Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase

Abstract

The hemitartrate salt of a compound represented by the following structural formula: (Formula I Hemitartrate), which may be used in pharmaceutical applications, are disclosed. Particular single crystalline forms of the Formula (I) Hemitartrate are characterized by a variety of properties and physical measurements. As well, methods of producing crystalline Formula (I) Hemitartrate, and using it to inhibit glucosylceramide synthase or lowering glycosphingolipid concentrations in subjects to treat a number of diseases, are also discussed. Pharmaceutical compositions are also described.

1 - 93 . (canceled) 
     
     
         94 . A method of treating a subject with Gaucher disease who has been assessed as being a poor, intermediate or extensive P450 metabolizer, the method comprising administering to the subject a compound represented by the following structural formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein if the subject is a poor metabolizer then the compound is administered in an effective amount at a first dose, and wherein if the subject is an intermediate or extensive metabolizer then the compound is administered in an adjusted effective amount at a second dose, wherein said second dose is greater than said first dose. 
       
     
     
         95 . The method of  claim 94 , wherein said P450 is CYP2D6 or CYP3A4. 
     
     
         96 . The method of  claim 94 , wherein said subject has been assessed as being a poor, intermediate or extensive metabolizer through genotyping. 
     
     
         97 . The method of  claim 96 , wherein said subject has been assessed as being a poor metabolizer as a result of carrying two mutant alleles of the CYP2D6 gene which result in complete loss of enzyme activity. 
     
     
         98 . The method of  claim 94 , wherein said subject has been assessed as being a poor metabolizer as a result of low expression of said P450. 
     
     
         99 . The method of  claim 94 , wherein said subject has been assessed as being a poor metabolizer as a result of being treated with a drug that is an inhibitor of said P450. 
     
     
         100 . The method of  claim 99 , wherein said subject possesses one reduced activity allele and one null allele of CYP2D6, or wherein said subject possesses at least one and no more than two normal functional alleles of CYP2D6. 
     
     
         101 . The method of  claim 99 , wherein said drug is paroxetine, fluoxetine or quinidine. 
     
     
         102 . The method of  claim 94 , wherein the compound is administered in a daily dose of from 25 milligrams to 150 milligrams. 
     
     
         103 . The method of  claim 94 , wherein the compound is administered in a daily dose of from 50 milligrams to 100 milligrams. 
     
     
         104 . The method of  claim 96 , wherein said subject has been assessed as being an intermediate metabolizer as a result of possessing one reduced activity allele and one null allele of the CYP2D6 gene. 
     
     
         105 . The method of  claim 96 , wherein said subject has been assessed as being an extensive metabolizer as a result of possessing at least one and no more than two normal functional alleles of the CYP2D6 gene. 
     
     
         106 . The method of  claim 94 , wherein the compound is administered at said second dose, this being a dose of greater than 100 milligrams per day. 
     
     
         107 . The method of  claim 106 , wherein the compound is administered in a daily dose of from 100 milligrams to 300 milligrams. 
     
     
         108 . The method of  claim 106 , wherein the compound is administered in a daily dose of greater than 150 milligrams per day. 
     
     
         109 . The method of  claim 104 , wherein the compound is administered in a daily dose from 150 milligrams to 200 milligrams. 
     
     
         110 . The method of  claim 94 , wherein said subject is a human patient. 
     
     
         111 . The method of  claim 94 , wherein said Gaucher disease is type 1 Gaucher disease. 
     
     
         112 . The method of  claim 94 , wherein the compound is represented by the hemitartrate salt of said structural formula.