Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-01
2003-11-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S617000, C514S247000, C514S252020, C514S252030, C514S336000, C564S155000, C564S091000, C564S147000, C564S153000, C544S224000, C544S238000, C560S035000, C560S037000, C558S414000
Reexamination Certificate
active
06645992
ABSTRACT:
The present invention relates to compounds of formula I,
in which R
1
, R
2
, A, and B have the meanings indicated below.
Compounds of formula I are valuable as pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of thromboembolic diseases and restenoses. They are inhibitors of the blood clotting enzymes, including factor VIIa, and can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure, treatment, or prevention of which an inhibition of factor VIIa is intended. The invention further relates to processes for the preparation of compounds of formula I, their use, for example, as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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.
Many significant disease states are related to abnormal haemostasis. For example, local thrombus formation due to rupture of atheroslerotic 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.
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 undesirable level 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 well-balanced intervention into the blood clotting system is required.
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 below). 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 (H. Cole,
Aust. J. Med. Sci.
16 (1995) 87; G. J. Broze,
Blood Coagulation and Fibrinolysis
6, Suppl. 1 (1995) S7). 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/TF 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/TF.
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. 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 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”). The 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.
Another exemplary clinical situation for which better anticoagulants are needed concerns subjects undergoing transluminal coronary angioplasty and subjects at risk for myocardial infarction or suffering from crescendo angina. The present, conventionally accepted therapy, which consists 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 procedures is of little value and can be detrimental.
The widely used blood-clotting inhibitors like heparin and related sulfated polysaccharides like LMWH and heparin sulfate exert their anticlotting 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. Hirudin and hirulog are two additional thrombin-specific anticoagulants presently in clinical trials. However, these anticoagulants which inhibit thrombin also are 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 inhibitors (L. A. Harker et al.,
Thromb. Hemostas.
74 (1995) 464).
Specific inhibition of the factor VIIa/TF catalytic complex using monoclonal antibodies (WO-A-92/0671 1) or a protein such as chloromethyl ketone inactivated factor VIla (WO-A-96/12800 and WO-A-97/47651) is an extremely effective means of controlling thrombus formation caused by acute arterial injury or the thrombotic complications related to bacterial septicemia. There is also experimental evidence suggesting that inhibition of factor VIIa/TF activity inhibits restenoses following balloon angioplasty (L. A. Harker et al.,
Haemostasis
26 (1996) S1:76). Bleeding studies have been conducted in baboons and indicate that inhibition of the factor VIIa/TF complex has the widest safety window with respect to therapeutic effectiveness and bleeding risk of any anticoagulant approach tested including thrombin, platelet, and factor Xa inhibition (L. A. Harker et al.,
Thromb. He
Klingler Otmar
Matter Hans
Nestler Hans-Peter
Schreuder Herman
Schudok Manfred
Aventis Pharma Deutschland GmbH
Balasubramanian Venkataraman
Finnegan Henderson Farabow Garrett & Dunner LLP
Shah Mukund J.
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