CA2717173A1 - Antiviral therapeutic agents - Google Patents
Antiviral therapeutic agents Download PDFInfo
- Publication number
- CA2717173A1 CA2717173A1 CA2717173A CA2717173A CA2717173A1 CA 2717173 A1 CA2717173 A1 CA 2717173A1 CA 2717173 A CA2717173 A CA 2717173A CA 2717173 A CA2717173 A CA 2717173A CA 2717173 A1 CA2717173 A1 CA 2717173A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- compound
- substituted
- aryl
- prodrug
- 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.)
- Abandoned
Links
- 239000003814 drug Substances 0.000 title claims description 25
- 230000000840 anti-viral effect Effects 0.000 title description 8
- 229940124597 therapeutic agent Drugs 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 286
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 239000003443 antiviral agent Substances 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 174
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 229940002612 prodrug Drugs 0.000 claims description 89
- 239000000651 prodrug Substances 0.000 claims description 89
- 150000003839 salts Chemical class 0.000 claims description 78
- -1 SO2-alkyl Chemical group 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 61
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 44
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 44
- 229910052760 oxygen Inorganic materials 0.000 claims description 39
- 125000002252 acyl group Chemical group 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- 125000003342 alkenyl group Chemical group 0.000 claims description 32
- 125000000304 alkynyl group Chemical group 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 28
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 229910052740 iodine Inorganic materials 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 25
- 208000036142 Viral infection Diseases 0.000 claims description 24
- 230000009385 viral infection Effects 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 241001465754 Metazoa Species 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000003107 substituted aryl group Chemical group 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 235000000346 sugar Nutrition 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 239000002777 nucleoside Substances 0.000 claims description 13
- 125000000464 thioxo group Chemical group S=* 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
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 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
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 239000001226 triphosphate Substances 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 10
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 10
- 230000003612 virological effect Effects 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims description 9
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 7
- 108020000999 Viral RNA Proteins 0.000 claims description 7
- 239000001177 diphosphate Substances 0.000 claims description 7
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 7
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 7
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 239000003112 inhibitor Substances 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
- 208000005176 Hepatitis C Diseases 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000003835 nucleoside group Chemical group 0.000 claims description 5
- 230000000069 prophylactic effect Effects 0.000 claims description 5
- 230000001225 therapeutic effect Effects 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
- 235000011178 triphosphate Nutrition 0.000 claims description 5
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 241000710886 West Nile virus Species 0.000 claims description 4
- 208000002672 hepatitis B Diseases 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 3
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims description 3
- 241001115402 Ebolavirus Species 0.000 claims description 3
- 241001466953 Echovirus Species 0.000 claims description 3
- 241000709661 Enterovirus Species 0.000 claims description 3
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 208000000474 Poliomyelitis Diseases 0.000 claims description 3
- 241000700647 Variola virus Species 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
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 229930014626 natural product Natural products 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- OSBKZZCHLHZCDB-PBXRRBTRSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxy-2-methylpentanal Chemical group O=C[C@@](O)(C)[C@H](O)[C@H](O)CO OSBKZZCHLHZCDB-PBXRRBTRSA-N 0.000 claims description 2
- KDKMTIRSYIHSTB-MROZADKFSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxypentanethial Chemical group OC[C@@H](O)[C@@H](O)[C@@H](O)C=S KDKMTIRSYIHSTB-MROZADKFSA-N 0.000 claims description 2
- NJYXSKVOTDPOAT-LMVFSUKVSA-N (2r,3r,4r)-2-fluoro-3,4,5-trihydroxypentanal Chemical group OC[C@@H](O)[C@@H](O)[C@@H](F)C=O NJYXSKVOTDPOAT-LMVFSUKVSA-N 0.000 claims description 2
- SQXRWAVEVYDDBF-LMVFSUKVSA-N (2r,3r,4r)-2-fluoro-3,4,5-trihydroxypentanethial Chemical group OC[C@@H](O)[C@@H](O)[C@@H](F)C=S SQXRWAVEVYDDBF-LMVFSUKVSA-N 0.000 claims description 2
- NJYXSKVOTDPOAT-WDCZJNDASA-N (2s,3r,4r)-2-fluoro-3,4,5-trihydroxypentanal Chemical group OC[C@@H](O)[C@@H](O)[C@H](F)C=O NJYXSKVOTDPOAT-WDCZJNDASA-N 0.000 claims description 2
- 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 description 2
- PYMIDWYUQAHNQK-WHFBIAKZSA-N (2s,4s)-2-fluoro-4,5-dihydroxypentanal Chemical group OC[C@@H](O)C[C@H](F)C=O PYMIDWYUQAHNQK-WHFBIAKZSA-N 0.000 claims description 2
- BKNVTPUCZNUJMP-WHFBIAKZSA-N (2s,4s)-2-fluoro-4,5-dihydroxypentanethial Chemical compound OC[C@@H](O)C[C@H](F)C=S BKNVTPUCZNUJMP-WHFBIAKZSA-N 0.000 claims description 2
- ANFWGLPWDSXJEH-CRCLSJGQSA-N (3s,4r)-3,4,5-trihydroxypentanethial Chemical group 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 group 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
- LFRDGHVRPSURMV-YFKPBYRVSA-N (4s)-4,5-dihydroxypentanal Chemical group OC[C@@H](O)CCC=O LFRDGHVRPSURMV-YFKPBYRVSA-N 0.000 claims description 2
- XFBDCPQESJYXPC-YFKPBYRVSA-N (4s)-4,5-dihydroxypentanethial Chemical compound OC[C@@H](O)CCC=S XFBDCPQESJYXPC-YFKPBYRVSA-N 0.000 claims description 2
- UADBLZFWTJHOJC-UHFFFAOYSA-N 2-(hydroxymethyl)cyclopentan-1-ol Chemical group OCC1CCCC1O UADBLZFWTJHOJC-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
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-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
- NTSRIMQXXYCAGF-UHFFFAOYSA-N 2-fluoro-5-(hydroxymethyl)cyclopentan-1-ol Chemical group OCC1CCC(F)C1O NTSRIMQXXYCAGF-UHFFFAOYSA-N 0.000 claims description 2
- DITIGNGDSVRJFX-UHFFFAOYSA-N 3-(hydroxymethyl)-4-methylidenecyclopentane-1,2-diol Chemical group OCC1C(O)C(O)CC1=C DITIGNGDSVRJFX-UHFFFAOYSA-N 0.000 claims description 2
- DWROYQTVCUQGJR-UHFFFAOYSA-N 3-(hydroxymethyl)cyclopent-3-ene-1,2-diol Chemical group OCC1=CCC(O)C1O DWROYQTVCUQGJR-UHFFFAOYSA-N 0.000 claims description 2
- MZQHDBUGKAFSOC-UHFFFAOYSA-N 3-(hydroxymethyl)cyclopentane-1,2-diol Chemical group OCC1CCC(O)C1O MZQHDBUGKAFSOC-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 group OCC1CNC(O)C1O UKDQIWLEEJYIDQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229930010555 Inosine Natural products 0.000 claims description 2
- 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 2
- 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 2
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- 108010022999 Serine Proteases Proteins 0.000 claims description 2
- GAADRFVRUBFCML-UHFFFAOYSA-N [2-(hydroxymethyl)cyclobutyl]methanol Chemical compound OCC1CCC1CO GAADRFVRUBFCML-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
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Chemical group OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Chemical group OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 2
- LMYOLOWXQDLHKQ-UHFFFAOYSA-N cyclopent-2-en-1-ylmethanol Chemical group OCC1CCC=C1 LMYOLOWXQDLHKQ-UHFFFAOYSA-N 0.000 claims description 2
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical group OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 claims description 2
- CCRXJMDIIXJVIC-CRCLSJGQSA-N diazonio-[(2s,3s)-1,2-dihydroxy-5-oxopentan-3-yl]azanide Chemical compound OC[C@@H](O)[C@H](CC=O)N=[N+]=[N-] CCRXJMDIIXJVIC-CRCLSJGQSA-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
- 229940125697 hormonal agent Drugs 0.000 claims description 2
- 229960003786 inosine Drugs 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 150000004712 monophosphates Chemical group 0.000 claims description 2
- QOTUIIJRVXKSJU-UHFFFAOYSA-N pyrrolidin-3-ylmethanol Chemical group OCC1CCNC1 QOTUIIJRVXKSJU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 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
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 8
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 4
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- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims 2
- BORAVSBFYTYKOE-UHFFFAOYSA-N 4-(hydroxymethyl)cyclopenten-1-ol Chemical group OCC1CC=C(O)C1 BORAVSBFYTYKOE-UHFFFAOYSA-N 0.000 claims 1
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- 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 1
- 229960004231 thymalfasin Drugs 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 17
- 238000010189 synthetic method Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- 238000010511 deprotection reaction Methods 0.000 description 117
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 230000015572 biosynthetic process Effects 0.000 description 64
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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| US61/079,370 | 2008-07-09 | ||
| PCT/US2009/036213 WO2009111653A2 (en) | 2008-03-05 | 2009-03-05 | Antiviral therapeutic agents |
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| EP2155758B1 (en) | 2007-05-10 | 2012-08-22 | Biocryst Pharmaceuticals, Inc. | Tetrahydrofuro[3,4-d]dioxolane compounds for use in the treatment of viral infections and cancer |
| US20090247750A1 (en) * | 2008-03-28 | 2009-10-01 | Biocryst Pharmaceuticals, Inc. | Process for preparing nucleoside analogs |
| CN102046626A (zh) | 2008-04-23 | 2011-05-04 | 吉里德科学公司 | 用于抗病毒治疗的carba-核苷类似物 |
| EP2313102A2 (en) | 2008-07-03 | 2011-04-27 | Biota Scientific Management | Bycyclic nucleosides and nucleotides as therapeutic agents |
| DK2480559T3 (da) | 2009-09-21 | 2013-08-05 | Gilead Sciences Inc | Fremgangsmåder og mellemprodukter til fremstillingen af 1'-cyano-carbanukleosid-analoger |
| TW201201815A (en) | 2010-05-28 | 2012-01-16 | Gilead Sciences Inc | 1'-substituted-carba-nucleoside prodrugs for antiviral treatment |
| PH12013500033A1 (en) | 2010-07-19 | 2017-07-26 | Gilead Sciences Inc | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
| MA34470B1 (fr) | 2010-07-22 | 2013-08-01 | Gilead Sciences Inc | Procédés et composés pour traiter des infections à virus paramyxoviridae |
| BR112013009029B1 (pt) | 2010-10-15 | 2021-06-29 | Biocryst Pharmaceuticals, Inc. | Métodos e composições para inibição de polimerase |
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- 2009-03-05 AU AU2009221770A patent/AU2009221770A1/en not_active Abandoned
- 2009-03-05 JP JP2010549889A patent/JP2011525171A/ja not_active Withdrawn
- 2009-03-05 PE PE2009000334A patent/PE20091727A1/es not_active Application Discontinuation
- 2009-03-05 BR BRPI0910388A patent/BRPI0910388A2/pt not_active IP Right Cessation
- 2009-03-05 CA CA2717173A patent/CA2717173A1/en not_active Abandoned
- 2009-03-05 WO PCT/US2009/036213 patent/WO2009111653A2/en not_active Ceased
- 2009-03-05 US US12/398,866 patent/US7994139B2/en not_active Expired - Fee Related
- 2009-03-05 CN CN2009801168793A patent/CN102834513A/zh active Pending
- 2009-03-05 MX MX2010009646A patent/MX2010009646A/es not_active Application Discontinuation
- 2009-03-05 KR KR1020107022136A patent/KR20100137494A/ko not_active Withdrawn
- 2009-03-05 NZ NZ588179A patent/NZ588179A/xx not_active IP Right Cessation
- 2009-03-05 AR ARP090100788A patent/AR071745A1/es not_active Application Discontinuation
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2010
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2011
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| MX2010009646A (es) | 2010-09-28 |
| US20090227524A1 (en) | 2009-09-10 |
| EP2265275A2 (en) | 2010-12-29 |
| IL207826A0 (en) | 2010-12-30 |
| WO2009111653A3 (en) | 2011-09-22 |
| KR20100137494A (ko) | 2010-12-30 |
| AU2009221770A1 (en) | 2009-09-11 |
| TW200942243A (en) | 2009-10-16 |
| PE20091727A1 (es) | 2009-12-04 |
| US20120142617A1 (en) | 2012-06-07 |
| AR071745A1 (es) | 2010-07-14 |
| BRPI0910388A2 (pt) | 2019-06-11 |
| US7994139B2 (en) | 2011-08-09 |
| EA201070988A1 (ru) | 2011-12-30 |
| WO2009111653A2 (en) | 2009-09-11 |
| NZ588179A (en) | 2012-09-28 |
| JP2011525171A (ja) | 2011-09-15 |
| CN102834513A (zh) | 2012-12-19 |
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