Phenylthioacetate compounds, compositions and methods of use

Abstract

Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         each R 1 , R 2 , R 3  and R 4  is selected from H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C7 cycloalkyl or a C-attached heterocycle; 
         R a  and R b  are selected from H, halogen, C1 to C6 alkyl; or R a  and R b , together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S; 
         M is H, C1 to C4 alkyl or a pharmaceutically acceptable cation; 
         W is N or CR w ;
 wherein R w  is H, CN, CF 3 , CH 3 , OCH 3 , F or Cl; 
 
         X is N or CR x ;
 wherein R x  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C7 cycloalkyl, —OH, —SH, —S(C1 to C6 alkyl), CH 2 OH, COOR x′ , CONHR x′  or SO 2 NH 2 ;
 wherein R x′  is H, or C1 to C6 alkyl; 
 
 
         R y  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; 
         R z  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R y  and R z  together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring is a saturated, unsaturated or aromatic ring; 
         provided that at least one of R 1 , R 2 , R 3 , R 4 , R w , R x , R y  or R z  is not H; 
         provided that if R 2  is Cl, then R x  is not SEt; and 
         provided that if R 2  is Cl, then R w  is not CN. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A compound of  claim 1 , wherein
 R y  is H; and   R z  is H.   
     
     
         5 . A compound of  claim 4 , wherein R x  is CN, CH 2 OH or C(O)NH 2 . 
     
     
         6 . A compound of  claim 5 , wherein M is H. 
     
     
         7 . A compound of  claim 5 , wherein M is a pharmaceutically acceptable cation. 
     
     
         8 . A compound of  claim 1 , wherein
 R a  is CH 3  and R b  is CH 3 ; or   R a  and R b  together with the carbon atom to which they are attached form a cyclobutyl ring.   
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A compound of  claim 1 , of formula (I-B): 
       
         
           
           
               
               
           
         
       
     
     
         12 . (canceled) 
     
     
         13 . A compound of  claim 1 , of formula (I-C): 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 1 , wherein
 R a  is CH 3 ; and   R b  is CH 3 .   
     
     
         15 . A compound of  claim 1 , wherein R a  and R b  together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring. 
     
     
         16 . A compound of  claim 15 , of formula (I-D): 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound of  claim 1 , wherein each R 1 , R 2 , R 3  and R 4  is H. 
     
     
         18 . (canceled) 
     
     
         19 . A compound of  claim 1 , wherein R 2  is fluorine. 
     
     
         20 . A compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . (canceled) 
     
     
         22 . A method of
 reducing serum uric acid levels in a human; or   treating hyperuricemia in a human; or   treating hyperuricemia in a human with gout; or   treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual,   
       comprising administering to the human an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein: 
       each R 1 , R 2 , R 3  and R 4  is selected from H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C7 cycloalkyl or a C-attached heterocycle; 
       R a  and R b  are selected from H, halogen, C1 to C6 alkyl; or R a  and R b , together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S; 
       M is H, C1 to C4 alkyl or a pharmaceutically acceptable cation; 
       W is N or CR w ;
 wherein R w  is H, CN, CF 3 , CH 3 , OCH 3 , F or Cl; 
 
       X is N or CR x ;
 wherein R x  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy, C3 to C7 cycloalkyl, —OH, —SH, —S(C1 to C6 alkyl), CH 2 OH, COOR x′ , CONHR x′  or SO 2 NH 2 ;
 wherein R x′  is H, or C1 to C6 alkyl; 
 
 
       R y  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; 
       R z  is H, halogen, —CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R y  and R z  together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring is a saturated, unsaturated or aromatic ring. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 22 , wherein the condition is gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 22 , further comprising administering a second agent effective for the treatment of the gout. 
     
     
         30 . The method of  claim 29 , wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof. 
     
     
         31 . The method of  claim 29 , wherein the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.