Organic compounds
Compounds of the formula provide pharmacological agents which bind to Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the present invention are useful for the treatment of conditions mediated by the PPAR receptor activity in mammals. Such conditions include dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease. The compounds of the present invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X.
1. A compound of the formula
wherein
R 1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;
R 2 and R 3 are independently hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, aryloxy, aralkoxy or heteroaralkoxy; or
R 2 and R 3 combined together with the carbon atoms they are attached to form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 2 and R 3 are attached to carbon atoms adjacent to each other;
R and R′ are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or
R and R′ combined together with the carbon atoms to which they are attached form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R and R′ are attached to carbon atoms adjacent to each other; or
X is —Z—(CH 2 ) p -Q-W in which
Z is O or S;
p is an integer from 1 to 8;
Q is a bond or
Q is —O(CH 2 ) r — in which
r is zero
W is cycloalkyl, aryl or heterocyclyl;
A-B is —NH—S(O) 2 —;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 of the formula
wherein
R 1 is hydrogen or optionally substituted alkyl;
R 2 and R 3 are independently hydrogen, halogen, trifluoromethyl, optionally substituted lower alkyl, alkoxy, aryl or heteroaryl; or
R 2 and R 3 combined together with the carbon atoms they are attached to form an optionally substituted fused 5- to 6-membered aromatic or heteroaromatic ring provided that R 2 and R 3 are attached to carbon atoms adjacent to each other
R and R′ are independently hydrogen, halogen, optionally substituted C 1-6 alkyl, C 1-8 alkoxy, aralkyl or heteroaralkyl;
p is an integer from 1 to 5;
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 wherein
R 2 and R 3 are independently hydrogen, halogen, trifluoromethyl, optionally substituted lower alkyl, alkoxy, aryl or heteroaryl; or
R 2 and R 3 combined together with the carbon atoms they are attached to form an optionally substituted fused 6-membered aromatic ring provided that R 2 and R 3 are attached to carbon atoms adjacent to each other;
R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-8 alkoxy;
R′ is hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 of the formula
wherein
R 2 and R 3 are independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or aryl,
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 of the formula
wherein
R 1 is hydrogen or optionally substituted lower alkyl;
R 2 and R 3 are independently hydrogen, halogen, lower alkyl or lower alkoxy;
R is hydrogen;
p is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 wherein
R 1 and R 3 are hydrogen;
R 2 is hydrogen, fluoro, chloro, C 1-3 alkyl or C 1-3 alkoxy;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 5 wherein
R 1 is hydrogen;
R 2 is hydrogen, fluoro, chloro, C 1-3 alkyl or C 1-3 alkoxy;
R 3 is fluoro, chloro, C 1-3 alkyl, or C 1-3 alkoxy;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 5 wherein
p is an integer of 1 or 2;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 5 wherein
p is an integer of 2 or 3;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 wherein
W is
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 9 wherein
W is
or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1 which is selected from the group consisting of:
6-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
6-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
3-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-biphenyl-4-carboxylic acid;
4-Chloro-2-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzene-sulfonylamino}-benzoic acid;
6-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
4-Chloro-2-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-benzoic acid;
2-{4-(5-Methyl-2-phenyloxazol-4-ylmethoxy)benzenesulfonylamino}-6-trifluoromethyl-benzoic acid;
4-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
3,5-Dimethyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
2-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]benzenesulfonylamino}-benzoic acid;
2-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-benzoic acid;
2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonylamino]benzoic acid;
4-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
2-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
4-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
4,5-Difluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
6-Methoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
5-Fluoro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
5-Chloro-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
3-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-naphthalene-2-carboxylic acid;
5-Methoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
5-Methyl-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
5-Acetylamino-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
4,5-Dimethoxy-2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid;
4-Chloro-5-{7-[2-(5-methyl-2-phenyl-oxazol-7-yl)-ethoxy]-benzenesulfonylamino}-benzoic acid;
3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-biphenyl-4-carboxylic acid;
2,3-Dimethoxy-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-benzoic acid;
2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonylamino}-benzoic acid;
2-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonylamino}-benzoic acid;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.
14. A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent.