BENZOIC ACID COMPOUNDS FOR REDUCING URIC ACID
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.