Ptk787 The Synthesis Study And Benzo Triazine Compound Design And Synthesis

Sarcomata are angiogenesis-dependent in some meanings, and angiogenesis is the rate-limited step in the whole pathological procedure. Thus the inhibition of angiogenesis could be an effective way to arrest tumor growth. Vascular endothelial growth factor receptor tyrosine kinase inhibitors have got the focus because of the central role of VEGF in regulating angiogenesis procedure.PTK787 is the most promising VEGF receptor- tyrosine kinase inhibitor in pipeline because of its potency in tumor inhibition and oral bioavailability. It is now undergoing Phase III clinical trail, and is scheduled to be launched in 2005. The synthetic route of PTK787 is studied in this discourse. PTK787 is synthesized in 5 steps from phthalide and 4-pyridinecarboxyaldehyde in a yield of 26.0%, equal to those reported in the references.Furthermore, the 3D-QSAR of 20 VEGF receptor tyrosine kinase inhibitors has been studied with Sybyl 6.6 programs. Guiding by the QSAR elicited, 23 3-substituded-1, 2, 3-benzotriazin-4-ones has been designed and synthesized, with 18 compounds having not been reported, all compounds were characterized by means of IR, ~1HNMR and MS. The benzotriazinones were screened virtually with DOCK, and 4 compounds amongst them, i.e. UB07, UC05, UC07, UC11, are respected to be more potent than PTK787 and SU6668, which are undergoing clinical trail, and are worthy of further studies. Moreover, the results of ADME revealed that all the 23 compounds possess good pharmacokinetic properties suitable for oral administration. The pharmacological tests are ongoing.