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Glucopyranose-based derivative and medical application thereof

An alkyl and alkenyl technology, applied in the field of glucopyranosyl derivatives, can solve the problems of lactic acidosis, hypoglycemia, improper use of glinides, etc., and achieve excellent hypoglycemia, good pharmacological activity, and excellent SGLT2 inhibitory activity. Effect

Active Publication Date: 2018-06-26
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at present, these hypoglycemic drugs are deficient. Biguanides can cause lactic acidosis, sulfonylureas can cause severe hypoglycemia, improper use of glinides can also cause hypoglycemia, and insulin sensitizers can cause edema, cardiac Exhaustion and weight gain, α-glucosidase inhibitors can cause abdominal flatulence and diarrhea, DPP-IV inhibitors need to be combined with metformin to achieve the ideal hypoglycemic effect

Method used

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  • Glucopyranose-based derivative and medical application thereof
  • Glucopyranose-based derivative and medical application thereof
  • Glucopyranose-based derivative and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0268] Example 1 (1S, 2S, 3S, 4R, 5S)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-fluoro-benzene Base]-1-(hydroxymethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol 1

[0269]

[0270] Step 1 5-Bromo-2-fluoro-benzoyl chloride 1b

[0271] N,N-Dimethylformamide (0.1 mL, 1.2 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-benzoic acid 1a (1.0 g, 4.57 mmol) in thionyl chloride (10 mL) at room temperature , heated to 75°C and reacted for 4 hours. After the reaction, it was concentrated under reduced pressure to remove the organic solvent to obtain the title compound 1b (1.1 g, brown oil), yield: 100%. The obtained product was directly used in the next reaction.

[0272] Step 2 (5-Bromo-2-fluoro-phenyl)-(2,3-dihydro-1,4-benzodioxin-6-yl)methanone 1c

[0273] At room temperature, the crude 5-bromo-2-fluoro-benzoyl chloride 1b (1.1 g, 4.62 mmol) obtained above was dissolved in dichloromethane (10 mL) solution, and 2,3-dihydro-1,4- After benzodioxin (0.62g, 4.57...

Embodiment 2

[0302] Example 2 (1S, 2S, 3S, 4R, 5S)-5-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-fluoro-benzene Base]-1-(1-hydroxy-1-methyl-ethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol 2

[0303]

[0304]

[0305] Step 1 (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-(2,3-dihydro-1,4-benzodioxin-6- Methyl)-4-fluoro-phenyl]-6,8-dioxobicyclo[3.2.1]octane-1-carboxylic acid 2a

[0306] At 0°C, the Dess-Martin oxidant (0.56g, 1.3mmol) was added to [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-(2 ,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-fluoro-phenyl]-6,8-dioxobicyclo[3.2.1]octane-1-yl] Methanol 1o (227 mg, 0.32 mmol) was dissolved in dichloromethane (10 mL), and the resulting mixture was heated to 40° C. and stirred for 16 hours. After the reaction, concentrate under reduced pressure, remove the organic solvent, add saturated sodium bicarbonate solution (30mL) to the residue, then extract with ethyl acetate (10mL×3), combine the organic phases, concentrate under reduced pressure, and pa...

Embodiment 3

[0315] Example 3 (1S, 2S, 3S, 4R, 5S)-5-[4-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)phenyl ]-1-(1-Hydroxy-1-methyl-ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 3

[0316]

[0317] Step 1 (2S,3R,4S,5R,6R)-2-[4-chloro-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)benzene base]-3,4,5-tris(trimethylsiloxy)-6-(trimethylsiloxymethyl)tetrahydropyran-2-ol 3b

[0318]Under nitrogen atmosphere, 6-[(5-bromo-2-chloro-phenyl)methyl]-2,3-dihydro-1,4-benzodioxin 3a (30.0g, 88.3mmol) was dissolved In anhydrous tetrahydrofuran (200mL), and cooled to -78 ° C, then slowly dropwise added n-butyllithium n-hexane solution (37mL, 89mol, 2.4M), after the dropwise addition was completed, stirred for 40 minutes, and then to the reaction Add (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2- A solution of ketone 1f (37.8 g, 81.0 mmol) in anhydrous THF (400 mL) was stirred for 16 hours. After the reaction was completed, slowly drop water (5mL) to q...

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Abstract

The invention relates to a glucopyranose-based derivative as a sodium-dependent glucose transporter (SGTLs) inhibitor, a pharmaceutical composition containing the derivative and a medical applicationof the derivative. The invention particularly relates to the glucopyranose-based derivative represented by a formula (I), or a pharmaceutically acceptable salt of the derivative, or all stereoisomersof the derivative, or the application of the pharmaceutical composition containing the derivative, the derivative and the pharmaceutical composition in preparing medicines for treating diabetes and diabetes-related diseases.

Description

technical field [0001] The present invention relates to a glucopyranosyl derivative as an inhibitor of sodium-dependent glucose transporters (SGLTs), a method for preparing them, a pharmaceutical composition comprising the derivative, and the use of the derivative and its composition in medicine on the application. More specifically, it is a compound represented by the general formula (I) or its pharmaceutically acceptable salt or its stereoisomer or a pharmaceutical composition containing the compound and the compound and pharmaceutical composition are used to prepare Use of drugs to treat diabetes and diabetes-related diseases. Background technique [0002] Diabetes is a common chronic disease characterized by hyperglycemia. The occurrence of diabetes is accompanied by insulin resistance in peripheral tissues, decreased insulin secretion in vivo, and increased gluconeogenesis in the liver. When the disease cannot be effectively controlled by diet and exercise, additional...

Claims

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Application Information

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IPC IPC(8): C07D407/10C07H9/02A61K31/7048A61K31/357A61P3/06A61P3/10A61P27/02A61P25/00A61P13/12A61P5/50A61P3/04A61P3/00A61P9/10A61P9/12
CPCC07D407/10C07H9/02
Inventor 顾峥伍武勇康盼盼覃浩雄曲桐黄伟明
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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