Partial and full agonists of A1 adenosine receptors
Disclosed are novel compounds that are partial and full A 1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, and myocardial infarction.
1. A compound of the formula:
wherein:
R 1 is hydrogen or lower alkyl;
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or
R and YR 1 when taken together with the nitrogen atom to which they are attached represents optionally substituted heterocyclyl;
R 2 is hydrogen, halo, trifluoromethyl, acyl, or cyano;
R 3 is optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl, or optionally substituted heterocyclyl,
R 4 and R 5 are independently hydrogen or acyl; and
X and Y are independently a covalent bond or optionally substituted alkylene;
with the proviso that when R 1 is methyl and Y is a covalent bond, R 3 cannot be phenyl when X is methylene or ethylene.
2. The compound of claim 1 , wherein R 3 is optionally substituted aryl or optionally substituted heteroaryl.
3. The compound of claim 2 , wherein R, R 2 , R 4 and R 5 are all hydrogen.
4. The compound of claim 3 , wherein R 3 is optionally substituted aryl.
5. The compound of claim 4 , wherein R 1 is optionally substituted cycloalkyl, X is a covalent bond, and R 3 is optionally substituted phenyl.
6. The compound of claim 5 , wherein Y is a covalent bond, R 1 is optionally substituted cyclopentyl and R 3 is phenyl substituted by halogen.
7. The compound of claim 6 , wherein R 1 is 2-hydroxycyclopentyl and R 3 is 2-fluorophenyl, namely (4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-2-{6-[(2-hydroxycyclopentyl)amino]-purin-9-yl}oxolane-3,4-diol.
8. The compound of claim 4 , wherein Y is optionally substituted lower alkylene, R 1 and R 3 are both optionally substituted phenyl, and X is a covalent bond.
9. The compound of claim 8 , wherein Y is —CH 2 CH 2 —, R 1 is phenyl, and R 3 is 2-methylphenyl.
10. The compound of claim 8 , wherein Y is —CH 2 CH 2 —, and R 1 and R 3 are both phenyl.
11. The compound of claim 8 , wherein Y is 3-phenylpropylene, R 1 is phenyl, and R 3 is 2,4-fluorophenyl.
12. The compound of claim 4 , wherein X and Y are both covalent bonds, R 1 is optionally substituted alkyl or optionally substituted phenyl, and R 3 is optionally substituted phenyl.
13. The compound of claim 12 , wherein R 1 is 2-fluorophenyl, and R 3 is phenyl.
14. The compound of claim 12 , wherein R 1 is pent-3-yl, and R 3 is 2-fluorophenyl.
15. The compound of claim 12 , wherein R 1 is 2-ethylhexyl, and R 3 is 2-fluorophenyl.
16. The compound of claim 12 , wherein R 1 is 2-methylbutyl, and R 3 is phenyl.
17. The compound of claim 3 , wherein R 3 is optionally substituted heteroaryl.
18. The compound of claim 17 , wherein X and Y are both covalent bonds, R 1 is optionally substituted cycloalkyl, and R 3 is optionally substituted 1,3-thiazol-2-yl.
19. The compound of claim 18 , wherein R 1 is bicyclo[2.2.1]hept-2-yl and R 3 is 4-methyl-1,3-thiazol-2-yl.
20. The compound of claim 17 , wherein Y is lower alkylene, R 1 is optionally substituted cycloalkyl or optionally substituted phenyl, and R 3 is optionally substituted 1,3-thiazol-2-yl.
21. The compound of claim 20 , wherein Y is ethylene, R 1 is 3-chlorophenyl, and R 3 is 4-methyl-1,3-thiazol-2-yl.
22. The compound of claim 20 , wherein Y is butylen-2-yl, R 1 is phenyl, and R 3 is 4-methyl-1,3-thiazol-2-yl.
23. The compound of claim 20 , wherein Y is methylene, R 1 is cyclopropyl, and R 3 is 2-methyl-1,3-thiazol-2-yl.
24. The compound of claim 17 , wherein Y is methylene, R 1 is cyclopropyl, and R 3 is 1,3-benzoxazol-2-yl.
25. The compound of claim 2 , wherein R 2 , R 4 and R 5 are all hydrogen and R and YR 1 when taken together with the nitrogen atom to which they are attached represents optionally substituted heterocyclyl.
26. The compound of claim 25 , wherein R 3 is optionally substituted phenyl or optionally substituted heteroaryl and X is a covalent bond.
27. The compound of claim 26 , wherein the optionally substituted heterocyclyl is pyrrolidin-1-yl and R 3 is 4-methyl-1,3-thiazol-2-yl.
28. A method of treating a disease state in a mammal that is alleviated by treatment with a partial or full A 1 adenosine receptor agonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I
wherein:
Ingredient
Weight %
Active Ingredient
5
Lactose
95
R is hydrogen or lower alkyl;
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or
R and YR 1 when taken together with the nitrogen atom to which they are attached represents optionally substituted heterocyclyl;
R 2 is hydrogen, halo, trifluoromethyl, acyl, or cyano;
R 3 is optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl, or optionally substituted heterocyclyl,
R 4 and R 5 are independently hydrogen or acyl; and
X and Y are independently a covalent bond or optionally substituted alkylene;
with the proviso that when R 1 is methyl and Y is a covalent bond, R 3 cannot be phenyl when X is methylene or ethylene.
29. The method of claim 28 , wherein the disease state is chosen from atrial fibrillation, supraventricular tachycardia and atrial flutter, congestive heart failure, epilepsy, stroke, diabetes, obesity, ischemia, stable angina, unstable angina, cardiac transplant, and myocardial infarction.
30. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I
wherein:
R is hydrogen or lower alkyl;
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or
R and YR 1 when taken together with the nitrogen atom to which the are attached represents optionally substituted heterocyclyl;
R 2 is hydrogen, halo, trifluoromethyl, acyl, or cyano;
R 3 is optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl; or optionally substituted heterocyclyl,
R 4 and R 5 are independently hydrogen or acyl; and
X and Y are independently a covalent bond or optionally substituted alkylene;
with the proviso that when R 1 is methyl and Y is a covalent bond, R 3 cannot be phenyl when X is methylene or ethylene.