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

A purine and receptor technology, applied in the field of adenosine A2A receptors, blocking adenosine receptors, can solve problems such as no side effects

Inactive Publication Date: 2004-05-12
VERNALIS RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, option A 2A Receptor antagonists could provide effective treatment for ADHD, but without the unwanted side effects of current treatments

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0170] Synthetic example

[0171] The invention may be illustrated by the following examples, as shown in Table 1.

[0172] Table 1

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[0211] The general synthetic methods used to prepare these examples are listed below as Methods A-BH. Table 2 lists the methods and analytical data used in each example.

[0212] HPLC was performed using the following conditions: Column: Waters Xterra RP18 (50×4.6 mm); Particle size 5 μM; Mobile phase: MeOH: 10 mM NH 4 OAc in water (pH 7 buffer); Gradient: 50:50 isocratic for 1 min, then 50:50 to...

Embodiment 211

[0420] A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (101 mg, 0.5 mmol) in DMF (2 mL) was treated with 2 - Treat with bromoacetophenone (100 mg, 0.5 mmol) and triethylamine (105 μL, 0.75 mmol), stir at room temperature for 3 days, dilute with water (100 mL) and filter. The resulting solid was purified by chromatography [SiO 2 ; Hexane:EtOAc, (3:1-1:1)], the title compound (20 mg, 13%) was obtained as a yellow solid.

[0421] Method AU

[0422] 7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine Hydrochloride (Example 213)

[0423] 6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridine-2-carbaldehyde ( 62 mg, 0.193 mmol) in MeOH (20 mL) was treated with acetic acid (5 mL), dimethylamine (2-M in MeOH, 1.93 mL, 3.86 mmol) and sodium cyanoborohydride (242 mg, 3.86 mmol), Stir for 16 hours and concentrate in vacuo. The residue was treated with saturated sodium bicarbonate solution (20 mL), ex...

Embodiment 220

[0426] 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5- A solution of amine (200 mg, 0.517 mmol) and sodium cyanide (51 mg, 1.03 mmol) in DMF (5 mL) was stirred at 60 °C for 16 h, poured into water (40 mL), extracted with EtOAc (3 x 8 mL), and The combined organic phases were dried (MgSO 4 ), concentrated in vacuo and purified by chromatography [SiO 2 ; isohexane:EtOAc (1:1)], the title compound (50 mg, 26%) was obtained as a yellow solid.

[0427] Method AW

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PUM

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Abstract

The use of a compound of formula (1): wherein R1 is selected from H, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, halogen, CN, NR5R6, NR4CONR5R6, NR4CONR5R6NR4CO2R7 and NR4SO2R7; R2 is selected from aryl attached via an unsaturated carbon; R3 is selected from H, alkyl, COR5, CO2R7, CONR5R6, CONR4NR5R6 and SO2R7; R4, R5 and R6 are independently selected from 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 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 A2A 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.

Description

technical field [0001] The present invention relates to triazolo[4,5-d]pyrimidine derivatives and their use in therapy. In particular, the invention relates to the treatment of diseases in which reduction of purinergic neurotransmission may be beneficial. In particular the present invention relates to the blocking of adenosine receptors, especially adenosine A 2A receptor, and treatment of movement disorders such as Parkinson's disease. Background technique [0002] Movement disorders are serious health problems, especially among older adults. These movement disorders are often the result of brain injury. Disorders involving the basal ganglia that lead to motor disorders include Parkinson's disease, Huntington's disease, and Wilson's disease. Furthermore, dyskinesias often occur as sequelae of cerebral ischemia and other neurological disorders. [0003] Parkinson's disease has four typical symptoms: tremor, stiffness, akinesia, and postural changes. The disease is also...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K31/198A61K31/505A61K31/519A61K45/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/20A61P25/24A61P25/28A61P43/00C07D487/04C07D519/00
CPCA61K31/00A61K31/519A61K31/505C07D487/04A61P21/04A61P25/00A61P25/02A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/24A61P25/28A61P27/02A61P43/00A61P9/00A61P9/02A61P9/10A61P3/10A61K31/195A61K2300/00
Inventor R·J·吉勒斯皮J·莱尔皮尼雷S·高尔S·J·巴姆福德G·C·斯特拉顿S·莱昂纳迪S·M·维斯
Owner VERNALIS RES
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