293301-33-4Relevant academic research and scientific papers
Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases
Thompson, Andrew M.,Delaney, Amy M.,Hamby, James M.,Schroeder, Mel C.,Spoon, Teresa A.,Crean, Sheila M.,Showalter, H. D. Hollis,Denny, William A.
, p. 4628 - 4653 (2007/10/03)
7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-teri-butylureas by alkylation with benzyl ω-iodoalkyl ethers, debenzylation, and animation, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (5-fold) or selectivity (20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.
Synthesis of 7-substituted 3-aryl-l,6-naphthyridin-2-amines and 7-substituted 3-aryl-l,6-naphthyridin-2(1H)-ones via diazotization of 3-aryl-l ,6-naphthyridine-2,7-diamines
Thompson, Andrew M.,Showalter, H.D. Hollis,Denny, William A.
, p. 1843 - 1852 (2007/10/03)
The preparation of 3-aryl-7-halo-l,6-naphthyridin-2-amines and 3-aryl-7-halo-l,6-naphthyridin-2(1H)-ones from the diazotization of 3-aryl-l,6-naphthyridine-2,7-diamines is reported. The reactions were investigated in various solvents (concentrated HC1, 50% HBF4, 70% HF-pyridine, 20% and 90% H2SO4, dilute HC;, and neat TFA). By appropriate choice of solvent and other conditions, good yields of the target compounds could be obtained, although in some cases a variety of different side products was also produced. Subsequent displacement of the 7-halogen substituents with alkylamines provides a route to more complex 7-substituted 1,6-naphthyridine derivatives that are potential tyrosine kinase inhibitors. The Royal Society of Chemistry 2000.
