Synthesis And Positive Inotropic Evaluation Of[1,2,4]Triazolo[3,4-A]Phthalazine And Tetrazolo[5,1-A]Phthalazine Derivatives Bearing Substituted Piperazine Moieties

At present, the death rate which caused by cardiovascular disease are gradually decreasing, however, the death rate which induced by congestive heart failure are still rising. Therefore, finding new inotropic agent for the treatment of CHF is still a great challenge in the cardiovascular field at current and in the near future.In our previous work to search for more potent positive inotropic agents, the compound PHR0007showed moderate positive inotropic activity. Then we found compound1was a phthalazines derivative which exhibited favorable activity compared with vesnarinone. Therefore, the author designed to optimize the structure of PHR0007, replacing the chinoline ring with a phthalazine ring, two novel series of [1,2,4]triazole and tetrazole-fused phthalazine derivatives bearing substituted piperazine moiety were designed and synthesized., and changing the substituents on the piperazine ring simultaneously, to find novel compounds with stronger activity and to investigate the structure-activity relationship.Four series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted piperazine moieties were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume in isolated rabbit-heart preparations. Several compounds were developed and showed favorable activities compared to the standard drag milrinone, with (4-([1,2,4]triazolo[3,4-a]phthalazin-6-yl)piperazin-1-yl)(p-tolyl)methanone (5g) being identified as the most potent with an increased stroke volume of19.15±0.22%(milrinone:2.46±0.07%) at a concentration of3×10-5M. A preliminary study of mechanism of action revealed that5g displayed its positive inotropic effect may be related to the PDE-cAMP-PKA signaling pathway. Compounds exhibiting inotropic effects were also evaluated in terms of the chronotropic effects. The compounds synthesized were characterized by IR,1H-NMR, MS.