COMPOUNDS FOR THERAPY AND DIAGNOSIS

• US 20110110850A1
• Filed: 12/05/2008
• Published: 05/12/2011
• Est. Priority Date: 12/07/2007
• Status: Active Grant

• Current Assignee: Prana Biotechnology Ltd.
• Original Assignee: Prana Biotechnology Ltd.
• Inventors: Barnham, Kevin Jeffrey, Kenche, Vijaya
• Granted Patent: US 8,389,506 B2
• Time in Patent Office: Days
• US Class Current: 424/1.11
• CPC Class Codes: A61K 49/0017 Fluorescence in vivo
• CPC Class Codes: A61K 51/0453 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• 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: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 15/0093 without a metal-carbon linkage

Abstract

The present invention relates to a transition metal complex represented by Formula (I) or salts thereof, or to a ligand represented by Formula (H) or salts thereof, wherein X represents a transition metal, preferably Pt, and methods for their use and preparation. In particular, the invention relates to compounds which may possess useful therapeutic activity in treating amyloid diseases, and in particular, Alzheimer'"'"'s disease. The invention also relates to the use of these compounds in methods of therapy, and diagnosis, and the manufacture of medicaments as well as compositions containing these compounds.

Claims

1. A transition metal complex of formula (I) or salts thereof:

2. A transition metal complex according to claim 1 wherein one or two of R₃-R₁₀ are substituted.

7. A transition metal complex according to any one of claims 1 to 6 wherein R₂ is a substituent group selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted oxyacyl, optionally substituted acyl, optionally substituted aminoacyl, optionally substituted oxythioacyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxythioacyloxy, optionally substituted amino, optionally substituted aminothioacyl, optionally substituted carbohydrate, and optionally substituted thioacyl.

8. A transition metal complex according to claim 7 wherein R₂ is an optionally substituted C_1-7 alkyl.

9. A transition metal complex according to claim 7 wherein R₂ is a C_1-4 alkyl group which has been terminally substituted.

10. A transition metal complex according to claim 9 where the substituent is selected from carboxyl (and derivatives such as esters), optionally substituted amino, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted sulfonyl.

11. A transition metal complex according to claim 10 where the optionally substituted amino group is selected from NH₂, C_1-4 monoalkylamino, optionally substituted monoarylalkylamino, C_1-4 dialkylamino, quaternary ammonium salts, optionally substituted benzoyl, optionally substituted sulfonyl, and residues of amino acids and peptides.

12. A transition metal complex according to claim 9 where the substituent is selected from

13. A transition metal complex according to any one of claims 1 to 11 wherein X is Pt, Pd or Ru.

30. A method of diagnosing an amyloid disorder comprising:

(i) administering a detectable quantity of a transition metal complex according to any one of claims 1 to 20 or a salt thereof to a patient, and

(ii) detecting the binding of the transition metal complex to an amyloid deposit in said patient,

wherein the transition metal complex or salt thereof is characterised with at least one label consisting of ¹³¹I, ¹²³I, ⁷⁶Br, ⁷⁵Br, ¹¹³F, ¹⁹F or a fluorescent moiety.

3. A transition metal complex of formula (I′

) or a salt thereof;

4. A transition metal complex according to claim 3 wherein one or two of R₃-R₈ and R₁₁-R₁₄ of compounds of formula (I′

) are substituted.

5. A transition metal complex according to claim 3 wherein one of R₃-R₈ and R₁₁-R₁₄ of compounds of formula (I′

) is substituted.

6. A transition metal complex according to claim 3 wherein R₃-R₈ and R₁₁-R₁₄ in compounds of formula (I′

) represent hydrogen.

14. A platinum complex of formula (I″

) or a salt thereof;

15. A platinum complex according to claim 14 wherein R₂ is a substituent group selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted oxyacyl, optionally substituted acyl, optionally substituted aminoacyl, optionally substituted oxythioacyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxythioacyloxy, optionally substituted amino, optionally substituted aminothioacyl, optionally substituted carbohydrate, and optionally substituted thioacyl.

16. A platinum complex according to claim 15 wherein R₂ is an optionally substituted alkyl.

17. A platinum complex according to claim 15 wherein R₂ is a substituted C_1-7 alkyl.

18. A platinum complex according to claim 16 wherein R₂ is a C_1-4 alkyl group which has been terminally substituted.

19. A platinum complex according to claim 16 where the substituent is selected from carboxyl (and derivatives such as esters), optionally substituted amino, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted sulfonyl.

20. A platinum complex according to claim 19 where the optionally substituted amino group is selected from NH₂, C_1-4 monoalkylamino, optionally substituted monoarylalkylamino, C_1-4 dialkylamino, quaternary ammonium salts, optionally substituted benzoyl, optionally substituted sulfonyl, and residues of amino acids and peptides.

21. A platinum complex according to claim 19 wherein the substituent is selected from

22. A platinum complex according to any one of claims 14 to 20 where n=2.

23. A platinum complex according to any one of claims 14 to 20 where n=4.

24. A platinum complex according to any one of claims 14 to 23 where each R₁ is chloro.

25. A platinum complex according to any one of claims 14 to 23 wherein n=2 or n=4 and each R₁ together with the Pt atom represent

26. A compound of formula (II) or a salt thereof:

27. A method for treating an amyloid disorder including the step of administering to a patient in need thereof a transition metal complex of formula (I) or a pharmaceutically acceptable salt thereof;

28. Use of a transition metal complex of formula (I) or a salt thereof:

29. A method of diagnosing an amyloid disorder comprising:

(i) administering a detectable quantity of a transition metal complex of formula (I) or a salt thereof to a patient;

31. A transition metal complex selected from the following: