JP2010515760A - 抗ウイルス性ヌクレオシド類似体 - Google Patents
抗ウイルス性ヌクレオシド類似体 Download PDFInfo
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- JP2010515760A JP2010515760A JP2009545720A JP2009545720A JP2010515760A JP 2010515760 A JP2010515760 A JP 2010515760A JP 2009545720 A JP2009545720 A JP 2009545720A JP 2009545720 A JP2009545720 A JP 2009545720A JP 2010515760 A JP2010515760 A JP 2010515760A
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- Prior art keywords
- alkyl
- substituted
- aryl
- compound according
- alkenyl
- Prior art date
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- 230000000840 anti-viral effect Effects 0.000 title abstract description 7
- 229940127073 nucleoside analogue Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 217
- 208000036142 Viral infection Diseases 0.000 claims abstract description 23
- 230000009385 viral infection Effects 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims abstract description 10
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims abstract description 10
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 8
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 6
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 5
- 241001115402 Ebolavirus Species 0.000 claims abstract description 4
- 241001466953 Echovirus Species 0.000 claims abstract description 4
- 241000709661 Enterovirus Species 0.000 claims abstract description 4
- 241000991587 Enterovirus C Species 0.000 claims abstract description 4
- 241000700647 Variola virus Species 0.000 claims abstract description 4
- 241000710886 West Nile virus Species 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 125
- -1 NH 2 Chemical group 0.000 claims description 113
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 77
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 66
- 229940002612 prodrug Drugs 0.000 claims description 57
- 239000000651 prodrug Substances 0.000 claims description 57
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 51
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000003342 alkenyl group Chemical group 0.000 claims description 36
- 125000000304 alkynyl group Chemical group 0.000 claims description 34
- 125000003107 substituted aryl group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 30
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 30
- 125000002252 acyl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 26
- 241001465754 Metazoa Species 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 235000000346 sugar Nutrition 0.000 claims description 16
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 13
- 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 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 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 claims description 12
- 229960000329 ribavirin Drugs 0.000 claims description 12
- 125000000539 amino acid group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000002777 nucleoside Substances 0.000 claims description 11
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 11
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 claims description 11
- 108010047761 Interferon-alpha Proteins 0.000 claims description 10
- 102000006992 Interferon-alpha Human genes 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 9
- 239000001226 triphosphate Substances 0.000 claims description 9
- 235000011178 triphosphate Nutrition 0.000 claims description 9
- 230000003612 virological effect Effects 0.000 claims description 9
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 8
- 108020000999 Viral RNA Proteins 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 239000001177 diphosphate Substances 0.000 claims description 7
- 235000011180 diphosphates Nutrition 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 238000001727 in vivo Methods 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- GERSIKCSWYDFSJ-UHFFFAOYSA-N 1,2,4-triazine-5-carboxylic acid Chemical compound OC(=O)C1=CN=NC=N1 GERSIKCSWYDFSJ-UHFFFAOYSA-N 0.000 claims description 4
- IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- KDKMTIRSYIHSTB-MROZADKFSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=S KDKMTIRSYIHSTB-MROZADKFSA-N 0.000 claims description 3
- NJYXSKVOTDPOAT-LMVFSUKVSA-N (2r,3r,4r)-2-fluoro-3,4,5-trihydroxypentanal Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](F)C=O NJYXSKVOTDPOAT-LMVFSUKVSA-N 0.000 claims description 3
- LFRDGHVRPSURMV-YFKPBYRVSA-N (4s)-4,5-dihydroxypentanal Chemical compound OC[C@@H](O)CCC=O LFRDGHVRPSURMV-YFKPBYRVSA-N 0.000 claims description 3
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 claims description 3
- AAJXJLYUWKMQNO-UHFFFAOYSA-N 4-chloro-2-(1,2-oxazol-5-yl)phenol Chemical compound OC1=CC=C(Cl)C=C1C1=CC=NO1 AAJXJLYUWKMQNO-UHFFFAOYSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 3
- 230000000340 anti-metabolite Effects 0.000 claims description 3
- 229940100197 antimetabolite Drugs 0.000 claims description 3
- 239000002256 antimetabolite Substances 0.000 claims description 3
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 3
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 3
- OSBKZZCHLHZCDB-PBXRRBTRSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxy-2-methylpentanal Chemical compound O=C[C@@](O)(C)[C@H](O)[C@H](O)CO OSBKZZCHLHZCDB-PBXRRBTRSA-N 0.000 claims description 2
- SQXRWAVEVYDDBF-LMVFSUKVSA-N (2r,3r,4r)-2-fluoro-3,4,5-trihydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](F)C=S SQXRWAVEVYDDBF-LMVFSUKVSA-N 0.000 claims description 2
- ANFWGLPWDSXJEH-CRCLSJGQSA-N (3s,4r)-3,4,5-trihydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](O)CC=S ANFWGLPWDSXJEH-CRCLSJGQSA-N 0.000 claims description 2
- MJMJUKHABPJQGX-CRCLSJGQSA-N (3s,4r)-3-fluoro-4,5-dihydroxypentanal Chemical compound OC[C@@H](O)[C@@H](F)CC=O MJMJUKHABPJQGX-CRCLSJGQSA-N 0.000 claims description 2
- JBFNVLCLNHQXCH-CRCLSJGQSA-N (3s,4r)-3-fluoro-4,5-dihydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](F)CC=S JBFNVLCLNHQXCH-CRCLSJGQSA-N 0.000 claims description 2
- LPXOUBDTZSHIOQ-UHFFFAOYSA-N 1,2,4-triazine-5-carbonitrile Chemical compound N#CC1=CN=NC=N1 LPXOUBDTZSHIOQ-UHFFFAOYSA-N 0.000 claims description 2
- IJIHMDVMMUTJEJ-UHFFFAOYSA-N 1,2,4-triazine-5-carboxamide Chemical compound NC(=O)C1=CN=NC=N1 IJIHMDVMMUTJEJ-UHFFFAOYSA-N 0.000 claims description 2
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical compound O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 claims description 2
- OIEIKVCEXBMETK-BYPYZUCNSA-N 2-[(1s)-1,2-dihydroxyethoxy]acetaldehyde Chemical compound OC[C@@H](O)OCC=O OIEIKVCEXBMETK-BYPYZUCNSA-N 0.000 claims description 2
- VQKBTEBRZHBIGE-BYPYZUCNSA-N 2-[(1s)-1,2-dihydroxyethyl]sulfanylacetaldehyde Chemical compound OC[C@@H](O)SCC=O VQKBTEBRZHBIGE-BYPYZUCNSA-N 0.000 claims description 2
- NGWKEVMCTIVMBA-UHFFFAOYSA-N 2-fluoro-4-(hydroxymethyl)pyrrolidin-3-ol Chemical compound OCC1CNC(F)C1O NGWKEVMCTIVMBA-UHFFFAOYSA-N 0.000 claims description 2
- DITIGNGDSVRJFX-UHFFFAOYSA-N 3-(hydroxymethyl)-4-methylidenecyclopentane-1,2-diol Chemical compound OCC1C(O)C(O)CC1=C DITIGNGDSVRJFX-UHFFFAOYSA-N 0.000 claims description 2
- WQSIEHZPHQVPFS-UHFFFAOYSA-N 3-fluoro-4-(hydroxymethyl)pyrrolidin-2-ol Chemical compound OCC1CNC(O)C1F WQSIEHZPHQVPFS-UHFFFAOYSA-N 0.000 claims description 2
- UKDQIWLEEJYIDQ-UHFFFAOYSA-N 4-(hydroxymethyl)pyrrolidine-2,3-diol Chemical compound OCC1CNC(O)C1O UKDQIWLEEJYIDQ-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229940121740 Inosine monophosphate dehydrogenase inhibitor Drugs 0.000 claims description 2
- 229940122055 Serine protease inhibitor Drugs 0.000 claims description 2
- 101710102218 Serine protease inhibitor Proteins 0.000 claims description 2
- 108010078233 Thymalfasin Proteins 0.000 claims description 2
- 102400000800 Thymosin alpha-1 Human genes 0.000 claims description 2
- GAADRFVRUBFCML-UHFFFAOYSA-N [2-(hydroxymethyl)cyclobutyl]methanol Chemical compound OCC1CCC1CO GAADRFVRUBFCML-UHFFFAOYSA-N 0.000 claims description 2
- WUMYBFXWUJTWTB-UHFFFAOYSA-N [hydroxy(methoxy)phosphoryl] phosphono hydrogen phosphate Chemical compound COP(O)(=O)OP(O)(=O)OP(O)(O)=O WUMYBFXWUJTWTB-UHFFFAOYSA-N 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- LMYOLOWXQDLHKQ-UHFFFAOYSA-N cyclopent-2-en-1-ylmethanol Chemical compound OCC1CCC=C1 LMYOLOWXQDLHKQ-UHFFFAOYSA-N 0.000 claims description 2
- RGAPPBGFFPGONM-CRCLSJGQSA-N diazonio-[(2s,3s)-1,2-dihydroxy-5-sulfanylidenepentan-3-yl]azanide Chemical compound OC[C@@H](O)[C@H](CC=S)N=[N+]=[N-] RGAPPBGFFPGONM-CRCLSJGQSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 229940125697 hormonal agent Drugs 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- DZONTPIFZFRSGP-UHFFFAOYSA-N methyl triazine-5-carboxylate Chemical compound COC(=O)C1=CN=NN=C1 DZONTPIFZFRSGP-UHFFFAOYSA-N 0.000 claims description 2
- 150000004712 monophosphates Chemical group 0.000 claims description 2
- 229930014626 natural product Natural products 0.000 claims description 2
- QOTUIIJRVXKSJU-UHFFFAOYSA-N pyrrolidin-3-ylmethanol Chemical compound OCC1CCNC1 QOTUIIJRVXKSJU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003001 serine protease inhibitor Substances 0.000 claims description 2
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 claims description 2
- 229950006081 taribavirin Drugs 0.000 claims description 2
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 claims description 2
- 229960004231 thymalfasin Drugs 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 4
- 229940124683 HCV polymerase inhibitor Drugs 0.000 claims 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims 2
- NJYXSKVOTDPOAT-WDCZJNDASA-N (2s,3r,4r)-2-fluoro-3,4,5-trihydroxypentanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](F)C=O NJYXSKVOTDPOAT-WDCZJNDASA-N 0.000 claims 1
- SQXRWAVEVYDDBF-WDCZJNDASA-N (2s,3r,4r)-2-fluoro-3,4,5-trihydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@H](F)C=S SQXRWAVEVYDDBF-WDCZJNDASA-N 0.000 claims 1
- XFBDCPQESJYXPC-YFKPBYRVSA-N (4s)-4,5-dihydroxypentanethial Chemical compound OC[C@@H](O)CCC=S XFBDCPQESJYXPC-YFKPBYRVSA-N 0.000 claims 1
- UADBLZFWTJHOJC-UHFFFAOYSA-N 2-(hydroxymethyl)cyclopentan-1-ol Chemical compound OCC1CCCC1O UADBLZFWTJHOJC-UHFFFAOYSA-N 0.000 claims 1
- DWROYQTVCUQGJR-UHFFFAOYSA-N 3-(hydroxymethyl)cyclopent-3-ene-1,2-diol Chemical compound OCC1=CCC(O)C1O DWROYQTVCUQGJR-UHFFFAOYSA-N 0.000 claims 1
- BSQXZHMREYHKOM-UHFFFAOYSA-N 4-(hydroxymethyl)pyrrolidin-3-ol Chemical compound OCC1CNCC1O BSQXZHMREYHKOM-UHFFFAOYSA-N 0.000 claims 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 claims 1
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 33
- 241000700605 Viruses Species 0.000 abstract description 10
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- 238000010189 synthetic method Methods 0.000 abstract description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 235000019439 ethyl acetate Nutrition 0.000 description 80
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
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- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 238000004440 column chromatography Methods 0.000 description 38
- 239000007787 solid Substances 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000004480 active ingredient Substances 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
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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
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
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- Life Sciences & Earth Sciences (AREA)
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- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| US88027807P | 2007-01-12 | 2007-01-12 | |
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| SI (1) | SI2114980T1 (enExample) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013535453A (ja) * | 2010-07-22 | 2013-09-12 | ギリード・サイエンシズ・インコーポレーテッド | パラミクソウイルス科ウイルス感染症を治療するための方法及び化合物 |
| JP2016504284A (ja) * | 2012-11-16 | 2016-02-12 | バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | 抗ウイルス性アザ糖を含有するヌクレオシド |
| JP2017186358A (ja) * | 2014-10-29 | 2017-10-12 | ギリアード サイエンシーズ， インコーポレイテッド | フィロウイルス科ウイルス感染症を処置するための方法 |
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| NZ599404A (en) * | 2009-09-21 | 2014-02-28 | Gilead Sciences Inc | Processes and intermediates for the preparation of 1’-substituted carba-nucleoside analogs |
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| JP2013535453A (ja) * | 2010-07-22 | 2013-09-12 | ギリード・サイエンシズ・インコーポレーテッド | パラミクソウイルス科ウイルス感染症を治療するための方法及び化合物 |
| JP2016216480A (ja) * | 2010-07-22 | 2016-12-22 | ギリード・サイエンシズ・インコーポレーテッド | パラミクソウイルス科ウイルス感染症を治療するための方法及び化合物 |
| JP2016504284A (ja) * | 2012-11-16 | 2016-02-12 | バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | 抗ウイルス性アザ糖を含有するヌクレオシド |
| JP2017186358A (ja) * | 2014-10-29 | 2017-10-12 | ギリアード サイエンシーズ， インコーポレイテッド | フィロウイルス科ウイルス感染症を処置するための方法 |
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| WO2008089105A2 (en) | 2008-07-24 |
| WO2008089105A3 (en) | 2008-09-12 |
| EP2114980B1 (en) | 2012-06-27 |
| PL2114980T3 (pl) | 2012-11-30 |
| HK1138286A1 (en) | 2010-08-20 |
| PH12012502284A1 (en) | 2015-10-12 |
| NZ598927A (en) | 2013-09-27 |
| AU2008206406A1 (en) | 2008-07-24 |
| IL199664A0 (en) | 2010-04-15 |
| SI2114980T1 (sl) | 2012-11-30 |
| SG177974A1 (en) | 2012-02-28 |
| DK2114980T3 (da) | 2012-09-24 |
| EP2535345A1 (en) | 2012-12-19 |
| HRP20120758T1 (hr) | 2012-10-31 |
| US20100015094A1 (en) | 2010-01-21 |
| MX2009007333A (es) | 2009-08-31 |
| CY1113282T1 (el) | 2016-04-13 |
| CA2674589A1 (en) | 2008-07-24 |
| CN101611046A (zh) | 2009-12-23 |
| ES2390188T3 (es) | 2012-11-07 |
| NZ578556A (en) | 2012-04-27 |
| EP2114980A2 (en) | 2009-11-11 |
| US8440813B2 (en) | 2013-05-14 |
| PT2114980E (pt) | 2012-09-25 |
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