C-aryl glucoside derivatives containing difluoromethylene group

A difluoromethoxy and trifluoromethyl technology, applied in the field of diabetes treatment, can solve the problems of unsatisfactory target enzyme selectivity, inactivation, and unsatisfactory SLGT-2 inhibitory activity

Inactive Publication Date: 2011-11-09
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the inhibitory activity of these compounds on SLGT-2 in the prior art is not satisfactory enough, the target enzyme selectivity is

Method used

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  • C-aryl glucoside derivatives containing difluoromethylene group
  • C-aryl glucoside derivatives containing difluoromethylene group
  • C-aryl glucoside derivatives containing difluoromethylene group

Examples

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preparation example Construction

[0062] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent (usually a polar aprotic solvent) at -30°C to solvent reflux temperature (preferably -20 to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0063] In a preferred example, the compound of formula (I) of the present invention can be prepared according to the following routes I-VII.

[0064] Route I: Synthesis of Intermediate 1i

[0065]

[0066] (1) At a suitable temperature, in a polar aprotic solvent, add a Lewis acid as a catalyst, and react 5-bromo-2-chlorobenzoyl chloride with tert-butyl (phenoxy)diphenylsilane to obtain an intermediate 1a. Polar aprotic solvents may be selected from (but not limited to): dichloromethane, chloroform, 1,2-dichloroethane; Lewis acids may be selected from (but not limited to): aluminum trichloride, dichloro Zinc chloride, ferric chloride, tin tetrachloride, titanium tetrachloride; the pref...

specific Embodiment approach

[0128] The present invention is explained more specifically in the following examples. It should be understood, however, that these examples are given to illustrate the invention and not to limit the scope of the invention in any way. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Parts and percentages are by weight unless otherwise indicated.

[0129] In all examples, the melting point is determined with an X-4 melting point apparatus, and the thermometer is not corrected; 1 H-NMR was recorded with a VarianMercury 400 nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); MS was measured with a Shimadzu LC-MS-2020 mass spectrometer. The silica gel used for separation is not specified and is 200-300 mesh, and the ratio of the eluent is the volume ratio.

Embodiment 1

[0131] (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-((4-ethoxyphenyl)difluoromethyl)phenyl)-tetrahydro-6-(hydroxymethyl) - Preparation of 2H-pyran-3,4,5-triol (compound 1)

[0132] Step 1: Preparation of (5-bromo-2-chlorophenyl)(4-(tert-butyl(phenoxy)diphenylsilane)phenyl)methanone 1a

[0133]

[0134] Dissolve 5-bromo-2-chlorobenzoyl chloride (12.7g, 50mmol) in dichloromethane (100mL), and add tert-butylphenoxydiphenylsilane (16.6g, 50mmol) and trichloromethane in sequence at 0°C Aluminum (8.0g, 60mmol), stirred at room temperature for 3.5h, TLC monitored the completion of the reaction, washed with 1N hydrochloric acid, 1N sodium hydroxide, water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated under reduced pressure, and purified by column chromatography to obtain the title compound 1a as a white solid (10.1 g, 36.7%). 1 H-NMR (300MHz, CDCl 3 ): δ1.11(s, 9H), 6.79-6.82(m, 2H), 7.26-7.51(m, 9H), 7.57-7.60(m,...

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Abstract

The invention relates to C-aryl glucoside derivatives containing a difluoromethylene group. Specifically, the invention provides novel sodium-dependent glucose transporter (SGLT-2) inhibitors, a preparation method thereof and application thereof in preparing drugs for the treatment of diseases related to SGLT-2, especially diabetes, obesity and diabetic complications. The C-aryl glucoside derivatives provided by the invention have stronger inhibition activity and higher selectivity for sodium-dependent glucose transporter (SGLT-2), and can obviously promote the emission of glucose in urine of animals.

Description

technical field [0001] The present invention relates to a novel sodium-dependent glucose transporter (SGLT-2) inhibitor, its preparation method and its use in the preparation of medicines for treating diseases related to SGLT-2, especially in the treatment of diabetes, obesity and diabetic complications application. Background technique [0002] Type II diabetes is a common chronic disease characterized by hyperglycemia, and its occurrence is accompanied by insulin resistance in peripheral tissues, a relative decrease in insulin secretion in the body, and an increase in hepatic gluconeogenesis[Exp.Opin.Ther.Patents , 2003, 13(4): 499-510]. Existing drugs include biguanides, sulfonylureas, insulin sensitizers (colinides), glinides, α-glucosidase inhibitors, and the recently marketed DPPIV inhibitor sitagliptin, etc. However, all of these antidiabetic drugs have their own limitations. For example: biguanides cause lactic acidosis, sulfonylureas cause severe hypoglycemia, in...

Claims

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Application Information

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IPC IPC(8): C07D309/10A61K31/351A61P3/10A61P3/04
Inventor 辛婷申朝辉卢鹏赵传生刘亦斌
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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