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

A pyridine, thiophene technology, used in obesity, treatment of diseases such as diabetes, protein kinase activator, use in inflammation, metabolic syndrome, preparation of thienopyridone, cancer field, can solve problems such as energy expenditure and weight loss

Active Publication Date: 2014-05-28
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

[0303] 2-Chloro-4-hydroxy-3-(2′-methoxybiphenyl-4-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-6- ketone

[0304] Step 1: Intermediate 1 Step 1 (2g, 4.50mmol), 2-methoxyphenylboronic acid (1.37g), cesium carbonate (4.40g) and tetrakis(triphenylphosphine)palladium (468mg) were mixed under argon ) in a mixture of toluene (55 mL) / ethanol (65 mL) / water (32 mL) was heated at 80° C. overnight. Filter the solution through Pad filter and dissolve in ethyl acetate. The organic solution was washed with hydrochloric acid solution (4M), then dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting crude solid (1.57 g) was washed with a mixture of petroleum ether / minimum ethyl acetate.

[0305] 1 H NMR (DMSO-d 6 , 300MHz) δ[ppm] 11.01(bs, 1H), 7.67-7.03(m, 13H), 6.99(s, 1H), 4.08(q, 2H), 3.96(s, 2H), 3.78(s, 3H) , 0.96(t,3H).

[0306] Step 2: A solution of the above compound (1.54 g, 3.27 mmol), N-chlorosuccinimide (0.48 g) in chloroform (20 mL...

Embodiment 2

[0312] 4-Hydroxy-3-(2'-hydroxybiphenyl-4-yl)-5-phenyl-6,7-dihydro-thieno[2,3-b]pyridin-6-one

[0313] Intermediate 1 (0.4 g, 1 mmol), 2-hydroxyphenylboronic acid (277 mg), cesium carbonate (981 mg) and tetrakis(triphenylphosphine)palladium (100 mg) were dissolved in dimethylformamide (10 mL) under argon. ) / toluene (1 mL) / ethanol (6 mL) / water (3 ml) mixture was heated at 80° C. overnight. Filter the solution through Pad, and concentrated under reduced pressure. Add acetonitrile. The precipitated solid (244 mg) was filtered and washed by water, hydrochloric acid solution (4M), acetonitrile and petroleum ether;

[0314] MS: 412.1(M+1);

[0315] 1 H NMR (DMSO-d 6 , 300MHz) δ [ppm] 7.52-7.45 (m, 4H), 7.37-7.23 (m, 6H), 7.17-7.11 (m, 1H), 7.04 (s, 1H), 6.96-6.84 (m, 2H).

Embodiment 3

[0317] 4-Hydroxy-3-(2'-hydroxybiphenyl-4-yl)-5-(pyridin-3-yl)-6,7-dihydro-thieno[2,3-b]pyridin-6-one

[0318] Intermediate 2 (1 g, 2.50 mmol), 2-hydroxyphenylboronic acid (0.69 g), cesium carbonate (2.45 g) and tetrakis(triphenylphosphine)palladium (260 mg) were dissolved in dimethylformamide under argon. A solution in a mixture of (25 mL) / benzene (2.6 mL) / ethanol (15 mL) / water (7.5 mL) was heated at 80° C. for 6 hours. pass the solution through Pad filtered and concentrated under reduced pressure. Add acetonitrile. The precipitated solid (629 mg) was filtered and washed with water, acetone, ethyl acetate and petroleum ether;

[0319] MS: 413(M+1);

[0320] 1H NMR (DMSO-d 6 , 300MHz) δ [ppm] 9.66 (bs, 1H), 8.90 (m, 1H), 8.79-8.77 (m, 1H), 8.56-8.53 (m, 1H), 8.06-8.01 (m, 1H), 7.54- 7.47 (m, 4H), 7.26-7.09 (m, 3H), 7.00-6.83 (m, 2H).

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Abstract

The present invention relates to compounds of formula (I) wherein R1, R2 and B1, B2 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 AMPK-activated protein kinase activators (AMPK). [0002] [0003] Formula (I) [0004] 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 [0005] 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. [0006] The present invention relates to compounds useful in the treatment and / or prevention of diseases such as diabetes, metabolic syndrome, obesity, cancer, inflammation. [0007] 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. [0008] Accordingly, the pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38C07D495/04A61P3/04A61P3/10A61P29/00A61P35/00
CPCC07D495/04C07D333/38A61P29/00A61P3/00A61P3/04A61P31/10A61P35/00A61P3/06A61P43/00A61P9/00A61P9/04A61P3/10
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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