TRICYCLIC HETEROAROMATIC COMPOUNDS AS ALPHA-SYNUCLEIN LIGANDS

• US 20130315825A1
• Filed: 05/03/2013
• Published: 11/28/2013
• Est. Priority Date: 05/03/2012
• Status: Abandoned Application

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Tu, Zhude, Mach, Robert, Yu, Lihai, Kotzbauer, Paul
• Application Number:
  US13/887,171
• Publication Number:
  US 20130315825A1
• Time in Patent Office: Days
• US Class Current: 424/1.81
• CPC Class Codes: A61K 51/0465 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: C07D 241/46 Phenazines
• CPC Class Codes: C07D 265/38 [b, e]-condensed with two six-membered rings
• CPC Class Codes: C07D 279/20 with hydrogen atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 279/30 with acyl radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Derivatives of phenothiazine, phenoxazine, and phenazine compounds and their use as α-synuclein ligands are described. Also described are methods of using these compounds and their radiolabeled analogs for the detection, monitoring, and treatment of synucleinopathies, including Parkinson'"'"'s disease.

Claims

1. A compound of Formula (I)

4. The compound of claim 1 wherein R is hydrogen, C₁-C₆ alkyl, or C₁-C₆ acyl.

5. The compound of claim 4 wherein R is hydrogen, methyl, or acetyl.

7. The compound of claim 1 wherein one or more of A₁, A₂, A₃, A₄, A₅, A₆, A₇, or A₈ is nitrogen.

8. The compound of claim 7 wherein either A₁ or A₃ is nitrogen and A₂ is C—

R₂, A₄ is C—

R₄, A₅ is C—

R₅, A₆ is C—

R₆, A₇ is C—

R₇, and A_g is C—

R₈.

9. The compound of claim 1, wherein A₁ is C—

R₁, A₂ is C—

R₂, A₃ is C—

R₃, A₄ is C—

R₄, A₅ is C—

R₅, A₆ is C—

R₆, A₇ is C—

R₇, and A₈ is C—

R₈.

10. The compound of claim 1 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each independently hydrogen, fluoro, bromo, iodo, hydroxy, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ alkoxy, cyano, nitro, amino, C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino.

11. The compound of claim 10 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each independently hydrogen, bromo, iodo, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, substituted or unsubstituted C₁-C₄ alkoxy, cyano, nitro, amino, C₁-C₄ alkylamino, or di-C₁-C₄ alkylamino.

13. The compound of claim 11 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are each independently hydrogen, bromo, iodo, hydroxy, methyl, trifluoromethyl, methoxy, propargyloxy (i.e., —

OCH₂C≡

CH), 2-fluoroethoxy (i.e., —

OCH₂CH₂F), 3-iodoallyloxy (i.e., —

OCH₂CH═

CHI), cyano, nitro, amino, methylamino, or dimethylamino.

15. The compound of claim 1 wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is methoxy, nitro, bromo, or iodo.

22. The compound of claim 1 wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is nitro and at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is methoxy.

23. The compound of claim 1 wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is nitro and at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is bromo or iodo.

24. The compound of claim 1, wherein the compound of Formula I is selected from the group consisting of:

25. The compound of claim 1 wherein the compound is radiolabeled with an isotope.

26. The compound of claim 25 wherein the isotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18, bromine-76, iodine-123, and iodine-125.

27. A method for diagnosing or monitoring a synucleinopathy in a human subject comprising:

administering a radiolabeled compound of claim 25 to the human subject; and

imaging the subject'"'"'s brain by positron emission tomography.

28. The method of claim 27 wherein the synucleinopathy is Parkinson'"'"'s disease, Dementia with Lewy Bodies, or multiple system atrophy.

29. A method of treating a synucleinopathy in a human subject in need thereof comprising administering a therapeutically effective amount a compound of claim 1 to the human subject.

30. The method of claim 29 wherein the synucleinopathy comprises Parkinson'"'"'s Disease, Dementia with Lewy Bodies, or multiple system atrophy.

2. (canceled)

3. (canceled)

6. (canceled)

12. (canceled)

14. (canceled)

16-21. -21. (canceled)

31. A method for determining the binding affinity of a compound to α

-synuclein fibrils comprising;

preparing a plurality of test mixtures comprising α

-synuclein fibrils, Thioflavin T (ThT) and a test compound, wherein the test mixtures contain varied concentrations of the test compound;

incubating the test mixtures;

measuring a fluorescence intensity of each test mixture at the maximum fluorescence emission wavelength and excitation wavelength of ThT; and

determining the amount of ThT inhibited from binding to α

-synuclein fibrils for each test mixture.

32. (canceled)