Stilbene derivatives and their use for binding and imaging amyloid plaques

• US 20060002853A1
• Filed: 09/06/2005
• Published: 01/05/2006
• Est. Priority Date: 08/27/2001
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Kung, Mei-Ping, Kung, Hank F., Zhuang, Zhi-Ping
• Granted Patent: US 7,297,820 B2
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 211/52 the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 323/25 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 323/34 the thio group being a mercapto group
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 307/56 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/66 Nitrogen atoms
• CPC Class Codes: C07D 311/16 substituted in position 7
• CPC Class Codes: C07D 333/28 Halogen atoms

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.

Claims

1-8. -8. (canceled)

9. A compound of general Formula II:

10. A compound of claim 9, wherein

R¹¹ is hydrogen.

11. A compound of claim 9, wherein

R⁹ and R¹⁰ are hydrogen or C_1-4 alkyl.

12. A compound of claim 9, wherein

Z is O.

13. A compound of claim 9, wherein

R⁹ is hydrogen,

R¹² is C_1-4 alkylthio, halo(C_1-4)alkoxy, hydroxy, C_1-4 alkoxy or NR¹³R¹⁴, wherein

R¹³ and R¹⁴ are hydrogen, fluoro(C_1-4)alkyl or C_1-4 alkyl.

14. A compound of claim 13, wherein

R¹⁰ is hydrogen.

15. A compound of claim 9, wherein

R¹² is methylthio, hydroxy, methoxy, or NR¹³R¹⁴,

wherein R¹³ and R¹⁴ are hydrogen, fluoro(C_1-4)alkyl or methyl.

16. A compound of claim 15, wherein

X′

is ¹²³I.

33. A compound of claim 16, wherein X′

is ¹⁸Fluoromethyl, ¹⁸Fluoroethyl or ¹⁸Fluoropropyl.

36. A pharmaceutical composition comprising a compound of claim 9.

37. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of claim 9;

and

a pharmaceutically acceptable excipient or diluent.

38. A method of imaging amyloid deposits, comprising:

a. introducing into a mammal a detectable quantity of a diagnostic composition of claim 37;

and

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.

39. A method of inhibiting amyloid plaque aggregation in a mammal, comprising administering a composition of claim 36 in an amount effective to inhibit amyloid plaque aggregation.

17. A compound of general Formula III:

18. A compound of claim 17, wherein Z is O.

19. A compound of claim 17, wherein Z is S.

20. A compound of claim 17, wherein Z is

CR¹⁵═

CR¹⁶, wherein

R¹⁵ and R¹⁶, in each instance, is as described above.

21. A compound of claim 17, wherein

R¹⁷ is NR²⁶R²⁷ wherein

R²⁶ and R²⁷ are as described above, and

R¹⁵, R¹⁶, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁸ are hydrogen.

22. A compound of claim 20, wherein n is equal to zero.

23. A compound of claim 17, wherein R²⁶ and R²⁷ are independently hydrogen or C_1-4 alkyl.

24. A compound of claim 23, wherein R²⁶ and R²⁷ are methyl.

25. A compound containing a radioisotope complex and having the Formula:

26. A compound of general Formula IV:

27. A compound of claim 26, wherein

R³⁴ is monoalkylaminophenyl or dialkylaminophenyl.

28. A compound of claim 26, wherein

R³⁴ is monomethylaminophenyl or dimethylaminophenyl,

R²⁹, R³⁰, R³¹, R³², R³³ and R³⁵ are hydrogen, and n is equal to zero.

29. A compound of claim 26, wherein

R³² is monoalkylaminophenyl or dialkylaminophenyl.

30. A compound of claim 29, wherein

R³² is monomethylaminophenyl or dimethylaminophenyl,

R²⁹, R³⁰, R³¹, R³³, R³⁴ and R³⁵ are hydrogen, and

n is equal to zero.

31. A compound containing a radioisotope complex and having the Formula:

32. (canceled)

34. A compound of general Formula V:

35. A compound of claim 34, wherein said protecting group is selected from the group consisting of methoxymethyl, methoxyethoxymethyl, p-methoxybenzyl or benzyl.