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Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors

A technology of precursors and enantiomers, applied in the field of compounds or their pharmaceutically acceptable salts, can solve problems such as limiting the duration of agonist action

Inactive Publication Date: 2007-12-05
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Often at nicotinic receptors, and of particular concern at α7-nicotinic receptors, desensitization limits the duration of action of administered agonists

Method used

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  • Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors
  • Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors
  • Novel pyrazole derivatives and their use as modulators of nicotinic acetylcholine receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1: 1-(5-Cyclopropyl-2-phenyl-2H-pyrazol-3-yl)-3-(4-ethoxyphenyl)urea

[0166]

[0167] A solution of 5-cyclopropyl-2-phenyl-2H-pyrazol-3-ylamine (60mg, 0.30mmol) and 4-ethoxyphenylisocyanate (49mg, 0.30mmol) in dichloromethane (5mL) After stirring at 70 °C for 2 h, the solvent was evaporated. The resulting residue was triturated with dichloromethane / hexane (1:2, 40 mL) overnight. The solid was collected by filtration, washed with dichloromethane / hexane (1:2, 3X), and air dried to give 1-(5-cyclopropyl-2-phenyl-2H-pyrazol-3-yl)- 3-(4-Ethoxyphenyl)urea (82 mg, 75%) as a white solid. MS (APCI+) 363 [M+1]+. 1 H-NMR (300MHz, d 6 -DMSO): δ8.74 (1H, s), 8.27 (1H, s), 7.58-7.46 (4H, m), 7.44-7.35 (1H, m), 7.27 (2H, d, J=9.0), 6.83 (2H, d, J = 9.0), 6.14 (1H, s), 3.96 (2H, q, J = 7.0), 1.94-1.80 (1H, m), 1.29 (3H, t, J = 7.0), 0.93- 0.83 (2H, m), 0.74-0.62 (2H, m).

Embodiment 2

[0168] Example 2: 1-(4-methylphenyl)-3-(2-phenyl-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-yl)urea

[0169]

[0170] 2-Phenyl-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-ylamine (60mg, 0.28mmol) and 4-methylphenylisocyanate (38mg, 0.28mmol ) in dichloromethane (5 mL) was stirred at 60 °C for 2 h, and the solvent was evaporated. The resulting residue was triturated with dichloromethane / hexane (1:2, 40 mL) overnight. The solid was collected by filtration, washed with dichloromethane / hexane (1:2, 3X), and air dried to give 1-(4-methylphenyl)-3-(2-phenyl-2,6-di Hydrogen-4H-thieno[3,4-c]pyrazol-3-yl)urea (32 mg, 32%) as a beige solid. MS (APCI+) 355 [M+1]+. 1 H-NMR (300MHz, d 6 -DMSO): δ8.81 (1H, s), 8.37 (1H, s), 7.58-7.47 (4H, m), 7.47-7.36 (1H, m), 7.28 (2H, d, J=8.1), 7.07 (2H, d, J = 8.1), 3.95 (2H, s), 3.89 (2H, s), 2.23 (3H, s).

[0171] The following compounds were prepared in substantially a similar manner to Example 1 or Example 2 using the appropriate amine and isocyana...

Embodiment 3

[0172] Example 3: 1-(4-Methoxy-phenyl)-3-(2-phenyl-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-yl)-urea

[0173]

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PUM

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Abstract

The present invention discloses compounds of formula I and pharmaceutically acceptable salts thereof, wherein A 1 、A 2 , D and E are as described in the specification, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy, especially for the treatment of conditions associated with reduced nicotinic transmission.

Description

technical field [0001] The present invention relates to compounds or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions comprising them and their use in therapy. In particular, the present invention relates to positive modulators of nicotinic acetylcholine receptors, such positive modulators having the ability to increase the potency of nicotinic receptor agonists. Background technique [0002] Cholinergic receptors often bind to the endogenous neurotransmitter acetylcholine (ACh), thereby triggering the opening of ion channels. ACh receptors in the mammalian central nervous system can be divided into muscarinic (mAChR) and nicotinic (nAChR) subtypes based on the agonist activities of muscarinic and nicotine, respectively. Nicotinic acetylcholine receptors are ligand-gated ion channels containing five subunits. Members of the nAChR subunit gene family have been divided, based on their amino acid sequences, into two group...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/415A61K31/4162A61P25/00A61P25/16A61P25/28A61P25/34C07D231/40C07D491/048
Inventor 格伦·E·厄恩斯特威廉·E·弗里特兹托马斯·R·辛普森
Owner ASTRAZENECA AB
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