Claims for Patent: 7,214,696

Summary for Patent: 7,214,696

Title:	Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
Abstract:	Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods, screening methods, as well as specific transthyretin stabilizing compounds are disclosed.
Inventor(s):	Kelly; Jeffery W. (LaJolla, CA), Sekijima; Yoshiki (Matsumoto, JP)
Assignee:	The Scripps Research Institute (La Jolla, CA)
Application Number:	11/256,026
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,214,696
Patent Claims:	1. A method of treating a transthyretin amyloid disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula ##STR00070## or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2-(trifluoromethyl)phenyl, or 3-(trifluoromethyl)phenyl. 2. The method of claim 1, wherein the compound is: 4-Carboxy-2-(3,5-difluorophenyl)-benzoxazole; 4-Carboxy-2-(2,6-difluorophenyl)-benzoxazole; 4-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole; 4-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole; 4-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole; 4-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole; 4-Carboxy-2-phenyl-benzoxazole; 5-Carboxy-2-(3,5-difluorophenyl)-benzoxazole; 5-Carboxy-2-(2,6-difluorophenyl)-benzoxazole; 5-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole; 5-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole; 5-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole; 5-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole; 5-Carboxy-2-phenyl-benzoxazole; 6-Carboxy-2-(3,5-difluorophenyl)-benzoxazole; 6-Carboxy-2-(2,6-difluorophenyl)-benzoxazole; 6-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole; 6-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole; 6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole; 6-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole; 6-Carboxy-2-phenyl-benzoxazole; 7-Carboxy-2-(3,5-difluorophenyl)-benzoxazole; 7-Carboxy-2-(2,6-difluorophenyl)-benzoxazole; 7-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole; 7-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole; 7-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole; 7-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole; or 7-Carboxy-2-phenyl-benzoxazole. 3. The method of claim 1, wherein the compound is 6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole. 4. The method of claim 1, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy. 5. The method of claim 2, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy. 6. The method of claim 3, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy. 7. The method of claim 1, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy. 8. The method of claim 2, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy. 9. The method of claim 3, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy. 10. The method of claim 1, wherein the transthyretin amyloid disease is senile systemic amyloidosis. 11. The method of claim 2, wherein the transthyretin amyloid disease is senile systemic amyloidosis. 12. The method of claim 3, wherein the transthyretin amyloid disease is senile systemic amyloidosis. 13. The method of claim 1, wherein the transthyretin amyloid disease is cardiac amyloidosis following liver transplantation. 14. The method of claim 2, wherein the transthyretin amyloid disease is cardiac amyloidosis following liver transplantation. 15. The method of claim 3, wherein the transthyretin amyloid disease is cardiac amyloidosis following liver transplantation. 16. The method of claim 1, wherein the compound is 5-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole. 17. The method of claim 16, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy. 18. The method of claim 16, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy. 19. The method of claim 16, wherein the transthyretin amyloid disease is senile systemic amyloidosis. 20. The method of claim 16, wherein the transthyretin amyloid disease is cardiac amyloidosis following liver transplantation. 21. The method of claim 1, wherein the compound is 4-Carboxy-2-(3,5-difluorophenyl)-benzoxazole. 22. The method of claim 1, wherein the compound is 4-Carboxy-2-(2,6-difluorophenyl)-benzoxazole. 23. The method of claim 1, wherein the compound is 4-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole. 24. The method of claim 1, wherein the compound is 4-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole. 25. The method of claim 1, wherein the compound is 4-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole. 26. The method of claim 1, wherein the compound is 4-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole. 27. The method of claim 1, wherein the compound is 4-Carboxy-2-phenyl-benzoxazole. 28. The method of claim 1, wherein the compound is 5-Carboxy-2-(3,5-difluorophenyl)-benzoxazole. 29. The method of claim 1, wherein the compound is 5-Carboxy-2-(2,6-difluorophenyl)-benzoxazole. 30. The method of claim 1, wherein the compound is 5-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole. 31. The method of claim 1, wherein the compound is 5-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole. 32. The method of claim 1, wherein the compound is 5-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole. 33. The method of claim 1, wherein the compound is 5-Carboxy-2-phenyl-benzoxazole. 34. The method of claim 1, wherein the compound is 6-Carboxy-2-(3,5-difluorophenyl)-benzoxazole. 35. The method of claim 1, wherein the compound is 6-Carboxy-2-(2,6-difluorophenyl)-benzoxazole. 36. The method of claim 1, wherein the compound is 6-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole. 37. The method of claim 1, wherein the compound is 6-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole. 38. The method of claim 1, wherein the compound is 6-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole. 39. The method of claim 1, wherein the compound is 6-Carboxy-2-phenyl-benzoxazole. 40. The method of claim 1, wherein the compound is 7-Carboxy-2-(3,5-difluorophenyl)-benzoxazole. 41. The method of claim 1, wherein the compound is 7-Carboxy-2-(2,6-difluorophenyl)-benzoxazole. 42. The method of claim 1, wherein the compound is 7-Carboxy-2-[(3-trifluoromethyl)phenyl]-benzoxazole. 43. The method of claim 1, wherein the compound is 7-Carboxy-2-[(2-trifluoromethyl)phenyl]-benzoxazole. 44. The method of claim 1, wherein the compound is 7-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole. 45. The method of claim 1, wherein the compound is 7-Carboxy-2-(2,6-dichlorophenyl)-benzoxazole. 46. The method of claim 1, wherein the compound is 7-Carboxy-2-phenyl-benzoxazole.