Thioacetate 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: 
         R a  and R b  are selected from H, halogen, C 1  to C 6  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, C 1-3  alkyl or a pharmaceutically acceptable cation; 
         X 1  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 2  is N or CH; 
         X 3  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 4  is N or CH; wherein one of X 1 , X 2 , X 3  or X 4  is N; 
         Y 1  is N or CR 1 ; 
         Y 2  is N or CR 2 ; 
         R 1  is H, CF 3 , CH 3 , OCH 3 , F or Cl; 
         R 2  is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 2′ , CONH 2 , CONHR 2′  or SO 2 NH 2 ; wherein R 2′  is H or C 1-3  alkyl; 
         R 3  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; and 
         R 4  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; or 
         R 3  and R 4  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, an unsaturated or an aromatic ring; 
         provided that the compound of formula (I) is not 1-(3-(4-cyanophenyl)-pyridin-4-ylthio)cyclopropanecarboxylic acid. 
       
     
     
         2 .- 6 . (canceled) 
     
     
         7 . A compound of  claim 1 , wherein
 R 3  is H, CH 3 , OCH 3 , CF 3 , F or Cl; and   R 4  is H, CH 3 , OCH 3 , CF 3 , F or Cl.   
     
     
         8 . (canceled) 
     
     
         9 . A compound of  claim 1 , wherein R 3  and R 4  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 maybe a saturated, an unsaturated or an aromatic ring. 
     
     
         10 . (canceled) 
     
     
         11 . A compound of  claim 1 , of formula (I-K): 
       
         
           
           
               
               
           
         
         wherein n is 1, 2, 3 or 4; and 
         each R 5  is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 5′ , CONH 2 , CONHR 5′  or SO 2 NH 2 ; wherein R 5′  is H or C 1-3  alkyl. 
       
     
     
         12 . A compound of  claim 1 , wherein
 R a  is H or CH 3 ; and   R b  is H or CH 3 .   
     
     
         13 . A compound of  claim 12 , wherein R a  and R b  are both CH 3 . 
     
     
         14 . (canceled) 
     
     
         15 . A compound of  claim 13 , wherein
 X 1  is CH;   X 2  is N;   X 3  is CH; and   X 4  is CH.   
     
     
         16 . A compound of  claim 15 , wherein
 Y 1  is CR 1 ; and   Y 2  is CR 2 .   
     
     
         17 . A compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . (canceled) 
     
     
         19 . A compound of  claim 16 , wherein R 1 , R 3  and R 4  are all H. 
     
     
         20 . 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, optionally containing one or two heteroatoms selected from O, N and S. 
     
     
         21 . (canceled) 
     
     
         22 . A compound of  claim 20 , wherein R a  and R b  together with the carbon atom to which they are attached form a 3-membered ring. 
     
     
         23 . A compound of  claim 1 , wherein M is H. 
     
     
         24 . A compound of  claim 1 , wherein M is C 1 -C 3  alkyl. 
     
     
         25 . A compound of  claim 1 , wherein M is a pharmaceutically acceptable cation. 
     
     
         26 . A compound of  claim 25 , wherein the pharmaceutically acceptable cation is Na + , Li + , K + , Ca 2+ , Mg 2+ , NH 4   + , tetramethylammonium, tetraethylammonium, methylamino, dimethylamino, trimethylamino or triethylamino. 
     
     
         27 . A method of reducing serum uric acid levels in a human, comprising administering to the human an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  and R b  are selected from H, halogen, C 1  to C 6  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, C 1-3  alkyl or a pharmaceutically acceptable cation; 
         X 1  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 2  is N or CH; 
         X 3  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 4  is N or CH; wherein at least one of X 1 , X 2 , X 3  or X 4  is N; 
         Y 1  is N or CR 1 ; 
         Y 2  is N or CR 2 ; 
         R 1  is H, CF 3 , CH 3 , OCH 3 , F or Cl; 
         R 2  is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 2′ , CONH 2 , CONHR 2′  or SO 2 NH 2 ; wherein R 2′  is H or C 1-3  alkyl; 
         R 3  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; and 
         R 4  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; or 
         R 3  and R 4  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 maybe a saturated, an unsaturated or an aromatic ring. 
       
     
     
         28 .- 30 . (canceled) 
     
     
         31 . A method of treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual comprising administering to the individual an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R a  and R b  are selected from H, halogen, C 1  to C 6  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, C 1-3  alkyl or a pharmaceutically acceptable cation; 
         X 1  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 2  is N or CH; 
         X 3  is N, CH, C(halogen) or C(C 1 -C 4  alkyl); 
         X 4  is N or CH; wherein at least one of X 1 , X 2 , X 3  or X 4  is N; 
         Y 1  is N or CR 1 ; 
         Y 2  is N or CR 2 ; 
         R 1  is H, CF 3 , CH 3 , OCH 3 , F or Cl; 
         R 2  is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF 3 , OH, OCH 3 , ethoxy, SH, SCH 3 , SCH 2 CH 3 , CH 2 OH, C(CH 3 ) 2 OH, Cl, F, CN, COOH, COOR 2′ , CONH 2 , CONHR 2′  or SO 2 NH 2 ; wherein R 2′  is H or C 1-3  alkyl; 
         R 3  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; and 
         R 4  is H, halogen, —CN, C 1  to C 6  alkyl, C 1  to C 6  alkoxy; or 
         R 3  and R 4  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 maybe a saturated, an unsaturated or an aromatic ring. 
       
     
     
         32 . The method of  claim 31 , 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. 
     
     
         33 .- 36 . (canceled) 
     
     
         37 . The method of  claim 31 , wherein the condition is kidney disease. 
     
     
         38 . The method of  claim 31 , wherein the condition is a cardiovascular disease. 
     
     
         39 . The method of  claim 31 , further comprising administration of a xanthine oxidase inhibitor. 
     
     
         40 . The method of  claim 39 , wherein the xanthine oxidase inhibitor is allopurinol or febuxostat.