CF3 CH N H83 N C-Ph CH N H84 N C-吡啶-4-基 CH N H85 N C-CN CH N H86 N C-NO2 CH N H87 CH N CH N H88 CH N C-Me N H89 CH N C-Et N H90 CH N C-iPr N H91 CH N C-F N H92 CH N C-Cl N H93 CH N C-Br N H94 CH N C-Ph N H95 CH N C-OH N H96 CH N C-OMe N H97 CH N C-OEt N H98 CH N C-OiPr N H99 CH N C-SH N H100 CH N C-SMe N H101 CH N C-S-CH2Ph N H102 CH N C-SPh N H103 CH N C-NH2 N H104 CH N C-NHMe N H105 CH N C-NMe2 N H106 CH N C-哌啶-1-基 N H107 CH N C-NH-Ph N H108 C-OH N C-SH N H109 C-OH N C-NH2 N H110 C-Me N C-OH N H111 N CH N CH H112 N C-F N CH H113 N C-Cl N CH H114 N C-F N C-Me H115 N C-Cl N C-Et H116 N C-OMe N C-OH H117 N C-NH2 N C-OH H118 N C-NHAc N C-OH H119 N C-SH N C-OH H120 N C-SMe N C-OH H表4No. G1 G2 G3 G4 R2121 N C-Me N C-NHMe H122 N C-Ph N C-OH H123 N C-Me N C-OH H124 N C-Me N C-S-Ph H125 N C-Me N C-Cl H126 N C-Me N C-OMe H127 N C-Me N C-OPh H128 N C-Me N C-吗啉-4-基 H129 CH CH N N H130 CH C-OH N N H131 CH C-Me N N H132 N CH N N H133 N C-Cl N N H134 N C-Me N N H135 N C-OMe N N H136 N C-NH2 N N H137 N C-NHAc N N H138 N C-吡啶-4-基 N N H139 N N CH N H140 N N C-Br N H141 N N C-OH N H142 N N C-OiPr N H143 N N C-NHPh N H144 N N C-噻唑-2-基 N H145 N N C-SH N H146 N N C-SMe N H147 N N C-Cl N H148 N N C-NHNH2 N H149 N N C-Ph N H150 N N C-吡啶-2-基 N H151 N N C-噻吩-2-基 N H152 N N C-NHMe N H153 N N C-NMe2 N H154 N CH C-F N H155 N CH CH N R2a156 N CH CH N R2a
通式[1]所代表的含氮杂环羧酰胺衍生物或其盐可市购或可以按照任何已知的方法或类似方法或由其组合生产。作为描述其生产方法的文章,可以参考“美国化学会志”,71,78(1949);“美国化学会志”,78,242-244(1956);“杂环化学杂志”,15(4),665-670(1978);“化学会志”;1379(1955);美国专利5597823等。
更具体而言,通式[1]所代表的含氮杂环羧酰胺衍生物或其盐可以根据下列生产方法1-3生产。生产方法1其中R1,R2,环A和虚线如上所定义,且R3表示羧基的保护基团。(1-a)通式[1]化合物可以通过通式[2]化合物与通式[4]化合物反应得到。
可以用于该反应中的溶剂不受特别限制,只要不对该反应产生不利影响。溶剂的例子包括醇类如甲醇、乙醇、异丙醇等;卤代烃类如二氯甲烷、氯仿、二氯乙烷等;芳族烃类如苯、甲苯、二甲苯等;醚类如二噁烷、四氢呋喃、茴香醚、二甘醇二乙醚、二甲基溶纤剂等;腈类如乙腈等;酰胺类如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等;以及亚砜类如二甲亚砜等。这些溶剂可以混合使用。
通式[4]化合物至少与通式[2]化合物等摩尔量使用,优选以1.0-5.0摩尔/摩尔通式[2]化合物的量使用。
该反应通常可以在0-100℃,优选20-80℃下进行5-24小时,优选30分钟-10小时。(1-b)通式[1]化合物可以通过将通式[3]化合物和通式[4]化合物进行脱水缩合反应而得到。
可以用于该反应中的溶剂不受特别限制,只要不对该反应产生不利影响。溶剂的例子包括醚类如二噁烷、四氢呋喃、茴香醚、二甘醇二乙醚、二甲基溶纤剂等;卤代烃类如二氯甲烷、氯仿、二氯乙烷等;以及酰胺类如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等。这些溶剂可以混合使用。
通式[4]化合物至少与通式[3]化合物等摩尔量使用,优选以1.0-2.0摩尔/摩尔通式[3]化合物的量使用。
可以用于该反应中的脱水缩合剂包括例如1,3-二环己基碳二亚胺、N,N’-羰基二咪唑、1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺等。
脱水缩合剂至少可以与通式[3]化合物等摩尔量使用,优选以1.0-2.0摩尔/摩尔通式[3]化合物的量使用。
通式[1]化合物可以通过将通式[5]化合物进行烷基-醚断裂而得到。
更具体而言,在R4为甲基时,该反应可以按照“有机合成中的保护基团”,第二版,John Wiley & Sons,pp.145-199(1991)的描述或由类似方法进行。生产方法3其中R1,环A和虚线如上所定义,且R2a表示酰基。
通式[1c]化合物可以通过将通式[1b]化合物在酸消除剂存在下进行酰化而得到。
可以用于该反应中的溶剂不受特别限制,只要不对该反应产生不利影响。溶剂的例子包括醚类如二噁烷、四氢呋喃、茴香醚、二甘醇二乙醚、二甲基溶纤剂等;芳族烃类如苯、甲苯、二甲苯等;卤代烃类如二氯甲烷、氯仿、二氯乙烷等;酰胺类如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等;水等。这些溶剂可以混合使用。
酰化剂至少可以与通式[1b]化合物等摩尔量使用,优选以1.0-2.0摩尔/摩尔通式[1b]化合物的量使用。
用于该反应中的酸消除剂包括例如吡啶、三乙胺、碳酸氢钠等。
酸消除剂至少可以与通式[1b]化合物等摩尔量使用,优选以1.0-2.0摩尔/摩尔通式[1b]化合物的量使用。
该反应通常可以在0-100℃,优选20-60℃下进行5分钟-24小时,优选30分钟-10小时。
在生产方法1-3中,通式[2],[3],[4],[5]和[1b]化合物可以分别用其盐代替。作为盐,可以使用与通式[1]化合物所述相同的盐。
通式[2],[3],[4],[5]和[1b]化合物及其盐中的一些可以具有各种异构体如光学异构体和位置异构体,以及溶剂化产物。在这些情况下,任何这些异构体和溶剂化物可以用于本发明中。
如此得到的通式[1c]化合物可以转化为其盐。该盐包括与通式[1]化合物所述相同的盐。
包含本发明通式[1]所示含氮杂环羧酰胺衍生物或其盐的抗病毒药的目标病毒包括A-、B-和C-型流感病毒,乳头瘤病毒,腺病毒,甲型肝炎病毒,乙型肝炎病毒,丙型肝炎病毒,脊髓灰质炎病毒,艾可病毒,柯萨奇病毒,肠道病毒,鼻病毒,轮状病毒,新城疫病毒,腮腺炎病毒,疱疹性口腔炎病毒和日本脑炎病毒。本发明的抗病毒药对流感病毒显示尤其高的作用。
通过将通式[1]所示的本发明含氮杂环羧酰胺衍生物或其盐与常规已知的赋形剂、助剂和添加剂组合,可以得到药物制剂如溶液、悬浮液、粉剂、颗粒剂、细颗粒剂、片剂、胶囊、糖浆、酏剂、醑剂、锭剂、含漱液、气雾剂等。这些药物制剂可以通过口服给药或通过非口服给药,即通过注射、经皮给药、直肠内给药、鼻孔内给药等。
本发明抗病毒药的给药方法、剂量和给药频率可以根据患者的年龄、体重和症状适当选择。通常对成人一次或分几次给予1-10mg/kg含氮杂环羧酰胺衍生物或其盐。
下面解释通式[1]所示的本发明含氮杂环羧酰胺衍生物或其盐的抗病毒活性和细胞毒性。
样品:将通式[1]所示含氮杂环羧酰胺衍生物或其盐溶于二甲亚砜中,制备浓度为10mg/ml的溶液。使用时,将该溶液用培养基稀释到预定的浓度,然后使用。
作为流感病毒的宿主细胞,使用MDCK细胞(犬肾细胞)。对于细胞毒性试验,使用Vero细胞(猴肾细胞)。
培养基:在MDCK细胞和Vero细胞的增殖中和在使用Vero细胞的细胞毒性试验中,使用已经加有10%胎牛血清的E’-MEM(Nissui的产品)。
在抗病毒活性的测量中,使用已经加有1%牛血清清蛋白的E’-MEM(Nissui的产品)。试验实施例1(抗流感活性)
将MDCK细胞以5×105细胞/孔接种于6孔板(CORNING的产品)并在35℃下于CO2-空气气氛中培养一夜。然后,将该板上的已培养MDCK细胞用已经用无血清培养基以200PFU/ml的浓度稀释的流感病毒A/PR/8/34株以0.5ml/孔处理1小时,完成接种和吸附。接种和吸附完成后,向细胞中加入含有0.6%Agar Noble,1%牛血清清蛋白和3μg/ml乙酰基胰蛋白酶且还含有预定浓度的试验化合物的E’-MEM培养基。充分凝结后,将该板上下翻转并培养三天。培养完成后,用1%中性红染色存活的细胞。然后用10%福尔马林固定细胞。用流水从中除去琼脂培养基。然后计量斑点的数目。斑点抑制率以与不含试验化合物的对照相比计算的百分数表示。
结果示于表5中,其中试验化合物号与表1-4中相同。
表5
No. 所加试验化合物的浓度(μg/ml) 抑制率(%)
1 1 91.9
2 100 32.4
9 100 50.0
41 100 25.0
65 1 100
66 100 39.2
67 100 35.2
83 100 39.8
84 100 39.5
87 100 85.7
95 100 30.5
129 100 28.0
139 100 49.3
141 100 26.3
145 100 36.8
154 100 23.0
155 10 35.5
156 100 36.0试验实施例2(细胞毒性)
将含有预定浓度试验化合物的培养基以100μl/孔加入96孔板(CORNING的产品)中。然后用培养基将Vero细胞调节为浓度为2×104细胞/ml。将该溶液以100μl/孔加入该板中并在37℃下于5%CO2-空气气氛中培养4天。当培养完成时,根据XTT方法[例如参见“癌研究”,第48卷,第4827-4833页(1988)]计量存活细胞的数目。
结果3-羟基-2-吡嗪羧酰胺(化合物1)的50%细胞生长抑制浓度(IC50)为250μg/ml或更大。
实施本发明的最佳方式
下面参照参考实施例和实施例解释本发明的化合物。本发明决不限于这些实施例。
在洗脱液中,混合比均按体积计算。
用于柱色谱中的载体为硅胶BW-127ZH(Fuji Silica Chemical Co.的产品)且用于反相柱色谱中的载体为LC-SORB SP-B-ODS(ChemcoCo.的产品)。
用于参考实施例和实施例中的符号标记具有下列含义:
DMSO-d6:氘代二甲亚砜参考实施例1
将0.30g根据文献[杂环化学杂志,34,27(1997)]所述方法得到的3-羟基-2-吡嗪羧酸甲酯悬浮于6ml二氯甲烷中。向该悬浮液中依次加入0.54ml三乙胺和0.29g盐酸甘氨酸甲基酯。将所得反应混合物在室温下搅拌5小时。冷却后,减压蒸除溶剂。将残余物通过反相柱色谱(洗脱液:水)纯化得到0.16g 2-{[(3-羟基-2-吡嗪基)羰基]氨基}乙酸甲酯。IR(KBr)cm-1:1750,1735,1685NMR(DMSO-d6)δ值:3.67(3H,s),4.12(2H,d,J=6Hz),7.70-8.30(2H,m),9.60-10.10(1H,m),13.10(1H,brs)参考实施例2
将17.00g根据文献[美国化学会志,2798-2800(1949)]所述方法得到的6-溴-3-氨基-2-吡嗪羧酸甲酯溶解于100ml浓硫酸中。在冰冷却的温度下将10.11g亚硝酸钠加入该悬浮液中,搅拌30分钟。将反应混合物倾入920ml甲醇中并在回流下加热5小时。将反应混合物冷却,然后在减压下浓缩。将如此得到的残余物加入500ml冰水和600ml氯仿的混合物中并分层。将有机层用饱和碳酸氢钠水溶液、水和饱和氯化钠水溶液依次洗涤并用无水硫酸镁干燥。然后减压蒸除溶剂得到6.30g 6-溴-3-甲氧基-2-吡嗪羧酸甲酯。IR(KBr)cm-1:1734NMR(CDCl3)δ值:3.97(3H,s),4.06(3H,s),8.37(1H,s)参考实施例3
在氮气气氛下将11.38g 6-溴-3-甲氧基-2-吡嗪羧酸甲酯溶解于227ml甲苯中。向该溶液中依次加入10.32g二苯酮亚胺,0.42g三(二亚苄基丙酮)二钯,0.86g(s)-(-)-2,2’-双(二苯基膦基)-1,1’-联萘和6.20g叔丁醇钠。将所得混合物在80℃下搅拌1小时。冷却并过滤反应混合物。滤液通过柱色谱(洗脱液:甲苯∶乙酸乙酯=20∶1)纯化。将如此得到的油状产品溶解于140ml四氢呋喃中,向其中加入7ml 2mol/ml的盐酸并将所得溶液在室温下搅拌15分钟。将所得反应混合物加入200ml氯仿和50ml水的混合物中并用1mol/ml氢氧化钠碱化,分离有机层。将有机层用氯化钠的饱和水溶液洗涤,用无水硫酸镁干燥并减压蒸除溶剂。将如此得到的残余物用柱色谱(洗脱液:甲苯∶乙酸乙酯=1∶1)纯化,得到3.64g 6-氨基-3-甲氧基-2-吡嗪羧酸甲酯。IR(KBr)cm-1:1716,1670NMR(DMSO-d6)δ值:3.80(3H,s),3.82(3H,s),7.20(2H,brs),7.77(1H,s)参考实施例4
将3.50g 6-氨基-3-甲氧基-2-吡嗪羧酸甲酯溶解于70ml甲醇中。导入氨气以用氨饱和该溶液。室温搅拌该溶液14小时。从反应混合物中减压蒸除溶剂得到3.1g 6-氨基-3-甲氧基-2-吡嗪羧酰胺。IR(KBr)cm-1:1684NMR(DMSO-d6)δ值:3.79(3H,s),5.87(2H,brs),7.30-7.75(3H,m)参考实施例5
在氮气气氛下,将1.50g 6-氨基-3-甲氧基-2-吡嗪羧酰胺在冰冷却下溶解于12ml 70%吡啶氢氟酸盐中。然后在-50℃下向其中加入0.71g亚硝酸钠并将所得溶液在10℃下搅拌1小时。将所得反应混合物在室温下搅拌另外1小时。然后向其中加入50ml冰水和100ml氯仿的混合物并将所得混合物分层。有机层用氯化钠饱和水溶液和碳酸氢钠饱和水溶液洗涤并用无水硫酸镁干燥。然后减压蒸除溶剂得到1.29g 6-氟-3-甲氧基-2-吡嗪羧酰胺。IR(KBr)cm-1:1706NMR(DMSO-d6)δ值:3.95(3H,s),7.55-8.15(2H,m),8.39(1H,d,J=8.3Hz)参考实施例6
将1.96g根据文献(JP-A-50-105675)所述方法得到的5-氨基-3-甲氧基-2-吡嗪羧酸甲酯悬浮于100ml甲醇中。通过在-20℃下向其中导入氨气而用氨饱和所得悬浮液。然后使如此得到的溶液在95℃下在不锈钢制的密封容器中反应24小时。冷却后减压蒸除溶剂得到1.57g 5-氨基-3-甲氧基-2-吡嗪羧酰胺。IR(KBr)cm-1:1654,1637NMR(DMSO-d6)δ值:3.82(3H,s),7.00(3H,brs),7.30(1H,brs),7.43(1H,s)参考实施例7
在氮气气氛下将0.5g 5-氨基-3-甲氧基-2-吡嗪羧酰胺在冰冷却下溶解于9ml 70%吡啶氢氟酸盐中。然后在-70℃下向其中加入0.23g亚硝酸钠并将所得溶液在30分钟内加热到-10℃的温度。另外,将该溶液在室温下搅拌30分钟。向其中加入30ml冰水和100ml氯仿的混合物并将所得混合物分层。有机层用氯化钠饱和水溶液洗涤并用无水硫酸镁干燥。减压蒸除溶剂。如此得到的残余物通过柱色谱(洗脱液:氯仿∶甲醇=10∶1)纯化,得到0.37g 5-氟-3-甲氧基-2-吡嗪羧酰胺。IR(KBr)cm-1:1705NMR(DMSO-d6)δ值:3.94(3H,s),7.65(1H,brs),7.85(1H,brs),8.12(1H,d,J=8.3Hz)
实施例1
将0.6g根据文献[药物化学杂志,1969,12(2),285-287]得到的6-溴-3-羟基-2-吡嗪羧酸甲酯悬浮于3ml甲醇中。然后向其中加入6ml 25%氨水并将所得溶液室温搅拌17小时。通过加入6mol/l盐酸将反应混合物调节至pH3。减压蒸除溶剂。向残余物中加入异丙醚和水并过滤得到0.33g 6-溴-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1700,1665NMR(DMSO-d6)δ值:7.50(2H,brs),8.08(1H,s),9.95(1H,brs)
实施例2
将0.5g根据文献[JP-A-54-79292]得到的3,5-二羟基-1,2,4-三嗪-6-羧酸悬浮于10ml二甲基甲酰胺中。然后向其中加入2.06g N,N’-羰基二咪唑并将所得溶液在室温下搅拌6小时。将反应混合物用冰冷却,用氨气饱和,然后在与上面相同的温度下搅拌15分钟。通过过滤收集沉积的晶体得到0.37g 3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6羧酰胺。IR(KBr)cm-1:1732,1710,1685,1656NMR(DMSO-d6)δ值:7.75(1H,s),7.97(1H,s),12.20-12.80(2H,m)
实施例3
将0.5g 3-羟基-2-吡嗪羧酰胺悬浮于5ml乙酸酐中。将所得溶液在110℃下搅拌1小时。通过过滤收集沉积的晶体得到0.5g N2-乙酰基-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1725,1695,1655NMR(DMSO-d6)δ值:2.25(3H,s),7.53(1H,d,J=4Hz),7.69(1H,d,J=4Hz),11.70(1H,brs)
实施例4
将0.25g根据文献[药物化学杂志,285-287(1969)]得到的6-氯-3-羟基-2-吡嗪羧酸甲酯悬浮于5ml 25%氨水中。将该悬浮液室温搅拌1小时。通过过滤收集沉积的晶体得到0.18g 6-氯-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1652NMR(DMSO-d6)δ值:7.22(2H,brs),7.91(1H,s)10.40(1H,brs)
实施例5
将1.00g 3-羟基-2-吡嗪羧酰胺悬浮于50ml四氢呋喃中。然后向其中依次加入3.5ml三乙胺和1.67ml苯甲酰氯。将所得溶液在60℃下搅拌5小时并冷却。通过过滤收集沉积的晶体。将如此得到的晶体悬浮于8ml水和1ml 1mol/ml盐酸的混合物中,室温搅拌30分钟并通过过滤收集得到0.41g N2-苯甲酰基-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1735NMR(DMSO-d6)δ值:7.20-8.40(7H,m),12.60(1H,brs)
根据上述相同方法,得到N2-(2,2-二甲基丙酰基)-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1725NMR(DMSO-d6)δ值:1.21(9H,s),7.49(1H,d,J=2Hz),7.95(1H,d,J=2Hz),14.80(1H,brs)
实施例6
将0.05g根据文献[欧洲药物化学杂志,15(2),157-163(1980)]得到的3-甲氧基-2-吡嗪羧酰胺-4-氧化物溶解于0.5ml 47%溴化氢水溶液中。将该溶液在45℃下搅拌2小时。通过过滤收集沉积的晶体并依次用乙醇和乙醚洗涤,得到0.03g 3-羟基-2-吡嗪羧酰胺-4-氧化物。IR(KBr)cm-1:1695NMR(DMSO-d6)δ值:7.19(1H,d,J=6Hz),7.56(1H,d,J=6Hz),7.70(1H,brs),7.95(1H,brs),10.75(1H,brs)
实施例7
将0.19g 2-{[(3-羟基-2-吡嗪基)羰基]氨基}乙酸甲酯悬浮于4ml甲醇中。通过在冰冷却下向其中导入氨气30分钟而将该悬浮液用氨饱和。将所得混合物在与上面相同的温度下搅拌1小时,然后在室温下搅拌15小时。减压蒸除溶剂。将如此得到的残余物溶解于4ml水和1ml甲醇的混合物中。向所得溶液中加入0.9ml 1mol/l盐酸。通过过滤收集沉积的晶体,得到0.16g N2-(2-氨基-2-氧代乙基)-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1675NMR(DMSO-d6)δ值:3.90(1H,d,J=5Hz),7.10(1H,brs),7.40(1H,brs),7.60-8.40(2H,m),9.50(1H,brs),13.0(1H,brs)实施例8
在氮气气氛下,将1.51g碘化钠溶解于22ml乙腈中。然后向其中加入1.10g三甲基甲硅烷基氯。将所得溶液在室温下搅拌20分钟。然后向其中加入0.43g 6-氟-3-甲氧基-2-吡嗪羧酰胺。将所得溶液在与上面相同的温度下搅拌18小时。然后将10ml水和200ml氯仿的混合物加入反应混合物中并分层。将如此得到的有机层依次用5%硫代硫酸钠水溶液和饱和氯化钠水溶液洗涤并用无水硫酸镁干燥。减压蒸除溶剂。通过柱色谱(洗脱液:己烷∶乙酸乙酯=2∶1)纯化如此得到的残余物,得到0.06g 6-氟-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1685,1670,1656NMR(CDCl3)δ值:5.40-7.80(2H,m),8.31(1H,d,J=7.82Hz),12.33(1H,s)
实施例9
将4.00g 3-羟基-2-吡嗪羧酰胺悬浮于24ml浓硫酸中。在冰冷却下向该悬浮液中加入3.09g硝酸钾。所得混合物在40℃下搅拌3小时。将反应化合物倾入240ml水中并通过过滤收集沉积的晶体。将如此得到的晶体悬浮于80ml水中并在回流下加热30分钟。冷却后,通过过滤收集晶体,得到2.45g 3-羟基-6-硝基-2-吡嗪羧酰胺。IR(KBr)cm-1:1705,1685,1655NMR(DMSO-d6)δ值:8.10(1H,brs),8.30(1H,brs),8.96(1H,s)
实施例10
将0.5g 2-氨基丙二酰胺悬浮于2.1ml水中。在冰冷却下向该悬浮液中加入0.43g乙醛酸乙酯,然后搅拌40分钟。然后向所得悬浮液中加入0.85ml 5mol/ml氢氧化钠,然后在与上面相同的温度下搅拌40分钟。通过加入1mol/l氢氧化钠将反应化合物调节至pH12并再一次制成溶液。然后通过加入6mol/ml盐酸而将该溶液调节至pH2。通过过滤收集沉积的晶体并依次用水和50%(w/w)乙醇洗涤,得到0.15g 3,5-二羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1660NMR(D2O)δ值:6.97(1H,s)
实施例11
将0.65ml 2-氧代丙二酸二乙酯(diethyl-2-oxomalonate)和0.5g 2-氨基丙二酰胺悬浮于2.0ml水中。在冰冷却下向其中加入0.85ml 5mol/ml氢氧化钠。搅拌所得溶液40分钟。然后在室温下向该溶液中加入2.55ml 5mol/ml氢氧化钠,然后另外搅拌30分钟。将乙醇加入反应混合物中并通过过滤收集沉淀得到0.24g 3,5-二羟基-6-乙氧基羰基-2-吡嗪羧酰胺。IR(KBr)cm-1:1655,1735NMR(D2O)δ值:1.17(3H,t,J=7Hz),4.15(2H,q,J=7Hz)
实施例12
将0.13g 3,5-二羟基-6-乙氧基羰基-2-吡嗪羧酰胺悬浮于1.0ml水和1.0ml乙醇的混合物中。在室温下将0.34ml 5mol/ml氢氧化钠加入该悬浮液中,然后搅拌16小时。通过加入1mol/ml盐酸将反应混合物调节至pH2。通过过滤收集沉积的晶体并用水洗涤得到0.07g 3,5-二羟基-6-羧基-2-吡嗪羧酰胺。IR(KBr)cm-1:1650
实施例13
在氮气气氛下,将0.09g 5-氟-3-甲基-2-吡嗪羧酰胺悬浮于3.6ml乙腈中。然后向该悬浮液中依次加入0.16g碘化钠和0.11g氯代三甲基硅烷,室温搅拌20小时。然后将2ml水和40ml氯仿加入反应混合物中并分层。分离有机层,依次用5%(w/v)硫代硫酸镁水溶液和饱和氯化钠水溶液洗涤并用无水硫酸镁干燥。然后减压蒸除溶剂。所得残余物通过柱色谱(洗脱液:氯仿)提纯,得到0.01g 5-氟-3-羟基-2-吡嗪羧酰胺。IR(KBr)cm-1:1670NMR(CDCl3)δ值:5.80(1H,s),7.45(1H,brs),7.93(1H,d,J=7.8Hz),12.93(1H,s)
实施例14
将0.1g根据文献(美国化学会志,1956,78,1258-1259)得到的5-氧代-3-硫代-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸乙酯溶于5ml乙醇中。在室温下将氨气导入该溶液中30分钟以使该溶液用氨饱和。将该溶液在与上面相同的温度下静置15小时后,通过过滤收集所得晶体。如此收集的晶体用乙醇洗涤(3×5ml),得到0.05g 5-氧代-3-硫代-2,3,4,5-四氢-1,2,4-三嗪-6-羧酰胺。IR(KBr)cm-1:1654NMR(DMSO-d6)δ值:3.30(4H,brs)
实施例15
根据文献(国际专利申请WO98130549)中描述的方法得到6-氧代-1,6-二氢-5-嘧啶羧酰胺。
实施例16
根据文献(Chemische Berichte,1964,97,3349-3353)中描述的方法得到3-氧代-2,3-二氢-4-哒嗪羧酰胺。
实施例17
将0.06g 5-氧代-4,5-二氢-1,2,4-三嗪-6-羧酸乙酯溶于5ml乙醇中。在10℃下通过向其中导入氨气20分钟而使该溶液用氨饱和。将该溶液在室温下静置15小时并通过过滤收集所得晶体。如此得到的晶体依次用乙醇(2×2ml)和甲醇(2×1ml)洗涤,得到0.03g 5-氧代-4,5-二氢-1,2,4-三嗪-6-羧酰胺。IR(KBr)cm-1:1654NMR(DMSO-d6)δ值:3.60(1H,brs),7.44(1H,brs),8.39(1H,s),9.74(1H,brs)
实施例18
将0.4g 3-羟基-2-吡嗪羧酸甲酯溶于4ml二甲亚砜中。然后向该溶液中依次加入0.27g L-天冬氨酸和0.85ml三乙胺,在50℃下搅拌6小时。滤出沉积的晶体并将滤液减压浓缩。然后将2ml水和0.2ml甲醇加入所得残余物中。过滤收集形成的沉淀,得到0.09g(2S)-2-{[(3-氧代-3,4-二氢-2-吡嗪基)羰基]氨基}-丁二酸。IR(KBr)cm-1:1695,1680,1665NMR(DMSO-d6)δ值:2.83(2H,d,J=5Hz),4.50-5.00(1H,m),7.60-8.05(2H,m),9.95(1H,d,J=9Hz),12.90(3H,brs)
实施例19
将0.42g L-丙氨酰基-L-丙氨酸三氟乙酸盐溶于5ml二甲亚砜中。然后向该溶液中依次加入1.07ml三乙胺和0.71g 3-羟基-2-吡嗪羧酸甲酯,在40℃下搅拌17小时。在减压下蒸除溶剂并向所得残余物中加入2ml水。通过过滤收集沉积的产物并通过柱色谱[洗脱液:氯仿∶甲醇=30∶1]提纯,得到0.035g(2S)-2-[((2S)-2-{[(3-氧代-3,4-二氢-2-吡嗪基)羰基]氨基}丙酰基)氨基]丙酸。IR(KBr)cm-1:1665,1675,1655NMR(DMSO-d6)δ值:1.28(3H,d,J=7Hz),1.32(3H,d,J=7Hz),3.95-4.95(2H,m),5.1(2H,brs),7.71(1H,d,J=3Hz),7.87(1H,d,J=3Hz),8.32(1H,d,J=7Hz),9.9(1H,brs)
工业应用性
包含通式[1]所示的含氮杂环羧酰胺衍生物或其盐的抗病毒药可以用于预防和治疗病毒感染,尤其是流感病毒感染。
Claims (7)
1.一种包含如下通式所示的含氮杂环羧酰胺衍生物或其盐的抗病毒药:其中环A代表取代或未取代的吡嗪、嘧啶、哒嗪或三嗪环;R1代表O或OH;R2代表氢原子、酰基或取代或未取代的氨基甲酰基烷基或羧基烷基;且虚线代表单键或双键。
2.根据权利要求1的抗病毒药,其中所述环A为取代或未取代的吡嗪、嘧啶或三嗪环。
3.根据权利要求2的抗病毒药,其中所述环A为取代或未取代的吡嗪环。
4.根据权利要求1-3中任一项的抗病毒药,其中所述病毒为流感病毒,乳头瘤病毒,腺病毒,甲型肝炎病毒,乙型肝炎病毒,丙型肝炎病毒,脊髓灰质炎病毒,艾可病毒,柯萨奇病毒,肠道病毒,鼻病毒,轮状病毒,新城疫病毒,腮腺炎病毒,疱疹性口腔炎病毒和日本脑炎病毒。
5.根据权利要求4的抗病毒药,其中所述病毒为流感病毒。
7.根据权利要求6的含氮杂环羧酰胺衍生物,其中所述环A’为卤素原子取代的吡嗪环;且R2代表氢原子。
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Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060834A1 (fr) * | 2000-02-16 | 2001-08-23 | Toyama Chemical Co., Ltd. | Nouveaux derives de pyrazine ou leurs sels, compositions pharmaceutiques contenant ces derives ou leurs sels et intermediaires utilises dans leur preparation |
MXPA04001361A (es) * | 2001-08-14 | 2004-05-27 | Toyama Chemical Co Ltd | Metodo novedoso para inhibir el crecimiento de virus y/o metodo virucida, y un analogo novedoso de un nucleotido de pirazina o de un nucleosido de pirazina. |
AU2002334205B2 (en) | 2001-10-26 | 2007-07-05 | Istituto Di Ricerche Di Biologia Molecolara P. Angeletti Spa | Dihydroxypyrimidine carboxamide inhibitors of HIV integrase |
CN102219750B (zh) | 2001-10-26 | 2013-05-29 | P.安杰莱蒂分子生物学研究所 | 关于hiv整合酶的n-取代的羟基嘧啶酮甲酰胺抑制剂 |
JP4200758B2 (ja) * | 2002-12-26 | 2008-12-24 | 株式会社日立ハイテクノロジーズ | パネルの樹脂塗布方法、ディスプレイ用パネルの製造方法及び樹脂塗布装置 |
EP1691747B1 (en) * | 2003-11-13 | 2012-05-23 | CardioPolymers, Inc. | Control of cardiac arrhythmias by modification of neuronal conduction within fat pads of the heart |
TWI355894B (en) * | 2003-12-19 | 2012-01-11 | Du Pont | Herbicidal pyrimidines |
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KR100700676B1 (ko) * | 2005-06-24 | 2007-03-28 | (주) 비엔씨바이오팜 | 6―(4―치환된―아닐리노)피리미딘 유도체, 그 제조방법및 이를 포함하는 항바이러스용 약학적 조성물 |
PT2123276E (pt) | 2007-02-16 | 2013-01-16 | Toyama Chemical Co Ltd | Composição farmacêutica que contem um derivado de pirazina, e processo de utilização de um derivado de pirazina em associação |
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WO2013161933A1 (ja) * | 2012-04-26 | 2013-10-31 | 富山化学工業株式会社 | 重水素化含窒素複素環カルボキサミド誘導体 |
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FR3000490B1 (fr) * | 2012-12-27 | 2015-03-13 | Anaconda Pharma | Procede de synthese d'une hydrazine utile dans le traitement du virus du papillome |
JP2018505183A (ja) | 2015-01-28 | 2018-02-22 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | エボラウイルス疾患の処置のための方法及び医薬組成物 |
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JPWO2022131117A1 (zh) | 2020-12-18 | 2022-06-23 | ||
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JPWO2022215616A1 (zh) | 2021-04-08 | 2022-10-13 | ||
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Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3472848A (en) * | 1966-11-17 | 1969-10-14 | Merck & Co Inc | 3-hydroxy and 3-mercapto-pyrazinoyl-guanidines,corresponding ethers and thioethers and processes for their preparation |
US3631036A (en) * | 1969-11-04 | 1971-12-28 | American Home Prod | 5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds |
US3745161A (en) * | 1970-04-20 | 1973-07-10 | Merck & Co Inc | Phenyl-hydroxy-pyrazine carboxylic acids and derivatives |
US4661145A (en) * | 1977-03-10 | 1987-04-28 | Rohm And Haas Company | Plant growth regulating 1-aryl-1,4-dihydro-4-oxo(thio)-pyridazines |
JPS5620576A (en) * | 1979-07-27 | 1981-02-26 | Nippon Soda Co Ltd | Pyrimidine derivative and selective herbicide |
CA1138872A (en) * | 1979-07-30 | 1983-01-04 | Rohm And Haas Company | Process for the preparation of 1-aryl-1,4- dihydro-4-oxopyridazine-3-carboxamides |
US4545810A (en) * | 1980-08-07 | 1985-10-08 | Sds Biotech Corporation | Herbicidal and plant growth regulant diphenylpyridazinones |
US4404203A (en) * | 1981-05-14 | 1983-09-13 | Warner-Lambert Company | Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents |
US4565814A (en) * | 1983-01-28 | 1986-01-21 | Sanofi | Pyridazine derivatives having a psychotropic action and compositions |
MX9202022A (es) * | 1991-05-01 | 1992-11-01 | Otsuka Pharma Co Ltd | Derivados de pirazina y proceso para su preparacion. |
FR2705344B1 (fr) | 1993-05-17 | 1995-06-30 | Synthelabo | Dérivés de 2-aminopyrazine-5-carboxamide, leur préparation et leur application en thérapeutique. |
US5597823A (en) * | 1995-01-27 | 1997-01-28 | Abbott Laboratories | Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists |
JPH09216883A (ja) * | 1996-02-09 | 1997-08-19 | Fujisawa Pharmaceut Co Ltd | ピラゾロピリジン化合物および該化合物を含有する医薬 |
US6159980A (en) * | 1996-09-16 | 2000-12-12 | Dupont Pharmaceuticals Company | Pyrazinones and triazinones and their derivatives thereof |
-
1999
- 1999-08-18 CZ CZ20010617A patent/CZ301763B6/cs not_active IP Right Cessation
- 1999-08-18 PL PL346172A patent/PL200955B1/pl unknown
- 1999-08-18 CN CNB998098973A patent/CN1154493C/zh not_active Expired - Lifetime
- 1999-08-18 CA CA002339272A patent/CA2339272C/en not_active Expired - Lifetime
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- 1999-08-18 CN CNB2004100325508A patent/CN1275947C/zh not_active Expired - Lifetime
- 1999-08-18 DK DK99938504T patent/DK1112743T3/da active
- 1999-08-18 NZ NZ509748A patent/NZ509748A/xx not_active IP Right Cessation
- 1999-08-18 PT PT99938504T patent/PT1112743E/pt unknown
- 1999-08-18 IL IL14115099A patent/IL141150A/xx not_active IP Right Cessation
- 1999-08-18 MX MXPA01001843A patent/MXPA01001843A/es active IP Right Grant
- 1999-08-18 ID IDW20010396A patent/ID28806A/id unknown
- 1999-08-18 WO PCT/JP1999/004429 patent/WO2000010569A1/ja active IP Right Grant
- 1999-08-18 AU AU53004/99A patent/AU756635B2/en not_active Expired
- 1999-08-18 DE DE69937405T patent/DE69937405T2/de not_active Expired - Lifetime
- 1999-08-18 KR KR1020017001690A patent/KR100585240B1/ko not_active IP Right Cessation
- 1999-08-18 RU RU2001104536/15A patent/RU2224520C2/ru active
- 1999-08-18 AT AT99938504T patent/ATE376418T1/de active
- 1999-08-18 JP JP2000565890A patent/JP3453362B2/ja not_active Expired - Lifetime
- 1999-08-18 BR BRPI9913097A patent/BRPI9913097B8/pt not_active IP Right Cessation
- 1999-08-18 EP EP99938504A patent/EP1112743B1/en not_active Expired - Lifetime
- 1999-08-18 ES ES99938504T patent/ES2296399T3/es not_active Expired - Lifetime
- 1999-08-18 HU HU0103453A patent/HU227475B1/hu unknown
-
2001
- 2001-02-19 NO NO20010836A patent/NO321026B1/no not_active IP Right Cessation
- 2001-02-20 US US09/788,992 patent/US6787544B2/en not_active Ceased
-
2007
- 2007-11-12 CY CY20071101459T patent/CY1107001T1/el unknown
-
2010
- 2010-08-26 US US12/869,074 patent/USRE43748E1/en not_active Expired - Lifetime
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WO2013139206A1 (zh) * | 2012-03-19 | 2013-09-26 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-氧代-3,4-二氢-2-吡嗪甲酰氨类衍生物、其药物组合物、其制备方法及用途 |
CN113563273A (zh) * | 2020-04-28 | 2021-10-29 | 中国人民解放军军事科学院军事医学研究院 | 一种抗病毒的吡嗪酰胺衍生物及其制备方法 |
CN113563273B (zh) * | 2020-04-28 | 2023-12-26 | 中国人民解放军军事科学院军事医学研究院 | 一种抗病毒的吡嗪酰胺衍生物及其制备方法 |
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