Design, synthesis, and inhibition of platelet aggregation for some 1- o-chlorophenyl-1,2,3,4-tetrahydroisoquinoline derivatives

Abstract

Based on ticlopidine active as an ADP receptor antagonist for inhibiting platelet aggregation in clinical test, and upon finding (±)-1,2-substituted-7-sulfonylamide/amide-1,2,3,4-tetrahydroisoquinoline ( 11– 31) inhibited of platelet aggregation, a series of (±)-1- o-chlorophenyl-2-substituted-tetrahydroisoquinoline derivatives was designed and synthesized. Four analogs proved to be potential antiplatelet aggregation agents, and compound 9 (TQP-3, applying for patent) which inhibits ADP-induced human platelet aggregation with IC 50 values of approximately 0.206 nM was the most active. Compound 2 is more active than compound 1, which (Type I) is similar to ticlopidine. This is because there is a spacial hindrance in compound 1, and the o-chloro group of compound 2 may play the same a role as o-chloro group of ticlopidine. On the other hand, with the different substitutions at different positions on the 2-substituted phenylacyl group, their inhibition of platelet aggregation differs. These compounds with m-substituted group ( 5, 7, 9) showed a higher IC 50 value for inhibiting ADP-induced human platelet aggregation than those with o-substituted group ( 4, 6) or p-substituted group ( 3, 8). It was observed that their inhibition is bromine-substituted derivative ( 9), chlorine-substituted derivative ( 7), and nitro-substituted derivative ( 5) in turn. Moreover, these compounds (Type II) may be more similar to clopidogrel than to ticlopidine due to the acyl group at 2 position of the nucleus playing a role as the ester group of clopidogrel. It was conjectured that these analogs function as a potential antiplatelet aggregation role by acting as ADP receptor antagonists.