Triazolo [4,5-d] pyrimidine derivatives and their use as purinergic receptor antagonists

A method of treating a disorder in which blocking of adenosine A2A 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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.

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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.

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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.

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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.

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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.

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
• R1 is selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4COR5, NR4CONR5R6, NR4CO2R7 and NR4SO2R7;
• R2 is an aryl attached via an unsaturated ring carbon of said aryl group;
• R3 is selected from the group consisting of H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7;
• R4, R5 and R6 are independently selected from the group consisting of H, alkyl and aryl, or where R5 and R6 are in an NR5R6 group, R5 and R6 may be linked to form a heterocyclic group, or where R4, R5 and R6 are in a (CONR4NR5R6) group, R4 and R5 may be linked to form a heterocyclic group;
• and
• R7 is selected from the group consisting of alkyl and aryl.