Substituted (aminoiminomethyl or aminomethyl)...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S337000, C514S407000, C514S414000, C548S364400, C548S454000, C546S122000, C546S284100, C549S058000, C549S467000

Reexamination Certificate

active

06599918

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benzopyrans that inhibit Factor Xa, pharmaceutical compositions comprising these compounds and their use for inhibiting Factor Xa or treating pathological conditions in a patient that may be ameliorated by administration of such compounds. This invention also relates to substituted (aminoiminomethyl or aminomethyl) dihydrobenzo-furans and benzopyrans which directly inhibit both Factor Xa and Factor IIa (thrombin), to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of simultaneously directly inhibiting both Factor Xa and Factor IIa (thrombin).
BACKGROUND OF THE INVENTION
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Moreover, Factor Xa inhibition is effected by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective Factor Xa inhibition is achieved by administering the compounds either orally, by continuous intravenous infusion, by bolus intravenous administration or by any other parenteral route such that it achieves the desired effect of inhibiting physiological events mediated by the catalytic activity of Factor Xa.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting (CABG) of the coronary or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors, resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems.
Accumulated experimental evidence has also indicated that prothrombin activation is only one of the biological activities of Factor Xa. For example, Factor Xa is believed to influence several vascular wall phenomena by interaction with EPR-1 (effector cell protease receptor-1, which recognizes Factor Xa). EPR-1 has been shown to be expressed on human umbilical vein endothelial cells, rat smooth muscle cells and platelets (C R McKenzie, et al., Arterioscler Thromb Vasc Biol 16 1285-91 (1996); F Bono, et al., J Cell Physiol 172 36-43 (1997); A C Nicholson, et al., J Biol Chem 271 28407-13 (1996); and J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). This protease-receptor interaction could mediate not only prothrombinase-catalyzed thrombin generation, but also diverse cellular functions such as cell proliferation, release of PDGF and DNA syntheses. The mitogenic effect of Factor Xa has been reported to be dependent on Factor Xa enzymatic activity (F Bono, et al., J Cell Physiol 172 36-43 (1997); and J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). TAP, for example, inhibited the mitogenesis of human and rat cultured vascular smooth muscle cells (F Bono, et al., J Cell Physiol 172 36-43 (1997)). In a study of the rabbit carotid artery air-drying injury model, increased EPR-1 expression was detected after vascular injury. Animals treated with the specific Factor Xa inhibitor, DX-9065a, exhibited less neointimal proliferation. The important regulatory role of Factor Xa in the coagulation process coupled with its mitogenic effects points to Factor Xa's involvement in the formation of thrombin at the luminal surface of the vessel wall and contribution to the atherothrombotic process and abnormal proliferation of vascular cells resulting in restenosis or angiogenesis.
Vascular injury caused by biochemical or physical perturbations, results in the activation of the coagulation system, culminating in the generation of thrombin. Thrombin promotes thrombus formation by catalyzing the transformation of fibrinogen to fibrin, by activating Coagulation Factor XIII that stabilizes the thrombus, and by activating platelets. Thrombin promotes further thrombus growth by positive feedback to the coagulation cascade (activation of Coagulation Factors V and VIII), resulting in the explosive production of thrombin. Thrombin is present, and active, in the thrombi of patients with thrombotic vascular disease. Thrombin inhibition prevents the action of thrombin after thrombin has been activated from prothrombin. An inhibitor of thrombin inhibits cleavage of fibrinogen to fibrin, activation of Factor XIIIa, activation of platelets, and feedback of thrombin to the coagulation cascade to generate more thrombin. Consequently, inhibition of thrombin activity with a direct thrombin inhibitor would be useful for preventing or treating disorders related to blood coagulation in mammals.
The combined Xa/IIIa inhibitors described here inhibit thrombin activity (via IIa inhibition) and thrombin production (via Factor Xa inhibition). Therefore, these agents inhibit any thrombin that may be present and also inhibit the further production of thrombin. Other agents that have this dual activity include heparin and low molecular weight heparins (LMWHs), which have demonstrated efficacy in thrombotic diseases. However, heparin and LMWHs act indirectly through a cofactor, antithrombin-III (ATIII), to inhibit Xa and IIa. The heparin/ATIII complex is too large, however, to inhibit thrombus-bound Xa and IIa, thus limiting their efficacy. Direct inhibitors of Xa and IIa, as described here, are capable of inhibiting soluble and thrombus-bound Xa and IIa, thus providing an important therapeutic advantage over currently available Xa/IIa inhibitors.
In view of the physiological conditions discussed above related to Factor Xa, inhibitors of Factor Xa would be useful in treating those and other conditions that would be ameliorated by a Factor Xa inhibitor.
SUMMARY OF THE INVENTION
This invention is directed to a compound of formula I:
n=1 or 2
W is H or a ring system substituent.
R is hydrogen, cyano, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroaryleycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, or fused heterocyclyiheteroaryl,
R
1
is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;
R
2
and R
3
are each hydrogen, or, taken together are ═NR
4
;
R
4
is hydrogen, R
5
O
2
C—, R
5
O—, HO—, cyano, R
5
CO—, HCO—, lower alkyl, nitro, or R
6
R
7
N;
R
5
is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R
6
and R
7
are

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