A3 adenosine receptor agonists

Patent metadata

Field	Value
Publication number	US-2017002007-A1
Application number	US-201415039778-A
Country	US
Kind code	A1
Filing date	Nov 20, 2014
Priority date	Nov 27, 2013
Publication date	Jan 5, 2017
Grant date	—

Abstract

Disclosed are compounds of the formula (I) and (II) which are A3 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 A3 receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, neuropathic pain.

First claim

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 Nor 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 optionally substituted with one or more substituents selected from halo, 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 6 -C 6 alkyl carbonylamino, hydroxy C 1 -C 6 alkyl, and hydrazinyl;
R 5 is selected from hydrogen, 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 or phenyl.

2 .- 5 . (canceled)

6 . 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 optionally 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.

7 .- 9 . (canceled)

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

11 . The compound or salt of claim 10 , wherein the compound is selected from:

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

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

14 . 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.

15 . The compound or salt of claim 14 , wherein the compound is selected from:

16 . (canceled)

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

18 .- 26 . (canceled)

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

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

29 . A method for selectively activating an A 3 adenosine receptor in a mammal or for treating or preventing neuropathic pain in a mammal in need thereof comprising administering to the mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

30 .- 31 . (canceled)

32 . A compound of the 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 3 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 substi

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

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• C07D473/34 Primary

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

• C07F15/02

  Iron compounds · CPC title