Compounds, compositions and methods for treating or preventing a symptom associated with gout or hyperuricemia

Abstract

The inventive subject matter provides compounds, compositions and methods for lowering serum acid (sUA) for the treatment of gout, and having reduced liver toxicity, associated with CYP2C9 metabolic pathway.

1 . A compound of Formula 1, or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         —X is —OH, —OR, —OC(O)R, —NH 2 , —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
         wherein —R 1 , —R 2 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkylsulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen; and 
         wherein at least one of —R 1 , —R 2 , —R 3 , —R 4  and —R 5  is -deuterium or a halogen when X is a halogen or —OH. 
       
     
     
         2 . The compound of  claim 1 , wherein X is —OH, and wherein each of —R 1 , —R 2 , —R 3 , and —R 4  is -deuterium, and R 5  is —H. 
     
     
         3 . The compound of  claim 1 , wherein X is —OH, wherein each of —R 1 , —R 2 , and —R 4  is —H, wherein —R 3  is a halogen, and wherein —R 5  is —H. 
     
     
         4 . The compound of  claim 3 , wherein —R 3  is —F. 
     
     
         5 . The compound of  claim 1 , wherein X is —F, wherein each of —R 1 , —R 2 , —R 3  and —R 4  is -deuterium, and wherein R 5  is —H. 
     
     
         6 . The compound of  claim 1 , where X is —F, and wherein each of —R 1 , —R 2 , and —R 4  is —H , wherein —R 3  is a halogen, and wherein —R 5  is —H. 
     
     
         7 . The compound of  claim 6 , where —R 3  is —F. 
     
     
         8 . The compound of  claim 1 , wherein —X is —F or —OH, wherein each of —R 2  and —R 4  is -deuterium, and wherein each of —R 1 , —R 3 , and —R 5  is —H. 
     
     
         9 . The compound of  claim 1 , wherein —X is —F or —OH, wherein each of —R 2  and —R 3  is -deuterium, and wherein each of —R 1 , —R 4 , and —R 5  is —H. 
     
     
         10 . A composition for the treatment of a condition associated with hyperuricemia or gout, comprising:
 a pharmaceutically acceptable carrier;   a compound of Formula 1 or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen; and 
 
         wherein the compound of Formula 1 is present in a therapeutically effective amount to treat a condition associated with hyperuricemia or gout. 
       
     
     
         11 . The composition of  claim 10 , wherein —R 2  is deuterium. 
     
     
         12 . The composition of  claim 11 , wherein —X is —F or —OH, wherein —R 1 , —R 2 , and —R 4  is -deuterium, and —R 5  is —H. 
     
     
         13 . The composition of  claim 12 , wherein —R 3  is -deuterium. 
     
     
         14 . The composition of  claim 10 , wherein —X is —F, wherein each of —R 2  and —R 3  is deuterium, and wherein each of —R 1 , —R 4 , and —R 5  is —H. 
     
     
         15 . The composition of  claim 10 , wherein each of —X and —R 5  is —F, and wherein each of —R 1 , —R 2 , —R 3  and —R 4  is deuterium. 
     
     
         16 . The composition of  claim 10 , wherein —X is —F or —OH, and wherein each of —R 1 , —R 2 , —R 4 , and —R 5  is —H , and wherein —R 3  is a halogen. 
     
     
         17 . The composition of  claim 16 , where —R 3  is —F. 
     
     
         18 . The composition of  claim 10 , wherein the condition is at least one of hyperuricemia, gout, hypertension, and diabetes. 
     
     
         19 . The composition of  claim 10 , further comprising a xanthine oxidase inhibitor. 
     
     
         20 . The composition of  claim 19 , wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositols. 
     
     
         21 . A method of treating a condition associated with hyperuricemia or gout, comprising:
 administering an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound of Formula 1, or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen. 
 
       
     
     
         22 . The method of  claim 21 , wherein —X is —F or —OH, wherein each of —R 1 , —R 2 , R 3 , and —R 4  is a deuterium, and wherein —R 5  is —H. 
     
     
         23 . The method of  claim 21 , wherein —X is —F or —OH, and wherein —R 3  is a halogen, wherein each of —R 1 , —R 2 , R 3 , and —R 5  is —H. 
     
     
         24 . The compound of  claim 23 , where —R 3  is —F. 
     
     
         25 . The method of  claim 21 , wherein each of —X and —R 5  is —F, wherein —R 2 , is deuterium, and wherein each of —R 1 , —R 3  and —R 4 , is —H. 
     
     
         26 . The method of  claim 21 , wherein each of —X and —R 5  is —F, and wherein each of —R 1 , —R 2 , —R 3  and —R 4  is deuterium. 
     
     
         27 . The method of  claim 21 , wherein between 50-300 mg of the compound of formula 1 is present in the composition, and wherein the composition is administered as a single dose. 
     
     
         28 . The method of  claim 21 , wherein the condition is at least one of hyperuricemia, gout, hypertension and diabetes. 
     
     
         29 . The method of  claim 21 , wherein the composition further comprises a xanthine oxidase inhibitor. 
     
     
         30 . The method of  claim 29 , wherein the xanthine oxidase inhibitor is allopurinol oxypurinol, febuxostat, topiroxostat, or inositols. 
     
     
         31 . A method of manufacturing a pharmaceutical composition for treating a condition associated with hyperuricemia or gout, comprising:
 formulating a oral formulation that contains a pharmaceutically acceptable carrier and a compound of formula 1 or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C6-alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen; and 
 
         wherein the compound of Formula 1 is present in a therapeutically effective amount to treat a condition associated with hyperuricemia. 
       
     
     
         32 . A method of manufacturing a liquid pharmaceutical composition for treating a condition associated with hyperuricemia or gout, comprising:
 formulating a liquid formulation that contains a pharmaceutically acceptable carrier and a compound of formula 1 or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen; and 
 
         wherein the compound of Formula 1 is present in a therapeutically effective amount to treat a condition associated with hyperuricemia. 
       
     
     
         33 . A method of inhibiting at least one kidney transporter responsible for uric acid reabsorption in renal tubules, comprising:
 administering a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen. 
 
       
     
     
         34 . The method of  claim 33 , wherein mediating renal reabsorption of uric acid comprises modulating URAT1 activity. 
     
     
         35 . A method of treating a condition, disorder or disease mediated by at least one kidney transporter responsible for uric acid reabsorption in renal tubules, comprising:
 administering an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound of formula 1 or a pharmaceutically acceptable salt thereof;   
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —OC(O)R, —NH 3 +, —NO 2 , —SO 2 R, —CN, —SO 3 H, —CHO, —COOH, —COCl, —CONH 2 , —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 2  is -deuterium or —H; and 
 wherein —R 1 , —R 3 , —R 4  and —R 5  are each independently selected from a group consisting of —H, -deuterium, —F, —Cl, —Br, —I, —CN, —C 1 -C 6 -alkyl, C 6 -C 14 -aryl, substituted —C 6 -C 14 -aryl, C 1 -C 14 -alkoxy, -hydroxyl, -carboxyl, —C 1 -C 6 -alkyl sulfonyl, -trifluoromethyl, —C 1 -C 6 -alkanoyloxy, —C 1 -C 6 -alkylthio, —C 1 -C 6 -alkylsulfonyl, —C 2 -C 6 -alkoxycarbonyl, —C 2 -C 6 -alkanoylamino, —O—R 6 , —S 2 R 6 , —SO 2 —R 6 , —NHSO 2 R 6  and —NHCO 2 R 6 , wherein —R 6  is phenyl or naphthyl, optionally substituted with one or three groups selected from —C 1 -C 6 -alkyl, —C 6 -C 10 -aryl, —C 1 -C 6 -alkoxy and halogen, and —C 4 -C 20 -hydroxyheteroaryl, and wherein the heteroatoms in —C 4 -C 20 -hydroxyheteroaryl are selected from the group consisting of nitrogen and oxygen. 
 
       
     
     
         36 . A compound of Formula 1, or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
         wherein:
 —X is —OH, —OR, —F, —Cl, —Br or —I, wherein —R is a —H, —C 1 -C 10  alkyl or a —C 1 -C 10  substituted alkyl; 
 wherein —R 3  is -deuterium or —F; and 
 wherein —R 1 , —R 2 , —R 4  and —R 5  are each —H, or -deuterium. 
 
       
     
     
         37 . Use of the compound of  claim 36  in the manufacture of a drug. 
     
     
         38 . Use of the compound of  claim 36  to treat a condition associated with hyperuricemia or gout. 
     
     
         39 . Use of the compound of  claim 36  to modulate URAT1 activity in a person. 
     
     
         40 . Use of the compound of  claim 36  to treat or prevent a disorder or disease mediated by URAT1 activity. 
     
     
         41 . Use of the compound of  claim 36  in combination with a xanthine oxidase inhibitor to treat a condition associated with hyperuricemia, gout or diabetes. 
     
     
         42 . The composition of  claim 10 , wherein the composition is an enantiomer-enriched composition. 
     
     
         43 . The composition of  claim 10 , wherein the composition is a single enantiomer composition.