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New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor

A glucopyranoside, aryl technology, applied in the field of pharmaceuticals, can solve the problems of liver toxicity, hypoglycemia, weight gain and so on

Active Publication Date: 2015-02-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs have good therapeutic effects, but there are safety problems in long-term treatment of diabetes, such as: liver toxicity, weight gain and hypoglycemia, etc.

Method used

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  • New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor
  • New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor
  • New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] (5-Bromo-2-chlorophenyl)(4-ethoxy-3-fluorophenyl)methanone (IIa-1)

[0067]

[0068] In a 100ml single-necked bottle equipped with a calcium chloride drying tube, 2-chloro-5-bromobenzoic acid (5.0g, 21.23mmol) was suspended in 20ml of dichloromethane, and oxalyl chloride (5.49ml, 63.69mmol) was added dropwise under stirring , after dropping, catalyze with a drop of DMF, react at room temperature for 3 hours, evaporate the solvent and excess oxalyl chloride under reduced pressure, dissolve the residue in 25ml of dichloromethane, cool to about -10°C in an ice-salt bath, and add AlCl in batches 3 (3.40g, 24.98mmol), after adding, stir evenly until the reaction solution turns from yellow-green to yellow thick liquid, start to add 2-fluorophenetole (2.84g, 20.84mmol), control the internal temperature below 0°C, , reacted at 0°C for about 45min, the reaction was completed, poured into cold 1N hydrochloric acid (100ml), stirred until the reddish-brown reaction solution beca...

Embodiment 2

[0084] 4-Bromo-1-chloro-2-(4-ethoxy-3-fluorobenzyl)benzene (II-1)

[0085]

[0086] In a 100ml single-neck bottle equipped with anhydrous calcium chloride drying tube, the raw material IIa-1 (5.3g, 15.0mmol) was dissolved in a mixed solvent of 20ml of dichloromethane and 20ml of acetonitrile, cooled to about -5°C in an ice-salt bath, Et was added dropwise with stirring 3 SiH (5.3ml, 33.0mmol), stir well and then add BF dropwise 3 ·Et 2O (3.8ml, 30.0mmol), after the addition, it was naturally raised to room temperature in an ice bath, stirred overnight, and 2N NaOH was added dropwise to the reaction solution under cooling in an ice-water bath to adjust the pH of the solution to about 8-9, and diluted with water. Dichloromethane (25ml×3) was extracted, the organic phase was washed with 1N hydrochloric acid (30ml×2), washed with saturated brine (40ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purified by chromat...

Embodiment 3

[0102] Ethyl 2-(4-(2-chloro-5-bromobenzoyl)phenoxy)acetate (3)

[0103]

[0104] In a 100ml round bottom flask, phenol (5.0g, 53.1mmol) and ethyl chloroacetate (6.7mL, 63.8mmol) were dissolved in 40mL of DMF, potassium carbonate (22.0g, 159.4mmol) was added in one portion while stirring, and stirred at room temperature for 3h. Add saturated sodium chloride solution to the reaction solution until potassium carbonate dissolves, extract with ethyl acetate (40ml×3), wash the organic phase with water (30ml×2), wash with 1N sodium hydroxide (20ml×2), and wash with saturated saline (25ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 0.86g of light yellow liquid.

[0105] In a 100ml single-necked bottle equipped with anhydrous calcium chloride drying tube, 2-chloro-5-bromobenzoic acid (5g, 21.2mmol) was suspended in 40mL of dry dichloromethane, a drop of DMF was added to catalyze, and 10mL o...

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Abstract

The invention discloses a new C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor, relates to the field of medicines associated with diabetes, and in particular relates to a new C-aryl glycosidase derivative shown as the general formula (I), a preparation method thereof, compositions thereof, and use thereof in preparing hypoglycemic drugs. The C-aryl glucoside derivative has excellent effect of promoting urine discharge and in-vivo hypoglycemic activity, and compounds with equal or better in-vivo hypoglycemic activity than that of dapagliflozin are screened out, and can be used for the prevention or treatment of diabetes.

Description

technical field [0001] The invention relates to the field of pharmacology related to diabetes, in particular to a new type 2 sodium-glucose transporter (SGLT2) inhibitor containing a polyaryl glucoside structure that has a therapeutic effect on diabetes. The invention also discloses its preparation The method, the pharmaceutical composition with the compounds as active components, and their application in the preparation of hypoglycemic drugs. Background technique [0002] At present, there are about 370 million diabetic patients in the world, most of whom are type 2 (ie non-insulin dependent) diabetic patients. Traditional drugs for the treatment of diabetes mainly include insulin, metformin, sulfonylureas, thiazolidinedione and α-glucosidase inhibitors. In recent years, new drugs for the treatment of diabetes include glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, etc. These drugs have good therapeutic effects, but there are safety ...

Claims

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Application Information

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IPC IPC(8): C07D309/10C07D407/10C07D407/14A61K31/351A61P3/10
CPCC07D309/10C07D407/10C07D407/14
Inventor 黄文龙钱海李政王学堃焦磊邱倩倩
Owner CHINA PHARM UNIV
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