Design, Synthesis and Pregnancy-Terminating Activity of 2-Aryl Imidazo[2,1-a]isoquinolines

Introduction Symmetrical trizol bioisosterisms, such as 2-aryl pyrazolo5,1-a]isoindoles and isoquinolines, pyrazolo- 1,5-a]indoles and quinolines, 2-aryl imidazo2,1-a]- isoquinolines and isoindoles, 3,5-diaryl-s-triazoles, were shown to be active as non-hormonal post-implantation contragestational agents in various animal species after parenteral administration.1-7 Some compounds had good oral activity.8 Among them, DL204-IT9 2-(3-ethoxy- phenyl)-5,6-dihydro-s-triazole5,1-a]isoquinoline…

Design, Synthesis and Pregnancy-Terminating Activity of 2-Aryl Imidazo[2,1-a]isoquinolines

In order to clarify the structural requirement of pregnancy‐terminating drugs, the quantitative structure‐activity relationship (QSAR) of 2‐aryl imidazo2, 1‐a]isoquinolines was studied on the basis of quantum mechanical calculation and multiple regression analysis. A Good correlation equation was obtained (r²=0.925, q²=0.871). Some new compounds were designed according to the equation. Two of them, compounds 21 and 22, were synthesized and evaluated in NIH mice. The results showed that the difference of activity between 21 (median effective dose ED%=0.943 mg/kg/day) and 22 (ED₅₀= 1.099 mg/kg/day) was small and both of them were potent. It is also agreed with the computational results. Compared with L14105 which is the most potent pregnancy‐terminating agent, these two compounds possess high activity. The evaluation of the anti‐implanting activity showed that they were 100% effective at tested dosage 50.0, 25.0, 12.5 mg/kg/day 3 days in oral administration, which proved the both of them had anti‐implanting activity and low first‐pass effects.