Compositions and methods for the treatment of zellweger spectrum disorder

Abstract

Provided herein are methods of treating Zellweger spectrum disorder (ZSD) in a subject in need thereof or improving peroxisome assembly in a cell in need thereof comprising administering to the subject a therapeutically effective amount of Compounds of Formula I or II.

What is claimed is: 
     
         1 . A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing, 
       wherein:
    is a single or a double bond; 
 X is NR 2  or CR 5 R 5  when   is a single bond or X is N or CR 5  when   is a double bond; 
 X 5  is N or CR 5 , provided that at least one of X and X 5  is N or NR 2 ; 
 each R 2  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, or an optionally substituted C 2 -C 8  alkenyl; 
 each R 5  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted C 2 -C 8  alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ; 
 each R 1  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; or an optionally substituted —NR 20 R 30 ; 
 each R 20  and R 30  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl; an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl; 
 each R 6  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, or hydroxy; and 
 m is 0, 1, or 2. 
 
     
     
         2 . A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing, 
       wherein:
 X 1  is O, S, or NR 2 ; 
 X 2  is N or CR 5 ; 
 each R 1  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; or an optionally substituted —NR 20 NR 30 ; 
 each R 2  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, or an optionally substituted C 2 -C 8  alkenyl; 
 each R 5  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted C 2 -C 8  alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ; 
 each R 20  and R 30  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl; 
 each R 3  and R 4  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; an optionally substituted C 2 -C 8  alkenyl, or a hydroxy; 
 Y and Z independently is O, S, or NR 2 ; 
 n is 0, 1, 2, or 3; 
 m is 0, 1, or 2; and 
 p is 0, 1, 2, or 3. 
 
     
     
         3 . A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Table 3, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the Zellweger spectrum is caused by a PEX gene mutation. 
     
     
         5 . The method of  claim 4 , wherein the PEX gene mutation causes abnormal peroxisome assembly. 
     
     
         6 . The method of  claim 2  or  3 , wherein the compound is naltriben or naltrindole. 
     
     
         7 . The method of  claim 2  or  3 , wherein the compound is naltriben methanesulfonate hydrate. 
     
     
         8 . The method of  claim 2  or  3 , wherein the compound is naltrindole hydrochloride. 
     
     
         9 . A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing, 
       wherein:
    is a single or a double bond; 
 X is NR 2  or CR 5 R 5  when   is a single bond or X is N or CR 5  when   is a double bond; 
 X 5  is N or CR 5 , provided that at least one of X and X 5  is N or NR 2 ; 
 each R 2  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, or an optionally substituted C 2 -C 8  alkenyl; 
 each R 5  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted C 2 -C 8  alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ; 
 each R 1  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; or an optionally substituted —NR 20 R 30 ; 
 each R 20  and R 30  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl; an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl; 
 each R 6  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, or hydroxy; and 
 m is 0, 1, or 2. 
 
     
     
         10 . A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing, 
       wherein:
 X 1  is O, S, or NR 2 ; 
 X 2  is N or CR 5 ; 
 each R 1  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; or an optionally substituted —NR 20 NR 30 ; 
 each R 2  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 5  alkoxy, or an optionally substituted C 2 -C 8  alkenyl; 
 each R 5  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 5  alkoxy, an optionally substituted C 2 -C 8  alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ; 
 each R 20  and R 30  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl; 
 each R 3  and R 4  independently is H, an optionally substituted C 1 -C 8  alkyl, an optionally substituted C 1 -C 8  alkoxy; an optionally substituted C 2 -C 8  alkenyl, or a hydroxy; 
 Y and Z independently is O, S, or NR 2 ; 
 n is 0, 1, 2, or 3; 
 m is 0, 1, or 2; and 
 p is 0, 1, 2, or 3. 
 
     
     
         11 . A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Table 3, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing. 
     
     
         12 . The method of any one of  claims 9 - 11 , wherein the peroxisome assembly is improved by from about 20% to about 96%. 
     
     
         13 . The method of any one of  claims 9 - 11 , wherein the peroxisome assembly is improved by at least 20%. 
     
     
         14 . The method of any one of  claims 9 - 11 , wherein the peroxisome assembly is improved by at least 40%. 
     
     
         15 . The method of any one of  claims 9 - 11 , wherein the peroxisome assembly is improved by at least 50%. 
     
     
         16 . The method of  claim 10  or  11 , wherein the compound is naltriben or naltrindole. 
     
     
         17 . The method of  claim 10  or  11 , wherein the compound is naltriben methanesulfonate hydrate. 
     
     
         18 . The method of  claim 10  or  11 , wherein the compound is naltrindole hydrochloride. 
     
     
         19 . The method of  claim 1  or  9 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing. 
     
     
         20 . The method of  claim 2  or  10 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the compound of Formula II, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing. 
     
     
         21 . The method of  claim 3  or  11 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the compound of Table 3, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing.