Curcumin analogs

• US 9,738,623 B2
• Filed: 08/06/2013
• Issued: 08/22/2017
• Est. Priority Date: 08/06/2012
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Ran, Chongzhao, Zhang, Xueli, Moore, Anna
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US14/419,985
• Publication Number:
  US 20150158841A1
• Time in Patent Office: 1,477 Days
• Field of Search: 546275, 5483137, 564443
• 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: C07C 225/16 and containing six-membered aromatic rings
• CPC Class Codes: C07C 225/22 having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 49/248 having unsaturation outside the aromatic rings
• CPC Class Codes: C07C 49/252 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/60 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
• CPC Class Codes: C07D 277/64 with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/06 Peri-condensed systems
• CPC Class Codes: C07F 5/022 without C-boron linkages

Abstract

Provided herein are curcumin analogues that are able to interact with amyloid β (Aβ) and to attenuate the copper-induced crosslinking of Aβ. Also provided herein are methods of using the compounds in the treatment of Alzheimer'"'"'s Disease or a related disorder.

Claims

1. A compound of Formula (I)

2. The compound of claim 1, wherein R⁴ and R⁵ are halo.

3. The compound of claim 2, wherein R⁴ and R⁵ are F.

4. The compound of claim 1, wherein R¹ and R² are the same.

5. The compound of claim 1, wherein the 5-membered N-containing heteroaryl is an imidazolyl.

6. The compound of claim 5, wherein the 5-membered N-containing heteroaryl is selected from the group consisting of:

9. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A method for treating Alzheimer'"'"'s Disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyrazolyl ring substituted by 1 or 2 groups independently selected from C_1-6 alkyl and C_6-10 aryl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is a pyrazolyl ring substituted by 1 or 2 groups independently selected from C_1-6 alkyl and C_6-10 aryl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are each a pyrazolyl ring substituted by 1 or 2 groups independently selected from C_1-6 alkyl and C_6-10 aryl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are each a pyrazolyl ring substituted by methyl and phenyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are each 5-methyl-1-phenyl-1H-pyrazol-4-yl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

X is -BR⁴R⁵;

R¹ and R² are each 5-methyl-1-phenyl-1H-pyrazol-4-yl;

R³ is H;

R⁴ and R⁵ are each F; and

n and m are each 1.

18. A method of inhibiting the crosslinking of amyloid beta in a cell, comprising contacting cell with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

19. A method of inhibiting the crosslinking of amyloid beta in a cell, comprising contacting the cell with a compound of claim 16, or a pharmaceutically acceptable salt thereof.

21. A method for treating Alzheimer'"'"'s Disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 16, or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (II):

8. A compound of Formula (III)

17. A compound selected from the group consisting of:

20. A method of inhibiting the crosslinking of amyloid beta in a cell, comprising contacting the cell with a compound of claim 17, or a pharmaceutically acceptable salt thereof.

22. A method for treating Alzheimer'"'"'s Disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof.