A1 adenosine receptor agonists and methods of use thereof
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsKenneth A. Jacobson, Dilip K. Tosh, Marc L. Reitman, Oksana Gavrilova
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Abstract
Disclosed are compounds of the formulas (I), (II), and (II): which are A1 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and a method of use of these compounds, wherein Y, R1-R6, R10-R15, and R20-R22 are as defined in the specification. These compounds are selective to the A1 adenosine receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, for inducing and/or maintaining a hypothermic and/or hypometabolic state for treatment of a mammal.
Claims29
A compound of formula (I), (II), or (III):
- wherein:
- in formula (I):
- Y is N or CH,
- R1 is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl, dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl, or dicyclodecylmethyl,
- R2 and R6 are independently selected from hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, C1-C6 alkylthio, C1-C6 alkoxy, and C1-C6 alkylamino;
- R3 and R4 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6 alkyl carbonylamino, hydroxy C1-C6 alkyl, and hydrazinyl;
- and
- R5 is selected from hydrogen, hydroxyl, halo, C1-C3 alkyl aminocarbonyl, hydroxy C1-C3 alkyl aminocarbonyl, di(C1-C3 alkyl) aminocarbonyl, C1-C3 alkylthio C1-C3 alkyl, halo C1-C3 alkyl, hydrazinyl, amino C1-C3 alkyl, hydroxy C1-C3 alkyl, C3-C6 cycloalkylamino, hydroxylamino, and C2-C3 alkenyl;
- in formula (II):
- Y is N or CH,
- R10 is dicyclobutylmethyl, dicyclopentylmethyl, dicyclohexylmethyl, dicycloheptylmethyl, dicyclooctylmethyl, dicyclononylmethyl, dicyclodecylmethyl, or endo-2-norbornyl,
- R11 and R15 are independently selected from hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, C1-C6 alkylthio, C1-C6 alkoxy, and C1-C6 alkylamino;
- R12 and R13 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6 alkyl carbonylamino, hydroxy C1-C6 alkyl, and hydrazinyl;
- and
- R14 is selected from hydrogen, C1-C3 alkoxycarbonyl, C1-C3 alkyl aminocarbonyl, hydroxy C1-C3 alkyl aminocarbonyl, di(C1-C3 alkyl) aminocarbonyl, C3-C8 cycloalkyl aminocarbonyl, C1-C3 alkylthio C1-C3 alkyl, C6-C10 arylthio C1-C3 alkyl, halo C1-C3 alkyl, hydrazinyl, amino C1-C3 alkyl, hydroxy C1-C3 alkyl, C3-C6 cycloalkylamino, hydroxylamino, and C2-C3 alkenyl, wherein the aryl portion is optionally substituted with one or more substituents selected from halo and C1-C3 alkoxy;
- with the proviso that when R11 is chloro and R14 is hydrogen, R10 is not dicyclopentylmethyl;
- and
- in formula (III),
- R20 is amino, C1-C3 alkoxy, C1-C3 alkylamino, hydroxy C1-C3 alkylamino, di(C1-C3 alkyl)amino, or C3-C8 cycloalkylamino, and
- R21 and R22 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6 alkyl carbonylamino, hydroxy C1-C6 alkyl, and hydrazinyl;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.