Curcumin analogs

Patent metadata

Field	Value
Publication number	US-9738623-B2
Application number	US-201314419985-A
Country	US
Kind code	B2
Filing date	Aug 6, 2013
Priority date	Aug 6, 2012
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

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.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
X is -BR 4 R 5 ;
R 1 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 2 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 3 is H or a (C 1 -C 6 )alkyl;
R 4 and R 5 are independently selected from the group consisting of H, halo, and OR 6 ;
R 6 is H or a (C 1 -C 6 )alkyl; and
n and m are each 1.

2. The compound of claim 1 , wherein R 4 and R 5 are halo.

3. The compound of claim 2 , wherein R 4 and R 5 are F.

4. The compound of claim 1 , wherein R 1 and R 2 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:

wherein each 5-membered N-containing heteroaryl is substituted by 1 or 2 substitutents indenpendently selected from C 1-6 alkyl and C 6-10 aryl, or unsubstituted.

7. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
X —BR 4 R 5 ,
R 1 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 2 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 3 is H;
R 4 and R 5 are independently selected from the group consisting of H, halo, and OR 6 ;and
R 6 is H or a (C 1 -C 6 )alkyl.

8. A compound of Formula (III)

or a pharmaceutically acceptable salt thereof, wherein:
X is-BR 4 R 5 ;
R 1 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 2 is an unsubstituted 5-membered N-containing heteroaryl or a 5-membered N-containing heteroaryl substituted by 1 or 2 groups independently selected from C 1-6 alkyl and C 6-10 aryl;
R 3 is H or a (C 1 -C 6 )alkyl;
R 4 and R 5 are independently selected from the group consisting of H, halo, and OR 6 ;
R 6 is H or a (C 1 -C 6 )alkyl;
n and m are each 1; and
wherein R 1 and R 2 are different.

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 R 1 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 R 2 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 R 1 and R 2 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 R 1 and R 2 are each a pyrazolyl ring substituted by methyl and phenyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 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 -BR 4 R 5 ;
R 1 and R 2 are each 5-methyl-1-phenyl-1H-pyrazol-4-yl;
R 3 is H;
R 4 and R 5 are each F; and
n and m are each 1.

17. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

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.

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.

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.

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.

Assignees

• Massachusetts Gen Hospital

Inventors

• Ran Chongzhao
• Zhang Xueli
• Moore Anna

Classifications

• C07F5/022

  without C-boron linkages · CPC title

• C07D471/06

  Peri-condensed systems · CPC title

• C07D277/64

  with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 · CPC title

• C07D233/60

  with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title