The Synthesis And Activity Evaluation Of Novel CETP Inhibitors

Cardiovascular disease is a common cause of death. Atherosclerosis is thepathological basis of cardiovascular disease. Extensive studies demonstratethat the increased HDL-C level is able to reduce atherosclerotic cardiovascularrisk. Therefore, it is very interesting to develop some new therapeutic drugsagainst cardiovascular disease.Clinical research has shown that HDL-C level might be raised efficientlyvia inhibition of Cholesterol Ester Transfer Protein (CETP). So it is desirablefor CETP inhibitor to function as therapeutic agents to treat and prevent theoccurrence of cardiovascular disease.In the course of our research, two classes of novel CETP inhibitors weredesigned and synthesized as follows:(1). Quinoxalinones CETP inhibitors: Starting from 4-chloro-3-nitrobenzotrifluoride, 48 target compounds and 9 intermediates weresynthesized by the reaction of nucleophilic substitution, reductive cyclization,acylation and alkylation etc.(2). Quinazolinones CETP inhibitors: Starting from 5-substituted-2-aminobenzamide, 12 target compounds and 12 intermediates were synthesized by the reaction of acylation, condensation, and alkylation etc.All the synthesized compounds were characterized by ~1H NMR, andsome of them were further confirmed with high resolution mass spectroscopy.Biological assays show that the synthesized quinoxalinones compoundsare inactive to CETP inhibition in vitro. Now, the biological evaluation ofquinazolinones compounds in vitro is under way.Meanwhile, a new methodology was established for the preparation of2,3-dihydro-4(1H)-quinzolinones and 1-N-ethoxycarbony1-5-substituted-2,3-dihydro-quinzolinones.(1). 2,3-dihydro-4(1H)-quinazolinones were obtained in high yields bycondensation reaction of anthranilamide with carbonyl compounds in therefluxing 2,2,2-trifluoroethanol without any catalyst. By comparison with theliterature method, it has some advantages such as mild condition, simpleworkup procedure and high yield.(2). Condensation reaction of the 5-substituted-2-(ethoxycarbony1)aminobenzamide with aldehydes afford the desired 1-N-ethoxy carbony1-5-substituted-2,3-dihydro-4(1H)-quinazolinones in the presence ofp-toluenesulfonic acid in refluxing 2,2,2-trifluoroethanol, and no studies havebeen reported about this event.