- Novel intramolecular aminohydroxylation toward the syntheses of 2′-amino-2′-ethynyl nucleosides
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Syntheses of both 2′-amino-2′-ethynyl guanosine and uridine, using an intramolecular aminohydroxylation reaction as the key step, are described. The corresponding 5′-O-triphosphates of the aforementioned nucleosides were obtained and the inhibitory activity was subsequently evaluated against the hepatitis C virus NS5B polymerase.
- Huang, Yuhua,Bennett, Frank,Buevich, Alexei,Girijavallabhan, Vinay,Kerekes, Angela D.,Huang, Hsueh-Cheng,Tawa, Paul,Bogen, Stephane L.,Davies, Ian W.
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supporting information
(2021/05/10)
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- Synthesis and biological evaluation of a novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection
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A novel β-D-2′-deoxy-2′-α-fluoro-2′-β-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18–1.13 μM) with low cytotoxicity (CC50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.
- Li, Ertong,Wang, Yafeng,Yu, Wenquan,Lv, Zhigang,Peng, Youmei,Liu, Bingjie,Li, Shiliang,Ho, Wenzhe,Wang, Qingduan,Li, Honglin,Chang, Junbiao
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p. 107 - 113
(2017/11/27)
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- Novel 2'-fluorouracil nucleoside and synthetic method
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The invention discloses a novel 2'-fluorouracil nucleoside and a synthetic method. A structural general formula of a compound is shown as the specification, and the synthetic method comprises the following steps in the specification. The synthesis method
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- Novel 2'-uridine azide and synthetic method thereof
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The invention discloses novel 2'-uridine azide and a synthetic method thereof. The structural formula of the compound is as shown in specification, and reaction steps of the synthetic method of the novel 2'-uridine azide are as shown in specification. The
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Paragraph 0016
(2018/11/22)
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- PROCESS FOR MAKING CHLORO-SUBSTITUTED NUCLEOSIDE PHOSPHORAMIDATE COMPOUNDS
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The present invention is directed to a process for making Chloro-Substituted Nucleoside Phosphoramidate Compounds of formula (I): which are useful for the treatment and prophylaxis of HCV infection. The present invention is also directed to compounds that are useful as synthetic intermediates for making the compounds of formula (I).
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Paragraph 0236; 0237; 0238; 0240; 0241; 0243
(2017/09/02)
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- Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof
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The invention provides an antiviral nucleoside phosphoramidate and a pharmaceutical composition and applications thereof. The nucleoside phosphoramidate compound is prepared by connecting nucleoside with phosphate through phosphorus-oxygen bonds. The structural formulas of the nucleoside phosphoramidate compound are represented by a, a1, a2, b, b1, and b2. The invention also discloses stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or crystals of the nucleoside phosphoramidate compound. The anti-hepatitis C activity of the provided novel nucleoside phosphoramidate is obviously better than that of sofosbuvir used in clinic. On the saccharide ring, the fluorine atoms are replaced by chlorine atoms, and the cytotoxicity of measure cell lines is prominently reduced. By systematically modifying and optimizing the basic groups, saccharide rings, and prodrugs, the anti-hepatitis C activity of partial synthesized compounds is 2 to 10 times higher than that of sofosbuvir. At the same time, the key parts of metabolism are optimized, the metabolism stability and chemical stability of synthesized compounds in plasma are better, compared with those of sofosbuvir.
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- IMPROVED FLUORINATION PROCESS
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A process comprising (i) providing a mixture comprising a compound of formula (I) or isomers, stereoisomers, diastereomers, enantiomers or salts thereof; (ii)subjecting the mixture provided in (i) to fluorinating conditions in the presence of a fluorination agent selected from the group consisting of diethylamino (difluoro) sulfonium tetrafluoroborate and difluoro(morpholino) sulfonium tetrafluoroborate obtaining a mixture comprising a compound of formula (II) or isomers, stereoisomers diastereomers, enantiomers or salts thereof; (iii) optionally subjecting the mixture obtained in (ii) to deprotection conditions, obtaining a mixture comprising the compound of formula (III) or isomers, stereoisomers, diastereomers, enantiomers or salts thereof.
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Page/Page column 96
(2016/05/19)
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- 2 -ALKYNYL SUBSTITUTED NUCLEOSIDE DERIVATIVES FOR TREATING VIRAL DISEASES
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The present invention relates to 2'-Alkynyl Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one 2'-Alkynyl Substituted Nucleoside Derivative, and methods of using the 2'-Alkynyl Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
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- Practical synthesis of (2′ R)-2′-deoxy-2′-C-methyluridine by highly diastereoselective homogeneous hydrogenation
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Diastereoselective hydrogenation of 2′-deoxy-2′-exo- methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale.
- Lemaire, Sebastien,Houpis, Ioannis,Wechselberger, Rainer,Langens, Jaak,Vermeulen, Wim A. A.,Smets, Nico,Nettekoven, Ulrike,Wang, Youchu,Xiao, Tingting,Qu, Haisheng,Liu, Renmao,Jonckers, Tim H.M.,Raboisson, Pierre,Vandyck, Koen,Nilsson, Karl M.,Farina, Vittorio
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p. 297 - 300
(2011/03/20)
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- Synthesis of dinucleotides with 2′-C to phosphate connections by ring-closing metathesis
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Four different nucleosides with olefinic 2′-modifications were prepared; 2′-C-methylene, 2′-C-(propen-1-yl), 2′-C-allyl and 2′-O-allyl uridines, respectively. These were incorporated into dinucleotides with allyl phosphate or vinyl phosphonate linkages. Hence, six different dinucleotides were studied as substrates for RCM reactions, and from four of these, cyclic dinucleotides with connections between 2′-C and phosphorus of 3-6 atoms were obtained.
- B?rsting, Philip,Christensen, Mikkel S.,Steffansen, Signe I.,Nielsen, Poul
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p. 1139 - 1149
(2007/10/03)
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- 2'deoxy-2'-alkylnucleotide containing nucleic acid
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2'-deoxy-2'-alkylnucleotides useful for stabilizing enzymatic nucleic acid molecules and antisense molecules.
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- Synthesis of branched nucleosides closely related to AZT, involving SN2′ opening of anhydronucleosides
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Three 2′,3′-unsaturated pyrimidine nucleosides, bearing an azido-methyl group at 2′ or 3′ were synthesized as potential anti-HIV agents. The key step involves an SN2′ opening of 2,2′ or 2,3′-anhydronucleosides by azide ion.
- Czernecki, Stanislas,Ezzitouni, Abdallah
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p. 315 - 318
(2007/10/02)
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- Stereoselective addition of a Wittig reagent to give a single nucleoside oxaphosphetane diastereoisomer. Synthesis of 2'(and 3')-deoxy-2'(and 3')-methyleneuridine (and cytidine) derivatives from uridine ketonucleosides
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Treatment of 3',5'(or 2',5')-bis-O-silyl-protected 2'(or 3')-ketouridine derivatives with methyltriphenylphosphonium bromide and sodium 2-methyl-2-butoxide in diethyl ether/benzene at 0-4 °C resulted in the slow formation of the corresponding 2'(or 3')-deoxy-2'(or 3')-methylene analogues. 1H- and 31P-NMR spectra were in harmony with formation of a single oxaphosphetane diastereoisomer during early stages of the Wittig reaction. Conversions of protected deoxymethyleneuridine to deoxymethylenecytidine derivatives were effected smoothly via 4-(1,2,4-triazol-1-yl) intermediates. Deprotection with tetrabutylammonium fluoride gave 2'(or 3')-deoxy-2'(or 3')-methylneuridine and cytidine nucleosides.
- Samano,Robins
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p. 283 - 288
(2007/10/02)
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- 2'-alkylidenepyrimidine nucleoside derivatives, process for production thereof, and uses thereof
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Disclosed are novel 2'-alkylidenepyrimidine nucleoside derivatives represented by formula [I]: STR1 wherein R1 is an amino gorup or a hydroxy group, R2 is a hydrogen atom, a halogen atom or a lower alkyl group, R3 is a hydrogen atom or a lower alkyl group, and R4 is a hydrogen atom or a phosphate residue, or salts thereof. These novel compounds can be produced from uridine or cytidine derivatives by alkylidenating the 2'-position in the sugar moiety thereof with Wittig's reagent. Furthermore, the compounds have remarkable antiviral activities and therefore can provide novel antiviral agents.
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- Synthesis and Anticancer and Antiviral Activities of Various 2'- and 3'-Methylidene-Substituted Nucleoside Analogues and Crystal Structure of 2'-Deoxy-2'-methylidenecytidine Hydrochloride
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Various 2'- and 3'-methylidene-substituted nucleoside analogues have been synthesized and evaluated as potential anticancer and/or antiviral agents.Among these compounds, 2'-deoxy-2'-methylidene-5-fluorocytidine (22) and 2'-deoxy-2'-methylidenecytidine (23) not only demonstrated potent anticancer activity in culture against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF-CEM lymphoblastic leukemia, producing ED50 values of 1.2 and 0.3 μM, 0.6 and 0.4 μM, 1.5 and 1.5 μM, and 0.05 and 0.03 μM, respectively, but also were active in mice against murine L1210 leukemia.Of all the tested drug dosage levels (25, 50, and 75 mg/kg, respectively) compound 23 had no toxic deaths and compound 22 yielded only one toxic death at the highest dosage level.On the contrary, in the same study, 1-β-D-arabinofuranosylcytosine (ara-C) resulted in 2/5, 5/5, and 5/5 toxic deaths, respectively.Both compounds 22 and 23 have shown better anticancer activity than ara-C, yielding higher T/C * 100 values and some long-term survivors ( > 60 days).In addition, compounds 22 and 23 were found to have, respectively, approximately 130 and 40 times lower binding affinity for cytidine/deoxycytidine deaminase derived from human KB cells compared to ara-C, suggesting that the two 2'-methylidene-substituted analogues may be more resistant to deamination.Cytoplasmic deoxycytidine kinase (dCK) was required for compounds 22 and 23 action.Furthermore, compounds 14, 22, 23, and 24 also have antiherpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) activity in cell culture.In addition, the crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride (23*HCl) was determined by X-ray crystallography.
- Lin, Tai-Shun,Luo, Mei-Zhen,Liu, Mao-Chin,Clarke-Katzenburg, Regina H.,Cheng, Yung-Chi,et al.
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p. 2607 - 2615
(2007/10/02)
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- Nucleosides and nucleotides. 97. Synthesis of new broad spectrum antineoplastic nucleosides, 2'-deoxy-2'-methylidenecytidine (DMDC) and its derivatives
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A new type of antineoplastic nucleoside, 2'-deoxy-2'-methylidenecytidine (DMDC) has been synthesized from the corresponding 2'-keto pyrimidine nucleosides 3 and 8 by the Wittig reaction. During the course of the reaction, we found that an intermediate bet
- Matsuda,Takenuki,Tanaka,Sasaki,Ueda
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p. 812 - 819
(2007/10/02)
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