Normal haemostasis 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 unless injury and blood loss occurs (EP-A-987274). Many significant disease states are related to abnormal haemostasis. For example, local thrombus formation due to rupture of atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel.
There continues to be a need for safe and effective therapeutic anticoagulants to limit or prevent thrombus formation. It is most desirable to develop agents that inhibit coagulation without directly inhibiting thrombin but by inhibiting other steps in the coagulation cascade like factor VIIa activity. Preclinical studies in baboons and dogs have shown that targeting enzymes involved at earlier stages of the coagulation cascade, such as factor Xa or factor VIIa, prevents clot formation without producing the bleeding side effects observed with direct thrombin inhibitors (L. A. Harker et al., Thromb. Hemostas. 74 (1995) 464). There is also experimental evidence suggesting that inhibition of factor VIIa/tissue factor activity inhibits restenosis following balloon angioplasty (L. A. Harker et al., Haemostasis 26 (1996) S1:76).
A specific inhibitor of factor VIIa which has a favourable property profile would have substantial practical value in the practice of medicine. In particular, a factor VIIa inhibitor would be effective under circumstances where the present drugs of choice, like heparin and related sulphated polysaccharides, are ineffective or only marginally effective.
Certain inhibitors of factor VIIa have already been described in WO02/28823, which disclose compounds inhibiting factor VIIa. However, the property profile of these compounds is still not ideal, and there is a need for further low molecular weight factor VIIa-specific blood clotting inhibitors especially with improved activity. The present inventions satisfy the above needs by providing novel compounds of the formulae I and Ia, which exhibit factor VIIa inhibitory activity and are favourable agents with better selectivity and high activity. Especially, the combination of the methyl residue between malonamide and phenyl residue in combination with X, Y and Z offers compounds with high selectivity and activity.
USPTO Backgrounds
USPTO Backgrounds