Claims
- 1. A compound having the structure
- 2. The compound of claim 1 wherein Ar5 comprises a benzene, pyridine, pyrimidine, or pyrazine ring.
- 3. The compound of claim 2 wherein the AR5 ring is substituted with one or two additional substitutents independently selected from a halogen, an amino, or a radical comprising 1 to 4 carbon atoms selected from an alkyl, a monosubstituted amino, a disubstituted amino, an alkoxy, or a haloalkoxy.
- 4. The compound of claim 1 wherein Ars is a benzene ring, optionally substituted with one additional substitutent selected from a halogen, an amino, or a radical comprising 1 to 4 carbon atoms selected from an alkyl, a monosubstituted amino, a disubstituted amino, an alkoxy, or a haloalkoxy.
- 5. The compound of claim 1 wherein the radical
- 6. The compound of claim 5 wherein B is absent.
- 7. The compound of claim 1 wherein the radical
- 8. The compound of claim 1 wherein the radical
- 9. The compound of claim 1 wherein the radical
- 10. The compound of claim 1 wherein the radical
- 11. The compound of claim 1 wherein R103 and R104, or R105 and R106, or R107 and R108 are connected together to form an ring comprising 3 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N.
- 12. The compounds of claim 1 wherein R103 and R104, or R105 and R106, or R107 and R1 08 are connected together to form a cycloalkyl comprising 3 to 6 carbon atoms.
- 13. The compound of claim 1 wherein the radical
- 14. The compound of claim 1 wherein Ar6 comprises a benzene, pyridine, pyrimidine, or pyrazine ring.
- 15. The compound of claim 14 wherein the Ar6 ring is additionally substituted with one, two or three substituents independently selected from halogens or a radical comprising 1 to 4 carbon atoms selected from an alkyl, a haloalkyl, an amino, a mono-substituted amino, a di-substituted amino, an alkoxy, or a haloalkoxy.
- 16. The compound of claim 1 wherein Ar6 has the structure
- 17. The compounds of claim 16 wherein R125 is not hydrogen.
- 18. The compound of claim 1 wherein Ar6 has the structure
- 19. The compound of claim 1 wherein Ar6 has the structure
- 20. The compound of claim 19 wherein ----- is present.
- 21. The compound of claim 1 wherein HAr has the structure
- 22. The compound of claim 1 wherein R110 g is hydrogen or an alkyl having 1 to 4 carbon atoms.
- 23. The compound of claim 1 wherein R109 is hydrogen.
- 24. The compound of claim 8 wherein R110 is hydrogen.
- 25. The compound of claim 24 wherein Ar6 has the structure
- 26. The compound of claim 25 wherein HAr has the structure
- 27. The compound of claim 25 wherein HAr has the structure
- 28. The compound of claim 27 in the form of a salt wherein HAr forms an anion having the structure
- 29. The compound of claim 28 wherein the cation is a pharmaceutically acceptable cation selected from metallic cations of aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, or an ammonium cations comprising a benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, t-butylamine, or tris(hydroxymethyl)aminomethane radical.
- 30. The compounds of claim 1 that are effective to lower serum glucose levels of KKAy or db/db mice maintained on a high fat diet by at least about 5% when orally administered to the mice at a concentration of about 0.3 mg/kg for 7 days, as compared to control mice that do not receive the compounds.
- 31. The compounds of claim 1 that are effective to lower serum triglyceride levels of KKAy or db/db mice maintained on a high fat diet by at least about 5% when orally administered to the mice at a concentration of about 0.3 mg/kg for 7 days, as compared to control mice that do not receive the compounds.
- 32. A compound of claim 1 that is effective, when applied at a concentration of about 1×10−6 M for a period of about 7 days, to induce sufficient differentiation of the mouse preadipocyte 3T3-L1 cells so as to increase the lipid content of the culture by at least about 20% of the lipid accumulation induced by 5-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione when it is applied to control cultures of mouse preadipocyte 3T3-L1 cells at a concentration of about 1×10−7M.
- 33. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective for treating diabetes, cancer, or atherosclerosis, or modulating lipid metabolism, carbohydrate metabolism, lipid and carbohydrate metabolism, or adipocyte differentiation, in a mammal.
- 34. A method of modulating lipid metabolism, carbohydrate metabolism, lipid and carbohydrate metabolism, or adipocyte differentiation comprising administering to a mammal diagnosed as needing such modulation the pharmaceutical composition of claim 34.
- 35. A method of modulating lipid metabolism, carbohydrate metabolism, lipid and carbohydrate metabolism, or adipocyte differentiation comprising administering to a mammal diagnosed as needing such modulation one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof.
- 36. A method of treating hypercholesterolemia comprising administering to a mammal diagnosed as needing such treatment one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof.
- 37. The method of claim 36, wherein the one or more compounds or salts are applied in an amount effective to decrease serum cholesterol levels by at least about 5%.
- 38. A method of treating dyslipidemia comprising administering to a mammal diagnosed as needing such treatment one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to decrease triglyceride levels in the animal.
- 39. The method of claim 38, wherein the one or more compounds or salts are applied in an amount effective to decrease triglyceride levels by at least about 5%.
- 40. A method of treating type 2 Diabetes comprising administering to a mammal diagnosed as needing such treatment one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat type 2 diabetes.
- 41. The method of claim 40, wherein the one or more compounds or salts are applied in an amount effective to decrease blood glucose levels by at least about 5%.
- 42. A method of treating Type 2 Diabetes comprising administering to a human diagnosed as needing such treatment one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to decrease serum glucose levels by at least about 5% and also decrease serum triglyeride levels by at least about 5%.
- 43. A method of treating cancer comprising administering to a mammal diagnosed as needing such treatment one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the cancer.
- 44. The method of claim 43 wherein the cancer is breast cancer.
- 45. A method of making the compound of claim 1 comprising
a) coupling
i) an AR5 precursor compound having the structure 106ii) with an AR6 precursor compound having the structure 107iii) to form a carbonyl containing precursor compound having the structure 108b) further reacting the carbonyl containing precursor compound so as to connect to the carbonyl of the carbonyl containing precursor an HAr heterocycle.
- 46. The method of claim 45 wherein the further reacting comprises condensing the carbonyl containing precursor compound with a compound having the structure
- 47. The method of claim 46 further comprising reacting the compound of claim 1 with a base to form a pharmaceutically acceptable salt.
- 48. A compound having the structure
- 49. The compound of claim 48 wherein the residue
- 50. The compound of claim 48 wherein the residue
- 51. A compound having the structure
- 52. A compound of Formula (200):
- 53. A compound having the formula:
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof.
- 54. A compound having the formula:
5-[3-(1 ,4,4,6-Tetramethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, 5-[4-Dimethylamino-3-(1 ,4,4,6-tetramethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[4-Dimethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1 ,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-chloro-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-4-chloro-benzylidene]-thiazolidine-2,4-dione, 5-[2-Fluoro-4-methoxy-3-(1 ,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Propyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, 5-[4-Dimethylamino-3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-2-fluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Isopropyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, 5-[4-Dimethylamino-3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, 5-[4-Ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 6-[2-Dimethyla ino-5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione, 5-[3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3 ,4-tetrahydro-quinolin-7-yl)-5-fluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, 5-(1′-Ethyl-4′,4′,6′-trimethyl-2′-oxo-1′,2′,3′,4′-tetrahydro-[4,7′]biquinolinyl-2-ylmethylene)-thiazolidine-2,4-dione, 5-[2,5-Difluoro-4-methoxy-3-(1 ,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, 5-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzylidene]-thiazolidine-2,4-dione, 5-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzylidene]-thiazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.
RELATED APPLICATIONS
[0001] This application claims priority to the U.S. Provisional Application Serial No. 60/362,702, filed Mar. 8, 2002, the disclosure of which application is hereby incorporated in its entirety by this reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60362702 |
Mar 2002 |
US |