Novel pharmaceutical salts and polymorphs of a factor xa inhibitor

Abstract

The present invention provides for salts comprising a compound of Formula I and an acid that has activity against mammalian factor Xa. The present invention is also directed to methods of making the compound of Formula I.

1 .- 11 . (canceled) 
     
     
         12 . A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a salt represented by the Formula II: 
       
         
           
           
               
               
           
         
       
       and a therapeutic agent selected from the group consisting of an anticoagulant agent, a thrombolytic agent, an antithrombotic, a platelet aggregation inhibitor, and a tissue plasminogen activator. 
     
     
         13 . The pharmaceutical composition of  claim 12  wherein the therapeutic agent is selected from the group consisting of urokinase, prourokinase, streptokinase, heparin, aspirin, and warfarin. 
     
     
         14 . The pharmaceutical composition of  claim 12  wherein the therapeutic agent is aspirin. 
     
     
         15 .- 16 . (canceled) 
     
     
         17 . A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a salt represented by the Formula II: 
       
         
           
           
               
               
           
         
       
       and a therapeutic agent selected from the group consisting of an anticoagulant agent, a thrombolytic agent, an antithrombotic, a platelet aggregation inhibitor, and a tissue plasminogen activator. 
     
     
         18 . The method of  claim 17 , wherein the condition is a member 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, thromboanglitis 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. 
     
     
         19 .- 28 . (canceled) 
     
     
         29 . The method of  claim 17  wherein the salt is administered in a pharmaceutical composition comprising the salt and a pharmaceutically acceptable carrier. 
     
     
         30 . The method of  claim 17 , wherein the salt is a crystalline polymorph form. 
     
     
         31 . The method of  claim 17 , wherein the salt has a powder X-ray diffraction pattern having at least four approximate characteristic peak locations selected from 4.9, 9.7, 13.8, 14.1, 15.2, 17.6, 18.5, 20.8, 21.6, 22.7, 24.1, 26.3, 26.8 degrees 2θ. 
     
     
         32 . The method of  claim 17 , wherein the salt has a powder X-ray diffraction pattern having at least eight approximate characteristic peak locations selected from 4.9, 9.7, 11.8, 13.8, 14.1, 15.2, 17.6, 18.5, 19.9, 20.8, 21.6, 22.7, 24.1, 25.0, 26.3, 26.8 degrees 2θ. 
     
     
         33 . The method of  claim 17 , wherein the salt has a powder X-ray diffraction pattern approximate to the powder X-ray diffraction pattern shown in  FIG. 1A  or  1 B. 
     
     
         34 . The method of  claim 17 , wherein the salt has a differential scanning calorimetry approximate to the differential scanning calorimetry pattern shown in  FIG. 2A . 
     
     
         35 . The method of  claim 17 , wherein the therapeutic agent is selected from the group consisting of urokinase, prourokinase, streptokinase, heparin, aspirin, and warfarin. 
     
     
         36 . A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a salt represented by the Formula II: 
       
         
           
           
               
               
           
         
       
       and aspirin. 
     
     
         37 . The method of  claim 36 , 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, thromboanglitis 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. 
     
     
         38 . The method of  claim 36  wherein the salt is administered in a pharmaceutical composition comprising the salt and a pharmaceutically acceptable carrier. 
     
     
         39 . The method of  claim 36 , wherein the salt is a crystalline polymorph form. 
     
     
         40 . The method of  claim 36 , wherein the salt has a powder X-ray diffraction pattern having at least four approximate characteristic peak locations selected from 4.9, 9.7, 13.8, 14.1, 15.2, 17.6, 18.5, 20.8, 21.6, 22.7, 24.1, 26.3, 26.8 degrees 2θ. 
     
     
         41 . The method of  claim 36 , wherein the salt has a powder X-ray diffraction pattern having at least eight approximate characteristic peak locations selected from 4.9, 9.7, 11.8, 13.8, 14.1, 15.2, 17.6, 18.5, 19.9, 20.8, 21.6, 22.7, 24.1, 25.0, 26.3, 26.8 degrees 2θ. 
     
     
         42 . The method of  claim 36 , wherein the salt has a powder X-ray diffraction pattern approximate to the powder X-ray diffraction pattern shown in  FIG. 1A  or  1 B. 
     
     
         43 . The method of  claim 36 , wherein the salt has a differential scanning calorimetry approximate to the differential scanning calorimetry pattern shown in  FIG. 2A .