Amine prodrugs of pharmaceutical compounds

Abstract

Disclose are amine prodrugs and methods of synthesis thereof. In particular, the amine prodrug comprises a drug molecule and at least one or more prodrug appendage moieties and the method for synthesis the amine prodmg comprises a step of coupling the drag molecule and at least one or more prodrug appendage moieties. Also disclosed are exemplary riluzole prodrugs and methods of synthesis thereof.

We claim: 
     
         1 . A prodrug comprising a drug molecule and at least one or more prodrug appendage moieties, the prodrug is formed as: 
       
         
           
           
               
               
           
         
       
       wherein the prodrug appendage moiety is coupled to amine of the drug molecule, and i is 1 or 2 and j is 0 or 1. 
     
     
         2 . The prodrug of  claim 1 , wherein prodrug appendage moiety is independently selected from the group of consisting of: 
       
         
           
           
               
               
           
         
         where R 1  is H, alkyl or particularly C 1 -C 8  alkyl; 
         R 2  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted or unsubstituted. 
         R 3  is H, metal, R 2  or a substituted or unsubstituted primary, secondary or tertiary amine; 
         R 4  is H, metal, ammonium salt or alkyl; 
         R 5  is a substituted or unsubstituted natural amino acid; 
         R a  or R b  is H, alkyl or aryl; or NR a  or NR b  is an amino acid; 
         X is C or O; 
         k is 1 or 2, m is 2-22, or (CH k ) m  is saturated, unsaturated or conjugated hydrocarbon; 
         n is0-2; 
         the metal is Na, K, Li, Ca, Mg, Ag or Zn. 
       
     
     
         3 . The prodrug of  claim 1  wherein i is 1 and j is 1, 
     
     
         4 . The prodrug of  claim 1 , wherein i is 2 and j is 0. 
     
     
         5 . The prodrug of  claim 1 , wherein the drug molecule riluzole. 
     
     
         6 . A method of preparing a riluzole prodrug, comprising a step of coupling one or more prodrug appendage moieties to a riluzole molecule 
       
         
           
           
               
               
           
         
         wherein the prodrug appendage moiety is coupled to amine of the riluzole molecule, and i is 1 or 2 and j is 0 or 1. 
       
     
     
         7 . The method of  claim 6 , wherein each prodrug appendage moiety is independently selected from the group of consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R 1  is H, alkyl or particularly C 1 -C 8  alkyl; 
         R 2  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted or unsubstituted, 
         R 3  is H, metal, R 2  or a substituted or unsubstituted primary, secondary or tertiary amine; 
         R 4  is H, metal, ammonium salt or alkyl; 
         R 5  is a substituted or unsubstituted natural amino acid; 
         R a  or R b  is H, alkyl or aryl; or NR a  or NR b  is an amino acid; 
         X is C or O; 
         k is 1 or 2, m is 2-22, or (CH k ) m  is saturated, unsaturated or conjugated hydrocarbon; 
         n is 0-2; 
         is 2-12; and 
         the metal is Na, K, Li, Mg, Ca, Ag or Zn. 
       
     
     
         8 . The method of  claim 6 , wherein i is 1 and is 1. 
     
     
         9 . The method of  claim 6 , wherein i is 2 and j is 0. 
     
     
         10 . The method of  claim 6 , wherein the riluzole prodrug is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R 1  is H, alkyl, or particularly C 1 -C 8  alkyl; 
         R 2  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted or unsubstituted; 
         R 3  is H, metal, R 2  or a substituted or unsubstituted primary, secondary or tertiary amine; 
         R 4  is H, metal, ammonium salt or alkyl; 
         R 5  is a substituted or unsubstituted natural amino acid; 
         R 6  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl; 
         k is 1 or 2, m is 2-22, or (CH k ) m  is saturated, unsaturated or conjugated hydrocarbon; 
         N′ is a primary, secondary and tertiary amine which is substituted or unsubstituted, or metal salts; 
         Y is PO 3 H, CH 2 PO 3 H or salt thereof; and 
         the metal is Na, K, Li, Ca, Mg, Ag or Zn. 
       
     
     
         11 . A method of synthesizing a riluzole prodrug, comprising a step of reacting riluzole with 
       
         
           
           
               
               
           
         
       
       to produce 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11 , further comprising a step of reacting 
       
         
           
           
               
               
           
         
       
       with a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R 2  is H, alkyl or particularly C 1 -C 8  alkyl 
         R 2  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted or unsubstituted; 
         R 4  is H, metal, ammonium salt, or alkyl, 
         k is 1 or 2, m is 2-22, or (CH k ) m  is saturated, unsaturated pr conjugated hydrocarbon; 
         Bc is a protecting group; 
         Y′ is H, PO 3 Bc 2 , CH 2 PO 2 Bc, or salt thereof, or N(R a ) 4   + , where Ra is H or alkyl; 
         M is Na, K, Li, Mg, Ca, Ag or Zn; and 
         R′ or R″ are cyclic or acyclic alkyl. 
       
     
     
         13 . A method of synthesizing a riluzole prodrug, comprising a step of reacting a riluzole, with CO 2 , Cs 2 CO 3  and reacting the resulting compound with 
       
         
           
           
               
               
           
         
       
       wherein Lg is a leaving group. 
     
     
         14 . A method of synthesizing a riluzole prodrug, comprising a step of reacting a riluzole with 
       
         
           
           
               
               
           
         
       
       wherein Lg is a leaving group and where R 1  is H, or C 1 -C 8  alkyl. 
     
     
         15 . A method of synthesizing a riluzole prodrug, comprising a step of reacting a riluzole with 
       
         
           
           
               
               
           
         
       
       wherein Lg is a leaving group. 
     
     
         16 . A method of synthesizing a riluzole prodrug, comprising a step of reacting riluzole with 
       
         
           
           
               
               
           
         
         wherein R I  is H, alkyl or particularly C 1 -C 8  alkyl: and 
         R 2  is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted or unsubstituted. 
       
     
     
         17 . A method of synthesizing a riluzole prodrug, col prising a step of reacting riluzole with ((PhCH 2 O) 2 PO) 2 O and sodium his(trimethylsily)amide (NaHMDS) and subsequently reacting the resulting compound with hydrogen: 
       
         
           
           
               
               
           
         
         wherein R 6  is alkyl, cycloalkyl, aryl,or heteroaryl, or haloalkyl; N′ is a primary, secondary and tertiary amine N, which is substituted or unsubstituted, or metal salts.