- NUCLEOSIDE DERIVATIVES AS INHIBITORS OF RNA-DEPENDENT RNA VIRAL POLYERMASE
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The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
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Paragraph 0771; 0772; 0773
(2017/07/14)
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- Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus
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2′-α-C-Methyl-2′-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure?activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2′-β-F by Arg158, 3′-OH by N291, and the Watson?Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.
- Zeng, Debin,Zhang, Rui,Nie, Quandeng,Cao, Lin,Shang, Luqing,Yin, Zheng
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supporting information
p. 1197 - 1201
(2016/12/18)
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- An efficient approach for the synthesis of 1′-O-α-methyl pyrrolo[2,3-d]pyrimidine isonucleosides
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A series of novel 1′-O-methyl isonucleosides were efficiently and stereoselectively synthesized with 1,2,3,5-tetra-O-acetyl-D-ribofuranose as the starting material. The key steps include regioselective and stereoselective deprotection of the 2,4-dichlorobenzyl group at C2, triflation, and substitution with appropriate nucleobases using cesium carbonate as the base. Removal of the residual 2,4-dichlorobenzyl groups and subsequent transformation afforded the title compounds in 30-37% overall yield. The products represent a new type of isonucleosides with 1-O-substitution. Georg Thieme Verlag Stuttgart New York.
- Song, Yang,Yang, Ruchun,Ding, Haixin,Sun, Qi,Xiao, Qiang,Ju, Yong
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p. 1213 - 1218
(2011/06/10)
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- Efficient synthesis of methyl 3,5-di-O-benzyl-α-D-ribofuranoside and application to the synthesis of 2′-C-β-alkoxymethyluridines
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Methyl 3,5-di-O-arylmethyl-α-D-ribofuranosides have been used extensively as synthons to construct 2'-C-branched ribonucleosides. Herein, we describe efficient access to methyl 3,5-di-O-arylmethyl-α-D- ribofuranosides (aryl: 2-ClC6H4, 3-ClC6H 4, 4-ClC6H4, 4-BrC6H4, 2,4-Cl2C6H3, Ph) in 72-82% yields from methyl D-ribofuranoside. We also demonstrate efficient access to the versatile precursor methyl 3,5-di-O-benzyl-α-D-ribofuranoside (3f) and the synthesis of 2′-C-β-methoxymethyl- and 2′-C-β-ethoxymethyluridine in six steps from 3f with overall yields of 18% and 32%, respectively.
- Li, Nan-Sheng,Lu, Jun,Piccirilli, Joseph A.
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p. 3009 - 3012
(2008/02/10)
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- Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds
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Infection by a Coronaviridae virus (e.g., a coronavirus) and/or illness due to a Coronaviridae virus are treated or protected against by administration of a therapeutically or prophylactically effective amount of certain nucleoside compounds and derivatives thereof, either alone or in a composition comprising the nucleoside compound or its derivative and a pharmaceutically acceptable carrier. In addition, replication of a Coronaviridae virus is inhibited by administration of the nucleoside compounds and derivatives thereof, either alone or in pharmaceutical compositions. The nucleosides are particularly suitable for use in treating or prophylaxis of an infection by the SARS virus and/or in treating or prophylaxis of SARS, and for use in inhibiting replication of the SARS virus. The nucleoside compounds and derivatives can optionally be administered in combination with other agents active against the Coronaviridae virus and/or an illness due to the virus. The nucleoside compounds are also for use in the manufacture of medicaments for the inhibition of Coronaviridae virus replication, for the treatment or prophylaxis of Coronaviridae virus infection, and/or for the treatment or prophylaxis of an illness due to a Coronaviridae virus (e.g., the SARS virus). In addition, the compounds are for use as medicaments for the inhibition of Coronaviridae virus replication, for the treatment or prophylaxis of Coronaviridae virus infection, and/or for the treatment or prophylaxis of an illness due to a Coronaviridae virus.
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Page/Page column 12; 13
(2010/02/09)
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- Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
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The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
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- 38. A new access to 2'-O-alkylated ribonucleosides and properties of 2'-O-alkylated oligoribonucleotides
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A general access to 2'-O-alkylated ribonucleosides using the key intermediate 5 is presented. The incorporation of 2'-O-'ethyleneglycol'- and 2'-O-'glycerol'-substituted (i.e., 2'-O-(2-hydroxyethyl)- and 2'-O-(2,3-dihydroxypropyl)-substituted) ribonucleosides into oligonucleotides affords a new generation of oligonucleotides with high affinity for RNA, high specificity, and increased nuclease resistance.
- Martin
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p. 486 - 504
(2007/10/02)
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