Synthesis And Anticoagulant Activity With Piperazinyl Substituted Thiophene And Pyridineester Compounds

Cardiovascular disease is a common threat to the health of the elderly. Thrombotic diseases are the one with the highest morbidity, mutilation rate and mortality. Therefore, the development of drugs for the prevention and treatment of thrombotic diseases was most concerned and had become a hot point in medical field recent years. Thienopyridine class ADP receptor antagonists are clinically used as common antithrombotic agents. The representative drugs are clopidogrel and prasugrel. They have advantages such as good stability and low toxicity. However, the technology for these drugs are monopolized by European and American for a long time. These drugs are expensive. Moreover, there are many defects. For example, clopidogrel had some side effects such as the presence of TTP and HUS. More seriously, due to the phenomenon of "clopidogrel resistance", it is ineffective for one third of patients. Although prasugrel has overcome these shortcomings, it is suffered from severe bleeding tendency. Therefore, the development of novel thienopyridine class of ADP receptor antagonists with higher activity and better security is very urgent.Through the research and analysis of the launched thienopyridine class ADP receptor antagonists, according to the relevant literature, using "me-too" method in drug research and development, applying association theory, the thienopyridine nucleus was reserved and a series of novel thienopyridine esters with substituted piperazinyl were designed and synthesized. Such compounds were synthesized from thienopyridine hydrochloride as a starting material, through N-acylation, N-alkylation and esterification reaction16novel compounds (3a-3p) were synthesized. Their structures were characterized by’H NMR and ESI-HRMS. None of them were reported by literatures.How the newly synthesized16compounds affected clotting time was tested on rats. Experimental results showed that the blood clotting time was prolonged by these compounds. Original QSAR study showed that when the substituent on piperazine group was phenyl ring, the anti-clotting activity was increased with the improvement of electron-withdrawing effect of the substituents on the phenyl ring. Di-substituted benzene ring by halogen was less active than mono-substituted. The activity of compounds3n,3m and3k was significantly better than the positive control drug ticlopidine. The growth rates of clotting time in rats were71.8%,58.0%and43.5%, respectively. Among these compounds,3k is a piperazine derivative substituted by pyrimidinyl group;3m and3n are piperazine derivatives substituted by phenylsulfonyl; all of them are anticipated to have some drug-like properties.