HYPDH Inhibitors and Methods of Use for the Treatment of Kidney Stones

Abstract

Provided herein are compounds of Formula I, Formula II, and Formula III, and compositions comprising the same, as well as methods of use thereof for controlling or inhibiting the formation of calcium oxalate kidney stones, inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting hydroxyproline dehydrogenase (HYPDH).

That which is claimed is: 
     
         1 . A compound of Formula I, a compound of Formula II, or a compound of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is O, S, NH, NMe or CR x R y , wherein R x R y  are each independently selected from H, alkyl and halo; 
 n is 0, 1, 2, 3, 4, 5 or 6; 
 m is 0, 1, 2, or 3; 
 R 1  is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy; 
 R 2  is selected from the group consisting of: H, alkyl, hydroxy, amine, and ═O; or R 2  is R 2a R 2b , wherein R 2a  and R 2b  are each independently selected from alkyl and hydroxy; 
 R 3  is selected from the group consisting of: H, hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; 
 R 4  is selected from the group consisting of: H, alkyl, and hydroxy; or R 4  is R 4a R 4b  wherein R 4a  and R 4b  are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy; and 
 each R 5  is independently selected from the group consisting of: H, alkyl, hydroxy, amine, and ═O; or R 5  is R 5a R 5b  wherein R 5a  and R 5b  are each independently selected from alkyl and hydroxy; or R 2  and an adjacent R 5  are taken together to form an aryl or heteroaryl, 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein said compound is a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is O, S, or CR x R y , wherein R x R y  are each H; and when X is S, the compound is a compound of Formula I(A): 
       
       
         
           
           
               
               
           
         
         
           n is 0 or 1, and n is 1 when X is CR x R y  and R 3  is hydroxy; 
           R 1  is carboxy; 
           R 2  is H; 
           R 3  is selected from the group consisting of: hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; and 
           R 4  is H, 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         3 . The compound of  claim 1 , wherein said compound is a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 X is CR x R y , wherein R x R y  are each H; 
 n is 0 or 1, and n is 1 when R 3  is hydroxy; 
 R 1  is carboxy; 
 R 2  is H; 
 R 3  is selected from the group consisting of: hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; and 
 R 4  is H, 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         4 . The compound of  claim 1 , wherein said compound is a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 X is S; 
 n is 0; 
 R 1  is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy; 
 R 2  is selected from the group consisting of: H and lower alkyl; 
 R 3  is selected from the group consisting of: H, hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; 
 R 4  is selected from the group consisting of: H and lower alkyl; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
       
     
     
         5 . The compound of  claim 1 , wherein said compound is a compound of Formula I(A): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy; and 
 R 3  is selected from the group consisting of: H, hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
       
     
     
         6 . The compound of  claim 1 , wherein said compound is a compound of Formula I(A): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is carboxy; and 
 R 3  is selected from the group consisting of: H, hydroxy, amine, and ═O; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         7 . The compound of  claim 1 , wherein said compound is a compound of Formula I(A): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is carboxy; and 
 R 3  is selected from the group consisting of: H, hydroxyl and amine; or R 3  is R 3a R 3b , wherein R 3a  and R 3b  are each independently selected from alkyl and hydroxy; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         8 . The compound of  claim 7 , wherein R 3  is hydroxy or R 3a R 3b , wherein R 3a R 3b  are each hydroxy, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         11 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         12 . A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt or prodrug of  claim 1 . 
     
     
         13 . The composition of  claim 12 , wherein said composition is formulated for oral administration. 
     
     
         14 . The composition of  claim 12 , wherein said composition is a food product formulation. 
     
     
         15 . The composition of  claim 12 , wherein said composition is a capsule, cachet, lozenge, or tablet. 
     
     
         16 . The composition of  claim 12 , wherein said formulation is provided in unit dosage form of from 1 mg to 10 grams of the compound, pharmaceutically acceptable salt or prodrug.