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.

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 GP IIb/IIIa receptor antagonist.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the GP IIb/IIIa receptor antagonist is selected from the group consisting of abciximab, eptifibatide, and tirofiban, or a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the GP IIb/IIIa receptor antagonist is abciximab. 
     
     
         5 . The method of  claim 1 , wherein the GP IIb/IIIa receptor antagonist is eptifibatide. 
     
     
         6 . The method of  claim 1 , wherein the GP IIb/IIIa receptor antagonist is tirofiban. 
     
     
         7 .- 18 . (canceled) 
     
     
         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 GP IIb/IIIa receptor antagonist 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 GP IIb/IIIa receptor antagonist 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 GP IIb/IIIa receptor antagonist 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 GP IIb/IIIa receptor antagonist 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 GP IIb/IIIa receptor antagonist; and   a pharmaceutically acceptable carrier.   
     
     
         27 . (canceled) 
     
     
         28 . The pharmaceutical composition of  claim 26 , wherein the GP IIb/IIIa receptor antagonist is selected from the group consisting of abciximab, eptifibatide, and tirofiban, or a combination thereof. 
     
     
         29 . The pharmaceutical composition of  claim 26 , wherein the GP IIb/IIIa receptor antagonist is abciximab. 
     
     
         30 . The pharmaceutical composition of  claim 26 , wherein the GP IIb/IIIa receptor antagonist is eptifibatide. 
     
     
         31 . The pharmaceutical composition of  claim 26 , wherein the GP IIb/IIIa receptor antagonist is tirofiban. 
     
     
         32 .- 43 . (canceled) 
     
     
         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 a GP IIb/IIIa receptor antagonist.   
     
     
         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.