Benzoic acid compounds for reducing uric acid

Abstract

Uric acid in mammalian subjects is reduced and excretion of uric acid is increased by administering a compound of Formula (I). The uric acid-lowering effects of the compounds of this invention are used to treat or prevent a variety of conditions including gout, hyperuricemia, elevated levels of uric acid that do not meet the levels customarily justifying a diagnosis of hyperuricemia, renal dysfunction, kidney stones, cardiovascular disease, risk for developing cardiovascular disease, tumor-lysis syndrome, cognitive impairment, early-onset essential hypertension, and Plasmodium falciparum -induced inflammation. In Formula I, t, q, r, R6, R7, X and A are as defined herein.

1 . A compound represented by Formula I 
       
         
           
           
               
               
           
         
         wherein 
         t is 0 or 1; 
         q is 0 or 1; 
         r is 0, 1 or 2; 
         R 7  is hydrogen or alkyl having from 1 to 3 carbon atoms; 
         R 6  is hydrogen, hydroxy, halo, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, nitro, thio, alkylthio, or cyano; 
         X is C(O) or NH(R 8 ) wherein R 8  is hydrogen or alkyl having from 1 to 3 carbon atoms; provided that when X is C(O), r is 0 and t is 0; 
         A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, perfluoromethoxy, nitro, and amino; or
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of Formula I by a ring carbon; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently monosubstituted by methyl or ethyl, 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein the compound is represented by Formula IA 
       
         
           
           
               
               
           
         
         and the variables are as defined in  claim 1 . 
       
     
     
         3 . The compound or salt of  claim 2 , wherein A is phenyl, unsubstituted or substituted by one, two or three groups selected from the group consisting of halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, perfluoromethoxy, nitro, and amino. 
     
     
         4 . The compound or salt of  claim 3 , wherein A is 2,6-dimethylphenyl. 
     
     
         5 . The compound or salt of  claim 3 , wherein the compound is represented by Formula IA1 
       
         
           
           
               
               
           
         
         two of R 1 , R 2 , R 3 , R 4  and R 5  are selected from the group consisting of hydrogen, halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy and perfluoromethoxy, the remainder are hydrogen; 
         R 7  is hydrogen or alkyl having from 1 to 3 carbon atoms; and 
         R 6  is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, or nitro. 
       
     
     
         6 . The compound or salt of  claim 5 , wherein the compound is represented by Formula IA1a 
       
         
           
           
               
               
           
         
         and the variables are as defined in  claim 5 . 
       
     
     
         7 . The compound or salt of  claim 6 , wherein R 1  is methyl and R 5  is methyl. 
     
     
         8 . The compound or salt of  claim 7 , wherein the compound is selected from the group consisting of:
 3-(2,6-dimethylbenzyloxy)-4-methylbenzoic acid;   3-(2,6-dimethylbenzyloxy)-4-nitrobenzoic acid;   3-(2,6-dimethylbenzyloxy)-4-methoxybenzoic acid; and   3-(2,6-dimethylbenzyloxy)-4-fluorobenzoic acid.   
     
     
         9 . A method of reducing the uric acid concentration in blood of, or increasing uric acid excretion from, a mammalian subject, comprising administering to the subject a compound or salt of  claim 1 , in an amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject. 
     
     
         10 . A method according to  claim 9 , for treating or preventing a condition selected from the group consisting of gout, hyperuricemia, elevated levels of uric acid that do not meet the levels customarily justifying a diagnosis of hyperuricemia, renal dysfunction, kidney stones, cardiovascular disease, risk for developing cardiovascular disease, tumor-lysis syndrome, cognitive impairment, early-onset essential hypertension, and  Plasmodium falciparum -induced inflammation. 
     
     
         11 . The method of  claim 9 , wherein the subject is a human. 
     
     
         12 . The method of  claim 9 , further comprising administering to the subject one or more other uric acid lowering drugs in a combined amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject. 
     
     
         13 . The method of  claim 12 , wherein the other uric acid lowering drug is selected from the group consisting of a xanthine oxidase inhibitor, a uricosuric agent, a urate transporter-1 inhibitor, a uricase, and a statin. 
     
     
         14 . The method of  claim 9 , wherein the compound is formulated for oral administration. 
     
     
         15 - 30 . (canceled) 
     
     
         31 . A method of reducing the uric acid concentration in blood of, or increasing uric acid excretion from, a mammalian subject, comprising administering to the subject a compound or salt of  claim 8 , in an amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject. 
     
     
         32 . A method according to  claim 31 , for treating or preventing a condition selected from the group consisting of gout, hyperuricemia, elevated levels of uric acid that do not meet the levels customarily justifying a diagnosis of hyperuricemia, renal dysfunction, kidney stones, cardiovascular disease, risk for developing cardiovascular disease, tumor-lysis syndrome, cognitive impairment, early-onset essential hypertension, and  Plasmodium falciparum -induced inflammation. 
     
     
         33 . The method of  claim 31 , wherein the subject is a human. 
     
     
         34 . The method of  claim 31 , further comprising administering to the subject one or more other uric acid lowering drugs in a combined amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject. 
     
     
         35 . The method of  claim 34 , wherein the other uric acid lowering drug is selected from the group consisting of a xanthine oxidase inhibitor, a uricosuric agent, a urate transporter-1 inhibitor, a uricase, and a statin. 
     
     
         36 . The method of  claim 31 , wherein the compound is formulated for oral administration.