Glycoside derivatives and uses thereof

Abstract

This invention relates to compounds represented by formula (I):wherein the variables are defined as herein above, which are useful for treating diseases and conditions mediated by the sodium D-glucose co-transporter (SGLT), e.g. diabetes. The invention also provides methods of treating such diseases and conditions, and compositions etc. for their treatment.

We claim: 
     
       1. A method of treating obesity, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. A method of treating obesity, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. A method of treating obesity, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. A method of treating obesity, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       5. A compound represented by the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or crystalline complex thereof. 
     
     
       6. The compound of claim 5, wherein said compound is an L-proline salt of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       7. The compound of claim 5, wherein said compound is a crystalline complex; and said crystalline complex is an L-proline co-crystal of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       8. The compound of claim 7, wherein said L-proline co-crystal has a 1:1 molar ratio of L-proline to (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       9. The compound of claim 7, wherein said L-proline co-crystal has powder X-ray diffraction peaks at about 17.3, about 20.4, about 18.0, about 18.0 and/or about 23.8 degrees 2θ. 
     
     
       10. The compound of claim 7, wherein said L-proline co-crystal has powder X-ray diffraction peaks that are substantially the same as those in Table 3A. 
     
     
       11. The compound of claim 7, wherein said L-proline co-crystal has a powder X-ray diffraction spectrum that is substantially the same as shown in FIG. 2. 
     
     
       12. The compound of claim 7, wherein said L-proline co-crystal has a 2:1 molar ratio of L-proline to (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       13. The compound of claim 7, wherein said L-proline co-crystal has a differential scanning calorimetry endotherm at about 176° C. 
     
     
       14. The compound of claim 7, wherein said L-proline co-crystal has powder X-ray diffraction peaks at about 6.1, 9.1, 12.8, 15.2, 16.5, 17.8, 18.9, 20.9 and/or about 28.4 degrees 2θ. 
     
     
       15. The compound of claim 7, wherein said L-proline co-crystal has a powder X-ray diffraction spectrum that is substantially the same as shown in FIG. 4. 
     
     
       16. A pharmaceutical composition comprising the compound of claim 5 or a pharmaceutically acceptable salt or crystalline complex thereof, and a pharmaceutically acceptable recipient. 
     
     
       17. The pharmaceutical composition of claim 16, wherein said compound is an L-proline salt of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       18. The pharmaceutical composition of claim 16, wherein said compound is a crystalline complex; and said crystalline complex is an L-proline co-crystal of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxmethyl-tetrahydropyran-3,4,5-triol. 
     
     
       19. The pharmaceutical composition of claim 18, wherein said L-proline co-crystal has a 1:1 molar ratio of L-proline to (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxmethyl-tetrahydropyran-3,4,5-triol. 
     
     
       20. The pharmaceutical composition of claim 18, wherein said L-proline co-crystal has a 2:1 molar ratio of L-proline to (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxmethyl-tetrahydropyran-3,4,5-triol. 
     
     
       21. A method for preparing (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol L-proline salt or co-crystal, comprising mixing (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol and L-proline. 
     
     
       22. The method of claim 21, comprising mixing (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol and L-proline in a molar ratio of 1:1. 
     
     
       23. The method of claim 21, comprising mixing (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol and L-proline in a molar ratio of 1:2. 
     
     
       24. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol L-proline salt, which is obtainable by the method of claim 21. 
     
     
       25. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol L-proline co-crystal, which is obtainable by the method of claim 21. 
     
     
       26. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol L-proline co-crystal, which is obtainable by the method of claim 22. 
     
     
       27. (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol L-proline co-crystal, which is obtainable by the method of claim 23. 
     
     
       28. A combination comprising a compound of Formula (V): 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is phenyl which is substituted with one substituent selected from halo, C 1-4 alkyl, and C 3-7 cycloalkyl; wherein Y a  is situated meta to the tetrahydropyran ring and the one substituent is situated para to the tetrahydropyran ring; 
 the structure represented by the following formula: 
 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and Ya is CH 2 ; 
         or a pharmaceutically acceptable salt or crystalline complex thereof; 
         and an agent selected from the group consisting of insulin, insulin derivative or mimetic; insulin secretagogue; insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulin sensitizer; biquanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic; DDP-IV inhibitor; HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid, and aspirin. 
       
     
     
       29. The combination of claim 28, wherein said compound of Formula (V) is an L-proline salt. 
     
     
       30. The combination of claim 28, wherein said compound of Formula (V) is a crystalline complex; and said crystalline complex is an L-proline co-crystal of said compound. 
     
     
       31. The combination of claim 28, wherein said compound of Formula (V) is represented by the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or crystalline complex thereof. 
     
     
       32. The combination of claim 31, wherein said compound is an L-proline salt of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol. 
     
     
       33. The combination of claim 32, wherein said compound is a crystalline complex; and said crystalline complex is an L-proline co-crystal of said (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxmethyl-tetrahydropyran-3,4,5-triol. 
     
     
       34. The combination of claim 33, wherein said L-proline co-crystal has a 1:1 molar ratio of L-proline to said compound. 
     
     
       35. The combination of claim 33, wherein said L-proline co-crystal has a 2:1 molar ratio of L-proline to said compound.