DE69933860T2 - 2'-fluoronukleoside - Google Patents
2'-fluoronukleoside Download PDFInfo
- Publication number
- DE69933860T2 DE69933860T2 DE69933860T DE69933860T DE69933860T2 DE 69933860 T2 DE69933860 T2 DE 69933860T2 DE 69933860 T DE69933860 T DE 69933860T DE 69933860 T DE69933860 T DE 69933860T DE 69933860 T2 DE69933860 T2 DE 69933860T2
- Authority
- DE
- Germany
- Prior art keywords
- use according
- fluoro
- purine
- acyl
- mmol
- 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.)
- Expired - Lifetime
Links
- -1 sulfonate ester Chemical class 0.000 claims abstract description 65
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 22
- 239000010452 phosphate Substances 0.000 claims abstract description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 19
- 150000002632 lipids Chemical class 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims abstract description 17
- 229940002612 prodrug Drugs 0.000 claims abstract description 17
- 239000000651 prodrug Substances 0.000 claims abstract description 17
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000001226 triphosphate Substances 0.000 claims abstract description 9
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 8
- 239000001177 diphosphate Substances 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011178 triphosphate Nutrition 0.000 claims abstract description 8
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims abstract description 8
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 7
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 7
- 150000004712 monophosphates Chemical class 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 238000001727 in vivo Methods 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 208000010710 hepatitis C virus infection Diseases 0.000 claims abstract description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229940104302 cytosine Drugs 0.000 claims description 14
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 12
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims description 12
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 12
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 11
- 229960000643 adenine Drugs 0.000 claims description 9
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims description 8
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 7
- 229930024421 Adenine Natural products 0.000 claims description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 6
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims description 6
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229940113082 thymine Drugs 0.000 claims description 6
- 229940035893 uracil Drugs 0.000 claims description 6
- 229960004413 flucytosine Drugs 0.000 claims description 5
- 229960002949 fluorouracil Drugs 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 3
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 229940024606 amino acid Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 2
- MGAXHFMCFLLMNG-UHFFFAOYSA-N 1h-pyrimidine-6-thione Chemical compound SC1=CC=NC=N1 MGAXHFMCFLLMNG-UHFFFAOYSA-N 0.000 claims description 2
- SVXNJCYYMRMXNM-UHFFFAOYSA-N 5-amino-2h-1,2,4-triazin-3-one Chemical compound NC=1C=NNC(=O)N=1 SVXNJCYYMRMXNM-UHFFFAOYSA-N 0.000 claims description 2
- HXXVIKZQIFTJOQ-UHFFFAOYSA-N 5-ethenylpyrimidine Chemical compound C=CC1=CN=CN=C1 HXXVIKZQIFTJOQ-UHFFFAOYSA-N 0.000 claims description 2
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 2
- NOYDQGFVFOQSAJ-UHFFFAOYSA-N 5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=CN=C1 NOYDQGFVFOQSAJ-UHFFFAOYSA-N 0.000 claims description 2
- PVRBGBGMDLPYKG-UHFFFAOYSA-N 6-benzyl-7h-purine Chemical compound N=1C=NC=2N=CNC=2C=1CC1=CC=CC=C1 PVRBGBGMDLPYKG-UHFFFAOYSA-N 0.000 claims description 2
- DBCMWACNZJYUHS-UHFFFAOYSA-N 6-ethenyl-7h-purine Chemical compound C=CC1=NC=NC2=C1NC=N2 DBCMWACNZJYUHS-UHFFFAOYSA-N 0.000 claims description 2
- 229930010555 Inosine Natural products 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229960003786 inosine Drugs 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 claims description 2
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 claims description 2
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims 3
- VBYYJZIWKPTMIE-UHFFFAOYSA-N 2-chloropurin-2-amine Chemical compound NC1(Cl)N=CC2=NC=NC2=N1 VBYYJZIWKPTMIE-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 20
- 206010028980 Neoplasm Diseases 0.000 abstract description 11
- 201000011510 cancer Diseases 0.000 abstract description 8
- 208000002672 hepatitis B Diseases 0.000 abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 abstract description 2
- 235000012000 cholesterol Nutrition 0.000 abstract description 2
- 230000002159 abnormal effect Effects 0.000 abstract 1
- 230000004663 cell proliferation Effects 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 182
- 239000002777 nucleoside Substances 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 55
- 239000000203 mixture Substances 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 50
- 230000015572 biosynthetic process Effects 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 125000003835 nucleoside group Chemical group 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 230000000694 effects Effects 0.000 description 33
- 229910052757 nitrogen Inorganic materials 0.000 description 32
- 239000000460 chlorine Substances 0.000 description 30
- 238000000034 method Methods 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- 229910052799 carbon Inorganic materials 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 21
- 150000003833 nucleoside derivatives Chemical class 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 241000725303 Human immunodeficiency virus Species 0.000 description 18
- 230000000840 anti-viral effect Effects 0.000 description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 239000011737 fluorine Substances 0.000 description 16
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 15
- 235000021317 phosphate Nutrition 0.000 description 14
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 12
- 235000000346 sugar Nutrition 0.000 description 12
- 241000711549 Hepacivirus C Species 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000010409 thin film Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 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 10
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 125000003729 nucleotide group Chemical group 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 7
- 239000003443 antiviral agent Substances 0.000 description 7
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- 229940079593 drug Drugs 0.000 description 7
- 150000002148 esters Chemical group 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 208000006454 hepatitis Diseases 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 6
- 230000036436 anti-hiv Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 150000001720 carbohydrates Chemical group 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 5
- 239000002841 Lewis acid Substances 0.000 description 5
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 5
- 239000004599 antimicrobial Substances 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 150000007517 lewis acids Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000002212 purine nucleoside Substances 0.000 description 5
- 150000003230 pyrimidines Chemical class 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- UNZUPHARAVPLBJ-HCLVMJGWSA-N 1-[(2R,3R,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-fluorooxolan-2-yl]-5-fluoropyrimidine-2,4-dione Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OC[C@H]1C[C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)F)F UNZUPHARAVPLBJ-HCLVMJGWSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 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 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
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- 238000002512 chemotherapy Methods 0.000 description 4
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- JTEGQNOMFQHVDC-UHFFFAOYSA-N 4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1OC(CO)SC1 JTEGQNOMFQHVDC-UHFFFAOYSA-N 0.000 description 3
- UNRIYCIDCQDGQE-UHFFFAOYSA-N 6-chloro-2-fluoro-7h-purine Chemical compound FC1=NC(Cl)=C2NC=NC2=N1 UNRIYCIDCQDGQE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D473/00—Heterocyclic compounds containing purine ring systems
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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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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- 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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Landscapes
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- Chemical & Material Sciences (AREA)
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- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Silicon Polymers (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
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| US75893P | 1998-02-25 | ||
| US8056998P | 1998-04-03 | 1998-04-03 | |
| US80569P | 1998-04-03 | ||
| PCT/US1999/004051 WO1999043691A1 (en) | 1998-02-25 | 1999-02-25 | 2'-fluoronucleosides |
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| DE69933860D1 DE69933860D1 (de) | 2006-12-14 |
| DE69933860T2 true DE69933860T2 (de) | 2007-05-31 |
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| US5703058A (en) | 1995-01-27 | 1997-12-30 | Emory University | Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent |
| IL138037A0 (en) * | 1998-02-25 | 2001-10-31 | Univ Emory | 2'-fluoronucleosides |
| HUP0301112A3 (en) | 2000-02-18 | 2005-04-28 | Shire Biochem Inc Laval | Method for the treatment or prevention of flavivirus infections using nucleoside analogues |
| US7094770B2 (en) | 2000-04-13 | 2006-08-22 | Pharmasset, Ltd. | 3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections |
| MY164523A (en) * | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| CZ301182B6 (cs) * | 2000-05-26 | 2009-12-02 | Idenix (Cayman) Limited | Použití nukleosidových derivátu pro výrobu farmaceutických prostredku pro lécení infekcí vyvolaných flaviviry a pestiviry |
| FR2810319A1 (fr) * | 2000-06-15 | 2001-12-21 | Ppg Sipsy | Composes alpha-phenylsulfinyl-alpha-halogeno-butyrolactone et halogeno-2-buten-2-olide-4 utiles pour la preparation de composes halogeno-2-oxymethyl-4-furanone (4h) |
| US20030008841A1 (en) * | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
| KR101005299B1 (ko) * | 2000-10-18 | 2011-01-04 | 파마셋 인코포레이티드 | 바이러스 감염 및 비정상적인 세포 증식의 치료를 위한 변형된 뉴클레오시드 |
| US8481712B2 (en) | 2001-01-22 | 2013-07-09 | Merck Sharp & Dohme Corp. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
| US7105499B2 (en) * | 2001-01-22 | 2006-09-12 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
| HUP0400726A3 (en) * | 2001-01-22 | 2007-05-29 | Merck & Co Inc | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
| US6900315B2 (en) | 2001-02-06 | 2005-05-31 | Yale University | 2-amino-9H-purin-9-yl compounds and methods for inhibiting/treating HIV infections and AIDS related symptoms |
| RU2003129164A (ru) | 2001-03-01 | 2005-03-20 | Фармассет Лтд. (Bb) | Способ синтеза 2`,3`-дидезокси-2`,3`-дидегидронуклеозидов |
| WO2002069903A2 (en) * | 2001-03-06 | 2002-09-12 | Biocryst Pharmaceuticals, Inc. | Nucleosides, preparation thereof and use as inhibitors of rna viral polymerases |
| GB0112617D0 (en) * | 2001-05-23 | 2001-07-18 | Hoffmann La Roche | Antiviral nucleoside derivatives |
| GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
| JP2005503358A (ja) | 2001-06-22 | 2005-02-03 | フアーマセツト・リミテツド | β−2’−または3’−ハロヌクレオシド |
| WO2003026589A2 (en) * | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating hepatitis c virus using 4'-modified nucleosides |
| US7049303B2 (en) * | 2001-11-07 | 2006-05-23 | Medical Research Council | Inhibition of viruses |
| WO2003063771A2 (en) * | 2001-12-14 | 2003-08-07 | Pharmasset Ltd. | N4-acylcytosine nucleosides for treatment of viral iinfections |
| US20040002476A1 (en) * | 2002-02-14 | 2004-01-01 | Stuyver Lieven J. | Modified fluorinated nucleoside analogues |
| US7608600B2 (en) * | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| CN101172993A (zh) * | 2002-06-28 | 2008-05-07 | 埃迪尼克斯(开曼)有限公司 | 用于治疗黄病毒感染的2′-c-甲基-3′-o-l-缬氨酸酯核糖呋喃基胞苷 |
| TW200500375A (en) | 2002-06-28 | 2005-01-01 | Idenix Cayman Ltd | Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae |
| WO2004002422A2 (en) * | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | 2’-c-methyl-3’-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| US20040067877A1 (en) | 2002-08-01 | 2004-04-08 | Schinazi Raymond F. | 2', 3'-Dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections |
| IL166640A0 (en) | 2002-08-01 | 2006-01-15 | Pharmasset Ltd | Compounds with the bicyclo Ä4.2.1Ü nonane system for the treatment of flaviviridae infections |
| US6884880B2 (en) * | 2002-08-21 | 2005-04-26 | Ash Stevens, Inc. | Process for the preparation of 9-β-anomeric nucleoside analogs |
| US7902203B2 (en) * | 2002-11-01 | 2011-03-08 | Abbott Laboratories, Inc. | Anti-infective agents |
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- 1999-02-25 WO PCT/US1999/004051 patent/WO1999043691A1/en not_active Ceased
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- 1999-02-25 JP JP2000533443A patent/JP2002504558A/ja active Pending
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- 1999-02-25 AU AU27871/99A patent/AU2787199A/en not_active Abandoned
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- 1999-02-25 DK DK99908437T patent/DK1058686T3/da active
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