Synthesis of 2-(4-substitutedmethylpiperazin-1-yl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)acetamides and their positive inotropic evaluation

In an attempt to search for more potent positive inotropic agents, a series of 2-(4-substitutedmethylpiperazin-1-yl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)acetamides were synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit heart preparations. Several compounds showed favorable activities compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)piperazin-1-yl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl) acetamide 4e showed the most potent activity with the 5.09 +/- 0.00% increased stroke volume (milrinone 1.67 +/- 0.64%) at a concentration of 1 X 10(-5) M in our in vitro study. The chronotropic effects of those compounds having significant inotropic effects were also evaluated in this work. (C) 2008 Elsevier Masson SAS. All rights reserved.