3-(4-benzyloxyphenyl)propanoic acid derivative

A technology of propionic acid and methoxy, applied in the direction of organic chemistry, etc., can solve the problems such as no disclosure of GPR40 receptor function regulation, no reported compounds, etc.

Inactive Publication Date: 2007-02-28
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0036] However, for these known therapeutic drugs for diabetes, there is no disclosure at all that they have a GPR40 receptor function modulating effect, and there is no report about a compound having a GPR40 receptor function modulating effect (used as a GPR40 agonist or a GPR40 antagonist)

Method used

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  • 3-(4-benzyloxyphenyl)propanoic acid derivative
  • 3-(4-benzyloxyphenyl)propanoic acid derivative
  • 3-(4-benzyloxyphenyl)propanoic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0772] 3-(4-{[2′-Methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoic acid methyl ester

[0773]

[0774] Methyl 3-(4-hydroxyphenyl)propionate (1.43 g, 7.94 mmol), [2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl- A solution of 3-yl]methanol (2.37 g, 7.94 mmol) and tributylphosphine (2.97 ml, 11.9 mmol) in toluene (120 ml) was stirred under ice-cooling, and 1,1'-( azodicarbonyl) bipiperidine (3.00 g, 11.9 mmol). The mixture was warmed to room temperature and stirred for 24 hours. Hexane (60 mL) was added to the reaction mixture, and the precipitated insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane-20% ethyl acetate / hexane) to obtain the title compound (3.05 g, yield 83%) as a colorless oil.

[0775] 1 H NMR (CDCl 3 )δ: 1.58-1.75 (3H, m), 1.85-1.90 (2H, m), 1.97-2.08 (1H, m), 2.23 (3H, s), 2.60 (2H, t, J=7.8Hz), 2.89 (2H, t, J=...

Embodiment 2

[0777] 3-(4-{[2′-Methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoic acid

[0778]

[0779]To 3-(4-{[2'-methyl-4'-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propionic acid methyl ester (0.599 g, 1.30 mmol) in methanol (6 mL) and tetrahydrofuran (6 mL) was added 2M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain colorless needle crystals of the title compound (0.436 g, yield 75%).

[0780] 1 H NMR (CDCl 3 )δ: 1.58-1.76 (3H, m), 1.85-1.90 (2H, m), 1.97-2.10 (1H, m), 2.23 (3H, s), 2.65 (2H, t, J=7.6Hz), 2.91 (2H, t, J=7.6Hz), 3.60-3.66(1H, m), 3.91-3.99(1H...

Embodiment 3

[0782] Methyl 3-{4-[(4′-hydroxy-2′-methylbiphenyl-3-yl)methoxy]phenyl}propanoate

[0783]

[0784] Methyl 3-(4-{[2'-methyl-4'-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propionate (3.78 g, 8.21 mmol) and p-toluenesulfonic acid monohydrate (0.156 g, 0.821 mmol) in methanol (60 mL) were stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate / hexane) to obtain the title compound (3.04 g, yield 98%) as a colorless viscous oil.

[0785] MS m / z 377 (MH + )

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PUM

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Abstract

The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

Description

technical field [0001] The present invention relates to a novel compound having a function modulating function of GPR40 receptor, which is used as a medicament for preventing or treating diabetes. Background technique [0002] It has been reported in recent years that the ligand of GPR40 as a G protein-coupled receptor (GPCR) is fatty acid, and GPR40 in pancreatic β cells is strongly involved in insulin secretion (Nature, 2003, Vol. 422, No. 173 -176 pages). Thus, GPR40 agonists promote insulin secretion, GPR40 antagonists inhibit insulin secretion, and the agonists and antagonists are used for the prevention or treatment of type II diabetes, obesity, impaired glucose tolerance, insulin resistance, neurodegenerative diseases ( Alzheimer's disease) and the like (WO03 / 068959 and WO02 / 057783). [0003] On the other hand, many compounds have been reported as agents for preventing or treating diabetes. [0004] For example, WO02 / 092590 discloses peroxisome proliferator activat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/12C07C69/734C07C59/68C07C59/72C07D277/24C07D213/30C07C217/20C07C233/11C07D295/18C07C323/12C07C317/18C07D335/02C07C205/35C07D207/26C07C233/18
Inventor 安间常雄北村周治根来伸行
Owner TAKEDA PHARMA CO LTD
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