Thiazolidinedione analogues
The present invention relates to thiazolidinedione analogues that are useful for treating metabolic inflammation mediated diseases such as diabetes.
1 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;
R 3 is hydrogen, halo, or optionally substituted aliphatic; and
Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1 at any chemically feasible position on ring A.
2 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy;
R 3 is hydrogen, halo, or optionally substituted aliphatic; and
Ring A is a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —CH 2 —R 1 at any chemically feasible position on ring A.
3 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and
R 3 is hydrogen, halo, or optionally substituted aliphatic.
4 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula V:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and
R 3 is hydrogen, halo, or optionally substituted aliphatic.
5 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula VI:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and
R 3 is hydrogen, halo, or optionally substituted aliphatic.
6 . The method of claim 1 , wherein R 1 is an optionally substituted straight or branched C 1-6 alkyl, an optionally substituted straight or branched C 2-6 alkenyl, or an optionally substituted straight or branched C 2-6 alkynyl.
7 . The method of claim 1 , wherein R 1 is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.
8 . The method of claim 1 , wherein R 1 is a hydrogen or a halo.
9 . The method of claim 1 , wherein R 2 is hydrogen, hydroxy, or oxo.
10 . The method of claim 1 , wherein R 2 is an optionally substituted C 1-6 aliphatic.
11 . The method of claim 1 , wherein R 2 is an optionally substituted straight or branched C 1-6 alkyl, an optionally substituted straight or branched C 1-6 alkenyl, or an optionally substituted straight or branched C 1-6 alkynyl.
12 . The method of claim 1 , wherein R 2 is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy.
13 . The method of claim 1 , wherein R 2 is methyl or ethyl, each of which is substituted with hydroxy.
14 . The method of claim 1 , wherein R 3 is hydrogen or halo.
15 . The method of claim 1 , wherein R 3 is an optionally substituted C 1-6 aliphatic.
16 . The method of claim 1 , wherein R 3 is an optionally substituted straight or branched C 1-6 alkyl, an optionally substituted straight or branched C 1-6 alkenyl, or an optionally substituted straight or branched C 1-6 alkynyl.
17 . The method of claim 1 , wherein R 3 is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.
18 . The method of claim 1 , wherein ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S.
19 . The method of claim 1 , wherein In other examples, ring A is a furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiaziole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl.
20 . The method of claim 1 , wherein ring A is a pyridine-yl.
21 . The method of claim 1 , wherein ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl.
22 . The method of claim 1 , wherein ring A is a pyridine-2-yl or pyridine-3-yl.
23 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound selected from
24 . A method of treating or reducing the severity of inflammatory disease comprising administering metformin and a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;
R 3 is hydrogen, halo, or optionally substituted aliphatic; and
Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1 at any chemically feasible position on ring A.
25 . A method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from dyslipidemia, central obesity, rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, multiple schlerosis, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), acute allergic reactions, transplant rejection, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, wherein said method comprises the step of contacting said patient with a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;
R 3 is hydrogen, halo, or optionally substituted aliphatic; and
Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1 at any chemically feasible position on ring A.
26 . A pharmaceutical composition useful for treating metabolic mediated disease comprising metformin and a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or an optionally substituted aliphatic;
R 2 is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic;
R 3 is hydrogen, halo, or optionally substituted aliphatic; and
Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1 at any chemically feasible position on ring A.