- Facile synthesis of the neuraminidase inhibitor peramivir
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An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of
- Jia, Fei,Hong, Juan,Sun, Ping-Hua,Chen, Jian-Xin,Chen, Wei-Min
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- Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors
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Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
- Wang, Peng-Cheng,Fang, Jim-Min,Tsai, Keng-Chang,Wang, Shi-Yun,Huang, Wen-I,Tseng, Yin-Chen,Cheng, Yih-Shyun E.,Cheng, Ting-Jen Rachel,Wong, Chi-Huey
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- 5, 7-DIAZAINDOLE AND 5, 7-DIAZAINDAZOLE DERIVATIVES AND THEIR USE IN THE TREATMENT, AMELIORATION OR PREVENTION OF INFLUENZA
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The present invention relates to a specific compound having the formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameloriating or preventing influenza.
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Page/Page column 45
(2017/12/27)
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- 4, 7-DIAZAINDOLE AND 4, 7-DIAZAINDAZOLE DERIVATIVES AND THEIR USE IN THE TREATMENT, AMELIORATION OR PREVENTION OF INFLUENZA
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The present invention relates to a compound having the formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameloriating or preventing influenza.
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Page/Page column 46; 47
(2017/12/28)
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- PYRIMIDINE AND PYRIDINE DERIVATIVES AND USE IN TREATMENT, AMELIORATION OR PREVENTION OF INFLUENZA THEREOF
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Provided herein is a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameliorating or preventing influenza.
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Page/Page column 129; 130
(2017/12/28)
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- Optical pure amino alcohol hydrochloride preparation method
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The invention relates to a preparation method for optically pure aminoalcohol hydrochloride. The optically pure aminoalcohol hydrochloride is any one selected from optically pure aminoalcohol hydrochloride 1 and optically pure aminoalcohol hydrochloride 2 and is prepared by subjecting a compound 4 to an esterification ring-opening reaction, an amino protection reaction, an ester reduction reaction and a deprotection salt forming reaction. The optically pure aminoalcohol hydrochloride 1 or optically pure aminoalcohol hydrochloride 2 prepared in the invention can be directly used for synthesis of abacavir and carbovir. The preparation method provided by the invention has the advantages of high product optical purity, stable product quality, high product yield, a small amount of environmental pollution, low production cost, easy industrialization, etc.
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- Compound, preparation method thereof and purpose of compound in preparing drug
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The invention provides a compound, a preparation method thereof and a purpose of the compound in preparing a drug. The compound is a compound shown in a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite or a pharmaceutically acceptable salt of the compound shown in the formula (I). The compound provided by the invention can transform peramivir in an injection dosage form into an inhalant dosage form, improves the medication compliance of the peramivir and enables the peramivir to have the characteristics of convenience in use and suitability for use in a wide range; and in addition, the drug directly acts on a respiratory tract and a lung infected with an influenza virus after being inhaled, so that single administration is hopefully realized, and the drug can effectively have double actions of prevention and treatment to the influenza. A chemical formula is described in the description.
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Paragraph 0106; 0109
(2017/08/30)
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- ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY
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Novel dual-targeted, bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents are disclosed. Exemplary drugs according to the invention include caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1), ZA-7-CA-amide (7) and ZA-7-Nap (43) for simultaneous inhibition of influenza virus neuraminidase and suppression of proinflammatory cytokines. Synthetic methods for preparation of these enhanced anti-influenza conjugate drugs are provided. The synthetic bifunctional ZA conjugates act synergistically towards protection of mice lethally infected by H1N1 or H5N1 influenza viruses. The efficacy of ZA-7-CA, ZA-7-CA-amide and ZA-7-Nap conjugates is much greater than the combination therapy of ZA with anti-inflammatory agents.
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Paragraph 0331
(2013/10/22)
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- PRODUCTION OF TRANS-4-AMINOCYCLOPENT-2-ENE-1-CARBOXYLIC ACID DERIVATIVES
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Methods of producing compositions of trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives are described. Also described is an amine salt of a compound having formula A, having components present in both cis and trans structures.
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- Use of hydrolases for the synthesis of cyclic amino acids
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The synthesis of several cyclic amino acids that have all the necessary structural features to make them ideal scaffolds for use in medicinal chemistry is described. A key step in each synthesis is the use of hydrolase enzymes to define a chiral centre. I
- Lloyd, Richard C.,Lloyd, Michael C.,Smith, Mark E. B.,Holt, Karen E.,Swift, Jonathan P.,Keene, Philip A.,Taylor, Stephen J. C.,McCague, Raymond
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p. 717 - 728
(2007/10/03)
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- PROCESS FOR PREPARATION OF 4-N-SUBSTITUTED AMINO-2-AZA-1-OXABICYCLO 3.3.0]OCT-2-ENE-6-CARBOXYLIC ACID ESTERS AND PROCESS FOR PREPARATION OF THEIR INTERMEDIATES
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4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid esters are produced by adding a Br?nsted acid to a mixture of a 2-azabicyclo[2.2.1]hept-5-en-3-one and an alcohol, thereby causing these components to react with each other to give a salt of cis-4-amino-2-cyclopentene-1-carboxylic acid ester, then allowing the salt of cis-4-amino-2-cyclopentene-1-carboxylic acid ester thus obtained to react with an amino-protecting group introducing compound in the presence of a base, thereby giving cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester, and then allowing this cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester to react with a hypohalogenite and an aldoxime.
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- Process for preparing (-)-(1S, 4R) N-protected 4-amino-2-cyclopentene-1-carboxylate esters
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The invention relates to a process for preparing (?)-(1S,4R) N protected 4-amino-2-cylcopentene-1-carboxylate esters represented by the formula (I) wherein R1 and R2 are as described within the specification.
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- Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity
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The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor - enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC50 values vs neuraminidase from influenza A and B of 50 values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.
- Chand,Montgomery,Kotian,Dehghani,El-Kattan,Lin,Hutchison,Babu,Bantia,Elliott
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p. 4379 - 4392
(2007/10/03)
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- An efficient route to all eight stereoisomers of a tri-functionalised cyclopentane scaffold for drug discovery
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A route to all eight stereoisomers of 3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl ester is presented; these products should prove to be valuable scaffolds in pharmaceutical discovery.
- Smith, Mark E.B.,Lloyd, Michael C.,Derrien, Nadine,Lloyd, Richard C.,Taylor, Stephen J.C.,Chaplin, David A.,Casy, Guy,McCague, Raymond
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p. 703 - 705
(2007/10/03)
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- Highly selective directed hydrogenation of enantiopure 4-(tert-butoxycarbonylamino)cyclopent-1-enecarboxylic acid methyl esters
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The use of both N-tert-butoxycarbonylamino- and hydroxyl-directed hydrogenation methodology to yield essentially single diastereomers of 3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl esters and 3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid methyl esters is described. These results incorporate the first reported carbamate-directed hydrogenations of functionalised cyclopentenes.
- Smith, Mark E.B.,Derrien, Nadine,Lloyd, Michael C.,Taylor, Stephen J.C.,Chaplin, David A.,McCague, Raymond
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p. 1347 - 1350
(2007/10/03)
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- Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase
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Several cyclopentene GABA analogues were synthesized as conformationally rigid analogues of the epilepsy drug vigabatrin and tested as inhibitors and substrates of γ-aminobutyric acid aminotransferase (GABA-AT). None of these compounds produced time-dependent inhibition. (1R,4S)-(+)-4-Amino-2- cyclopentene-1-carboxylic acid ((+)-3), (4R)-(-)-4-amino-1-cyclopentene-1- carboxylic acid ((-)-4), and d,l-3-amino-1-cyclopentene-1-carboxylic acid (6) are good substrates. The K(m) and k(cat) values for the latter two compounds are very similar to those of GABA, suggesting that they bind in an orientation similar to that of GABA. The K(m) value for (+)-3 is 24 times lower than that for GABA, although its k(cat) value is only one-fourth that for GABA; nonetheless, it is a better substrate for GABA-AT than is GABA. All of these compounds, as well as the enantiomers of 3 and 4 and d,l-trans-4- amino-2-cyclopentene-1-carboxylic acid (5), are competitive inhibitors of GABA-AT. These results demonstrate the effects of the carboxylate group orientation and the stereochemistry of the amino and carboxylate groups on the substrate activity and inhibitor activity, and this should be important to the future design of inhibitors of GABA-AT.
- Qiu, Jian,Pingsterhaus, Joyce M.,Silverman, Richard B.
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p. 4725 - 4728
(2007/10/03)
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- An Enantioselective Synthesis of cis-4-tert-Butoxycarbamoyl-1-methoxycarbonyl-2-cyclopentene - A Useful, General Building Block
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The amino acid derivative in the title represents an important building block for the synthesis of a number of biologically important targets such as the antiviral carbanucleosides and amidinomycin.By using asymmetric palladium-catalyzed desymmetrization of meso-2-ene-1,4-diols, cis-1,4-dibenzoyloxy-2-cyclopentene can be converted to the enantiomerically pure title compound in only four steps.Chemoselective ester reduction allows entry into the domain of carbanucleosides, whereas double-bond reduction provides the precursor for amidinomycin.In an ancillary study, a facile diastereoselective cis-hydroxylation provides aminocyclopentitols, compounds that have proven to be potent glycosidase inhibitors. - Keywords: allylic substrates; amidinomycin; asymmetric syntheses; carbanucleosides; palladium catalysts
- Trost, Barry M.,Stenkamp, Dirk,Pulley, Shon R.
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p. 568 - 572
(2007/10/03)
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