N-guanidinoalkylamides, their preparation, their use, and...

Details N-guanidinoalkylamides, their preparation, their use, and... N-guanidinoalkylamides, their preparation, their use, and...

2002-08-26

2003-12-16

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S269000, C514S307000, C514S309000, C514S312000, C514S357000, C546S141000, C546S146000, C546S156000, C546S332000, C546S329000, C546S335000

Reexamination Certificate

active

06664393

ABSTRACT:

The present invention relates to compounds of the formula I,
in which A, L, Y, and k are as defined below. Compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesirable activity of factor Xa and/or factor VIIa is present, or for the cure or prevention of conditions in which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
The ability to form blood clots is vital to survival. The formation of a blood clot or a thrombus is normally the result of tissue injury which initiates the coagulation cascade and has the effect of slowing or preventing blood flow in wound healing. Other factors which are not directly related to tissue injury like atherosclerosis and inflammation may also initiate the coagulation cascade. In general, a relationship exists between inflammation and the coagulation cascade. Inflammation mediators regulate the coagulation cascade and coagulation components influence the production and activity of inflammation mediators.
However, in certain disease states the formation of blood clots within the circulatory system reaches an undesired extent and is itself the source of morbidity, potentially leading to pathological consequences. It is nevertheless not desirable in such disease states to completely inhibit the blood clotting system because life threatening hemorrhage would ensue. In the treatment of such states, a finely tuned intervention into the blood clotting system is required, and there is still a need for substances exhibiting a suitable pharmacological activity profile for achieving such a result.
Blood coagulation is a complex process involving a progressively amplified series of enzyme activation reactions in which plasma zymogens are sequentially activated by limited proteolysis. Mechanistically, the blood coagulation cascade has been divided into intrinsic and extrinsic pathways, which converge at the activation of factor X. Subsequent generation of thrombin proceeds through a single common pathway (see Scheme 1). Present evidence suggests that the intrinsic pathway plays an important role in the maintenance and growth of fibrin formation, while the extrinsic pathway is critical in the initiation phase of blood coagulation. It is generally accepted that blood coagulation is physically initiated upon formation of a factor VIIa/tissue factor (TF) complex. Once formed, this complex rapidly initiates coagulation by activating factors IX and X. The newly generated activated factor X, i.e., factor Xa, then forms a one-to-one complex with factor Va and phospholipids to form a prothrombinase complex, which is responsible for converting soluble fibrinogen to insoluble fibrin via the activation of thrombin from its precursor prothrombin.
As time progresses, the activity of the factor VIIa/tissue factor complex (extrinsic pathway) is suppressed by a Kunitz-type protease inhibitor protein, TFPI, which, when complexed to factor Xa, can directly inhibit the proteolytic activity of factor VIIa/tissue factor complex. In order to maintain the coagulation process in the presence of an inhibited extrinsic system, additional factor Xa is produced via the thrombin-mediated activity of the intrinsic pathway. Thus, thrombin plays a dual autocatalytic role, mediating its own production and the conversion of fibrinogen to fibrin. The autocatalytic nature of thrombin generation is an important safeguard against uncontrolled bleeding, ensuring that, once a given threshold level of prothrombinase is present, blood coagulation will proceed to completion. Thus, it is desirable to develop agents that inhibit coagulation without directly inhibiting thrombin but rather by inhibiting other steps in the coagulation cascade, like factor Xa and/or factor VIIa activity.
In many clinical applications, there is a great need for the prevention of intravascular blood clots or for some anticoagulant treatment. For example, nearly 50% of patients who have undergone a total hip replacement develop deep vein thrombosis (DVT). Currently available drugs, like heparin and derivatives thereof, are not satisfactory in many specific clinical applications. The currently approved therapies include fixed dose low molecular weight heparin (LMWH) and variable dose heparin. Even with these drug regimes, 10% to 20% of patients develop DVT, and 5% to 10% develop bleeding complications.
Better anticoagulants are also needed for subjects undergoing transluminal coronary angioplasty and subjects at risk for myocardial infarction or suffering from crescendo angina. The present conventionally accepted therapy of administering heparin and aspirin is associated with a 6% to 8% abrupt vessel closure rate within 24 hours of the procedure. The rate of bleeding complications requiring transfusion therapy due to the use of heparin also is approximately 7%. Moreover, even though delayed closures are significant, administration of heparin after termination of the procedure is of little value and can be detrimental.
Widely used blood clotting inhibitors, such as heparin, and related sulfated polysaccharides such as LMWH and heparin sulfate, exert their anticlotting effects by promoting the binding of a natural regulator of the clotting process, antithrombin III, to thrombin and to factor Xa. The inhibitory activity of heparin primarily is directed toward thrombin, which is inactivated approximately 100 times faster than factor Xa. Hirudin and hirulog are two additional thrombin specific anticoagulants. However, these anticoagulants which inhibit thrombin are also associated with bleeding complications. 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 inhibition.
Several specific inhibitors of factor Xa have been reported. Both synthetic and protein inhibitors of factor Xa have been identified, these include, for example, antistasin (ATS) and tick anticoagulant peptide (TAP). ATS, which is isolated from the leech,
Haementerin officinalis
, contains 119 amino acids and has a K
i
for factor Xa of 0.05 nM. TAP, which is isolated from the tick,
Omithodoros moubata
, contains 60 amino acids and has a K
i
for factor Xa of about 0.5 nM.
The effectiveness of recombinantly produced ATS and TAP have been investigated in a number of animal model systems. Both inhibitors decrease bleeding time compared to other anticoagulants, and prevent clotting in a thromboplastin induced, ligated jugular vein model of deep vein thrombosis. The results achieved in this model correlate with results obtained using the current drug of choice, heparin.
Subcutaneous ATS also was found to be an effective treatment in a thromboplastin induced model of disseminated intravascular coagulation (DIC). TAP effectively prevents “high shear” arterial thrombosis and “reduced flow” caused by the surgical placement of a polyester (DACRON) graft at levels that produced a clinically acceptable prolongation of the activated partial thromboplastin time (aPTT), i.e., less than about two fold prolongation. By comparison, standard heparin, even at doses causing a five fold increase in the aPTT, did not prevent thrombosis and reduced flow within the graft. The aPTT is a clinical assay of coagulation which is particularly sensitive to thrombin inhibitors.
ATS and TAP have not been developed clinically. One major disadvantage of these two inhibitors is that administration of the require

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