Aryl and heteroaryl compounds and methods to modulate coagulation

Abstract

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are useful in a variety of applications including the management, treatment and / or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.

Description

STATEMENT OF RELATED APPLICATION [0001] The present application is a divisonal application of U.S. patent application Ser. No. 10 / 637,900, filed Aug. 8, 2003, which claims priority under 35 USC 119 from the U.S. Provisional Application No. 60 / 402,272, filed Aug. 9, 2002, entitled “Aryl and Heteroaryl Compounds and Methods to Modulate Coagulation,” the entirety of which are herein incorporated by reference.FIELD OF THE INVENTION [0002] This invention relates to compounds which are antagonists of the intrinsic clotting pathway by binding to and inhibiting the function of factor IX. BACKGROUND OF THE INVENTION [0003] Hemostasis, the arrest of bleeding from an injured blood vessel, requires the concerted activity of vascular, platelet, and plasma factors to eventually form a hemostatic seal or a blood clot. In normal hemostasis, the combined activity of these factors is counterbalanced by regulatory mechanisms to limit the accumulation of platelets and fibrin in the area of injury. [000...

AI Technical Summary

Benefits of technology

The present invention provides compounds and methods for treating cardiovascular diseases by inhibiting the clotting activity of factor IX in the intrinsic clotting pathway. These compounds can be used in managing, treating, controlling, and / or as an adjunct of diseases caused by the intrinsic clotting pathway. The compounds can be administered as pharmaceutical compositions and can be useful in the management of cardiopulmonary bypass, stroke, myocardial infarction, deep vein thrombosis, acute and chronic inflammation, and clotting associated with hemodialysis.

Problems solved by technology

Damage to the blood vessel or a negatively charged surface initiates blood clotting by the intrinsic pathway.

A slight imbalance between the processes of clot formation and dissolution can lead to excessive bleeding or thrombosis.

With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism.

Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterized by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure.

Heparin, the most widely used clinical anticoagulant administered intravenously, has not been shown to be universally effective in the treatment or prevention of acute arterial thrombosis or rethrombosis [Prins, M. H. and Hirsh, J., J. Am. Coll. Cardiol., 67: 3A (1991)].

As for arterial thrombosis, there is currently no effective pharmacologic treatment for the prevention of vascular restenosis following mechanical recanalization.

This approach carries the inherent risk of bleeding, since the hemostatic system is no longer fully responsive to potential injury.

Therefore, antithrombotic benefits are normally associated with antihemostatic risks.

But, this approach still blocks the common (intrinsic and extrinsic) pathway of thrombin generation (see FIG. 1), and thereby thrombin-dependent platelet activation.

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