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
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- ring
- virus
- pyrazine
- general formula
- group
- 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.)
- Granted
Links
- 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
- 241000702670 Rotavirus Species 0.000 claims description 2
- 244000030166 artemisia Species 0.000 claims description 2
- 206010014599 encephalitis Diseases 0.000 claims description 2
- 208000003265 stomatitis Diseases 0.000 claims description 2
- 241000701161 unidentified adenovirus Species 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 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
- 238000006243 chemical reaction Methods 0.000 description 15
- 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
- 239000000376 reactant Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 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
- 238000005406 washing Methods 0.000 description 8
- 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
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 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
- 230000005494 condensation Effects 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- 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
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 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
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 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
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 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
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 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
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- VBJZFSACZFAYAE-UHFFFAOYSA-N 2-benzoyl-3-oxo-1,4-dihydropyrazine-2-carboxamide Chemical class C(C1=CC=CC=C1)(=O)C1(NC=CN=C1O)C(=O)N VBJZFSACZFAYAE-UHFFFAOYSA-N 0.000 description 1
- ADAFSVZZOBXXAH-UHFFFAOYSA-N 2-hydroxy-6-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC=C(O)N=C1O ADAFSVZZOBXXAH-UHFFFAOYSA-N 0.000 description 1
- FJZRUSFQHBBTCC-UHFFFAOYSA-N 2-oxo-1h-pyrazine-3-carboxylic acid Chemical compound OC(=O)C1=NC=CNC1=O FJZRUSFQHBBTCC-UHFFFAOYSA-N 0.000 description 1
- CXDHJGCWMIOAQP-UHFFFAOYSA-N 2-pyridin-3-yl-1,4,5,6-tetrahydropyrimidine;hydrochloride Chemical compound Cl.C1CCNC(C=2C=NC=CC=2)=N1 CXDHJGCWMIOAQP-UHFFFAOYSA-N 0.000 description 1
- KVYRCBOUKXJXDK-UHFFFAOYSA-N 3,4-dimethylphenazine-1,2-diamine hydrochloride Chemical compound Cl.C1=CC=CC2=NC3=C(C)C(C)=C(N)C(N)=C3N=C21 KVYRCBOUKXJXDK-UHFFFAOYSA-N 0.000 description 1
- PLKNGGRZZIWWLD-UHFFFAOYSA-N 3,5-dioxo-2h-1,2,4-triazine-6-carboxylic acid Chemical compound OC(=O)C1=NN=C(O)N=C1O PLKNGGRZZIWWLD-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- KZBREXQQUFIWKD-UHFFFAOYSA-N 5-bromo-2-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC(Br)=CN=C1O KZBREXQQUFIWKD-UHFFFAOYSA-N 0.000 description 1
- UCJQYEYEPZJJOF-UHFFFAOYSA-N 5-carbamoyl-2-hydroxy-6-oxo-1H-pyrazine-3-carboxylic acid Chemical class NC(=O)C1=NC(C(O)=O)=C(O)N=C1O UCJQYEYEPZJJOF-UHFFFAOYSA-N 0.000 description 1
- XERRFWUVFFKJNT-UHFFFAOYSA-N 5-chloro-2-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC(Cl)=CN=C1O XERRFWUVFFKJNT-UHFFFAOYSA-N 0.000 description 1
- OSFLEHUTGSKIPE-UHFFFAOYSA-N 5-nitro-2-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC([N+]([O-])=O)=CN=C1O OSFLEHUTGSKIPE-UHFFFAOYSA-N 0.000 description 1
- DEDHADHBMLKNKP-UHFFFAOYSA-N 5-oxo-2h-1,2,4-triazine-6-carboxamide Chemical class NC(=O)C1=NN=CNC1=O DEDHADHBMLKNKP-UHFFFAOYSA-N 0.000 description 1
- QYFDZZWHZSTXCD-UHFFFAOYSA-N 5-oxo-2h-1,2,4-triazine-6-carboxylic acid Chemical compound OC(=O)C1=NN=CN=C1O QYFDZZWHZSTXCD-UHFFFAOYSA-N 0.000 description 1
- JCGZZQLIHDCTNY-UHFFFAOYSA-N 6-fluoro-2-oxo-1h-pyrazine-3-carboxamide Chemical class NC(=O)C1=NC=C(F)N=C1O JCGZZQLIHDCTNY-UHFFFAOYSA-N 0.000 description 1
- ZHCAZQRACAKDHE-UHFFFAOYSA-N 6-oxo-1h-pyridazine-5-carboxamide Chemical class NC(=O)C1=CC=NN=C1O ZHCAZQRACAKDHE-UHFFFAOYSA-N 0.000 description 1
- ZOSXLRUOBVSFQV-UHFFFAOYSA-N 6-oxo-1h-pyrimidine-5-carboxamide Chemical class NC(=O)C1=CN=CN=C1O ZOSXLRUOBVSFQV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001500351 Influenzavirus A Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- GLJPYGONZAPOSG-UHFFFAOYSA-N aminomethyl acetate Chemical compound CC(=O)OCN GLJPYGONZAPOSG-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical class NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- GSTNAAOCEHQZDY-UHFFFAOYSA-N formic acid phosphane Chemical compound [PH4+].[O-]C=O GSTNAAOCEHQZDY-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960001269 glycine hydrochloride Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229950001891 iprotiazem Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- CQDMJJVHDPDPHO-UHFFFAOYSA-L magnesium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=S CQDMJJVHDPDPHO-UHFFFAOYSA-L 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CNXSIRHOIFRMOB-UHFFFAOYSA-N methyl 3-amino-6-bromopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Br)=CN=C1N CNXSIRHOIFRMOB-UHFFFAOYSA-N 0.000 description 1
- HHFMFCVOODVACN-UHFFFAOYSA-N methyl 5-bromo-2-oxo-1h-pyrazine-3-carboxylate Chemical compound COC(=O)C1=NC(Br)=CN=C1O HHFMFCVOODVACN-UHFFFAOYSA-N 0.000 description 1
- QJUBTZMSLDLOPZ-UHFFFAOYSA-N methyl 5-chloro-2-oxo-1h-pyrazine-3-carboxylate Chemical compound COC(=O)C1=NC(Cl)=CN=C1O QJUBTZMSLDLOPZ-UHFFFAOYSA-N 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical class NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940083538 smallpox vaccine Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- 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
- 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
-
- 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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cosmetics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Thiazole And Isothizaole Compounds (AREA)
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***、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***、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***、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,***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%***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***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,***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。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP25044198 | 1998-08-20 | ||
JP250441/1998 | 1998-08-20 | ||
JP14592299 | 1999-05-26 | ||
JP145922/1999 | 1999-05-26 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100325508A Division CN1275947C (zh) | 1998-08-20 | 1999-08-18 | 含氮杂环羧酰胺衍生物或其盐 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1313768A true CN1313768A (zh) | 2001-09-19 |
CN1154493C CN1154493C (zh) | 2004-06-23 |
Family
ID=26476908
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998098973A Expired - Lifetime CN1154493C (zh) | 1998-08-20 | 1999-08-18 | 含氮杂环羧酰胺衍生物或其盐以及含有二者的抗病毒药 |
CNB2004100325508A Expired - Lifetime CN1275947C (zh) | 1998-08-20 | 1999-08-18 | 含氮杂环羧酰胺衍生物或其盐 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100325508A Expired - Lifetime CN1275947C (zh) | 1998-08-20 | 1999-08-18 | 含氮杂环羧酰胺衍生物或其盐 |
Country Status (25)
Country | Link |
---|---|
US (2) | US6787544B2 (zh) |
EP (1) | EP1112743B1 (zh) |
JP (1) | JP3453362B2 (zh) |
KR (1) | KR100585240B1 (zh) |
CN (2) | CN1154493C (zh) |
AT (1) | ATE376418T1 (zh) |
AU (1) | AU756635B2 (zh) |
BR (1) | BRPI9913097B8 (zh) |
CA (1) | CA2339272C (zh) |
CY (1) | CY1107001T1 (zh) |
CZ (1) | CZ301763B6 (zh) |
DE (1) | DE69937405T2 (zh) |
DK (1) | DK1112743T3 (zh) |
ES (1) | ES2296399T3 (zh) |
HU (1) | HU227475B1 (zh) |
ID (1) | ID28806A (zh) |
IL (1) | IL141150A (zh) |
MX (1) | MXPA01001843A (zh) |
NO (1) | NO321026B1 (zh) |
NZ (1) | NZ509748A (zh) |
PL (1) | PL200955B1 (zh) |
PT (1) | PT1112743E (zh) |
RU (1) | RU2224520C2 (zh) |
TR (1) | TR200100574T2 (zh) |
WO (1) | WO2000010569A1 (zh) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101289455B (zh) * | 2007-04-17 | 2010-11-10 | 靳广毅 | 一种抗流感病毒前体药及其应用 |
CN101454295B (zh) * | 2006-05-31 | 2011-09-21 | 富山化学工业株式会社 | 猪科动物或羊用抗***病毒药剂 |
CN102348458A (zh) * | 2009-03-13 | 2012-02-08 | 富山化学工业株式会社 | 含有6-氟-3-羟基-2-吡嗪甲酰胺的片剂和粒状粉剂 |
CN102603658A (zh) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | 6-氟-3-羟基-2-吡嗪酰胺的制备方法 |
CN102603657A (zh) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | 6-溴-3-羟基-2-吡嗪酰胺的制备方法 |
CN102617491A (zh) * | 2011-07-01 | 2012-08-01 | 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 |
CN102850282A (zh) * | 2011-07-01 | 2013-01-02 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-烷氧基取代-2-吡嗪甲酰氨类化合物及其用途 |
WO2013004148A1 (zh) * | 2011-07-01 | 2013-01-10 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-(丁基氧基)-2-吡嗪甲酰氨的制备方法和用途 |
WO2013004092A1 (zh) * | 2011-07-01 | 2013-01-10 | 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 |
CN103209967A (zh) * | 2010-09-30 | 2013-07-17 | 富山化学工业株式会社 | 6-氟-3-羟基-2-吡嗪甲酰胺的葡甲胺盐 |
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 |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1256588E (pt) * | 2000-02-16 | 2005-05-31 | Toyama Chemical Co Ltd | Derivados de pirazina originais ou os seus sais, preparacoes farmaceuticas, contendo os derivados ou os seus sais e produtos intermedios para a preparacao de ambos |
CA2456292A1 (en) * | 2001-08-14 | 2003-02-27 | Toyama Chemical Co., Ltd. | Novel virus growth inhibitor and/or virucidal method, and novel pyrazine nucleotide or pirazine nucleoside analog |
JP4351053B2 (ja) | 2001-10-26 | 2009-10-28 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | ジヒドロキシピリミジンカルボキサミド系hivインテグラーゼ阻害薬 |
UA77454C2 (en) | 2001-10-26 | 2006-12-15 | N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase | |
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 |
US20050119704A1 (en) * | 2003-11-13 | 2005-06-02 | Peters Nicholas S. | 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 |
CN1560035A (zh) * | 2004-03-12 | 2005-01-05 | 沈阳药科大学 | 5-羟基吲哚-3-羧酸脂类衍生物 |
KR100700676B1 (ko) * | 2005-06-24 | 2007-03-28 | (주) 비엔씨바이오팜 | 6―(4―치환된―아닐리노)피리미딘 유도체, 그 제조방법및 이를 포함하는 항바이러스용 약학적 조성물 |
CN101610772B (zh) * | 2007-02-16 | 2013-01-16 | 富山化学工业株式会社 | 包含吡嗪衍生物的药物组合物和使用吡嗪衍生物的联合用药的方法 |
JP5739618B2 (ja) * | 2009-03-18 | 2015-06-24 | 富山化学工業株式会社 | 3−ヒドロキシ−2−ピラジンカルボキサミドの製造法 |
SG189161A1 (en) | 2010-09-30 | 2013-05-31 | Toyama Chemical Co Ltd | Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
BR112013011418B1 (pt) * | 2010-11-12 | 2021-03-16 | Fujifilm Toyama Chemical Co., Ltd | Derivado de pirazino[2,3-d]isoxazol, métodos para a produção de um derivado de pirazino [2,3-d]isoxazol e compostos |
TW201348214A (zh) * | 2012-04-26 | 2013-12-01 | Toyama Chemical Co Ltd | 氘化含氮雜環羧醯胺衍生物 |
WO2013180149A1 (ja) * | 2012-05-30 | 2013-12-05 | 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またはその塩 |
FR3000490B1 (fr) * | 2012-12-27 | 2015-03-13 | Anaconda Pharma | Procede de synthese d'une hydrazine utile dans le traitement du virus du papillome |
WO2016120301A1 (en) | 2015-01-28 | 2016-08-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of ebola virus disease |
CN106588786B (zh) * | 2015-10-14 | 2019-03-08 | 山东省药学科学院 | 一种高纯度法匹拉韦杂质的制备方法 |
CN105687152B (zh) * | 2016-03-22 | 2020-04-07 | 山东齐都药业有限公司 | 一种法匹拉韦快速释放药物制剂及制备方法 |
CN106083745B (zh) * | 2016-08-15 | 2018-08-21 | 山东百诺医药股份有限公司 | 6-氟-3-羟基-2-吡嗪酰胺的合成方法 |
CN107226794A (zh) * | 2017-07-17 | 2017-10-03 | 郑州大学 | 一种法匹拉韦的合成方法 |
CN111556752A (zh) | 2017-12-28 | 2020-08-18 | 富士胶片富山化学株式会社 | 冻干制剂的制造方法 |
JP7369143B2 (ja) | 2018-12-25 | 2023-10-25 | 富士フイルム富山化学株式会社 | ピラジン誘導体と細胞内におけるピラジン誘導体リボース三リン酸体の量を増加させる化合物とを組み合わせてなるrnaウイルス感染症治療剤 |
EP4129291A4 (en) | 2020-03-30 | 2024-04-10 | FUJIFILM Toyama Chemical Co., Ltd. | CORONAVIRUS INFECTION TREATMENT MEDICATION |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
CN112300083B (zh) * | 2020-04-20 | 2021-08-03 | 常州制药厂有限公司 | 一种法匹拉韦的制备方法 |
EP4144353A1 (en) | 2020-04-30 | 2023-03-08 | FUJIFILM Toyama Chemical Co., Ltd. | Coronavirus infection therapeutic agent formed through combination of pyrazine derivative and another coronavirus infection therapeutic drug |
RU2744429C1 (ru) * | 2020-05-02 | 2021-03-09 | Андрей Александрович Иващенко | Противо-РНК вирусное, в том числе противокоронавирусное средство - замещенный хиноксалин, фармацевтическая композиция и применения |
RU2731932C1 (ru) | 2020-05-07 | 2020-09-09 | Общество с ограниченной ответственностью "Кромис" (ООО "Кромис") | Противо-COVID-19 (SARS-CoV-2) вирусная фармацевтическая композиция |
WO2021241613A1 (ja) | 2020-05-27 | 2021-12-02 | 富士フイルム富山化学株式会社 | ピラジン誘導体とチオプリン誘導体を組み合わせてなるrnaウイルス感染症治療剤 |
CN111704582B (zh) * | 2020-06-23 | 2021-06-11 | 杭州煌森生物科技有限公司 | 一种法匹拉韦及其衍生物的制备方法 |
WO2022131112A1 (ja) | 2020-12-18 | 2022-06-23 | 富士フイルム富山化学株式会社 | 医薬組成物 |
EP4265253A1 (en) | 2020-12-18 | 2023-10-25 | FUJIFILM Toyama Chemical Co., Ltd. | Pharmaceutical composition |
WO2022215616A1 (ja) | 2021-04-08 | 2022-10-13 | 富士フイルム富山化学株式会社 | コロナウイルス感染症治療剤 |
WO2022239823A1 (ja) | 2021-05-14 | 2022-11-17 | 富士フイルム富山化学株式会社 | 新型コロナウイルスの変異ウイルスに対する感染症治療剤 |
JPWO2023008530A1 (zh) | 2021-07-30 | 2023-02-02 |
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 |
CA2067663A1 (en) * | 1991-05-01 | 1992-11-02 | Hitoshi Tone | Pyrazine derivatives |
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 |
ATE213495T1 (de) * | 1996-09-16 | 2002-03-15 | Du Pont Pharm Co | Eine resorbierbare röntgenopake markierung enthaltendes chirurgisches implantat und verfahren zum verriegeln desselben in einem körper |
-
1999
- 1999-08-18 MX MXPA01001843A patent/MXPA01001843A/es active IP Right Grant
- 1999-08-18 RU RU2001104536/15A patent/RU2224520C2/ru active
- 1999-08-18 KR KR1020017001690A patent/KR100585240B1/ko not_active IP Right Cessation
- 1999-08-18 WO PCT/JP1999/004429 patent/WO2000010569A1/ja active IP Right Grant
- 1999-08-18 CZ CZ20010617A patent/CZ301763B6/cs not_active IP Right Cessation
- 1999-08-18 CN CNB998098973A patent/CN1154493C/zh not_active Expired - Lifetime
- 1999-08-18 CA CA002339272A patent/CA2339272C/en not_active Expired - Lifetime
- 1999-08-18 TR TR2001/00574T patent/TR200100574T2/xx unknown
- 1999-08-18 AU AU53004/99A patent/AU756635B2/en not_active Expired
- 1999-08-18 CN CNB2004100325508A patent/CN1275947C/zh not_active Expired - Lifetime
- 1999-08-18 ID IDW20010396A patent/ID28806A/id unknown
- 1999-08-18 JP JP2000565890A patent/JP3453362B2/ja not_active Expired - Lifetime
- 1999-08-18 PL PL346172A patent/PL200955B1/pl unknown
- 1999-08-18 NZ NZ509748A patent/NZ509748A/xx not_active IP Right Cessation
- 1999-08-18 ES ES99938504T patent/ES2296399T3/es not_active Expired - Lifetime
- 1999-08-18 DE DE69937405T patent/DE69937405T2/de not_active Expired - Lifetime
- 1999-08-18 DK DK99938504T patent/DK1112743T3/da active
- 1999-08-18 PT PT99938504T patent/PT1112743E/pt unknown
- 1999-08-18 AT AT99938504T patent/ATE376418T1/de active
- 1999-08-18 EP EP99938504A patent/EP1112743B1/en not_active Expired - Lifetime
- 1999-08-18 BR BRPI9913097A patent/BRPI9913097B8/pt not_active IP Right Cessation
- 1999-08-18 IL IL14115099A patent/IL141150A/xx not_active IP Right Cessation
- 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
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101454295B (zh) * | 2006-05-31 | 2011-09-21 | 富山化学工业株式会社 | 猪科动物或羊用抗***病毒药剂 |
CN101289455B (zh) * | 2007-04-17 | 2010-11-10 | 靳广毅 | 一种抗流感病毒前体药及其应用 |
US8513261B2 (en) | 2009-03-13 | 2013-08-20 | Toyama Chemical Co., Ltd. | Tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
CN102348458A (zh) * | 2009-03-13 | 2012-02-08 | 富山化学工业株式会社 | 含有6-氟-3-羟基-2-吡嗪甲酰胺的片剂和粒状粉剂 |
CN103209967B (zh) * | 2010-09-30 | 2015-04-08 | 富山化学工业株式会社 | 6-氟-3-羟基-2-吡嗪甲酰胺的葡甲胺盐 |
CN103209967A (zh) * | 2010-09-30 | 2013-07-17 | 富山化学工业株式会社 | 6-氟-3-羟基-2-吡嗪甲酰胺的葡甲胺盐 |
CN102617491B (zh) * | 2011-07-01 | 2015-05-06 | 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 |
CN102850282A (zh) * | 2011-07-01 | 2013-01-02 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-烷氧基取代-2-吡嗪甲酰氨类化合物及其用途 |
WO2013004141A1 (zh) * | 2011-07-01 | 2013-01-10 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-烷氧基取代-2-吡嗪甲酰氨类化合物及其用途 |
WO2013004148A1 (zh) * | 2011-07-01 | 2013-01-10 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-(丁基氧基)-2-吡嗪甲酰氨的制备方法和用途 |
WO2013004092A1 (zh) * | 2011-07-01 | 2013-01-10 | 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 |
CN102617491A (zh) * | 2011-07-01 | 2012-08-01 | 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 |
CN102850282B (zh) * | 2011-07-01 | 2015-09-16 | 中国人民解放军军事医学科学院毒物药物研究所 | 3-取代氧基-2-吡嗪甲酰胺类化合物及其用途 |
CN102603657A (zh) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | 6-溴-3-羟基-2-吡嗪酰胺的制备方法 |
CN102603657B (zh) * | 2011-10-18 | 2015-02-04 | 山东齐都药业有限公司 | 6-溴-3-羟基-2-吡嗪酰胺的制备方法 |
CN102603658A (zh) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | 6-氟-3-羟基-2-吡嗪酰胺的制备方法 |
CN102603658B (zh) * | 2011-10-18 | 2014-04-30 | 山东齐都药业有限公司 | 6-氟-3-羟基-2-吡嗪酰胺的制备方法 |
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 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1313768A (zh) | 含氮杂环羧酰胺衍生物或其盐以及含有二者的抗病毒药 | |
CN109311854B (zh) | 具有仲酰胺官能团的苯并氮杂卓二甲酰胺化合物 | |
JP4939527B2 (ja) | 抗ウィルス剤の機能を有する両複素環連結化合物、その応用および当該化合物を含有する組成物 | |
AU2015277312B2 (en) | Synthesis of polycyclic-carbamoylpyridone compounds | |
EA008380B1 (ru) | 3-β-D-РИБОФУРАНОЗИЛТИАЗОЛО[4,5-d]ПИРИМИДИННУКЛЕОЗИДЫ И ИХ ПРИМЕНЕНИЯ | |
CN1939922A (zh) | 可抑制细胞释放肿瘤坏死因子的5H-噻吩[3,4-c]吡咯-4,6-二酮衍生物 | |
KR20090074237A (ko) | 5-아미노-3-(2'-O-아세틸-3'-데옥시-β-D-리보퓨라노실)-3H-티아졸로[4,5-d]파이리미딘-2-온의 P-톨루엔 설폰산염 및 이의 제조 방법 | |
CN1259131A (zh) | 化合物 | |
CN103360398B (zh) | 一种***并嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 | |
CN1259517A (zh) | 2,5-二氨基-4,6-二氯嘧啶的制备方法 | |
CN100344615C (zh) | 制备N-(吡咯并[2,3-d]嘧啶-5-基)酰基谷氨酸衍生物的方法及中间体 | |
CN1161342C (zh) | 制备取代的嘧啶的方法 | |
CN110016026B (zh) | 一类具有抗肿瘤活性的嘧啶并吡啶酮类化合物、制备方法和用途 | |
CN109503518A (zh) | 一种取代的双芳香基酰胺化合物及其制备方法和应用 | |
CN1931869A (zh) | 5′-脱氧-5-氟胞苷类衍生物,它的制备方法及其用途 | |
CN1317265C (zh) | 氰基丙烯酸酯衍生物及制备方法和生物活性 | |
CN1166650C (zh) | 1,2,3-噻二唑类化合物及其制备方法和生物活性 | |
CN1890244A (zh) | 用于制备经取代氨基醇的方法 | |
CN1259132A (zh) | 化合物 | |
CN1324034C (zh) | 具有释放NO功能的噁二唑并[3,4-d]嘧啶苷类化合物及其药学上的用途 | |
CN1233618C (zh) | 具有除草活性的苯甲酰基环己酮胺类化合物 | |
CN116120297A (zh) | 1,3-双环氧丙基-5-取代环状三聚脲类化合物及其作为铁死亡诱导剂的用途 | |
ZA200101101B (en) | Nitrogenous heterocyclic carboxamide derivatives of salts thereof and antiviral agents containing both. | |
CN1670020A (zh) | 吡唑并嘧啶酮类化合物及其应用 | |
CN1101912A (zh) | 新头孢烯化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term |
Granted publication date: 20040623 |
|
CX01 | Expiry of patent term |