Heterocycle derivatives that inhibit Factor Xa

Abstract

In this patent from Zeneca Ltd., the inventors describe novel compounds that possess antithrombotic and anticoagulant activities, arrising from the specific inhibition of Factor Xa. Factor Xa is a serine protease in the blood coagulation cascade that resides at the juncture of the intrinsic and extrinsic clotting pathways. Specifically, Factor Xa is responsible for the conversion of prothrombin to thrombin in the presence of Factor Va, calcium, and a phospholipid surface. Inhibition of the production of thrombin would prevent the conversion of fibrinogen to fibrin, which is the insoluble matrix of clots. Therefore, inhibition of Factor Xa could provide an effective anticoagulant therapy. The iv. administration of Factor Xa inhibitors should have application in the treatment of unstable angina, non-Q wave myocardial infarction, as an adjunct to balloon angioplasty and/or stents, or as an adjunct to thrombolysis. Orally active Factor Xa inhibitors would have a broader range of therapeutic indications, including the treatment of deep vein thrombosis following major orthopaedic surgery, major fractures and/or abdominal surgery, heart failure, myocardial infarction and atrial fibrillation. Recently, several small molecule specific Factor Xa inhibitors have been described in the patent and scientific literature. All of these compounds, contain an amidino group which has been shown to specifically bind in the recognition (P1) pocket of Factor Xa. Unfortunately, compounds that contain such highly basic groups are generally limited with respect to their oral bioavailability. Unlike previously reported Factor Xa inhibitors, the compounds described in WO9821188 contain pyrimidinyl, pyridyl and pyradazinyl groups that presumably bind in the recognition pocket of Factor Xa. Therefore, these compounds may have the potential to possess increased oral activity.

• anticoagulants
• antithrombotics
• deep vein thrombosis
• Factor Xa inhibitors