Alpha-synuclein ligands

• US 10,300,155 B2
• Filed: 12/29/2016
• Issued: 05/28/2019
• Est. Priority Date: 12/31/2015
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Tu, Zhude, Li, Junfeng, Yue, Xuyi, Kotzbauer, Paul
• Primary Examiner(s): Hartley, Michael G.
• Assistant Examiner(s): Samala, Jagadishwar R
• Application Number:
  US15/393,673
• Publication Number:
  US 20170189566A1
• Time in Patent Office: 880 Days
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 51/0459 having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
• CPC Class Codes: A61K 51/0463 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• 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: C07B 59/002 Heterocyclic compounds

Abstract

The present invention generally relates to various compounds that are useful as α-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson'"'"'s disease (PD).

Claims

1. A compound having the structure of Formula (III-A):

5. A pharmaceutical composition comprising a radiolabeled compound of claim 1 and at least one excipient.

6. A pharmaceutical composition comprising a compound of claim 1 wherein the composition comprises from about 0.001 mg to about 10 g of the compound and at least about 10 wt. % of the compound in the pharmaceutical composition is radiolabeled.

7. A method of diagnosing or monitoring a synucleinopathy in a human subject comprising administering a pharmaceutical composition comprising a compound of claim 1 to a human subject;

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

8. The compound of claim 1 wherein A¹³ is nitrogen.

9. The compound of claim 1 wherein A¹¹ is C—

R¹¹;

A¹² is C—

R¹²; and

A¹⁵ is C—

R¹⁵.

10. The compound of claim 8 wherein A¹¹ is C—

R¹¹;

A¹² is C—

R¹²; and

A¹⁵ is C—

R¹⁵.

11. The compound of claim 1 wherein R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰, and R²¹ are independently hydrogen, nitro, halo, hydroxy, carboxyl, C₁ to C₆ alkyl, halo-substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, halo-substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ alkyl-substituted amino, amido, C₁ to C₆ alkyl-substituted amido, C₁ to C₆ alkyl-substituted carboxylate, or C₁ to C₆ haloalkyl-substituted carboxylate.

12. The compound of claim 1 wherein R¹⁴ and R¹⁹ are independently nitro, halo, hydroxy, carboxyl, C₁ to C₆ alkyl, halo-substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, halo-substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ alkyl-substituted amino, amido, C₁ to C₆ alkyl-substituted amido, C₁ to C₆ alkyl-substituted carboxylate, or C₁ to C₆ haloalkyl-substituted carboxylate.

13. The compound of claim 1 wherein R¹⁴ and R¹⁹ are independently nitro, halo, hydroxy, carboxyl, C₁ to C₆ alkyl, halo-substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, or halo-substituted C₁ to C₆ alkoxy.

14. The compound of claim 1 wherein R¹⁹ is halo, C₁ to C₆ alkyl, halo-substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, or halo-substituted C₁ to C₆ alkoxy.

15. The compound of claim 1 wherein R¹⁴ is C₁ to C₆ alkyl or C₁ to C₆ alkoxy.

16. The compound of claim 14 wherein R¹⁴ is C₁ to C₆ alkyl or C₁ to C₆ alkoxy.

17. The compound of claim 1 wherein each of R¹⁶, R¹⁷, R¹⁸, R²⁰, and R²¹ is hydrogen.

18. The compound of claim 1 wherein at least two of A¹¹, A¹², A¹³, A¹⁵ are each nitrogen.

19. The compound of claim 1 wherein the synthetic radioactive isotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18, bromine-76, iodine-123, and iodine-125.

2. A compound selected from the group consisting of:

3. The compound of claim 2 wherein the compound is radiolabeled with a synthetic radioactive isotope.

4. The compound of claim 3 wherein the synthetic radioactive isotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18, bromine-76, iodine-123, and iodine-125.

20. A method of diagnosing or monitoring a synucleinopathy in a human subject comprising administering a pharmaceutical composition comprising a compound of claim 3 to a human subject;

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