- Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase
-
To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2′- and/or 4′-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2′-OH with 2′-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2′-fluorination, the introduction of fluorine at the ribose 4′-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2′-C-ethynyl-4′-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.
- Wang, Gang,Lim, Siew Pheng,Chen, Yen-Liang,Hunziker, Jürg,Rao, Ranga,Gu, Feng,Seh, Cheah Chen,Ghafar, Nahdiyah Abdul,Xu, Haoying,Chan, Katherine,Lin, Xiaodong,Saunders, Oliver L.,Fenaux, Martijn,Zhong, Weidong,Shi, Pei-Yong,Yokokawa, Fumiaki
-
p. 2324 - 2327
(2018/05/28)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF SOFOSBUVIR
-
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Sofosbuvir. The present invention involves use of reagents that are less expensive, easier to handle and eco-friendly process.
- -
-
Page/Page column 5; 8
(2018/02/20)
-
- Nucleoside phosphoramidate compound optical isomer and its application
-
The invention belongs to the field of medicinal chemistry, and in particular relates to a nucleoside phosphoramidate compound optical isomer or its hydrate, solvate, crystal or a pharmaceutically acceptable salt, process for their preparation and pharmaceutical compositions containing these compounds and these compounds or compositions used as virus infectious disease treating drug use, in particular as viral hepatitis treatment drug use. The experimental result shows, the compounds of this invention to hepatitis c virus 1 b subtype and 1 a subtype exhibit good inhibitory activity, while at the same time to the host cell has very low toxicity, high effectiveness, the safety is good, suitable for the treatment and/or prevention of diseases associated with HCV infection.
- -
-
Paragraph 0089-0091
(2018/07/30)
-
- Biphenyl nucleoside phosphoramidate application of compound
-
The invention belongs to the field of medicinal chemistry, provided the present invention of the formula 1 compound or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or crystallization in preparation for the treatment of flavivirus, especially hepatitis c virus infection after the drug resistance of the patient, and/or prevention of drug-resistant patient disease onset or recurrence of the application of the medicament. The invention of the formula 1 compound has good medicine chest activity of HCV.
- -
-
Paragraph 0033; 0034; 0035
(2018/07/07)
-
- Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
-
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. According to the method, (2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentonic acid GAMMA-lactone is taken as a raw material and is subjected to reduction and protection, a fluoro ribose fragment with three identical protection groups is obtained and directly reacts with uracil, deprotection is performed, and a target compound is obtained. Compared with an existing technical route adopting an eight-step reaction, the route of the preparation method is shortened to adopt four steps, and the problems that the existing technical route adopts complicated steps, the atom economy is low, the cost is high and the like are effectively solved; besides, an obtained intermediate can be recrystallized and refined, the whole route is simple, and the method is convenient to operate, high in yield and suitable for large-scale industrial production.
- -
-
Paragraph 0045-0047
(2017/04/29)
-
- Intermediate compound for synthesis of sofosbuvir and synthetic method thereof
-
The invention discloses an intermediate compound for synthesis of sofosbuvir and a synthetic method thereof; the intermediate compound comprises 4 intermediate products and 1 target compound, wherein the 4 intermediate products include methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl) benzoate, methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-chloro-4-methyltetrahydrofuran-2-yl) benzoate, (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate, and ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methyltetrahydrofuran-2-yl) methyl benzoic acid, and the target compound is (2'R)-2'-deoxy-2'-fluoro-2'-methylcytidine. Compared with existing synthetic methods, the synthetic method has high content of target compound and has little impurities generated in the synthetic process; the results of the synthetic method are stable, the synthetic method is simple to perform and is applicable to large-scale industrial production and technical popularization.
- -
-
-
- Synthesis method of sofosbuvir
-
The invention provides a synthesis method of sofosbuvir. The synthesis method of the sofosbuvir comprises the following steps: performing mitsunobu reaction on ((2R,3R,4R)-3-benzoyloxy)-4-fluorine-5-hydroxyl-4-methyltetrahydrofuran-2-yl)methyl benzoate to produce sulfonate to obtain a compound 1; abutting the compound 1 and N-benzoylcytosine to produce a compound 2. The method adopts mitsunobu reaction to avoid production of an isomer, and the isomer is reduced to 5 percent or below; according to the method, sulfonate and N-benzoylcytosine are abutted, so the use ofa stannic chloride raw material is avoided; furthermore, the yield is high and few solid waste is generated during aftertreatment, so that the method is suitable for large-scale industrialized production.
- -
-
-
- A (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside preparation method (by machine translation)
-
The invention discloses a (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside (type I) synthetic method. Cheap and easily available starting material, through the hydroxyl protection, cyclization, the links such as fluoride, obtains the type I compound. (by machine translation)
- -
-
-
- A nucleoside phosphoramide prodrug and its preparation method and its application
-
The invention relates to a nucleoside phosphamide prodrug as well as a preparation method and application of the nucleoside phosphamide prodrug. The nucleoside phosphamide prodrug is selected from any one of a compound I and a compound II, wherein in the formulas of the compound I and the compound II, X is selected from any one of F, Cl, Br and I. Compared with GS7977andGS7851, The compound I or II disclosed by the invention has more excellent resistance to hepatitis C virus, wherein the formulas I and II are respectively as shown in specifications.
- -
-
-
- A ribofuranose method for the preparation of phosphoric acid ester derivative
-
Disclosed in the present invention is a method for preparing ribofuranose phosphate derivatives, and the preparation steps thereof comprises: coupling starting materials of isopropyl L-alanine hydrochloride, phenol dichlorophosphate and substituted phenol under the action of alkali; reducing carbonyl into alcoholic hydroxyl by means of treating (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro pentonic acid GAMMA-lactone 3,5-dibenzoate with a strong reducing agent in the solvent of dichloromethane or ethers; reacting the intermediate of formula 2-1 with p-toluene sulfonyl chloride under the action of alkali to obtain p-toluene sulfonate; coupling the intermediate of formula 2-2 with a benzoyl cytosine derivative under the action of a condensation agent; converting cytosine of the intermediate of formula 2-3 into uracil under the action of an organic acid; removing benzoyl acting as protecting group from the intermediate of formula 2-4 under the action of an alkaline reagent; and coupling the intermediate of formula 2-5 with formula 1 under the action of a Grignard reagent to obtain Sofosbuvir.
- -
-
-
- IMPROVED FLUORINATION PROCESS
-
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.
- -
-
-
- NOVEL ANTIVIRAL AND ANTITUMORAL COMPOUNDS
-
The present invention relates to novel phosphate-modified nucleosides, such as phosphoramidate nucleosides. The invention also relates to the use of these novel phosphate-modified nucleosides to treat or prevent viral infections and proliferative diseases
- -
-
-
- Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication
-
In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2′-C-methyl containing nucleosides, 2′-C-Me-cytidine, 2′-C-Me-uridine and 2′-C-Me-2′-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5′-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ~550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.
- Maiti, Munmun,Maiti, Mohitosh,Rozenski, Jef,De Jonghe, Steven,Herdewijn, Piet
-
p. 5158 - 5174
(2015/05/13)
-
- METHODS FOR TREATING HCV
-
This invention relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.
- -
-
Page/Page column 101
(2013/03/28)
-
- NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
-
Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.
- -
-
Page/Page column 35
(2010/02/17)
-
- Discovery of a luoro-2′-β- C -methyluridine Nucleotide Prodrug (PSI-7977) for the treatment of hepatitis C virus
-
Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5′-phosphate derivative of the β-d-2′-deoxy-2′-α- fluoro-2′-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.
- Sofia, Michael J.,Bao, Donghui,Chang, Wonsuk,Du, Jinfa,Nagarathnam, Dhanapalan,Rachakonda, Suguna,Reddy, P. Ganapati,Ross, Bruce S.,Wang, Peiyuan,Zhang, Hai-Ren,Bansal, Shalini,Espiritu, Christine,Keilman, Meg,Lam, Angela M.,Steuer, Holly M. Micolochick,Niu, Congrong,Otto, Michael J.,Furman, Phillip A.
-
experimental part
p. 7202 - 7218
(2010/12/25)
-
- N- [ (2 ' R) -2 ' -DEOXY-2 ' -FLUORO-2 ' -METHYL-P-PHENYL-5 ' -URIDYLYL] -L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR ITS PRODUCTION
-
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.
- -
-
Page/Page column 39-40
(2010/12/18)
-
- Design, synthesis, and antiviral activity of 2′-deoxy-2′- fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
-
The pyrimidine nucleoside beta-D-2′-deoxy-2′-fluoro-2′-C- methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-D- arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2- methyl-3,5-di-O-benzoyl-β-D-ribofuranosyl]cytosine (7a). The protected 2′-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2′-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2′-C-methylcytidine and low cellular toxicity.
- Clark, Jeremy L.,Hollecker, Laurent,Mason, J. Christian,Stuyver, Lieven J.,Tharnish, Phillip M.,Lostia, Stefania,McBrayer, Tamara R.,Schinazi, Raymond F.,Watanabe, Kyoichi A.,Otto, Michael J.,Furman, Phillip A.,Stec, Wojciech J.,Patterson, Steven E.,Pankiewicz, Krzysztof W.
-
p. 5504 - 5508
(2007/10/03)
-