Synthesis of pyrido[2,3-d]pyridazines and pyrazino[2,3-d]-pyridazines -: novel classes of GABAA receptor benzodiazepine binding site ligands

Novel syntheses of 2,3,8-trisubstituted pyrido[2,3-d]pyridazines and 2,3,5-trisubstituted pyrazino[2,3-d]pyridazines are described. Two complementary routes to pyrido[2,3-d] pyridazines were developed, the first of which began by constructing the pyridine ring, and the second of which started by constructing the pyridazine ring. Pyrazino[2,3-d]pyridazines were prepared in a route employing an aza-Wadsworth-Emmons cyclization as the key step. The resulting compounds were found to be high affinity ligands for the GABA(A) receptor benzodiazepine binding site. (c) 2006 Elsevier Ltd. All rights reserved.