ACYLSULFAMIDE INHIBITORS OF FACTOR VIIa

Abstract

Compounds having the general formula I are useful for inhibiting serine protease enzymes, such as Tissue Factor VIIa, factor Xa, thrombin and kallikrein and have improved permeability properties. These compounds may be used in methods of preventing and / or treating clotting disorders.

Description

[0001] This non-provisional application filed under 37 CFR §1.53(b), claims the benefit under 35 USC § 19(e) of U.S. Provisional Application Ser. No. 60 / 471,804 filed on May 20, 2003.FIELD OF THE INVENTION [0002] In one aspect, the invention relates to novel compounds which are inhibitors of Tissue Factor (TF) / factor VIIa, factor VIIa, factor Xa, thrombin and / or kallikrein, as well as compositions containing these compounds. The compounds are useful for inhibiting these factors and for treating disorders mediated thereby. For example, the compounds are useful for preventing thrombosis or treating abnormal thrombosis in a mammal by inhibiting TF / factor VIIa, factor Xa, thrombin and / or kallikrein. BACKGROUND OF THE INVENTION [0003] Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface, maintain the fluidity of blood ...

AI Technical Summary

Benefits of technology

[0046] Prodrug forms of Formula I compounds, e.g. where Pr1 and / or Pr2 forms a prodrug moiety, may possess improved pharmacokinetic, e.g. oral bioavailability, properties.

Problems solved by technology

Furthermore, a high percentage of patients undergoing surgery, particularly in the lower extremities, suffer thrombus formation in the venous vascular system which results in reduced blood flow to the affected area.

In the venous vasculature, many patients undergoing surgery, particularly in the abdominal and lower body regions, experience thrombus formation which reduces blood flow and can lead to a pulmonary embolism.

Disseminated intravascular coagulopathy in both the venous and arterial systems occurs commonly during septic shock, some viral infections, and cancer and may lead to rapid and widespread thrombus formation and organ failure.

Also, typically the cost of monitoring blood levels far exceeds the cost of coumarin and heparin type anticoagulant therapy.

However, arterial thrombosis following these procedures remains a leading cause of failure.

Heparin, the most widely used anticoagulant, has not been shown to be entirely effective in the treatment and prevention of acute arterial thrombosis or rethrombosis.

The synthesis and development of small molecule inhibitors based on the known three-dimensional structure of proteins is a challenge of modern drug development.

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