Inhibitors of glucosylceramide synthase

Abstract

The hemitartrate salt of a compound represented by the following structural formula:(Formula 1 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 human patient with type 1 Gaucher disease who has been assessed as being a poor CYP2D6 P450 metabolizer as determined by CYP2D6 genotyping comprising administering to said patient an effective amount of a hemitartrate salt of the compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein the effective amount is 100 milligrams. 
     
     
         95 : The method of  claim 94 , wherein the effective amount of the hemitartrate salt of the compound of formula (I) is administered in an oral dosage form once per day. 
     
     
         96 : The method of  claim 95 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline Form A. 
     
     
         97 : The method of  claim 96 , wherein the crystalline Form A is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°. 
     
     
         98 : The method of  claim 97 , wherein the X-ray powder diffraction peaks are obtained by using Cu Kα radiation. 
     
     
         99 : The method of  claim 95 , wherein the oral dosage form is a capsule. 
     
     
         100 : The method of  claim 95 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline form having at least three X-ray powder diffraction peaks at 20 angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°. 
     
     
         101 : The method of  claim 100 , wherein the X-ray powder diffraction peaks are obtained by using Cu Kα radiation. 
     
     
         102 : A method of treating a human patient with type 1 Gaucher disease who has been assessed as being an intermediate CYP2D6 P450 metabolizer as determined by CYP2D6 genotyping comprising administering to said patient an effective amount of a hemitartrate salt of the compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein the effective amount is 100 milligrams administered in an oral dosage form twice per day. 
     
     
         103 : The method of  claim 102 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline Form A. 
     
     
         104 : The method of  claim 103 , wherein the crystalline Form A is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°. 
     
     
         105 : The method of  claim 104 , wherein the X-ray powder diffraction peaks are obtained by using Cu Kα radiation. 
     
     
         106 : The method of  claim 102 , wherein the oral dosage form is a capsule. 
     
     
         107 : The method of  claim 102 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline form having at least three X-ray powder diffraction peaks at 2θ angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°. 
     
     
         108 : A method of treating a human patient with type 1 Gaucher disease who has been assessed as being an extensive CYP2D6 P450 metabolizer as determined by CYP2D6 genotyping comprising administering to said patient an effective amount of a hemitartrate salt of the compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein the effective amount is 100 milligrams administered in an oral dosage form twice per day. 
     
     
         109 : The method of  claim 108 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline Form A. 
     
     
         110 : The method of  claim 109 , wherein the crystalline Form A is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°. 
     
     
         111 : The method of  claim 110 , wherein the X-ray powder diffraction peaks are obtained by using Cu Kα radiation. 
     
     
         112 : The method of  claim 108 , wherein the oral dosage form is a capsule. 
     
     
         113 : The method of  claim 108 , wherein the hemitartrate salt of the compound of formula (I) is in crystalline form having at least three X-ray powder diffraction peaks at 20 angles selected from the group consisting of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°, wherein the specified 2θ angle means the specified value±0.2°.