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C-aryl glucoside derivative, preparation method and applications thereof

A technology of glycoside derivatives and glucose, applied in the field of derivatives in the field of chemical medicine, can solve problems such as strong inhibitory activity, and achieve the effects of high inhibitory activity and selectivity, good in vivo hypoglycemic effect, and high drug safety.

Inactive Publication Date: 2014-10-22
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

All these antidiabetic drugs have their own limitations: common adverse reactions of sulfonylureas are increased gastric acid secretion, nausea, and hypoglycemia more likely to occur to other classes of oral hypoglycemic agents; the main adverse reactions of biguanides are gastrointestinal Reactions and lactic acidosis, insulin sensitizers are mainly liver toxicity, α-glucosidase inhibitors can cause abdominal flatulence and diarrhea, DPPIV inhibitors need to be combined with metformin to achieve the ideal hypoglycemic effect
Although these structural modifications have improved the inhibitory activity of the compound on SGLT-2, some compounds have stronger inhibitory activity on SGLT-1

Method used

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  • C-aryl glucoside derivative, preparation method and applications thereof
  • C-aryl glucoside derivative, preparation method and applications thereof
  • C-aryl glucoside derivative, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-(tetrahydrofuran-2-yl)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro Preparation of -2H-pyran-3,4,5-triol (compound 1)

[0052] Step 1. Synthesis of 5-bromo-2-chlorobenzyl alcohol (Formula 1a)

[0053]

[0054] Dissolve 2-chloro-5-bromobenzoic acid (4.0g, 0.0170mol) in 24ml of anhydrous tetrahydrofuran, under argon protection, add dimethyl sulfide borane (8.7ml, 0.0849mol) dropwise at 0°C, and react at room temperature After 5 hours, TLC monitored until the reaction was complete, and ice-water bath, slowly added water dropwise, extracted with ethyl acetate, and spin-dried to obtain 3.6 g of white solid, the crude product was directly put into the next reaction.

[0055] Step 2. Synthesis of (5-bromo-2-chlorobenzyloxy) tert-butyldiphenylsilane (Formula 1b)

[0056]

[0057] 5-bromo-2-chlorobenzyl alcohol (formula 1a) (3.6g, 0.0163mol) was dissolved in 30ml of methylene chloride, imidazole (imidazole, 5.6g, 0.0815mol) an...

Embodiment 2

[0094] Example 2 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl)phenyl) Preparation of -6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 2)

[0095]

[0096] Compound 2 was prepared in a similar manner to Example 1. Wherein, steps 1-8 are identical with embodiment 1.

[0097] Step 9. Synthesis of 4-(4-bromophenyl)-pyran-4-ol (Formula 2e)

[0098]

[0099] Under argon atmosphere, dissolve p-bromoiodobenzene (5.66g, 0.02mol) in 30ml tetrahydrofuran (THF), cool to -40°C, add isopropylmagnesium chloride (26ml, 0.026mol) dropwise, keep the reaction for 1h, add dropwise THF (10ml) solution of tetrahydropyrone (1.66g, 0.0166mol) was slowly raised to room temperature within 3h, detected by TLC, quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was successively watered, saturated Washed with brine, dried, filtered, spin-dried, washed with petroleum ether to obtain a white solid (2.73g, 53%), which ...

Embodiment 3

[0112] Example 3 (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-(tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-6-( Preparation of hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 3).

[0113]

[0114] Compound 3 was prepared in a similar manner to Example 1. Wherein, steps 1-8 are the same as embodiment 1.

[0115] Step 9. Synthesis of 2-(4-tributyltinphenyl)furan (Formula 3-2)

[0116]

[0117] The operation was the same as step 12 in Example 1, but compound 2c was changed to compound 3-1 (preparation reference WO20060125526) (989mg, 4.10mmol), Pd(PPh 3 ) 4 The dosage was changed to 237mg (0.205mmol), Bu 3 Sn-SnBu 3 The dosage was changed to 4.76g (8.20mmol).

[0118] Step 10. Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-furan-2-)phenyl)pyran-3, 4,5-Triacetate (Formula 3-3)

[0119]

[0120] The operation was the same as step 13 in Example 1, but compound 2d was changed to compound 3-2 (284 mg, 0.627 mmol). LC-MS of the obtained product: 639.2 [M...

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Abstract

The invention discloses a C-aryl glucoside derivative, a preparation method and applications thereof. The derivative can be a compound represented by the formula (I), an optical isomer or a pharmaceutically acceptable salt of the compound, wherein the R is selected from H, chlorine, or methyl; and the R1 is selected from components whose structural formula is represented in the description. The C-aryl glucoside derivative has a novel biological structure, and has a higher SGLT-2 activity and selectivity inhibiting effect than that of the conventional SGLT-2 inhibitors. The drugs, which are prepared from the derivative, for treating SGLT-2 related diseases have a better in-vivo sugar reducing effect and higher drug application safety.

Description

technical field [0001] The present invention relates to a derivative in the field of chemical medicine, in particular to a SGLT-2 (sodium-glucose co-transporter 2, SGLT-2) inhibitor——C-aryl glucoside derivative and its preparation method and apply. Background technique [0002] Type II diabetes is a kind of non-insulin-dependent diabetes mellitus, which has the characteristics of hyperglycemia caused by the failure of sensitive tissues to respond to insulin and B cell dysfunction (American Diabetes Association: Standards of medical care in diabetes 2008. Diabetes Care, 2008, 31, Suppl 1, S12–S54). In November 2010, the latest survey by the Chinese Diabetes Association found that the number of diabetics in China was close to 100 million, surpassing India to become the largest country with diabetes, and more than 90% of them were type II diabetes. [0003] Currently commonly used drugs for the treatment of diabetes include sulfonylureas, biguanides, insulin sensitizers (coli...

Claims

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Application Information

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IPC IPC(8): C07D407/10C07D309/10C07D309/22A61K31/351A61K31/357A61P3/10A61P3/04
CPCC07D407/10C07D309/10C07D309/20
Inventor 陈友喜付小旦李兴伟
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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