COMBINATION TREATMENT FOR METABOLIC DISORDERS
Various metabolic disorders, such as insulin resistance syndrome, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis can be treated with a compound selected from an incretin mimetic and a dipeptidyl peptidase IV inhibitor in combination with a Compound of Formula I or a pharmaceutically acceptable salt thereof Three of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and the remainder are independently selected from the group consisting of hydrogen, halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, and perfluoromethoxy; and m is 0, 2 or 4. R 6 is hydrogen, O or hydroxy, and X is —OR 7 , wherein R 7 is hydrogen or alkyl having from 1 to 3 carbon atoms; or R 6 is hydrogen, and X is —NR 8 R 9 , wherein R 8 is hydrogen or hydroxy and R 9 is hydrogen, methyl or ethyl. When X is —NR 8 R 9 , hydroxy none of R 1 , R 2 , R 3 , R 4 and R 5 is hydroxy.
1 . A method of treating a mammalian subject having a condition selected from the group consisting of insulin resistance syndrome, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, comprising administering to the subject a Compound of Formula I or a pharmaceutically acceptable salt thereof
wherein:
m is 0, 2 or 4; and
X is —OR 7 , wherein R 7 is hydrogen or alkyl having from 1 to 3 carbon atoms;
R 6 is hydrogen, O or hydroxy; and
three of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and the remainder are independently selected from the group consisting of hydrogen, halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, and perfluoromethoxy;
or X is —NR 8 R 9 , wherein R 8 is hydrogen or hydroxy and R 9 is hydrogen, methyl or ethyl;
R 6 is hydrogen; and
three of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen and the remainder are independently selected from the group consisting of hydrogen, halo, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, and perfluoromethoxy;
in combination with an incretin mimetic or a dipeptidyl peptidase IV inhibitor in a combined amount effective to treat the metabolic condition.
2 . The method of claim 1 , wherein R 1 is methyl and R 5 is methyl.
3 . The method of claim 1 , wherein X is —OR 7 , wherein R 7 is hydrogen or alkyl having from 1 to 3 carbon atoms.
4 . The method of claim 1 , wherein X is —NR 8 R 9 , wherein R 8 is hydrogen or hydroxy and R 9 is hydrogen, methyl or ethyl.
5 . The method of claim 1 , wherein the Compound is represented by Formula IA.
6 . The method of claim 5 , wherein R 1 is methyl and R 5 is methyl.
7 . The method of claim 6 , wherein the Compound is 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid.
8 . The method of claim 6 , wherein the Compound is 3-(2,6-Dimethylbenzyloxy)-phenylacetic acid.
9 . The method of claim 6 , wherein the Compound is 4-3-(2,6-Dimethylbenzyloxy)-phenyl)-4(R)-hydroxybutanoic acid.
10 . The method of claim 6 , wherein the Compound is N-Hydroxy-2-[3-(2,6-dimethylbenzyloxy)phenyl]acetamide.
11 . The method of claim 1 , wherein the incretin mimetic is selected from the group consisting of an exendin, an exendin agonist, a non-peptide small molecule GLP-1 receptor agonist, their polymer-modified and acylated forms and pharmaceutically acceptable salts, hydrates, and solvates, and hydrates and solvates of such salts.
12 . The method of claim 1 , wherein the exendin is exendin-4 or exendin-4 amide.
13 . The method of claim 1 , wherein the dipeptidyl peptidase IV inhibitor is selected from the group consisting of vildagliptin, sitagliptin, saxagliptin, alogliptin, ABT-279, BI 1356, ALS 2-0426 and PT630.
14 . The method of claim 1 , wherein the subject is a human.
15 . The method of claim 1 , wherein the incretin mimetic or the dipeptidyl peptidase IV inhibitor is administered in an amount that is less than the usual therapeutic dose when administered alone.
16 . The method of claim 1 , wherein the combined amount is selected so that the treatment results in one or more of weight loss and appetite reduction in the subject.
17 . The method of claim 1 , wherein the Compound of Formula I is administered orally and the incretin mimetic is administered by subcutaneous injection.
18 . The method of claim 1 , wherein the condition is pre-diabetes or Type II diabetes.
19 . The method of claim 18 , wherein the pre-diabetes comprises one or both of insulin resistance and impaired glucose tolerance.
20 . The method of claim 1 , wherein the treatment reduces a symptom of Type II diabetes or the chances of developing a symptom of Type II diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with Type II diabetes.