DK143069B - Analogifremgangsmaade til fremstilling af et 3-substitueret 1,2,4-triazol-nucleosid - Google Patents
Analogifremgangsmaade til fremstilling af et 3-substitueret 1,2,4-triazol-nucleosid Download PDFInfo
- Publication number
- DK143069B DK143069B DK237072AA DK237072A DK143069B DK 143069 B DK143069 B DK 143069B DK 237072A A DK237072A A DK 237072AA DK 237072 A DK237072 A DK 237072A DK 143069 B DK143069 B DK 143069B
- Authority
- DK
- Denmark
- Prior art keywords
- triazole
- ribofuranosyl
- nucleoside
- substituted
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title description 11
- -1 3-SUBSTITUTED 1,2,4-TRIAZOL NUCLEOSIDE Chemical class 0.000 title description 6
- 239000002777 nucleoside Substances 0.000 title description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 12
- 230000000840 anti-viral effect Effects 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 5
- 239000003443 antiviral agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- QMPFMODFBNEYJH-UHFFFAOYSA-N methyl 1h-1,2,4-triazole-5-carboxylate Chemical compound COC(=O)C1=NC=NN1 QMPFMODFBNEYJH-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 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 4
- 241000699670 Mus sp. Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 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 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 241000700647 Variola virus Species 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- MHSVUSZEHNVFKW-UHFFFAOYSA-N bis-4-nitrophenyl phosphate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1OP(=O)(O)OC1=CC=C([N+]([O-])=O)C=C1 MHSVUSZEHNVFKW-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- FWWYEYLRPMUTSE-DBRKOABJSA-N 3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2h-triazole-1-carboxamide Chemical compound C1=CN(C(=O)N)NN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 FWWYEYLRPMUTSE-DBRKOABJSA-N 0.000 description 1
- FFLUMYXAPXARJP-JBBNEOJLSA-N 3-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrrole-2,5-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CC(=O)NC1=O FFLUMYXAPXARJP-JBBNEOJLSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- PZKFSRWSQOQYNR-UHFFFAOYSA-N 5-methyl-1h-1,2,4-triazole Chemical compound CC1=NC=NN1 PZKFSRWSQOQYNR-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- FFLUMYXAPXARJP-UHFFFAOYSA-N D-showdomycin Natural products OC1C(O)C(CO)OC1C1=CC(=O)NC1=O FFLUMYXAPXARJP-UHFFFAOYSA-N 0.000 description 1
- 208000010454 Experimental Liver Neoplasms Diseases 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 208000000903 Herpes simplex encephalitis Diseases 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000287433 Turdus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 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
- 239000002253 acid Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003622 anti-hsv Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- HMFHBZSHGGEWLO-TXICZTDVSA-N beta-D-ribose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-TXICZTDVSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000007360 debenzoylation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000007499 fusion processing Methods 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- OLQDKJGHMNCLOH-HKUMRIAESA-N methyl 1-[(2r,3r,4r,5r)-3,4-diacetyloxy-5-(acetyloxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxylate Chemical compound N1=C(C(=O)OC)N=CN1[C@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1 OLQDKJGHMNCLOH-HKUMRIAESA-N 0.000 description 1
- PUHIETBGRWTVIS-PMHJDTQVSA-N methyl 1-[(2r,3r,4r,5r)-3,4-dibenzoyloxy-5-(benzoyloxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxylate Chemical compound N1=C(C(=O)OC)N=CN1[C@H]1[C@H](OC(=O)C=2C=CC=CC=2)[C@H](OC(=O)C=2C=CC=CC=2)[C@@H](COC(=O)C=2C=CC=CC=2)O1 PUHIETBGRWTVIS-PMHJDTQVSA-N 0.000 description 1
- RFJYLFZDYHCYNF-UAKXSSHOSA-N methyl 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxylate Chemical compound N1=C(C(=O)OC)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RFJYLFZDYHCYNF-UAKXSSHOSA-N 0.000 description 1
- VQBGAUXDGQKKNT-UHFFFAOYSA-N methyl 1-trimethylsilyl-1,2,4-triazole-3-carboxylate Chemical compound COC(=O)C=1N=CN([Si](C)(C)C)N=1 VQBGAUXDGQKKNT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
-
- 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
- C07H19/056—Triazole or tetrazole radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
i (11) FREMLÆGGELSESSKRIFT 1^3069 > DANMARK c 07 h iom §(21) Ansøgning nr. 2570/72 (22) Indleveret den 12. maj 1972 (24) Løbedag 12. maj 1972 (44) Ansøgningen fremlagt og fremlaeggelsesekrrftet offentliggjort den 25 · mar. 1 981
DIREKTORATET FOR
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begæret fra den
1. jun. 1971, 14901 7, us 51 . mar. 1972, 240252, US
(71) ICN PHARMACEUTICALS INC., 2727, Campus Drive, Irvine, California, US.
(72) Opfinder: Joseph T. Witkowski, 24906 LaPlata, Laguna Niguel, California, US: Roland K. Robins, 10050 Highcliff Drive, Santa Ana, California 92705, us.
(74) Fuldmægtig under sagens behandling:
Ingeniørfirmaet Giersing & Stellinger.
(54) Analogifremgangsmåde til fremstilling af et 5-substitueret 1,2,4-tria*= zol-nucleosid.
Opfindelsen angår en analogifremgangsmåde til fremstilling af et 3-substitueret 1,2,4-triazolnucleoaid med formlen 0
II
H2N-^r—N
U
H0-. ^
A
V-r
OH OH
2 143069
Fox* øjeblikket ex* de to eneste kendte nucleosidiske antibiotiske midler med 5-leddede heterocycliske ringe showdomycin og pyrazomycin, som angives at have strukturerne 1, henholdsvis 2:
_ O
HN-f II H
.v -¾ Η0Ί o HO-i
OH OH II
OH OH
(1) (2)
Blandt de for øjeblikket kendte syntetiske nucleosidiske an-tivirale midler er de mest vigtige 5-iodo-2*-deoxyuridin (5-IDU), 9-6-D-arabinofuranosyladenin (Ara-A) og Ι-β-D-arabinofuranosylcyto-sin (Ara-C). Af disse midler er kun 5-IDU (i 0,1 vægt# opløsning) kommercielt tilgængelig specifikt som et antiviralt middel, og denne forbindelse lider af en ulempe i form af lav opløselighed og høj toxicitet, hvilket har givet anledning til den uønskede store fortynding, i hvilken stoffet nu anvendes.
Alonso, et al rapporterer i J. Heterocyclic Chem. 7» 1269-72 (197Ο) om præparationen af 1-(β-D-ribofur anosyl)-4-carboxamido- I, 2,3-triazol, men omtaler ingen biologisk aktivitet. Witkowski og Robins foreslår i "The Chemical Synthesis of the 1,2,4-Triazol-Nucleosider related to Uridin, 2*-Deoxyuridin, Thymidin and Cytidine" J. Org.Chem. 35m 2635-41 (1970) forskellige 1,2,4-triazol-nucleosidanaloge som muligheder for biologisk prøvning, men ingen særlig virk-ningsfuldhed bemærkes, og senere prøvninger har vist, at kun 5-bromo- 3-nitro-l-(2,3,5-tri-0-acetyl^-D-ribofuranosyl) -1,2,4-triazol af de på dette sted omhandlede analoge udviser endog svag antiviral aktivitet, og endog antages det at denne aktivitet kan tilskrives forbindelsens cytotoxicitet.
Den indledningsvis angivne forbindelse med formel (i) fremstilles ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved, at en 3-substitueret l-(0-acylblokeret-0-D-ribofuranosyl)-l,2,4-triazol med den almene formel 3 143069 γχ Ti—Ν Ν \\
Ac O-ι V? OAc OAc hvor Ac betegner en acylgruppe og Y betegner en alkoxycarbonyl-gruppe, bringes til at reagere med ammoniak, hvorefter acylblokeren-de grupper fjernes ved forsæbning. Den således fremstillede forbindelse, l-(P-D-ribofuranosyl)-l,2,4-triazol-3-carboxamid, udviser et bredt spektrum af antiviral aktivitet samt antitumoraktivitet, og den har væsentlig større vandig opløselighed end tidligere kendte nucleosidiske antivirale midler.
Antivirale midler indeholdende forbindelsen fremstillet ved fremgangsmåden ifølge opfindelsen er blever prøvet for aktivitet mod både små og store viruser af både DNA og RNA typer ved virus rating (VR)-metoden ifølge Sidwell et al Appl. Michrobiol. 22, 797 (1971). V.R. > 1,0 indikerer afgjort antiviral aktivitet, V.R. på 0,5 - 0,9 indikerer moderat antiviral aktivitet og V.R. <10,5 tyder på svag eller ingen udpræget antiviral aktivitet. De nedenfor rapporterede resultater, som for sammenlignings skyld omfatter data taget med forskellige kendte antivirale midler, opnåedes ved prøvning på Microtest II (Falcon Plastics) plastik plader med et monolag af KG eller RK13 celler.
Af de i prøven anvendte virusser er Herpes type 1 inddraget i labialis, Herpes keratitis og Herpes encephalitis. Herpes type 2 forårsager Herpes genitalis, en almindelig og smitsom form for venerisk syge. Myxoma forårsager død hos tamme og vilde kaniner, forårsaget af respirationssygdom og svær svulstdannelse. Pseudora-bies forårsager infektiøs paralyse hos kvæg, får, svin, hunde og minke. Parainfluenzavirus forårsager en mild øvre respirationssygdom hos mennesker, specielt små børn, og er impliceret i kvægconjuncti-vitis. Vaccinia er en avirulent form for koppevirus, som anvendes til koppevaccination, og dets brug resulterer lejlighedsvis i uønskede bivirkninger. Rhino type 13 er en af de mange virus arter, som er involveret i den almindelige forkølelse.
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Forbindelse 1 ovenfor er blevet afprevet på kaniner og hamstere og udviser i ikke toxiske doser betydelig anti-HSV keratitis aktivitet. Forbindelsen hæmmer significant udviklingen af HSV-induce-rede læsioner i musehaler, når det tilføres lokalt til infektionen.
Det er også blevet afprøvet på mus mod influenza A2t influenza B og parainfluenza 1 med betydelig antiviral aktivitet iagttaget i disse eksperimenter. Det bemærkes af tabel 1, at denne forbindelse udviser et spektrum af antiviral aktivitet, som er betydelig bredere end det, som udvistes af IDU, Ara-A eller Ara-C. Udover den antivirale aktivitet, som er dokumenteret ovenfor, har man fundet, at 1-(β-D-ribofurano-syl)-l,2,4-triazol-3-carboxamid hæmmer væksten af bakterierae Pseudomonas aeruginosa og svajene Candida albicans og Cryptococcus difflu-ents.
Forbindelsen 1 ovenfor udviste lav cytotoxioitet og var opløselig i vandigt medium.
1-(p-D-ribofuranoeyl)-l,2,4-triazol-3-carboxa*id udviser også interessant antitumoraktivitet. Tre grupper af C 57 Blk/6 mus (6 dyr pr. gruppe) fik indgivet subcutane indgivelser af adenocarci-noma-755· To grupper modtog forbindelsen (lOO mg/kg x 7 dage og 200 mg/kg x 7 dage) intraperitonealt, hvorimod den tredie kontrolgruppe kun modtog salt. På den 16. dag udviste de behandlede dyr 18 $ og 63 $ hæmning af tumoren i forhold til kontrollerne. Ved et lignende eksperiment udviste DBA/2 mus innoculeret med L-1210 leukæmi (l x 10^ celler per dyr) en 31 % forøgelse i gennemsnitlig overlevelsestid i forhold til kontrollør, når de behandledes ned forbindelsen (250 mg/kg x 7 dage). Når den blev givet i en dosis af 250 mg/kg x 14 dage frembragte forbindelsen 80 56 overlevende af schweiziske mus med intra-peritoneal indgivelse af Ehrlich Ascites carcinoma. Marginal in vivo aktivitet mod Novikoff hepatoma blev også iagttaget.
Methyl-1,2,4-triazol-3-carboxylat or forløber for det i-følge opfindelsen fremstillede 1,2,4-triazol-nucleosid. Forbindelsen kan konventionelt fremstilles ved oxidation af 3-methyl-l,2,4-triazol fulgt eif esterificering af den resulterende syre ifølge Cipens og Grinsteins' fremgangsmåde Latvijas PSR Zinatnu Akad. Vestis., Kin.Ser. (1965) (2) 204-08 (C.A. 63» 13243» 1965)· Ved syntesen dannes tri-methylsilylderivatet af methyl-l,2,4-triazol~3-carboxylatet i kvantitativ udbytte ved reaktion med hexamethyldisilazan under tilbagesvaling og reageres med en passende O-acyleret halosukker GX til at drøne f.eks. en blanding af O-benzoyleret 1-(β-D-ribofuranosyl)-1,2,4-triazol-3-carboxylsyremethylester og 5-carboxylsyremethylester, dvs.
6 143069 o
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z z , hvori Bz er benzoylo 3-carboxy1syrernethylesteren fraskilles ved fraktionel krystallisation eller, fortrinsvis, ved kolonnechromato-grafi over silikagel. Amino lyse og debenzoylering giver l-(P-D-ribo-furanosyl )-1,2,3-triazol-3-carboxamidet.
Den foretrukne syntesemetode er ved syrekatalyseret fusion af en egnet substitueret triazol med den O-acylblokerede sukkerart (i dette tilfælde l-O-acetyl-2,3>5-tri-0-benzoyl-P-D-ribofuranose) fulgt af amino lyse og afblokering, dvs.
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Selvom opfindelsen er blevet beskrevet med speciel henvisning til acetyl- eller benzoyl-blokering af 2«-, 3'- og 5'-hydroxyler i gly-cosylhalvdelen, forstås det, at en vilkårlig acylgruppe kan anvendes til at bevare disse hydroxyler mod sidereaktioner såsom dehydrering under syntesen af den aktive forbindelse.
7 143089
Medens den 1'-"efterladende gruppe" af de ovenfor diskuterede sukkerreagenser er blevet karakteriseret som acetyl eller, i s±-lyleringsprocessen, som halo-, forstås det, at en vilkårlig forskydelig halvdel kan anvendes som ansvarlig for biproduktadskillelse.
Opfindelsen skal yderligere illustreres og beskrives i de følgende eksempler, hvor alle dele og procenter er efter vægt og alle temperaturer i °C, med mindre andet er angivet. Eksemplerne 1-3 omhandler fremstillingen af udgangaforbindelser. Alle fordampningsprocesser udførtes i en rotationsfordamper under formindsket tryk ved 35°C.
Eksempel 1 l-(2,3,5-tri-0-benzoyl-p-D-ribofuranosyl)-l,2,4-triazol-3-carboxyl-syremethylester og l-(2,3,5-tri-0-benzoyl-P-D-ribofuranosyl)-l,2,4-triazol-5-carboxylsyremethylester. (Silyleringsprocessen).
(A) Fremstilling af methyl N-(trimethylsilyl)-1,2,4-triazol-3- carboxylat.
En suspension af methyl l,2,4-triazol-3-carboxylat (l4,0 g, 110 mmol) og hexamethyldisilazan (100 ml) blev tilbagesvalet under omrøring til udviklingen af ammoniak ophørte (ca. 2 timer). Det overskydende hexamethyldisilazan fjernedes under formindsket tryk til at give 20,6 g (100$) af N-trimethylsilylderivatet af methyl 1,2,4-triazol-3-carboxylat.
(b) Ribosylering med halosukker.
En opløsning indeholdende methyl Ii-(trimethylsilyl)-lt2,4-triazol-3-carboxylat (20,6 g, 110 mmol) og 2,3>5-tri-0-benzoyl-D-ribofuranosylbromid (52,5 g, 100 mmol) i vandfrit acetonitril (300 ml) holdtes ved 25° i tre dage. Opløsningsmidlet fjernedes, og resten krystalliseredes i ethanol. Rekrystalliseringen af materialet i ethylacetat-ethanol og søjlechromatografi af filtraterne over sili-kagel med chloroform gav ren l-(2,3,5-tri-0-benzoyl-P-D-ribofurano-syl)-l,2,4-triazol-3-carboxylsyremethylester (25,1 g, 44,0$) med smeltepunkt 137-1390.
Analyse. Beregnet for C^H^N^O; C 63,04$ H 4,4lj N 7»35.
Fundets C 62,91f H 4,17» N 7,10.
Den hurtigt vandrende komponent fra silikagelsøjlen krystalliseredes i ethanol til at give l-(2,3,5-tri-0-benzoyl-$-D-r±bofura-nosyl)-1,2,4-triazol-5-carboxylsyremethylester (13,2 g, 23,1$) med smeltepunkt 122-124°.
δ 143069
Analyse. Pundet: C 63,20; H 4,35; N 7,12.
Eksempel 2 1-(2,3,5-tri-0-benzoyl-8-D-ribofuranosyl)-1,2,4-triazo1-3-carboxyl-svremethylester. (fusionsprocessen).
En blanding af methyl-1,2,4-triazol-3-carboxylat (12,7 g, 100 ramol) og l-0-acetyl-2,3,5-tri-0-benzoyl-3-D-ribofuranose (55,4 g, 110 mmol) opvarmedes i et oliebad, som blev holdt ved 16O-I650. Efter at sukkeret var smaltet, tilsattes bis(p-nitrophenyl)phosphat (kOO mg) ved omrøring, og blandingen opvarmedes under formindsket tryk til 16Ο-1650 i 15-20 min. Krystallisation af resten i ethylace-tat-ethanol gav 42,5 g (74,5$) produkt med smeltepunkt 137-139°·
Eksempel 3 1-(2,3,5-tri-O-acetyl-P-D-ribofuranosyl)-1,2,4-triazol-3-carboxyl-svremethvlester.
En blanding af methyl-l,2,4-triazol-3-carboxylat (12,7 g, 0,10 mol) og l,2,3,5-tetra-0-acetyl^-D-ribofuranose (31,8 g, 0,10 mol) opvarmedes i et oliebad, som blev holdt ved 160-165°C, indtil sukkeret var smeltet. Bis-(p-nitrophenyl)phosphat (250 mg) tilsattes, og opvarmning til I6O-I650 fortsattes med omrøring under formindsket tryk i 15-20 min. Resten opløstes i varm benzen, opløsningen filtreredes, og der tilsattes cyclohexan til filtratet til at give det krystallinske produkt (30,0 g, 77,8$) med smeltepunkt 107-109°·
Analyse. Beregnet for C Il^N 0^: C 46,75; H 4,97; N 10,91. Fundet: C 46,88; H 5,03; N 10,64.
Eksempel 4 (A) 1-(β-D-ribofuranosyl)-1,2,4-triazol-3-carboxamid. Metode 1
En opløsning af 1-(2,3,5-tri-0-benzoyl-P~D-ribofuranosyl)- 1,2,4-triazo1-3-carboxylsyremethylester (l6,0 g, 28,0 mmol) i methanol (300 ml, forud mættet med vandfri ammoniak ved 0°) holdtes i en lukket trykflaske ved 25° i tre dage. Opløsningsmidlet fjernedes, og produktet krystalliseredes i ethanol til at give 6,7 g (98 $) materiale med smeltepunkt 174-176°. Rekrystallisation af produktet i vandig ethanol gav en anden krystallinsk form for nucleosidet med smeltepunkt 166-168°.
Analyse. Beregnet for . c 39,34; H 4,95; N 22,94.
Fundet: C 39,08; II 5,10; N 22,67· 9 143069 (B) 1-(S-D-ribofuranosyl)-1,2,4-triazol-3-carboxamjd. Metode 2.
En opløsning af l-(2,3»5-tri-0-acetyl-P-D-ribofuranosyl)- l,2,4-triazol-3-carboxylsyremethylester (10,0 g, 26,0 mmol) i methanol (70 ml) mættet ved 0° med vandfri ammoniak holdtes i en lukket trykflaske ved 25° i 18 timer. Produktet krystalliseredes i ethanol til at give 1-(β-D-ribofuranosyl)-1,2,4-triazol-3-carboxamid (5,70 g, 90,0%).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK509776A DK145101C (da) | 1971-06-01 | 1976-11-12 | Analogifremgangsmaade til fremstilling af 1,2,4-triazol-nucleosider |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14901771A | 1971-06-01 | 1971-06-01 | |
| US14901771 | 1971-06-01 | ||
| US24025272A | 1972-03-31 | 1972-03-31 | |
| US24025272 | 1972-03-31 |
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| Publication Number | Publication Date |
|---|---|
| DK143069B true DK143069B (da) | 1981-03-23 |
| DK143069C DK143069C (da) | 1981-11-02 |
Family
ID=26846393
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK237072A DK143069C (da) | 1971-06-01 | 1972-05-12 | Analogifremgangsmaade til fremstilling af et 3-substitueret 1,2,4-triazol-nucleosid |
| DK509876A DK509876A (da) | 1971-06-01 | 1976-11-12 | 1,2,4-triazol nucleosider |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK509876A DK509876A (da) | 1971-06-01 | 1976-11-12 | 1,2,4-triazol nucleosider |
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| JP (5) | JPS5527076B1 (da) |
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| BE (1) | BE784195A (da) |
| BG (1) | BG22827A3 (da) |
| CA (1) | CA997756A (da) |
| CH (1) | CH614452A5 (da) |
| DD (1) | DD99791A5 (da) |
| DE (1) | DE2220246A1 (da) |
| DK (2) | DK143069C (da) |
| EG (1) | EG11406A (da) |
| ES (1) | ES403142A1 (da) |
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Families Citing this family (98)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984396A (en) * | 1971-06-01 | 1976-10-05 | Icn Pharmaceuticals, Inc. | 1-(β,-D-ribofuranosyl)-1,2,4-triazole acid esters |
| DE2401449A1 (de) * | 1973-01-16 | 1974-07-25 | Voorhees | Pharmazeutische zusammensetzung zur linderung von hautproliferationserkrankungen |
| US3888843A (en) * | 1973-06-12 | 1975-06-10 | Toyo Jozo Kk | 4-carbamoyl-1-' -d-ribofuranosylimidazolium-5-olate |
| AR207138A1 (es) * | 1974-03-18 | 1976-09-15 | Icn Pharmaceuticals | Metodo para la obtencion de 1,2,4-triazoles n-substituidos y sus sales de adicion |
| GB1482736A (en) * | 1974-03-18 | 1977-08-10 | Icn Pharmaceuticals | 1-(beta-d-ribofuranosyl)-1,2,4-triazole acid derivatives |
| US3960836A (en) * | 1974-07-22 | 1976-06-01 | Eli Lilly And Company | Acylated derivatives of pyrazofurin and process for their preparation |
| US4007198A (en) * | 1975-05-01 | 1977-02-08 | American Cyanamid Company | Substituted 1,2,4-triazole carboxamide |
| US4138547A (en) * | 1977-12-22 | 1979-02-06 | Icn Pharmaceuticals, Inc. | Process for preparing 1,2,4-triazole nucleosides |
| JPS57146593A (en) * | 1981-03-09 | 1982-09-10 | Ajinomoto Co Inc | Preparation of ribofuranosyltriazole derivative |
| US4451648A (en) * | 1981-08-19 | 1984-05-29 | The United States Of America As Represented By The Department Of Health And Human Services | Process for the production of 2-β-D-ribofuranosylthiazole-4-carboxamide |
| US4531001A (en) * | 1982-03-23 | 1985-07-23 | Brigham Young University | 2-β-D-ribofuranosylselenazole-4-carboxamide compounds |
| US4446315A (en) * | 1982-09-24 | 1984-05-01 | The United States Of America As Represented By The Department Of Health And Human Services | Adenosine 5'-triphosphate-4-carboxamide-ribofuranosylthiazole |
| JPS5964648U (ja) * | 1982-10-22 | 1984-04-28 | 阿波野 政晴 | 日覆用骨格 |
| BE902199A (fr) * | 1984-10-29 | 1985-07-31 | Vira Tek Inc | Procede de traitement medical de maladies virales utilisant le 1-beta-d-ribofurannosyl-1, 2,4-triazole-3-carboxamide. |
| NZ213370A (en) * | 1985-01-16 | 1989-03-29 | Vira Tek Inc | Method of treating viral infections of selected trees and field crops using ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) or the 2,3,5-triacetyl or 5'-butyryl derivative thereof |
| DE3606634A1 (de) * | 1986-02-28 | 1987-09-03 | Mack Chem Pharm | Isohexid-nucleoside, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| WO1987005807A1 (en) * | 1986-03-27 | 1987-10-08 | Harry Edward Gruber | A method of increasing adenosine excretion |
| US4925930A (en) * | 1988-11-02 | 1990-05-15 | Nucleic Acid Research Institute | Synthesis and anti-leukemic activity of alkyl-1-(β-D-ribofuranosyl)[1,2,4]triazole-3-carboximidates |
| US5438131A (en) * | 1992-09-16 | 1995-08-01 | Bergstrom; Donald E. | 3-nitropyrrole nucleoside |
| SK8612002A3 (en) * | 1999-12-23 | 2003-03-04 | Ribapharm Inc | Compositions and methods for L-nucleosides, L-nucleotides, and their analogs |
| US6455508B1 (en) * | 2000-02-15 | 2002-09-24 | Kanda S. Ramasamy | Methods for treating diseases with tirazole and pyrrolo-pyrimidine ribofuranosyl nucleosides |
| US6495677B1 (en) * | 2000-02-15 | 2002-12-17 | Kanda S. Ramasamy | Nucleoside compounds |
| US7638496B2 (en) * | 2000-02-15 | 2009-12-29 | Valeant Pharmaceuticals North America | Nucleoside analogs with carboxamidine modified monocyclic base |
| MY164523A (en) * | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| JP5230052B2 (ja) * | 2000-05-26 | 2013-07-10 | イデニクス（ケイマン）リミテツド | フラビウイルスおよびペスチウイルス治療のための方法および組成物 |
| US6815542B2 (en) * | 2000-06-16 | 2004-11-09 | Ribapharm, Inc. | Nucleoside compounds and uses thereof |
| CA2416748A1 (en) * | 2000-08-22 | 2002-02-28 | Ribapharm Inc. | Improved specificity in treatment of diseases |
| US6878364B2 (en) * | 2000-12-01 | 2005-04-12 | Cornell Research Foundation, Inc. | Animal model for flaviviridae infection |
| US20040014696A1 (en) * | 2000-12-07 | 2004-01-22 | Johnson Lau | Specificity in treatment of diseases |
| US6720000B2 (en) * | 2001-03-19 | 2004-04-13 | Three Rivers Pharmaceutical, Llc | Process for producing wet ribavirin pellets |
| EP1281715B1 (en) * | 2001-07-30 | 2003-10-22 | Clariant Life Science Molecules (Italia) SpA | Process for the preparation of ribavirin |
| WO2003026589A2 (en) * | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating hepatitis c virus using 4'-modified nucleosides |
| BR0213861A (pt) * | 2001-11-02 | 2004-12-21 | Sandoz Ag | Processo para a preparação de composições de ribavirina de carga elevada, de dissolução rápida |
| KR100411398B1 (ko) | 2001-12-06 | 2003-12-18 | 주식회사유한양행 | 베타-디-리보푸라노즈 유도체의 제조방법 |
| NZ537662A (en) * | 2002-06-28 | 2007-10-26 | Idenix Cayman Ltd | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| TW200500375A (en) | 2002-06-28 | 2005-01-01 | Idenix Cayman Ltd | Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae |
| US7608600B2 (en) * | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| AP2005003213A0 (en) * | 2002-06-28 | 2005-03-31 | Univ Cagliari | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections. |
| US20040067877A1 (en) * | 2002-08-01 | 2004-04-08 | Schinazi Raymond F. | 2', 3'-Dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections |
| US7538094B2 (en) * | 2002-09-19 | 2009-05-26 | Three Rivers Pharmacueticals, Llc | Composition containing ribavirin and use thereof |
| US7824851B2 (en) | 2002-11-15 | 2010-11-02 | Idenix Pharmaceuticals, Inc. | 2′-branched nucleosides and Flaviviridae mutation |
| MXPA05006230A (es) * | 2002-12-12 | 2005-09-20 | Idenix Cayman Ltd | Proceso para la produccion de nucleosidos ramificados-2'. |
| AU2003300434A1 (en) * | 2002-12-23 | 2004-07-22 | Idenix (Cayman) Limited | Process for the production of 3'-nucleoside prodrugs |
| CN1980678A (zh) * | 2003-03-28 | 2007-06-13 | 法莫赛特股份有限公司 | 治疗黄病毒感染的化合物 |
| CN100503628C (zh) | 2003-05-30 | 2009-06-24 | 法莫赛特股份有限公司 | 修饰的氟化核苷类似物 |
| CN1852915A (zh) * | 2003-07-25 | 2006-10-25 | 艾登尼科斯（开曼）有限公司 | 治疗包括丙型肝炎的黄病毒科病毒所致疾病的嘌呤核苷类似物 |
| WO2005018330A1 (en) * | 2003-08-18 | 2005-03-03 | Pharmasset, Inc. | Dosing regimen for flaviviridae therapy |
| US20050187192A1 (en) * | 2004-02-20 | 2005-08-25 | Kucera Pharmaceutical Company | Phospholipids for the treatment of infection by togaviruses, herpes viruses and coronaviruses |
| AU2005256963A1 (en) * | 2004-06-23 | 2006-01-05 | Centre National De La Recherche Scientifique | 5-aza-7-deazapurine derivatives for treating infections with flaviviridae |
| CN101023094B (zh) * | 2004-07-21 | 2011-05-18 | 法莫赛特股份有限公司 | 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 |
| BRPI0515279A (pt) * | 2004-09-14 | 2008-07-15 | Pharmasset Inc | preparação de ribofuranosil pirimidinas e purinas 2'fluoro-2'-alquil- substituìdas ou outras opcionalmente substituìdas e seus derivados |
| KR101294467B1 (ko) * | 2005-07-25 | 2013-09-09 | 인터뮨, 인크. | Ｃ형 간염 바이러스 복제의 신규 거대고리형 억제제 |
| BRPI0617274A2 (pt) * | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| ES2422290T3 (es) * | 2005-12-23 | 2013-09-10 | Idenix Pharmaceuticals Inc | Procedimiento para preparar un producto intermedio sintético para la preparación de nucleósidos ramificados |
| UA100666C2 (uk) | 2006-04-11 | 2013-01-25 | Новартіс Аг | Інгібітори нсv/віл та їх застосування |
| US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| EP2201953A4 (en) | 2007-08-27 | 2011-08-03 | Univ Nagoya Nat Univ Corp | USE OF RIBAVIRIN IN BLOOD CLEANING DISORDERS |
| US20110045535A1 (en) | 2007-08-27 | 2011-02-24 | National University Corporation Nagoya University | Activator for Blood Coagulation Factor VII Promoter and Utilization of the Same |
| US20090082414A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched viramidine |
| WO2009105258A1 (en) | 2008-02-22 | 2009-08-27 | Nektar Therapeutics Al, Corporation | Oligomer conjugates of heteropentacyclic nucleosides |
| TW200946541A (en) * | 2008-03-27 | 2009-11-16 | Idenix Pharmaceuticals Inc | Solid forms of an anti-HIV phosphoindole compound |
| MX2010011306A (es) * | 2008-04-15 | 2010-11-09 | Intermune Inc | Nuevos inhibidores macrociclicos de la replicacion del virus de la hepatitis c. |
| US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
| CN102216321A (zh) * | 2008-10-15 | 2011-10-12 | 因特蒙公司 | 治疗性抗病毒肽 |
| WO2010077613A1 (en) | 2008-12-09 | 2010-07-08 | Gilead Sciences, Inc. | Modulators of toll-like receptors |
| US8551973B2 (en) * | 2008-12-23 | 2013-10-08 | Gilead Pharmasset Llc | Nucleoside analogs |
| EP2376515A1 (en) * | 2008-12-23 | 2011-10-19 | Pharmasset, Inc. | Synthesis of purine nucleosides |
| CA2748057C (en) * | 2008-12-23 | 2018-07-03 | Pharmasset, Inc. | Nucleoside phosphoramidates |
| US20110182850A1 (en) | 2009-04-10 | 2011-07-28 | Trixi Brandl | Organic compounds and their uses |
| US8512690B2 (en) | 2009-04-10 | 2013-08-20 | Novartis Ag | Derivatised proline containing peptide compounds as protease inhibitors |
| TWI598358B (zh) | 2009-05-20 | 2017-09-11 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
| US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| CN105001302A (zh) * | 2009-09-28 | 2015-10-28 | 英特穆恩公司 | C型肝炎病毒复制的环肽抑制剂 |
| WO2011041551A1 (en) * | 2009-10-01 | 2011-04-07 | Intermune, Inc. | Therapeutic antiviral peptides |
| WO2011076923A1 (en) | 2009-12-23 | 2011-06-30 | Institut National De La Sante Et De La Recherche Medicale | Inhibitor for inosine monophosphate (imp) dehydrogenase and/or viral rna polymerase for treatment of hepatitis e |
| US8933110B2 (en) | 2010-01-25 | 2015-01-13 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| EA201201031A1 (ru) * | 2010-01-25 | 2013-02-28 | Энанта Фармасьютиклз, Инк. | Ингибиторы вируса гепатита с |
| CL2011000718A1 (es) | 2010-03-31 | 2012-04-09 | Gilead Pharmasset Llc | Proceso para la preparacion de compuestos fosforados enantiomericos. |
| PL3290428T3 (pl) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tabletka zawierająca krystaliczny (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropirymidyn-1(2H)-ylo)-4-fluoro-3-hydroksy-4-metylotetrahydrofuran-2-ylo)metoksy)(fenoksy)fosforylo)amino)propanian izopropylu |
| AU2011311880B2 (en) | 2010-10-08 | 2014-07-24 | Novartis Ag | Vitamin E formulations of sulfamide NS3 inhibitors |
| PT3042910T (pt) | 2010-11-30 | 2019-04-16 | Gilead Pharmasset Llc | 2'-espiro-nucleósidos para utilização na terapia da hepatite c |
| WO2012087596A1 (en) | 2010-12-20 | 2012-06-28 | Gilead Sciences, Inc. | Combinations for treating hcv |
| CA2752008A1 (en) | 2011-09-13 | 2013-03-13 | Universite De Montreal | Combination therapy using ribavirin as elf4e inhibitor |
| AU2012308295B2 (en) | 2011-09-16 | 2017-10-26 | Gilead Sciences, Inc. | Methods for treating HCV |
| US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
| WO2014068265A1 (en) | 2012-10-29 | 2014-05-08 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
| US20140205566A1 (en) | 2012-11-30 | 2014-07-24 | Novartis Ag | Cyclic nucleuoside derivatives and uses thereof |
| MY172166A (en) | 2013-01-31 | 2019-11-15 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
| EP3650014B1 (en) | 2013-08-27 | 2021-10-06 | Gilead Pharmasset LLC | Combination formulation of two antiviral compounds |
| EA201692507A1 (ru) | 2014-06-23 | 2017-04-28 | Сановель Илач Санайи Ве Тиджарет А.Ш. | Фармацевтические комбинации софосбувира и рибавирина |
| US20170128482A1 (en) | 2014-06-23 | 2017-05-11 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Modified release pharmaceutical compositions of sofosbuvir and ribavirin |
| US20170151272A1 (en) | 2014-06-23 | 2017-06-01 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A novel pharmaceutical composition of sofosbuvir and ribavirin |
| EP4140485A1 (en) | 2014-07-11 | 2023-03-01 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
| EA201790369A1 (ru) | 2014-09-16 | 2017-10-31 | Джилид Сайэнс, Инк. | Твердые формы модулятора толл-подобного рецептора |
| UY37381A (es) | 2016-08-30 | 2018-03-23 | Glaxosmithkline Ip No 2 Ltd | Compuestos que inhiben proteasas 3c y 3cl y métodos de uso de los mismos |
| CN110713464B (zh) * | 2019-10-31 | 2023-03-31 | 重庆大学 | 一种芳基1,2,4-三氮唑核苷化合物及其制备方法和应用 |
| US20230218644A1 (en) | 2020-04-16 | 2023-07-13 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
| CN116621899B (zh) * | 2023-05-18 | 2026-02-06 | 中国人民解放军军事科学院军事医学研究院 | 非天然核苷类似物及其用途 |
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1972
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- 1972-04-25 DE DE19722220246 patent/DE2220246A1/de not_active Withdrawn
- 1972-05-11 AU AU42157/72A patent/AU461900B2/en not_active Expired
- 1972-05-11 IL IL39416A patent/IL39416A/xx unknown
- 1972-05-12 IE IE638/72A patent/IE36478B1/en unknown
- 1972-05-12 DK DK237072A patent/DK143069C/da not_active IP Right Cessation
- 1972-05-13 JP JP4760172A patent/JPS5527076B1/ja active Pending
- 1972-05-13 GB GB2241972A patent/GB1353565A/en not_active Expired
- 1972-05-15 IS IS2075A patent/IS913B6/is unknown
- 1972-05-20 EG EG203/72A patent/EG11406A/xx active
- 1972-05-24 ES ES403142A patent/ES403142A1/es not_active Expired
- 1972-05-25 CH CH776572A patent/CH614452A5/xx not_active IP Right Cessation
- 1972-05-26 NL NL7207156A patent/NL7207156A/xx not_active Application Discontinuation
- 1972-05-26 NO NO1858/72A patent/NO138805C/no unknown
- 1972-05-29 DD DD163262A patent/DD99791A5/xx unknown
- 1972-05-30 AR AR242262A patent/AR199463A1/es active
- 1972-05-31 FR FR7219501A patent/FR2140126B1/fr not_active Expired
- 1972-05-31 CA CA143,816A patent/CA997756A/en not_active Expired
- 1972-05-31 BG BG020615A patent/BG22827A3/xx unknown
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- 1972-05-31 HU HUIE507A patent/HU167614B/hu unknown
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- 1972-06-01 RO RO7200071105A patent/RO62435A/ro unknown
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1974
- 1974-05-09 IN IN1026/CAL/1974A patent/IN142290B/en unknown
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1976
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1978
- 1978-01-13 JP JP325978A patent/JPS5387356A/ja active Granted
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- 1978-01-13 JP JP326078A patent/JPS53124271A/ja active Pending
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