Synthesis And Positive Inotropic Activity Of Some Toborinone Analogs

Generally speaking, the mortality caused by cardiovascular diseases is declining, but the mortality caused by severe congestive heart failure (CHF) is rising steadily, which has come up to 50% according to the statistic data from America Heart Association. Therefore, Scientists have made great efforts to develop new positive inotropic agents, but there are still short of effective drugs for CHF in clinical use up to now.Toborinone (OPC-18790) is 2(1H)-quinolinone derivative having favorable cardiac contractile activity and increased cardiac output activity simultaneously with little effect on heart rate and blood pressure. Toborinone was found to be the novel and most promising agent for CHF clinical treatment, which has been registered in Japan and received an approval from the FDA to conduct phase III clinical trial.In this paper the author designed and synthesized new heterocyclic compounds, triazoquinolines, by introducing triazole ring into the 1,2-position of 2(1H)-quinolinone in toborinone and changing the substituent on the benzene ring at the side chain of toporinone in order to obtain desirable compounds with the better inotropic positive activity.Thus, 30 triazoquinoline derivatives were synthesized through four steps including sulfuration, cyclization, etherification, and ring opening reaction by using 6-hydroxy-3,4-dihydro-2(1H)-quinolinone as a starting material and their structures were confirmed by ¹HNMR, ¹³CNMR and MS.10 compounds out of 30 were examined for their positive inotropic and chronotropjc effects by use of isolated rat heart preparations and the compounds (PHR0618, PHR0621, PHR0622) showed significant biological activities without any chronotropic effects.