1H-pyrazole and 1h-pyrole-azabicyclic compounds for the treatment of disease

a technology of azabicyclic compounds and pyrazole, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of limiting the functional assays that can be used, the receptor is rapidly inactivated, and the test is difficult to prove, etc., to achieve the effect of reducing toxicity, reducing toxicity, and reducing toxicity

Inactive Publication Date: 2006-06-01
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0421] The compounds of the present invention have the exo orientation at the C-2 carbon and S configuration at the C-1 carbon and the R configuration at the C-2 and the C-4 carbons of the 7-azabicyclo[2.2.1]heptane ring. Unexpectedly, the inventive compounds exhibit much higher activity relative to compounds lacking the exo, 1S, 2R, and 4R stereochemistry. For example, the ratio of activities for compounds having the exo, 1S, 2R, and 4R configuration to other stereochemical configurations may be greater than about 100. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. For example, pharmaceutical compositions can include one or more compounds, each having an exo, 1S, 2R, and 4R configuration, or mixtures of compounds having exo, 1S, 2R, and 4R and other configurations. In mixtures of compounds, those species possessing stereochemical configurations other than exo, 1S, 2R, and 4R act as diluents and tend to lower the activity of the pharmaceutical composition. Typically, pharmaceutical compositions including mixtures of compounds possess a larger percentage of species having the exo, 1S, 2R, and 4R configuration relative to other configurations.
[0457] The azabicyclic moiety of Formula I is connected to W by a urea or thiourea linkage. This type of linkage imparts different physical properties to the compounds compared to the corresponding amide or thioamide. The different physical properties offer advantages in ease of formulation, reduced toxicity or a different metabolism profile.

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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  • 1H-pyrazole and 1h-pyrole-azabicyclic compounds for the treatment of disease
  • 1H-pyrazole and 1h-pyrole-azabicyclic compounds for the treatment of disease
  • 1H-pyrazole and 1h-pyrole-azabicyclic compounds for the treatment of disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

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

[0684]

[0685] A solution of 4-bromopyrazole (0.52 g, 3.5 mmol) in 30 mL EtOAc is added to excess phosgene (10 mL, 20% solution in toluene) in EtOAc. After complete addition, the solution is refluxed for 1 h, cooled and concentrated in vacuo. EtOAc is added, and the mixture is concentrated again. The residue is treated with 20 mL THF, (R)-(+)-3-aminoquinuclidine dihydrochloride (0.71 g, 3.5 mmol) and excess TEA (5.0 mL, 68.1 mmol). After 60 h, 1N NaOH solution is added. The mixture is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography (Biotage 40S, 90:9:1 CHCl3 / MeOH / NH4OH). The hydrochloride salt is prepared and recrystallized from MeOH / EtOAc to afford 289 mg (25%) of a white solid. HRMS (FAB) calcd for C11H15BrN4O+H 299.0508, found 299.0516.

example 2

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

[0686]

[0687] Phenyl chloroformate (0.75 mL, 6.0 mmol) is added dropwise to a solution of 4-iodopyrazole (1.05 g, 5.4 mmol) and triethylamine (0.9 mL, 6.5 mmol) in 15 mL CH2Cl2. The reaction is stirred at RT. After 60 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. Hexane is added and the solvent is removed in vacuo. A white solid forms on standing to provide 1.6 g (95%) of phenyl 4-iodo-1H-pyrazole-1-carboxylate. MS (EI) m / z 315.1 (M+).

[0688] Phenyl 4-iodo-1H-pyrazole-1-carboxylate (1.6 g, 5.2 mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0 g, 5.2 mmol) are suspended in 10 mL DMF. DIEA (2.7 mL, 15.5 mmol) is added dropwise. After 36 h, 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 (Biota...

example 3

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

[0689]

[0690] Hydrazine hydrate (0.55 mL, 11.3 mmol) is added to a suspension of 2-chlorophenylmalondialdehyde dissolved in 20 mL EtOH. The mixture is heated under reflux for 3 min, then allowed to stir at RT overnight. The solvent is removed in vacuo to provide 4-(2-chlorophenyl)-1H-pyrazole as a yellow solid. MS (EI) m / z 177.0 (M−).

[0691] 4-Nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) are dissolved in 30 mL CH2Cl2 and cooled to 0° C. TEA (1.7 mL, 12.0 mmol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25 g) and TEA are added. After 1 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7 g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-...

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Abstract

The invention provides compounds of Formula I: wherein Azabicyclo is W is where the variables have the definitions discussed herein. 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 a disease or condition in which α7 is known to be involved.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application Ser. No. 60 / 400,339 filed on Aug. 1, 2002, under 35 USC 119(e)(i), which is incorporated herein by reference in its 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 addictive nature and the low ratio between efficacy and safety. The present invention relates to molecules that have a greater effect upon the α7 nAChRs as compared to other closely related member...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4745A61K31/46C07D453/04C07D487/04A61K31/4375A61K31/55A61K45/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28C07D453/02C07D471/08
CPCC07D453/02C07D471/08A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28
Inventor PIOTROWSKI, DAVID W.JACOBSEN, ERIC JONACKER, BRAD A.WALKER, DANIEL PATRICKWISHKA, DONN G.GROPPI, VINCENT E. JR.
Owner PFIZER INC
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