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Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators

A technology of thiophene and pyridine, applied in the field of thienopyridone derivatives of formula, can solve problems such as energy expenditure and weight loss

Active Publication Date: 2011-03-30
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Finally, increased energy expenditure will lead to weight loss

Method used

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  • Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators
  • Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators
  • Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0394] 4-Hydroxy-3-phenyl-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one

[0395] Step 1: 3-pyridylacetic acid (0.842 g, 4.85 mmol) in acetonitrile (30 mL) was cooled at 0 °C. HBTU (2.169g) and diisopropylethylamine (2.64g) were added. After stirring for 20 minutes, a solution of 2-amino-3-ethoxycarbonyl-4-phenylthiophene (1 g, 4.04 mmol) in acetonitrile was added dropwise. After stirring at room temperature for 15 hours, the solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The organic solution was washed with sodium bicarbonate solution, water and then dried over sodium sulfate. The organic solvent was removed under reduced pressure and the crude was purified on silica gel (heptane / ethyl acetate 4 / 6). A yellow oil (407 mg) was recovered.

[0396] 1 HNMR (DMSO-d 6 , 300MHz): 11.45(br.s, 1H), 8.64-8.59(m, 2H), 7.87-7.84(m, 1H), 7.44-7.39(m, 1H), 7.31-7.24(m, 5H), 6.60 (s, 1H), 4.03(q, 2H), 3.88(s, 2H), 0.89(t, 3H)

...

Embodiment 2

[0399] Example 2: 4-Hydroxy-5-(2-hydroxyphenyl)-3-phenyl-2-methyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

[0400] Step 1: To a solution of propiophenone (30 mL, 0.226 mol) in ethanol (670 mL) was added ethyl cyanoacetate (24 mL) dropwise. After 20 minutes at 60°C, morpholine (68.9 mL) was added and after 5 minutes sulfur (14.5 g) was added. Heated for 72 hours, then the solvent was removed under reduced pressure. The crude was dissolved in dichloromethane, filtered through a pad of silica gel, and the solvent was removed under reduced pressure. The crude was purified over silica gel (heptane / ethyl acetate 9 / 1) and a yellow solid (18.4 g) was recovered;

[0401] 1 HNMR (CDCl 3 , 300MHz): δ(ppm): 7.34-7.27(m, 3H), 7.12-7.15(m, 2H), 3.91(q, 2H), 2.02(s, 3H), 0.78(t, 3H)

[0402] Step 2: to two Add 2-methoxyphenylacetyl chloride (678mg) dropwise to the aforementioned compound (800mg) in alkanes (5mL) solution in alkanes (5 mL). The solution was heated to reflux for 15 ho...

Embodiment 3

[0408] Example 3: 2-Chloro-4-hydroxy-3-(3-methoxyphenyl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

[0409] Step 1: Ethyl cyanoacetate was added dropwise to a solution of 3'-methoxyacetophenone (13.7 mL, 0.1 mol) in ethanol (335 mL). After 20 minutes at 60°C, morpholine (30.5 mL) was added and after 5 minutes sulfur (6.4 g) was added. Heated for 72 hours, then filtered through a pad of silica gel, and the solvent was removed under reduced pressure. The crude was purified on silica gel (heptane / ethyl acetate 9 / 1). A yellow solid (3.5 g) was recovered;

[0410] 1 HNMR (CDCl 3 , 300MHz): δ(ppm): 7.26-7.20(m, 1H), 6.88-6.80(m, 3H), 6.07(br.s, 1H), 4.04(q, 2H), 3.81(s, 3H), 0.95(t,3H).

[0411] Step 2: To the aforementioned compound (1.5g, 5.40mmol), two Phenylacetyl chloride (858 μL) was added dropwise to a solution of alkanes (9.3 mL) and pyridine (523 μL). The reaction mixture was heated to 105 °C for 1 hour, then the solvent was evaporated. The crude was dissolv...

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Abstract

The present invention relates to compounds of formula (I) wherein R1, R2 and R3 are as defined in claim 1, including pharmaceutical compositions thereof and for their use in the treatment and / or prevention of diseases and disorders modulated by AMP agonists. The invention is also directed to intermediates and to a method of preparation of compounds of formula (I).

Description

field of invention [0001] The present invention relates to thienopyridone derivatives of formula (I), which are activators of AMPK-activated protein kinase (AMPK). [0002] [0003] The present invention also relates to the preparation of these thienopyridones and their use in the treatment of disorders such as diabetes, metabolic syndrome, obesity, cancer, inflammation. Background of the invention [0004] The object of the present invention was to find new compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0005] The present invention relates to compounds useful in the treatment and / or prevention of diseases such as diabetes, metabolic syndrome, obesity, cancer, inflammation. [0006] The invention also provides methods of treating diseases and conditions treatable by activating AMPK comprising administering an effective amount of a compound of the invention. [0007] Accordingly, the present invention rel...

Claims

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Application Information

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IPC IPC(8): A61K31/4365C07D495/04A61P3/00A61P9/00A61P35/00A61P29/00
CPCC07D495/04A61P29/00A61P3/00A61P3/04A61P35/00A61P43/00A61P9/00A61P3/10
Inventor D·克拉沃F·莱皮弗S·哈莱库-波塞克C·查隆
Owner MERCK PATENT GMBH
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