Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist

Abstract

A crystalline polymorph of a bislulfate salt of a thrombin receptor antagonist compound, which exhibits a powder x-ray diffraction profile substantially the same as that shown in FIG. 1, or which exhibits a differential scanning calorimtery profile substantially the same as that shown in FIG. 3, and is represented by the formula for Compound 2: and processes for preparing Compound 2 are disclosed. Pharmaceutical compositions comprising the polymorph of the bisulfate salt and at least one excipient or carrier, and methods of using the polymorph of Compound 2 to treat a variety of physiological disorders, such as thrombosis, are also disclosed.

1 . A crystalline polymorph Form 1 of Compound 2 of the formula:  
     
       
         
         
             
             
         
       
     
     that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 11.2, 16.4, 19.2 and 21.0 degrees 2θ.  
   
   
       2 . The crystalline polymorph of Compound 2 of  claim 1  that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 9.9, 11.2, 16.4, 19.2, 21.0, 22.1, 23.7 and 26.7 degrees 2θ.  
   
   
       3 . The crystalline polymorph of Compound 2 of  claim 1  that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 9.9, 11.2, 12.6, 14.5, 16.4, 19.2, 21.0, 22.1, 23.7, 26.7, 28.2 and 30.8 degrees 2θ.  
   
   
       4 . The crystalline polymorph of Compound 2 of  claim 1  that exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern shown in  FIG. 1 .  
   
   
       5 . A crystalline polymorph Form 1 of Compound 2 of the formula:  
     
       
         
         
             
             
         
       
     
     that exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in  FIG. 3 .  
   
   
       6 . A process for preparing Compound 2 from Compound 1 according to the reaction:  
     
       
         
         
             
             
         
       
     
     comprising: 
 d) mixing Compound 1 in an organic solvent to form a mixture;  
 e) heating the mixture to a temperature of about 40-80° C.; and  
 f) adding sulfuric acid to the heated mixture.  
 
   
   
       7 . The process of  claim 6 , wherein the organic solvent is selected from the group consisting of alcohols, nitrites, esters, ketones, ethers and mixtures thereof.  
   
   
       8 . The process of  claim 7 , wherein the organic solvent is acetonitrile.  
   
   
       9 . The process of  claim 6  wherein the sulfuric acid is in a mixture with acetonitrile.  
   
   
       10 . The process of  claim 6  wherein the temperature is about 50° C.  
   
   
       11 . A pharmaceutical composition comprising the crystalline polymorph Form 1 of Compound 2 according to  claim 1 , and at least one excipient or carrier.  
   
   
       12 . A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of the crystalline polymorph Form 1 of Compound 2 of  claim 1 .  
   
   
       13 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, inflammatory disorders, cerebral ischemia or cancer, comprising administering to a mammal in need of such treatment an effective amount of the crystalline polymorph Form 1 of Compound 2 of  claim 1 .  
   
   
       14 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, inflammatory disorders, cerebral ischemia or cancer, comprising administering to a mammal in need of such treatment an effective amount of the crystalline polymorph Form 1 of Compound 2 of claim 1 in combination with at least one additional cardiovascular agent.  
   
   
       15 . The method of  claim 14  wherein the at least one additional cardiovascular agent is selected from the group consisting of thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphate inhibitors, cyclooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, and platelet aggregation inhibitors.  
   
   
       16 . The method of  claim 15  wherein the at least one additional cardiovascular agent is aspirin or clopidogrel bisulfate.  
   
   
       17 . A purified form of the crystalline polymorph Form 1 of Compound 2 of  claim 1 .  
   
   
       18 . A crystalline polymorph Form 1 of Compound 2 that is the product of the process of  claim 6.