A3 adenosine receptor agonists

Patent metadata

Field	Value
Publication number	US-9963450-B2
Application number	US-201415039778-A
Country	US
Kind code	B2
Filing date	Nov 20, 2014
Priority date	Nov 27, 2013
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

Disclosed are compounds of the formula (I) and (II) which are A 3 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and a method of use of these compounds, wherein X, Y, Z, R 2 -R 6 , and R 103 -R 106 are as defined in the specification. These compounds are selective to the A 3 receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, neuropathic pain.

First claim

The invention claimed is:

1. A compound of the 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,
with the proviso that, 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.

2. The compound or salt of claim 1 , wherein X is NHR 1 , R 1 is C 1 -C 6 alkyl, R 2 is C 6 -C 10 aryl, wherein the aryl group is substituted with one or more substituents selected from halo, trifluoromethyl, hydroxyalkyl, alkoxy, and any combination thereof, or R 2 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.

3. The compound or salt of claim 1 , wherein the compound is selected from:

4. The compound or salt of claim 3 , wherein the compound is selected from:

5. The compound or salt of claim 1 , wherein the compound is:

6. The compound or salt of claim 1 , wherein the compound is selected from:

7. The compound or salt of claim 1 , wherein R 1 is C 6 -C 14 aryl C 3 -C 8 cycloalkyl, wherein the aryl is optionally substituted with C 1 -C 6 alkyl, methyl, F, Cl, and Br.

8. The compound or salt of claim 7 , wherein the compound is selected from:

9. The compound or salt of claim 1 , wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Us Health
• Univ Saint Louis

Inventors

• Jacobson Kenneth A
• Tosh Dilip K
• Salvemini Daniela

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07F15/02

  Iron compounds · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title