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Benzofuranyl derivatives used as glucokinase inhibitors

A technology of benzofuran and compounds, applied in the field of benzofuran-based derivatives, can solve problems such as weight gain, induced edema and anemia

Active Publication Date: 2014-04-23
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Frequent use of these drugs can lead to weight gain and can induce edema and anemia

Method used

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  • Benzofuranyl derivatives used as glucokinase inhibitors
  • Benzofuranyl derivatives used as glucokinase inhibitors
  • Benzofuranyl derivatives used as glucokinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0069] Unless otherwise specified, raw materials are usually obtained from the following commercial sources, for example: Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, UK), Tyger Scientific (Princeton, NJ) and AstraZeneca Pharmaceuticals (UK, London). The following materials can be purchased from corresponding sources:

[0070] 5-Methyl-2-furaldehyde-Sigma-Aldrich (Milwaukee, WI);

[0071] 5-Methyl-2-aminopyrazine-Princeton Bimolecular Research, Inc (Monmouth Junction, NJ);

[0072] 5-Methoxypyrazine-2-amine-Anichem (Monmouth Junction, NJ);

[0073] 5-Chloropyrazine-2-carboxylic acid-Ark Pharma, Inc (Libertyville, IL);

[0074] 1-Methyl-1H-pyrazol-3-ylamine-Matrix Scientific (Columbia, SC);

[0075] 5-Bromo-pyrimidine-2-carboxylic acid-Ark Pharma, Inc (Libertyville, IL).

[0076] General experimental procedure

[0077] At room temperature and 400MHz, in Varian Unity TM NMR spect...

Embodiment 1

[0127] N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl-benzofuran-4-yloxy)pyrazine-2- Preparation of formamide (1):

[0128]

[0129] 5-Methyl-2-aminopyrazine (6.8 g, 63 mmol) was dissolved in 70 mL of dimethyl ether and cooled to 0°C. Dimethyl aluminum chloride (131 mmol, 1 M hexane) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 30 minutes. Next, ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-1d:10.1g , 27.3 mmol) of dimethyl ether solution (70 mL) was added to the active amine solution. The combined solution was heated to reflux overnight. The reaction was cooled on ice and slowly quenched by the dropwise addition of aqueous Rochelle salt (concentrated, 100 mL). The mixture was stirred for 20 minutes. The mixture is separated. The organic layer was washed with aqueous Rochelle salt (30 mL), 1N HCl (30 mL), brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The cr...

Embodiment 2

[0133] N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4-yloxy)pyrimidine-2- Preparation of formamide (2):

[0134]

[0135] At 0℃, Me 2 AlCl (1M hexane solution) (715 mL) was added to a 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethyl ether solution in a three-necked flask equipped with an overhead stirrer and condenser ( 315mL). The mixture was warmed to room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a: 52.6g, 142.5 mmol) was dissolved in dimethyl ether (210 mL). This mixture is then added to the complex amine. The gum precipitates and dissipates into a solid when scraping the flask. The resulting reaction was refluxed for 3.5 hours, and HPLC showed that the reaction was 93% complete. 5 liters of Rochelle salt and 2 liters of 2-methyltetrahydrofuran prepared in water were added to the mixture. The reaction mixture was then poured into the...

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Abstract

The present invention provides compounds of formula (I) that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glukokinase.

Description

Technical field [0001] The invention relates to a substituted benzofuranyl derivative, a pharmaceutical composition thereof, and use as a glucokinase activator. Background technique [0002] Diabetes has become a major public health problem due to its increased prevalence and related health risks. This disease is characterized by metabolic defects in the process of manufacturing and using carbohydrates, which results in the inability to maintain proper blood sugar levels. Two main types of diabetes have been recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of absolute insulin deficiency. Type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), usually occurs with normal or even elevated insulin levels, and seems to be the result of tissues and cells failing to respond appropriately to insulin. It is necessary to use drugs to aggressively control NIDDM, otherwise it will develop into IDDM. [0003] As blood sugar increases, i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14A61K31/497A61K31/506A61P3/04A61P3/10
CPCC07D405/14A61P3/00A61P3/04A61P31/10A61P43/00A61P3/10A61K31/497A61K31/506
Inventor A·L·凌J·A·普费弗科恩
Owner PFIZER INC
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