Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (pkan) and methods for the synthesis of such compounds

Abstract

The invention relates to (S)-acyl-4′-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment of neurodegenerative diseases, such as PKAN.

What is claimed is: 
     
         1 . A compound of Structure I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  is —H, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —C═NR 11 , —CN, —OR 11 , —OC(O)R 11 , —NR 11 R 12 , —NR 11 C(O)R 12 , —NO 2 , —N—CR 11 R 12 , or -halogen; 
 
         R 2  and R 3  are independently selected from the group consisting of: -methyl, -ethyl, -phenyl, acetoxymethyl (AM), pivaloyloxymethyl (POM), 
       
       
         
           
           
               
               
           
         
       
       or
 R 2  and R 3  jointly form a structure selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  is —H or -alkyl; 
 R 5  is —H or -alkyl; 
 R 6  is —H, -alkyl, or —CH 2 (CO)OCH 3 ; 
 R 7  is —H, -alkyl, or -halogen; 
 R 8  is —H or -alkyl; 
 R 9  is —H or -alkyl; 
 R 10  is —H or -alkyl; 
 R 11  and R 12  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  and R 3  are identical residues. 
     
     
         3 . A pharmaceutical composition comprising a compound of Structure I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, adjucant, or vehicle, wherein:
 R 1  is —H, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —C═NR 11 , —CN, —OR 11 , —OC(O)R 11 , —NR 11 R 12 , —NR 11 C(O)R 12 , —NO 2 , —N—CR 11 R 12 , or -halogen; 
 R 2  and R 3  are independently selected from the group consisting of: —H, -methyl, -ethyl, -phenyl, acetoxymethyl (AM), pivaloyloxymethyl (POM), 
 
       
       
         
           
           
               
               
           
         
       
       or
 R 2  and R 3  jointly form a structure selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  is —H or -alkyl; 
 R 5  is —H or -alkyl; 
 R 6  is —H, -alkyl, or —CH 2 (CO)OCH 3 ; 
 R 7  is —H, -alkyl, or -halogen; 
 R 8  is —H or -alkyl; 
 R 9  is —H or -alkyl; 
 R 10  is —H or -alkyl; and 
 R 11  and R 12  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen. 
 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein R 2  and R 3  are each H. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein R 1  is methyl. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein R 1  is methyl, and R 2  and R 3  are each H. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein the compound is a D stereoisomer. 
     
     
         8 . The pharmaceutical composition of  claim 3 , wherein the compound is a D stereoisomer, in which R 1  is methyl, and R 2  and R 3  are each H. 
     
     
         9 . The pharmaceutical composition of  claim 3 , wherein the pharmaceutically acceptable salt or solvate thereof is a calcium salt. 
     
     
         10 . The pharmaceutical composition of  claim 3 , wherein the compound is a D stereoisorner, in which R 1  is methyl, and R 2  and R 3  are each H, and wherein the pharmaceutically acceptable salt or solvate thereof is a calcium salt. 
     
     
         11 . The pharmaceutical composition of  claim 3 , being in an oral form. 
     
     
         12 . The pharmaceutical composition of  claim 3 , being a tablet or capsule. 
     
     
         13 . The pharmaceutical composition of  claim 3 , being a syrup. 
     
     
         14 . A method of producing the compound of  claim 1 , comprising the step of reacting 4′-phosphopantothenate with an (S)-substituted mercaptoethylamine to yield an (S)-substituted-4′-phosphopantetheine. 
     
     
         15 . A method of producing the compound of  claim 1 , comprising the step of reacting an (S)-substituted pantetheine with a phosphorylating agent to obtain a phosphate ester of the (S)-substituted 4′-phosphopantetheine. 
     
     
         16 . The method of  claim 15 , comprising the steps of:
 a) reacting pantothenate with an (S)-substituted mercaptoethylamine to yield the (S)-substituted pantetheine;   b) reacting the (S)-substituted pantetheine with a phosphorylating agent to obtain a phosphate ester of the (S)-substituted 4′-phosphopantetheine; and   c) converting the phosphate ester of the (S)-substituted-4′-phosphopantetheine to 4-phosphopantetheine.