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US 12,102,695 B2Granted
Half-curcuminoids as amyloid-beta pet imaging agents
AssigneeThe General Hospital Corporation
InventorsChongzhao Ran, Anna Moore, Jian Yang
Life of this patent
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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.
Claims20
A method of imaging amyloid beta in a subject, comprising:
- i) administering to the subject a compound of Formula (I):
- a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
- X is BR4R5;
- R1 is selected from the group consisting of C3-10 cycloalkyl, C6-10 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 R1A groups;
- each R1A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R2 is selected from the group consisting of C1-6 alkyl, C3-10 cycloalkyl, C6-10 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 R2A groups;
- each R2A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R3 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- R4 and R5 are each independently selected from the group consisting of H, halo, and C1-6 alkoxy;
- each R6 is independently selected from the group consisting of OH, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and —(C1-6 alkoxy)-(C1-6 haloalkoxy);
- each RN1 is independently selected from the group consisting of H and C1-6 alkyl;
- each RN2 is independently selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- and
- m is 1 or 2;
- and
- ii) imaging the cell or tissue with an imaging technique.
13 more elements
A method of diagnosing a disease associated with amyloid beta, comprising:
- i) administering to the subject a compound of Formula (I):
- a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
- X is BR4R5;
- R1 is selected from the group consisting of C3-10 cycloalkyl, C6-10 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 R1A groups;
- each R1A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R2 is selected from the group consisting of C1-6 alkyl, C3-10 cycloalkyl, C6-10 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 R2A groups;
- each R2A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R3 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- R4 and R5 are each independently selected from the group consisting of H, halo, and C1-6 alkoxy;
- each R6 is independently selected from the group consisting of OH, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and —(C1-6 alkoxy)-(C1-6 haloalkoxy);
- each RN1 is independently selected from the group consisting of H and C1-6 alkyl;
- each RN2 is independently selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- and
- m is 1 or 2;
- and
- ii) imaging the cell or tissue with an imaging technique.
13 more elements
A method for treating a disease selected from the group consisting of senile dementia of AD type (SDAT), Parkinson's disease, Lewis body dementia, vascular dementia, mild cognitive impairment (MCI), age-associated memory impairment (AAMI) and problems associated with ageing, post-encephalitic Parkinsonism, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, (MS) and Down syndrome in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
- a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:
- X is BR4R5;
- R1 is selected from the group consisting of C3-10 cycloalkyl, C6-10 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 R1A groups;
- each R1A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R2 is selected from the group consisting of C1-6 alkyl, C3-10 cycloalkyl, C6-10 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 R2A groups;
- each R2A is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, NRN1RN2, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
- R3 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- R4 and R5 are each independently selected from the group consisting of H, halo, and C1-6 alkoxy;
- each R6 is independently selected from the group consisting of OH, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and —(C1-6 alkoxy)-(C1-6 haloalkoxy);
- each RN1 is independently selected from the group consisting of H and C1-6 alkyl;
- each RN2 is independently selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
- and
- m is 1 or 2.
10 more elements
Dependencies are inferred from the claim text.