Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-02-23
2004-09-21
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C530S331000, C530S332000
Reexamination Certificate
active
06794365
ABSTRACT:
The present invention relates to compounds of the formula I,
in which R(1), R(2), R(3), R(4), R(5), and R(6) have the meanings as indicated below. The compounds of formula I are valuable pharmacologically active compounds. They exhibit an 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 enzyme factor Xa and can in general be applied in conditions in which an undesired activity of factor Xa is present or for the cure or prevention of which an inhibition of factor Xa is intended. The invention also relates to processes for the preparation of the compounds of formula I, to methods of inhibiting factor Xa activity and of inhibiting blood clotting, to the use of the compounds of formula I in the treatment and prophylaxis of diseases which can be treated or prevented by the inhibition of factor Xa activity such as thromboembolic diseases, and to the use of the compounds of formula I in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing a compound of formula I in admixture or otherwise in association with an inert carrier, as well as pharmaceutical compositions containing a compound of formula I together with pharmaceutically acceptable carrier substances and auxiliary substances.
The ability to form blood clots is vital to survival. In certain disease states, however, the formation of blood clots within the circulatory system reaches an undesired extent and is itself a source of morbidity potentially leading to pathological consequences. It is nevertheless not desirable in such disease states to completely inhibit the clotting system because life threatening hemorrhage would ensue. In the treatment of such states a well-balanced 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 the 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 tissue factor (TF)/factor VIIa 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. 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 and it ensures that, once a given threshold level of prothrombinase is present, blood coagulation will proceed to completion, effecting, for example, an end of the hemorrhage. Thus, 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 Xa.
In many clinical applications there is a great need for the prevention of intravascular blood clots or for anti-coagulant therapy. For example, nearly 50% of patients who have undergone a total hip replacement develop deep vein thrombosis (DVT). The currently approved therapies are 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.
Another clinical situation for which better anticoagulants are needed concerns subjects undergoing transluminal coronary angioplasty and subjects at risk for myocardial infarction or angina. The present, conventionally accepted therapy which consists of administering heparin and aspirin, is associated with a 6% to 8% abrupt vessel closure rate with 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 procedures is of little value and can be detrimental.
The most widely used blood-clotting inhibitors are heparin and the related sulfated polysaccharides, LMWH and heparin sulfate. These molecules exert their anti-clotting effects by promoting the binding of a natural regulator of the clotting process, anti-thrombin 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. Although relative to heparin, heparin sulfate and LMWH are somewhat more potent inhibitors of Xa than of thrombin, the differences in vitro are modest (3-30 fold) and effects in vivo can be inconsequential. Hirudin and hirulog are two additional thrombin-specific anticoagulants that have been tested in clinical trials. However, these anticoagulants, which inhibit thrombin, also are associated with bleeding complications.
Preclinical studies in baboons and dogs have shown that specific inhibitors of factor Xa prevent clot formation without producing the bleeding side effects observed with direct thrombin inhibitors.
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 Ki for factor Xa of 0.05 nM. TAP, which is isolated from the tick,
Ornithodoros moubata
, contains 60 amino acids and has a Ki 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
Al-Obeidi Fahad A.
Walser Armin
Wildgoose Peter
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Low Christopher S. F.
Lukton David
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