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C-triaryl glucoside SGLT-2 inhibitor

A technology of glucoside and alkyl, applied in the field of medicine, can solve the problems of low bioavailability and anti-diabetic drugs

Active Publication Date: 2014-09-24
JIANGSU ALICORN PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In recent years, more and more researchers have used SGLT-2 as a molecular target. The first SGLT-2 inhibitor to be evaluated was phlorizin isolated from the root bark of apple trees, but It has not been developed as an antidiabetic drug due to its low bioavailability due to its easy hydrolysis by phlorizin hydrolase in the small intestine

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1 Preparation of Compound 1

[0082]

[0083] Preparation of Compound 1-3:

[0084] Add 70.6 g of 2-chloro-5-bromobenzoic acid (1-1) and 500 mL of tetrahydrofuran into a round-bottomed flask, and slowly add 200 mL of 2M borane dimethyl sulfide complex dropwise at 0°C; 25°C) and stirred overnight; at 0°C, methanol was slowly added dropwise until no bubbles emerged; the reaction liquid was concentrated and evaporated to dryness under reduced pressure; 300 mL of water and 300 mL of ethyl acetate were added to the residue, and the layers were extracted, and the organic phase was washed with saturated brine Once, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain compound 1-2, which was directly carried out to the next step without purification.

[0085] Add 60g PCC and 60g silica gel powder into a round bottom flask, mix well, add 500mL dichloromethane, cool to 0°C, add dropwise 45g of compound 1-2 in dichlorome...

Embodiment 2

[0098] Example 2 Preparation of Compound 2

[0099]

[0100] Preparation of intermediate 4-bromo-4'-fluorobiphenyl

[0101] Add 4 g of p-bromoiodobenzene, 2.9 g of 4-fluorophenylboronic acid, 0.84 g of tetrakis(triphenylphosphine) palladium, 5.8 g of potassium carbonate and 100 mL of toluene or N,N-dimethylmethane into a 250 mL round bottom flask amides. Heated to 100°C under the protection of nitrogen, and detected the progress of the reaction with a thin-layer chromatography plate. After the reaction was completed, add 100 mL of water and 150 mL of ethyl acetate to separate the liquids. The organic phase was washed with 1N hydrochloric acid and saturated brine respectively, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether as the eluent) to obtain 4- Bromo-4'-fluorobiphenyl 1.6 g, 46% yield, MS m / z (ESI) 272.9 [M+Na] + .

[0102] The preparation method of compound 2 refers to Example 1, and th...

Embodiment 3

[0105] Example 3 Preparation of compound 3

[0106]

[0107] The preparation method of intermediate 4-bromo-4'-chlorobiphenyl refers to the preparation of 4-bromo-4'-fluorobiphenyl in Example 2, except that 4-chlorophenylboronic acid is used instead of 4-fluorophenylboronic acid.

[0108] The preparation method of compound 3 refers to Example 1, and the intermediate 4-bromo-4'-chlorobiphenyl is used to replace the 4-bromobiphenyl in Example 1, and the total yield is 30%.

[0109] 1 H NMR (400 MHz, DMSO-d 6 ) δ7.58-7.56(m, 2H), 7.49-7.48(m, 2H), 7.47-7.46(m, 2H), 7.40-7.37(m, 2H), 7.28-7.23(m, 3H), 4.94( m, 2H), 4.84(d, J=6.0 Hz, 2H), 4.43(m, 2H), 4.14-3.99(m, 3H), 3.70-3.66(m, 1H), 3.46-3.40(m,1H) , 3.27-3.08(m, 4H).

[0110] MS m / z (ESI) 498.1 [M+Na] + .

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Abstract

The present invention relates to a C-triaryl glucoside SGLT-2 inhibitor shown as formula (I), preparation methods therefor, pharmaceutical compositions thereof and uses thereof for treating diseases that benefit from inhibiting SGLT-2. Such diseases are diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood level of fatty acids, elevated blood level of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, atherosclerosis or hypertension. The compounds of the present invention have strong inhibition activity against SGLT-2, higher selectivity, improved drug metabolism properties in oral treatment, and good druggability.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a C-triarylglucoside SGLT-2 (sodium-dependent glucose transporter-2) inhibitor and a preparation method thereof, and also to a drug combination containing the SGLT-2 inhibitor Compounds and uses thereof for the treatment of diseases benefiting from inhibition of SGLT-2. Background technique [0002] Diabetes is mainly divided into type 1 diabetes and type 2 diabetes. The former is due to the inability of pancreatic beta cells to produce enough insulin (absolute insulin deficiency), and the latter is due to insufficient insulin secretion or insulin resistance (relative insulin deficiency). About 90-95% of diabetic patients belong to type II diabetes. Currently common drugs for the treatment of type Ⅱ diabetes include insulin sensitizers (such as biguanides), insulin secretagogues (such as sulfonylureas), and DPP-IV inhibitors that have been marketed in recent years. However, these antid...

Claims

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Application Information

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IPC IPC(8): C07D309/10C07H15/04C07C25/18C07C17/35C07C39/367C07C37/00C07C43/225C07C41/18A61K31/351A61P3/10A61P9/10A61P25/00A61P13/12A61P17/02A61P5/50A61P3/06A61P3/04A61P3/00A61P9/12
CPCA61K31/351C07D309/10C07C25/18C07C39/367C07C43/225C07H15/04A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/10A61P9/12A61P13/12A61P17/02A61P25/00
Inventor 赵军岭胡文辉徐登峰丁宇洋杨玲徐宏江
Owner JIANGSU ALICORN PHARMATECH CO LTD
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