WO2006110726A2 - Dosage formulations and methods of treatment and prevention - Google Patents

Abstract

The present invention relates to combinations of 4-methyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-β-D-xylopyranoside and factor Xa inhibitors, methods for producing said combinations, and methods of using said combinations for the treatment and prevention of various thromboembolic disorders in mammals, particularly humans.

Description

DOSAGE FORMULATIONS AND METHODS OF TREATMENT AND PREVENTION

Field of the Invention

The present invention relates to combinations of 4-methyl-2-oxo-2H-1 -benzopyran-

7-yl-5-thio-β-D-xylopyranoside ("odiparcil") and factor Xa inhibitors, methods for producing said combinations, and methods of using said combinations for the treatment and prevention of various thromboembolic disorders in mammals, particularly humans.

Background of the Invention

Many medical problems relate to thromboses. For example, atrial fibrillation (AF), myocardial infarction (Ml), heart failure, surgery (especially major orthopedic surgery, including knee or hip replacement surgery), valvular heart disease, coronary artery disease, peripheral arterial occlusive disease, cerebrovascular disease, various cancers, and diabetes are associated with thrombogenesis and/or embolism, which can result in stroke or myocardial infarction.

In particular, patients undergoing major orthopedic surgery such as total hip arthroplasty (THA) have a high risk of developing thromboembolic complications in the immediate post-operative period. In addition, atrial fibrillation is a common cardiac arrhythmia, and stroke is its most devastating complication. Most ischemic strokes associated with atrial fibrillation are probably due to embolism of stasis-associated thrombi forming in the left atrium and particularly its appendage. Similarly, thrombosis within the venous system is mostly related to blood stasis and endothelial damage, leading to activation of the clotting system.

As thromboses consist of platelets, fibrin (and often erythrocytes), various approaches have been taken for the prevention and/or treatment of thromboses, including the use of antiplatelet drugs, anticoagulant drugs, and thrombolytic agents.

Anticoagulants are designed to inhibit or antagonize one or more aspects of the coagulation cascade, in order to ultimately inhibit the formation of fibrin. These effects may be achieved by targeting thrombin, which acts on fibrinogen and factor XIlI to form fibrin and crosslinked fibrin polymer, respectively. For example, an anticoagulant may be designed to limit functional prothrombin synthesis, attenuate thrombin generation, or inhibit formed thrombin. For example, warfarin inhibits the synthesis of factors dependent on vitamin K, i.e., prothrombin, factors VII, IX and X, protein C, and protein S. Heparin binds to antithrombin III thereby inactivating thrombin Ma, factor IXa, and factor Xa (unfractionated heparin having action against XIIa, XIa, IXa, Vila and thrombin; low molecular weight heparin (LMWH) having action primarily against Xa). Direct thrombin inhibitors like melagatran, argatroban, and hirudin bind directly in the thrombin active site and thereby inhibit its formation.

One thrombin inhibitor that is present endogenously in the circulation is Heparin Cofactor Il (HCII). HCII is a Serpin (serine protease inhibitor) activated by glycosaminoglycans (GAGs), including heparin, heparin sulfate, and dermatan sulfate. It has been reported that HCII is capable of inhibiting both fibrin-bound and clot-bound thrombin.

Available anti-thrombotic therapies for stroke prevention in AF include aspirin and warfarin. Anti-thrombotic therapy for DVT prophylaxis includes primarily LMWH, with some usage of warfarin. Post-MI patients have been treated primarily with aspirin, and also with clopidogrel, ticlopidine, LMWH and warfarin. Antithrombotic prophylaxis has been routinely indicated in patients undergoing major orthopedic surgery such as THA. It has been recommended by international guidelines (Grade 1 A Recommendation) that prophylaxis with either low molecular weight heparins (LMWHs) or adjusted-dose warfarin (international normalized ratio [INR] target = 2.5; range of 2.0 to 3.0) be administered for 7 to 10 days following surgery for elective hip or knee replacement.

The incidence of asymptomatic VTE following hospital discharge is substantial (e.g., ranging from 12% to 39% as assessed by venography). Prophylaxis beyond 7-10 days after surgery and hospitalization, or "extended prophylaxis," with LMWHs has been demonstrated to reduce the rate of asymptomatic VTE by approximately 50%. The practice of continuing prophylaxis for 3-6 weeks after discharge is becoming more common; however, the optimum duration of prophylaxis remains uncertain. Guidelines have suggested the use of extended prophylaxis with LMWHs only for high-risk patients, i.e., patients with an ongoing risk factor (Grade 2A Recommendation). The occurrence of asymptomatic VTE is common in the natural course following major orthopedic surgery, and in the majority of patients the thrombi resolve spontaneously. Routine duplex ultrasound screening at the time of hospital discharge or follow-up is not recommended for asymptomatic patients because it does not reduce the incidence of VTE.

In contrast, the risk of symptomatic VTE is very low (e.g., about 2%) during the subsequent 3-month period. A meta-analysis of nine randomized studies investigated the effectiveness of extended prophylaxis (30-42 days) with LMWH or unfractionated heparin, as compared with placebo or no treatment, in patients undergoing total hip or knee replacement. The meta-analysis demonstrated a reduction in the incidence of symptomatic VTE from 3.3% to 1.3% and that the reduction was greater in patients undergoing total hip replacement (4.3% to 1.4%) Although this meta-analysis suggests that symptomatic VTE may be reduced with extended prophylaxis with LMWH, only two of the nine studies included demonstrated a clear statistical advantage for such treatment. It would appear that additional studies are needed to critically evaluate the efficacy and cost effectiveness of extended prophylaxis in reducing the incidence of symptomatic VTE. Because of these uncertainties, extended prophylaxis is not yet considered the standard of care globally, and only those orthopedic patients reporting symptomatic VTE in the period following hospital discharge are routinely evaluated.

The standard therapy for prevention of stroke in chronic atrial fibrillation is adjusted-dose warfarin. However warfarin has issues that result in its underutilization. These include multiple drug interactions, variability of pharmacodynamic effect, need for monitoring, and a narrow therapeutic window. Diet, alcohol, poor food intake in sick patients, and the effect of antibiotics on vitamin K-producing bacteria can result in a high variability of warfarin pharmacodynamic effect. This high variability combined with the narrow therapeutic window requires close monitoring of warfarin and increases bleeding risk. Bleeding risk is increased primarily by increased intensity of anticoagulation, although the following factors may be contributory, age >65 years, a history of stroke or gastrointestinal bleeding, the presence of serious comorbid conditions such as renal insufficiency or anemia, and increased duration of dosing. There is accordingly a need for improved treatments for the prevention of stroke in atrial fibrillation.

The compound, 4-methyl-2-oxo-2H-1 -benzopyran-7-yl-5-thio-β-D-xylopyranoside, is depicted by the following chemical structure:

and is alternatively referred to herein as "odiparcil". Odiparcil and its preparation is disclosed in U.S. Patent No. 5,169,838, issued to Samreth et al. on Dec 8, 1992. This patent discloses, inter alia, the use of the disclosed benzopyranone-β-D-thioxyloside compounds in the treatment of venous and arterial thrombosis, and treatment and prevention of diseases associated with circulatory disorders.

Without intending to be limited or bound by theory, odiparcil is believed to induce glycosaminoglycan (GAG) production and subsequent elevation of anti-lla activity via heparin cofactor Il (HCII), leading to prevention of thrombosis. Anti-lla activity, expressed in dermatan sulfate units, may serve as a pharmacodynamic marker of the effect of odiparcil. The specific antithrombotic activity of odiparcil, which is similar to the selective inhibition of thrombin observed with dermatan sulfate that also activates HCII, may result in a reduced bleeding risk compared with unfractionated, low molecular weight heparins (LMWHs) and direct thrombin inhibitors, while providing antithrombotic efficacy. Odiparcil has exhibited pronounced oral efficacy in experimental animal models of venous and arterial thrombosis. Therefore, odiparcil may effectively prevent and/or treat thromboembolism, e.g., associated with prothrombotic or hypercoagulable states. Accordingly, odiparcil may effectively prevent and/or treat venous thromboembolism (such as associated with orthopedic surgery, e.g., deep vein thromboses [DVT]), stroke and other systemic embolic events (such as associated with atrial fibrillation).

Factor Xa inhibitors may operate directly or indirectly. For purposes of this disclosure, indirect factor Xa inhibitors refers to compounds that inhibit factor Xa but not primarily through direct interaction of the inhibitor with Factor Xa, but rather through activation or inactivation of other factors which in turn inhibit the activity of the prothrombotic enzyme factor Xa. For example, the glycosoaminoglycan heparin is well known to inhibit thrombin through cooperative interaction between heparin and antithrombin. Heparin is also known to inhibit factor Xa through its interactions with antithrombin which in turn inhibits factor Xa. Shorter glycosoaminoglycans typically have less antithrombin activity but may still retain activity against factor Xa via their interaction and activation of antithrombin. For purposes of this invention, the term "factor Xa inhibitors" refers to direct and indirect inhibitors of factor Xa. Compounds that inhibit factor Xa indirectly while also inhibiting other thrombotic pathways (directly or indirectly) will be considered factor Xa inhibitors, for purposes of this invention, if one of skill in the art would recognize or believe that at least some of the antithrombotic clinical benefit of said compound is attributable to its indirect inhibition of factor Xa.

Direct thrombin inhibitors, in contrast, are typically small molecule inhibitors which bind directly to factor Xa and inhibit the enzyme activity. Accordingly, these direct inhibitors of factor Xa are not typically regarded as requiring additional cofactors or proteins (such as antithrombin) to exert their antithrombotic effect(s). The antithrombotic effects of direct factor Xa inhibitors has been demonstrated in several animal models. Further background is provided in the following references: Agnelli G, Sonaglia F. Prevention of venous thromboembolism in high risk patients.. Haematologica, 1997;82:496-502.

Berqqvist D, Benoni G, Bjorgell O, et al. Low molecular weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. New Engl J Med, 1996;335:696-700.

A.D. Blann et al., BMJ Vol. 325, Oct 5, 2002, 762-765.

Robinson KS, Anderson DR, Gross M, ET AL. Ultrasonic screening before hospital discharge for deep vein thrombosis after arthroplasty. Ann Intern Med, 1997;127:439-45). Lassen MR, Dahl OE, Borris LC, et al. Efficacy and safety of prolonged prophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty - The Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res, 1998;89:281-7. Claqett GP, Anderson FA, Geerts W, et al. Prevention of venous thromboembolism. Chest, 1998;114:531 S-60S. Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery ~ Results of a double-blind prospective randomized placebo- controlled study with dalteparin. Thromb Haemost, 1998;77:26-31. Eikelboom JW, Quinlan DJ, Douketis JD Extended-duration prophylaxis against venous thromboembolism after total hip or total knee replacement: A meta-analysis of the randomized trials. Lancet, 2001 ;358:9-15.

Fuster, V. et al., 1997. Hemostasis, thrombosis, fibrinolysis, and cardiovascular disease. Heart Disease, Braunwald E 1809-1842. Philadelphia, PA: WB Saunders Company. Geerts WH. Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest, 2001 ;119:132S-75S. R.G. Hart et al., Atrial Fibrillation and Stroke, Stroke 2001 ; 32:803-808 2001.

Heit JA, Elliott CG, Trowbridge A, et al. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. Ann Intern Med, 2000:132;853-61. Herbert JM, Bernat A, DoI F, et al. DX 9065A, a novel, synthetic, selective and orally active inhibitor of factor Xa: in vitro and in vivo studies. J Pharmacol Exp Ther. 1996; 276: 1030-1038.

Hirsh J, Dalen JE, Guyatt G. The Sixth (2001) ACCP Guidelines for Antithrombotic Therapy for Prevention and Treatment of Thrombosis. Chest, 2001 ;119:1 S-2S. R.D. Hull et al., Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis In Patients after Elective Hip Arthoplasty: A Systematic

Review, Ann Intern Med 2001 ; 135:858-869 2001.

The Physician's Desk Reference. JA Huntinqton, Journal of Thrombosis & Haemostasis. 1 (7):1535-49, JuI 2003, and

Masson, PJ et al., The effect of the β-D-xyloside naroparcil on circulating plasma glycosaminoglycans, J. Biol Chem 1995; 270:2662-2668.

J. A. Huntinαton et al., TRENDS in Pharmacological Sciences, VoI 24, No 11 , Nov 2003

589-595. Kim Dl, Kambayashi J, Shibuya T, et al. In vivo evaluation of DX-9065a, a synthetic factor

Xa inhibitor, in experimental vein graft. J Atheroscler Thromb. 1996; 2: 110-116.

Leclerc JR, Gent M, Hirsh J, ET AL The incidence of venographic venous thromboembolism during and after prophylaxis with enoxaparin: A multi-institutional cohort study in patients who underwent hip or knee arthroplasty. Arch Intern Med, 1998;158:873- 8.

Mascellani et al.. Thrombosis Research. 84(1):21 -32, Oct 1 , 1996.

Muravama N, McMahon H, Young CG, et al. Pharmacokinetics of the anticoagulant 14C-

DX-9065a in the healthy male volunteer after a single intravenous dose. Xenobiotica.

2000; 30: 515-521. Ofosu FA, Modi GJ, Smith LM, et al. Heparin sulphate and dermatan sulphate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood,

1984;64:742-7.

P. Petersen et al., Ximelagatran Versus Warfarin for Stroke Prevention in Patients with

Nonvalvular Atrial Fibrillation, JnI of the Amer College of Cardiology, VoI 41 , No. 9, 1445- 1451 , 2003.

Planes A, Samama MM, Lensing AWA, et al. Prevention of deep vein thrombosis after hip replacement. Comparison between two low-molecular-weight heparins, tinzaparin and enoxaparin. Thromb Haemost, 1999;81 :22-5.

Planes A, Vochelle N, Darmon J-Y, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomized comparison of enoxaparin versus placebo. Lancet, 1996;348:224-8.

Robinson KS, Anderson DR, Gross M, ET AL. Ultrasonic screening before hospital discharge for deep vein thrombosis after arthroplasty. Ann Intern Med, 1997; 127:439-45.

Rogers KL, Chi L, Rapundalo ST, et al. Effects of a factor Xa inhibitor, DX-9065a, in a novel rabbit model of venous thrombosis. Basic Res Cardiol. 1999; 94: 15-22. Yamazaki M, Asakura H, Aoshima K, et al. Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats. Thromb Haemost. 1994; 72: 392-396. Yokovama T, Kelly AB, Marzec UM, et al. Antithrombotic effects of orally active synthetic antagonist of activated factor X in nonhuman primates. Circulation. 1995; 92: 485-491.

The present invention provides additional approaches to treating and/or preventing thromboembolic disorders by providing combination therapy with odiparcil and a factor Xa inhibitor. Summary of the Invention

The present invention relates to methods, processes and dosage formulations comprising odiparcil and a factor Xa inhibitor.

In some embodiments, this invention describes a composition comprising odiparcil and a factor Xa inhibitor. In some embodiments, the invention describes such a composition which is suitable for oral administration. In some embodiments, the invention describes such a composition further comprising at least one pharmaceutical excipient.

In some embodiments, the factor Xa inhibitors used in the combinations of this invention is a direct inhibitor of Factor Xa. In some embodiments, the inhibitor of factor Xa useful in the combinations of this invention is a compound of formula (I), as described herein.

In some embodiments, the dosage formulations comprising odiparcil and a factor Xa inhibitor comprise a single dosage unit. In some such embodiments, the odiparcil and the inhibitor of factor Xa are admixed together. In some embodiments, the dosage formulations of this invention additionally comprise at least one pharmaceutical excipient.

In some embodiments, the dosage formulations of this invention comprise a single package containing odiparcil and an inhibitor of factor Xa wherein the odiparcil and inhibitor of factor Xa are each contained in separate dosage delivery devices and packaged together.

In some embodiments, this invention describes a dosage formulation wherein the odiparcil and/or the factor Xa inhibitor is present in a subtherapeutic amount. In some embodiments, this invention provides a method of treating a thromboembolic disorder in a mammal comprising the administration of a combination of odiparcil and an inhibitor of factor Xa to a mammal in need thereof.

In some embodiments, the method comprises the administration of a dosage formulation of this invention.

In some embodiments, the administration route is oral.

In some embodiments, the mammal to be treated by the methods of this invention is a human.

In some embodiments, the administration of odiparcil and a factor Xa inhibitor is simultaneous.

In some embodiments, the administration of odiparcil and a factor Xa inhibitor is sequential.

In some embodiments, the administration of odiparcil and a factor Xa inhibitor is in combination. In some embodiments, the thromboembolic disorder to be treated are selected from myocardial infarction, sudden heart death, stroke, venous thromboembolism, embolism, and unstable angina.

In some embodiments, this invention provides a method of preparing a combination treatment comprising admixing of odiparcil and a factor Xa inhibitor, and optionally one or more pharmaceutical excipients.

In some embodiments, this invention describes a combination of odiparcil and a factor Xa inhibitor for use in the manufacture of a medicament for treatment of a thromboembolic disorder in a mammal.

It is to be understood that the present invention covers all possible combinations of the various embodiments described hereinabove.

Brief Description of the Drawings

Figure 1 represents a surface showing the Proportional Multiplicative Inhibition Model based on prior studies of odiparcil and Compound A mono-therapies.

Figure 2 represents a mono-therapy of odiparcil and 4 fixed proportion odiparcil/Compound A combination series from a factorial design, of Example 4. Figure 3 represents the Proportional Multiplicative Inhibition (no enhanced response) Model for a factorial design study region, of Example 4.

Figure 4 represents estimated log (IC₅₀) values versus the proportion of Compound A of Example 4.

Figure 5 represents an example analyses of trends in the clot mass response associated with increasing levels of Compound A added to a fixed dose of odiparcil (in Figure 5, odiparcil fixed at 10 mg/kg), of Example 4.

Figure 6 represents the estimated inhibition surface for the total dose of Example 4.

Figure 7 represents the estimated inhibition surface for the total dose plus linear Compound A models of Example 4.

Detailed Description of the Invention

The invention described herein relates to combinations of odiparcil and factor Xa inhibitors. The term "combination" as used herein includes fixed dose combinations wherein the particular dosage form comprises both the odiparcil as well as the factor Xa inhibitor. The term "combination" may also refer to a combination package wherein both components are contained within a single packaging unit, but are in separate dosage forms. For purposes of the methods of this invention, the term "combination" can refer to the administration of combinations as just described, but also applies to administration of odiparcil and a direct inhibitor of factor Xa wherein the odiparcil and factor Xa inhibitor are administered as separate components and wherein said administration may be simultaneous or sequential, providing only that the combination is being administered for the treatment of a thromboembolic disorder and are administered in such a way that at least at some point, the odiparcil and factor Xa inhibitor are simultaneously present in the subject's plasma. The combinations as herein described for the compositions and methods of treatment of the invention may further comprise additional active ingredients or inactive ingredients (such as pharmaceutically acceptable carriers, excipients, and the like).

For purposes of this invention, the term "thromboembolic disorder" refers to disorders associated with inappropriate or undesired thromboses formation resulting in undesired venous or arterial blockages or constriction of blood flow both at the primary site of thrombosis and in the case of embolisms, a more remote site. In the case of an embolism, the initial thrombus which is formed, fragments at least partially and the part to fragment off (embolus) is transported in the plasma where it can sometimes occlude a remote blood vessel, often resulting in serious or even fatal consequences.

As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use.

The term "dosage delivery device" refers to a dosage delivery unit or vehicle. For example, a dosage delivery device may be a solid material such as, for example, a tablet or capsule, or may be a liquid, for example, such as an IV formulation.

The preparation of the compounds for use in the methods and dosage formulations of this invention are known to those of skill in the art.

Odiparcil and its preparation is disclosed in U.S. Patent No. 5,169,838. The term "odiparcil" as used herein refers to the β-D-xylopyranoside and is normally provided consisting substantially of that enantiomer. In some embodiments, the odiparcil used herein has at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 98%, or at least 99% of the D-xylopyranoside configuration. Odiparcil as referred to herein is preferred as its β-anomer. In some embodiments, odiparcil as used herein is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 98%, or at least 99% of its β-anomer.

The description and identity of factor Xa inhibitors are well known to those of skill in the art. In some embodiments, the inhibitor of factor Xa useful in the combinations of this invention is a compound of formula (I),

wherein: R¹ represents hydrogen, -C^alkyl, -C₃.₆aikenyl, -C_2-3alkylNR^bR⁰, -C₂.₃alkylNHCOR^b, phenyl or a 5- or 6- membered aromatic heterocyclic group, the phenyl or 5- or 6- membered aromatic heterocyclic group being optionally substituted by halogen, or R¹ represents a group X-W, wherein X represents -Ci_-3alkylene- and W represents -CN, - CO₂H, -CONR^bR^c, -COCi-ealkyl, -COA-ealkyl, phenyl or 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one or more substitutents selected from: -C_1-3alkyl, -Ci_-3alkoxy, -C_1-3alkylOH, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH;

R² and R³ independently represent hydrogen, -C₁.₃alkyl or -CF₃ with the proviso that one of R² and R³ is -C^alkyl or -CF₃ and the other is hydrogen; R^b and R^c independently represent hydrogen or -Ci_-3alkyl; A represents a group selected from:

wherein

Z represents one or two optional substituents independently selected from halogen and

OH₁

W represents an optional substituent -C_1-3alkyl, alk represents C_2-3alkylene or C₂-₃alkenylene, and

T represents a heteroatom selected from O, S or N; and

B represents one or more optional substituents on ring carbon atoms selected from:

(i) one or more substituents selected from -CF₃, -F, -CO₂H, -C_1-6alkyl, -Ci.₆alkylOH, -(Ci-

₃alkyl)NR^bR^c, -(C₀.₃alkyl)CONR^bR^c, -(C₀.₃alkyl)CO₂C_1-3alkyl, -CONHC^alkylOH, -

CH₂NHC_2-3alkyl0H, -CH₂OC_1-3alkyl and -CH₂SO₂Ci.₃alkyl; (ϋ) a group -Y-R^e, wherein Y represents -C_1-3alkylene-, -CO-, -C^alkylNH-, -d-salkylNHCO-, -Ci. 3alkylNHSO₂-, -CH₂NHSO₂CH₂- or a direct link, and

R^e represents phenyl, a 5- or 6- membered cycloalkyl or a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -C_1-3alkyl, -C^salkoxy, -C^alkylOH, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH; or

(iii) a second ring R^f which is fused to the heterocyclic ring, wherein R^f represents phenyl, a 5- or 6- membered cycloalkyl group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: -d.₃alkyl, -Ci_-3alkoxy, -C_1-3alkyl0H, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, when R¹ represents a group X-W: X represents -Ci_-3alkylene- or, in some embodiments, -methylene-.

In some embodiments, W represents -CN, -CO₂H, -CONR^bR^c, -COCi.₆alkyl, - CO₂Ci.₆alkyl or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. Preferably, R¹ represents hydrogen, -Ci_-6alkyl, -C_{2- 6}alkenyl or a group X-W wherein X represents -C_1-3alkylene- and W represents -CN, - CO₂H, -CONR^bR^c, -COCi_-6alkyl, -COjA-ealkyl or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. More preferably, R¹ represents a group selected from hydrogen, -CH₂CN, -CH₂CONH₂, - CH₂COC-ι_₆alkyl and -CH₂CO₂C_1-6alkyl.

In some embodiments, R¹ represents hydrogen, -C_1-6alkyl, -C₃.₆alkenyl, -C_{2- 3}alkylNR^bR^c, -C_2-3alkylNHCOR^b, phenyl or a 5- or 6- membered aromatic heterocycle, or R¹ represents a group X-W wherein X represents -C^alkylene- and W represents -CN, - CO₂H, -C0NR^bR^c, -COC_1-6alkyl, -CO₂Ci.₆alkyl, or a 5- or 6- membered aromatic or non- aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. In some embodiments, R¹ represents hydrogen, -Ci_-6alkyl, -C₃.₆alkenyl, -C₂-₃alkylNR^bR°, - C_2-3alkylNHCOR^b, or R¹ represents a group X-W wherein X represents -C^alkylene- and W represents -CN, -CO₂H, -CONR^bR°, -COC^alkyl, -CO₂C₁.₆alkyl, or a 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. In some embodiments, R¹ represents a group selected from: hydrogen, - C_1-6alkyl, -CH₂CH=CH₂, -CH₂CH₂N(CHg)₂, -CH₂CH₂NHCOCH₃₁ -CH₂CN, -CH₂CO₂H, - CH₂CO₂CH₃, -CH₂C0₂t-Buty!, -CH₂CONH₂, -CH₂COCH₂CH₃, -CH₂COt-BuIyI, - CH₂CO₂CH₂CHs,

—

Λ <_\ // )>

In some embodiments, R² represents -C^alkyl or hydrogen. In some embodiments R² represents methyl or hydrogen.

In some embodiments, R³ represents -C_1-3alkyl or hydrogen. In some embodiments R³ represents methyl or hydrogen. In some embodiments, B represents hydrogen or a substituent selected from -C_{1- 6}a!kyl, -(C^alkyONR^kR⁰, -(C₀.₃alkyl)CONR^bR°, -CONHC^alkylOH, -CH₂NHC_2-3alkyl0H, - CH₂OCi .₃alkyl, -CH₂SO₂Ci _-3alkyl and a group -Y-R^Θ where Y represents -CO- or -CH₂- and R^e represents a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N, S. In some embodiments, the substitution is in the 2-position relative to the oxygen atom in the morpholine ring. In some embodiments, B represents hydrogen

or a substituent selected from -d-ealkyl, -CONHCH₃, -CONHCH₂CH(OH)CH₃, - CH₂NH(CHs)₂, -CH₂OCH₃, -CH₂SO₂CH₃, and -CH₂NHCH₂CH(OH)CH₃.

In some embodiments, B represents hydrogen or methyl. In some embodiments,

B represents hydrogen.. In some embodiments, Z represents halogen. In some embodiments, Z represents chlorine.

In some embodiments, A represents a substituent selected from:

In some embodiments, A represents a substituent selected from:

In some embodiments, A represents a substituent selected from:

In some embodiments, A represents (chlorothienyl)ethene. In some embodiments, A represents chloronaphthylene, chlorobenzothiophene, chlorobithiophene or chlorophenylethene. In some embodiments, A represents a group selected from: 6-chloronaphthyl, 5'-chloro-2,2'-biothiophene, (4-chlorophenyl)ethene, and 6-chloro-1 -benzothiophene.

In some embodiments, the factor Xa inhibitor is selected from the group consisting of (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethylJ-2- oxopyrrolidin-3-yl}ethenesulfonamide (alternatively referred to herein as "Compound A"); 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)phenyl]-1 ,3-oxazolidin-5-yl}-methyl)-2- thiophenecarboxamide (Rivaroxaban); (2S)-2-(4-{[(3S)-1 -(aminocarbonyl)-3- pyrrolidinyl]oxy}phenyl)-3-{7-[amino(imino)methyl]-2-naphthalenyl}propanoic acid (DX- 9065a); Λ/-(2-({5-[amino(imino)methyl]-2-hydroxyphenyl}oxy)-3,5-difluoro-6-{[3-(1-methyl- 4,5-dihydro-1 H-imidazol-2-yl)phenyl]oxy}-4-pyridinyl)-Λ/-methylglycine (ZK807834,

Fidexaban); 1 -[3-(aminomethyl)phenyl]-W-[3-fluoro-2'-(methylsulfonyl)-4-biphenylyl]-3- (trifluoromethyl)-i H-pyrazole-5-carboxamide (DPC-423); 1-[2-(aminomethyl)phenyl]-Λ/-[3- fluoro-2'-(methylsulfonyl)-4-biphenylyl]-3-(trifluoromethyl)-1 /-/-pyrazole-5-carboxamide (DPC-602); 1 -(3-amino-1 ,2-benzisoxazol-5-yl)-N-[4-[2-[dimethylamino]methyl]-1 H- imidazol-1 -yl]-2-fluorophenyl-3-(trifluoromethyl)-1 H-pyrazol-5-carboxamide (razaxaban); Λ/-[2'-(aminosulfonyl)-3-f luoro-4-biphenylylJ-1 -(2,7a-dihydro-1 ,2-benzisoxazol-5-yl)-1 H- tetrazole-5-carboxamide (SR374); 4-{[(£)-2-(5-chloro-2-thienyl)ethenyl]sulfonyl}-1 -(1 H- pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-piperazinone (RPR209685); (2E)-3-(1 -amino-7- isoquinolinyl)-Λ/-[2'-(aminosulfonyl)-3-bromo-4-biphenylyl]-2-fluoro-2-butenamide; (2E)-A/-[2'-(aminosulfonyl)-3-bromo-4-biphenylyl]-2-fluoro-3-{3-[(2)-

(hydroxyamino)(imino)methyl]phenyl}-2-butenamide; Λ/-[2'-(aminosulfonyl)-4-biphenylyl]-2- [1 -(3-f luoro-2-naphthalenyl)-3-methyl-1 H-pyrazol-5-yl]acetamide; 3-methyl-Λ/-[2'- (methylsulfonyl)-4-biphenylyl]-1-[3-(methylsulfonyl)-2-naphthalenyl]-1 H-pyrazole-5- carboxamide; [(({7-[amino(imino)methyl]-2-naphthalenyl}methyl){4-[(1-ethanimidoyl-4- piperidinyl)oxy]phenyl}amino)sulfonyl]acetic acid (YM60828); Λ/-({7-[amino(imino)methyl]- 2-naphthalenyl}methyl)-Λ/-{4-[(1-ethanimidoyl-4-piperidinyl)oxy]phenyl}-b-alanine (YM169964); /V-{3-[amino(imino)methyl]phenyl}-2-{6-[(1 -ethanimidoyl-4-piperidinyl)oxy]- 2,2-dioxido-4-oxo-3,4-dihydro-1 H-2,1 ,3-benzothiadiazin-1~yl}acetamide (YM 169920); 2-(R)-(3-Carbamimidoylbenzyl)-3-(R)-[4-(1 -oxypyridin-4-yl)benzoylamino]- butyric acid methyl ester (Otamixaban);1 -amino-Λ/-{2-oxo-1 -phenyl-2-[4-(4-pyridinyl)-1 - piperazinyl]ethyl}-7-isoquinolinecarboxamide (PMD3112); and Λ/-{(1 F?)-2-[4-(1 -rnethyl-4- piperidinyl)-1 -piperazinyl]-2-oxo-1 -phenylethyl}-1 H-indole-6-carboxamide (LY517717); 4,5,6,7-tetrahydro-i -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1 -piperidinyl)phenyl]-1 H- pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban or BMS-562247 (Bristol Myers Squibb)); or a pharmaceutically acceptable salt or solvate of any of the foregoing.

Some non-limiting examples of additional factor Xa inhibitors which are also useful for the purposes of this invention are described in WO02/100886; WO02/100830; WO03/043981 ; WO03/053925; WO04/052851 ; WO04/110997; WO04/110434; WO04/111045; and WO04/110435; which are herein incorporated by reference. As used herein, the terms "alkyl" and "alkoxy" mean both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl (-CH₃), ethyl (-C₂H₅), propyl (-C₃H₇) and butyl (-C₄H₉). Examples of alkoxy groups include methoxy (-OCH₃) and ethoxy (-OC₂H₅).

As used herein, the term "alkylene" means both straight and branched chain saturated hydrocarbon linker groups. Examples of alkylene groups include methylene (- CH₂-) and ethylene (-CH₂CH₂-).

As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups, wherein the unsaturation is present only as double bonds. Examples of alkenyl groups include ethenyl (-CH=CH₂) and propenyl (-CH=CHCH₃ or -CH₂CH=CH₂).

As used herein, the term "alkenylene" means both straight and branched chain unsaturated hydrocarbon linker groups, wherein the unsaturation is present only as double bonds. Examples of alkenylene groups includes ethenylene (-CH=CH-) and propenylene (-CH₂-CH=CH- Or -CH=CH-CH₂-). As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups, wherein the unsaturation is present only as triple bonds. Examples of alkynyl groups include propynyl (e.g. -CH₂-C=CH).

As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. As used herein, the term "cycloalkyl group" means an aliphatic ring (saturated carbocyclic ring). Examples of cycloalkyl groups include cyclopentyl and cyclohexyl. As used herein, the term "heterocyclic group" means a ring containing one or more heteroatoms selected from: nitrogen, sulphur and oxygen atoms. The heterocycle may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Examples of 5-membered groups include thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl and furanyl, 6-membered groups include pyridyl, pyrazyl and pyrimidyl, morpholinyl, thiomorpholinyl, 7- membered groups include azepinyl.

Factor Xa inhibitors used herein, when referred to specifically by name with the designation of a single enantiomer are to be understood to refer to compounds that substantially consist of that enantiomer. In some embodiments, the factor Xa inhibitor is at least 60%; or at least 70%; or at least 80%; or at least 90%; or at least 95%; or at least 98%; or at least 99% of the enantiomer listed.

Compounds of the combinations of this invention may in some cases be preferred as pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts include those derived from inorganic or organic, acids or bases. Solvates may be in any form where the solvate molecule(s) are pharmaceutically acceptable, or if not generally pharmaceutically acceptable, at least acceptable in the quantity present.

The combinations and methods employing combinations described herein may be used in conjunction with any suitable administration form. For example, the administration may be orally, lingually, sublingually, bucally, rectally, topically, intravenously, intraarterially, intracardiacally, subcutaneously, intranasally, transdermal^, intramuscularly, or intraperitoneally. The mode of administration may be the same, or different for each of the drugs of the combination of this invention.

The components of this invention, odiparcil and a factor Xa inhibitor, may be administered in combination, simultaneously or sequentially. Dosage formulation combinations of this invention may be prepared in any manner acceptable and within the purview of one of skill in the art. For example, dosage combinations wherein odiparcil and the factor Xa inhibitor are part of the same dosage unit may be prepared. In this case, the two separate components may be combined and admixed prior to being loaded into or processed into the desired dosage delivery device. Alternatively, the two separate components may be loaded separately into the dosage delivery device, resulting in an end formulation which may be either homogeneous or not homogeneous. The two components may also be dissolved in solution together, and said solution may in turn be evaporated onto or into a suitable medium appropriate for the formulation contemplated. The active components may be milled or otherwise processed together and loaded into or processed into the dosage delivery device.

In some cases, the delivery of the two components sequentially is preferred. For example, the monitoring physician or health care worker may find it preferable to administer one of the components followed by a set period, or followed by a period determined on the basis of some determination or monitoring, and after that period administer the other component. This process may be repeated. Thus, the administration, where sequential, may occur over a number of iterations and with an order and frequency that is determined as the circumstances and judgment might dictate. When the administration is sequential, the second component will be administered at a time where the patient being treated still has at least some of the first drug in his or her system. Dosage formulation combinations may also be in a form suitable for the sequential or simultaneous administration of combinations of the invention wherein each of the two components is administered in a liquid vehicle. In such cases, the two components may be together in the same vehicle wherein the administration of the liquid would result in simultaneous, or essentially simultaneous administration of the combination. Or, the two components may be in separate vehicles wherein the vehicles themselves may be either the same or different. In this case, the two components may be administered sequentially or simultaneously. In the case of sequential administration, it is preferred that the patient still has at least some of the first to be administered drug in his or her bloodstream prior to the addition of the second agent.

It will be appreciated that treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

The amount of each drug of the combination to be administered depends upon the particular combination contemplated, the particular thromboembolic disorder being treated, relevant patient characteristics (sex, weight, age, etc), the presence or absence of other conditions, etc.

As a general matter, the odiparcil to be used will typically be administered in an amount of from 1 mg to 700 mg per dose, on, two, three or more times per day. In some embodiments, the odiparcil will be used in a dose of between 50 mg to 700 mg, one, two, three or more times per day; 100 mg and 500 mg, one, two, three or more times per day, and in some embodiments, between 100 mg and 300 mg, one, two, three or more times per day. In some embodiments, the odiparcil might be used at less than 10 mg, or less than 25 mg, or less than 50 mg, or less than 100 mg, or less than 200 mg, per administration period (e.g., any or all dose amounts at one, two, three or more times per day).

Factor Xa inhibitor dosing will, of course, depend on all of those factors discussed previously, supra, but generally, a dose of between 1 mg and 1000 mg, one, two, three or more times per day is a contemplated starting range. In some embodiments, the factor Xa inhibitor will be used in a range of 10 mg to 1000 mg, one, two, three or more times per day; 10 mg to 500 mg, one, two, three or more times per day, in some embodiments, 10 mg to 250 mg one, two, three or more times per day, in some embodiments, 10 mg to 100 mg, one, two, three or more times per day, in some embodiments, 10 mg to 50 mg, one, two, three or more times per day. In some embodiments, the dose of a factor Xa inhibitor is less than 5 mg, or less than 10 mg, or 10 mg to 25 mg, or 5 mg to 10 mg, or 5 mg to 25 mg, or 10 mg to 50 mg, or 25 mg to 100 mg, or 25 mg to 250 mg, or 50 mg to 250 mg, wherein the doses are given one, two, three or multiple times per day.

In some embodiments, the dosages of odiparcil and factor Xa inhibitor are in therapeutic amounts. In other embodiments, either or both the odiparcil and the factor Xa inhibitor are present in subtherapeutic amounts. For purposes of this invention, any reference to a "subtherapeutic" amount of an active refers to an amount of the active which when used as a monotherapy, would not be deemed sufficient for treatment of the particular thromboembolic disorder being contemplated. It is preferred that wherein either or both of the actives of the combination is present in a subtherapeutic amount, that the combination still be therapeutic for the treatment of the particular thromboembolic disorder being contemplated. Therapeutic levels for a given compound may be determined from values provided in prescribing information, and/or by those skilled in the art in view of efficacy data, and may be used to determine subtherapeutic levels. Despite the dosage recommendations entailed herein, it may nevertheless be advisable to diverge from the recommended amounts due to a particular mode of administration, patient weight or physiological function, severity of disorder, etc. Accordingly, it might in some cases be preferred to use an amount of one or both drugs of the combination which may fall outside the ranges specified. The pharmaceutical compositions comprising combinations of the invention may additionally contain one or more pharmaceutically acceptable excipients and may be prepared according to conventional pharmaceutical blending, compounding or mixing techniques. The excipient(s) may take a wide variability in form and percent of composition depending upon the particular drug, drug combination and/or method of delivery contemplated. Examples of excipients are disclosed, for example, in Handbook of Pharmaceutical Excipients, 2^nd Edition, Editors A. Wade and PJ. Weller, American Pharmaceutical Association, 1994; Handbook of Pharmaceutical Additives, M. and I. Ash, Gower, 1995; and Remington, The Science and Practice of Pharmacy, 20^th Edition, Editor A. Gennaro et al., Lippincott Williams & Wilkins, 2000. For liquid oral dosage formulations (such as an elixir or syrup), useful excipients may include, for example, water, glycols, saline, alcohols, flavoring agents, and the like. In the case of a solid dosage oral formulation (such as, for example, capsules, tablets, or dry powder), useful excipients may include, for example, starches, sugars, diluents, lubricants, disintegrants, binders, fillers, and the like. Solid oral dosage delivery forms may be coated or uncoated. Coatings include enteric and non-enteric coatings. For administration by injection, the carrier is typically a sterile aqueous solution, sometimes containing additional ingredients including preservatives, salts, buffers, etc. Injectable suspensions may also be prepared wherein a suspending agent is chosen along with a selected liquid vehicle carrier.

In some embodiments, the combinations of this invention are used in conjunction with antiplatelet therapy or additional antithrombotic therapy. In such an embodiment, the particular drug used, and the time and integration of the use of the additional drug is typically recommended by the treating physician in view of the knowledge and/or experience in the art.

Duration of treatment will vary depending upon the particular thromboembolic disorder being treated, the patient being treated, the treatment setting, etc. In some cases, treatment might consist of a single administration of the combination, either as a single dosage unit, or separately and simultaneously, or separately and sequentially. In some embodiments, the combinations of this invention will be administered multiple times over a period of time sufficient to meet the needs of the particular situation. In some extended treatment regimens, the combination is given regularly or fairly regularly, for the entire duration of the patients need, without limit. In some embodiments, the combination is given regularly or fairly regularly for a period of from 1 to 365 days, in some embodiments, from between 1 to 120 days, in some embodiments, from 1 to 60 days, in some embodiments, from 1 to 30 days. In some embodiments, the combinations of this invention are administered for a period of from between 6-10 days or 7-10 days.

In some embodiments, the combinations of this invention are administered on a need to treat basis. Accordingly, under such a regimen, the combinations may not be administered regularly, but rather may be administered according to the need of the particular individual. In such a scenario, the individual being treated might be treated once, or a number of times and the effect of the treatment monitored, measured or otherwise diagnosed, and if necessary, additional treatment undertaken as needed or desired.

The compounds of this invention may be administered in a fasted or non-fasted state. In some embodiments, the combinations of this invention are administered in the fed state. Odiparcil tends to increase systemic exposure and maximum plasma concentration when administered in the fed state.

In some embodiments, the combinations of this invention are administered to a mammal, more particularly a human, in need thereof.

EXAMPLES

Example 1 - Preparation of combined odiparcil/(E)-2-(5-Chlorothien-2-vπ-N-((3S)-1-r(1S)- 1-methyl-2-morpholin-4-yl-2-oxoethvn-2-oxopyrrolidin-3-vπethenesulfonamide ("Compound A") solid oral dosage formulation(s) The preparation of odiparcil/Compound A solid oral dosage formulation(s) can be effected in the many ways known to one of skill in the art of combining drugs for solid oral dosage formulations. This may include combining the drugs in dry powder form in the weight ratio desired in the dosage formulation, optionally combining with one or more excipients, and converting into the unit dosage form. For example, 2 parts by weight of odiparcil are combined with 1 part by weight Compound A. The combined powders are then optionally milled to desired particle size range. The combination of the two drugs is then further combined with a wetting agent, disintegrant and/or filler and compressed into tablets of the following strengths: 50 mg odiparcil/25 mg Compound A; 100 mg odiparcil/50 mg Compound A; 200 mg odiparcil/100 mgCompound A; 250 mg odiparcil/125 mg Compound A; and 300 mg odiparcil/150 mg Compound A. The tablets may be coated as desired, for example, with an enteric coating. Additional tablets may be made with different ratios of the drug substances by varying the relative proportions of the powders of each drug which are combined.

Example 2 - Preparation of combined odiparcil/rivaroxaban solid oral dosage formulation

The preparation of odiparcil/rivaroxaban solid oral dosage formulation(s) can be effected in the many ways known to one of skill in the art of combining drugs for solid oral dosage formulations. This may include combining the drugs in dry powder form in the weight ratio desired in the dosage formulation, optionally combining with one or more excipients, and converting into the unit dosage form. For example, 2 parts by weight of odiparcil are combined with 1 part by weight rivaroxaban. The combined powders are then optionally milled to desired particle size range. The combination of the two drugs is then further combined with a wetting agent, disintegrant and/or filler and compressed into tablets of the following strengths: 50 mg odiparcil/25 mg rivaroxaban; 100 mg odiparcil/50 mg rivaroxaban; 200 mg odiparcil/100 mg rivaroxaban; 250 mg odiparcil/125 mg rivaroxaban. The tablets may be coated as desired, for example, with an enteric coating. Additional tablets may be made with different ratios of the drug substances by varying the relative proportions of the powders of each drug which are combined.

Example 3 - Preparation of separate odiparcil/(E)-2-(5-Chlorothien-2-yl)-N-((3S)-1-r(1S)-1- methyl-2-morpholin-4-yl-2-oxoethyll-2-oxopyrrolidin-3-yl)ethenesulfonamide ("Compound A") solid oral dosage formulation(s) contained in same package

In some embodiments of the dosage formulations of this invention, the odiparcil is separately tableted, capsuled, or otherwise formulated into a delivery device wherein it is the sole active antithrombotic agent; wherein such dosage formulation is contained in a package additionally containing a dosage formulation of a factor Xa inhibitor wherein said factor Xa inhibitor is in a capsule, tablet, or otherwise formulated into a delivery device. In this embodiment of the invention, the two drug substances, however presented, are contained within the same package. Thus, although the individual substances comprise separate dosage delivery devices, they are in some form packaged together. The term "packaged" as used herein refers to both the verb and adjective form of the term. Thus, the term "packaged" can refer to the verb form wherein the two drug substances are actively placed together within the same package. Thus, where the drug substances, such as the drug substances of this invention, are packaged together in the verb sense of the word, they will be considered to have been packaged together, even if they are later separated. Packaged together also means, when used in the adjective sense, a description of the relationship between the drug substances; they are together in the same package, regardless of how they came to be together.

In some embodiments, tablets or capsules containing 100 mg of odiparcil together with one or more pharmaceutical excipients are included in a package with tablets or capsules of containing 50 mg of Compound A. The package is comprised of a blister pack which contains separately enclosed units of the odiparcil tablets or capsules and separately enclosed Compound A tablets or capsules. In other embodiments, the odiparcil tablets or capsules are blister packaged together with the Compound A tablets or capsules, wherein a capsule or tablet of each drug substance is enclosed within a single blistered space. Of course, there are many different ways that the drug substance combinations of this invention may be packaged together and the examples of the invention are only some examples and are in no way meant to limit the embodiments of the invention.

Example 4 - In Vivo pharmacological (antithrombotic) evaluations of the combinations of the invention

The following venous thrombosis model may be used to evaluate the antithrombotic effects of combination treatments of this invention: Venous Thrombosis Model: Male Sprague-Dawley rats (350-40Og) are anaesthetized with sodium pentobarbital (50 mg/kg, i.p.). The trachea is surgically exposed and an endotracheal tube (PE tubing 240) inserted. The left carotid artery is cannulated for withdrawal of blood samples at the end of the experiment. Blood is centrifuged at 3000 rpm for 10 minutes to obtain plasma for quantification of dermatan sulfate-like GAGs. For thrombus formation, a ventral midline incision is made and the descending vena cava exposed and separated from the descending aorta. Just distal to the renal veins a suture is placed under the vena cava and the vessel tied against a 26g needle. Then just proximal to the iliac veins; the vena cava is clamped using a non- serrated clamp. The section of vena cava between the ligature and the clamp forms a "vena cava sac". Thrombus formation is induced by injecting 2.0 ml hypotonic saline (0.25%) into the venous sac using a second 26g needle attached to a syringe via PE20 tubing. Following the hypotonic injection, the distal clamp is released and the 26g needle removed from the proximal ligature (time 0). The remaining suture restricts the vena cava to a 26g (opening) non-occlusive stenosis. The experiment is continued for 60 minutes, after which blood samples are collected, the animal sacrificed, and the thrombus excised and its weight determined.

Both odiparcil and Compound A have shown the ability to significantly reduce thrombus mass according to the above Venous Thrombosis Model.

A study was conducted to determine the effect of various combinations of odiparcil and (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2- oxopyrrolidin-3-yl}ethenesulfonamide) ("Compound A") on clot mass response using the above Venous Thrombosis Model.

The design of the study is based on the use of mono-therapy ED₅₀ dose response models and data from previous mono-therapy thrombus mass studies for odiparcil and Compound A. These previous studies gave estimates of both the range of the response and the variability for a given dosage level. The drug combination approach selected for this study is an approach that uses different dosage levels of drug combinations with fixed portions of odiparcil and Compound A.

The study used a factorial design to create a grid of combination pairs plus vehicle and odiparcil mono-therapy dose combinations. The added Compound A was limited to 50% or less of the total drug combination dose. The analysis of the clot mass responses at these grid values resulted in an estimated response surface. The factorial design also allowed comparison of the total dose IC_5O estimates for different combination proportions of added Compound A, and the identification of any statistically significant trends with added Compound A at fixed odiparcil doses.

The study used a Proportional Multiplicative Inhibition Model, a response surface model for the expected inhibition response from a two drug combination treatment without an assumed increase in the potency of the combination. This model assumes that the observed response is inhibited proportionally by both mono-therapies. These individual inhibition proportions combine multiplicatively to give the modeled combination response. A surface showing the Proportional Multiplicative Inhibition Model based on prior studies of odiparcil and Compound A mono-therapies is shown in Figure 1 , plotted as plog dose (Notes: odiparcil and Compound A have similar IC₅₀ estimates at about 5 mg/kg. The white balloons represent the predicted data values for the study drug combinations. The more lightly shaded surface region is less than 0.3 of the maximum response). An example of how the mono-therapy inhibitions are combined to model the combined responses is as follows:

Maximum clot mass response = 50 mg Drug A response from a 1 mg/kg dose = 20 mg

20 / 50 = 0.4 observed mono-therapy A proportional inhibition response Drug B response from a 5 mg/kg dose = 15 mg

15 / 50 = 0.3 observed mono-therapy B proportional inhibition response Proportional Multiplicative Inhibition Model (Drug A at 1 mg/kg and Drug B at 5 mg/kg) 0.4 ^* 0.3 = 0.12 modeled drug combination proportional inhibition response

The factorial design included a mono-therapy of odiparcil and 4 fixed proportion drug combination series as shown in Figure 2 (log scaled). Figure 2 shows the fixed proportion drug combination series as the diagonal lines with increasing dosages of the fixed portions. The vertically aligned points are drug combinations with fixed levels of odiparcil and increasing amounts of added Compound A. The design also included vehicle treatments, however these combinations can not be shown in Figure 2 with log scaling of the dosage levels. The specific treatment doses are listed in Table 1.

Table 1

Figure 3 shows the proportional multiplicative inhibition (no enhanced response) model for the factorial design study region plotted as plog dose (Notes: Odiparcil and Compound A have similar IC₅₀ estimates at about 5 mg/kg. The white balloons represent the predicted data values for the study drug combinations. The more lightly shaded surface region is less than 0.3 of the maximum response).

Odiparcil is prepared as a suspension in 0.5% carboxymethylcellulose and administered by oral gavage 3 hours prior to thrombus induction. Compound A is dissolved in 0.5% DMSO / 47.5% polyethylene glycol (PEG200), and administered by oral gavage 1 hour prior to thrombus induction.

The nominal sample size per drug combination is 4 animals per drug combination plus 12 vehicle treatments. This nominal sample size is estimated to have a standard error of the mean percent mass reduction of about 15% (a sample size of 6 would reduce the standard error to about 12.5% and a sample size of 10 is required to reduce the value to 10%). The larger sample size for the vehicle is based on the analysis of previous studies where the number of outlier responses and the natural variability of the responses are largest for the vehicle treated animals. Based on the proposed combinations and the sample sizes, the total study nominally uses 112 animals (5 fixed portion series multiplied by 5 dosage levels per series multiplied by 4 samples per dosage combination set, plus 12 samples for the vehicle dosage).

The analyses used three types of comparisons:

1. Comparison of the IC₅₀ estimate from odiparcil mono-therapy versus the total dose IC₅₀ from different combination series with specific proportions of added Compound A.

2. Comparison of the clot mass response trend with increasing Compound A levels at fixed doses of odiparcil.

3. Comparison of the odiparcil plus Compound A dose response surface model from the study data versus the response surface from a no drug combination enhancement model based on prior mono-therapy studies. Statistical Methods:

The analyses of the factorial design used three methods of viewing the data structure, corresponding to the three comparison approaches described earlier. 1. Analysis of the IC₅₀ levels with different proportions of added Compound A: These analyses used four parameter logistic models to estimate the IC₅₀ and the standard error of the estimate for the log (Total Dose) of each selected proportion. Two sample Z tests were the basis for the statistical comparisons of the IC₅₀ estimates from the different proportions versus that of the odiparcil mono-therapy. These comparisons showed no significant difference for the comparisons (no adjustment for multiple comparisons); the study combinations did not exhibit statistically significant lower total dose IC₅₀ estimates than the odiparcil monotherapy. Figure 4 shows the estimated log (IC₅₀) values versus the proportion of Compound A (Notes: Confidence limits are at 95%. The odiparcil monotherapy has a Compound A proportion equal to zero). A statistical test for a linear trend in the log (IC₅₀) values using the total dose response surface model also showed no significant IC₅₀ differences associated with the proportion of Compound A in the total dose.

2. Analysis of trends in the clot mass response for different odiparcil dose levels: These analyses used the Jonckheere-Terpstra Test, a non-parametric test for monotonic trends, to identify significant trends associated with increasing levels of Compound A added to a fixed dose of odiparcil. These analyses showed no significant trends with added Compound A; no statistically significant reductions in the clot mass response were observed with the addition of Compound A to fixed doses of odiparcil. Figure 5 shows an example (odiparcil dose fixed at 10 mg/kg; Compound A plotted as plog dose). 3. Comparisons of the total dose response surface from the study data versus the proportional multiplicative inhibition model based on the prior mono-therapy studies: The total dose response surface model showed that the most important independent variable was the total dose (odiparcil plus Compound A). The addition of the proportion Compound A as a model parameter was not statistically significant (the model fit was not improved significantly when either the IC₅₀ or the lowest clot mass value were treated as linear functions of the proportion Compound A - total dose plus linear Compound A model). The estimated inhibition surfaces for the total dose only and for the total dose plus linear Compound A models, plotted as plog dose, are shown in Figures 6 and 7 (Fig. 6 Notes: Odiparcil and Compound A have similar ICs₀ estimates at about 5 mg/kg. Fig. 6, 7 Notes: The white balloons represent the predicted data values for the study drug combinations. The more lightly shaded surface region is less than 0.3 of the maximum response). These graphs are on the same scale as Figure 3 (the proportional multiplicative inhibition model, which assumed no enhanced response from the drug combinations and was based on the prior mono-therapy studies). The regions with inhibition responses below 0.3 are similar for all three models with the increased regions being at the highest odiparcil dose level. The similarity of these regions for the drug combination models and the proportional multiplicative inhibition model indicate that the drug combination treatments did not greatly enhance the potency compared to that projected using the prior mono-therapy studies. A comparison of the inhibition levels of the models also showed no drug combination enhancement in the therapeutic region (drug combination inhibition responses below 0.3 of the maximum clot mass). In the therapeutic region, none of the total dose plus linear Compound A model values showed statistically different inhibition responses from the proportional multiplicative inhibition model. These comparisons used two sample Z tests at the design study combinations and at a grid of intermediate points within the study design region. These Z tests were not corrected for multiple comparisons.

No statistically significant differences were observed between the models for those regions with drug combination inhibitions below 30% of the maximum clot mass response.

The various references to journals, patents, and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims.

It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above. A given embodiment includes but is not limited to all disclosed embodiments encompassed thereby. The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation the following claims:

Claims

What is claimed is:

1. A dosage formulation suitable for administration to a mammal comprising:

(a) 4-methyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-β-D-xylopyranoside;

(b) an inhibitor of factor Xa; and optionally

(c) a pharmaceutically acceptable excipient.

2. The dosage formulation of claim 1 , wherein said dosage formulation is suitable for oral administration.

3. The dosage formulation of any preceding claim, wherein said inhibitor of factor Xa is a direct inhibitor of factor Xa.

4. The dosage formulation of any one of the preceding claims, wherein said inhibitor of factor Xa is a compound of formula (I),

wherein:

R¹ represents hydrogen, -Ci.₆alkyl, -C₃-₆alkenyl, -C₂-₃alkylNR^bR^c,

-C_MalkylNHCOR¹³, phenyl or a 5- or 6- membered aromatic heterocyclic group, the phenyl or 5- or 6- membered aromatic heterocyclic group being optionally substituted by halogen, or R¹ represents a group X-W, wherein X represents -d.₃alkylene- and W represents -CN, -CO₂H, -CONR^bR^c, -COC_1-6alkyl, -CO₂C_1-6alkyl, phenyl or 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one or more substitutents selected from: -C_1-3alkyl, -C₁^aIkOXy₁ -C^alkylOH, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH;

R² and R³ independently represent hydrogen, -Ci.₃alkyl or -CF₃ with the proviso that one of R² and R³ is -C_1-3alkyl or -CF₃ and the other is hydrogen; R^b and R^Q independently represent hydrogen or -C_1-3alky!; A represents a group selected from:

wherein

Z represents one or two optional substituents independently selected from halogen and OH,

W represents an optional substituent -d.₃alkyl, alk represents C_2-3alkylene or C₂-₃alkenylene, and

T represents a heteroatom selected from O, S or N; and

B represents one or more optional substituents on ring carbon atoms selected from:

(i) one or more substituents selected from -CF₃, -F, -CO₂H, -C^alkyl, -Cj_-6alkylOH, -(d.₃alkyl)NR^bR^c, -(C_0-3alkyl)CONR^bR^c and -(C₀.₃alkyl)CO₂C_1-3alkyl, -CONHC₂.₃alkylOH, - CH₂NHC₂-₃alkyl0H, -CH₂OC_{1 -3}alkyl and -CH_≥SO^A-salkyl;

(ii) a group -Y-R^e, wherein:

Y represents -C_1-3alkylene-, -CO-,

-C_{1- 3}alkylNHSO₂-, -CH₂NHSO₂CH₂- or a direct link,

R^e represents phenyl, a 5- or 6- membered cycloalkyl or a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -C_1-3alkyl, -C_1-3alkoxy, - C^alkylOH, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH; or

(iii) a second ring R^f which is fused to the heterocyclic ring, wherein R^f represents phenyl, a 5- or 6- membered cycloalkyl group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from:

-C_1-3alkyl, -Ci_-3alkoxy, -Ci.₃alkylOH, halogen, -CN, -CF₃, -NH₂, -CO₂H and -OH; or a pharmaceutically acceptable salt or solvate thereof.

5. The dosage formulation of any of claims 1 through 3, wherein said factor Xa inhibitor is selected from the group consisting of: a) (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide; b) 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}-methyl)-2-thiophenecarboxamide (Rivaroxaban); c) (2S)-2-(4-{[(3S)-1-(aminocarbonyl)-3-pyrrolidinyl]oxy}phenyl)-3-{7- [amino(imino)methyl]-2-naphtha!enyl}propanoic acid (DX-9065a); d) Λ/-(2-({5-[amino(imino)methyl]-2-hydroxyphenyl}oxy)-3,5-difluoro-6-{[3-(1- methyl-4,5-dihydro-1 H-imidazol-2-yl)phenyl]oxy}-4-pyridinyl)-N-methylglycine (ZK807834, Fidexaban); e) 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-4-biphenylyl]-3- (trifluoromethy))-1 H-pyrazole-5-carboxamide (DPC-423); f) 1-[2-(aminomethyl)phenyl]-W-[3-fluoro-2'-(methylsulfonyl)-4-biphenylyl]-3- (trifluoromethyl)-i H-pyrazole-5-carboxamide (DPC-602); g) 1 -(3-amino-1 ,2-benzisoxazol-5-yl)-N-[4-[2-[dimethylamino]methyl]-1 H- imidazol-1 -yl]-2-fluorophenyl-3-(trifluoromethyl)-1 H-pyrazol-5-carboxamide (razaxaban); h) N-[2'-(aminosulfonyl)-3-fluoro-4-biphenylyl]-1 -(2,7a-dihydro-1 ,2- benzisoxazol-5-yl)-1 /-/-tetrazole-5-carboxamide (SR374); i) 4-{[(£)-2-(5-chloro-2-thienyl)ethenyl]sulfonyl}-1 -(1 H-pyrrolo[3,2-c]pyridin-2- ylmethyl)-2-piperazinone (RPR209685); j) (2£)-3-(1-amino-7-isoquinolinyl)-Λ/-[2'-(aminosulfonyl)-3-bromo-4- biphenylyl]-2-fluoro-2-butenamide; k) (2E)-Λ/-[2'-(aminosulfonyl)-3-bromo-4-biphenylyl]-2-ftuoro-3-{3-[(Z)- (hydroxyamino)(imino)methyl]phenyl}-2-butenamide; Λ/-[2'-(aminosulfonyl)-4-biphenylyl]-2- [1-(3-fluoro-2-naphthalenyl)-3-methyl-1 H-pyrazol-5-yl]acetamide; I) 3-methyl-A/-[2'-(methylsulfony!)-4-biphenylyl]-1-[3-(methylsulfonyl)-2- naphthalenyl]-1 H-pyrazole-5-carboxamide; ^m) [(({7-[amino(imino)methyl]-2-naphthalenyl}methyl){4-[(1-ethanimidoyl-4- piperidinyl)oxy]phenyl}amino)sulfonyl]acetic acid (YM60828); n) Λ/-({7-[amino(imino)mΘthyl]-2-naphthalθnyl}methyl)-Λ/-{4-[(1 -ethanimidoyl-4- piperidinyl)oxy]phenyl}-b-alanine (YM169964); o) N-{3-[amino(imino)methyl]phenyl}-2-{6-[(1-ethanimidoyl-4-piperidinyl)oxy]- 2,2-dioxido-4-oxo-3,4-dihydro-1 H-2,1 ,3-benzothiadiazin-1 -yljacetamide (YM169920); p) 2-(R)-(3-Carbamimidoylbenzyl)-3-(R)-[4-(1-oxypyridin-4-yl)benzoylamino]- butyric acid methyl ester (Otamixaban); q) 1 -amino-Λ/-{2-oxo-1 -phenyl-2-[4-(4-pyridinyl)-1 -piperazinyl]ethyl}-7- isoquinolinecarboxamide (PMD3112); and r) Λ/-{(1 R)-2-[4-(1 -methyl-4-piperidinyl)-1 -piperazinyl]-2-oxo-1 -phenylethyl}- 1 /-/-indole-6-carboxamide (LY517717); and s) 4,5,6,7-tetrahydro-1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1 - piperidinyl)phenyl]-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban or BMS-562247); or a pharmaceutically acceptable salt or solvate of any of the foregoing.

6. The dosage formulation of any preceding claim, wherein said odiparcil and said factor Xa inhibitor comprise a single dosage unit.

7. The dosage formulation of claim 6, wherein odiparcil and the inhibitor of factor Xa are admixed together.

8. The dosage formulation of any one of claims 1 through 5, wherein odiparcil and the inhibitor of factor Xa are each contained in separate dosage delivery devices and packaged together.

9. The dosage formulation of any one of claims 1 through 8, comprising from 1 mg to 700 mg (including but not limited to, 1 mg to 200 mg) of the odiparcil.

10. The dosage formulation of any one of claims 1 through 9, comprising from 1 mg to 1000 mg (including, but not limited to, 1 mg to 250 mg) of the factor Xa inhibitor.

11. The dosage formulation of any one of claims 1 through 8, wherein the odiparcil and/or factor Xa inhibitor is present in a subtherapeutic amount.

12. A method of treating a thromboembolic disorder (for example, myocardial infarction, sudden heart death, stroke, venous thromboembolism, embolism, and unstable angina) in a mammal, comprising the administration of a combination of odiparcil and a factor Xa inhibitor.

13. A method of treating a thromboembolic disorder (for example, myocardial infarction, sudden heart death, stroke, venous thromboembolism, embolism, and unstable angina) in a mammal, comprising the administration of a dosage form of any of claims 1 through 11.

14. The method of claim 12 or 13, wherein said administration is oral.

15. The method of any one of claims 12 through 14, wherein the mammal to be treated is a human.

16. The method of any one of claims 12 through 15, wherein the administration of the odiparcil and factor Xa inhibitor is simultaneous.

17. The method of any one of claims 12 through 15, wherein the administration is sequential.

18. The method of any one of claims 12-17, wherein from 1 mg to 700 mg (including but not limited to, 1 mg to 200 mg) of the odiparcil is administered one, two, three or more times per day.

19. The method of any one of claims 12-18, wherein from 1 mg to 1000 mg (including, but not limited to, 1 mg to 250 mg) of the factor Xa inhibitor is administered one, two, three or more times per day.

20. A process for preparing a dosage formulation of odiparcil and a factor Xa inhibitor, comprising admixing odiparcil, the factor Xa inhibitor, and optionally a pharmaceutically acceptable excipient, followed by conversion into a dosage delivery device.