Inhibitors 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 - 49 . (canceled) 
     
     
         50 . A pharmaceutical composition comprising:
 a hemitartrate salt of a compound represented by the following structural formula:   
       
         
           
           
               
               
           
         
         at least one water-soluble filler; 
         at least one water-insoluble filler; 
         at least one binder; and 
         at least one lubricant. 
       
     
     
         51 . (canceled) 
     
     
         52 . The pharmaceutical composition of  claim 50 , wherein the water-soluble filler is selected from the group consisting of anhydrous lactose, lactose monohydrate, mannitol, sodium chloride, powdered sugar, sorbitol, sucrose, inositol, and pregelatinized starch. 
     
     
         53 . The pharmaceutical composition of  claim 50 , wherein the water-insoluble filler is selected from the group consisting of microcrystalline cellulose, calcium phosphate, and starch. 
     
     
         54 . The pharmaceutical composition of  claim 50 , wherein the binder is selected from the group consisting of pre-gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copolyvidone, gelatin, natural gums, starch paste, sucrose, corn syrup, polyethylene glycols, and sodium alginate. 
     
     
         55 . The pharmaceutical composition of  claim 50 , wherein the lubricant is selected from the group consisting of hydrogenated vegetable oil, calcium stearate, and glyceryl behenate. 
     
     
         56 . The pharmaceutical composition of  claim 50 , wherein the water-soluble filler is selected from the group consisting of anhydrous lactose, lactose monohydrate, mannitol, sodium chloride, powdered sugar, sorbitol, sucrose, inositol, and pregelatinized starch; the water-insoluble filler is selected from the group consisting of microcrystalline cellulose, calcium phosphate, and starch; the binder is selected from the group consisting of pre-gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, copolyvidone, gelatin, natural gums, starch paste, sucrose, corn syrup, polyethylene glycols, and sodium alginate; and the lubricant is selected from the group consisting of hydrogenated vegetable oil, calcium stearate, and glyceryl behenate. 
     
     
         57 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 26 wt % to 50 wt % of the water-soluble filler on a dry solids basis. 
     
     
         58 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 8 wt % to 32 wt % of the water-insoluble filler on a dry solids basis. 
     
     
         59 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 8 wt % to 24 wt % of the water-insoluble filler on a dry solids basis. 
     
     
         60 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 12 wt % to 20 wt % of the water-insoluble filler on a dry solids basis. 
     
     
         61 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 14 wt % to 18 wt % of the water-insoluble filler on a dry solids basis. 
     
     
         62 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 2 wt % to 6 wt % of the binder on a dry solids basis. 
     
     
         63 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 0.1 wt % to 2 wt % of a lubricant on a dry solids basis. 
     
     
         64 . The pharmaceutical composition of  claim 56 , wherein the composition comprises 35 wt % to 40 wt % of the hemitartrate salt, 26 wt % to 50 wt % of the water-soluble filler; 8 wt % to 32 wt % of the water-insoluble filler; 2 wt % to 6 wt % of the binder; and 0.1 wt % to 2 wt % of the lubricant, all on a dry solids basis. 
     
     
         65 . The pharmaceutical composition of  claim 56 , wherein the water-soluble filler is lactose monohydrate; the water-insoluble filler is microcrystalline cellulose; the binder is hydroxypropyl methylcellulose; and the lubricant is glyceryl behenate. 
     
     
         66 . The pharmaceutical composition of  claim 65 , wherein the composition comprises 35 wt % to 40 wt % of the hemitartrate salt, 26 wt % to 50 wt % of the lactose monohydrate; 8 wt % to 32 wt % of the microcrystalline cellulose; 2 wt % to 6 wt % of the hydroxypropyl methylcellulose; and 0.1 wt % to 2 wt % of the glyceryl behenate, all on a dry solids basis. 
     
     
         67 - 93 . (canceled) 
     
     
         94 . The pharmaceutical composition of  claim 50 , wherein the hemitartrate salt is an amorphous salt. 
     
     
         95 . The pharmaceutical composition of  claim 50 , wherein at least 70% by weight of the hemitartrate salt is crystalline. 
     
     
         96 . The pharmaceutical composition of  claim 50 , wherein at least 70% by weight of the hemitartrate salt is in a single crystalline form. 
     
     
         97 . The pharmaceutical composition of  claim 50 , wherein at least 99% by weight of the hemitartrate salt is crystalline. 
     
     
         98 . The pharmaceutical composition of  claim 50 , wherein at least 99% by weight of the hemitartrate salt is in a single crystalline form. 
     
     
         99 . The pharmaceutical composition of  claim 50 , wherein the hemitartrate salt is selected from D-hemitartrate, L-hemitartrate, hemimesotartaric acid or racemic D,L-hemitartrate. 
     
     
         100 . The pharmaceutical composition of  claim 50 , wherein the hemitartrate salt is L-hemitartrate. 
     
     
         101 . The pharmaceutical composition of  claim 96 , wherein at least 70% by weight of the salt is the single crystalline form Form A. 
     
     
         102 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by at least one major x-ray powder diffraction peak at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 
     
     
         103 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by at least two major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 
     
     
         104 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by at least three major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 
     
     
         105 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by at least four major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 
     
     
         106 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by major x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 15.9°, and 21.7°. 
     
     
         107 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 5.1°, 6.6°, 10.7°, 11.0°, 13.3°, 15.1°, 15.9°, 16.5°, 17.6°, 18.6°, 18.7°, 19.0°, 20.2°, 21.7° and 23.5°. 
     
     
         108 . The pharmaceutical composition of  claim 96 , wherein the single crystalline form is characterized by x-ray powder diffraction pattern of  FIG. 1 .