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Heterocyclic derivative having ampk activating effect

A technology of compounds and heterocyclic groups, applied in the field of heterocyclic derivatives with AMPK activation, can solve the problems of unclear activation of AMPK and no literature information.

Inactive Publication Date: 2017-08-29
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] When conducting a structure search using SciFinder (on-line search database), the following compounds were accidentally discovered, but there is no literature information, and the activation of AMPK is unclear

Method used

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  • Heterocyclic derivative having ampk activating effect
  • Heterocyclic derivative having ampk activating effect
  • Heterocyclic derivative having ampk activating effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0698] [chemical formula 40]

[0699]

[0700] At room temperature, Ruphos (40.5 mg, 0.087 mmol), Pd 2 (dba) 3 (39.7mg, 0.043mmol) and NaOt-Bu (167mg, 1.73mmol) were stirred under microwave irradiation at 120°C for 10 minutes. The reaction solution was purified by silica gel column chromatography, whereby Compound 3 (274 mg, 0.400 mmol, 46%) was obtained as a colorless liquid.

[0701] Compound 3; retention time = 3.30 min, mass (M+H) = 683.35, method = C.

[0702] A THF solution of TBAF (1M solution, 6.00 mL, 6.00 mmol) was added to Compound 3 (274 mg, 0.400 mmol), and stirred at 80° C. for 6 hours. The reaction solution was purified by silica gel column chromatography and solidified with hexane / ethyl acetate to obtain Compound I-1-1 (81.4 mg, 0.186 mmol, 46%) as a white solid.

[0703]

Embodiment 2

[0705] [chemical formula 41]

[0706]

[0707]

[0708] At room temperature, Ruphos (40.5mg, 0.087mmol), Pd 2 (dba) 3 (39.7mg, 0.043mmol) and NaOt-Bu (167mg, 1.73mmol) were stirred under microwave irradiation at 120°C for 10 minutes. The reaction solution was purified by silica gel column chromatography, whereby Compound 5 (274 mg, 0.404 mmol, 47%) was obtained as a yellow liquid.

[0709] Compound 5; retention time = 3.26 min, mass (M+H) = 677.45, method = C.

[0710] Trifluoroacetic acid (1.2 mL, 15.8 mmol) was added to a solution of compound 5 (245 mg, 0.362 mmol) in dichloromethane (1.2 mL), followed by stirring at 0° C. for 1 hour. Under ice-cooling, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain a crude product (196 mg) containing compound 6, which was directly used in the next reaction.

[0711]Add pyridine (0.069mL, 0.857mm...

Embodiment 3

[0715] [chemical formula 42]

[0716]

[0717] To compound 1 (50mg, 0.087mmol), Pd(OAc) 2 (1.947mg, 0.00867mmol), BINAP (5.40mg, 0.00867mmol), K 2 CO 3 (41.9mg, 0.303mmol), and aniline (9.50 mu L, 0.104 mmol) was added toluene (1 mL), and stirred at 150° C. for 30 minutes under microwave irradiation. Water was added to the reaction liquid, followed by extraction with ethyl acetate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel chromatography, whereby Compound 8 (36 mg, 0.057 mmol, 66%) was obtained as a colorless liquid.

[0718]

[0719] Retention time = 3.40 min, mass (M+H) = 633.15, method = C.

[0720] To compound 8 (36mg, 0.057mmol) in dichloromethane (360 mu L) Add TFA (360 mu L), stirred at room temperature for 18 hours. After confirming the disappearance of the raw materials, THF and 2 mol / L sodium hydroxide aqueous solution were added, and the mixture was stirred at room temperature for 3...

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PUM

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Abstract

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In formula (I): L represents NR2R3, SR7, SO2R8, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkenyl; R2 represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or the like; R3 represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or the like; R7 represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or the like; R8 represents a hydrogen atom, a substituted or unsubstituted alkyl (but not an unsubstituted methyl or an unsubstituted ethyl), a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or the like; Y represents a substituted or unsubstituted alkyl (but not an unsubstituted methyl or an unsubstituted ethyl), a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, or the like; Z represents -CR6= or -N=; R1 represents a hydrogen atom or a substituted or unsubstituted alkyl; and R4, R5, and R6 are each independently a hydrogen atom, a halogen, a hydroxyl, a cyano, a nitro, a carboxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or the like.

Description

technical field [0001] The present invention relates to a compound that has an activation effect on adenosine monophosphate-activated protein kinase (AMPK for short) and is effective as a medicine. Background technique [0002] AMPK is a serine-threonine kinase activated by AMP and has 3 subunits α , β , gamma , there are multiple isoforms in each subunit ( α 1, α 2, β 1, β 2, gamma 1, gamma 2, gamma 3). [0003] As an energy sensor in the body, AMPK is involved in various physiological functions such as inhibition of gluconeogenesis and fatty acid synthesis in the liver, sugar uptake in skeletal muscle, and hyperoxidation of fatty acids, and has attracted attention as a target molecule for diabetes therapeutics. Therefore, AMPK activators are expected to be effective in treating diabetes as insulin resistance-improving drugs having insulin-independent blood sugar lowering or lipid-improving effects (Non-Patent Document 1). [0004] Patent Documents 1 to 15 and 26...

Claims

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Application Information

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IPC IPC(8): C07D235/26A61K31/4184A61K31/437A61P43/00C07D471/04C07D519/00A61P3/10
CPCA61K31/4184A61K31/437C07D235/26C07D471/04C07D519/00C07D493/04A61P3/00A61P9/12A61P3/10A61K31/34A61K31/382A61K31/415A61K31/4188A61K31/5375C07D401/12C07D403/14C07D405/14C07D419/14
Inventor 儿岛荣一日向优和田俊博
Owner SHIONOGI & CO LTD
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