Treatment of chronic headaches

Patent metadata

Field	Value
Publication number	US-12397010-B2
Application number	US-202017431318-A
Country	US
Kind code	B2
Filing date	Feb 14, 2020
Priority date	Feb 15, 2019
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

Disclosed herein are methods and compositions for the treatment and prevention of migraine, migraine-like headaches such as post-traumatic headache, and other related headaches by administering to a subject in need thereof a selective agonist for the human adenosine A3 receptor (A3AR) subtype.

First claim

What is claimed is:

1. A method for the treatment of migraine, trigeminal autonomic cephalalgias, medication overuse headache, or post-traumatic headache, the method comprising: administering a selective agonist for the human adenosine A3 receptor (A3 AR) subtype to a patient in need thereof, wherein the selective agonist for the human adenosine A3 receptor subtype is a compound of Formula (I):

wherein:
X is selected from NHR 1 , CH 3 , and CH═C(R a )(R b ) wherein R a and R b are independently selected from hydrogen, hydroxyl, C 1 -C 6 alkyl, and C 6 -C 14 aryl;
Y is N or CH;
R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, C 3 -C 8 dicycloalkyl C 1 -C 6 alkyl, C 7 -C 12 bicycloalkyl, C 7 -C 12 bicycloalkyl C 1 -C 6 alkyl, C 7 -C 14 tricycloalkyl C 1 -C 6 alkyl, C 6 -C 14 aryl, C 6 -C 14 aryl C 1 -C 6 alkyl, C 6 -C 14 diaryl C 1 -C 6 alkyl, C 6 -C 14 aryl C 1 -C 6 alkoxy, heterocyclyl C 1 -C 6 alkyl, heterocyclyl, 4-[[[4-[[[(2-amino C 1 -C 6 alkyl) amino]-carbonyl]-C 1 -C 6 alkyl]anilino]carbonyl]C 1 -C 6 alkyl]C 6 -C 14 aryl, and C 6 -C 14 aryl C 3 -C 8 cycloalkyl, wherein the aryl or heterocyclyl portion of R 1 is optionally substituted with one or more substituents selected from halo, amino, hydroxyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 14 aryloxy, hydroxy C 1 -C 6 alkyl, hydroxy C 2 -C 6 alkenyl, hydroxy C 2 -C 6 alkynyl, carboxy C 1 -C 6 alkyl, carboxy C 2 -C 6 alkenyl, carboxy C 2 -C 6 alkynyl, aminocarbonyl C 1 -C 6 alkyl, aminocarbonyl C 2 -C 6 alkenyl, aminocarbonyl C 2 -C 6 alkynyl, and any combination thereof; and the alkyl or cycloalkyl portion of R 1 is optionally substituted with one or more substituents selected from halo, amino, alkyl, alkoxy, aryloxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminocarbonylalkoxy, and arylalkoxy, and any combination thereof;
R 2 is selected from C 6 -C 12 aryl, C 3 -C 8 cycloalkyl, heteroaryl, and metallocenyl, wherein the aryl group is substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, arylcarbonyl, and any combination thereof, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halo, trifluoromethyl, amino, alkyl, hydroxyalkyl, aryl, benzo, alkoxy, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, alkylcarbonyl, arylcarbonyl, and any combination thereof;
R 3 and R 4 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C 1 -C 6 alkyl carbonylamino, hydroxy C 1 -C 6 alkyl, and hydrazinyl;
R 5 is selected from C 1 -C 3 alkyl aminocarbonyl, di(C 1 -C 3 alkyl) aminocarbonyl, C 1 -C 3 alkylthio C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, hydrazinyl, amino C 1 -C 3 alkyl, hydroxy C 1 -C 3 alkyl, C 3 -C 6 cycloalkylamino, hydroxylamino, and C 2 -C 3 alkenyl; and
R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heteroaryl, and C 1 -C 6 aminoalkyl;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein when R 1 is methyl, R 3 and R 4 are both hydroxyl, R 6 is hydrogen, and R 5 is methylaminocarbonyl, R 2 is not 2-pyridyl or phenyl.

3. The method of claim 1 , when R 1 is methyl, R 3 and R 4 are both hydroxyl, R 6 is hydrogen, and R 5 is methylaminocarbonyl, R 2 is not 2-pyridyl.

4. The method of claim 1 , wherein R 6 is hydrogen.

5. The method of claim 1 , wherein Y is N.

6. The method of claim 1 , wherein R 5 is selected from C 1 -C 3 alkyl aminocarbonyl or di(C 1 -C 3 alkyl)aminocarbonyl.

7. The method of claim 1 , R 3 and R 4 are both hydroxyl.

8. The method of claim 1 , wherein X is NHR 1 and R 1 is C 1 -C 6 alkyl.

9. The method of claim 1 , wherein R 2 is C 6 -C 10 aryl, wherein the aryl group is substituted with one or more substituents independently selected from halo, trifluoromethyl, hydroxyalkyl, and alkoxy.

10. The method of claim 1 , wherein R 2 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents independently selected from hydroxy, halo and alkyl.

11. The method of claim 1 , wherein the compound is selected from:

salt of any one thereof.

12. The method of claim 1 , wherein the selective agonist for the adenosine A3 human receptor subtype is a compound of Formula (II):

wherein:
X is selected from NHR 101 , CH 3 , and CH═C(R a )(R b ) wherein R a and R b are independently selected from hydrogen, hydroxyl, C 1 -C 6 alkyl, and C 6 -C 14 aryl;
Y is N or CH;
R 101 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, C 3 -C 8 dicycloalkyl C 1 -C 6 alkyl, C 7 -C 12 bicycloalkyl, C 7 -C 12 bicycloalkyl C 1 -C 6 alkyl, C 7 -C 14 tricycloalkyl C 1 -C 6 alkyl, C 6 -C 14 aryl, C 6 -C 14 aryl C 1 -C 6 alkyl, C 6 -C 14 diaryl C 1 -C 6 alkyl, C 6 -C 14 aryl C 1 -C 6 alkoxy, heterocyclyl C 1 -C 6 alkyl, heterocyclyl, 4-[[[4-[[[(2-amino C 1 -C 6 alkyl) amino]-carbonyl]-C 1 -C 6 alkyl]anilino]carbonyl]C 1 -C 6 alkyl]C 6 -C 14 aryl, and C 6 -C 14 aryl C 3 -C 8 cycloalkyl, wherein the aryl or heterocyclyl portion of R 101 is optionally substituted with one or more substituents selected from halo, amino, hydroxyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 14 aryloxy, hydroxy C 1 -C 6 alkyl, hydroxy C 2 -C 6 alkenyl, hydroxy C 2 -C 6 alkynyl, carboxy C 1 -C 6 alkyl, carboxy C 2 -C 6 alkenyl, carboxy C 2 -C 6 alkynyl, aminocarbonyl C 1 -C 6 alkyl, aminocarbonyl C 2 -C 6 alkenyl, aminocarbonyl C 2 -C 6 alkynyl, and any combination thereof; and the alkyl or cycloalkyl portion of R 101 is optionally substituted with one or more substituents selected from halo, amino, alkyl, alkoxy, aryloxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminocarbonylalkoxy, and arylalkoxy, and any combination thereof;
Z is halo, azido, or a group of the formula:

wherein R 102 is selected from C 6 -C 12 aryl, C 6 -C 12 aryl-C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heteroaryl, and metallocenyl, wherein the aryl group is optionally substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, arylca

Assignees

• Univ Saint Louis
• Univ Maryland

Inventors

• Salvemini Daniela
• Akerman Simon
• Romero-Reyes Marcela

Classifications

• A61P25/06

  Antimigraine agents · CPC title

• C07D473/16

  two nitrogen atoms · CPC title

• A61K31/708 Primary

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• A61P29/00 Primary

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title