Claims for Patent: 7,301,050

Summary for Patent: 7,301,050

Title:	4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
Abstract:	The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR delta modulators to treat or inhibit the progression of, for example, dyslipidemia.
Inventor(s):	Gee-Hong Kuo, Rui Zhang, Aihua Wang, Alan R. DeAngelis
Assignee:	Janssen Pharmaceutica NV
Application Number:	US10/942,478
Patent Claims:	1. A compound of Formula (I): wherein X is selected from a covalent bond, S, or O; Y is S or O; - - - W - - - represents a group selected from ═—CH—, —CH═, —CH2—, —CH2—CH2—, ═CH—CH2, —CH2—CH═, ═CH—CH═, and —CH═CH—; Z is selected from O, CH, and CH2, provided when Y is O, Z is O; R1 and R2 are independently selected from H, C1-3alkyl, C1-3alkoxy, halo, and NRaRb wherein Ra and Rb are independently H or C1-3alkyl; R3 and R4 are independently selected from H, halo, cyano, hydroxy, acetyl, C1-5alkyl, C1-4alkoxy, and NRcRd wherein Rc and Rd are independently H or C1-3alkyl, provided that R3 and R4 are not both H; R5 is selected from halo, phenyl, phenoxy, (phenyl)C1-5alkoxy, (phenyl)C1-5alkyl, C2-5heteroaryloxy, C2-5heteroarylC1-5alkoxy, C2-5heterocyclyloxy, C1-9alkyl, C1-8alkoxy, C2-9alkenyl, C2-9alkenyloxy, C2-9alkynyl, C2-9alkynyloxy, C3-7cycloalkyl, C3-7cycloalkoxy, C3-7cycloalkyl-C1-7alkyl, C3-7cycloalkyl-C1-7alkoxy, C3-7cycloalkyloxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-5alkoxy-C1-5alkoxy, or C3-7cycloalkyloxy-C1-7alkoxy; R6 is H when - - - W - - - represents a group selected from —CH═, —CH2, —CH2—CH2, —CH2—CH═, and —CH═CH—, or R6 is absent when - - - W - - - represents a group selected from ═CH—, ═CH—CH2, and ═CH—CH═; and n is 1 or 2; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein X is S or O. 3. The compound of claim 1 wherein X is a covalent bond. 4. The compound of claim 2 wherein X is O. 5. The compound of claim 1 wherein Y is O. 6. The compound of claim 1 wherein Y is S. 7. The compound of claim 1 wherein Z is O. 8. The compound of claim 1 wherein Z is CH or CH2. 9. The compound of claim 1 wherein - - - W - - - represents —CH2— or —CH2—CH2. 10. The compound of claim 9 wherein - - - W - - - represents —CH2—. 11. The compound of claim 1 wherein - - - W - - - represents ═CH—, —CH═, ═CH—CH2—, —CH2—CH═, ═CH—CH═, or —CH═CH—. 12. The compound of claim 1 wherein R3 and R4 are independently selected from H, halo, cyano, C1-4alkyl, and C1-3alkoxy. 13. The compound of claim 1 wherein R1 and R2 are independently selected from H, C1-3alkyl, C1-3alkoxy, F, Cl, and Br. 14. The compound of claim 13 wherein R1 and R2 are independently selected from H, methyl, methoxy, F and Cl. 15. The compound of claim 1 wherein R3 and R4 are independently selected from H, halo, cyano, hydroxy, C2-4acyl, C1-4alkyl, and C1-3alkoxy. 16. The compound of claim 12 wherein R3 is independently selected from H, F, Cl, methyl, and methoxy. 17. The compound of claim 12 wherein R4 is independently selected from F, Cl, methyl, methoxy, trifluoromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy and trifluoromethoxy. 18. The compound of claim 1 wherein R3 is selected from methyl, methoxy, H, Cl, Br, I, CH, —CH(CF3)2, CF3, —OCF3, —N(CH3)2, —O—CH2COOH, and —COCH3, and R4 is selected from H, Cl, and methyl. 19. The compound of claim 1 wherein R5 is selected from C1-7alkyl, C1-6alkoxy, C2-7alkenyl, C2-7alkenyloxy, C2-7alkynyl, C2-7alkynyloxy, C3-7cycloalkyl, C3-7cycloalkoxy, C1-6alkoxy-C1-6alkyl, C1-5alkoxy-C1-5alkoxy, and C3-7cycloalkyloxy-C1-7alkoxy. 20. The compound of claim 1 wherein R5 is selected from phenoxy, (phenyl)C1-5alkoxy, (phenyl)C1-5alkyl, C2-5heteroaryloxy, C2-5heteroarylC1-5alkoxy, C2-5heterocyclyloxy, C3-7cycloalkyl-C1-7alkyl, C3-7cycloalkyl-C1-7alkoxy, and C3-7cycloalkyloxy-C1-6alkyl. 21. The compound of claim 1 wherein R6 is H. 22. The compound of claim 1 wherein R3 is selected from H, F, Cl, methyl, and methoxy, and R4 is selected from F, Cl, methyl, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and methoxy. 23. The compound of claim 1 wherein R1 is selected from H, CF3, methyl, Cl, and methoxy, and R2 is selected from H, Cl, and methyl. 24. The compound of claim 23 wherein X is a covalent bond. 25. The compound of claim 23 wherein X is covalent bond, Y is S and Z is O. 26. The compound of claim 1 wherein X is O and Y is O. 27. The compound of claim 1 wherein X is O and Y is S. 28. The compound of claim 1 wherein Y is O and Z is O. 29. The compound of claim 1 wherein Y is S and Z is O. 30. The compound of claim 1 wherein R6 is H and R5 is selected from C1-7alkyl, C1-6alkoxy, C2-7alkenyl, C2-7alkenyloxy, C1-6alkoxy-C1-6alkyl, and C1-5alkoxy-C1-5alkoxy. 31. The compound of claim 30 wherein R5 is selected from C1-5alkyl, C1-4alkoxy, C2-5alkenyl, C2-5alkenyloxy, and C1-5alkoxy-C1-5alkoxy. 32. The compound of claim 30 wherein R5 is selected from C1-3alkyl, C1-3alkoxy, C2-4alkenyl, C2-4alkenyloxy, and C1-3alkoxy-C1-3alkoxy. 33. The compound of claim 30 wherein R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxy-methoxy, methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl, and ethoxy-ethyl. 34. The compound of claim 1 wherein R1 is selected from H, CF3, methyl, Cl, and methoxy; R2 is selected from H, Cl, and methyl; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl, fluoromethoxy, difluoromethyl, difluoromethoxy, and methoxy. 35. The compound of claim 1 wherein X is O; Y is O; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 36. The compound of claim 1 wherein X is O; Y is S; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 37. The compound of claim 1 wherein X is covalent bond; Y is S; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3, and methoxy. 38. The compound of claim 1 wherein Y is O; Z is O; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 39. The compound of claim 1 wherein Y is S; Z is O; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 40. The compound of claim 1 wherein R3 is selected from H, F, Cl, methyl, and methoxy; R4 is selected from F, Cl, methyl, CF3, OCF3, and methoxy; R5 is selected from C1-7alkyl, C1-6alkoxy, C2-7alkenyl, C2-7alkenyloxy, C1-6alkoxy-C1-6alkyl, and C1-5alkoxy-C1-5alkoxy; and R6 is H. 41. The compound of claim 1 wherein X is O; Y is O; R5 is selected from C1-3alkyl, C1-3alkoxy, C2-4alkenyl, C2-4alkenyloxy, and C1-3alkoxy-C1-3alkoxy; and R6 is H. 42. The compound of claim 1 wherein X is O; Y is S; R5 is selected from C1-3alkyl, C1-3alkoxy, C2-4alkenyl, C2-4alkenyloxy, and C1-3alkoxy-C1-3alkoxy; and R6 is H. 43. The compound of claim 1 wherein X is O; Y is O; R1 is selected from H, CF3, methyl, Cl, and methoxy; R2 is selected from H, Cl, and methyl; R3 is selected from H, F, Cl, methyl, and methoxy; R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy; and n is 1. 44. The compound of claim 1 wherein X is O; Y is S; R1 is selected from H, CF3, methyl, Cl, and methoxy; R2 is selected from H, Cl, and methyl; R3 is selected from H, F, Cl, methyl, and methoxy; and R4 is selected from F, Cl, methyl, CF3, OCF3 and methoxy. 45. The compound of claim 44, wherein n=1. 46. The compound of claim 45 wherein R5 is selected from C1-3alkyl, C1-3alkoxy, C2-4alkenyl, C2-4alkenyloxy, and C1-3alkoxy-C1-3alkoxy; and R6 is H. 47. The compound of claim 1 which is selected from {4-[2-Ethoxy-3-(4-trifluoromethvl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; and (S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 48. The compound of claim 1 which is {4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 49. The compound of claim 1 which is (R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 50. The compound of claim 1 which is (S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 51. A compound of claim 1 selected from {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid; {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-pentylsulfanyl]-phenoxy}-acetic acid; {4-[4-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; {3-Chloro-4-[2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenyl}-acetic acid; {4-[2-Ethoxymethyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[4-Ethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; and {4-[2-(5-Chloro-thiophen-2-ylmethoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 52. A compound of claim 1 selected from {4-[3-Cyano-2-(4-trifl uoromethyl-phenoxymethyl )-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[5-Cyano-2-(4-trifl uoromethyl-phenoxymethyl )-pent-4-enylsulfanyl]-2-methyl-phenoxy}-acetic acid; {3-Chloro-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenyl}-acetic acid; {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-acetic acid; {4-[2-Benzyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[2-(4-Butyryl-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propenylsulfanyl]-phenoxy}-acetic acid; {2-Methyl-4-[2-methylsulfanylmethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-phenoxy}-acetic acid; {4-[2,4-Diethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; and {4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-acetic acid. 53. A compound of claim 1 selected from {4-[2-(4-Trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid; {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-heptylsulfanyl]-phenoxy}-acetic acid; {4-[4-Methoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-acetic acid; {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-3,6-d ihydro-2H-pyran-2-ylmethylsulfanyl]-phenoxy}-acetic acid; and {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-phenoxy}-acetic acid. 54. A compound of claim 1, selected from (R)-{4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[3-(4-Chloro-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[3-(4-tert-Butyl-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic acid; (R)-{4-[2-(4-Chloro-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{4-[2-(4-tert-Butyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic acid; (R)-{3-Chloro-4-[2-ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-phenyl}-acetic acid; (R)-{3-Chloro-4-[3-(4-chloro-phenoxy)-2-ethoxy-propylsulfanyl]-phenyl}-acetic acid; (R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic acid; (R)-{4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic acid; (R)-{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic acid; and (R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic acid. 55. A pharmaceutical composition comprising a compound of any of claim 1, 27, 30, 31, 32, 34, 36, 37, 39, 40, 42, 44, 45, 46, 47, 51, 52, 53 and 54. 56. The compound of claim 45 wherein R6 is H and R5 is selected from C1-7 alkyl, C1-6 alkoxy, C2-7 alkenyl, C2-7 alkenyloxy, C1-6 alkoxy-C1-6 alkyl, and C1-5-C1-5alkoxy. 57. The compound of claim 45 wherein R6 is H and R5 is selected from C1-5 alkyl, C1-4 alkoxy, C2-5 alkenyl, C2-5 alkenyloxy, and C1-5alkoxy-C1-5alkoxy. 58. The compound of claim 45 wherein R6 is H and R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy, isopropenyloxy, ethoxymethoxy, methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl, and ethoxy-ethyl.