Fluorinated derivatives of 3-hydroxypyridin-4-ones

Abstract

Provided are compounds of Formula I which are derivatives of 3-Hydroxypyridin-4-ones. The compounds may be used in treatment of a medical condition related to a toxic concentration of iron. The compounds may be used for preparation of a medicament for treatment of a medical condition related to a toxic concentration of iron. The medical condition related to a toxic concentration of iron may be selected from the group consisting of: cancer, pulmonary disease, progressive kidney disease and Frederich's Ataxia.

What is claimed is: 
     
         1 . An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein: 
         G 1  is C 1 -C 4  alkyl; 
         G 2  is H; 
         G 3  is H; and 
         G 4  is the amine-containing substituent —CH(CF 3 )(R 8 ), wherein
 R 8  is NR 1 R 2  or imidazolyl; and 
 R 1  and R 2  are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, wherein
 R 1  and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, allyl, and propargyl; or 
 R 1  and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4  alkyl)-substituted piperazinyl, and piperidinyl. 
 
 
       
     
     
         2 . The compound according to  claim 1 , wherein G 1  is ethyl. 
     
     
         3 . The compound according to  claim 2 , wherein R 8  of G 4  is NR 1 R 2 . 
     
     
         4 . The compound according to  claim 3 , wherein R 1  and R 2  are methyl. 
     
     
         5 . The compound according to  claim 3 , wherein R 1  and R 2  are ethyl. 
     
     
         6 . The compound according to  claim 3 , wherein R 1  is H and R 2  is methyl. 
     
     
         7 . The compound according to  claim 3 , wherein R 1  is H and R 2  is cyclopropyl. 
     
     
         8 . The compound according to  claim 3 , wherein NR 1 R 2  is piperazinyl. 
     
     
         9 . The compound according to  claim 3 , wherein R 1 R 2  is N-methylpiperazinyl. 
     
     
         10 . The compound according to  claim 3 , wherein NR 1 R 2  is piperidinyl. 
     
     
         11 . The compound according to  claim 2 , wherein G 4  is imidazolyl. 
     
     
         12 . The compound according to  claim 1  configured to treat a medical condition related to a toxic concentration of iron. 
     
     
         13 . The compound according to  claim 1  configured to prepare a medicament for treatment of a medical condition related to a toxic concentration of iron. 
     
     
         14 . The compound according to  claim 12  wherein the medical condition related to a toxic concentration of iron is selected from the group consisting of: cancer, pulmonary disease, progressive kidney disease and Frederich's Ataxia. 
     
     
         15 . A method of medical treatment comprising administering a therapeutically effective amount of  claim 1  to a subject having or suspected of having a medical condition related to a toxic concentration of iron. 
     
     
         16 . The method of  claim 15  wherein the medical condition related to a toxic concentration of iron is selected from the group consisting of: cancer, pulmonary disease, progressive kidney disease and Frederich's Ataxia. 
     
     
         17 . A method for the preparation of a compound of Formula VIII 
       
         
           
           
               
               
           
         
         wherein:
 G 1  is C 1 -C 4  alkyl; 
 R 8  is NR 1 NR 2  or imidazolyl; and 
 R 1  and R 2  are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, wherein
 R 1  and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, allyl, and propargyl; or 
 R 1  and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4  alkyl)-substituted piperazinyl, and piperidinyl; and 
 
 
         wherein the method comprises the following steps: 
       
       
         
           
           
               
               
           
         
         
           a. Reacting a compound of formula (A), wherein G 1  is C 1 -C 4  alkyl, with thionyl chloride in an inert solvent to give a compound of formula (B); and 
           b. Reacting the compound of formula (B) from step a with R 8 H, wherein R 8  is NR 1 NR 2  or imidazolyl, to give a compound of formula VIII. 
         
       
     
     
         18 . The method of  claim 17 , wherein the compound of formula (A) is prepared by a method comprising the following steps: 
       
         
           
           
               
               
           
         
         a. Reacting a compound of formula (C), wherein G 1  is C 1 -C 4  alkyl, with CF 3 CH(OR)OH, wherein R is CH 3  or CH 2 CH 3 , in the presence of potassium carbonate to give a compound of formula (D); 
         b. Heating a compound of formula (D) from step a in ammonium hydroxide to give a compound of formula (A). 
       
     
     
         19 . The method of  claim 17 , wherein the compound of formula (A) is prepared by a method comprising the following steps: 
       
         
           
           
               
               
           
         
         a. Heating a compound of formula (C), wherein G 1  is C 1 -C 4  alkyl, with ammonium hydroxide to give a compound of formula (E); and 
         b. Reacting the compound CF 3 CH(OCH 3 )OH with the compound of formula (E) from step (a) in the presence of sodium hydroxide and sodium bicarbonate in water to give a compound of formula (A). 
       
     
     
         20 . The compound according to  claim 13  wherein the medical condition related to a toxic concentration of iron is selected from the group consisting of: cancer, pulmonary disease, progressive kidney disease and Frederich's Ataxia.