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Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease

a carboxamide and bicyclic technology, applied in the field of nicotinic acetylcholine receptors, can solve the problems of limiting the functional assays that can be used, the receptor is rapidly inactivated, and the target is a difficult target for testing

Inactive Publication Date: 2005-09-29
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The synthesized compounds provide therapeutic benefits for conditions such as Alzheimer's disease, schizophrenia, and other cognitive disorders with improved efficacy and reduced side effects by selectively targeting α7 nicotinic acetylcholine receptors.

Problems solved by technology

The α7 nAChR is one receptor system that has proved to be a difficult target for testing.
Another feature that makes functional assays of α7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated.
This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.

Method used

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  • Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
  • Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
  • Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]pyrrolo[1,2-c]pyrimidine-3-carboxamide hydrochloride

[1071]

[1072] Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid hydrochloride (0.33 g, 1.66 mmol) and TEA (2.0 mL, 14.35 mmol) are dissolved in 15 mL THF. Diphenylphosphinic chloride (0.47 g, 1.99 mmol) is added dropwise. After 1h, (R)-(+)-3-aminoquinuclidine dihydrochloride is added and the reaction is allowed to stir at RT. After 1day, 1N NaOH is added and the mixture is extracted with CHCl3. The combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3 / MeOH / NH4OH) to afford 0.45 g (100%) of product. The hydrochloride salt is prepared and recrystallized from CH3CN / Et2O. HRMS (FAB) calcd for C15H18N4O+H 271.1555, found 271.1559.

example 2

N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]pyrrolo[1,2-c]pyrimidine-3-carboxamide hydrochloride

[1073]

[1074] Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid hydrochloride (0.16 g, 0.82 mmol), HATU (0.47 g, 1.22 mmol) and 2-methyl-2.2.2-Amine (0.21 g, 1.0 mmol) are suspended in 15 mL CH3CN. DEA (1.4 mL, 8.0 mmol) is added dropwise. After 2 days, the solvent is removed and the residue is taken up in 1N NaOH and CHCl3. The aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3 / MeOH / NH4OH), and the hydrochloride salt is prepared and recrystallized from CH3CN / Et2O to provide 0.059 g (23%) of the product. HRMS (FAB) calcd for C16H20N4O+H 285.1715, found 285.1717.

example 3

N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]pyrrolo[1,2-c]pyrimidine-3-carboxamide dihydrochloride

[1075]

[1076] A mixture of exo-3R,5R-[3.2.1]-Amine (0.221 g, 1.11 mmol), pyrrolo[1,2-c]pyrimidine-3-carboxylic acid hydrochloride (0.220 g, 1.11 mmol), THF (18 mL), DIEA (0.77 mL, 4.4 mmol), and DMF (4 mL) is cooled in an ice bath and treated with HATU (0.426 g, 1.12 mmol). The mixture is allowed to warm to RT overnight and is evaporated. The residue is purified by flash column chromatography (1:9:90; conc. NH4OH—MeOH—CHCl3). The dihydrochloride salt is formed and triturated with EtOH / Et2O to yield the desired product (0.360 g, 94%). MS (ESI) for C15H18N4O—(HCl)2 (MH)+m / z=270.

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Abstract

The invention provides compounds of Formula I: These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals to treat conditions or diseases in which α7 is known to be involved.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of U.S. Ser. No. 10 / 366,855, filed on Feb. 14, 2003, which claims the benefit of U.S. provisional application Ser. No. 60 / 357917 filed on 19 Feb. 2002, under 35 USC 119(e)(i), and U.S. provisional application Ser. No. 60 / 423157 filed on 1 Nov. 2002, under 35 USC 119(e)(i), all of which are incorporated herein by reference in their entirety.FIELD OF INVENTION [0002] Nicotinic acetylcholine receptors (nAChRs) play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/439A61K31/519A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/06C07D519/00
CPCC07D519/00A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/06
Inventor ROGERS, BRUCE N.PIOTROWSKI, DAVID W.WALKER, DANIEL PATRICKJACOBSEN, ERIC JONACKER, BRAD A.WISHKA, DONN G.GROPPI, VINCENT E. JR.
Owner PFIZER INC