Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor

Abstract

The present invention is directed to methods of using combination therapies containing [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide for the treatment of thrombotic disease(s) and pharmaceutical compositions thereof.

What is claimed is: 
     
         1 . A method for treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) a therapeutic agent selected from the group consisting of an antiplatelet agent, an anticoagulant agent, an anti-inflammatory agent, a blood-pressure lowering agent, and combinations thereof.   
     
     
         2 . The method of  claim 1 , comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) an antiplatelet agent.   
     
     
         3 . The method of  claim 2 , wherein the antiplatelet agent is selected from the group consisting of a GP IIb/IIIa receptor antagonist, a P2Y 12  receptor antagonist, a phosphodiesterase III inhibitor, a thromboxane synthase inhibitor, a thromboxane A2 receptor antagonist, a thrombin receptor antagonist, and an inhibitor of p Selectin. 
     
     
         4 . The method of  claim 2 , wherein the antiplatelet agent is selected from the group consisting of abciximab, eptifibatide, tirofiban, acetylsalicylic acid, cangrelor, ticagrelor, clopidogrel, ticlopidine, prasugrel, dipyridamole, aggrenox, ifetroban, cilostazol, isbogrel, furegrelate, ramatroban, ridogrel, terbogrel, ethyl (1R,3aR,4aR,6R,8aR,9S,9aS)-9-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1-methyl-3-oxododecahydronaphtho[2,3-C]furan-6-ylcarbamate, 3-{6-[(4-chlorophenylsulfonyl)amino]-2-methyl-5,6,7,8-tetrahydronaphth-1-yl}propionic acid and ozagrel. 
     
     
         5 . The method of  claim 4 , wherein the antiplatelet agent is eptifibatide. 
     
     
         6 . The method of  claim 4 , wherein the antiplatelet agent is clopidogrel. 
     
     
         7 . The method of  claim 1  comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and 
 (2) an anticoagulant agent. 
 
     
     
         8 . The method of  claim 7 , wherein the anticoagulant agent is selected from the group consisting of specific inhibitors of thrombin, factor IXa, factor XIa, factor XIIa or factor VIa, synthetic pentasaccharides, low molecular weight heparin, anti-tissue factor antibody and combinations thereof. 
     
     
         9 . The method of  claim 7 , wherein the anticoagulant agent is an injectable anticoagulant agent. 
     
     
         10 . The method of  claim 7 , wherein the anticoagulant agent is selected from the group consisting of bivalirudin, dabigatran, argatroban, lepirudin, warfarin, phenocoumarol, fondaparinux, danaparoid, enoxaparin, dalteparin and unfractionated heparin. 
     
     
         11 . The method of  claim 10 , wherein the anticoagulant agent is enoxaparin. 
     
     
         12 . The method of  claim 1 , comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) an anti-inflammatory agent.   
     
     
         13 . The method of  claim 12 , wherein the anti-inflammatory agent is selected from the group consisting of a non-steroidal anti-inflammatory agent, a tumor necrosis factor antagonist, an interleukin 1 receptor antagonist, a cyclooxygenase-2 inhibitor and a rheumatoid arthritis agent. 
     
     
         14 . The method of  claim 12 , wherein the anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid, piroxicam, indomethacin, mesalamine, sulfasalazine, methotrexate, leflunomide, etanercept, infliximab, adalimubab, and anakinra. 
     
     
         15 . The method of  claim 14 , wherein the anti-inflammatory agent is acetylsalicylic acid. 
     
     
         16 . The method of  claim 1 , comprising administering to said mammal a therapeutically effective amount of the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) a blood pressure lowering agent.   
     
     
         17 . The method of  claim 16 , wherein the blood pressure lowering agent is selected from the group consisting of a diuretic, a beta blocker, an angiotensin converting enzyme inhibitor, an angiotensin 2 receptor antagonist, and a calcium channel blocker. 
     
     
         18 . The method of  claim 16 , wherein the blood pressure lowering agent is selected from the group consisting of verapamil, diltiazem, amiodarone, metoprolol, and carvedilol. 
     
     
         19 . The method of  claim 1 , wherein at least one of [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and the therapeutic agent is administered in a sub-therapeutic dosage. 
     
     
         20 . The method of  claim 1 , wherein both of [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and the therapeutic agent are administered in sub-therapeutic dosages. 
     
     
         21 . The method of  claim 1 , wherein [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and the therapeutic agent are administered simultaneously. 
     
     
         22 . The method of  claim 1 , wherein [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and the therapeutic agent are administered sequentially. 
     
     
         23 . The method of  claim 1 , wherein the pharmaceutical acceptable salt of [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide is the maleate salt. 
     
     
         24 . The method of  claim 1 , wherein the method further comprises administering to said mammal a therapeutically effective amount of:
 (3) a third therapeutic agent selected from another antiplatelet agent, another anticoagulant agent, a thrombin inhibitor, a thrombolytic agent, an anti-arrhythmic agent, a blood pressure lowering agent, a cholesterol or triglyceride lowering agent.   
     
     
         25 . The method of  claim 1 , wherein the condition is selected from the group consisting of:
 acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.   
     
     
         26 . A pharmaceutical composition, comprising the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof,   (2) a therapeutic agent selected from the group consisting of an antiplatelet agent, an anticoagulant agent, an anti-inflammatory agent, a blood pressure-lowering agent, and combinations thereof, and   a pharmaceutically acceptable carrier.   
     
     
         27 . The pharmaceutical composition of  claim 26 , comprising the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof,   (2) an antiplatelet agent;   and a pharmaceutically acceptable carrier.   
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the antiplatelet agent is selected from the group consisting of a GP IIb/IIIa receptor antagonist, a P2Y 12  receptor antagonist, a phosphodiesterase III inhibitor, a thromboxane synthase inhibitor, a thromboxane A2 receptor antagonist, a thrombin receptor antagonist, and an inhibitor of p Selectin. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the antiplatelet agent is selected from the group consisting of: abciximab, eptifibatide, tirofiban, acetylsalicylic acid, cangrelor, ticagrelor, clopidogrel, ticlopidine, prasugrel, dipyridamole, aggrenox, ifetroban, cilostazol, isbogrel, furegrelate, ramatroban, ridogrel, terbogrel, ethyl (1R,3aR,4aR,6R,8aR,9S, 9aS)-9-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1-methyl-3-oxododecahydronaphtho[2,3-C]furan-6-ylcarbamate, 3-{6-[(4-chlorophenylsulfonyl)amino]-2-methyl-5,6,7,8-tetrahydronaphth-1-yl}propionic acid and ozagrel. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the antiplatelet agent is eptifibatide. 
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the antiplatelet agent is clopidogrel. 
     
     
         32 . The pharmaceutical composition of  claim 26 , comprising the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) an anticoagulant agent;   and a pharmaceutically acceptable carrier.   
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the anticoagulant agent is selected from the group consisting of specific inhibitors of thrombin, factor IXa, factor Xa, factor XIIa, factor XIa or factor VIa, synthetic pentasaccharide, low molecular weight heparin, anti tissue factor antibodies and combinations thereof. 
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the anticoagulant agent is an injectable anticoagulant agent. 
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein the anticoagulant agent is selected from the group consisting of bivalirudin, dabigatran, argatroban, lepirudin, warfarin, phenocoumarol, fondaparinux, danaparoid, enoxaparin, dalteparin and unfractionated heparin. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the anticoagulant agent is enoxaparin. 
     
     
         37 . The pharmaceutical composition of  claim 26 , comprising the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) an anti-inflammatory agent;   and a pharmaceutically acceptable carrier.   
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the anti-inflammatory agent is selected from the group consisting of a non-steroidal anti-inflammatory agent, a tumor necrosis factor antagonist, a interleukin 1 receptor antagonist, a cyclooxygenase-2 inhibitor and a rheumatoid arthritis agent. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid, piroxicam, indomethacin, mesalamine, sulfasalazine, methotrexate, leflunomide, etanercept, infliximab, adalimubab, and anakinra. 
     
     
         40 . The pharmaceutical composition of  claim 37 , wherein the anti-inflammatory agent is acetylsalicylic acid. 
     
     
         41 . The pharmaceutical composition of  claim 26 , comprising the following two therapeutic agents:
 (1) [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) a blood pressure lowering agent;   and a pharmaceutically acceptable carrier.   
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the blood pressure lowering agent is selected from the group consisting of a diuretic, a beta blocker, an angiotensin converting enzyme inhibitor, an angiotensin 2 receptor antagonist and a calcium channel blocker. 
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein the blood pressure lowering agent is selected from the group consisting of verapamil, diltiazem, amiodarone, metoprolol, and carvedilol. 
     
     
         44 . The pharmaceutical composition of  claim 26 , wherein at least one of the therapeutic agents is present in a sub-therapeutic dosage. 
     
     
         45 . The pharmaceutical composition of  claim 26 , wherein both of the therapeutic agents are present in sub-therapeutic dosages. 
     
     
         46 . The pharmaceutical composition of  claim 26 , wherein the pharmaceutical acceptable salt of [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide is the maleate salt. 
     
     
         47 . The pharmaceutical composition of  claim 26 , further comprising:
 (3) a third therapeutic agent selected from another antiplatelet agent, another anti-coagulant, a thrombin inhibitor, a thrombolytic agent, an anti-arrhythmic agent, a blood pressure lowering agent, a cholesterol or triglyceride lowering agent.   
     
     
         48 . A kit, comprising:
 (1) a first container, wherein said container contains [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide, or a pharmaceutically acceptable salt thereof, and   (2) a second container, wherein said container contains another therapeutic agent selected from the group consisting of antiplatelet agents, anticoagulant agents, anti-inflammatory agents and blood pressure lowering agents.   
     
     
         49 . The kit of  claim 48 , further comprising:
 (3) a package insert stating that the two therapeutic agents can be used together.   
     
     
         50 . The kit of  claim 48 , wherein the pharmaceutically acceptable salt of [2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide is the maleate salt. 
     
     
         51 . The kit of  claim 48 , wherein at least one of the therapeutic agents is present in a sub-therapeutic dosage. 
     
     
         52 . The kit of  claim 48 , wherein both of the therapeutic agents are present in sub-therapeutic dosages.