Factor VIIa is a plasma serine protease involved in the regulation of hemostasis. It binds with high affinity to Tissue Factor in the presence of calcium ions to form a complex. The complex exhibits enhanced proteolytic activity and is the primary initiator of the extrinsic pathway of blood coagulation. See Carson, S. D. and Brozna, J. P. Blood Coag. Fibrinol. 1993, 4, 281–292. The complex initiates blood coagulation by activating factor X to factor Xa, factor IX to factor IXa and additional factor VII to factor VIIa. Ultimately, the activity of factor VIIa induces the conversion of prothrombin to thrombin. Thrombin functions to convert fibrinogen to fibrin, which forms a clot through polymerization.
While blood coagulation is a necessary and important part in the regulation of an organism's hemostasis, blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel, blocking circulation and inducing a heart attack.
Because of the role of serine proteases in blood coagulation, researchers have postulated that the inhibition of factor VIIa could be used to treat or prevent disease states involving thrombosis. Work has accordingly been performed to identify and optimize factor VIIa inhibitors. For example, U.S. Pat. No. 5,859,010 discusses factor VIIa/Tissue Factor inhibitors that are dihydroxamates having a spacing from 0.37 nm to about 0.77 nm; U.S. Pat. No. 5,843,442 reports monoclonal-type antibodies or antibody fragments possessing inhibitory activity; and, U.S. Pat. No. 5,023,236 presents peptides and peptide derivatives that specifically inhibit the proteolytic active site of serine protease coagulation factor VII/VIIa.
In addition to the above, bicyclic pyrimidinones are known in the art. For example, PCT International publication WO 01/87851 describes substituted polycyclic aryl and heteroaryl pyrimidinones useful as inhibitors of the coagulation cascade. U.S. Pat. No. 5,962,487 and related PCT International publication WO 99/31122 describe a generic scope of peptidyl compounds including, but not limited to, bicyclic pyrimidinones, useful as picomaviral 3C inhibitors. U.S. Pat. Nos. 5,847,135; 5,756,466; 5,656,627; 5,716,929; 6,103,711; and 5,973,111 describe a generic scope of compounds including, but not limited to, substituted bicyclic pyrimidinone compounds as peptide inhibitors of interleukin-1β converting enzyme. U.S. Pat. No. 4,252,807 describes bicyclic pyrimidinones useful as anti-atherosclerotic agents. The scope of the present invention is considered not to be exemplified nor suggested by the above references.
While a number of factor VIIa inhibitors have been discussed in the art, improved inhibitors, especially non-peptide inhibitors, of serine proteases for the treatment of thromboembolic disorders are always desirable. The present invention discloses non-peptide serine protease inhibitors which are bicyclic pyrimidinones useful in the treatment of thromboembolic disorders.
In addition, it is also desirable to find new compounds with improved pharmacological characteristics compared with known serine protease inhibitors. For example, it is preferred to find new compounds with improved factor XIa inhibitory activity and selectivity for factor XIa versus other serine proteases. It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but are not limited to: (a) pharmaceutical properties; (b) dosage requirements; (c) factors which decrease blood concentration peak-to-trough characteristics; (d) factors that increase the concentration of active drug at the receptor; (e) factors that decrease the liability for clinical drug-drug interactions; (f) factors that decrease the potential for adverse side-effects; and, (g) factors that improve manufacturing costs or feasibility.