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Piperidine derivatives for Gpr119 agonist

A derivative, piperidine technology, applied in the field of piperidine derivatives used as GPR119 agonists, can solve the problems of reduced response to treatment, weight gain, hypoglycemia, etc.

Inactive Publication Date: 2015-02-18
CHONG KUN DONG CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some of these therapeutics have problems that include more than one drawback being hypoglycemia, weight gain, gastrointestinal problems and decreased response to treatment over time

Method used

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  • Piperidine derivatives for Gpr119 agonist
  • Piperidine derivatives for Gpr119 agonist
  • Piperidine derivatives for Gpr119 agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0722] 1-(2-fluoro-2-methylpropyl)-4-((4'-(methylsulfonyl)biphenyl-4-yloxy)methyl)piperidine

[0723]

[0724] Step 1. tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate: 4-piperidinemethanol (10.00 g, 86.83 mmol) was dissolved in CH 2 Cl 2 200 mL, and cooled in an ice bath. Di-tert-butyl dicarbonate was added thereto, followed by slowly raising the temperature to room temperature, and stirring for 3 hours. The resulting reaction mixture was sequentially washed with water, saturated NH 4 Cl aqueous solution and saturated saline solution were washed. The washed reaction mixture was washed with MgSO 4 Dry and filter. The solid matter was removed, and then the organic solvent was removed from the filtrate under reduced pressure to give the title compound (18.35 g, 98%) as a white solid.

[0725] Step 2. tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate: tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (18.35g, 85.24mmol ) in CH 2 Cl 2 Dissolve in ...

Embodiment 2

[0735]

[0736] Step 1. tert-butyl 4-((5-bromopyridin-2-yloxy)methyl)piperidine-1-carboxylate: Dissolve N-Boc-4-piperidinemethanol (500 mg, 2.32 mmol) in DMF 10 mL . 2,5-Bromopyridine (600 mg, 2.55 mmol) and 95% NaH (83 mg, 3.48 mmol) were slowly added thereto at 0°C, followed by raising the temperature and stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with EtOAc. The resulting organic layer was washed with saturated NH 4 Cl aqueous solution and saturated saline solution were washed three times. The resulting organic layer was washed with Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography (0-20% EtOAc / Hexane) to give the title compound (67 mg, 78%) as a white solid.

[0737] Step 2. tert-butyl 4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate: 4-((5-bromopyridine -2-ylox...

Embodiment 3

[0744]

[0745] Step 1. tert-butyl 4-((6-chloropyridin-3-yloxy)methyl)piperidine-1-carboxylate:

[0746] N-Boc-4-piperidinemethanol (0.50g, 2.32mmol) was dissolved in CH 2 Cl 2 5mL, and then slowly dropwise added Et at 0°C 3 N (0.48 mL, 3.48 mmol) and MsCl (0.32 g, 2.79 mmol). The mixture was stirred for 30 minutes, then the temperature was raised and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was washed three times with excess water. The resulting organic layer was washed with Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure to give the title compound (0.68 g, 100%) as a white solid. The product was dissolved in DMF 10 mL. Slowly add K to it 2 CO 3 (1.13g, 3.48mmol) and 2-chloro-5-hydroxypyridine (0.3g, 2.32mmol). The temperature was raised, and then the mixture was stirred with heating at 100°C for 3 hours. After the reaction was completed, the reaction mixture was washed three...

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PUM

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Abstract

The present invention relates to novel piperidine derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof; methods for preparing the compound; and pharmaceutical compositions comprising the compound. The novel piperidine derivatives, according to the present invention, having an effect as GPR119 agonist can be used for treatment of metabolic disorders, including diabetes mellitus (especially type II) and related disorders.

Description

technical field [0001] The present invention relates to novel compounds useful in the treatment of metabolic disorders, including diabetes (Type I and II) and related disorders, pharmaceutical compositions comprising said compounds and therapeutic uses of said compounds. Background technique [0002] Diabetes is a serious condition affecting an increasing number of people around the world. It is mentioned in the forecast of the International Diabetes Federation (International Diabetes Federation), that by 2025, the total number of people suffering from diabetes in the world will be 380,000,000 (380 million). In many countries, the incidence of diabetes increases along with the increasing trend of obesity. The serious effects of diabetes include an increased risk of stroke, heart attack, kidney failure, blindness and amputation. Cardiovascular disorders account for more than 70% of all major causes of death in people with type 2 diabetes mellitus (T2DM) [B. Pourcet et al. E...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/14A61K31/444A61P3/10
CPCC07D401/14C07D401/12C07D211/60C07D211/22C07D211/42A61K31/454A61K31/4545C07D409/12C07D487/04A61K31/4985C07D211/62C07D405/12A61P43/00A61P3/10A61K2300/00A61K31/445A61K31/452A61K31/4523A61K31/497A61K31/506
Inventor 李昌埴张泽水催大奎高武成金度勋金昭映闵在基金佑湜林泳兑
Owner CHONG KUN DONG CORP
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