870673-87-3Relevant academic research and scientific papers
Antiviral phosphoramidates
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Page/Page column 39, (2008/06/13)
The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
, p. 7215 - 7226 (2007/10/03)
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
Preparation of 3-substituted cephalosporins
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, (2008/06/13)
There is described a process for preparing an enamine of formula (IX): STR1 where R2 is a carboxylic acid protecting group and R3 is the residue of a carboxylic acid derived acyl group and where R5 and R6 are the same or different C1-4 alkyl or C7-10 aralkyl groups; or taken together with the adjacent nitrogen atom form a heterocyclic ring containing from 4 to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting a compound of formula (XII): STR2 with an amine of formula HNR5 R6, the reactant of formula (XII) being prepared by reaction of an appropriate enol derivative with a phosphorus reagent. The enamines of formula (IX) are useful in the preparation of 3-hydroxycephalosporins.
