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

• Published in: European journal of medicinal chemistry Vol. 44; no. 7; pp. 3027 - 3031
• Main Authors: Liu, Xue-Kun, Cui, Xun, Hong, Lan, Sun, Liang-Peng, Quan, Zhe-Shan, Piao, Hu-Ri
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.07.2009; Elsevier
• Subjects: 3,4-Dihydro-3-oxo-2 H-benzo[ b][1,4]oxazine; Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Animals; Atrial Function, Left - drug effects; Biological and medical sciences; Cardiotonic agents; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiovascular system; Chemistry, Medicinal; Heart Atria - drug effects; Life Sciences & Biomedicine; Medical sciences; Oxazines - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Positive inotropic activity; Quinolones - chemistry; Rabbits; Reference Standards; Science & Technology; Spectrum Analysis; Stroke volume; Stroke Volume - drug effects; 3,4-Dihydro-3-oxo-2 H-benzo[ b][1,4]oxazine; Positive inotropic activity; Stroke volume; MORTALITY; VESNARINONE; 3,4-Dihydro-3-oxo-2H-benzo[b][1,4]oxazine; ATRIA; SEVERE HEART-FAILURE; Heart; Cardiotonic agent; Aminoamide; Nitrogen heterocycle; Lactam; Rabbit; Lagomorpha; Muscle contraction; In vitro; Vertebrata; Mammalia; Structure activity relation; Animal; Six membered ring; Bicyclic compound; Carboxamide; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.08.006

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-2 H-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-2 H-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 × 10 −5 M in our in vitro study. The chronotropic effects of those compounds having significant inotropic effects were also evaluated in this work. A series of 2-(4-substitutedmethylpiperazin-1-yl)- N-(3,4-dihydro-3-oxo-2 H-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. [Display omitted]