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Glucopyranosyl derivative and application thereof in medicines

An alkyl and aryl technology, applied to glucopyranosyl derivatives and their application in medicine, can solve problems such as improper use of glinides, hypoglycemia, lactic acidosis, etc., and achieve good pharmacological activity, high Bioavailability, good absorption effect

Active Publication Date: 2016-04-06
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are deficiencies in these hypoglycemic drugs at present. 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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  • Glucopyranosyl derivative and application thereof in medicines
  • Glucopyranosyl derivative and application thereof in medicines
  • Glucopyranosyl derivative and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] (1R,2S,3S,4R,5S)-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-1- (1-Hydroxyethyl)-6,8-dioxbicyclo[3.2.1]octane-2,3,4-triol 1

[0179]

[0180]

[0181] step 1

[0182] 2-(Cyclopropoxy)ethanol 1b

[0183] At room temperature, the Mg (24.0g, 994.2mmol), I 2 (4.2 g, 16.6 mmol) was added to stirring tetrahydrofuran (200 mL). The temperature was raised to 45°C, and the solution of 1,2-dibromoethane (124.0g, 662.8mmol) in tetrahydrofuran (500mL), 2-(2-bromoethyl)-1,3-dioxolane 1a(30.0 g, 165.7 mmol) was added dropwise to the reaction solution, and stirring was continued at 45°C for 16 hours. After the reaction was completed, the reaction was quenched with 100 mL of saturated aqueous ammonium chloride solution, and the resulting mixture was filtered under reduced pressure with suction. The filtrate was washed with saturated brine (300 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the cru...

Embodiment 2

[0236] (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-1- (1-hydroxy-1-methyl-ethyl)-6,8-dioxbicyclo[3.2.1]octane-2,3,4-triol 2

[0237]

[0238] step 1

[0239] (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]benzene Yl]methyl]phenyl]-6,8-dioxbicyclo[3.2.1]octane-1-carboxylic acid 2a

[0240] At 0℃, add sodium bicarbonate aqueous solution (12mL, 8.65mmol, 0.72M), potassium bromide (18.7mg, 0.157mmol), tetramethylpiperidine (12.3mg, 0.078mmol) to [(1S, 2S ,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl ]Phenyl]-6,8-dioxbicyclo[3.2.1]octan-1-yl]methanol 1p (0.60g, 0.786mmol, see Example 1, step 13) in tetrahydrofuran (12mL) solution, and then Sodium hypochlorite solution (10.8mL, 12.7mmol, effective chlorine content of 3.5%) was dropped into the reaction system, and the reaction solution was stirred at 0°C for 2 hours. After the reaction, 1M hydrochloric acid was added to adjust t...

Embodiment 3

[0255] (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-tetrahydrofuran-3-yl-oxyphenyl)methyl]phenyl)-1-(1-hydroxy- 1-methyl-ethyl)-6,8-dioxbicyclo[3.2.1]octane-2,3,4-triol 3

[0256]

[0257]

[0258] step 1

[0259] (S)-Tetrahydrofuran-3-yl-4-methylbenzenesulfonate 3b

[0260] At room temperature, add p-toluenesulfonyl chloride (6.5g, 34.0mmol) to the dichloromethane solution of (S)-tetrahydrofuran-3-ol 3a (1.82mL, 22.7mmol) and imidazole (3.86g, 56.7mmol) ( 60 mL), a catalytic amount of 4-dimethylaminopyridine was added, and the resulting reaction system was stirred at room temperature for 16 hours. After the completion of the reaction, add 20 mL of water and 50 mL of dichloromethane to the reaction solution, stir and separate the layers. The separated organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [petroleum ether / eth...

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Abstract

The invention relates to a glucopyranosyl derivative used as a sodium-dependent glucose transporter (SGLT) inhibitor, a medicinal composition containing the derivative, and an application of the derivative and the medicinal composition in medicines, and especially relates to the glucopyranosyl derivative represented by formula (I) or a pharmaceutically acceptable salt or all stereoisomers thereof, or the medicinal composition containing the derivative, and a use of the derivative and the medicinal composition in the preparation of medicines for treating diabetes and diabetes related diseases.

Description

Technical field [0001] The present invention relates to a glucopyranosyl derivative or intermediates thereof as inhibitors of sodium-dependent glucose transporters (SGLTs), a preparation method thereof, and applications in medicine, especially those represented by general formula (I) Glucopyranosyl derivatives or their pharmaceutically acceptable salts or all their stereoisomers or pharmaceutical compositions containing the derivatives and said derivatives and pharmaceutical compositions are used for the preparation of the treatment of diabetes and diabetes-related Use of drugs for diseases. Background technique [0002] Diabetes is a common chronic disease characterized by high blood sugar. The occurrence of diabetes is accompanied by insulin resistance in peripheral tissues, decreased insulin secretion in the body, and increased liver gluconeogenesis. When the disease cannot be effectively controlled through diet and exercise, it is necessary to additionally use insulin or ora...

Claims

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Application Information

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IPC IPC(8): C07H9/04C07D493/08A61P3/10A61P27/02A61P25/00A61P13/12A61P5/50A61P3/06A61P3/04A61P9/10A61P9/12A61P7/02A61P29/00A61P37/02A61P11/06A61P19/10A61P35/00A61P17/06A61P25/28A61P25/18A61P31/00
Inventor 顾峥温甲平唐万军王伟华邓炳初伍武勇曲桐
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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