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Azabenzimidazole derivative having AMPK-activating activity

A compound, chemical formula technology, applied in the direction of organic chemistry, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of AMPK activation is not documented, azabenzimidazole derivatives are not disclosed, etc.

Inactive Publication Date: 2014-05-07
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In Patent Document 7, the following compound is described as an effective compound for hypertension, true diabetes, etc., but there is no disclosure about azabenzimidazole derivatives such as the compound of the present invention, and there is no description about AMPK activation

Method used

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  • Azabenzimidazole derivative having AMPK-activating activity
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  • Azabenzimidazole derivative having AMPK-activating activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0479] [chemical formula 17]

[0480]

[0481] While stirring a suspension of Compound 1 (20 g, 115 mmol) in absolute ethanol (970 mL), chlorine gas was bubbled into it at 0° C. for 1 hour. Then, stirring the reaction liquid, after bubbling nitrogen gas there over 1 hour at room temperature, it stirred at 0 degreeC for 30 minutes. The reaction suspension was collected by filtration and washed with diisopropyl ether, whereby a solid was obtained. The solvent in the obtained filtrate was distilled off under reduced pressure, and the precipitated solid was collected by filtration and washed with diisopropyl ether to obtain a further solid. The above two filtered solids were combined to obtain Compound 2 (18.1 g, 76%) as a yellow solid.

[0482] Compound 2; 1 H-NMR (DMSO-d 6 ) δ: 8.33 (brs, 2H), 8.59 (s, 1H).

[0483] Iron (48.6g, 870mmol) and ammonium chloride (46.5g, 870mmol) were added to compound 2 (36.2g, 174mmol) in ethanol (775mL), water (310mL) solution, stirred at...

Embodiment 2

[0494] [chemical formula 18]

[0495]

[0496]To a suspension of sodium hydride (18.5mg, 0.46mmol) in N,N-dimethylformamide (2mL) was added compound 9 (66.2mg, 0.46mmol) in N,N-dimethylformamide at 0°C Amide (1 mL) solution was stirred at room temperature for 30 minutes. Then, compound 8 (120 mg, 0.21 mmol) was added to the reaction suspension at 0°C, and stirred at room temperature for 1 hour. Further, compound 9 (66.2mg, 0.46mmol) and sodium hydride (18.5mg, 0.46mmol) were sequentially added to the reaction suspension at 0°C, and stirred at room temperature for 30 minutes. Saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction liquid for extraction, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Compound 10 (91.9 mg, 0.16 mmol, 75%) as a colorless amorphous ...

Embodiment 3

[0501] [chemical formula 19]

[0502]

[0503] Sodium hydride (219 mg, 5.47 mmol) was slowly added to a solution of compound 11 (1 g, 4.97 mmol) in DMF (10 mL), and stirred under ice-cooling for 45 minutes. Methyl 2-bromoacrylate was added dropwise thereto, and the temperature was raised to room temperature, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed twice with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate=1:1 to 1:4) to obtain Compound 12 (1.03 g, 72%) as a yellow solid.

[0504] Compound 12; 1 H-NMR (CDCl 3 ) δ: 1.62 (3H, d, J = 7.60 Hz), 3.75 (3H, s), 4.99 (2H, s), 5.54 (1H, q, J = 7.44 Hz), 5.99 (1H, d, J = 2.53 Hz), 6.04 (1H, dd, J = 7.60, 2.53 Hz), 7.19 (1H, d, J = 7.60 Hz), 7.35-7.40 (5H, m).

[0505] Pd / C (50 mg) was ...

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Abstract

Provided is a compound useful as an AMPK activator. A compound represented by formula (wherein R4 represents a hydrogen atom or a substituted or unsubstituted alkyl group; R1, R2 and R3 independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a substituted or unsubstituted alkyl group, or the like, wherein a case in which R1, R2 and R3 represent a hydrogen atom simultaneously is excluded; X represents a single bond, -S-, -O-, -NR5-, -C(=O)-, or the like; R5 represents a hydrogen atom, or a substituted or unsubstituted alkyl group; and Y represents a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, or the like), or a pharmaceutically acceptable salt thereof.

Description

Technical field [0001] The present invention involves a compound with an adenosine Monophosphate-Activated Protein Kinase (ADENOSINE MONOPHOSPHOSPHOSPHOSPHOSPHOAAOATEEAAAAOAEEATEAAAOAOOAOOAOOAOOAOOAOOAOAOAOAOAOAAAAOOAAAAAsedsedationationationationationationationationationctctationationctctctctctctctctct way way way way way way way way way way way way way who his his),,,, as an effective compound of drugs. Background technique [0002] AMPK is a activated linginine-sulphosine kinase activated through AMP. It has 3 sub-units α, β, γ, and multiple types of the same type in each sub-unit (α1, α2, β1, β2, γ1, γ3)Essence [0003] As an energy sensor in the body, AMPK participates in various physiological functions such as glycogen inhibitory or fatty acid synthesis obstacles, sugar intake in skeletal muscles, and hyperthyroidism in the skeletal muscle.Therefore, AMPK activists are expected to be effective in diabetes treatment (non -patented literature 1) as the effectiveness of insuli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/4545A61K31/496A61K31/5377A61K31/675A61P3/10A61P43/00C07F9/6561
CPCC07D471/04C07D519/00A61P3/00C07F9/6561C07D451/06
Inventor 儿岛荣一殿垣圭介田中伸幸加藤学井埜章岩津理史藤冈正彦日向优大薮巨树
Owner SHIONOGI & CO LTD
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