Glycolipids as treatment for disease

Abstract

This invention provides compounds, compositions, and methods for treating a disorder selected from cancer, hyperinsulinemia, hypoglycemia, hyperinsulinemia with hypoglycemia, atypical Parkinson's disease, Huntington's disease, multiple systems atrophy, GM3 synthase deficiency, GM2 synthase deficiency or tauopathy.

1 . A method of treating a subject having a disorder associated with a ganglioside deficiency, said method comprising administering to the subject a therapeutic amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein Z is O, S, C(R 10 ) 2  and NR 2 , X is H, D, —OR 11 , —NR 11 R 12 , —SR 11 , and —CHR 11 R 12 , and R 10 , R 11  and R 12  independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, —C(═B)R 13 , —C(═B)-Z-R 13 , —SO 2 R 13 , and —SO 3  functional moieties; B, B′, and Z independently selected from O, NR 14  or S; Y is selected from H, D, —OR 15 , —SR 15 , —NR 15 R 16 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl moieties; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 13 , R 14  independently selected from H, D, —OR 17 , —NR 17 R 18 , —SR 19 , and —CHR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl moieties; R 15 , R 16 , R 17 , R 18 , and R 19  independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl moieties, —C(═B′)R 20 , —C(═B′)—Z—R 20 , —SO 2 R 20 , and —SO 3  functional moieties; R 20  is selected from H, D, —OR 21 , —SR 21 , —NR 21 R 22 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl moieties; R 21  and R 22  are independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl moieties; n is an integer from 1 to 30. 
     
     
         2 . The method of  claim 1 , wherein the disorder is selected from cancer, hyperinsulinemia, hypoglycemia, hyperinsulinemia with hypoglycemia, Huntington's disease, multiple systems atrophy, GM3 synthase deficiency, GM2 synthase deficiency or tauopathy. 
     
     
         3 . The method of  claim 1 , wherein the glycolipid is selected from the group consisting of LacC er, GA2, GA1, GM1b, GD1c, GD1α, GM3, GM2, GM1a, GD1a, GT1a, GT1a, GD3, GD2, GD1b, GT1b, GQ1b, GQ1bα, GT3, GT2, GT1c, GQ1c, GP1c, and GP1cα. 
     
     
         4 . The method of  claim 2 , wherein the affected disorder has a deficiency in tissue level of any one or more of the gangliosides selected from GA2, GA1, GM1b, GD1c, GD1α, GM3, GM2, GM1a, GD1a, GT1a, GT1α, GD3, GD2, GD1b, GT1b, GQ1b, GQ1bα, GT3, GT2, GT1c, GQ1c, GP1c, and GP1cα. 
     
     
         5 . The method of  claim 1 , wherein the saccharide moiety of a ganglioside selected from GM3, GM2, GM1a, GD1a, GT1a, or GT1α. 
     
     
         6 . The method of  claim 1 , wherein the saccharide is a mono-, di-, tri-, tetra-, penta-, hexa-, or hepta-saccharide. 
     
     
         9 . The method of  claim 1 , wherein the fatty acid has at least one cis double bond. 
     
     
         10 . The method of any one of  claims 1 , wherein the saccharide is selected from the group consisting of
 Neu5Acα3Galβ4Glc-;   GalNAcβ4(Neu5Acα3)Galβ4Glc-;   Galβ3GalNAcβ4(Neu5Acα3)Galβ4Glc-;   Neu5Acα3Galβ3GalNAcβ4(Neu5Acα3)Galβ4Glc-; and   Neu5Acα8Neu5Acα3Galβ3GalNAcβ4(Neu5Acα3)Galβ4Glc-.   
     
     
         11 . The method of  claim 1 , wherein the fatty acid is α-hydroxylated. 
     
     
         12 . The method of  claim 1 , wherein the subject is human. 
     
     
         13 . The method of  claim 1 , wherein the cancer is a hematologic cancer or a solid tumor. 
     
     
         14 . The method of any of  claim 1  wherein the disorder is associated with a deficiency in a ganglioside level and the compound of formula (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) has the saccharide moiety of the deficient ganglioside. 
     
     
         16 . The method of  claim 14 , wherein the medicament is formulated for parenteral administration. 
     
     
         17 . The method of  claim 14 , wherein the fatty acid moiety is α-hydroxylated. 
     
     
         18 . The method of  claim 14  wherein the glycolipid comprises an α-hydroxylated fatty acid moiety. 
     
     
         19 . A pharmaceutical composition comprising a compound of Formula (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) and a pharmaceutically acceptable excipient for use in treating a disorder selected from cancer, hyperinsulinemia, hypoglycemia, hyperinsulinemia with hypoglycemia, Huntington's disease, multiple systems atrophy, GM3 synthase deficiency, GM2 synthase deficiency or tauopathy.