Compounds and Their Use for Reducing Uric Acid Levels

Abstract

Bifunctional compounds that increase uric acid excretion and reduce uric acid production, and monofunctional compounds that either increase uric acid excretion or reduce uric acid production. Methods of using these compounds for reducing uric acid levels in blood or serum, for treating disorders of uric acid metabolism, and for maintaining normal uric acid levels in blood or serum are also provided. Pharmaceutical compositions comprising the bifunctional and monofunctional compounds are also provided.

What is claimed is: 
     
         1 . A compound selected from the group consisting of
 a) compounds having a structure represented by Formula (I):   
       
         
           
           
               
               
           
         
       
       wherein
 W is selected from O, S, and NR 2 , Y is selected from OH and N(R 2 ) 2 , X is selected from O, S, and NR 2 ; 
 T is —CONR 2 —, —C(NR 2 )NH—, —C(NOR 2 )NH—, —C(N—NR 2 )NH—, —C(SR 2 )N—, or —NHC(O)—; 
 A is phenyl, heteroaryl, C5-C10 branched or unbranched cycloalkyl, C6-C10 bicycloalkyl or C5-C10 spirocycloalkyl; 
 each Z is independently present or absent and, if present, is independently selected from one or more halogen atoms, —CN, —CF 3 , —OR 2 , —C(O)R 2 , SR 2 , —S(O) g R 3  where g is 1 or 2, —N(R 2 ) 2 , —NO 2 , —CO 2 R 2 , —OCO 2 R 3 , OC(O)R 2 , —CON(R 2 ) 2 , —NR 2 C(O)R 2 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —NR 2 SO 2 N(R 2 ) 2  or —NR 2 C(O)N(R 2 ) 2 , —C(O)NHOR 2 , alkyl, aryl, alkenyl and alkynyl; 
 
       wherein each R 2  is independently H, alkyl or aryl; 
       wherein each R 3  is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR 2 ; and 
       wherein a, b, c, d, and e are each independently carbon or nitrogen, or four of a, b, c, d, and e are each independently carbon or nitrogen and one of a, b, c, d, and e is O, with the proviso that at least one of a, b, c, d and e is nitrogen, and Z is not connected directly to nitrogen or oxygen; and
 tautomers thereof, 
 b) compounds having a structure represented by Formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein
 W is selected from O, S, and NR 2 , Y is selected from OH and N(R 2 ) 2 , X is selected from O, S, and NR 2 ; 
 each R 2  is independently H, alkyl or aryl; and
 f is divalent —CR 2 —, —C(O)—, —SR 2 , —S(O) g — where g is 1 or 2, —N(R′) 2 —; or —C(—O(CR 2 ) n O—)— where n=2-3; and 
 
 tautomers thereof, 
 c) compounds having a structure represented by Formula (IV): 
 
       
         
           
           
               
               
           
         
       
       wherein
 W is selected from O, S, and NR 2 , Y is selected from OH and N(R 2 ) 2 , X is selected from O, S, and NR 2 ; 
 each R 2  is independently H, alkyl or aryl; and
 f is divalent —CR 2 —, —C(O)—, —S(O) g — where g is 1-2, —N(R 2 ) 2 —; or —C(—O(CR 2 ) n o-)- where n is 2-3; and 
 
 tautomers thereof, 
 d) compounds having a structure represented by Formula (V): 
 
       
         
           
           
               
               
           
         
       
       wherein
 W is selected from O, S, and NR 2 , Y is selected from OH and N(R 2 ) 2 , X is selected from O, S, and NR 2 ; and 
 
       each R 2  is independently H, alkyl or aryl; and
 tautomers thereof, 
 e) compounds having a structure represented by Formula (VI): 
 
       
         
           
           
               
               
           
         
       
       wherein
 W and X are each independently O, S, NR 2  or N(R 2 ) 2 ; 
 A is phenyl, heteroaryl, C5-C10 branched or unbranched cycloalkyl, C6-C10 bicycloalkyl or C5-C10 spirocycloalkyl; 
 each Z is independently present or absent and, if present, is independently selected from one or more halogen atoms, —CN, —CF 3 , —OR 2 , —C(O)R 2 , SR 2 , —S(O) g R 3  where g is 1 or 2, —N(R 2 ) 2 , —NO 2 , —CO 2 R 2 , —OCO 2 R 3 , OC(O)R 2 , —CON(R 2 ) 2 , —NR 2 C(O)R 2 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —NR 2 SO 2 N(R 2 ) 2  or —NR 2 C(O)N(R 2 ) 2 , —C(O)NHOR 2 , alkyl, aryl, alkenyl and alkynyl; 
 U is —O—, —S—, —NR 2 — or —S(O) g — where g is 1 or 2; 
 
       wherein each R 2  is independently H, alkyl or aryl; 
       wherein each R 3  is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR 2 ; and 
       wherein a, b, c, d, and e are each independently carbon or nitrogen, or four of a, b, c, d, and e are each independently carbon or nitrogen and one of a, b, c, d, and e is O, with the proviso that at least one of a, b, c, d and e is nitrogen, and Z is not connected directly to nitrogen or oxygen; and
 tautomers thereof, 
 f) compounds having a structure represented by Formula (VII): 
 
       
         
           
           
               
               
           
         
       
       wherein
 X and Y are each independently O, S, NR 2  or N(R 2 ) 2 ; 
 Z is present or absent and, if present, is selected from one or more halogen atoms, —CN, —CF 3 , —OR 2 , —C(O)R 2 , SR 2 , —S(O) g R 3  where g is 1 or 2, —N(R 2 ) 2 , —NO 2 , —CO 2 R 2 , —OCO 2 R 3 , OC(O)R 2 , —CON(R 2 ) 2 , —NR 2 C(O)R 2 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —NR 2 SO 2 N(R 2 ) 2  or —NR 2 C(O)N(R 2 ) 2 , —C(O)NHOR 2 , alkyl, aryl, alkenyl and alkynyl, 
 
       wherein each R 2  is independently H, alkyl or aryl; 
       wherein each R 3  is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR 2 ; and 
       wherein a, b, c, d, and e are each independently carbon or nitrogen, or four of a, b, c, d, and e are each independently carbon or nitrogen and one of a, b, c, d, and e is O, with the proviso that at least one of a, b, c, d and e is nitrogen, and Z is not connected directly to nitrogen or oxygen; and
 tautomers thereof, and 
 g) compounds having a structure represented by Formula (VIII): 
 
       
         
           
           
               
               
           
         
       
       wherein
 W, X, and Y are each independently O, S, NR 2  or N(R 2 ) 2 ; 
 T is —CONR 2 —, —C(NR 2 )NH—, —C(NOR 2 )NH—, —C(N—NR 2 )NH—, —C(SR 2 )N—, or —NHC(O)—; 
 A is phenyl, heteroaryl, C5-C10 branched or unbranched cycloalkyl, C6-C10 bicycloalkyl or C5-C10 spirocycloalkyl; 
 each Z is independently present or absent and, if present, is independently selected from one or more halogen atoms, —CN, —CF 3 , —OR 2 , —C(O)R 2 , SR 2 , —S(O) g R 3  where g is 1 or 2, —N(R 2 ) 2 , —NO 2 , —CO 2 R 2 , —OCO 2 R 3 , OC(O)R 2 , —CON(R 2 ) 2 , —NR 2 C(O)R 2 , —SO 2 N(R 2 ) 2 , —NR 2 SO 2 R 3 , —NR 2 SO 2 N(R 2 ) 2  or —NR 2 C(O)N(R 2 ) 2 , —C(O)NHOR 2 , alkyl, aryl, alkenyl and alkynyl; 
 
       wherein each R 2  is independently H, alkyl or aryl; 
       wherein each R 3  is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR 2 ; and
 tautomers thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein the 5-member heterocyclic ring is a substituted or unsubstituted triazole. 
     
     
         3 . The compound according to  claim 1 , wherein-XR 1  is —SCH 3  or —OCH 3 . 
     
     
         4 . The compound according to  claim 1  wherein, in Formula (I):
 a) X and W are each independently O or S; 
 b) Y is OH or NH 2 ; 
 c) T is —C(NH)NH—, —NHC(O)—, —C(SCH 3 )N—, —C(NOH)NH—, —C(N—NH 2 )NH—, or —CONH; 
 d) each R 2  on the barbiturate ring is independently H or CH 3 ; 
 e) A is phenyl, branched cycloalkyl, or unbranched cycloalkyl; and 
 f) Z, if present, is phenyl or CF 3 . 
 
     
     
         5 . The compound according to  claim 1 , wherein, in Formula (III), f is —S(O) 2 —. 
     
     
         6 . The compound according to  claim 1  wherein, in Formula (IV), f is —NH—, —C(O)— or —C(—O(CH 2 ) 2 O—)—. 
     
     
         7 . The compound according to  claim 6 , wherein X on the fused ring structure is O. 
     
     
         8 . The compound according to  claim 1  wherein, in Formula (V), each R 2  is H. 
     
     
         9 . The compound according to  claim 1  wherein, in Formula (VI), U is —O— or —NH—, and the 5-member heterocyclic ring is triazole. 
     
     
         10 . The compound according to  claim 1  wherein, in Formula (VII), the unfused 5-member heterocyclic ring is triazole. 
     
     
         11 . A pharmaceutical composition comprising a compound having a structure represented by any of Formulae (I), and (III)-(VIII); a tautomer of any of Formulae (I), and (III)-(VIII), or a combination thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , which is formulated for controlled or extended release of the compound or combination thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of water or saline, a solvent, a dispersing agent, a coating, a surfactant, a preservative, an emulsion, an alcohol, a polyol, and an isotonic agent. 
     
     
         14 . A method for reducing uric acid levels in blood or serum of a subject, or preventing elevation of uric acid levels in blood or serum of a subject, comprising administering to a subject in need thereof a compound having a structure represented by any of Formulae (I), and (III)-(VIII)); a tautomer of any of Formulae (I), and (III)-(VIII), or a combination thereof, in an amount effective to reduce blood or serum uric acid levels. 
     
     
         15 . The method according to  claim 14 , wherein administering the compound treats or prevents a disorder of uric acid metabolism caused by, or associated with, hyperuricemia. 
     
     
         16 . The method of  claim 14 , wherein the disorder of uric acid metabolism is selected from the group consisting of gout, hyperuricemia, tumor lysis syndrome, kidney disease, arthritis, kidney stones, kidney failure, urolithiasis, plumbism, hyperparathyroidism, psoriasis, inborn genetic errors of metabolism, Lesch-Nyhan syndrome, sarcoidosis, cardiovascular disease, atherosclerosis, and disorders of uric acid metabolism associated with transplantation of blood, bone marrow or solid organs. 
     
     
         17 . The method according to  claim 14 , wherein a daily dose of about 20 to about 1,500 mg/m 2 /day is administered. 
     
     
         18 . The method according to  claim 14 , wherein the compound or combination thereof is administered by injection, infusion, or oral administration. 
     
     
         19 . The method according to  claim 18 , wherein the compound or combination thereof is administered by intravenous infusion or bolus injection.