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Compound having GPR119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component

A compound and pharmaceutical technology, applied in the fields of compounds with GPR119 agonist activity, preparation thereof and pharmaceutical compositions containing the same as effective components, can solve the problems of loss of curative effect, lack of effect and the like

Active Publication Date: 2017-08-18
DONG A ST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the current lead materials, clinical development of JNJ-38431055 and GSK1292263 has been discontinued due to loss or lack of efficacy with repeated administration, while MBX-2982 is still in Phase II development

Method used

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  • Compound having GPR119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component
  • Compound having GPR119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component
  • Compound having GPR119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0207] (R)-5-(4-(3(3,5-difluoro-4-(4-methyl-4,5-dihydro Azol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4- Preparation of oxadiazole

[0208] (Step 1-1) Preparation of 4-(3-hydroxypropyl)piperidine-1-carbonitrile (chemical formula 3)

[0209]

[0210] 3-(piperidin-4-yl)propan-1-ol hydrochloride (10g, 69.8mmol) of chemical formula 2 was dissolved in a mixed solution of dichloromethane (MC, 75.0ml) and water (55.0ml); Sodium bicarbonate (NaHCO 3 , 16.36g, 195.0mmol) was added thereto; then cyanogen bromide (6.48g, 61.2mmol) was added thereto; stirred at room temperature for 15 hours. An excess of aqueous ammonium chloride was added thereto; extracted with dichloromethane; then washed with brine. with MgSO 4 Moisture was removed from the organic layer, which was then filtered and concentrated under reduced pressure to obtain the desired form of compound 4-(3-hydroxypropyl)piperidine-1-carbonitrile in quantitative yield, which was used in the next step reactio...

preparation example 2

[0240] 3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4- Oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-methyl-1,2,4- Preparation of oxadiazole

[0241] (Step 2-1) Preparation of 3-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)propan-1-ol

[0242]

[0243] 3-(piperidin-4-yl)propan-1-ol (10g, 69.8mmol) and 5-bromo-2-chloropyrimidine (13.5g, 69.8mmol) of chemical formula 2 were dissolved in N,N-dimethyl Formamide (DMF, 10ml), then potassium carbonate (K 2 CO 3 , 10.6g, 76.8mmol) was added thereto, and the reaction was carried out at 80°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate (EA, 150ml), and washed with brine. with MgSO 4 Water was removed from the organic layer, which was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired form of compound 3-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)propan-1-ol in 82% ...

preparation example 3

[0276] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5 -Methyl-1,3,4- Preparation of oxadiazole

[0277] (Step 3-1) Preparation of methyl 4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorobenzoate

[0278]

[0279] 2,6-difluoro-4-hydroxybenzoic acid methyl ester (1.72g, 9.16mmol) was dissolved in N,N-dimethylformamide (DMF, 30ml), and then 3-(1-(5- Ethylpyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate (3.3g, 10.08mmol) and potassium carbonate (K 2 CO 3 , 3.8g, 27.5mmol) was added to the reaction solution. The reaction solution was stirred at 65°C for 12 hours, then diluted with water and extracted with EA. with MgSO 4 Moisture was removed from the organic layer, the organic layer was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired form of compound 4-(3-(1-(5-ethyl pyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorobenzoic ac...

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Abstract

The present invention relates to a novel compound having a GPR119 agonistic activity, a method for preparing the same, and a pharmaceutical composition including the same as an effective component. The present invention has an effective hypoglycemic action and an effect on pancreatic beta cells, and also improves lipid metabolism which is a chronic cardiovascular risk factor, thereby having a treatment and / or prevention effect of a metabolic disease such as diabetes.

Description

technical field [0001] The present invention relates to a compound having GPR119 agonist activity, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an effective ingredient. Background technique [0002] Metabolic disease refers to syndromes associated with risk factors such as obesity, diabetes, hypertriglyceridemia, hypertension, other cardiovascular diseases, and coagulation disorders. According to the U.S. National Cholesterol Education Program (US National Cholesterol Education Program, NCEP) ATP III published in 2001, when patients display at least three of the following five risk factors, a diagnosis of metabolic syndrome can be made: ① Abdominal obesity, manifestations A waist circumference of 40 inches (102 cm) or more in men and a waist circumference of 35 inches (88 cm) or more in women, ② hypertriglyceridemia, manifested by triglycerides of 150 mg / dL or more, ③ in men HDL cholesterol of 40 mg / dL or less in women, 50...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D417/14A61K31/506A61K31/4245A61K31/497A61P3/10A61P3/04A61P9/12A61P9/00A61P7/02
CPCC07D413/14C07D417/14A61P3/10A61K31/42A61K31/425A61K31/506C07D401/04C07D413/04
Inventor 梁在盛白桂林金玧贞安致荣李在永郑日熏金美庆姜素美李晓珠蔡洧娜郑睿楻金泰亨梁银京孙文虎申昌烈
Owner DONG A ST CO LTD
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