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New alkyl esters of cyclic amino alcohols with muscarinic m3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder

A compound and substituent technology, applied in the field of substituted alkyl ester compounds, can solve the problems of insufficient treatment, short duration, and inconvenience to patients

Inactive Publication Date: 2009-07-22
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when administered by inhalation, a significant proportion of the muscarinic receptor antagonist is usually absorbed into the systemic circulation, with reported side effects such as dry mouth
In addition, the duration of action of most muscarinic receptor antagonists is relatively short, requiring multiple daily doses of the antagonist
This multiple daily dosing regimen is not only inconvenient for the patient, but also poses a significant risk of inadequate treatment due to the patient's failure to adhere to the frequently repeated dosing schedule

Method used

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  • New alkyl esters of cyclic amino alcohols with muscarinic m3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder
  • New alkyl esters of cyclic amino alcohols with muscarinic m3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder
  • New alkyl esters of cyclic amino alcohols with muscarinic m3 receptor antagonist activity, useful for treating e.g. chronic bronchial obstruction, asthma and overactive bladder

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] 4-{[(2S)-2-cyclopentyl-2-phenylpropionyl]oxy}-1,1-dimethylpiperidinium iodide

[0267]

[0268] a) Cyclopentyl (phenyl) methyl acetate

[0269]

[0270] A methanol (200 mL) solution of α-phenylcyclopentaneacetic acid (10 g) was treated with trimethylchlorosilane (20 mL), and the resulting mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with 25% diethyl ether in isohexane) to obtain the subtitle compound (10.5 g) as an oil.

[0271] 1 HNMR(400MHz, CDCl 3 )δ 7.35-7.22 (m, 5H), 3.64 (s, 3H), 3.28 (d, 1H), 2.60-2.50 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.40 (m, 5H) ), 1.30 to 1.20 (m, 1H), 1.03 to 0.97 (m, 1H).

[0272] b) Methyl 2-cyclopentyl-2-phenylpropionate

[0273]

[0274] A lithium diisopropylamide in heptane / tetrahydrofuran / ethylbenzene solution (1.8 molar concentration, 40.1 mL) was added to anhydrous tetrahydrofuran (60 mL), and the result...

Embodiment 2

[0298] 4-{[(2R)-2-cyclopentyl-2-phenylpropionyl]oxy}-1,1-dimethylpiperidinium iodide

[0299]

[0300] a) (4R)-4-benzyl-3-[(2R)-2-cyclopentyl-2-phenylpropionyl]-1,3-oxazolidin-2-one

[0301]

[0302] A toluene (100 mL) solution of 2-cyclopentyl-2-phenyl-propionic acid (the compound prepared in Example 1c, 4.93 g) was treated with thionyl chloride (30 mL), and the resulting mixture was heated at 100°C 2 hours. The solvent was removed under reduced pressure, and the resulting residue was azeotroped with toluene 3 times. The residue was dissolved in anhydrous tetrahydrofuran (20mL), and the resulting mixture was added to -78°C (R)-4-benzyl-2-oxazolone (4.00g) in anhydrous tetrahydrofuran (100mL) in one portion Solution (this solution has been pretreated with a hexane solution of n-butyllithium (1.6 molar concentration, 14.1 mL) at -78°C). The resulting reaction mixture was stirred at -78°C for 30 minutes and then at room temperature for 1 hour. At the end, the mixture was partiti...

Embodiment 3

[0319] 4-[(2-Cyclopropyl-2-phenylpropionyl)oxy]-1,1-dimethylpiperidinium iodide

[0320]

[0321] a) 2-Cyclopropyl-2-phenylpropionic acid (1-methyl-piperidin-4-yl) ester

[0322]

[0323] Treat 2-cyclopropyl-2-phenyl-propionic acid with oxalyl chloride (0.5mL) and N,N-dimethylformamide (20mg) (according to Journal of Organic Chemistry (1989), 54(21), p. Prepared by the method described on pages 5054-63, 110 mg) in dichloromethane (10 mL), and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue azeotroped with dichloromethane (x3). The resulting residue was dissolved in dichloromethane (2 mL), and then added to a solution of 4-hydroxy-N-methylpiperidine (150 mg) in dichloromethane (2 mL). The resulting reaction mixture was heated at 40°C for 18 hours. The resulting mixture was then partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the organic layer was dried over anhydr...

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Abstract

The invention provides compounds of formula (I), wherein R, R, R, R, R and X are as defined in the specification. The invention also provides a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions and their use as shown in the formula (I).

Description

Technical field [0001] The present invention relates to substituted alkyl ester compounds of cyclic amino alcohols, preparation methods of the compounds, pharmaceutical compositions containing the compounds, preparation methods of the pharmaceutical compositions, and their therapeutic uses. Background technique [0002] The muscarinic receptor (muscarinic receptor) is a family of G protein-coupled receptors (GPCR), which has 5 family members, namely M 1 , M 2 , M 3 , M 4 And M 5 . Among the 5 muscarinic receptor subtypes, 3 are known (M 1 , M 2 And M 3 ) Has a physiological effect on human lung tissue. [0003] The parasympathetic nerve is the main nerve conduction used to reflect the contraction of the human airway bronchi, and regulates the airwaytone of the airway by releasing acetylcholine into the muscarinic receptors. In patients suffering from respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), the tone of the respiratory tract is increas...

Claims

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Application Information

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IPC IPC(8): C07D211/46A61K31/4409A61K31/4535A61K31/4545A61P11/00A61P13/10C07D401/12C07D409/12
Inventor 安德鲁·贝利安东尼奥·米特加里·佩劳迪厄迈克尔·斯托克斯马克·温洛克
Owner ASTRAZENECA AB
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