Free Health and Medical Articles: Method of treating diabetes and related disease states

Abstract

The instant invention is concerned with acetylphenols which are useful as antiobesity and antidiabetic compounds. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering or modulating triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility or for treating atherosclerosis are also disclosed.

Patent number: 5847008
Filing date: Jan 31, 1997
Issue date: Dec 8, 1998
Inventors: Thomas W. Doebber, Joel P. Berger, Gregory D. Berger, Mark D. Leibowitz, David E. Moller, John T. Olson, Arthur A. Patchett, Richard B. Toupence
Assignee: Merck & Co., Inc.

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What is claimed is:

1. A method for the treatment or prevention of diabetes which comprises administering to a diabetic patient a pharmaceutically effective amount of a compound of formula XI or XII: ##STR15## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkenyl of 2 to 6 carbon atoms which may be straight chain or branched; trifluoromethyl; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; SH; thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched; phenyl; phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen; benzyl; phenethyl; halogen, amino; N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched; COOR.sub.4 ; CH.sub.2 OR.sub.4 ; formyl; CN; trifluoromethylthio; or nitro;

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR16## Y' is sulfur, sulfoxide,sulfone; ##STR17## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR18## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR19## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR20## wherein each s is independently 0-3; R.sub.16 is

A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or

B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR21## or R.sub.4 OCH.sub.2 --.

2. A method according to claim 1 wherein the compound is Y is oxygen and Y' is sulfur, sulfoxide, sulfone, amino or cyanamido.

3. A method according to claim 1 wherein each m is 1.

4. A method according to claim 1 wherein the compound is

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3 -dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2,3-dichlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxy-propylsulfonyl)-2,3-dichlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneacetic acid and its methyl ester;

Sodium Salt of 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneacetic acid, monohydrate and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-2-fluorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneacetic acid; and 4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)- 1 -propenylsulfonyl)-2-fluorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylthio-3-fluorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzeneacetic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio)-3 -chlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzeneacetic acid-S-oxide and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneacetic acid and its methyl ester;

4-(3 -(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-thio)benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-propylthio)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-benzeneacetic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3 -fluorobenzoic acid and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propylthio)-3-fluorobenzoic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acid and its methyl ester;

4-(3 -(4-Acetyl-3 -hydroxy-2-propylphenoxy)-propylthio)-3 -fluorobenzoic acid-S-oxide, methyl ester and its methyl ester;

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-sulfonyl)-3-fluorobenzoic acid and its methyl ester; and

4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl-cyanamido)-benzeneacetic acid and its methyl ester.

5. A method for the treatment or prevention of diabetes which comprises administering to a diabetic patient an effective amount of a compound of claim 1 in combination with a sulfonylurea, fibrate, HMG-CoA reductase inhibitor, beta-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, .alpha.-glucosidase inhibitors, insulin secretogogue or insulin.

6. A method for treating obesity which comprises administering to a patient in need thereof an effective amount of a compound of formula XI or XII: ##STR22## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR23## Y' is sulfur, sulfoxide,sulfone; ##STR24## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR25## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR26## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR27## wherein each s is independently 0-3; R.sub.16 is

R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of I to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of I to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR28## or R.sub.4 OCH.sub.2 --.

7. A method according to claim 6 in combination with a fenfluramine, dexfenfluramine, phentiramine or .delta.3 adrenergic receptor agonist.

8. A method for lowering triglyceride levels which comprises administering to a patient needing lower triglyceride an effective amount of a compound of formula XI or XII: ##STR29## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR30## Y' is sulfur, sulfoxide,sulfone; ##STR31## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR32## wherein R .sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR33## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR34## wherein each s is independently 0-3; R.sub.16 is

R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR35## or R.sub.4 OCH.sub.2 --.

9. A method for halting, preventing or reducing the risk of developing atherosclerosis and related diseae events in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula XI or XII: ##STR36## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR37## Y' is sulfur, sulfoxide,sulfone; ##STR38## R.sub.1 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR39## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR40## each R.sub.6 is independently H or atkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR41## wherein each s is independently 0-3; R.sub.16 is

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR42## or R.sub.4 OCH.sub.2 --.

10. A method according to claim 9 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta.binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta.transactivation assay.

11. The method of claim 10 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

12. The method of claim 11 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

13. The method of claim 12 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

14. A method for raising high densisty lipoprotein plasma levels in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula XI or XII: ##STR43## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:

each R' is independently R.sub.4 ; OR.sub.4 ; COOR.sub.4 ; N(R.sub.4).sub.2 ; SR.sub.4 ; CH.sub.2 OR.sub.4 ; CHO; or together R' and R' are O; CH.sub.2 ; or ##STR44## Y' is sulfur, sulfoxide,sulfone; ##STR45## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; alkanoyl of 1-4 carbon atoms which may be straight chain or branched; phenylsulfonyl; tosyl; NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched; or ##STR46## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched; N--CN, CH.sub.2, or C.dbd.O;

Y is Y' and oxygen;

each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;

each m is independently an integer from 0-6;

R.sub.2 is ##STR47## each R.sub.6 is independently H or alkyl of 1-4 carbons; each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;

each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;

R.sub.5 is COOR.sub.4 ; CH.sub.2 OH; CHO; tetrazole; NHSO.sub.2 R.sub.14 ; hydroxymethylketone; CN; CON(R.sub.7).sub.2 ; a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group; or COOR.sub.15 where R.sub.15 is ##STR48## wherein each s is independently 0-3; R.sub.16 is

r an q are each independently 0-20 provided that the total of r and q does not exceed 20;

p is 0 or 1;

R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;

R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched; alkoxy of 1 to 6 carbon atoms which may be straight chain or branched; or (CH.sub.2).sub.r R.sub.5 ; and

R.sub.10 is H; alkyl of 1 to 6 carbon atoms which may be straight chain or branched; ##STR49## or R.sub.4 OCH.sub.2 --.

15. A method according to claim 14 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. transactivation assay.

16. The method of claim 15 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

17. The method of claim 16 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

18. The method of claim 17 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

19. A method for halting, preventing or reducing the risk of developing atherosclerosis and related disease events which comprises administering to a patient in need thereof an effective amount of a compound of claim 9 in combination with a sulfonylurea, fibrate, HMG-CoA reductase inhibitor, beta-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, .alpha.-glucosidase inhibitors, insulin secretogogue or insulin.

20. A method according to claim 19 wherein the compound has an IC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 .mu.M in the hPPAR.delta. transactivation assay.

21. The method of claim 20 wherein the compound has an IC.sub.50 equal to or less than 100 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 100 nM in the hPPAR.delta. transactivation assay.

22. The method of claim 21 wherein the compound has an IC.sub.50 equal to or less than 50 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 50 nM in the hPPAR.delta. transactivation assay.

23. The method of claim 22 wherein the compound has an IC.sub.50 equal to or less than 10 nM in the hPPAR.delta. binding assay and an EC.sub.50 equal to or less than 10 nM in the hPPAR.delta. transactivation assay.

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Method of treating diabetes and related disease states