Half-curcuminoids as amyloid-beta PET imaging agents

Patent metadata

Field	Value
Publication number	US-11135318-B2
Application number	US-201716314153-A
Country	US
Kind code	B2
Filing date	Jun 29, 2017
Priority date	Jun 29, 2016
Publication date	Oct 5, 2021
Grant date	Oct 5, 2021

Abstract

Provided herein are curcumin analogues that are able to interact with amyloid beta (Aβ) and to attenuate the copper-induced crosslinking of Aβ. Also provided herein are methods of using the compounds as imaging agents of amyloid beta and for the treatment of diseases associated with amyloid beta. Methods of preparing unlabeled and radiolabeled compounds useful for interacting with amyloid beta and pharmaceutical compositions are also provided.

First claim

What is claimed is:

1. A compound of Formula I:

a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
X is BR 4 R 5 ;
R 1 is selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected R 1A groups;
each R 1A is independently selected from the group consisting of halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —OCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 F, NR N1 R N2 , C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 6 groups;
R 2 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 2A groups;
each R 2A is independently selected from the group consisting of halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR N1 R N2 C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 6 groups;
R 3 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
R 4 and R 5 are each independently selected from the group consisting of H, halo, and C 1-6 alkoxy;
each R 6 is independently selected from the group consisting of OH, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —(C 1-6 alkoxy)-(C 1-6 haloalkoxy);
each R N1 is independently selected from the group consisting of H and C 1-6 alkyl;
each R N2 is independently selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and
m is 1 or 2.

2. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 1 is selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected R 1A groups.

3. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein each R 1A is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR N1 R N2 , and C 6-10 aryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, and C 6-10 aryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 6 groups.

4. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, and phenyl, wherein the C 3-6 cycloalkyl and phenyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 2A groups.

5. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 3 is H.

6. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 4 and R 5 are each halo.

7. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein m is 1.

8. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
X is BR 4 R 5 ;
R 1 is selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected R 1A groups;
each R 1A is independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR N1 R N2 , and C 6-10 aryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, and C 6-10 aryl are each optionally substituted by 1, 2, 3, or 4 independently selected R 6 groups;
R 2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, and phenyl, wherein the C 3-6 cycloalkyl and phenyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 2A groups;
R 3 is H;
R 4 and R 5 are each halo; and
m is 1.

9. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
X is BR 4 R 5 ;
R 1 is selected from the group consisting of phenyl and 5-6 membered heteroaryl, each of which may be optionally substituted by 1, 2, 3, or 4 independently selected R 1A group;
R 1A is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR N1 R N2 , and phenyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, and phenyl are each optionally substituted by 1 or 2 independently selected R 6 groups;
R 2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, and phenyl;
R 3 is H;
R 4 and R 5 are each halo; and
m is 1.

10. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
X is BR 4 R 5 ;
R 1 is selected from the group consisting of phenyl, imidazolyl, pyrazolyl, triazolyl, and pyridyl, each of which may be optionally substituted by 1 or 2 independently selected R 1A groups;
each R 1A is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR N1 R N2 , and phenyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, and phenyl are each optionally substituted by 1 or 2 independently selected R 6 groups;
R 2 is selected from the group consisting of methyl, cyclobutyl, and phenyl;
R 3 is H;
R 4 and R 5 are each halo; and
m is 1.

11. The compound of claim 1 , wherein the compound of Formula I, a pharmaceutically acceptable salt thereof, or a tautomer thereof, comprises at least one radioisotope.

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

a pharmaceutically acceptable salt thereof, or a tautomer thereof.

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:

a pharmaceutically acceptable salt thereof, or a tautomer thereof.

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

Assignees

• Massachusetts Gen Hospital

Inventors

• Ran Chongzhao
• Moore Anna
• Yang Jian

Classifications

• C07C49/252

  containing six-membered aromatic rings and other rings · CPC title

• C07C49/248

  having unsaturation outside the aromatic rings · CPC title

• C07F5/02

  Boron compounds · CPC title

• A61K51/04

  Organic compounds · CPC title

• A61K51/0423

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title