ZA200206184B - Novel pyrazine derivatives or salts thereof, and pharmaceutical composition containing the same. - Google Patents
Novel pyrazine derivatives or salts thereof, and pharmaceutical composition containing the same. Download PDFInfo
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- ZA200206184B ZA200206184B ZA200206184A ZA200206184A ZA200206184B ZA 200206184 B ZA200206184 B ZA 200206184B ZA 200206184 A ZA200206184 A ZA 200206184A ZA 200206184 A ZA200206184 A ZA 200206184A ZA 200206184 B ZA200206184 B ZA 200206184B
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- South Africa
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- virus
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- pharmaceutical composition
- lower alkyl
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- 150000003839 salts Chemical class 0.000 title claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 150000003216 pyrazines Chemical class 0.000 title claims description 7
- 241000700605 Viruses Species 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 208000006454 hepatitis Diseases 0.000 claims description 5
- 231100000283 hepatitis Toxicity 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 241000712461 unidentified influenza virus Species 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 229910052731 fluorine Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 241000709661 Enterovirus Species 0.000 claims 2
- 241000711404 Avian avulavirus 1 Species 0.000 claims 1
- 241000709687 Coxsackievirus Species 0.000 claims 1
- 241001466953 Echovirus Species 0.000 claims 1
- 241000991587 Enterovirus C Species 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 claims 1
- 241000710842 Japanese encephalitis virus Species 0.000 claims 1
- 241000711386 Mumps virus Species 0.000 claims 1
- 241001631646 Papillomaviridae Species 0.000 claims 1
- 241000702670 Rotavirus Species 0.000 claims 1
- 241000711975 Vesicular stomatitis virus Species 0.000 claims 1
- 241000701161 unidentified adenovirus Species 0.000 claims 1
- -1 1odomethyl Chemical group 0.000 description 115
- 125000000217 alkyl group Chemical group 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 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 3
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 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
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical group OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 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
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 125000006033 1,1-dimethyl-2-propenyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 241000713325 Visna/maedi virus Species 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 125000001980 alanyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 1
- 229960001280 amantadine hydrochloride Drugs 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000003500 enol ether group Chemical group 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- CJXGPJZUDUOZDX-UHFFFAOYSA-N fluoromethanone Chemical group F[C]=O CJXGPJZUDUOZDX-UHFFFAOYSA-N 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 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
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004626 naphthothienyl group Chemical group C1(=CSC2=C1C1=CC=CC=C1C=C2)* 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 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
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229960005486 vaccine Drugs 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
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
‘ . ~v n
Wo486 230/16 1
NOVEL PYRAZINE DERIVATIVES OR SALTS THEREOF, AND
PHARMACEUTICAL COMPOSITION CONTAINING THE
SAME
The present invention relates to novel pyrazine derivatives or salts thereof, and a pharmaceutical composition containing the same.
E As the antiviral agents clinically used : | today, acyclovir and vidarabine for controlling herpesvirus, ganciclovir and foscarnet for controlling cytomegalovirus, and interferon, etc. for controlling hepatitis virus can be referred to.. Further, : : prevention by the use of vaccine is extensively adopted against influenza virus, and low molecular compounds such as amantadine hydrochloride and ribavirin are also used for this purpose. Further, zanamivir is also used lately. :
On the other hand, as to the antiviral activity of nucleoside- and nucleotide-analogues having a pyrazine ring as a base, for example, it has hitherto been reported that the compounds of the following general formula:
Amended Sheet — 2003-07-30 a
CC :
HO OH wherein R’ represents hydrogen atom, methyl group or
CioHz;, have an antiviral activity. However, this type ’ compounds show no "Visna virus activity" [Nucleosides & _.
Nucleotides, Vol. 15, Nos. 11 and 12, Pages 1849-1861 (1996) ]. Further, nucleoside- and nucleotide-analogues having a pyrazine ring substituted with a carbamoyl group have not yet been reported so far. :
As problems of amantadine, that it is not effective against B type influenza even though it is effective against A type influenza, because of its action mechanism, that its resistance virus can appear, that it causes a nerve disturbance, etc. have been mentioned. On the other hand, although ribavirin shows
Co a polymerase-inhibitory activity and effective against
A type and B type influenza, it exhibits no sufficient clinical effect when used orally.
Thus, it has been desired to develop an antiviral agent having an infection-preventive effect oo against various viruses and especially against - 20 influenza virus and exhibiting a therapeutic effect.
Amended Sheet — 2003-07-30
. ¢ : With the aim of solving the problems mentioned above, the present inventors have conducted extensive studies. As a result, it has been found that a pyrazine derivative represented by the following general formula [1]: . | .
Room a © (Hz [1]
R* R® wherein R' represents a hydrogen atom or a halogen atom;
R? represents a hydrogen atom; R® and R® represent a hydrogen atom; R' and R® represent a substituted or ) unsubstituted, protected or unprotected hydroxyl group;
A represents an oxygen atom; n represents 0; and Y represents an oxygen atom, or a salt thereof has an excellent antiviral activity. Based on this finding, the present invention... Co has been accomplished.
Hereunder, the present invention will be detailed.
As used in this specification, meanings of the following terms are as follows, unless otherwise defined. The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine Te atom; "halogenated methyl group" means a mono-, di- or
Amended Sheet — 2003-07-30 tri-substituted halogenated methyl group such as fluoromethyl, chloromethyl, bromomethyl, 1odomethyl, dichloromethyl, trifluoromethyl, trichloromethyl and the like; "halogenated carbonyl group" means a fluorocarbonyl, chlorocarbonyl, bromocarbonyl or } iodocarbonyl group; "lower alkyl group" means a Cis alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and . the like; "lower alkoxy group” means a C,.s alkoxy group . such as methoxy, ethoxy, N-propoxy, 1sopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy _ and the like; "lower alkoxycarbonyl group" means a C,. : : alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
NB 15 n-butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like; "lower alkylamino group" means a mono- or di-C,.s alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, oo | 20 methylethylamino and the like; ."halogeno-lower alkyl HERE group" means a halogeno-C,s alkyl group such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl and the like; "lower alkenyl group" means
Co a C,; alkenyl group such as vinyl, allyl and the like; : "cycloalkyl group" means a C..e cycloalkyl group such as oT ~ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
Amended Sheet — 2003-07-30 g thé like; "aryl group" means a phenyl group, a naphthyl group or the like; and "heterocyclic group" means a 4- to 6-membered or fused heterocyclic group containing at least one hetero atom selected from oxygen atom, nitrogen atom and sulfur atom, such as azetidinyl, oo thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, ’ ... imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4- Ca oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, '1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, : thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenyl, indolizinyl, ‘isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, 20. triazolopyridyl, tetrazolopyridazinyl, META : tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzthiazolyl, 1,2,3,4- tetrahydroquinolyl, imidazo[l,2-b] [1,2,4]-triazinyl, quinuclidinyl and the like.
In cases where the compound of the present invention and production intermediate thereof have a Te : hydroxyl group, a mercapto group, an amino group, a : Amended Sheet — 2003-07-30
: ; carbamoyl group or a carboxyl group, those substituents may be protected with known protecting groups.
The terms "monophosphoric acid group", "diphosphoric acid group" and "triphosphoric acid 5S group" mean groups of the following general formula: (Ly,
H oF X
OH : wherein k is 1, 2 and 3, respectively. ]
As protecting groups for the monophosphoric - acid group, diphosphoric acid group and triphosphoric acid group, all the groups conventionally usable for + 10 protection of phosphoric acid groups can be referred to. Examples thereof include lower alkyl groups such as methyl, cyclopropylmethyl, tert-butyl, ethan-1,2- diyl and the like; halogeno lower alkyl groups such as 2,2,2-trichlorethyl, 2,2,2-trichloro-1,1l-dimethylethyl, 2,2,2-tribromethyland the like; acyl lower alkyl groups
PE such as l-acetylethyl and the like; cyano lower alkyl TL groups such as 2-cyanoethyl and the like; lower alkylsulfonyl lower alkyl groups such as 2- methylsulfonylethyl and the like; arylsulfonyl lower alkyl groups such as 2-phenylsulfonylethyl and the like; alkenyl groups such as allyl and the like; aryl groups such as phenyl, o-hydroxyphenyl, o-chlorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, p-nitrophenyl, 2- oT dimethylamino-4-nitrophenyl, 2-tert-butylphenyl, 2-
Amended Sheet — 2003-07-30 chloromethyl-4-nitrophenyl, o-phenylene and the like; ar-lower alkyl groups such as benzyl, o-nitrobenzyl, p- nitrophenylethyl and the like; heterocyclic groups such as 8-quinolyl, 5-chloro-8-quinolyl and the like; etc.
One or more kinds of the above-mentioned protecting groups may be used for the protection.
As protecting groups for carboxyl group, all the groups conventionally usable for protection of ’ carboxyl group can be referred to. Examples. thereof SE include lower alkyl groups such as methyl, ethyl, n- propyl, isopropyl, 1,1l-dimethylpropyl, n-butyl, tert-
N butyl and the like; aryl groups such as rhenyl, naphthyl and the like; ar-lower alkyl groups such as oo benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p- methoxybenzyl, bis (p-methoxyphenyl)-methyl and the like; acyl-lower alkyl groups such as acetylmethyl, ~ benzoylmethyl, p-nitrobenzoylmethyl, p-_ : . bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 20. 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; Co halogeno-lower alkyl GrOuDS such as 2,2,2-trichlorethyl and the like; lower alkyl-silyl-alkyl groups such as 2- (trimethylsilyl) ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxy- methyl and the like; nitrogen-containing heterocycle- lower alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such oT as cyclohexyl and the like; lower alkoxy-lower alkyl . Amended Sheet — 2003-07-30 groups such as methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and the like; ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl and the like; lower alkylthio-lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; ] arylthio-lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,1- dimethyl-2-propenyl, 3-methyl-3-butynyl, allyl and the : : ol : like; and lower alkyl-substituted.silyl groups: such as ee trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl, diphenylmethylsilyl, tert- butylmethoxyphenylsilyl and the like. . As protecting groups for amino and lower alkylamino groups, all the groups conventionally usable : for protection of amino groups can be referred to. : Examples thereof include acyl groups. such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o- bromobenzyloxycarbonyl, (mono-=, di- and tri-) Sa IE chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert- butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 4- (phenylazo)benzyloxy- carbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, TT leucyl, l-adamantyloxycarbonyl, 8-quinolyloxycarbonyl
Amended Sheet - 2003-07-30
: and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkane- or allene-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di- lower alkylamino-lower alkylidene groups such as N,N- dimethylaminomethylene and the like; ar-lower alkylidene groups such as benzylidene, 2- ’
Ce hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, .2- cee hydroxy-l-naphthylmethylene and the like; nitrogen- containing heterocyclic alkylidene groups such as 3-
IE hydroxy-4-pyridylmethylene and the like: cycloalkylidene groups such as cyclohexylidene, 2- ethoxycarbonylcyclohexylidene, 2- ethoxycarbonylcyclopentylidene, 2- oo acetylcyclohexylidene, 3,3-dimethyl-5- oo oxycyclohexylidene and the like; di-aryl or di-ar-lower alkyl phosphoryl groups such as diphenyl phosphoryl, dibenzyl phosphoryl and the like; oxygen-containing
Ce 20 heterocyclic alkyl groups such as 5-methyl-2-oxo0=2H- RE 1,3-dioxol-4-ylmethyl and the like; and lower alkyl- substituted silyl groups such as trimethylsilyl group and the like.
As protecting group for hydroxyl group and mercapto group, all the groups conventionally usable for protection of hydroxyl groups can be referred to.
Examples thereof include acyl groups such as TT benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-
Amended Sheet — 2003-07-30
: bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1- dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2- trichlorethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-(phenylsulfonyl)- ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, ’ oo .. . 2-furfuryloxycarbonyl, l-adamantyloxycarbonyl, EE os -vinyloxycarbonyl, allyloxycarbonyl, S- benzylthiocarbonyl, 4-ethoxy-l-naphthyloxycarbonyl, 8- - quinoclyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the : : 15 like; lower alkyl groups such as methyl, tert-butyl,
So 2,2,2-trichlorethyl, 2-trimethylsilylethyl and the like; lower alkenyl groups such as allyl and the like; ar-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the 20: like; oxygen-containing and sulfur-containing deli vo heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2- : trichlorethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, : l-ethoxyethyl and the like; alkane- or allene-sulfonyl ST groups such as methanesulfonyl, p-toluenesulfonyl and
Amended Sheet — 2003-07-30 the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl, diphenylmethylsilyl, tert- butylmethoxyphenylsilyl and the like; substituted aryl groups such as hydroquinone, p-methoxyphenol and the like; enol-ether groups such as (2-methyl-3-oxo-1- cyclopenten-1-yl) and the like. :
SE RE As protecting groups for carbamoyl group,.all.. .. : 10 the groups conventionally usable for protection of carbamoyl group can be referred to. Examples thereof include ar-lower alkyl groups such as benzyl, 4-- a methoxybenzyl, 2,4-dimethoxybenzyl and the like; lower : alkoxyalkyl groups such as methoxymethyl and the like; : 15 ar-lower alkoxy groups such as benzyloxymethyl and the ~~ like; substituted silyl lower alkoxy-lower alkyl groups such as tert-butyldimethylsiloxymethyl and the like; : lower alkoxy groups such as methoxy and the like; ar- lower alkoxy groups such as benzyloxy and the like; lower alkylthio groups such as methylthio, Co : oe triphenylmethylthio and the like; ar-lower alkylthio groups such as benzylthio and the like; substituted silyl groups such as tert-butyldimethylsilyl and the like; aryl groups such as 4-methoxyphenyl, 4- : 25 methoxymethylphenyl, 2-methoxy-l-naphthyl and the like; acyl groups such as trichloroethoxycarbonyl, trifluoroacetyl, tert-butoxycarbonyl and the like; etc. oT
As the substituent for the hydroxyl group
Amended Sheet — 2003-07-30 represented by R’, R', R®, R®, 2%, 2’, 2‘ and 2° which may be substituted, a protected or unprotected carboxyl group, a lower alkyl group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a halogeno-lower alkyl group and a : heterocyclic group can be referred toc. One or more kinds selected from these substituents may be used for the substitution. :
TLL ..... As the substituent for the amino group... ... ER represented by R’, R', R®, R%, 2%, 2’, z' and 2° which may be substituted, a protected or unprotected carboxyl, hydroxyl, amino and lower alkylamino groups, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a halogeno-lower alkyl group and a heterocyclic group can be referred to. one or more substituents selected from the above-mentioned
Co groups may be used for the substitution. : As the substituent for the phenylsulfanyl ‘group, phenylsulfinyl group and phenylsulfonyl group len represented by R*, lower alkyl groups such as methyl, ethyl and the like can be referred to.
As the salts of the compounds of general formulas [1], usually known salts at the site of basic group such as amino group, etc. and salts at the site of acidic group such as hydroxyl group, phosphoryl group, carboxyl group, etc. can be referred to. The CT salts at the site of basic group include, for example,
Amended Sheet — 2003-07-30
Claims (8)
1. A pyrazine derivative represented by the following general formula: Y TSE : R?—0 Al Sy © (CH,) 4 wherein R' represents a hydrogen atom or a halogen atom; ~ R? represents a hydrogen atom; R® and R® represent a hydrogen atom; R* and R® represent a substituted or } unsubstituted, protected or unprotected hydroxyl group; A represents an oxygen atom; n represents 0; and Y : represents an oxygen atom,or a salt thereof.
2. A pyrazine derivative or a salt thereof according to Claim 1, wherein R' and R® represent a hydroxyl group.
C3 + A:.pyrazine derivative ar. a salt thereof : SO according to any one of Claims 1-2, wherein R' represents a hydrogen atom or a fluorine atom.
4. A pharmaceutical composition comprising a compound or a salt thereof according to any one of Claims 1-3.
5. A pharmaceutical composition according to Claim 4, wherein said pharmaceutical composition is an oT antiviral agent. Amended Sheet — 2003-07-30
~~ L 2
. 6. A pharmaceutical composition according to Claim S, wherein the virus is influenza virus, RS : virus, AIDS virus, papilloma virus, adenovirus, hepatitis virus A, hepatitis virus B, hepatitis virus C, poliovirus, echo virus, coxsackie virus, enterovirus, rhinovirus, rotavirus, newcastle disease virus, mumps virus, vesicular stomatitis virus, and Japanese encephalitis virus. : SE 7. A pharmaceutical composition according to ER } Claim 6, wherein said virus is influenza virus.
8. A pharmaceutical composition according to Claim 6, wherein said virus is hepatitis virus C. Amended Sheet — 2003-07-30 d .
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| CN101230043B (en) * | 2008-02-18 | 2010-11-24 | 靳广毅 | 3-oxide-2-methylamide derivatives as well as preparation method and use thereof |
| US8586741B2 (en) * | 2009-01-28 | 2013-11-19 | Nippon Soda Co., Ltd. | Method for producing dichloropyrazine derivative |
| CN102775358B (en) * | 2012-08-22 | 2015-05-27 | 山东齐都药业有限公司 | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide |
| CN103833812A (en) * | 2012-11-23 | 2014-06-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Pyrazine derivative and medical application thereof |
| CN104496917B (en) * | 2014-12-15 | 2017-06-20 | 南京华威医药科技开发有限公司 | A kind of synthetic method of Favipiravir |
| CN106866553B (en) * | 2017-03-28 | 2020-02-04 | 中南大学 | Synthesis method of Favipiravir |
| CN113248450B (en) * | 2020-02-07 | 2024-04-12 | 北京四环制药有限公司 | Fapila preparation method of pyrrosia lingua |
| CN112300083B (en) * | 2020-04-20 | 2021-08-03 | 常州制药厂有限公司 | Preparation method of Favipiravir |
| WO2021255681A1 (en) * | 2020-06-17 | 2021-12-23 | Hikal Limited | A simple process for the preparation of favipiravir and its intermediates thereof |
| CN116003372B (en) * | 2022-09-14 | 2024-08-06 | 多氟多新材料股份有限公司 | Preparation method of fluoroethylene carbonate |
| CN115536599B (en) * | 2022-09-26 | 2024-06-25 | 合肥利夫生物科技有限公司 | Preparation method of fampicin intermediate 3, 6-difluoro-2-pyrazinecarbonitrile |
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| US4518599A (en) * | 1982-09-30 | 1985-05-21 | Merck & Co., Inc. | 2-Amino-3-cyano-5-halo-6-(substituted)pyrazine |
| DE3374863D1 (en) * | 1982-11-12 | 1988-01-21 | Merck & Co Inc | Substituted nitropyrazine compounds, process for their preparation and pharmaceutical compositions containing them |
| US4609659A (en) * | 1985-01-16 | 1986-09-02 | Merck & Co., Inc. | 2,6-disubstituted derivatives of 3-nitropyrazines useful as adjuncts to radiation therapy |
| DE59209008D1 (en) * | 1991-08-17 | 1997-12-11 | Hoechst Ag | 2-fluoropyrazines, process for their preparation and their use in liquid-crystalline mixtures |
| JPH10262691A (en) * | 1997-03-24 | 1998-10-06 | Mitsubishi Chem Corp | Production of 3-hydroxy nitrogen-containing 6-membered ring compound |
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