- Enzyme-Catalyzed Kinetic Resolution of Chiral Precursors to Antiviral Prodrugs
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Nucleoside analogues are among the most common medications given for the treatment of viral infections and cancers. The therapeutic effectiveness of nucleoside analogues can be dramatically improved by phosphorylation. The ProTide approach was developed u
- Xiang, Dao Feng,Bigley, Andrew N.,Desormeaux, Emily,Narindoshvili, Tamari,Raushel, Frank M.
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- PROCESS FOR THE PREPARATION OF (Sp)-SOFOSBUVIR AND INTERMEDIATES THEREOF
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The present invention is directed towards process for preparation of an optically pure (Sp)-Sofosbuvir of Formula-(I) and its intermediate namely (Sp)-isomer of isopropyl alanyl phosphoramidate of Formula (III) thereof.
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Page/Page column 11
(2018/03/28)
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- (S)- 2 - [(s)- (4 - nitro - phenoxy) - phenoxy - phosphoryl amino] isopropyl propionate preparation method
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The invention relates to a preparation method of (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate. The (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate, which is excellent in chemical purity and optical purity, is prepared by the following steps: preparing a compound as shown in a formula (III) from phenoxy dichlorophosphite as shown in a formula (I) and nitrophenol as shown in a formula (II), preparing a compound as shown in formula (V) from the compound as shown in the formula (III) and L-alanine isopropyl ester hydrochloride, and implementing solvent recrystallization on the compound as shown in the formula (V). The preparation method disclosed by the invention has the beneficial effects that the method for preparing the (s)-2-[(s)-(4-nitro-phenoxy)-phenoxy-phosphoryl amino] isopropyl propionate is simple in technological process and convenient to operate, and meanwhile the method is high in both purity and yield and is applicable to mass production.
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Paragraph 0023; 0029; 0030; 0031
(2017/08/25)
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- DIOXOLANE ANALOGUES OF URIDINE FOR THE TREATMENT OF CANCER
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The invention provides compounds of formula (I), wherein: R1 is OR11, or NR5R5'; R2 is H or F; R5 is H, C1-C6alkyl, OH, C(=O)R6, O(C=O)R6 or O(C=O)OR6; R5′ is H or C1-C6alkyl; R6 is C1-C6alkyl or C3-C7cycloalkyl; R13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R22; and the other variables are as defined in the claims, which are of use in the treatment of cancer, and related aspects.
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Page/Page column 52; 53
(2016/03/22)
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- STABILIZED NUCLEOTIDES FOR MEDICAL TREATMENT
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5′-Deuterated nucleosides and nucleotides and modifications thereof are provided for use in medical therapies, including as antiviral, anti-tumor and anti-neoplastic agents. In one embodiment, compounds, methods and uses are provided for the treatment of
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Paragraph 0696-0697; 0700-0701
(2016/02/12)
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- Discovery of the first C -nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients
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Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1′-cyano-2′-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.
- Cho, Aesop,Zhang, Lijun,Xu, Jie,Lee, Rick,Butler, Thomas,Metobo, Sammy,Aktoudianakis, Vangelis,Lew, Willard,Ye, Hong,Clarke, Michael,Doerffler, Edward,Byun, Daniel,Wang, Ting,Babusis, Darius,Carey, Anne C.,German, Polina,Sauer, Dorothea,Zhong, Weidong,Rossi, Stephen,Fenaux, Martijn,McHutchison, John G.,Perry, Jason,Feng, Joy,Ray, Adrian S.,Kim, Choung U.
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p. 1812 - 1825
(2014/04/03)
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- 1'-SUBSTITUTED PYRIMIDINE N-NUCLEOSIDE ANALOGS FOR ANTIVIRAL TREATMENT
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Provided are compounds of Formula I: nucleosides, nucleoside phosphates and prodrugs thereof, wherein R6 is CN, ethenyl, 2-haloethen-1-yl, or (C2-C8)-alkyn-1-yl. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections.
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Page/Page column 70
(2012/10/23)
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- METHODS FOR THE PREPARATION OF DIASTEROMERICALLY PURE PHOSPHORAMIDATE PRODRUGS
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Provided are methods and intermediates for preparing diastereomerically pure phosphoramidate prodrugs of nucleosides of Formulas (la) and (lb): The compounds of Formula la and lb are useful for the treatment Hepatitis C infections.
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- Synthesis of diastereomerically pure nucleotide phosphoramidates
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Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5′-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.
- Ross, Bruce S.,Ganapati Reddy,Zhang, Hai-Ren,Rachakonda, Suguna,Sofia, Michael J.
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p. 8311 - 8319
(2012/01/03)
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- N- [ (2 ' R) -2 ' -DEOXY-2 ' -FLUORO-2 ' -METHYL-P-PHENYL-5 ' -URIDYLYL] -L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR ITS PRODUCTION
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Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.
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Page/Page column 50
(2010/12/18)
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