ES2963716T3 - Profármacos de nucleósido fosforamidato - Google Patents
Profármacos de nucleósido fosforamidato Download PDFInfo
- Publication number
- ES2963716T3 ES2963716T3 ES14169060T ES14169060T ES2963716T3 ES 2963716 T3 ES2963716 T3 ES 2963716T3 ES 14169060 T ES14169060 T ES 14169060T ES 14169060 T ES14169060 T ES 14169060T ES 2963716 T3 ES2963716 T3 ES 2963716T3
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- Prior art keywords
- virus
- alkyl
- compound
- infection
- dmso
- 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.)
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- 229940002612 prodrug Drugs 0.000 title abstract description 7
- 239000000651 prodrug Substances 0.000 title abstract description 7
- -1 Nucleoside phosphoramidate Chemical class 0.000 title description 75
- 239000002777 nucleoside Substances 0.000 title description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 208000036142 Viral infection Diseases 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 4
- 230000009385 viral infection Effects 0.000 claims abstract description 4
- 208000015181 infectious disease Diseases 0.000 claims description 23
- 241000700605 Viruses Species 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 12
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 11
- 241000711549 Hepacivirus C Species 0.000 claims description 10
- 239000003443 antiviral agent Substances 0.000 claims description 10
- 241000725619 Dengue virus Species 0.000 claims description 6
- 241000709661 Enterovirus Species 0.000 claims description 6
- 241000710842 Japanese encephalitis virus Species 0.000 claims description 6
- 241000710772 Yellow fever virus Species 0.000 claims description 6
- 229940051021 yellow-fever virus Drugs 0.000 claims description 6
- 241000709721 Hepatovirus A Species 0.000 claims description 5
- 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 5
- 241000710886 West Nile virus Species 0.000 claims description 5
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229960000329 ribavirin Drugs 0.000 claims description 5
- 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 5
- 208000000474 Poliomyelitis Diseases 0.000 claims description 4
- 229940127073 nucleoside analogue Drugs 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 3
- 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 3
- 229950006081 taribavirin Drugs 0.000 claims description 3
- 241000991587 Enterovirus C Species 0.000 claims description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 28
- 241000124008 Mammalia Species 0.000 abstract description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 125000001800 methanetriyl group Chemical group C(*)(*)* 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 125000003342 alkenyl group Chemical group 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- 239000000460 chlorine Substances 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 229910052731 fluorine Inorganic materials 0.000 description 27
- 229910052801 chlorine Inorganic materials 0.000 description 26
- 229910052794 bromium Inorganic materials 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
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- 230000002829 reductive effect Effects 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000000304 alkynyl group Chemical group 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 17
- 229910052740 iodine Inorganic materials 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 125000002252 acyl group Chemical group 0.000 description 16
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- 229910052739 hydrogen Inorganic materials 0.000 description 15
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- 241000711557 Hepacivirus Species 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
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- 229910052698 phosphorus Inorganic materials 0.000 description 12
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- 239000011541 reaction mixture Substances 0.000 description 11
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 10
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
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- 125000001188 haloalkyl group Chemical group 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- ARKKGZQTGXJVKW-VPCXQMTMSA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ARKKGZQTGXJVKW-VPCXQMTMSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
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- 125000001424 substituent group Chemical group 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 108700026244 Open Reading Frames Proteins 0.000 description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
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- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 7
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- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
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- 108010076039 Polyproteins Proteins 0.000 description 5
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 5
- 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 5
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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- 125000004122 cyclic group Chemical group 0.000 description 4
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Applications Claiming Priority (3)
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| US90931507P | 2007-03-30 | 2007-03-30 | |
| US98230907P | 2007-10-24 | 2007-10-24 | |
| US12/053,015 US7964580B2 (en) | 2007-03-30 | 2008-03-21 | Nucleoside phosphoramidate prodrugs |
Publications (1)
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| ES2963716T3 true ES2963716T3 (es) | 2024-04-01 |
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| ES08732818T Active ES2492470T5 (en) | 2007-03-30 | 2008-03-26 | Nucleoside phosphoramidate prodrugs |
| ES14169060T Active ES2963716T3 (es) | 2007-03-30 | 2008-03-26 | Profármacos de nucleósido fosforamidato |
| ES14179358T Active ES2745462T3 (es) | 2007-03-30 | 2008-03-26 | Composición que comprende un inhibidor de NS3 proteasa de VHC y un profármaco de fosforamidato de nucleósido de 2'-desoxi-2'fluoro-2'-C-metiluridina |
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| ES08732818T Active ES2492470T5 (en) | 2007-03-30 | 2008-03-26 | Nucleoside phosphoramidate prodrugs |
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| ES14179358T Active ES2745462T3 (es) | 2007-03-30 | 2008-03-26 | Composición que comprende un inhibidor de NS3 proteasa de VHC y un profármaco de fosforamidato de nucleósido de 2'-desoxi-2'fluoro-2'-C-metiluridina |
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