Process research and development for the kilogram manufacture of the SRC kinase inhibitor AZD0530
Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medic
Ford, J. Gair,Pointon, Simon M.,Powell, Lyn,Siedlecki, Paul S.,Baum, John,Chubb, Richard,Fieldhouse, Robin,Muxworthy, James,Nivlet, Alex,Stenson, Rachel,Warwick, Eleanor
p. 1078 - 1087
(2011/04/12)
CHEMICAL PROCESS
The present invention relates to chemical processes useful in the manufacture of the compound 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinazoline (the active entity within AZD0530), to intermed
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t1/2 = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.
Hennequin, Laurent F.,Allen, Jack,Breed, Jason,Curwen, Jon,Fennell, Michael,Green, Tim P.,Lambert-Van Der Brempt, Christine,Morgentin, Rémy,Norman, Richard A.,Olivier, Annie,Otterbein, Ludovic,Plé, Patrick A.,Warin, Nicolas,Costello, Gerard
p. 6465 - 6488
(2007/10/03)
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