TW201242974A - Compounds - Google Patents
Compounds Download PDFInfo
- Publication number
- TW201242974A TW201242974A TW100143959A TW100143959A TW201242974A TW 201242974 A TW201242974 A TW 201242974A TW 100143959 A TW100143959 A TW 100143959A TW 100143959 A TW100143959 A TW 100143959A TW 201242974 A TW201242974 A TW 201242974A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- hydrogen
- iii
- group
- fluorenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 293
- 241000711549 Hepacivirus C Species 0.000 claims abstract description 57
- 241000725619 Dengue virus Species 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 804
- 239000001257 hydrogen Substances 0.000 claims description 468
- 229910052739 hydrogen Inorganic materials 0.000 claims description 468
- 150000002431 hydrogen Chemical class 0.000 claims description 365
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 175
- 125000003118 aryl group Chemical group 0.000 claims description 173
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 169
- 239000000203 mixture Substances 0.000 claims description 161
- -1 amino fluorenyl group Chemical group 0.000 claims description 142
- 150000003839 salts Chemical class 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 95
- 229910052799 carbon Inorganic materials 0.000 claims description 84
- 239000002207 metabolite Substances 0.000 claims description 84
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 83
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 72
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 70
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 65
- 241000700605 Viruses Species 0.000 claims description 60
- 125000005843 halogen group Chemical group 0.000 claims description 52
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 51
- 239000003814 drug Substances 0.000 claims description 46
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000006239 protecting group Chemical group 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 30
- 150000002923 oximes Chemical class 0.000 claims description 30
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 239000012038 nucleophile Substances 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 26
- 125000001624 naphthyl group Chemical group 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 24
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 24
- 150000001412 amines Chemical class 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- PBZULRQYJBYFPM-UHFFFAOYSA-N O=P1OC=CO1 Chemical compound O=P1OC=CO1 PBZULRQYJBYFPM-UHFFFAOYSA-N 0.000 claims description 14
- 150000001540 azides Chemical class 0.000 claims description 14
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 14
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
- 241000283690 Bos taurus Species 0.000 claims description 13
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 12
- 206010012310 Dengue fever Diseases 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- 208000025729 dengue disease Diseases 0.000 claims description 11
- 229920002554 vinyl polymer Polymers 0.000 claims description 11
- 101000585507 Solanum tuberosum Cytochrome b-c1 complex subunit 7 Proteins 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- 230000003612 virological effect Effects 0.000 claims description 10
- 229940126062 Compound A Drugs 0.000 claims description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
- 239000007789 gas Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 208000001490 Dengue Diseases 0.000 claims description 8
- 241000709661 Enterovirus Species 0.000 claims description 8
- 241000710772 Yellow fever virus Species 0.000 claims description 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 8
- 229940051021 yellow-fever virus Drugs 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 241000710886 West Nile virus Species 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 7
- 239000000052 vinegar Substances 0.000 claims description 7
- 235000021419 vinegar Nutrition 0.000 claims description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 241000710842 Japanese encephalitis virus Species 0.000 claims description 6
- JZTPOMIFAFKKSK-UHFFFAOYSA-N O-phosphonohydroxylamine Chemical compound NOP(O)(O)=O JZTPOMIFAFKKSK-UHFFFAOYSA-N 0.000 claims description 6
- 206010036790 Productive cough Diseases 0.000 claims description 6
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 210000003802 sputum Anatomy 0.000 claims description 6
- 208000024794 sputum Diseases 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 241000991587 Enterovirus C Species 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 5
- 230000003834 intracellular effect Effects 0.000 claims description 5
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 239000001226 triphosphate Substances 0.000 claims description 5
- 235000011178 triphosphate Nutrition 0.000 claims description 5
- 241000282320 Panthera leo Species 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- OHRBIPDRQWZHPM-UHFFFAOYSA-N 5H-dioxaphosphole Chemical compound P=1OOCC1 OHRBIPDRQWZHPM-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 239000013522 chelant Substances 0.000 claims description 3
- 229910052805 deuterium Inorganic materials 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 230000000087 stabilizing effect Effects 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 claims description 3
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000005001 aminoaryl group Chemical group 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 2
- 208000010710 hepatitis C virus infection Diseases 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 2
- XQBLMOCHFJXAAJ-UHFFFAOYSA-N 2-oxo-11alpha-senecionyl-5beta,6alpha,7alpha(H)-guaia-3,10-dien-6,12-olide Natural products CC(=CC(=O)OC1(C)C2CCC(=C3C(C2OC1=O)C(=CC3=O)C)C)C XQBLMOCHFJXAAJ-UHFFFAOYSA-N 0.000 claims 1
- 239000004135 Bone phosphate Substances 0.000 claims 1
- SYZOFRXZMALRGI-JYJNAYRXSA-N CC1=C(NCC(F)(F)F)C(=O)N(C=C1)[C@@H](CC1CC1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)C#N Chemical compound CC1=C(NCC(F)(F)F)C(=O)N(C=C1)[C@@H](CC1CC1)C(=O)N[C@@H](C[C@@H]1CCNC1=O)C#N SYZOFRXZMALRGI-JYJNAYRXSA-N 0.000 claims 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 244000166124 Eucalyptus globulus Species 0.000 claims 1
- DRGILVWCDWIXFC-UHFFFAOYSA-N O=P1OCC=CO1 Chemical compound O=P1OCC=CO1 DRGILVWCDWIXFC-UHFFFAOYSA-N 0.000 claims 1
- 101001077374 Oryza sativa subsp. japonica UMP-CMP kinase 3 Proteins 0.000 claims 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 claims 1
- 235000011613 Pinus brutia Nutrition 0.000 claims 1
- 241000018646 Pinus brutia Species 0.000 claims 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims 1
- 239000012907 medicinal substance Substances 0.000 claims 1
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims 1
- 210000000278 spinal cord Anatomy 0.000 claims 1
- 150000003568 thioethers Chemical class 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- 239000002777 nucleoside Substances 0.000 abstract description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 236
- 239000000243 solution Substances 0.000 description 212
- 238000002360 preparation method Methods 0.000 description 131
- 235000019439 ethyl acetate Nutrition 0.000 description 122
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 239000002904 solvent Substances 0.000 description 80
- 239000012071 phase Substances 0.000 description 55
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 52
- 229910001868 water Inorganic materials 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- 101150041968 CDC13 gene Proteins 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 32
- 239000012267 brine Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- 235000018102 proteins Nutrition 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 239000003112 inhibitor Substances 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 229940123066 Polymerase inhibitor Drugs 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 14
- 238000004679 31P NMR spectroscopy Methods 0.000 description 13
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 125000003835 nucleoside group Chemical group 0.000 description 13
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 13
- 239000002609 medium Substances 0.000 description 12
- 150000003833 nucleoside derivatives Chemical class 0.000 description 12
- 239000002773 nucleotide Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 11
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 125000003729 nucleotide group Chemical group 0.000 description 11
- 229910052698 phosphorus Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 239000003443 antiviral agent Substances 0.000 description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- 239000011574 phosphorus Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
- 101710144111 Non-structural protein 3 Proteins 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 150000001768 cations Chemical class 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229940035893 uracil Drugs 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000710831 Flavivirus Species 0.000 description 6
- 101710172711 Structural protein Proteins 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000004104 aryloxy group Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- TTZHDVOVKQGIBA-YBSJRAAASA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-YBSJRAAASA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804417A (zh) * | 2012-11-13 | 2014-05-21 | 北京美倍他药物研究有限公司 | 抗乙肝病毒药物 |
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| SI2604620T2 (sl) | 2003-05-30 | 2024-10-30 | Gilead Pharmasset Llc | Modificirani fluorirani nukleozidni analogi |
| US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
| US8716263B2 (en) * | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
| PL3290428T3 (pl) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tabletka zawierająca krystaliczny (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropirymidyn-1(2H)-ylo)-4-fluoro-3-hydroksy-4-metylotetrahydrofuran-2-ylo)metoksy)(fenoksy)fosforylo)amino)propanian izopropylu |
| EP2646453A1 (en) | 2010-11-30 | 2013-10-09 | Gilead Pharmasset LLC | Compounds |
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-
2011
- 2011-11-30 EP EP11794350.6A patent/EP2646453A1/en not_active Withdrawn
- 2011-11-30 JP JP2013542138A patent/JP6069215B2/ja not_active Expired - Fee Related
- 2011-11-30 CA CA2818853A patent/CA2818853A1/en not_active Abandoned
- 2011-11-30 AU AU2011336632A patent/AU2011336632B2/en not_active Ceased
- 2011-11-30 TW TW100143959A patent/TW201242974A/zh unknown
- 2011-11-30 PT PT16152130T patent/PT3042910T/pt unknown
- 2011-11-30 US US13/307,256 patent/US8841275B2/en active Active
- 2011-11-30 AR ARP110104450A patent/AR084044A1/es not_active Application Discontinuation
- 2011-11-30 WO PCT/US2011/062643 patent/WO2012075140A1/en not_active Ceased
- 2011-11-30 EP EP16152130.7A patent/EP3042910B1/en active Active
- 2011-11-30 ES ES16152130T patent/ES2716158T3/es active Active
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2014
- 2014-07-15 US US14/332,255 patent/US9394331B2/en active Active
-
2016
- 2016-02-26 JP JP2016036456A patent/JP6286462B2/ja not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804417A (zh) * | 2012-11-13 | 2014-05-21 | 北京美倍他药物研究有限公司 | 抗乙肝病毒药物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3042910A3 (en) | 2016-09-07 |
| US8841275B2 (en) | 2014-09-23 |
| AU2011336632A1 (en) | 2013-05-02 |
| JP2016138120A (ja) | 2016-08-04 |
| WO2012075140A1 (en) | 2012-06-07 |
| AU2011336632B2 (en) | 2015-09-03 |
| JP2013544286A (ja) | 2013-12-12 |
| AR084044A1 (es) | 2013-04-17 |
| ES2716158T3 (es) | 2019-06-10 |
| PT3042910T (pt) | 2019-04-16 |
| EP3042910B1 (en) | 2019-01-09 |
| US20120142626A1 (en) | 2012-06-07 |
| JP6286462B2 (ja) | 2018-02-28 |
| US9394331B2 (en) | 2016-07-19 |
| EP2646453A1 (en) | 2013-10-09 |
| EP3042910A2 (en) | 2016-07-13 |
| JP6069215B2 (ja) | 2017-02-01 |
| CA2818853A1 (en) | 2012-06-07 |
| US20150018300A1 (en) | 2015-01-15 |
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