Triazolo [4,5-d] pyrimidine derivatives and their use as purinergic receptor antagonists
The use of a compound of formula (I): wherein R 1 is selected from H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ; R 2 is selected from aryl attached via an unsaturated carbon; R 3 is selected from H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ; R 4 , R 5 and R 6 are independently selected from H, alkyl and aryl or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and R 7 is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A receptors, may be beneficial, particularly wherein said disorder is a movement disorder such as Parkinson's disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se.
1. A method of treating a disorder selected from a group consisting of:
acute pain; chronic pain; cerebral ischaemia; myocardial ischaemia; muscle ischaemia; retinal ischaemia-reperfusion injury; diabetic neuropathy; and depression;
the method comprising administering to a subject in need of such treatment an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
2. The method according to claim 1 wherein the subject has cerebral ischaemia.
3. The method according to claim 1 wherein the subject has myocardial ischaemia.
4. The method according to claim 1 the subject has muscle ischaemia.
5. The method according to claim 1 wherein the subject has retinal ischaemia-reperfusion injury or diabetic neuropathy.
6. The method according to claim 1 wherein the subject has acute pain.
7. The method according to claim 1 wherein the subject has chronic pain.
8. The method according to claim 1 wherein the subject has depression.
9. The method according to claim 1 wherein the subject has a disorder selected from the group consisting of depression, acute pain and chronic pain.
10. The method according to claim 1 wherein the subject is human.
11. The method of claim 1 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
12. The method of claim 2 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
13. The method of claim 3 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
14. The method of claim 7 , wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
15. The method of claim 8 , wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
16. The method of claim 9 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
17. The method of claim 6 , wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
18. A method of treating a disorder in which blocking of adenosine A 2A receptors is beneficial, wherein the disorders are selected from a group consisting of: acute pain; chronic pain; cerebral ischaemia; myocardial ischaemia; muscle ischaemia; retinal ischaemia-reperfusion injury; diabetic neuropathy; and depression
the method comprising administering to a subject in need of such treatment an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
19. The method according to claim 18 wherein the subject has a disorder caused by hyperfunctioning of the receptors.
20. A method of treating a patient suffering from Parkinson's disease comprising administering to the patient an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
21. A method of treating a patient suffering from drug-induced Parkinsonism, or Parkinsonism induced by poisoning comprising administering to the patient an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
22. A method of treating a patient suffering from post-encephalitic Parkinsonism or post-traumatic Parkinson's disease comprising administering to the patient an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
23. A method of treating a patient suffering from Dopa-responsive dystonia-Parkinsonism comprising administering to the patient an effective dose of a pharmaceutical composition comprising a compound of formula (B or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
24. The method of claim 20 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.
25. A method of treating a patient suffering from Huntington's disease comprising administering to a subject in need of such treatment an effective dose of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier:
wherein
R 1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ;
R 2 is an aryl attached via an unsaturated ring carbon of said aryl group;
R 3 is selected from the group consisting of H, alkyl, COR 5 , CO 2 R 7 , CONR 5 R 6 , CONR 4 NR 5 R 6 and SO 2 R 7 ;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl and aryl, or where R 5 and R 6 are in an NR 5 R 6 group, R 5 and R 6 may be linked to form a heterocyclic group, or where R 4 , R 5 and R 6 are in a (CONR 4 NR 5 R 6 ) group, R 4 and R 5 may be linked to form a heterocyclic group; and
R 7 is selected from the group consisting of alkyl and aryl.
26. The method of claim 25 wherein the compound of formula (I) is 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine, or a pharmaceutically acceptable salt thereof.