WO1999051619A1 - Arabinofuranosyl benzimidazoles comme agents antiviraux - Google Patents
Arabinofuranosyl benzimidazoles comme agents antiviraux Download PDFInfo
- Publication number
- WO1999051619A1 WO1999051619A1 PCT/US1999/007308 US9907308W WO9951619A1 WO 1999051619 A1 WO1999051619 A1 WO 1999051619A1 US 9907308 W US9907308 W US 9907308W WO 9951619 A1 WO9951619 A1 WO 9951619A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- benzimidazole
- dichloro
- compounds
- Prior art date
Links
- -1 Arabinofuranosyl benzimidazoles Chemical class 0.000 title claims abstract description 80
- 239000003443 antiviral agent Substances 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 162
- 238000000034 method Methods 0.000 claims abstract description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 51
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- BSDCIRGNJKZPFV-CHWFTXMASA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-5-(2,5,6-trichlorobenzimidazol-1-yl)oxolane-3,4-diol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Cl BSDCIRGNJKZPFV-CHWFTXMASA-N 0.000 claims abstract description 10
- FMPHEGJDUSHUMB-CHWFTXMASA-N (2s,3s,4s,5r)-2-(1h-benzimidazol-2-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=NC2=CC=CC=C2N1 FMPHEGJDUSHUMB-CHWFTXMASA-N 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 91
- 230000009385 viral infection Effects 0.000 claims description 34
- 208000036142 Viral infection Diseases 0.000 claims description 33
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 13
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 230000005727 virus proliferation Effects 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 208000006454 hepatitis Diseases 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 206010011831 Cytomegalovirus infection Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 208000037803 restenosis Diseases 0.000 claims description 6
- 241000701074 Human alphaherpesvirus 2 Species 0.000 claims description 4
- 230000007170 pathology Effects 0.000 claims description 4
- 108091033319 polynucleotide Proteins 0.000 claims description 3
- 239000002157 polynucleotide Substances 0.000 claims description 3
- 102000040430 polynucleotide Human genes 0.000 claims description 3
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims description 2
- 102000002068 Glycopeptides Human genes 0.000 claims description 2
- 108010015899 Glycopeptides Proteins 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims description 2
- 206010057212 Hepatitis viral infections Diseases 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 206010019972 Herpes viral infections Diseases 0.000 claims 3
- 208000010710 hepatitis C virus infection Diseases 0.000 claims 1
- 230000029812 viral genome replication Effects 0.000 abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 150000002431 hydrogen Chemical class 0.000 abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000004480 active ingredient Substances 0.000 description 35
- 241000700605 Viruses Species 0.000 description 33
- 238000009472 formulation Methods 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 241000282414 Homo sapiens Species 0.000 description 18
- 239000002777 nucleoside Substances 0.000 description 17
- 241000711549 Hepacivirus C Species 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000011282 treatment Methods 0.000 description 15
- 231100000135 cytotoxicity Toxicity 0.000 description 13
- 230000003013 cytotoxicity Effects 0.000 description 13
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 12
- 241001529453 unidentified herpesvirus Species 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 150000001556 benzimidazoles Chemical class 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 229960002963 ganciclovir Drugs 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 9
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 241000700721 Hepatitis B virus Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000006071 cream Substances 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 8
- 201000006747 infectious mononucleosis Diseases 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- 229960002555 zidovudine Drugs 0.000 description 8
- 241000701083 Bovine alphaherpesvirus 1 Species 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 241000701093 Suid alphaherpesvirus 1 Species 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 108020004707 nucleic acids Proteins 0.000 description 7
- 102000039446 nucleic acids Human genes 0.000 description 7
- 150000007523 nucleic acids Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229960005102 foscarnet Drugs 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- KEZMBKQTCPNSOF-UHFFFAOYSA-N 2-bromo-5,6-dichloro-1h-benzimidazole Chemical compound C1=C(Cl)C(Cl)=CC2=C1NC(Br)=N2 KEZMBKQTCPNSOF-UHFFFAOYSA-N 0.000 description 5
- XHSQDZXAVJRBMX-DDHJBXDOSA-N 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1 XHSQDZXAVJRBMX-DDHJBXDOSA-N 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 208000007514 Herpes zoster Diseases 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 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 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 241000700584 Simplexvirus Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 235000019197 fats Nutrition 0.000 description 5
- 125000003843 furanosyl group Chemical group 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- SUQYOUJCBGMSLV-UHFFFAOYSA-N 2,5,6-trichloro-1h-benzimidazole Chemical compound ClC1=C(Cl)C=C2NC(Cl)=NC2=C1 SUQYOUJCBGMSLV-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 241000701027 Human herpesvirus 6 Species 0.000 description 4
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 208000002672 hepatitis B Diseases 0.000 description 4
- 210000005260 human cell Anatomy 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 125000003835 nucleoside group Chemical group 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 201000006082 Chickenpox Diseases 0.000 description 3
- 208000005176 Hepatitis C Diseases 0.000 description 3
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 3
- HMFHBZSHGGEWLO-HWQSCIPKSA-N L-arabinofuranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@H]1O HMFHBZSHGGEWLO-HWQSCIPKSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 206010046980 Varicella Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000004264 monolayer culture Methods 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- BSDCIRGNJKZPFV-GWOFURMSSA-N (2r,3s,4r,5r)-2-(hydroxymethyl)-5-(2,5,6-trichlorobenzimidazol-1-yl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Cl BSDCIRGNJKZPFV-GWOFURMSSA-N 0.000 description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MTVWFVDWRVYDOR-UHFFFAOYSA-N 3,4-Dihydroxyphenylglycol Chemical compound OCC(O)C1=CC=C(O)C(O)=C1 MTVWFVDWRVYDOR-UHFFFAOYSA-N 0.000 description 2
- IPRDZAMUYMOJTA-UHFFFAOYSA-N 5,6-dichloro-1h-benzimidazole Chemical compound C1=C(Cl)C(Cl)=CC2=C1NC=N2 IPRDZAMUYMOJTA-UHFFFAOYSA-N 0.000 description 2
- 241000700585 Bovine alphaherpesvirus 2 Species 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000037952 HSV-1 infection Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241000701043 Lymphocryptovirus Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 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 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 208000005252 hepatitis A Diseases 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- NMAMPJIAXSGTLN-GWOFURMSSA-N (2r,3r,4s,5r)-2-(2-bromo-5,6-dichlorobenzimidazol-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Br NMAMPJIAXSGTLN-GWOFURMSSA-N 0.000 description 1
- FMPHEGJDUSHUMB-ZNSHCXBVSA-N (2r,3s,4s,5r)-2-(1h-benzimidazol-2-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@H]1C1=NC2=CC=CC=C2N1 FMPHEGJDUSHUMB-ZNSHCXBVSA-N 0.000 description 1
- VQJDOEMQZNKEMJ-WISYIIOYSA-N (2r,3s,4s,5r)-2-(benzimidazol-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=CC=CC=C2N=C1 VQJDOEMQZNKEMJ-WISYIIOYSA-N 0.000 description 1
- XHSQDZXAVJRBMX-SGUBAKSOSA-N (2r,3s,5r)-2-(5,6-dichlorobenzimidazol-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@H]1C(O)[C@@H](CO)O[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1 XHSQDZXAVJRBMX-SGUBAKSOSA-N 0.000 description 1
- BMLMGCPTLHPWPY-REOHCLBHSA-N (4R)-2-oxo-4-thiazolidinecarboxylic acid Chemical compound OC(=O)[C@@H]1CSC(=O)N1 BMLMGCPTLHPWPY-REOHCLBHSA-N 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical class C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- KGDABCRHPADRLP-FEFKUCBWSA-N 1-[(2r,3s,4r,5r)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)oxolan-2-yl]-2,5,6-trichlorobenzimidazole Chemical compound C([C@H]1O[C@H]([C@H]([C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)N1C2=CC(Cl)=C(Cl)C=C2N=C1Cl)OCC1=CC=CC=C1 KGDABCRHPADRLP-FEFKUCBWSA-N 0.000 description 1
- RBEXWVGCIBHYAD-HTQZYQBOSA-N 1-[(2r,5r)-4-hydroxy-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C(O)[C@@H](CO)O1 RBEXWVGCIBHYAD-HTQZYQBOSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- ASOMNDIOOKDVDC-UHFFFAOYSA-N 1h-indol-2-yl-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl]methanone Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=CC=C3C=2)CC1 ASOMNDIOOKDVDC-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- PJCQXOISTHKDDB-UHFFFAOYSA-N 2,4,5,6-tetrachloro-1h-benzimidazole Chemical compound ClC1=C(Cl)C=C2NC(Cl)=NC2=C1Cl PJCQXOISTHKDDB-UHFFFAOYSA-N 0.000 description 1
- BOSXUUUAOBZQGK-UHFFFAOYSA-N 2,4,6-trichloro-1h-benzimidazole Chemical compound C1=C(Cl)C=C2NC(Cl)=NC2=C1Cl BOSXUUUAOBZQGK-UHFFFAOYSA-N 0.000 description 1
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BCSLVBZWCFTDPK-UDJQAZALSA-N 2-amino-9-[(2r,3r,4s)-3,4-bis(hydroxymethyl)oxetan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)[C@H]1CO BCSLVBZWCFTDPK-UDJQAZALSA-N 0.000 description 1
- SCBFBAWJWLXVHS-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-2-(hydroxymethyl)butyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CC(CO)CCO)C=N2 SCBFBAWJWLXVHS-UHFFFAOYSA-N 0.000 description 1
- WSOKCAFQLYHTKH-UHFFFAOYSA-N 2-bromo-4,5,6-trichloro-1h-benzimidazole Chemical compound ClC1=C(Cl)C(Cl)=CC2=C1N=C(Br)N2 WSOKCAFQLYHTKH-UHFFFAOYSA-N 0.000 description 1
- QNGCATRZCQIDLA-UHFFFAOYSA-N 2-bromo-4,6-dichloro-1h-benzimidazole Chemical compound ClC1=CC(Cl)=C2NC(Br)=NC2=C1 QNGCATRZCQIDLA-UHFFFAOYSA-N 0.000 description 1
- AYPSHJCKSDNETA-UHFFFAOYSA-N 2-chloro-1h-benzimidazole Chemical class C1=CC=C2NC(Cl)=NC2=C1 AYPSHJCKSDNETA-UHFFFAOYSA-N 0.000 description 1
- SFAAOBGYWOUHLU-UHFFFAOYSA-N 2-ethylhexyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CC)CCCC SFAAOBGYWOUHLU-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- WUUGFSXJNOTRMR-IOSLPCCCSA-N 5'-S-methyl-5'-thioadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-IOSLPCCCSA-N 0.000 description 1
- MJVDZXWFJQYHIU-UHFFFAOYSA-N 5,6-dibromo-1h-benzimidazole Chemical compound C1=C(Br)C(Br)=CC2=C1NC=N2 MJVDZXWFJQYHIU-UHFFFAOYSA-N 0.000 description 1
- WTEBTXWQAAHZCX-XLNBVVSQSA-N 5-[(e)-2-bromoethenyl]-1-[(2r,4r)-2-(hydroxymethyl)-1,3-oxathiolan-4-yl]pyrimidine-2,4-dione Chemical class S1[C@H](CO)OC[C@@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 WTEBTXWQAAHZCX-XLNBVVSQSA-N 0.000 description 1
- WKVDSZYIGHLONN-RRKCRQDMSA-N 5-chloro-1-[(2r,4s,5r)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](F)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Cl)=C1 WKVDSZYIGHLONN-RRKCRQDMSA-N 0.000 description 1
- WUUGFSXJNOTRMR-UHFFFAOYSA-N 5alpha-Hydroxy-3abeta,5beta,8-trimethyl-1-(1,5-dimethyl-hexen-(4)-yl)-4abetaH,7abetaH-dicyclopentano[a.d]cyclooctaen-(8) Natural products OC1C(O)C(CSC)OC1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N 9-[3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 208000014912 Central Nervous System Infections Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- HMFHBZSHGGEWLO-ZRMNMSDTSA-N D-arabinofuranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H]1O HMFHBZSHGGEWLO-ZRMNMSDTSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- HOOWCUZPEFNHDT-UHFFFAOYSA-N DHPG Natural products OC(=O)C(N)C1=CC(O)=CC(O)=C1 HOOWCUZPEFNHDT-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 241001466953 Echovirus Species 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 201000005866 Exanthema Subitum Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000701047 Gallid alphaherpesvirus 2 Species 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019791 Hepatitis post transfusion Diseases 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 241000175212 Herpesvirales Species 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 125000003264 L-arabinofuranosyl group Chemical group [H]OC([H])([H])[C@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]1([H])O[H] 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000283923 Marmota monax Species 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 208000035999 Recurrence Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 206010051497 Rhinotracheitis Diseases 0.000 description 1
- 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 description 1
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 102000007501 Thymosin Human genes 0.000 description 1
- 108010046075 Thymosin Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108010021119 Trichosanthin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- IHNHAHWGVLXCCI-FDYHWXHSSA-N [(2r,3r,4r,5s)-3,4,5-triacetyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O IHNHAHWGVLXCCI-FDYHWXHSSA-N 0.000 description 1
- RIFVPOHZBSIFRL-IZZDOVSWSA-N [(e)-1-pyridin-2-ylethylideneamino]thiourea Chemical compound NC(=S)N\N=C(/C)C1=CC=CC=N1 RIFVPOHZBSIFRL-IZZDOVSWSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 244000037640 animal pathogen Species 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001113 coital effect Effects 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 231100000223 dermal penetration Toxicity 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004141 dimensional analysis Methods 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 230000000652 homosexual effect Effects 0.000 description 1
- 208000024697 human cytomegalovirus infection Diseases 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940078545 isocetyl stearate Drugs 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002941 microtiter virus yield reduction assay Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000012587 nuclear overhauser effect experiment Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 244000039328 opportunistic pathogen Species 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 150000002926 oxygen Chemical group 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008251 pharmaceutical emulsion Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000002962 plaque-reduction assay Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 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 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 150000008223 ribosides Chemical class 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 231100000337 synergistic cytotoxicity Toxicity 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=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(C)C)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(C)C)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)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000007442 viral DNA synthesis Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 208000010484 vulvovaginitis Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention pertains to the general field of benzimidazole nucleoside analogs and their use as antiviral agents. More particularly, this invention pertains to benzimidazole nucleoside analogs wherein the sugar group is an arabinofuranosyl group and derivatives thereof. The present invention also pertains to methods of making such benzimidazole nucleoside analogs and derivatives, compositions comprising such compounds, the use of such compounds in antiviral treatment.
- viruses infect humans and animals include those belonging to herpes family, such as herpes simplex viruses (HSV) 1 and 2, varicella- zoster (which causes chickenpox and shingles); Epstein-Barr virus (EBV, which causes mononucleosis), and human cytomegalovirus (HCMV), as well as non-herpes viruses such as hepatitis B and C (HBV and HCV).
- Animal viruses include bovine rhinotracheitis virus, Bovine Herpesvirus-1 (BHV-1), and bovine mammillitis virus, among others.
- HSV-1 and HSV-2 have a wide host-cell range, multiply efficiently and rapidly destroy infected cells.
- Others e.g., EBV, HHV6 have a narrow host-cell range or, in the case of HCMV, replicate slowly.
- gancyclovir foscarnet
- cidofivir Three drugs have been widely used for the treatment of HCMV infections: gancyclovir, foscarnet and cidofivir.
- DRB analogs modified on the heterocyclic ring for example, the 2-substituted-5,6-dichloro-benzimidazole ribonucleosides such as 2,5,6- trichloro-l-( ⁇ -D-ribofuranosyl) benzimidazole (TCRB) and 2-bromo-5,6-dichloro-l-( ⁇ -D- ribofuranosyl) benzimidazole (BDCRB), as significant inhibitors of HCMV and this activity was well separated from its cytotoxicity. See for example, the United States Patent No. 5,248,672, issued to Townsend and Drach.
- TCRB 2,5,6- trichloro-l-( ⁇ -D-ribofuranosyl) benzimidazole
- BDCRB 2-bromo-5,6-dichloro-l-( ⁇ -D- ribofuranosyl) benzimidazole
- the present invention provides benzimidazole nucleoside analogs wherein the sugar group is an arabinofuranosyl group or a derivative thereof.
- One embodiment of the present invention pertains to a ⁇ -D-arabinofuranosyl compound of the structure:
- Q is a substituted benzimidazole group attached at the benzimidazole 1 -position, and the 2- substituent of the benzimidazole is a group other than -H;
- R 12 is -OH, -H, halo, -N 3 , or -X-R 13 , wherein X is -O- or -S- and R 13 is an alkyl of 1 to 8 carbon atoms; or a pharmaceutically acceptable salt, prodrug or derivative thereof; provided that: a) when R 10 is -H, R ⁇ is not -H, and the compound is not a ⁇ -compound; and b) the compound is not 2,5,6-trichloro-l-( ⁇ -D-arabinofuranosyl) benzimidazole.
- the compound is a ⁇ -D-arabinofuranosylbenzimidazole compound having the structure:
- R 2 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of:
- R 8 is -H or an alkyl group of 1-8 carbon atoms
- R 12 is -OH, -H, halo, -N 3 , or -X-R 13 , wherein X is -O- or -S- and R 13 is an alkyl group of 1 to 8 carbon atoms; or a pharmaceutically acceptable salt, prodrug or derivative thereof; provided that: a) when each of R 4 , R 5 , R 6 , and R 7 is a hydrogen, R 2 is a group other than hydrogen; b) when R 10 is -H, R n is not -H, and the compound is
- This invention further provides methods of preventing or inhibiting viral replication and/or infection in a cell by contacting the cell with an effective amount of a compound or composition as described herein.
- a cell includes a plurality of cells, including mixtures thereof.
- compositions and methods include the recited elements, but not excluding others.
- Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination.
- a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
- Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention. Embodiments defined by each of these transition terms are within the scope of this invention.
- composition is intended to mean a combination of active agent and another compound or composition, inert or active, such as an adjuvant.
- a “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
- the term "pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting
- compositions also can include stabilizers and preservatives.
- stabilizers and preservatives For examples of carriers, stabilizers and adjuvants, see Martin, REMINGTON'S PHARM. SCI., 15th Ed. (Mack Publ. Co., Easton (1975).
- “Pharmaceutically acceptable salt, prodrug or derivative” as used herein, relate to any pharmaceutically acceptable salt, ester, ether, salt of an ester, solvate, such as ethanolate, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof.
- Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g. , by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
- salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
- acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
- acids such as oxalic
- bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C,_ 4 alkyl.
- salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and unde
- “In vivo” use of a material is defined as introduction of the material into a living human, mammal, or vertebrate.
- “Ex vivo” use of a compound is defined as using a compound for treatment of a biological material outside a living human, mammal, or vertebrate, where that treated biological material is intended for use inside a living human, mammal, or vertebrate.
- removal of blood from a human, and introduction of a compound into that blood is defined as an ex vivo use of that compound if the blood is intended for reintroduction into that human or another human.
- Reintroduction of the human blood into that human or another human would be in vivo use of the blood, as opposed to the ex vivo use of the compound. If the compound is still present in the blood when it is reintroduced into the human, then the compound, in addition to its ex vivo use, is also introduced in vivo.
- salts of the compounds of the present invention will be pharmaceutically acceptable.
- salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
- effective amount includes “prophylactically effective amount” as well as “therapeutically effective amount” and refers to an amount effective in preventing or treating a viral infection in a patient either as monotherapy or in combination with other agents. Effective amounts are easily determined by those of skill in the art and will vary with the cell, virus being effected and the purpose of the treatment. For example, when utilizing the drug in cell culture, it is important that the amount of drug not be cytotoxic to the cells.
- a “prophylactically effective amount” is an amount which inhibits viral infection, reproduction and proliferation in a subject challenged with the virus without toxicity to the cells and subject being treated.
- subject refers to a host such as a mammal, a mouse, bovine, rat or a human patient or a host cell that is virally infected.
- a "cell” is intended to include, but not be limited to a mammalian cell, e.g. , a mouse cell, a bovine cell, a rat cell, a woodchuck cell, a simian cell, or a human cell.
- terapéuticaally effective amount refers to the effective amount for "treatment,” that is, for alleviation of symptoms of a particular disorder in a patient or for the improvement of an ascertainable measurement associated with a particular disorder, for example, a reduction of viral titer in the host.
- treatment that is, for alleviation of symptoms of a particular disorder in a patient or for the improvement of an ascertainable measurement associated with a particular disorder, for example, a reduction of viral titer in the host.
- One of skill in the art can determine when a host has been "treated” by noting a reduction in viral load or an alleviation in symptoms associated with viral infection.
- a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.
- the term "biologically acceptable carrier” refers to a carrier or adjuvant that may be administered to a host or patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver an effective amount of the antiviral compound.
- suitable carriers include liquid phase carriers, such as sterile or aqueous solutions, as well as those described below.
- the compounds of the present invention comprise a benzimidazole group which is attached via the 1 -position to an arabinofuranosyl ring via the 1 '-position.
- the sugar arabinofuranose is characterized by a 2' -OH and 4'-CH 2 OH on the same side of the furanosyl plane and a 3'-OH is on the opposite side of the furanosyl plane.
- the benzimidazole ring is on the same side of the furanosyl plane as the 3' -OH, whereas in the case of 1- ⁇ -arabinofuranosyl benzimidazole, the benzimidazole ring is on the opposite side of the furanosyl plane as the 3'-OH.
- arabinofuranosyl compounds can be ⁇ -D- ⁇ -L, ⁇ -D, or ⁇ -L.
- ⁇ -D-arabinofuranosylbenzimidazoles having the general structure:
- Q is a substituted benzimidazole group attached at the benzimidazole 1 -position, and the 2- substituent of the benzimidazole is a group other than -H;
- the present invention includes the above compounds and their pharmaceutically acceptable salts, prodrugs and derivatives.
- arabinofuranosyl prodrugs of the present invention include, for example, those with chemically protected hydroxyl groups (e.g., with O-acetyl groups), such as 2'-O-acetyl-arabinofuranosyl; 3'-0-acetyl- arabinofuranosyl; 5'-0-acetyl-arabinofuranosyl; 2',3'-di-O-acetyl-arabinofuranosyl and 2',3',5'-tri-0-acetyl-arabinofuranosyl.
- derivatives of a compound as used herein means a chemically modified compound wherein the chemical modification takes place either at a functional group of the compound or on the aromatic ring.
- Non-limiting examples of arabinofuranosyl derivatives of the present invention include N-acetyl, N-methyl, N-hydroxy groups at any of the available nitrogens in the compound. Additional derivatives may include those having a trifluoromethyl group on the benzimidazole ring or on the arabinofuranose ring.
- ⁇ -D-arabinofuranosyl benzimidazole compounds have the following structure:
- R 2 , R 4 , R 5 , R 6 , and R 7 are independently the same or different and are selected from the group consisting of: -H, -F, -Cl, -Br, -I, -NO 2 , -NH 2 , -NHR 8 , - N(R 8 ) 2 , -OR 8 , -SR 8 , and -CF 3 ; wherein R 8 is -H or an alkyl group of 1-8 carbon atoms; and R 10 , R", and R 12 are independently the same or different and are -H or a hydroxyl protecting group; with the proviso that: a) when each of R 4 , R 5 , R 6 , and R 7 is a hydrogen, R 2 is a group other than hydrogen; b) when R 10 is -H, R 11 is not -H, and the compound is not a ⁇ -compound; and c) the compound is not 2,5,6-trichloro-
- alkyl as used herein include, but is not limited to, fully saturated, partially unsaturated, and fully unsaturated hydrocarbyl groups which may be aliphatic, alicyclic, or aromatic.
- R 8 is selected from the group consisting of straight chain, branched or cyclic alkyl groups, including but not limited to, methyl, ethyl, 1 -propyl (i.e., n-propyl), 2-propyl (i.e., iso-propyl), cyclopropyl, 1 -butyl (i.e., n- butyl), 2-butyl (i.e., sec-butyl), 2-methylprop-l-yl, (i.e., iso-butyl) 2-methylprop-2-yl (i.e., tert-butyl), pentyl, isopentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, cyclo
- the present invention includes not only the ⁇ -D-arabinofuranosylbenzimidazoles, but also their ⁇ -D- ⁇ -L, and ⁇ -L analogs.
- R 2 can be an amino group (i.e., -NH 2 ), a substituted amino group (e.g., -NH 2 , -
- NHR 8 , -N(R 8 ) 2 a cyclic amino group; a halo group (e.g., -F, -Cl, -Br, -I), a nitro group (i. e. , -NO 2 ), an oxy group (/ ' . e. , -OR 8 ), a sulfhydryl group (i. e. , -SH), a thioether group ( . e. ,
- R 2 is preferably selected from the group consisting of: -H, -F, -Cl, -Br, -I,-NH 2 , -
- R 2 is a Cl, -Br, -NH 2 , -NHR 8 , and -N(R 8 ) 2 group, most preferably, is a Cl, or -N(R 8 ) 2 group, wherein the R 8 group is an isopropyl group.
- R 4 and R 7 are both -H.
- R 5 and R 6 are independently the same or different and selected from the group consisting of: -H, -F, -Cl, -Br, and -I.
- R 5 and R 6 are both chloro.
- the benzimidazole group is a halobenzimidazole, such as halo-, dihalo-, trihalo-, tetrahalo-, and pentahalobenzimidazoles, including but not limited to, 5,6-dihalobenzimidazole (e.g., 5,6-dichlorobenzimidazole, 5,6-dibromobenzimidazole),
- 2,5,6-trihalobenzimidazole e.g., 2,5,6-trichlorobenzimidazole, 2-bromo-5,6- dichlorobenzimidazole
- 2,4,6-trihalobenzimidazole e.g., 2,4,6-trichlorobenzimidazole, 2- bromo-4,6-dichlorobenzimidazole
- 2,4,5,6-tetrahalobenzimidazole e.g., 2,4,5,6- tetrachlorobenzimidazole, 2-bromo-4,5,6-trichlorobenzimidazole.
- the benzimidazole is a 5,6-dichlorobenzimidazole with a chloro or isopropylamino substituent at the 2-position.
- esters of the compounds of the present invention include carboxylic acid esters obtained by esterification of the 2'-, 3'- and/or 5 '-hydroxy groups, in which the carboxylic acid moiety is further substituted by a group selected from (1) straight or branched chain alkyl (for example, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen,
- sulfonate esters such as alkylsulfonyl (e.g., methanesulfonyl) or aralkylsulfonyl; (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono- di- or triphosphate esters.
- the phosphate esters may be further esterified by, for example, a C, .20 alcohol or reactive derivative thereof, or by a 2,3-di-(C 6 . 24 )acyl glycerol.
- any alkyl moiety present advantageously-contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
- Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
- Any aryl moiety present in such esters advantageously comprises a phenyl group.
- substituents on the carboxyl moiety suitable for ester formation at the 2'-, 3'- and 5'- position include, but are not limited to, CH 3 , C 6 H 5 groups.
- the present invention includes 2'-deoxy, 3'-deoxy, and 5'-deoxy arabinofuranosyl benzimidazoles.
- each of the above-described compounds can exist in a D or L conformation and each of that conformation can be an ⁇ or a ⁇ anomer.
- this invention contemplates following groups of compounds: ⁇ -D-arabinofuranosyl benzimidazole; ⁇ -L-arabinofuranosyl benzimidazole; ⁇ -D- arabinofuranosyl benzimidazole; ⁇ -L-arabinofuranosyl benzimidazole; ⁇ -D-2'deoxy- arabinofuranosyl benzimidazole; ⁇ -L-2'-deoxy-arabinofuranosyl benzimidazole; ⁇ -D- 3'deoxy-arabinofuranosyl benzimidazole; ⁇ -L-3'-deoxy-arabinofuranosyl benzimidazole; ⁇ - D-3'-deoxy-arabinofuranosyl benzimidazole; ⁇ - D-3'-deoxy
- Some specific compounds provided by this invention include: l-( ⁇ -L-arabinofuranosyl)-2,5,6-trichloro-benzimidazole; l-( ⁇ -L-arabinofuranosyl)-2-bromo-5,6-dichloro-benzimidazole; l-( ⁇ -L-arabinofuranosyl)-2-methylamino-5,6-dichloro-benzimidazole; l-( ⁇ -L-arabinofuranosyl)-2-isopropylamino-5,6-dichloro-benzimidazole; l-( ⁇ -L-arabinofuranosyl)-2-cyclopropylamino-5,6-dichloro-benzimidazole; and l-( ⁇ -L-arabinofuranosyl)-2-cycloheptylamino-5,6-dichloro-benzimidazole.
- the invention also includes pharmaceutically acceptable salts, prodrugs and derivatives of the above-described compounds.
- Benzimidazoles compounds, and methods for their preparation are known in the art and described in detail below. See also U.S. Patent Nos. 5,248,672 and 5,360,795.
- compositions containing the above noted compounds, prodrugs, salts, and derivatives thereof, alone or in combination with each other, and a carrier, are further provided.
- the carrier is a solvent. This combination may be useful in the synthesis of further derivatives of the disclosed compounds.
- the carrier is a pharmaceutically acceptable carrier which is useful in the prophylactic and therapeutic methods described below. It should be understood, although not always explicitly stated that the compositions can contain one or more of the above noted compounds, prodrugs, salts, and derivatives thereof or alternatively, additional art recognized compounds and/or yet to be discovered compounds.
- Formulations within the scope of this invention include, but are not limited to, ointments, gels, pastes, creams, sprays, lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or nonaqueous diluents, syrups, granulates or powders.
- One aspect of the present invention provides methods for inhibiting viral replication and/or propagation by contacting the virus with an effective amount of one or more compounds and/or compositions of the present invention.
- the contacting is conducted under suitable conditions to inhibit viral replication and/or propagation.
- This invention also provides methods of preventing viral infection and/or propagation in a cell or tissue by contacting the cell or tissue with an effective amount of the compounds and/or compositions as defined above. The contacting is conducted under suitable conditions to such that viral infection and/or propagation are inhibited.
- the present invention encompasses not only the treatment and prevention of viral infections, it also provides compositions and methods for treating and/or preventing pathologies associated with some viral infections. For example, restinosis has been correlated with prior HCMV infections in individuals.
- suitable conditions includes in vitro, ex vivo or in vivo conditions.
- In vitro use of a material is defined as a use of a material or compound outside a living human, mammal, or vertebrate, where neither the material nor compound is intended for reintroduction into a living human, mammal, or vertebrate.
- an in vitro use would be the analysis of components of a blood sample using laboratory equipment or use of a compound in a cell culture to prevent or inhibit viral infection, proliferation or replication.
- contacting may be effected by incubating virally infected cells with an effective amount of one or more compounds or compositions of the present invention.
- the compounds or compositions can be added directly to the culture media or combined with a carrier prior to addition to the cells.
- the invention provides a means to treat or prevent a viral infection by administering to an infected subject or a susceptible subject a composition of a pharmaceutically acceptable carrier or a biologically acceptable carrier and a therapeutically or prophylactically effective amount of one or more compounds as described herein.
- an effective amount of the compound or compositions is adminstered to the subject.
- Administration can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the target virus, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the compounds can be found below.
- the methods of this invention are useful to treat and/or prevent viral infection, e.g., virus of herpes and non-herpes origins.
- viral infection e.g., virus of herpes and non-herpes origins.
- Herpes viruses belong to a large family of viruses that affect humans and animals.
- HSV herpes simplex viruses
- B- virus herpes simplex viruses
- varicella-zoster which causes chickenpox and shingles
- Epstein-Barr virus EBV, which causes mononucleosis
- lymphocrypto virus human herpesvirus 6 (HHV6); human herpesvirus 7 (HHV7) kaposi-associated herpes virus (KHV); human herpesvirus 8 (HHV8) and herpesvirus simiae, among others.
- Human cytomegalovirus (HCMV) also a human herpes virus, is a leading opportunistic pathogen among immunosuppressed individuals. See, for example, Gallant J. E. et al, J.
- Animal pathogens of herpesviral origin include infectious bovine rhinotracheitis virus, bovine mammillitis virus, and cercopithecine herpesvirus 1 (B-virus), among others.
- the human viruses of non-herpes origin that are contemplated to be treatable with the compounds and according to the methods of the present invention include influenza viruses A, B and C; parainfiuenza viruses -1,2, 3 and 4; adenovirus; reovirus; respiratory syncytial virus; rhino virus; coxsackle virus; echo virus; rubeola virus; hepatitis viruses of the types B and C (HBV and HCV); and papovavirus.
- the animal viruses of non-herpes origin include pseudorabies virus (PRV, of swine), equine rhinopneumonitis and coital exanthema viruses (varicellaviruses); lymphocryptovirus; Marek's disease virus (of fowl), among others.
- PRV pseudorabies virus
- variantaviruses equine rhinopneumonitis and coital exanthema viruses
- lymphocryptovirus of fowl
- a herpesvirus of economic importance in the cattle industry is Bovine Herpesvirus- 1 (BHV-1), which has been associated with a variety of clinical disease manifestations, including rhinotracheitis, vulvovaginitis, abortions, conjunctivitis, encephalitis and generalized systemic infections. Gibbs et al, "Bovine herpesviruses. I: Bovine herpesvirus- 1," Vet. Bull.
- the herpesvirus Pseudorabies virus also called Aujeszky's disease virus (ADV)
- PRV herpesvirus Pseudorabies virus
- ADV Aujeszky's disease virus
- PRV herpesvirus Pseudorabies virus
- the pig is the natural host of ADV. Accordingly, compounds of the present invention can be presented for use in the form of veterinary formulations, which may be prepared, for example, by methods that are conventional in the art.
- herpesviruses A variety of disease symptoms and a complex clinical course are caused by herpesviruses. In the case of a first infection in an adult human, the symptoms may be very severe. Herpesviruses can cause recurrent infections, and the disability associated with these recurrences is a significant health problem. In the case of EBV and HCMV, acute
- Mononuclear cells are the major candidate as cells involved in the latent state of HCMV infection, and infectious mononucleosis may follow blood transfusions from seropositive to seronegative individuals. Seronegative individuals may also become infected via transplantation of cells or organs from seropositive donors.
- HBV hepatitis B virus
- infection is typically via contaminated blood or body fluids, and thus HBV infection is prevalent among intravenous drug abusers, homosexuals, and in countries with less developed health care systems where the risk of exposure to contaminated blood products is high. It has recently been estimated that throughout the world there are approximately 250 million people who are chronic carriers of HBV.
- hepatitis C virus An additional member of the hepatitis virus family that can be treated as defined herein is hepatitis C virus (HCV).
- Hepatitis C which is neither hepatitis A nor hepatitis B, forms 95 to 100% of post-transfusion hepatitis and 40 to 50% of sporadic hepatitis and easily becomes chronic, further changing at high rates to cancer of liver via chronic hepatitis or hepatic cirrhosis.
- HCV hepatitis C virus
- the method comprises: (a) providing a composition containing the compound of this invention to be tested; (b) providing an extracorporeal cell system capable of being infected by HCV; (c) providing a biological sample containing infective HCV; (d) incubating the compositions of (a) and (c) with the cell system of (b) under conditions that would, in the absence of (a), allow infection of HCV in the cell
- Preferred cell systems as disclosed in U.S. Patent No. 5,679,342 include hepatocytes, macrophages, more preferably Kupffer macrophages, and B lymphocytes. Cell lines derived from organs of hepatocytic origin also are suitable for use in the assay described above, The Houghton method can also be used for prophylactic screening of the compounds of the present invention for their activity against HCV or other viruses in general.
- Another method well known in the art for testing the antiviral activity of compounds against HCV is the helicase inhibition assay. See, for example, Lain et al, Nucleic Acids Resl, 69:1720-1726, (1991) and Kim et al., Biochem. Biophys, Res. Comm., 160-166, (1995).
- interferon has been known as an agent having inhibitory effect on the proliferation of hepatitis C virus
- problems such as its low rate in the effectiveness as little as 30 to 40%, the 60 to 70% recrudescence after discontinuance of the dosage thereof, the appearance of influenza-like symptoms, such as pyrexia, headache and vomiting, and of diverse side effects such as leukopenia, at the high rates. Accordingly, there exists currently no effective treatment or preventive with acceptable efficacy and toxicity profile.
- compositions and methods of this invention also provide methods for treating, preventing or ameliorating the symptoms or disorders associated with the viral infection.
- inclusion disease blindness, mononucleosis, restenosis (HCMV); chickenpox, shingles (varicella-zoster virus); infectious mononucleosis, glandular, fever, and Burkittis lymphoma (Epstein-Barr virus); cold sores (herpes simplex virus 1); genital herpes (herpes simplex virus 2); roseola infantum (human herpes virus 6, human herpes virus 7); and kaposi sarcoma (human herpes virus 8).
- this invention also provides methods of ameliorating, preventing, or treating disorders or symptoms associated with viral infection, e.g., HCMV or HSV-1 infection, e.g., restenosis, opportunistic infections (such as retinal infections, gastrointestinal infections, pneumonia,
- Restensosis is the narrowing of the blood vessels which can occur after injury to the vessel wall and is characterized by excessive proliferation of smooth muscle cells in the walls of the blood vessel treated. Restenosis can occur following a number of surgical techniques, for example, transplant surgery, vein grafting, coronary by-pass grafting and, most commonly, following angioplasty. Alternatives to the balloon catheter, such as pulsed lasers and rotary cutters, have been developed with a view to reducing or preventing restenosis following angioplasty, but have met with limited success. A number of drugs including anti-coagulants and vasodilators have also been tried with disappointing or equivocal results. Because restinosis appears to be associated with viral infections, the compounds of this invention can be used in methods to prevent or treat restenosis in a susceptible subject or patient.
- a viral infection or when inhibiting viral replication or proliferation, wherein the virus is a hepatitis virus, such as a hepatitis B or hepatitis C
- the virus is a hepatitis virus, such as a hepatitis B or hepatitis C
- compounds specifically provided by the present invention and those disclosed hereinabove as within the scope of this invention, but also compounds such as unsubstituted arabinofuranosyl benzimidazoles, 1 -( ⁇ -D-arabino furanosyl)-2,5 ,6-trichlorobenzimidazole, and ⁇ -D-2'-deoxy-arabinofuranosyl benzimidazoles with the preferred substitutions disclosed above, can be used.
- the same compounds, their salts, prodrugs or derivatives can also be used in preparing medicaments to be used in treating or preventing a viral infection or in inhibiting viral replication or propagation.
- compositions When a subject such as a human patient is being treated, the compositions can be administered topically, orally, intranasally, parenterally or by inhalation therapy, and may take the form of pharmaceutically acceptable carriers such as tablets, lozenges, granules, capsules, pills, ampoules, suppositories or aerosol form. More particularly, a compound of the formula of the present invention also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parental (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary. It will also be
- a suitable dose for each of the above-named viral infections is in the range of about 0.1 to about 250 mg per kilogram body weight of the recipient per day, preferably in the range of about 1 to about 100 mg per kilogram body weight per day and most preferably in the range of about 5 to about 20 mg per kilogram body weight per day.
- all weights of active ingredient are calculated as the parent compound of the formula of the present invention for salts or esters thereof, the weights would be increased proportionately.
- the desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
- sub-doses may be administered in unit dosage forms, for example, containing about 10 to about 1000 mg, preferably about 20 to about 500 mg, and most preferably about 100 to about 400 mg of active ingredient per unit dosage form. It will be appreciated that appropriate dosages of the compounds and compositions of the invention may depend on the type and severity of the viral infection and can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the antiviral treatments of the present invention.
- the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 2 ⁇ M to about lOO ⁇ M, preferably about 5 ⁇ M to about 70 ⁇ M, most preferably about 1 to about 50 ⁇ M.
- This may be achieved, for example, by the intravenous injection of about 0.1 to about 5% solution of the active ingredient, optionally in saline, or orally administered, for example, as a tablet, capsule or syrup containing about 0.1 to about 250 mg per kilogram of the active ingredient.
- Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg per kilogram of the active ingredient.
- the use of operative combinations is contemplated to provide therapeutic combinations requiring a lower total dosage of each component antiviral agent than may be required when each individual therapeutic compound or drug is used alone, thereby reducing adverse effects, e.g., cytotoxicity.
- the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising at least one active ingredient, as defined above, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic agents.
- Each carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented a bolus, electuary or paste.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. , povidone, gelatin, hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross- linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying
- Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- compositions for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol or oil.
- a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents.
- the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, about 0.075 to about 20% w/w, preferably about 0.2 to about 25% w/w and most preferably about 0.5 to about 10% w/w.
- the active ingredient may be employed with either a paraffmic or a water- miscible ointment base.
- the active ingredients may be formulated in a cream with an oil-in-water cream base.
- the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane- 1, 3 -diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
- the oily phase of the emulsions of this invention may be constituted from known ingredients in an known manner. While this phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at lease one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at lease one emulsifier with a fat or an oil or with both a fat and an oil.
- a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is
- Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
- Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
- the active ingredient is preferably present in such formulation in a concentration of about 0.5 to about 20%, advantageously about 0.5 to about 10%) particularly about 1.5% w/w.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, such carriers as are known in the art to be appropriate.
- Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid
- Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer include aqueous or oily solutions of the active ingredient.
- Formulations suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
- the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose, as herein above-recited, or an appropriate fraction thereof, of an active ingredient.
- the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable of oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
- the compounds of this invention also can be administered in combination with other known therapeutic agents for the inhibition of the replication or propagation of the above virus and associated conditions.
- Combination therapies according to the present invention comprise the administration of at least one compound of the present invention and at least one other pharmaceutically active ingredient.
- the compounds of the invention could be used in combination therapies to treat viral infections, such as HCMV and HSV-1 infections, in AIDS patients already receiving the antiviral drug zidovudine (AZT) and/or 3TC.
- Combination therapies with AZT may provide the advantage of less toxicity over the combination of ganciclovir with AZT.
- the combination of the compounds of this invention with AZT may produce less cytotoxicity (i.e.
- the active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either the same or different pharmaceutical formulations or sequentially in any order.
- the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
- the combination therapy involves the administration of one compound according to the invention and one of the agents mentioned herein below.
- the term "operative combination" is intended to include any chemically compatible combination of a compound of the present invention with other compounds of the present invention or other compounds outside the present invention (such as ganciclovir, AZT, and focarnet), as long as the combination does not eliminate the antiviral activity of the compound of the present invention.
- agents that are effective for the treatment of viral infections or associated conditions are (1 -alpha, 2-beta, 3-alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl] guanine [(-)BHCG, SQ-34514], oxetanocin-G(3,4-bis- (hydroxymethyl)-2-oxetanosyl]guanine), acyclic nucleosides (e.g., acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates (e.g., (S)-l-(3- hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), ribonucleotide reductase inhibitors such as 2-acetylpyridine 5-[(2-chloroa nilino)thiocarbonyl] thiocarbonohydrazone, 3
- inhibitors such as 7-chloro-5-(2-pyrryl)-3H-l,4-benzodiazepin-2-(H)one (Ro5-3335), 7- chloro- 1 ,3-dihydro-5-( 1 H-pyrrol-2-yl)-3H- 1 ,4-benzodiazepin-2-amine (Ro24-7429), interferons such as ( ⁇ -interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, ( ⁇ -trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD 4 and genetically engineered derivatives thereof, or non- nucleoside reverse transcriptase inhibitors such as nevirapine (BI-RG
- the inventors have provided certain new benzimidazole compounds with antiviral activity.
- the compounds of this invention are useful as a positive control in screening for new drugs or agents having antiviral activity.
- To practice the screen one performs the steps of: a) measuring anti-viral activity of a compound of this invention; b) measuring anti- viral activity of a potential anti-viral agent.
- the potential agent is a candidate therapeutic if its viral activity equals or exceeds the anti- viral activity of the compound of this invention.
- the candidate therapeutic also has little or no cytotoxicity.
- the measuring anti-viral activity consists of: a) contacting a virus-infected cell with an agent or compound; and b) assaying the virus-infected cell for inhibition of viral proliferation whereby the extent of inhibition of viral proliferation indicates anti-viral activity.
- the contacting can be in vtro, in vivo, or ex vivo.
- the agent can be one or more of: a small molecule, a polynucleotide, a polypeptide, a polysaccharide, a glycopeptide, or a peptidonucleic acid.
- the agent is a nucleic acid
- the nucleic acid can be introduced into the virus-infected cell using a gene delivery vehicle such as a viral vector or liposome.
- the agent when it is a nucleic acid, it can be contacted or introduced into the cell by methods well known in the art, which includes, but is not limited to, incorporating the nucleic acid into an expression or insertion vector.
- Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operatively linked are well known in the art. Examples of vectors are viruses, such as baculovirus and retrovirus, bacteriophage, cosmid, plasmid, fungal vectors and other recombination vehicles used in the art.
- nucleic acid or proteins of this invention can be conjugated to antibodies or binding fragments thereof which bind cell surface antigens, e.g., TCR, CD3 or CD4.
- liposomes that also comprise a targeting antibody or fragment thereof can be used in the methods of this invention.
- 2,3,5-tri-O-acetyl-glyco-furanosyl nucleosides can be prepared by a modified Vorbriiggen procedure from 1,2,3,5-tetra-O-acetyl-glycosides. See, for example, Vorbruggen, H. et al. , "Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as Catalyst," Chem. Ber., 114:1256-1268, (1981). The anomeric configuration is predominately trans, with respect to the 1' -heterocyclic moiety and 2'-O-acetyl group, in most cases. See, for example, Baker, B. R.
- tetra-O-acetyl-L-arabinofuranose (compound 1) was prepared, in three steps in 61% yield after silica gel chromatography, from a procedure developed by Guthrie, R. D. and Smith, S. C, "An improved preparation of 1,2,3,5-tetra-O-acetyl- ⁇ -D-ribofuranose," Chem. Ind, 547-548, (1968) and generalized
- the 2-chloro substituent of 1 -substituted benzimidazoles can be conveniently displaced by a variety of nucleophiles. See, for example, Harrison, D. and Ralph, J. T., "Nucleophilic substitution reaction of 2-chlorobenzimidazoles. Part 1. Formation of benzimidazolin-2-ones and 2-alkoxybenzimidazoles," J. Chem. Soc, 236-239, (1965). Following this approach, 5,6-dichloro-2-methylamino-l-( ⁇ -L- arabinofuranosyl)benzimidazole (compound 5) was prepared in one step (64% yield) by the direct treatment of compound 4 with a 2 M solution of methylamine in methanol at room temperature.
- compound 1 (a protected L- arabinofuranose) was reacted with an appropriately substituted benzimidazole to result in a protected ⁇ -L-arabinofuranosyl benzimidazole (2), which was deprotected and the deprotected nucleoside was then isolated by using an appropriate eluent on flash column chromatography. It is within the ordinary skill to prepare a ⁇ -L-arabinofuranosyl benzimidazole according to this reaction scheme and isolate it from its ⁇ -anomer by selecting the appropriate eluent. Further, by substituting a D-arabinofuranose in the above reaction scheme, one can obtain the ⁇ -D- compounds of the present invention
- the above ⁇ -L- and ⁇ -D- analogs of the ⁇ -L-arabinofuranosyl benzimidazoles of the present invention can be prepared from the methodology disclosed by the U.S. Patent 5,360,795. This patent describes in detail the preparation and isolation of ⁇ -D-arabinofuranosyl benzimidazole, the contents of which Patent are hereby incorporated by reference.
- PCT publication WO 97/25337 discloses the preparation of 2'-deoxy- ⁇ -L- ribofuranosylbenzimidazole and PCT publication WO 94/08456 discloses the preparation of 2'-deoxy- ⁇ -D-ribofuranosylbenzimidazole. Since a 2'-deoxyribofuranosyl is equivalent to a 2'-deoxyarabinofuranosyl, one of skill in the art would readily understand that the above publications disclose the preparation of 2'-deoxy- ⁇ -L and ⁇ -D-arabinofuranosyl compounds. Analogous methods can be employed to prepare 2'-deoxy- ⁇ -L and ⁇ -D- arabinofuranosyl compounds. Additionally, Howell, H.G.
- Stock HCMV was prepared by infecting HFF cells at a multiplicity of infection (m.o.i.) of ⁇ 0.01 plaque-forming units (p.f.u.) per cell as detailed previously. See, for example, Turk, S. R. et al, "Pyrrolo[2,3- ]pyrimidine Nucleosides as Inhibitors of Human Cytomegalovirus," Antimicrob. Agents Chemother., 31 :544-550, (1987). High titer HSV- 1 stocks were prepared by infecting KB cells (ATCC) at an m.o.i. of ⁇ 0.1 also as detailed previously. See, for example, Turk, S. R.
- Virus titers were determined using monolayer cultures of HFF cells for HCMV and monolayer cultures of BSC-1 cells for HSV-1 as described earlier. See, for example, Prichard, M. N. et al, "A Microtiter Virus Yield Reduction Assay for the Evaluation of Antiviral Compounds against Human Cytomegalovirus and Herpes Simplex Virus,” J. Virol. Methods, 28:101-106, (1990).
- HFF or BSC-1 cells were planted as described above in 96-well cluster dishes and incubated overnight at 37°C. The next day cultures were inoculated with HCMV or HSV-1 and serially diluted 1 :3 across the remaining eleven columns of the 96- well plate. After virus adsorption the inoculum was replaced with fresh medium and cultures were incubated for seven days for HCMV, two or three days for HSV-1. Plaques were enumerated under 20-fold magnification in wells having the dilution which gave 5 to 20 plaques per well. Virus titers were calculated according to the following formula: Titer
- HFF cells in 24-well cluster dishes were infected with approximately 100 p.f.u. of HCMV per cm ⁇ cell sheet using the procedures detailed above. Following virus adsorption, compounds dissolved in growth medium were added to duplicate wells in four to eight selected concentrations. After incubation at 37°C for 7 to 10 days, cell sheets were fixed, stained with crystal violet and microscopic plaques enumerated as described above.
- Drug effects were calculated as a percentage of reduction in number of plaques in the presence of each drug concentration compared to the number observed in the absence of drug.
- HSV-1 An ELISA was employed to detect HSV-1. See, for example, Prichard, M. N. and Shipman, C, Jr., "A Three Dimensional Model to Analyze Drug-Drug Interactions," Antiviral Res., 14:181-206, (1990).
- MEM(E) Three Dimensional Model to Analyze Drug-Drug Interactions
- Antiviral Res. 14:181-206, (1990).
- Ninety-six-well cluster dishes were planted with 10,000 BSC-1 cells per well in 200 ⁇ L per well of MEM(E) plus 10% calf serum. After overnight incubation at 37°C, selected drug concentrations in quadruplicate and HSV-1 at a concentration of 100 p.f.u./well were added.
- Cytotoxicity produced in stationary HFF cells was determined by microscopic inspection of cells not affected by the virus used in plaque assays. See, for example, Turk, S. R. et al, "Pyrrolo[2,3-cT]pyrimidine Nucleosides as Inhibitors of Human Cytomegalovirus," Antimicrob. Agents Chemother., 31:544-550, (1987).
- the effect of compounds during two population doublings of KB cells was determined by crystal violet staining and spectrophotometric quantitation of dye eluted from stained cells as described earlier. See, for example, Prichard, M. N.
- test compound was added in quadruplicate at six to eight concentrations. Plates were incubated at 37°C for 48 hours in a CO 2 incubator, rinsed, fixed with 95% ethanol, and stained with 0.1% crystal violet. Acidified ethanol was added and plates read at 570 nm in a spectrophotometer designed to read 96-well ELISA assay plates.
- Dose-response relationships were constructed by linearly regressing the percent inhibition of parameters derived in the preceding sections against log drug concentrations. Fifty-percent inhibitory concentrations (IC5Q'S) or ICgo's were calculated from the regression lines. Samples containing positive controls (acyclovir for HSV-1, ganciclovir for HCMV, and 2-acetylpyridine thiosemicarbazone for cytotoxicity) were used in all assays.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU33791/99A AU3379199A (en) | 1998-04-03 | 1999-04-02 | Arabinofuranosyl benzimidazoles as antiviral agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8071598P | 1998-04-03 | 1998-04-03 | |
US60/080,715 | 1998-04-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999051619A1 true WO1999051619A1 (fr) | 1999-10-14 |
Family
ID=22159151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/007308 WO1999051619A1 (fr) | 1998-04-03 | 1999-04-02 | Arabinofuranosyl benzimidazoles comme agents antiviraux |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU3379199A (fr) |
WO (1) | WO1999051619A1 (fr) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6455506B1 (en) | 1997-07-30 | 2002-09-24 | Smithkline Beecham Corporation | Lyxofuranosyl benzimidazoles as antiviral agents |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7112600B1 (en) | 1999-12-27 | 2006-09-26 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7511145B2 (en) | 2003-08-01 | 2009-03-31 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
EP2206715A1 (fr) | 2004-02-24 | 2010-07-14 | Japan Tobacco, Inc. | Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV |
US7977331B1 (en) | 2004-02-24 | 2011-07-12 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
CN115721606A (zh) * | 2021-08-27 | 2023-03-03 | 博美利克斯技术公司 | 胶束、其制备方法以及包含其的药物组合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992007867A1 (fr) * | 1990-11-01 | 1992-05-14 | The Regents Of The University Of Michigan | Benzimidazoles polysubstitues utilises comme agents antiviraux |
-
1999
- 1999-04-02 AU AU33791/99A patent/AU3379199A/en not_active Abandoned
- 1999-04-02 WO PCT/US1999/007308 patent/WO1999051619A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992007867A1 (fr) * | 1990-11-01 | 1992-05-14 | The Regents Of The University Of Michigan | Benzimidazoles polysubstitues utilises comme agents antiviraux |
US5360795A (en) * | 1990-11-01 | 1994-11-01 | The Regents Of The University Of Michigan | Polysubstituted benzimidazoles as antiviral agents |
Non-Patent Citations (3)
Title |
---|
OIVANEN, M. AND LÖNNBERG, H.: "Mechanism for acid-catalyzed hydrolysis of nucleoside and acyclonucleoside analogues of benzimidazole", NUCLEOSIDES, NUCLEOTIDES, vol. 8, no. 1, 1989, pages 133 - 44, XP000646575 * |
TOWNSEND, L.B. ET AL.: "Conformation of nucleosides", PROC. NATL. ACAD. SCI. USA, vol. 76, no. 2, 1979, pages 553 - 6, XP002109773 * |
TOWNSEND, L.B. ET AL.: "Design, synthesis and antiviral activity of alpha-L-arabinofuranosyl derivatives of 2-substituted 5,6-dichlorobenzimidazoles", NUCLEOSIDES, NUCLEOTIDES, vol. 17, no. 12, 1998, pages 2389 - 2401, XP002109779 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6455506B1 (en) | 1997-07-30 | 2002-09-24 | Smithkline Beecham Corporation | Lyxofuranosyl benzimidazoles as antiviral agents |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7112600B1 (en) | 1999-12-27 | 2006-09-26 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7285551B2 (en) | 1999-12-27 | 2007-10-23 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
US7511145B2 (en) | 2003-08-01 | 2009-03-31 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
EP2206715A1 (fr) | 2004-02-24 | 2010-07-14 | Japan Tobacco, Inc. | Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV |
US7977331B1 (en) | 2004-02-24 | 2011-07-12 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
CN115721606A (zh) * | 2021-08-27 | 2023-03-03 | 博美利克斯技术公司 | 胶束、其制备方法以及包含其的药物组合物 |
US11998530B2 (en) | 2021-08-27 | 2024-06-04 | Biometrix Technology Inc. | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation method thereof and use thereof as anticancer agent or antiviral agent comprising the same |
Also Published As
Publication number | Publication date |
---|---|
AU3379199A (en) | 1999-10-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6342501B1 (en) | Pyrrolo[2,3-d] pyrimidines as antiviral agents | |
AU740792C (en) | Benzimidazole derivatives | |
EP0769017B1 (fr) | Composes therapeutiques | |
SK287875B6 (sk) | Use of 4'-substituted nucleosides for the manufacture of a medicament for the treatment of diseases mediated by the Hepatitis C Virus | |
JPH02180894A (ja) | 抗ウイルス剤 | |
US5840743A (en) | Modified benzimidazole nucleosides as antiviral agents | |
US6455506B1 (en) | Lyxofuranosyl benzimidazoles as antiviral agents | |
WO1999051619A1 (fr) | Arabinofuranosyl benzimidazoles comme agents antiviraux | |
US5874413A (en) | 5'-substituted-ribofuranosyl benzimidazoles as antiviral agents | |
WO1997033591A1 (fr) | Procede de traitement d'affections associees aux cytokines chez les mammiferes | |
EP0970100B1 (fr) | Derives de benzimidazole | |
Zou et al. | Design, synthesis, and antiviral evaluation of 2-deoxy-D-ribosides of substituted benzimidazoles as potential agents for human cytomegalovirus infections | |
US20010011075A1 (en) | 5'-substituted-ribofuranosyl benzimidazoles as antiviral agents | |
CZ2000299A3 (cs) | D-nebo L-lyxofuranosyl-benzimidazolová sloučenina, způsob její výroby a prostředek ji obsahující | |
Girardet et al. | Design, synthesis and antiviral activity of α-L-arabinofuranosyl derivatives of 2-substituted-5, 6-dichlorobenzimidazoles | |
MXPA00001046A (en) | Lyxofuranosyl benzimidazoles as antiviral agents | |
MXPA98005953A (en) | Benzymidazol nucleosides modified as antivira agents | |
CN1258300A (zh) | 作为抗病毒剂的修饰的苯并咪唑核苷 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: KR |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase |