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Glucokinase activator containing glucosamide and pyridine structure and application of glucokinase activator

A technology of compounds, acetyl groups, used in organic chemistry, metabolic diseases, drug combinations, etc.

Inactive Publication Date: 2015-05-13
FOSHAN SAIWEISI MEDICINE SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As there are currently no commercially available glucokinase activators, there remains a need for a range of glucokinase activators that appropriately lower the Km of glucose to 2-5 mM at lower activator concentrations

Method used

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  • Glucokinase activator containing glucosamide and pyridine structure and application of glucokinase activator
  • Glucokinase activator containing glucosamide and pyridine structure and application of glucokinase activator
  • Glucokinase activator containing glucosamide and pyridine structure and application of glucokinase activator

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The synthesis of embodiment 1 compound I

[0024]

[0025] A. Synthesis of Compound IV

[0026] Compound II 1.54g (10mmol) and Compound III 1.38g (10mmol) were dissolved in 20mL of dry THF, stirred at room temperature, DCC 2.48g (12mmol) and 4-dimethylaminopyridine (DMAP) 0.50g were added, and the reaction mixture was then After stirring overnight at room temperature, the reaction was complete by TLC check. After cooling the mixture was poured into 100 mL ice water, using 50 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV, a white solid, ESI-MS, m / z=275 ([M+H] + ).

[0027] B. Synthesis of Compound VI

[0028] Compound IV 1.64g (6mmol) and compound V 2.26g (6mmol) were dissolved in 30mL dr...

Embodiment 2

[0031] The synthesis of embodiment 2 reference compound D-1

[0032]

[0033] A. Synthesis of Compound IV-2

[0034] Compound II-21.09g (10mmol) and compound III-21.24 (10mmol) were dissolved in 20mL dry THF, stirred at room temperature, DCC 2.48g (12mmol) and 4-dimethylaminopyridine (DMAP) 0.50g were added, and the reaction mixture After stirring overnight at room temperature, TLC showed the reaction was complete. After cooling the mixture was poured into 100 mL ice water, using 50 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-2, a white solid, ESI-MS, m / z=216 ([M+H] + ).

[0035] B. Synthesis of Compound VI-2

[0036] Compound IV-21.29g (6mmol) and Compound V 2.26g (6mmol) were dissolved i...

Embodiment 3

[0039] Activation of the compound of embodiment 3 to glucokinase in vitro

[0040] In vitro glucokinase test

[0041] The in vitro activity of the glucokinase activators of the present invention was evaluated in two independent tests: with EC 50 Test to evaluate the potency of each compound at a fixed, physiologically relevant concentration of glucose, and the glucose S at a fixed, near-saturating (if possible) concentration of the compound 0.5 Test to evaluate its Vm and S for glucose 0.5 role. For each of these tests, glucokinase activity was estimated by monitoring the increase in absorbance at 340 nm in a coupled assay system containing NAD+ and glucose 6-phosphate dehydrogenase. Assays were performed at 30°C using a thermostatically controlled absorbance plate reader and clear, 96-well, flat bottom, polystyrene plates (Costar 3695, Coming). Each 50 μL test mixture contains 10 mM K+MOPS, pH 7.2, 2 mM MgCl 2 , 50mM KCl, 0.01% Triton X-100, 2% DMSO, 1mM DTT, 1mM ATP, ...

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Abstract

The invention relates to the field of type 2 diabetes-related medicaments. Specifically, the invention relates to a glucokinase activator containing a glucosamide and pyridine structure, a preparation method thereof and application in preparation of the type 2 diabetes-related medicaments. The formula is as described in the specification.

Description

technical field [0001] The invention relates to the pharmaceutical field for the treatment of type 2 diabetes. More specifically, the present invention relates to a glucokinase activator containing glucosamide and pyridyl structure, its preparation method and its application in pharmacy, which have a therapeutic effect on type 2 diabetes. Background technique [0002] Diabetes is a collection of syndromes characterized by the body's inability to produce enough insulin or use it normally. Most diabetic patients can be clinically classified as insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Almost all forms of diabetes result from decreased insulin secretion and blood levels or tissue response to insulin (insulin resistance), usually associated with elevated levels of a hormone that acts opposite to insulin (glucagon). These abnormalities result in changes in carbohydrate, lipid, and protein metabolism. The hallmark of this syn...

Claims

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Application Information

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IPC IPC(8): C07D405/14A61P3/10
CPCC07D405/14
Inventor 蔡子洋
Owner FOSHAN SAIWEISI MEDICINE SCI & TECH
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