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 is 0 or 1; q is 0 or 1; and 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.
1. A method of reducing the uric acid concentration in blood of, or increasing uric acid excretion from, a mammalian subject having 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, tumor-lysis syndrome, and Plasmodium falciparum -induced inflammation,
comprising administering to the subject a compound represented by Formula IA or a pharmaceutically acceptable salt thereof, in an amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject
wherein
t is 0 or 1;
q is 0;
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;
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, perfluoromethoxy, nitro, and amino.
2. The method of claim 1 , wherein A is 2,6-dimethylphenyl.
3. The method of claim 1 , wherein the compound is represented by Formula IA1
wherein 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.
4. The method of claim 3 , wherein the compound is represented by Formula IA1a
and the variables are as defined in claim 3 .
5. The method of claim 4 , wherein R 1 is methyl and R 5 is methyl.
6. A method of reducing the uric acid concentration in blood of, or increasing uric acid excretion from, a mammalian subject having 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, tumor-lysis syndrome, and Plasmodium falciparum -induced inflammation, comprising administering to the subject a compound 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;
3-(2,6-dimethylbenzyloxy)-4-fluorobenzoic acid;
and a pharmaceutically acceptable salt thereof,
in an amount effective to reduce the uric acid concentration in blood of, or increase uric acid excretion from, the subject.
7. The method of claim 1 , wherein the subject is a human.
8. The method of claim 1 , 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.
9. The method of claim 8 , 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.
10. The method of claim 1 , wherein the compound is formulated for oral administration.