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Claims for Patent: 7,807,135

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Claims 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): Kung; Hank F. (Wynnewood, PA), Kung; Mei-Ping (Wynnewood, PA), Zhuang; Zhi-Ping (Lansdale, PA)
Assignee: The Trustees of the University of Pennsylvania (Philadelphia, PA)
Application Number:11/305,333
Patent Claims: 1. A compound of Formula I, ##STR00023## or a pharmaceutically acceptable salt or prodrug thereof, wherein: R.sup.1 is NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are independently hydrogen or C.sub.1-4 alkyl; R.sup.1' is hydrogen; R.sup.2 is selected from the group consisting of i. hydroxyl, C.sub.1-4Alkoxy, (C.sub.1-C.sub.4)-alkyloxoAlk(C.sub.1-C.sub.4)oxy, (C.sub.1-C.sub.4)-alkyloxo(C.sub.1-C.sub.4)-alkyloxo(C.sub.1-C.sub.4)alko- xy, (C.sub.1-C.sub.4)-alkyloxo(C.sub.1-C.sub.4)-alkyloxo(C.sub.1-C.sub.4)-- alkyloxo(C.sub.1-C.sub.4)alkoxy, carboxy(C.sub.1-C.sub.4)Alkyl, halo(C.sub.1-C.sub.4)alkoxy, halo(C.sub.1-C.sub.4)-alkyloxo (C.sub.1-C.sub.4)alkoxy, halo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)-a- lkyloxy, halo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.- sub.4)alkyloxo(C.sub.1-C.sub.4)alkyloxy, halo(C.sub.1-C.sub.4)alkyl, NR.sup.6R.sup.6', phenyl(C.sub.1-C.sub.4)alkyl, .sup.18F(C.sub.1-C.sub.4)alkoxy, .sup.18F(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)alkoxy, .sup.18F(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.- 4)alkyloxy, .sup.18F(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.4)alkyloxo(C.sub.1-C.sub.- 4)alkyloxo(C.sub.1-C.sub.4)alkyloxy, .sup.18F(C.sub.1-C.sub.4)alkyl, wherein R.sup.6 and R.sup.6' are independently selected from the group consisting of hydrogen, hydroxy(C.sub.1-C.sub.4)alkyl and C.sub.1-C.sub.4alkyl; ##STR00024## where q is an integer from one to 10; Z is selected from the group consisting of .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted (C.sub.1-4)alkoxy, .sup.18F substituted benzyloxy, optionally .sup.18F-phenoxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy, and a .sup.18F substituted C.sub.6-10 aryl, optionally .sup.18F-phenyl; and R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl and hydroxy(C.sub.1-4)alkyl; ##STR00025## where Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are as described above; ##STR00026## where Y is selected from the group consisting of .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy optionally .sup.18F-phenoxy and .sup.18F substituted C.sub.6-10 aryl, optionally .sup.18F-phenyl; U is selected from the group consisting of hydrogen, hydroxy, .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy, optionally .sup.18F-phenoxy and .sup.18F substituted C.sub.6-10 aryl, optionally .sup.18F-phenyl; and R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38, R.sup.39 and R.sup.40 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, and hydroxy(C.sub.1-4)alkyl; and R.sup.7 and R.sup.8 are in each instance independently selected from the group consisting of halogen, hydrogen, hydroxy, amino, methylamino, dimethylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, and hydroxy(C.sub.1-4)alkyl, wherein at least one of R.sup.7 and R.sup.8 is halogen.

2. The compound of claim 1 wherein R.sup.7 and R.sup.8 are hydrogen or fluorine, wherein at least one of R.sup.7 and R.sup.8 is fluorine.

3. The compound of claim 1, wherein R.sup.2 is ##STR00027## wherein Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 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 R.sup.30, R.sup.31, R.sup.32 and R.sup.33 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 .sup.18F.

8. The compound of claim 7, having the following formula: ##STR00028## wherein one of R.sup.7 and R.sup.8 is hydrogen, and the other is halogen.

9. The compound of claim 7, having the following formula: ##STR00029## wherein one of R.sup.7 and R.sup.8 is hydrogen, and the other is halogen.

10. The compound of claim 1, wherein R.sup.2 is ##STR00030## wherein Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are as described above.

11. The compound of claim 10, wherein Z is .sup.18F.

12. The compound of claim 11, wherein R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are, in each instance, hydrogen.

13. The compound of claim 1, wherein R.sup.2 is ##STR00031## wherein U is hydroxy.

14. The compound of claim 13, wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38, R.sup.39 and R.sup.40 are, in each instance, hydrogen.

15. The compound of claim 14, having the following structure: ##STR00032## wherein one of R.sup.7 and R.sup.8 is hydrogen, and the other is halogen.

16. A compound of Formula II, ##STR00033## wherein, R.sup.1 is selected from the group consisting of: a. NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are independently hydrogen, C.sub.1-4 alkyl, (CH.sub.2).sub.dX, where X is .sup.18F, and d is an integer between 1 and 4, or R.sup.a and R.sup.b are both oxygen to form a nitro; b. hydroxy, c. C.sub.1-4 alkoxy, and d. hydroxy(C.sub.1-4)alkyl; R.sup.2 is selected from the group consisting of: ##STR00034## wherein q is an integer from 2 to 10; Z is selected from the group consisting of .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted (C.sub.1-4)alkoxy, .sup.18F substituted benzyloxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy, and a .sup.18F substituted C.sub.6-10 aryl; and R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are in each instance independently selected from the group consisting of hydrogen, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl and hydroxy(C.sub.1-4)alkyl; ##STR00035## wherein Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are as described above, and ##STR00036## wherein Y is selected from the group consisting of .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy, and .sup.18F substituted C.sub.6-10 aryl; U is selected from the group consisting of hydrogen, hydroxy, .sup.18F, .sup.18F substituted benzoyloxy, .sup.18F substituted phenyl(C.sub.1-4)alkyl, .sup.18F substituted aryloxy, and .sup.18F substituted C.sub.6-10 aryl; and R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38, R.sup.39 and R.sup.40 are in each instance independently selected from the group consisting of hydrogen, .sup.18F, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, and hydroxy(C.sub.1-4)alkyl; and R.sup.7 and R.sup.8 are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, and hydroxy(C.sub.1-4)alkyl.

17. The compound of claim 16, wherein R.sup.1 is NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are independently hydrogen or C.sub.1-4 alkyl.

18. The compound of claim 17, wherein R.sup.2 is ##STR00037## where Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 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 R.sup.7 and R.sup.8 are each hydrogen.

21. The compound of claim 20, wherein R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are, in each instance, hydrogen.

22. The compound of claim 21, having the following formula: ##STR00038##

23. The compound of claim 21, having the following formula: ##STR00039##

24. The compound of claim 17, wherein R.sup.2 is ##STR00040## wherein Z, R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are as described above.

25. The compound of claim 24, wherein Z is .sup.18F.

26. The compound of claim 25, wherein R.sup.7 and R.sup.8 are each hydrogen.

27. The compound of claim 26, wherein R.sup.30, R.sup.31, R.sup.32 and R.sup.33 are, in each instance, hydrogen.

28. The compound of claim 17, wherein R.sup.2 is ##STR00041## wherein U is hydroxy.

29. The compound of claim 28, wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38, R.sup.39 and R.sup.40 are, in each instance, hydrogen.

30. The compound of claim 29, having the following structure: ##STR00042##

31. A compound of Formula III: ##STR00043## wherein, n is an integer between 1 and 4; R.sup.7 and R.sup.8 are in each instance independently selected from the group consisting of hydrogen, hydroxy, amino, methylamino, dimethylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, and hydroxy(C.sub.1-4)alkyl; and R.sup.41 is selected from the group consisting of hydroxy and NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are independently hydrogen, C.sub.1-4 alkyl, or R.sup.a and R.sup.b are both oxygen to form a nitro.

32. The compound of claim 31, wherein n is one, and R.sup.41 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.
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