- MACROCYCLIC HEPATITIS C PROTEASE INHIBITORS
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The present invention provides novel macrocyclic compounds that mimic peptide substrates of the hepatitis C viral protease and inhibit the viral protease, more particularly as inhibitors of the NS3 serine protease from hepatitis C virus. Methods for synthesis of the compounds are also provided. The compounds find utility as antiviral agents directed at hepatitis C. The invention further provides methods of employing such inhibitors, alone or in combination with other therapeutic agents, to treat hepatitis C infection in a subject in need of such treatment.
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Page/Page column 51
(2008/12/07)
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- Epimerization reaction of a substituted vinylcyclopropane catalyzed by ruthenium carbenes: Mechanistic analysis
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A novel ruthenium carbene-catalyzed epimerization of vinylcyclopropanes is reported. The reaction rate strongly depends on the presence of ruthenium ligands in solution. When the first-generation Grubbs catalyst is employed, a 5.3:1 equilibrium ratio of epimers is established quickly, but when a first-generation Hoveyda catalyst is employed, epimerization is observed only if an additional phosphine or nitrogen ligand is added. NMR and kinetic studies suggest that the isomerization reaction occurs through the intermediacy of a ruthenacyclopentene. The observation suggests that cyclopropylmethylidene ruthenium carbenes of synthetic utility may be accessible via ruthenacyclopentenes obtained via other routes.
- Zeng, Xingzhong,Wei, Xudong,Farina, Vittorio,Napolitano, Elio,Xu, Yibo,Zhang, Li,Haddad, Nizar,Yee, Nathan K.,Grinberg, Nelu,Shen, Sherry,Senanayake, Chris H.
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p. 8864 - 8875
(2007/10/03)
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- Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid vinyl-ACCA derivatives: Key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease
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(1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such as BILN 2061, which was recently shown to dramatically reduce viral load after administration to patients infected with HCV genotype 1. We have developed a scalable process that delivers derivatives of this unusual amino acid in >99% ee. The strategy was based on the dialkylation of a glycine Schiff base using trans-1,4-dibromo-2-butene as an electrophile to produce racemic vinyl-ACCA, which was subsequently resolved using a readily available, inexpensive esterase enzyme (Alcalase 2.4L). Factors that affect diastereoselection in the initial dialkylation steps were examined and the conditions optimized to deliver the desired diastereomer selectively. Product inhibition, which was encountered during the enzymatic resolution step, initially resulted in prolonged cycle times. Enrichment of racemic vinyl-ACCA through a chemical resolution via diastereomeric salt formation or the use of forcing conditions in the enzymatic reaction both led to improvements in throughput and the development of a viable process. The chemistry described herein was scaled up to produce multikilogram quantities of this building block.
- Beaulieu, Pierre L.,Gillard, James,Bailey, Murray D.,Boucher, Colette,Duceppe, Jean-Simon,Simoneau, Bruno,Wang, Xiao-Jun,Zhang, Li,Grozinger, Karl,Houpis, Ioannis,Farina, Vittorio,Heimroth, Heidi,Krueger, Thomas,Schnaubelt, Juergen
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p. 5869 - 5879
(2007/10/03)
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