Design, Synthesis And Activity Assay Of 1-benzyl- Tetrahydroisoquinoline Derivatives

Thrombotic diseases commonly include deep vein thrombosis, coronary thrombosis and cerebral arterial thrombosis, which seriously affect and distress people’s lives. Platelet plays a key role in thrombus formation process. However, P2Y12 receptor antagonists dominant in anti-platelet drugs have shown many defects in their clinical use, such as side effects and the significant individual differences of efficacy. Therefore, it remains huge space to study new P2Y12 receptor antagonists.Neferine was extracted from Chinese medicinal plant and could inhibit ADP-induced platelet aggregation. Therefore, neferine was used as lead compound during the molecular design. Considering the active metabolite of P2Y12 receptor antagonist clopidorel, a novel class of 1-benzyl-tetrahydroisoquinoline compounds targeting P2Y12 receptor were designed based on computer-aided drug design in this paper.Starting from p-methoxyphenethylamine hydrochloride and three kinds of phenylacetic acid derivatives, four methoxycarbonyl-methyl-substituted amide derivatives 5a-5d were synthesized via acylation reaction, alkylation reaction and phenylmercapto removal reaction. Then twenty novel 1-benzyl-tetrahydroisoquinoline derivatives 6(a-d)-10(a-d) were synthe-sized by Bischler-Napieralski cyclization reaction, reduction reaction and finally modified with acetyl, p-nitrophenylacetyl, glycine and benzyl. These twenty compounds were not previously reported in literatures. In addition, all the compounds except 1,2 and 3c were new compounds in experimental part. All compounds were characterized by NMR and mass.The in-vitro antiplatelet aggregation activity for 1-benzyl-tetrahydroisoquinoline derivatives was evaluated using the platelet from healthy rabbits with ADP as inducer. Clopidogrel sulfate was adopted as positive control. The results showed that 6a-9a,10c,9d and 10d with higher antiplatelet aggregation activity than clopidogrel sulfate under the test concentration.6a,7a,9a and 10d showed inhibition rates of 97.5% (350 μmol/L),20.9% (60 μmol/L),14.8% (39μmol/L) and 13.3%(163 μmol/L) respectively. Following conclusions were from preliminary activity screening results:substituent group Ri in 1-benzyl-tetra-hydroisoquinoline derivatives had significantly influence on the inhibitory activity. Modification of nitrogen in 1-benzyl-tetrahydroisoquinoline derivatives could contribute to the increment of antiplatelet aggregation activity.