Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-22
2001-01-30
Shah, Mukund J. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S092000
Reexamination Certificate
active
06180625
ABSTRACT:
FIELD OF INVENTION
The present invention relates to reagents useful as anticoagulants. More specifically, the invention relates to the use of compounds having the formula I, and pharmaceutical salts thereof, as anticoagulants. The compounds inhibit the ability of factor VIIa (fVIIa) in complex with tissue factor (TF) to cleave a low-molecular weight substrate and/or factor X and, as a result, blood coagulation initiated by tissue factor is inhibited. The invention further relates to the use of compound I as an inhibitor of clotting activity, and methods of inhibiting clotting activity, tissue factor activity, and FVIIa activity as well as methods for treatment of coagulation related diseases states.
The invention also relates to novel compounds with anticoagulative effect and pharmaceutical compositions comprising such compounds.
BACKGROUND OF INVENTION
Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually gives rise to a fibrin clot. Generally, the blood components which participate in what has been referred to as the coagulation “cascade” are proenzymes or zymogens, enzymatically inactive proteins, which are converted to proteolytic enzymes by the action of an activator, itself an activated clotting factor. Coagulation factors that have undergone such a conversion and generally referred to as “active factors”, and are designated by the addition of the letter “a” to the name of the coagulation factor (e.g. fVIIa).
Activated factor X (fXa) is required to convert prothrombin to thrombin, which then converts fibrinogen to fibrin as a final stage in forming a fibrin clot. There are two systems, or pathways that promote the activation of factor X. The “intrinsic pathway” refers to those reactions that lead to thrombin formation through utilisation of factors present only in plasma. A series of protease-mediated activations ultimately generates factor IXa, which, in conjunction with factor Villa, cleaves factor X into Xa. An identical proteolysis is effected by fVIIa and its cofactor TF in the “extrinsic pathway” of blood coagulation. TF is a membrane bound protein and does not normally circulate in plasma. Upon vessel disruption, however, it is exposed and forms a complex with fVIIa to catalyse factor X activation or factor IX activation in the presence of Ca
2+
and phospholipid (Nemerson and Gentry,
Biochemistry
25:4020-4033 (1986)). While the relative importance of the two coagulation pathways in hemostasis is unclear, in recent years fVIIa and TF have been found to play a pivotal role in the initiation and regulation of blood coagulation.
FVII is a trace plasma glycoprotein that circulates in blood as a single-chain zymogen. The zymogen is catalytically inactive (Williams et al.,
J. Biol. Chem
. 264:7536-7543 (1989); Rao et al.,
Proc. Natl. Acad. Sci. USA
. 85:6687-6691 (1988)). Single-chain fVII may be converted to two-chain fVIIa by factor Xa, factor XIIa, factor IXa, fVIIa or thrombin in vitro. Factor Xa is believed to be the major physiological activator of fVII. Like several other plasma proteins involved in hemostasis, fVII is dependent on vitamin K for its activity, which is required for the gamma-carboxylation of multiple glutamic acid residues that are clustered in the amino terminus of the protein. These gamma-carboxylated glutamic acids are required for the metal-associated interaction of fVII with phospholipids.
The conversion of zymogen fVII into the activated two-chain molecule occurs by cleavage of an internal Arg152-Ile153 peptide bond (Hagen et al.,
Proc. Natl. Acad. Sci. USA
83: 2412-2416 (1986); Thim et al.,
Biochemistry
27:7785-7793 (1988)). In the presence of TF, phospholipids and calcium ions, the two-chain fVIIa rapidly activates factor X or factor IX by limited proteolysis.
It is often desirable to selectively block or inhibit the coagulation cascade in a patient. Anticoagulants such as heparin, coumarin, derivatives of coumarin, indandione derivatives, thrombin inhibitors, factor Xa inhibitors, modified fVII or other agents may be used.
Inhibition of coagulation is beneficial in a number of diseased states, for example 25 during kidney dialysis, or to treat deep vein thrombosis, disseminated intravascular coagulation (DIC) and a host of other medical disorders. For example, heparin treatment or extracorporeal treatment with citrate ions (U.S. Pat. No. 4,500,309) may be used in dialysis to prevent coagulation during the course of treatment. Heparin is also used in preventing deep vein thrombosis in patients undergoing surgery. Treatment with heparin and other anticoagulants may, however, have undesirable side effects. Available anticoagulants generally act throughout the body, rather than acting specifically at the site of injury, i.e. the site at which the coagulation cascade is active. Heparin, for example, may cause severe bleedings. Furthermore, with a half-life of approximately 80 minutes, heparin is rapidly cleared from the blood, necessitating frequent administrating. Because heparin acts as a cofactor for antithrombin III (AT III), and AT III is rapidly depleted in DIC treatment, it is often difficult to maintain the proper heparin dosage, necessitating continuous monitoring of AT III and heparin levels. Heparin is also ineffective if AT III depletion is extreme. Further, prolonged use of heparin may also increase platelet aggregation and reduce platelet count, and has been implicated in the development of osteoporosis. Indandione derivatives may also have toxic side effects.
Other known anticoagulants comprise thrombin and factor Xa inhibitors derived from bloodsucking organisms. Antithrombins, hirudin, hirulog and hirugen are recombinant proteins or peptides derived from the leach
Hirudo medicinalis
, whereas the factor Xa inhibitor antistatin and the recombinant derivative rTAP are tick-derived proteins. Inhibitors of platelet aggregation such as monoclonal antibodies or synthetic peptides, which interfere with the platelet receptor GPIIb/IIa are also effective as anticoagulants.
Bleeding complications are observed as an undesired major disadvantage of anti-thrombin, anti-factor Xa, as well as anti-platelet reagents. This side effect is strongly decreased or absent with inhibitors of the fVIIa/TF activity. Such anticoagulants comprise the physiological inhibitor TFPI (tissue factor pathway inhibitor) and modified fVII (fVIIai), which is fVIIa modified in such a way that it is catalytically inactive but still binds to TF and competes with active fVIIa.
In addition to the anticoagulants briefly described above, several naturally occurring proteins have been found to have anticoagulant activity. For example, Reutelingsperger (U.S. Pat. No. 4,736,018) isolated anticoagulant proteins from bovine aorta and human umbilical vein arteries. Maki et al. (U.S. Pat. No. 4,732,891) disclose human placenta-derived anticoagulant proteins. In addition, AT III has been proposed as a therapeutic anticoagulant (Schipper et al.,
Lancet
1 (8069): 854-856 (1978); Jordan, U.S. Pat. No. 4,386,025; Bock et al., U.S. Pat. No. 4,517,294).
Proliferation of smooth muscle cells (SMCs) in the vessel wall is an important event in the formation of vascular lesions in atherosclerosis, after vascular reconstruction or in response to other vascular injury. For example, treatment of atherosclerosis frequently includes the clearing of blocked vessels by angioplasty, endarterectomy or reduction atherectomy, or by bypass grafting, surgical procedures in which atherosclerotic plaques are compressed or removed through catheterization (angioplasty), stripped away from the arterial wall through an incision (endarterectomy) or bypassed with natural or synthetic grafts. These procedures remove the vascular endothelium, disturb the underlying intimal layer, and result in the death of medial SMCs. This injury is followed by medial SMC roliferation and migration into the intima, which typically occurs within the first few weeks nd up to six months after injury and stops when the overlying endothelial cell
Jakobsen Palle
Persson Egon
Worsaae Helle
Novo Nordisk A S
Rozek, Esq. Carol E.
Shah Mukund J.
Truong Tamthom N.
Zelson, Esq. Steve T.
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