Design,Synthesis And Biological Activity Of The New [5,6,6] Tricyclines FXa Inhibitor

Thromboembolic diseases is a common cardio-cerebral vascular disease, is caused by blood clots blood vessel cavity stenosis or occlusion, the major organs of the body infarction, or ischemic causing various diseases of the body dysfunction.Venous Thrombus Embolism(VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), common in cancer patients and patients with hip or knee joint replacement surgery all, is one of the reasons for the clinical death and disability.Traditional anticoagulants, such as heparins and vitamin K antagonists (VKAs), have proved to be effective in the prevention and treatment of these diseases, but several inherent drawbacks restricted their long term clinical use. Factor Xa (FXa) is a key enzyme in the coagulation cascade and inhibiting its activity will lead to the reduction of thrombin generation and thereby the inhibition of thrombosis formation. Due to exerting no influence on the existed thrombin, selective FXa inhibitors have less bleeding risk. Compared to the traditional anticoagulants, selective FXa inhibitors showed several advantages, such as improved curative effect and safety, broad spectrum of disease, stable dose-response relationship, easy to oral administration, less drug-drug interaction and no need of clinical monitoring.Apixaban is a selective, oral effective direct FXa inhibitors, developed jointly by Pfizer and bristol-myers squibb company, used for hip or knee replacement surgery VTE prevention and prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.Our team has always been committed to the research of anticoagulant drugs, according to the role of the Rivaroxaban in FXa model and space conformation, and three-ring conformational restrictions strategy, on the YG-001 was a major success. Then we further experiments and literature tried to put the policy extended to fellow FXa inhibitors of Apixaban. On the basis of existing literature, combining with the experience of synthetic research in the past, design line, respectively synthesized by six new tricyclic FXa inhibitors[6,6,5] of mother nucleus. Compound I, II, III, V, VI activity is not perfect, but good IV vitro activity. Then select I and V represented by computer aided analysis of the compounds and FXa compound crystal X-ray diffraction diagram, the conclusion is proved that the "three-ring" strategy in the structure of the FXa inhibitors has its own structure, also found some disadvantages. Show that the strategy needs to be enriched and perfect, also has a further research, exploration value.