Glycosylated valproic acid analogs and uses thereof

Abstract

Glycosylated valproic acid and its analogs are provided. In some embodiments, the glycosylated valproic acid and its analogs have improved solubility and are ideal for drug delivery to treat a variety of diseases.

What is claimed: 
     
         1 . A compound of formula I, II, III, IV, V, or VI: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is saccharide; 
         R 2  is C 1-10  alkyl or alkene having one carbon substituted by 1-3 of halogen atoms, amino, hydroxy, carboxylic acid group, ester, amide, or cyano wherein one or more of the hydroxy, carboxylic acid or amide group is optionally glycosylated with a saccharide group; 
         R 3  is H, halo or loweralkyl; 
         each R 4  and R 5  is independently amine, cyano, hydroxyl, or carboxylic acid each of which may be glycosylated; 
         R x  is oxo or hydroxy; 
         each of R 6  and R 7  is independently a linear or branched, saturated or partially unsaturated aliphatic C 2 -C 20  hydrocarbon chain; 
         each of R 8  and R 9  is independently a linear or branched aliphatic C 2 -C 20  hydrocarbon chain which is optionally substituted with a C 3 -C 9  aliphatic or aromatic cyclohydrocarbon or heterocyclic group or having 1-3 substituents independently selected from the group consisting of halogen atoms, amino, hydroxy, carboxylic acid group, ester, amide, and cyano wherein one or more of the hydroxy, carboxylic acid, amine, or amide group is optionally glycosylated with a saccharide group; 
         R 10  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ; 
         R 11  is a saturated, unsaturated with at least one double or triple bond, branched or unbranched C 1-30  alkyl group, optionally substituted with an aliphatic or aromatic C 3-9  cyclohydrocarbon or heterocyclic group; 
         Y is a bond or —CH 2 -aryl-O—, wherein the aryl group is optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  thioalkyl, —N(C 1 -C 3  alkyl)(C 1 -C 3  alkyl), —NH(C 1 -C 3  alkyl), —NH 2 , —NO 2 , and —CN; 
         each of m and n is independently an integer having a value of 0, 1, 2, 3, 4, 5, or 6; and 
         o is 1, 2, or 3; 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is a monosaccharide, disaccharide, or trisaccharide. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is a furanose or a pyranose. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is 2,3-desoxy-2,3-dehydroglucose, glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, 2,3-desoxy-2,3-dehydromaltoside, 2,3-desoxymaltoside, lactoside, 2,3-desoxy-2,3-dehydro-lactoside, 2,3-desoxylactoside, glucouronate, glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, or N-acetylmannosamine. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is glucose, mannose, galactose, 2-NAc glucose, or 2-deoxyglucose. 
     
     
         6 . The compound of  claim 1 , wherein the saccharide is linked at the C-1 or C-6 position of the saccharide. 
     
     
         7 . The compound of  claim 1 , wherein
 R 1  is 2,3-desoxy-2,3-dehydroglucose, glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, 2,3-desoxy-2,3-dehydromaltoside, 2,3-desoxymaltoside, lactoside, 2,3-desoxy-2,3-dehydro-lactoside, 2,3-desoxylactoside, glucouronate, glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, or N-acetylmannosamine;   R 2  is C 1-10  alkyl or alkene having 1-3 substituents independently selected from the group consisting of halogen atoms, amino, hydroxy, carboxylic acid group, ester, and amide;   R 3  is H or loweralkyl;   each R 4  and R 5  is independently amine, hydroxyl, or carboxylic acid;   R x  is hydroxyl;   each of R 6  and R 7  is independently a linear or branched, saturated aliphatic C 2 -C 10  hydrocarbon chain;   each of R 8  and R 9  is independently a linear or branched aliphatic C 2 -C 10  hydrocarbon chain, having 1-3 substituents independently selected from the group consisting of halogen atoms, amino, hydroxy, carboxylic acid group, ester, and amide   R 10  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ;   R 11  is a saturated, unsaturated with at least one double or triple bond, branched or unbranched C 1-30  alkyl group;   Y is a bond or —CH 2 -aryl-O—, wherein the aryl group is optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  thioalkyl, —N(C 1 -C 3  alkyl)(C 1 -C 3  alkyl), —NH(C 1 -C 3  alkyl), —NH 2 , —NO 2 , and —CN;   each of m and n is independently an integer having a value of 0, 1, 2, 3, 4, 5, or 6; and   o is 1, 2, or 3.   
     
     
         8 . The compound of  claim 1 , wherein
 R 1  is 2,3-desoxy-2,3-dehydroglucose, glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, 2,3-desoxy-2,3-dehydromaltoside, 2,3-desoxymaltoside, lactoside, 2,3-desoxy-2,3-dehydro-lactoside, 2,3-desoxylactoside, glucouronate, glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, or N-acetylmannosamine;   R 2  is C 1-10  alkyl or alkene having 1-3 substituents independently selected from the group consisting of halogen atoms, amino, or hydroxyl;   R 3  is H or loweralkyl;   each R 4  and R 5  is independently amine, hydroxyl, or carboxylic acid;   R x  is hydroxyl;   each of R 6  and R 7  is independently a linear or branched, saturated aliphatic C 2 -C 10  hydrocarbon chain;   each of R 8  and R 9  is independently a linear or branched aliphatic C 2 -C 10  hydrocarbon chain, having 1-3 substituents independently selected from the group consisting of halogen atoms, amino, and hydroxyl;   R 10  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ;   R 11  is a saturated, unsaturated with at least one double or triple bond, branched or unbranched C 1-30  alkyl group; and   Y is a bond or —CH 2 -phenyl-O—, wherein the phenyl group is optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  thioalkyl, —N(C 1 -C 3  alkyl)(C 1 -C 3  alkyl), —NH(C 1 -C 3  alkyl), —NH 2 , —NO 2 , and —CN.   
     
     
         9 . The compound of  claim 1 , wherein
 R 1  is glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, lactoside, glucouronate, glucosamine, galactosamine, or mannosamine;   R 2  is C 1-6  alkyl;   R 3  is H or C 1-4  alkyl;   each R 4  and R 5  is independently amine, hydroxyl, or carboxylic acid;   R x  is hydroxyl;   each of R 6  and R 7  is independently a linear or branched, saturated aliphatic C 2 -C 6  hydrocarbon chain;   each of R 8  and R 9  is independently a linear or branched aliphatic C 2 -C 6  hydrocarbon chain;   R 10  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ;   R 11  is a saturated, unsaturated with at least one double or triple bond, branched or unbranched C 1-30  alkyl group; and   Y is a bond,   
       
         
           
           
               
               
           
         
       
       wherein the phenyl group is optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  thioalkyl, —N(C 1 -C 3  alkyl)(C 1 -C 3  alkyl), —NH(C 1 -C 3  alkyl), —NH 2 , —NO 2 , and —CN. 
     
     
         10 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is a saccharide; 
         R 2  is C 1-10  alkyl or alkene having one carbon substituted by 1-3 of halogen atoms, amino, hydroxy, carboxylic acid group, ester, amide, or cyano wherein one or more of the hydroxy, carboxylic acid or amide group is optionally glycosylated with a saccharide group; 
         R 3  is H, halo or loweralkyl; 
         Y is a bond, 
       
       
         
           
           
               
               
           
         
       
       wherein the phenyl group is optionally substituted with one or more substituents independently selected from C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, C 1 -C 3  thioalkyl, —N(C 1 -C 3  alkyl)(C 1 -C 3  alkyl), —NH(C 1 -C 3  alkyl), —NH 2 , —NO 2 , and —CN; and
 n is an integer from 0-6; or a pharmaceutically acceptable salt thereof. 
 
     
     
         11 . The compound of  claim 10 , wherein R 1  is a monosaccharide, disaccharide, or trisaccharide. 
     
     
         12 . The compound of  claim 10 , wherein R 1  is a furanose or a pyranose. 
     
     
         13 . The compound of  claim 10 , wherein
 R 1  is 2,3-desoxy-2,3-dehydroglucose, glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, 2,3-desoxy-2,3-dehydromaltoside, 2,3-desoxymaltoside, lactoside, 2,3-desoxy-2,3-dehydro-lactoside, 2,3-desoxylactoside, glucouronate, glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, or N-acetylmannosamine;   R 2  is C 1-10  alkyl or alkene;   R 3  is H or loweralkyl;   Y is a bond,   
       
         
           
           
               
               
           
         
       
       and
 n is an integer from 1-4. 
 
     
     
         14 . The compound of  claim 10 , wherein R 1  is glucose, mannose, galactose, 2-NAc glucose, or 2-deoxyglucose;
 R 2  is C 1-6  alkyl;   R 3  is H;   Y is a bond,   
       
         
           
           
               
               
           
         
       
       and
 n is 2. 
 
     
     
         15 . A method of treating, ameliorating, or preventing viral infections comprising administering to an animal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         16 . The method of  claim 15 , wherein the viral infection is an HIV infection. 
     
     
         17 . A method of inhibiting neuroinflammation associated with traumatic brain injury comprising administering to an animal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         18 . A method of treating a disease or a condition associated with degeneration of muscle tissue, comprising identifying a subject suffering from a disease or condition associated with degeneration of muscle tissue, nerve tissue, or hematopoietic tissue and administering to the subject a therapeutically effective amount of glycosylated valproic acid or analog of  claim 1 . 
     
     
         19 . A method of treating a central nervous system (CNS) disease in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of glycosylated valproic acid or an analog thereof according to  claim 1 . 
     
     
         20 . A method of treating a central nervous system according to  claim 19 , wherein the subject has Alzheimer's disease, Senile dementia, Huntington's disease, torsion dystonia, spasmodic torticollis, Gilles de la Tourette syndrome, and/or Parkinson's disease.