Claims for Patent: 7,807,135

Summary for Patent: 7,807,135

Title:	Stilbene derivatives and their use for binding and imaging amyloid plaques
Abstract:	This invention relates to a method of imaging amyloid deposits and to labeled compounds, and methods of making labeled compounds useful in imaging amyloid deposits. This invention also relates to compounds, and methods of making compounds for inhibiting the aggregation of amyloid proteins to form amyloid deposits, and a method of delivering a therapeutic agent to amyloid deposits.
Inventor(s):	Hank F. Kung, Mei-Ping Kung, Zhi-Ping Zhuang
Assignee:	University of Pennsylvania Penn
Application Number:	US11/305,333
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,807,135
Patent Claims:	1. A compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 is NRaRb, wherein Ra and Rb are independently hydrogen or C1-4 alkyl; R1′ is hydrogen; R2 is selected from the group consisting of i. hydroxyl, C1-4Alkoxy, (C1-C4)-alkyloxoAlk(C1-C4)oxy, (C1-C4)-alkyloxo(C1-C4)-alkyloxo(C1-C4)alkoxy, (C1-C4)-alkyloxo(C1-C4)-alkyloxo(C1-C4)-alkyloxo(C1-C4)alkoxy, carboxy(C1-C4)Alkyl, halo(C1-C4)alkoxy, halo(C1-C4)-alkyloxo (C1-C4)alkoxy, halo(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)-alkyloxy, halo(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)alkyloxy, halo(C1-C4)alkyl, NR6R6′, phenyl(C1-C4)alkyl, 18F(C1-C4)alkoxy, 18F(C1-C4)alkyloxo(C1-C4)alkoxy, 18F(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)alkyloxy, 18F(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)alkyloxo(C1-C4)alkyloxy, 18F(C1-C4)alkyl, wherein R6 and R6′ are independently selected from the group consisting of hydrogen, hydroxy(C1-C4)alkyl and C1-C4alkyl; where q is an integer from one to 10; Z is selected from the group consisting of 18F, 18F substituted benzoyloxy, 18F substituted (C1-4)alkoxy, 18F substituted benzyloxy, optionally 18F-phenoxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy, and a 18F substituted C6-10 aryl, optionally 18F-phenyl; and R30, R31, R32 and R33 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl and hydroxy(C1-4)alkyl; where Z, R30, R31, R32 and R33 are as described above; where Y is selected from the group consisting of 18F, 18F substituted benzoyloxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy optionally 18F-phenoxy and 18F substituted C6-10 aryl, optionally 18F-phenyl; U is selected from the group consisting of hydrogen, hydroxy, 18F, 18F substituted benzoyloxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy, optionally 18F-phenoxy and 18F substituted C6-10 aryl, optionally 18F-phenyl; and R34, R35, R36, R37, R38, R39 and R40 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, and hydroxy(C1-4)alkyl; and R7 and R8 are in each instance independently selected from the group consisting of halogen, hydrogen, hydroxy, amino, methylamino, dimethylamino, C1-4 alkoxy, C1-4 alkyl, and hydroxy(C1-4)alkyl, wherein at least one of R7 and R8 is halogen. 2. The compound of claim 1 wherein R7 and R8 are hydrogen or fluorine, wherein at least one of R7 and R8 is fluorine. 3. The compound of claim 1, wherein R2 is wherein Z, R30, R31, R32 and R33 are as described above. 4. The compound of claim 3, wherein q is an integer from 2 to 5. 5. The compound of claim 4, wherein R30, R31, R32 and R33 are, in each instance, hydrogen. 6. The compound of claim 5, wherein q is an integer from 3 to 4. 7. The compound of claim 6, wherein Z is 18F. 8. The compound of claim 7, having the following formula: wherein one of R7 and R8 is hydrogen, and the other is halogen. 9. The compound of claim 7, having the following formula: wherein one of R7 and R8 is hydrogen, and the other is halogen. 10. The compound of claim 1, wherein R2 is wherein Z, R30, R31, R32 and R33 are as described above. 11. The compound of claim 10, wherein Z is 18F. 12. The compound of claim 11, wherein R30, R31, R32 and R33 are, in each instance, hydrogen. 13. The compound of claim 1, wherein R2 is wherein U is hydroxy. 14. The compound of claim 13, wherein R34, R35, R36, R37, R38, R39 and R40 are, in each instance, hydrogen. 15. The compound of claim 14, having the following structure: wherein one of R7 and R8 is hydrogen, and the other is halogen. 16. A compound of Formula II, wherein, R1 is selected from the group consisting of: a. NRaRb, wherein Ra and Rb are independently hydrogen, C1-4 alkyl, (CH2)dX, where X is 18F, and d is an integer between 1 and 4, or Ra and Rb are both oxygen to form a nitro; b. hydroxy, c. C1-4 alkoxy, and d. hydroxy(C1-4)alkyl; R2 is selected from the group consisting of: wherein q is an integer from 2 to 10; Z is selected from the group consisting of 18F, 18F substituted benzoyloxy, 18F substituted (C1-4)alkoxy, 18F substituted benzyloxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy, and a 18F substituted C6-10 aryl; and R30, R31, R32 and R33 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl and hydroxy(C1-4)alkyl; wherein Z, R30, R31, R32 and R33 are as described above, and wherein Y is selected from the group consisting of 18F, 18F substituted benzoyloxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy, and 18F substituted C6-10 aryl; U is selected from the group consisting of hydrogen, hydroxy, 18F, 18F substituted benzoyloxy, 18F substituted phenyl(C1-4)alkyl, 18F substituted aryloxy, and 18F substituted C6-10 aryl; and R34, R35, R36, R37, R38, R39 and R40 are in each instance independently selected from the group consisting of hydrogen, 18F, hydroxy, C1-4 alkoxy, C1-4 alkyl, and hydroxy(C1-4)alkyl; and R7 and R8 are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C1-4 alkoxy, C1-4 alkyl, and hydroxy(C1-4)alkyl. 17. The compound of claim 16, wherein R1 is NRaRb, wherein Ra and Rb are independently hydrogen or C1-4 alkyl. 18. The compound of claim 17, wherein R2 is where Z, R30, R31, R32 and R33 are as described above. 19. The compound of claim 18, wherein q is an integer from 2 to 5. 20. The compound of claim 19, wherein R7 and R8 are each hydrogen. 21. The compound of claim 20, wherein R30, R31, R32 and R33 are, in each instance, hydrogen. 22. The compound of claim 21, having the following formula: 23. The compound of claim 21, having the following formula: 24. The compound of claim 17, wherein R2 is wherein Z, R30, R31, R32 and R33 are as described above. 25. The compound of claim 24, wherein Z is 18F. 26. The compound of claim 25, wherein R7 and R8 are each hydrogen. 27. The compound of claim 26, wherein R30, R31, R32 and R33 are, in each instance, hydrogen. 28. The compound of claim 17, wherein R2 is wherein U is hydroxy. 29. The compound of claim 28, wherein R34, R35, R36, R37, R38, R39 and R40 are, in each instance, hydrogen. 30. The compound of claim 29, having the following structure: 31. A compound of Formula III: wherein, n is an integer between 1 and 4; R7 and R8 are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C1-4 alkoxy, C1-4 alkyl, and hydroxy(C1-4)alkyl; and R41 is selected from the group consisting of hydroxy and NRaRb, wherein Ra and Rb are independently hydrogen, C1-4 alkyl, or Ra and Rb are both oxygen to form a nitro. 32. The compound of claim 31, wherein n is one, and R41 is selected from the group consisting of hydroxy, methylamino and dimethylamino. 33. A pharmaceutical composition comprising a compound of claim 1, 16 or 31. 34. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of claim 1, 16 or 31. 35. A method of imaging amyloid deposits, comprising: a. introducing into a mammal a detectable quantity of a diagnostic composition of claim 34; b. allowing sufficient time for the labeled compound to be associated with amyloid deposits; and c. detecting the labeled compound associated with one or more amyloid deposits.