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Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug

A heterocyclic and aromatic heterocyclic technology is applied in the application field of preparing medicines for the treatment of diabetes and metabolic syndrome, and can solve the problems of side effects, weight gain, edema side effects and the like

Inactive Publication Date: 2016-05-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing methods for the treatment of diabetes all have certain defects.
Examples include insulin injections and sulfonylureas, which may cause hypoglycemia and weight gain; metformin, alpha-glucosidase inhibitors, and GLP-1 analogs, which may cause gastrointestinal side effects; PPAR-γ agonists, which may cause weight gain and edema side effects; DPP-IV inhibitors may cause suprapharyngitis, headache and infection side effects

Method used

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  • Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug
  • Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug
  • Novel nitrogen-containing heterocyclic derivative and preparation method thereof and application of derivative by serving as drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] (6-Hydroxy-1-benzofuran-3-yl)methyl acetate

[0083]

[0084] Ethyl 4-chloroacetoacetate (4.25ml, 31.43mmol) was dissolved in 20ml of concentrated sulfuric acid at 0°C, and the formed pale yellow viscous solution was cooled to about -5°C in an ice bath, and resorcinol ( 3.15g, 28.57mmol), the internal temperature was controlled below 0°C, the addition was completed, stirred at room temperature for 2h, the reaction solution was poured into 50ml of ice water, a white solid precipitated, suction filtered, washed with water (5ml×2) filter cake, and dried to obtain rice White solid 5.6g, crude product yield 82%.

[0085]Take the above crude product (2g, 9.50mmol) in a 200ml single-necked bottle, add 1N NaOH solution (100ml), the solution immediately becomes thick yellow, the above solution is placed in an oil bath and heated to reflux for 2h, after the reaction is complete, cool to room temperature, and Adjust the pH to 2-3 with sulfuric acid, extract the resulting solut...

Embodiment 2

[0088] (6-Hydroxy-2,3-dihydro-1-benzofuran-3-yl)methyl acetate (V)

[0089]

[0090] The raw material methyl ester (2g, 9.71mmol) was dissolved in methanol, a catalytic amount of palladium carbon was added 0.2g, replaced by hydrogen three times, hydrogen was introduced and stirred at room temperature for 24h, after the reaction was completed, filter with diatomaceous earth as a bedding, and wash the filter cake , The solvent was distilled off from the filtrate under reduced pressure to obtain 1.93 g of an off-white powdery solid, with a yield of 95%. 1 HNMR (300MHz, CDCl 3 )δ: 6.97 (d, J = 8.71Hz, 1H, ArH), 6.31-6.34 (m, 2H, ArH), 4.82 (brs, 1H, ArOH), 4.75 (t, J = 9.10Hz, 1H, -OCH 2 ), 4.26, 4.24 (dd, J=5.72, 9.10Hz, 1H, -OCH 2 ), 3.74-3.84 (m, 1H, ArCH), 3.72 (s, 3H, -OCH 3 ), 2.74, 2.69 (dd, J=5.72, 16.41Hz, 1H, -COCH 2 ), 2.55, 2.50 (dd, J=9.11, 16.41Hz, 1H, -COCH 2 ).

Embodiment 3

[0092] 2-(6-(3-(piperidin-1-yl)benzyloxy)-2,3-dihydro-1-benzofuran-3-yl)acetic acid (I-1)

[0093]

[0094] The first step: methyl 3-iodobenzoate (1g, 3.82mmol), piperidine (0.76ml, 7.63mmol), potassium carbonate (2.11g, 15.26mmol), cuprous iodide (0.15g, 0.76mmol), L-proline (0.18g, 1.53mmol) was miscible in 20ml of DMSO, heated at 60°C for 8h under nitrogen protection, diluted with 200ml of water, extracted with ethyl acetate (30ml×3), combined the organic phases, and washed with saturated saline (15ml×2), washed with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a yellow-brown oil, which was purified by column chromatography (petroleum ether / ethyl acetate, 95:5, v / v) to obtain Color oil VI-10.61g, yield 84%.

[0095] 1 HNMR (300MHz, DMSO-d 6 )δ: 7.43 (s, 1H, ArH), 7.33-7.29 (m, 2H, ArH), 7.24-7.18 (m, 1H, ArH), 3.82 (s, 3H, -OMe), 3.22-3.10 (m, 4H, 2×NCH 2 ), 1.71-1.44 (m, 6H, -CH 2 CH 2 ...

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Abstract

The invention relates to a novel nitrogen-containing heterocyclic derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The nitrogen-containing heterocyclic derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.

Description

technical field [0001] The invention relates to the field of pharmacology related to diabetes, in particular to a novel nitrogen-containing heterocyclic derivative, its preparation method and the application of a pharmaceutical composition containing the derivative in the preparation of medicines for treating diabetes and metabolic syndrome. The structure of the nitrogen-containing heterocyclic derivative involved in the present invention is unique and novel in the structure modification of this type of compound. Background technique [0002] Diabetes is a disease of energy metabolism and is divided into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes). At present, there are about 366 million diabetic patients in the world, accounting for 6.4% of the world's population, and type 2 diabetic patients account for about 90-95% of the total number of diabetic patients. [0003] Diabetes can be treated with diet and exercise. When...

Claims

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Application Information

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IPC IPC(8): C07D307/79C07D405/12A61P3/10A61P3/00
CPCC07D307/79C07D405/12
Inventor 黄文龙钱海李政杨建勇苏欣潘渺博
Owner CHINA PHARM UNIV
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