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Quinuclidinol derivatives as muscarinic receptor antagonists

A compound and alkyl technology, applied in the field of quinol derivatives as muscarinic receptor antagonists, can solve the problems of insufficient treatment, short duration of action, inconvenience to patients and the like

Inactive Publication Date: 2009-12-23
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 muscarinic receptor antagonists is often absorbed into the systemic circulation, leading to reported side effects such as dry mouth
In addition, most muscarinic antagonists have a relatively short duration of action, requiring several daily doses
This multiple daily dosing regimen is not only inconvenient for the patient, but also poses a significant risk of inadequate treatment due to patient non-adherence to the frequently repeated dosing regimen

Method used

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  • Quinuclidinol derivatives as muscarinic receptor antagonists
  • Quinuclidinol derivatives as muscarinic receptor antagonists
  • Quinuclidinol derivatives as muscarinic receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0408] Example 1: (3R)-1-(3-phenoxypropyl)-3-[(2-phenyl-2-(piperidin-1-yl)propionyl)oxy]-1-bromide Nitrobicyclo[2.2.2]octane

[0409]

[0410] a) Methyl 2-phenyl-2-(piperidin-1-yl)propionate

[0411]

[0412]A solution of methyl 2-bromo-2-phenylpropanoate (1 g) in acetonitrile (30 mL) was treated with piperidine (1 mL). The solution was stirred and heated at reflux for 3 hours, then concentrated to dryness. The residue was purified by flash column chromatography on silica gel using diethyl ether / isohexane (3:7) to give the racemic subtitle compound as a colorless oil (0.8 g).

[0413] 1 H NMR (400MHz, CDCl 3 ( 2H, m,), 1.60-1.51 (4H, m,), 1.56 (3H, s), 1.48-1.39 (2H, m).

[0414] b) 2-Phenyl-2-(piperidin-1-yl)propanoic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester

[0415]

[0416] Under a nitrogen atmosphere, while stirring, add (3R)-quinuclidin-3-ol (available from AcrosOrganics 1 A solution of methyl 2-phenyl-2-(piperidin-1-yl)propionate (Example 1a, 0.6 g) i...

Embodiment 2

[0423] Example 2: Bromide (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(2S)-2-phenyl-2-( Piperidin-1-yl)propionyl]oxy}-1-azoniumbicyclo[2.2.2]octane (isomer 1)

[0424]

[0425] a) Methyl 2-phenyl-2-(piperidin-1-yl)propanoate (enantiomers 1 and 2)

[0426]

[0427] Racemic methyl 2-phenyl-2-(piperidin-1-yl)propanoate was synthesized according to the procedure described in Example 1a. Separation of the enantiomeric mixture by chiral HPLC using an isocratic system of 80% isohexane / ethanol and a chiracel OJ-H column afforded the two enantiomers (2S)-2-phenyl-2- Methyl (piperidin-1-yl)propionate (isomer 1) and methyl (2R)-2-phenyl-2-(piperidin-1-yl)propionate (isomer 2).

[0428] Methyl (2S)-2-phenyl-2-(piperidin-1-yl)propionate (isomer 1)

[0429]

[0430] Chiral HPLC 80:20 isohexane:ethanol (isocratic). Chiracel OJ-H 4.6mmx50mm

[0431] The retention time is 1.09min.

[0432] 1 H NMR (400MHz, CDCl 3 )δ7.56-7.49 (2H, m), 7.35-7.20 (3H, m), 3.68 (3H, s), 2.54-2....

Embodiment 3

[0448] Example 3: Bromide (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(2R)-2-phenyl-2-( Piperidin-1-yl)propionyl]oxy}-1-azoniumbicyclo[2.2.2]octane (isomer 2)

[0449]

[0450] a) (2R)-2-Phenyl-2-(piperidin-1-yl)propanoic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester (isomer 2)

[0451]

[0452] The subtitle compound was followed the procedure described in Example 1b using (2R)-2-phenyl-2-(piperidin-1-yl)propanoic acid methyl ester (Example 2a, Isomer 2, 0.47g), ( 3R)-Quinuclidin-3-ol (0.6 g) and sodium hydride (175 mg, 60% dispersion in mineral oil) were prepared. The subtitle compound was isolated as a gum (450mg).

[0453] 1H NMR (400MHz, DMSO) δ7.58-7.50 (2H, m), 7.39-7.21 (3H, m), 4.70-4.60 (1H, m), 3.43-3.28 (1H, m), 3.13-3.01 (1H , m), 2.77-2.29 (7H, m), 1.83-1.76 (1H, m), 1.64-1.19 (14H, m).

[0454] Example 3: Bromide (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(2R)-2-phenyl-2-( Piperidin-1-yl)propionyl]oxy}-1-azoniumbicyclo[2.2.2]octane (isomer 2)

...

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Abstract

The invention provides compounds of formula (I) wherein R is a group of formula (II) or (III) and R, R, R, R, R, a, b, Z, Y and X are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.

Description

technical field [0001] The present invention relates to N-linked heterocyclic-substituted alkyl esters of polycyclic amino alcohols, processes for their preparation, pharmaceutical compositions containing them, processes for the preparation of pharmaceutical compositions, their use in therapy and their preparation Intermediates used. Background technique [0002] Muscarinic receptors are a family of G-protein coupled receptors (GPCRs) with 5 family members M 1 , M 2 , M 3 , M 4 and M 5 . Of the five muscarinic subtypes, three are known (M 1 , M 2 and M 3 ) have physiological effects on human lung tissue. [0003] The parasympathetic nerve is the main route of reflex bronchoconstriction in the human airways, regulating airway tone by releasing acetylcholine to muscarinic receptors. Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), therefore muscarinic receptor antagonists have been develo...

Claims

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Application Information

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IPC IPC(8): A61P11/12A61K31/439C07D205/04C07D409/06C07D453/02C07D295/037
CPCC07D519/00C07D453/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P11/12A61P11/14A61P13/02A61P13/08A61P13/10A61P13/12A61P15/00A61P15/02A61P15/10A61P17/02A61P17/04A61P17/06A61P17/08A61P17/14A61P19/02A61P19/04A61P19/06A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/04A61P25/06A61P25/28A61P27/02A61P27/14A61P29/00A61P3/14A61P31/04A61P31/08A61P31/12A61P31/16A61P31/18A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P7/02A61P7/04A61P7/10A61P9/10A61P9/14A61P3/10C07D295/037A61K31/439
Inventor 罗南·福特安东尼奥·米特伊恩·米利奇普巴里·特奥鲍德
Owner ASTRAZENECA AB