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Phenethanolamine derivatives as beta2 adrenoreceptor agonists

A halogen and compound technology, applied in drug combinations, active ingredients of heterocyclic compounds, respiratory diseases, etc., can solve problems such as slow onset of effect, hindering rescue treatment and maintenance treatment

Inactive Publication Date: 2009-03-25
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Salmeterol is also slow-acting, which precludes its use as rescue and maintenance therapy

Method used

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  • Phenethanolamine derivatives as beta2 adrenoreceptor agonists
  • Phenethanolamine derivatives as beta2 adrenoreceptor agonists
  • Phenethanolamine derivatives as beta2 adrenoreceptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0510] 8-Hydroxy-5-{(1R)-1-hydroxyl-2-[({1-[2-(2-phenylethoxy)ethyl]piperidin-4-yl}methyl)amino]ethyl Base} quinolin-2(1H)-one

[0511]

[0512] i) [1-[2-(2-phenylethoxy)ethyl]-piperidin-4-yl]-methanol

[0513] A solution of 2-phenylethoxyacetaldehyde (WO 94 / 27601) (0.72 g) and piperidine-4-methanol (0.5 g) in methanol (20 mL) was treated with AcOH (20 mg) and stirred at room temperature for 30 minutes. At the end, sodium cyanoborohydride (103 mg) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added by adding concentrated NH 3 The aqueous solution (1 mL) was basified and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (using 1% concentrated NH 3 aqueous and 5% ethanol in DCM) to afford the subtitle compound. Yield: 0.1 g.

[0514] 1 H NMR (CDCl 3 )δ 7.30-7.18 (m, 5H), 3.67-3.64 (m, 2H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 2.95-2.87 (m, 4H), 2.58-2.55 (m, 2H),...

Embodiment 2

[0523] 8-Hydroxy-5-{(1R)-1-hydroxy-2-[(trans-4-{[2-(2-phenylethoxy)ethyl]amino}cyclohexyl)amino]ethyl} Quinolin-2(1H)-one

[0524]

[0525] i) 8-(Benzyloxy)-5-(bromoacetyl)quinolin-2(1H)-one

[0526]To a solution of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (WO2005 / 123684) (18.05 g) in DCM (200 mL) was added dropwise trifluorotrifluoroethylene over 15 minutes at 0°C Boronide etherate (9.2 mL), the mixture was then warmed to room temperature to form a thick yellow suspension. The mixture was heated at 40 °C and a solution of bromine (3.4 mL) in DCM (100 mL) was added slowly over 40 min. After an additional 15 minutes, the mixture was allowed to come to room temperature and the volatiles were removed on a rotary evaporator. The residue was triturated with excess 10% aqueous sodium carbonate for 1 hour. The gummy solid was collected by filtration and further washed with H 2 O washed, and the solid was dried under vacuum at 40 °C overnight. The solid was purified by furthe...

Embodiment 3

[0549] 8-Hydroxy-5-[(1R)-1-hydroxy-2-({1-[3-(2-phenylethoxy)propyl]piperidin-4-yl}amino)ethyl]quinoline -2(1H)-one

[0550]

[0551] i) 4-[(1R)-2-azido-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one

[0552] Sodium iodide (0.47 g) and sodium azide (0.74 g) were added to the product (8-(benzyloxy)-5-[(1R)-2-bromo-1- Hydroxyethyl] quinolin-2(1H)-one) (1.07g) in anhydrous DMSO (10mL). The reaction mixture was heated at 65 °C for 2 h. The mixture was allowed to cool to room temperature, then washed with EtOAc and H 2 O was diluted and the layers were separated. The aqueous material was further extracted with EtOAc (x4), and the combined organic extracts were then washed with saturated aqueous NaCl. The organic phase was collected and dried (Na 2 SO 4 ) followed by removal of volatiles in vacuo to yield a yellow solid. The solid residue was purified by trituration with 1:1 ether / EtOAc to afford the subtitle compound as a white solid. Yield: 0.71 g.

[0553] MS APCI+33...

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Abstract

The present invention relates to compounds according to formula (I), a process for preparing them, the intermediate compounds of the process and the use of the compounds in the manufacture of a medicament for use in treating diseases such as ARDS, pulmonary emphysema, bronchitis, bronchiectasis, COPD, asthma and rhinitis. The compounds are beta2 adrenoreceptor agonists.

Description

technical field [0001] The present invention relates to phenylethanolamine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. Background technique [0002] Adrenergic receptors are a class of G protein-coupled receptors that are divided into two major subfamilies, alpha and beta. These subfamilies are further divided into subtypes, of which the β subfamily has at least 3 members: β1, β2 and β3. The β2 adrenergic receptor (hereinafter referred to as β2 receptor) is mainly expressed on smooth muscle cells. [0003] Stimulation of beta2 receptors on airway smooth muscle causes relaxation and thus bronchodilation. By this mechanism, beta2 agonists act as functional antagonists of all bronchoconstrictor substances such as the naturally occurring histamine and acetylcholine and the experimental substances methacholine and carba choline. The widespread use of beta2 agonists in the treatment of airway diseases, inc...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/137A61K31/428A61K31/445A61K31/454A61K31/4704A61K31/4709A61P11/00A61P11/06A61P11/08C07C211/36C07D211/26C07D215/26C07D417/12
Inventor 莉莲·阿尔卡拉兹安德鲁·贝利罗纳·考克斯普雷姆吉·梅格哈尼加里·佩劳迪厄迈克尔·斯托克斯
Owner ASTRAZENECA AB
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