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Carboxamide derivatives as muscarinic receptor antagonists

A technology of solvates and diphenylhexanamide, applied in the field of compounds of general formula: can solve problems such as limiting the dose of inhaled drugs

Active Publication Date: 2008-09-17
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After inhalation administration of therapeutic amounts of non-selective muscarinic antagonists currently in clinical use, a commonly reported side effect is xerostomia, which, although reported only of moderate intensity, does limit the given inhaled drug dose

Method used

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  • Carboxamide derivatives as muscarinic receptor antagonists
  • Carboxamide derivatives as muscarinic receptor antagonists
  • Carboxamide derivatives as muscarinic receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0938] 5-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylcapronitrile

[0939]

[0940] A solution of the product of Preparation 11 (3.31 g, 8.07 mmol) in THF (90 mL) was cooled to -20°C. Zirconium chloride (3.76 g, 16.15 mmol) was added and the reaction mixture was stirred at -20°C for 1 hour. Then, methylmagnesium chloride (3M in tetrahydrofuran, 24 mL, 72 mmol) was added dropwise and the mixture was stirred for 2 hours keeping the temperature below -10°C. The reaction was quenched with 1M aqueous sodium hydroxide solution (25 mL), then, via Celite Filter and wash well with ethyl acetate (2 x 50 mL). The filtrate was washed with brine (70 mL), concentrated in vacuo, and the residue was recrystallized from hexane / ethyl acetate to afford the title compound as a pale orange crystalline solid, 59% yield, 2 g.

[0941] 1 HNMR (400MHz, CD3OD) δ: 0.99(s, 3H), 1.04(s, 3H), 1.23-1.27(m, 2H), 1.85-1.93(m, 1H), 2.07-2.16(m, 1H), 2.40 -2.45(m, 2H), 2.58-2.67(m, 2H), 2.72...

Embodiment 2

[0943] 5-Methyl-5-[(3S)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylhexanamide

[0944]

[0945] Potassium hydroxide (5.10 g, 91.98 mmol) was added to a solution of the product of Example 1 (1.95 g, 4.60 mmol) in 3-methyl-3-pentanol (40 ml), and the mixture was heated under reflux for 24 hours . The reaction mixture was then cooled to room temperature, concentrated in vacuo, and the residue partitioned between ethyl acetate (70 mL) and water (40 mL). The aqueous layer was separated, extracted with ethyl acetate (50 mL), and the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue was then recrystallized from hexane / ethyl acetate and dried in vacuo for 18 hours to afford the title compound as a white solid in 82% yield, 1.66 g.

[0946] 1 HNMR (400MHz, CD 3 OD)δ: 0.97(s, 3H), 1.02(s, 3H), 1.19-1.33(m, 2H), 1.82-1.91(m, 1H), 2.02-2.17(m, 1H), 2.37-2.47(m , 2H), 2.48-2.64(m, 2H), 2.65-2.75(m, 1H), 2.81-2.89(m, 1H), 4.75(m, 1H), 6.76...

Embodiment 3

[0948] 5-Methyl-5-[(3R)-3-phenoxypyrrolidin-1-yl]-2,2-diphenylcapronitrile

[0949]

[0950] A solution of the product of Preparation 12 (0.84 g, 2.05 mmol) in THF (15 mL) was cooled to -10°C. Titanium(IV) chloride (0.23 mL, 2.05 mmol) was added and the reaction mixture was stirred at -10°C for 15 minutes. Then, methylmagnesium bromide (3M in diethyl ether, 4.1 mL, 12.3 mmol) was added dropwise and the mixture was stirred below -5°C for 10 minutes and at room temperature for 18 hours. The reaction mixture was quenched slowly with water (4 mL), diluted with ethyl acetate (20 mL), and decanted. The residual solid was extracted with ethyl acetate (3 x 20 mL), and the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 60:40 ethyl acetate:hexanes) to afford the title compound in 54% yield, 0.47 g.

[0951] LRMS APCI m / z 425[M+H] + .

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PUM

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Abstract

The invention relates to compounds of Formula (I) processes and intermediates for their preparation, their use as muscarinic antagonists and pharmaceutical composition containing them.

Description

technical field [0001] The present invention relates to compounds of general formula (I): [0002] [0003] Among them, R 1 , R 2 , R 3 , A, A 1 , and p have the meanings shown below; the present invention also relates to methods and intermediates for the preparation of these derivatives, compositions containing these derivatives, and applications of these derivatives. Background technique [0004] Cholinergic muscarinic receptors are members of the superfamily of G-protein coupled receptors and are further divided into 5 subclasses, M 1 to M 5 . Muscarinic receptor subclasses are widely and differentially expressed in vivo. For all 5 subclasses, genes have been cloned, and where M 1 , M 2 and M 3 Receptors have been extensively characterized pharmacologically in animal and human tissues. m 1 Receptors are expressed in the brain (cerebral cortex and hippocampus), glands, and in ganglia of the sympathetic and parasympathetic nerves. m 2 Receptors are expresse...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12A61K31/397C07D413/12A61K31/40C07D211/46A61K31/4409C07D205/04A61P37/00
CPCC07D205/04C07D211/26C07D205/02C07D207/12C07D207/04C07D211/46C07D413/12A61P11/00A61P11/06A61P11/08A61P25/00A61P29/00A61P31/10A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61K31/397A61K31/40A61K31/4409
Inventor P·A·格洛索普S·J·曼特尔R·S·斯特朗C·A·L·沃森A·伍德
Owner PFIZER INC
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