Heterocyclic congeners of PD 128,907 with a partially hydrogenated benzomorpholine moiety as potential dopamine D-3-receptor ligands

With a straightforward seven-step synthesis, racemic perhydro[1,4]benzoxazi n-6-on was synthesized in overall good yields via regioselective epoxid rin g-opening to the corresponding beta-aminoalcohol. The oxazine derivative wa s the key intermediate for the preparation of heteroaromatic analogues of t he dopamine D-3-receptor preferring agonist PD 128,907. The morpholine moie ty of PD 128,907 was incorporated in diazole and diazine compounds obtained by different ring closure reactions. The target compounds obtained were st ructurally related to non-ergot heteroaromatic dopamine agonists which disp lay preferential activity at the D-3 receptor, e.g., quinpirole, quinerolan e, or pramipexole. The five membered aminothiazole, aminoselenazole, and py razole derivatives showed at least one order of magnitude higher binding at the human D-3 receptor than that at the D-2L receptor. Although the novel compounds displayed K-i values only in the micromolar concentration range, the most active ones showed full agonist activity in a functional assay on mitogenesis. (C) 1999 Editions scientifiques et medicales Elsevier SAS.