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Treatment of diseases with alpha-7nACh receptor full agonists

An agonist, disease technology, applied in metabolic diseases, skin diseases, sensory diseases, etc., can solve problems such as limitations

Inactive Publication Date: 2006-04-26
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This rapid inactivation severely limits functional assays for measuring channel activity

Method used

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  • Treatment of diseases with alpha-7nACh receptor full agonists
  • Treatment of diseases with alpha-7nACh receptor full agonists
  • Treatment of diseases with alpha-7nACh receptor full agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0785] Embodiment (H): N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-1H-pyrazole-1-carboxamide hydrochloride:

[0786]

[0787] A solution of 4-bromopyrazole (0.52 g, 3.5 mmol) in 30 mL of EtOAc was added to a solution of excess phosgene (10 mL, 20% in toluene) in EtOAc. After the addition was complete, the solution was refluxed for 1 hour, cooled and concentrated in vacuo. EtOAc was added and the mixture was concentrated again. The residue was treated with 20 mL of THF, (R)-(+)-3-aminoquinucidine dihydrochloride (0.71 g, 3.5 mmol) and excess TEA (5.0 mL, 68.1 mmol). After 60 hours 1N NaOH solution was added. Mixture with CHCl 3 Extracted, dried (MgSO 4 ), filtered and concentrated. The residue was subjected to flash chromatography (Biotage 40S, 90:9:1 CHCl 3 / MeOH / NH 4 OH) purification. After preparing Example 1(H), it was recrystallized from MeOH / EtOAc to afford 289 mg (25%) of a white solid. to C 11 h 15 BrN 4 HRMS (FAB) calcd for O+H 299.0508, found 299.051...

Embodiment 2

[0788] Example 2(H) : N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-iodo-1H-pyrazole-1-carboxamide hydrochloride:

[0789]

[0790] Phenyl chloroformate (0.75 mL, 6.0 mmol) was added dropwise to a solution of 4-iodopyrazole (1.05 g, 5.4 mmol) and TEA (0.9 mL, 6.5 mmol) in 15 mL of CH 2 Cl 2 in solution. The reaction was stirred at room temperature. After 60 hours water was added. Mixture with CH 2 Cl 2 Extracted, dried (MgSO 4 ), filtered and concentrated. After addition of hexane the solvent was removed in vacuo. A white solid formed on standing, yielding 1.6 g (95%) of phenyl 4-iodo-1H-pyrazole-1-carboxylate. MS (EI) m / z 315.1 (M + ).

[0791] 4-Iodo-1H-pyrazole-1-carboxylic acid phenyl ester (1.6g, 5.2mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0g, 5.2mmol) Suspended in 10 mL DMF. DIEA (2.7 mL, 15.5 mmol) was added dropwise. After 36 hours the solvent was removed and the residue was taken into 1N NaOH and CHCl 3 middle. CHCl for aqueous layer 3 Ex...

Embodiment 3

[0792] Embodiment 3 (H): N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenyl)-1H-pyrazole-1-carboxamide hydrochloride:

[0793]

[0794] Hydrazine hydrate (0.55 mL, 11.3 mmol) was added to a solution of 2-chlorophenylpropanedial dissolved in 20 mL of EtOH. The mixture was heated to reflux for 3 minutes, then stirred at room temperature overnight. The solvent was removed in vacuo to give 4-(2-chlorophenyl)-1H-pyrazole as a yellow solid. MS (EI) m / z 177.0 (M - ).

[0795] Dissolve 4-nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) in 30 mL CH 2 Cl 2 , cooled to 0°C. TEA (1.7 mL, 12.0 mmol) was added and the reaction was allowed to warm to room temperature. After 30 minutes additional 4-nitrophenyl chloroformate (0.25 g) and TEA were added. Water was added after 1 hour. Mixture with CH 2 Cl 2 Extracted, dried (MgSO 4 ), filtered and concentrated to give a solid. The solid was triturated with hexane, filtered an...

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Abstract

The present invention relates to compositions and methods for treating related diseases or conditions by reducing tumor necrosis factor-alpha levels and / or by stimulating angiogenesis using alpha-7 nicotinic acetylcholine receptor (AChR) full agonists.

Description

technical field [0001] The present invention relates to compositions and compositions for treating related diseases or conditions by reducing tumor necrosis factor-alpha levels or by stimulating angiogenesis using full agonists of the alpha-7 nicotinic acetylcholine receptor (AChR) (relative to nicotine) method. Background technique [0002] Nicotinic acetylcholine receptors (nAChRs) have important roles in central nervous system (CNS) activity and in various tissues throughout the body. They are known to be involved in a variety of functions including, but not limited to, cognitive, learning, emotional, affective, and neuroprotective functions. Several types of nicotinic acetylcholine receptors have been identified, each of which appears to exhibit distinct functions. Certain nicotinic receptors modulate CNS function; some receptors regulate pain, inflammation, cancer, and diabetes through control of tumor necrosis factor alpha (TNF-α); still others regulate angiogenesis;...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/439A61P9/10A61P19/02
CPCA61K31/407A61K31/439A61K31/4745A61P1/06A61P11/06A61P17/02A61P19/02A61P19/08A61P19/10A61P21/00A61P25/28A61P27/16A61P29/00A61P31/04A61P31/18A61P31/20A61P31/22A61P35/00A61P37/00A61P37/06A61P43/00A61P9/04A61P9/10A61P3/10Y02A50/30
Inventor 小文森特·E·格罗皮布鲁斯·N·罗杰斯丹尼尔·G·拉德曼
Owner PHARMACIA & UPJOHN CO
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