Design, Synthesis And Bioactivity Of Pazopanib And Study On The Synthesis Of Pemetrexed

Pazopanib (Votrient, made by GlaxoSmithKline) is a novel multitargetedreceptor tyrosine kinase inhibitor. As a representative anti-angiogenesis drug, it hasbeen approved by FDA for the treatment of patients with advanced renal cellcarcinoma and soft tissue sarcoma. In spite of the advantages in multi-targets andgood oral bioavailability, pazopanib may inevitably cause hepatotoxicity,hypertension, diarrhea and other symptoms.In order to obtain more safe and efficient pazopanib drugs, with pazopanib as alead compound, and retained the basic pharmacophore such as indazole andpyrimidine ring, a new series of pazopanib derivatives (7a-7h) were designed basedon biological isostere principle. These target compounds were synthesized from6-nitro-1H-indazole via five steps of N-methylation, reduction, nucleophilicsubstitution and so on. Their inhibitory activity against VEGFR-2, PDGFR-α andc-kit tyrosine kinases were evaluated by HTRF. The results indicated that all the eightcompounds exhibited definite kinase inhibition. In which compound7h presented thebest inhibiting against all three tyrosine kinases, and much better than the positivecontrol drug pazopanib.Pemetrexed disodium (Alimta), a new-generation multi-targeted antifolate, isthe first drug approved by FDA to treat malignant pleural mesothelioma. Clinical trialexperimental results indicated that pemetrexed has the advantages of broad-spectrumanticancer potency and less prone to resistance.The second part of this paper focused on the synthetic methods of pemetrexeddisodium. An efficient synthetic method for the pemetrexed disodium has beendeveloped from methyl4-iodobenzoate via Heck reaction, bromination, cyclizationreaction, hydrolysis, coupling reaction and saponification. The optimized syntheticprocess is simple and suitable for industrial production. Pemetrexed disodium wasobtained in the total yield of24.9%and its purity was99.8%, and the structure ofpemetrexed disodium were characterized by1HNMR,13CNMR, IR and HR-MS.