Glucopyranosyl derivative and application thereof in medicine

An alkyl and hydroxyl technology, applied in the field of glucopyranosyl derivatives, can solve the problems of undiscovered and low risk of hypoglycemia

Active Publication Date: 2017-06-27
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, Sotagliflozin can also produce a significant hypoglycemic effect on type II diabetic patients with renal impairment by inhibiting SGLT-1. More importantly, its mechanism of hypoglycemic action is not dependent on insulin, thus causing hypoglycemia. The risk is low, and no gastrointestinal adverse reactions such as diarrhea related to SGLT-1 have been found to be inhibited so far, so it has better safety, tolerance and clinical compliance (B Zambrowicz1 et al., Clinical trial, 2012, 92 (2 )158-169; Zhou Zhixing et al., Modern Drugs and Clinics, 30(4), 2015, 465-469)

Method used

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  • Glucopyranosyl derivative and application thereof in medicine
  • Glucopyranosyl derivative and application thereof in medicine
  • Glucopyranosyl derivative and application thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1 (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-[[4-[[(2S)-oxirane-2-yl]methoxy]phenyl] Methyl]phenyl]-6-methylthiotetrahydropyran-3,4,5-triol 1

[0184]

[0185]

[0186] Step 1 (3aS, 3bR, 7aS, 8aS)-2,2,5,5-Tetramethyltetrahydro-3aH-[1,3]dioxolano[4′,5′: 4, 5] Furo[3,2-d][1,3]dioxane 1b

[0187] Magnesium sulfate (160g, 1.33mol) and concentrated sulfuric acid (9.9mL, 190mmol) were added to (2S,3R,4S)-2,3,4,5-tetrahydroxypentanal 1a (99.0g, 659mmol) at room temperature In acetone (1.2 L) solution, the resulting reaction system was stirred for 12 hours. The reaction mixture was suction-filtered, washed with acetone (300mL×2), the filtrates were combined, and the pH value was adjusted to 7 with 25% ammonia water. Solids were precipitated, then suction-filtered again, and washed with acetone (150mL×2). The filtrates were combined and concentrated under reduced pressure to obtain the title compound 1b as a yellow oil (128.0 g, 84.3%).

[0188] 1 H NMR (600MHz, CDCl ...

Embodiment 2

[0231] Example 2 (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-[[4-[(2S)-3-ethoxy-2-hydroxypropoxy]phenyl]methanol Base]phenyl]-6-methylthiotetrahydropyran-3,4,5-triol 2

[0232]

[0233]

[0234] At room temperature, chopped metallic sodium (195 mg, 8.48 mmol) was added into absolute ethanol (20 mL), and stirred until the sodium block completely disappeared. (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-[[4-[[(2S)-oxirane-2-yl]methoxy]phenyl]methyl ]Phenyl]-6-methylthiotetrahydropyran-3,4,5-triol 1 (0.48g, 1.1mmol) in ethanol (10mL) was added to the above reaction solution, heated to 60°C, and stirred for reaction 6 hours. Add glacial acetic acid (1mL) to quench, concentrate under reduced pressure to remove the solvent, add ethyl acetate (20mL) and saturated aqueous sodium bicarbonate solution (20mL) to the residue, let the layers stand, and wash the organic phase with saturated brine (10mL× 3), concentrated under reduced pressure, and the residue was purified by silica gel column chromat...

Embodiment 3

[0237]Example 3 (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-[[4-[[(2R)-oxirane-2-yl]methoxyl]phenyl] Methyl]phenyl]-6-methylthiotetrahydropyran-3,4,5-triol 3

[0238]

[0239] At room temperature, the compound (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-[(4-alkylphenyl)methyl]phenyl]-6-methylthiotetrahydropyridine Furan-3,4,5-triol 1o (see step 13 of Example 1, 58 mg, 0.15 mmol) was dissolved in ethanol (2 mL), and (2S)-2-(chloromethyl)oxirane (0.4 mL, 5mmol) and potassium carbonate (15mg, 0.11mmol), the temperature was raised to 73°C, and the reaction was stirred for 5 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [100% ethyl acetate] to obtain the title compound 3 as a white solid (12 mg, 16.4%, HPLC: 90.5%).

[0240] MS (ESI, pos.ion) m / z: 475.2 [M+Na] + ;

[0241] 1 H NMR (600MHz, CD 3 OD) δ (ppm): 7.38 (d, 1H), 7.26 (d, 2H), 7.14 (d, 2H), 6.88 (d, 2H), 4.40 (d, 1H), 4.29 (dd, 1H), 4.1...

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Abstract

The invention relates to a glucopyranosyl derivative as a sodium-dependent glucose transporter (SGLT) inhibitor, a pharmaceutical composition containing the derivative and an application thereof in medicine, and in particular to the glucopyranosyl derivative as shown in a formula (I) or a pharmaceutically acceptable salt or all stereisomers thereof, or use of the pharmaceutical composition containing the derivative and the derivative and the pharmaceutical composition for preparing medicines 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): C07H15/14C07H1/00A61K31/7048A61K31/7042A61K31/7028A61P3/10A61P27/02A61P25/00A61P13/12A61P5/50A61P3/06A61P3/04A61P9/10A61P9/12
CPCC07H1/00C07H15/14
Inventor 顾峥伍武勇曲桐覃浩雄康盼盼邓炳初
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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