Substituted 2-aminothiazoles for treating neurodegenerative diseases
The invention relates to substituted 2-aminothiazole derivatives useful in treating disorders that are mediated by A 2a receptor function, including neurodegenerative diseases including Parkinson's disease and inflammation. The compounds have general formula I:
1 . A compound of formula I
wherein
R 1 is selected from the group consisting of H, C 1 -C 20 hydrocarbon, heteroaryl, heteroarylalkyl, substituted alkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl and substituted heteroarylalkyl;
R 2 is selected from the group consisting of C 1 -C 20 hydrocarbon, C 3 -C 20 hydrocarbon in which from one to three —CH 2 — are replaced by a heteroatom; heterocyclyl, heterocyclylalkyl, substituted alkyl, substituted aryl, substituted heterocyclyl, substituted
arylalkyl and substituted heterocyclylalkyl;
X is selected from the group consisting of CH 2 , C═O and C═NOH;
R 3 is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl;
R 4 is selected from the group consisting of oxygen-heteroaryl, sulfur-heteroaryl, substituted oxygen-heteroaryl and substituted sulfur-heteroaryl.
2 . A compound according to claim 1 wherein X is C═O.
3 . A compound according to claim 1 wherein R 4 is selected from the group consisting of 5-member oxygen-heteroaryl ring and 5-member sulfur-heteroaryl ring.
4 . A compound according to claim 3 wherein R 4 is furan.
5 . A compound according to claim 1 wherein R 3 is selected from phenyl and substituted phenyl.
6 . A compound according to claim 4 wherein X is C═O and R 3 is phenyl or substituted phenyl, of formula:
wherein R 30 is selected from the group consisting of H, halogen, C 1 -C 3 alkyl C 1 -C 3 alkoxy, NO 2 and CN.
7 . A compound according to claim 1 wherein R 1 is selected from the group consisting of H, C 1 -C 4 alkyl and benzyl.
8 . A compound according to claim 6 wherein R 2 is arylalkyl or heteroarylalkyl, of formula:
wherein R 1a is selected from the group consisting of H and methyl; and Het is aryl or heteroaryl.
9 . A compound according to claim 8 wherein Het is selected from the group consisting of thienyl, phenyl and substituted phenyl.
10 . A compound according to claim 9 wherein Het is thienyl, of formula:
11 . A compound according to claim 9 wherein Het is substituted phenyl, of formula:
wherein R 21 and R 22 are independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NO 2 and CN.
12 . A compound according to claim 4 wherein R 1 is H and R 3 is selected from the group consisting of phenyl and substituted phenyl, of formula:
wherein R 2a is selected from the group consisting of C 3 -C 6 hydrocarbon and C 3 -C 6 hydrocarbon in which one carbon is replaced with —O—.
13 . A compound according to claim 1 wherein R 2 is
wherein R 5 is selected from H, loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
14 . A compound according to claim 13 wherein R 5 is selected from H, phenyl and fluorophenyl.
15 . A compound according to claim 1 wherein X is C═N—OH.
16 . A compound according to claim 1 wherein X is CH 2 .
17 . A compound according to claim 1 , wherein X is CH 2 and one of the following conditions is true:
(a) at least one of R 1 and R 2 is substituted aryl;
(b) at least one of R 1 and R 2 is optionally substituted alkyl of at least 5 carbons;
(c) at least one of R 1 and R 2 is optionally substituted alkenyl of at least 5 carbons; or
(d) at least one of R 1 and R 2 is optionally substituted alkynyl of at least 5 carbons.
18 . A compound according to claim 1 , wherein X is CO and one of the following conditions is true:
(a) at least one of R 1 and R 2 is substituted aryl;
(b) at least one of R 1 and R 2 is optionally substituted alkyl of at least 5 carbons;
(c) at least one of R 1 and R 2 is optionally substituted alkenyl of at least 5 carbons;
(d) at least one of R 1 and R 2 is optionally substituted alkynyl of at least 5 carbons; or
(e) R 4 is optionally substituted sulfur-heteroaryl.
19 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1 .
20 . A composition according to claim 19 further comprising a second active ingredient selected from the group consisting of: (1) an agent useful in the treatment of Parkinson's disease, (2) an agent useful in the treatment of movement disorders, and (3) an agent useful in the treatment of depression.
21 . A composition according to claim 20 wherein said second active ingredient is a dopaminergic receptor agonist.
22 . A method of treating a disorder which is mediated by adenosine receptor function, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
23 . A method according to claim 22 wherein the disorder is a disorder associated with adenosine A 2a receptors.
24 . A method according to claim 22 wherein the disorder is selected from the group consisting of central nervous system and peripheral nervous system diseases; neurodegenerative diseases; cardiovascular diseases; cognitive disorders; CNS injury; renal ischemia; acute and chronic pain; affective disorders; cognitive disorders; central nervous system injury, cerebral ischemia; myocardial ischemia; muscle ischemia; sleep disorders; eye disorders and diabetic neuropathy.
25 . A method according to claim 24 wherein the CNS and PNS disorders are movement disorders.
26 . A method according to claim 25 wherein the movement disorder is selected from the group consisting of (1) diskinetic disorders of the basal ganglia; (2) Huntington's disease, (3) multiple system atrophy, (4) progressive supernuclear palsy, (5) essential tremor, (6) myoclonus, (7) corticobasal degeneration, (8) Wilson's disease, (9) progressive pallidal atrophy, (10) Dopa-responsive dystoma-Parkinsonism, (11) spasticity, (12) Alzheimer's disease and (13) Parkinson's disease.
27 . A method according to claim 26 wherein the movement disorder is Parkinson's disease.
28 . A method according to claim 22 wherein said method is for neuroprotection in a subject at risk of neural ischemia.
29 . A method according to claim 22 wherein said method is for treating of injuries to the central nervous system.
30 . A method according to claim 22 for treating restless leg syndrome.