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Alpha-aryl ethanolamines and their use as beta-3 adrenergic receptor agonists

A technology of ethanol and alkyl, applied in anti-inflammatory agents, antiviral agents, non-central analgesics, etc., can solve problems such as unclear mechanism

Inactive Publication Date: 2004-01-21
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, as β 3 Compounds that are agonists have hypoglycemic activity, but the mechanism of this effect is unclear

Method used

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  • Alpha-aryl ethanolamines and their use as beta-3 adrenergic receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] {2-[-4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester

[0144] [2-(4-Carbamoyl-phenoxy)-ethyl]-carbamate benzyl ester (322mg, 1.02mmol) and 1-bromo-2,2-dimethoxypropane (3.8g, 20.4mmol ) were combined in a round bottom flask and heated at about 130°C for about 30 minutes. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (1:1 hexane / ethyl acetate) to obtain the desired oxazole product (167 mg, 47% yield). LRMS([M+H] + ) = 353.1.

Embodiment 2

[0146] 2-[4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethylamine

[0147] The title compound {2-[4-(4-methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester (166 mg, 0.47 mmol) of Example 1 was dissolved in methanol ( 5 ml), 10% Pd / C (50 mg) and 1,4-cyclohexadiene (192 mg, 2.4 mmol) were added to the resulting solution. The mixture was stirred for about 16 hours, then filtered through celite, washing the filter pad with methanol. Concentrate the filtrate to dryness in vacuo, 1 The resulting product (92 mg, 90% yield) as determined to be pure compound by H NMR was used without further purification. LRMS([M+H] + ) = 219.2.

Embodiment 3

[0149] 4-Hydroxythiobenzamide

[0150] In a round bottom flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol) and water (8 ml) were heated at about 80° C. for about 30 minutes with stirring. A further 10 ml of water were then added to the suspension, and the solution was heated for a further approximately 1 hour. The mixture was stirred at room temperature for about 16 hours and extracted with water and 1:1 ether / ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexane to ethyl acetate). The product was isolated as a yellow solid (5.54 g, 87% yield). 1 H NMR (CD 3 OD): δ 6.74 (d, 2H, J = 9.1 Hz), 7.83 (d, 2H, J = 8.7 Hz).

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PUM

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Abstract

The present invention provides β shown in formula (I) 3 Adrenergic receptor agonists, wherein Ar is pyridyl, oxazolyl, thiazolyl or phenyl; R 5 is a 5- or 6-membered heterocycle; X is a bond or oxygen; and Y is a bond, alkylene, OCH 2 、CH 2 O or oxygen; stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs. The present invention also provides intermediates for the preparation of compounds of formula (I), compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs Combination with anti-obesity agents.

Description

field of invention [0001] The present invention relates to the following formula (I) compound, described compound is β 3 Adrenergic receptor agonists, and thus have applications as hypoglycemic and anti-obesity agents. [0002] The present invention also relates to an intermediate for the preparation of compound (I); a combination of a compound of formula (I) and an anti-obesity agent; a pharmaceutical composition comprising said compound and combination; using said compound, combination and pharmaceutical composition to treat breastfeeding β in animals 3 Methods for adrenergic receptor mediated diseases, conditions or disorders. The compounds and combinations of the present invention also have application in increasing the lean meat content of edible animals, ie ungulates such as cattle, pigs etc. and poultry. [0003] The compounds and combinations of the present invention are also useful in the treatment of intestinal motility disorders, depression, prostate disease, dys...

Claims

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Application Information

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IPC IPC(8): A61K31/137A61K31/365A61K31/4164A61K31/421A61K31/426A61K31/4439A61K31/444A61K31/48A61K38/22A61K45/00A61P1/04A61P1/12A61P3/04A61P3/06A61P3/10A61P9/00A61P11/04A61P11/06A61P13/00A61P13/08A61P25/24C07D231/12C07D233/54C07D233/64C07D263/32C07D271/06C07D271/10C07D277/24C07D277/28C07D285/06C07D401/04C07D401/12C07D401/14C07D409/14C07D413/12C07D417/04C07D417/12C07D417/14C07D521/00
CPCC07D231/12C07D277/24C07D417/04C07D271/10C07D409/14C07D413/12C07D271/06C07D401/14C07D401/12C07D285/06C07D263/32C07D417/14C07D249/08C07D233/64C07D417/12C07D233/56A61P1/00A61P1/04A61P1/06A61P1/12A61P11/00A61P11/04A61P11/06A61P13/00A61P13/02A61P13/04A61P13/08A61P25/24A61P29/00A61P3/00A61P31/18A61P3/04A61P3/06A61P9/00A61P9/10A61P3/10
Inventor R·F·戴J·A·拉方丹
Owner PFIZER PRODS ETAT DE CONNECTICUT
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