Complex of azepine-fused triazole ring and indole carboxylic acid and salt, preparation method and medical application thereof

A technology for compounds and mixtures, applied in the field of their preparation, complexes of heterozotriazole rings and indole carboxylic acids and their salts, can solve problems such as no effective medicines yet

Active Publication Date: 2021-03-23
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Metformin is currently the most widely used antidiabetic drug. It is generally believed that it lowers blood sugar by inhibiting hepatic gluconeogenesis; while in the field of glycogen degradation, there is no effective drug

Method used

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  • Complex of azepine-fused triazole ring and indole carboxylic acid and salt, preparation method and medical application thereof
  • Complex of azepine-fused triazole ring and indole carboxylic acid and salt, preparation method and medical application thereof
  • Complex of azepine-fused triazole ring and indole carboxylic acid and salt, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 3-[(5-chloro-1H-indole-2-carboxamido)methyl]-7,8-dihydro-4H-[1,2,3]triazole[1,5-a ][1,4]diazepine-5(6H)-tert-butyl carboxylate

[0039]

[0040]Dissolve 5-chloroindole-2-carboxylic acid (200mg, 1.02mmol) in DMF (10mL), add EDCI (235mg, 1.23mmol), HOBT (165.6mg, 1.23mmol), DIPEA (0.54mL, 3.08mmol), under nitrogen protection, stirred at 0°C for 30min, added 3-(aminomethyl-7,8-dihydro-4H-[1,2,3]triazole[1,5-a][1,4 ]diazepine-5(6H)-tert-butyl carboxylate (272.3mg, 1.02mmol), then stirred overnight at room temperature, poured the reaction solution into ice water, extracted with ethyl acetate (15mL×3), and washed with saturated salt The organic phase was washed with water (15mL×3), dried over anhydrous magnesium sulfate for 2-3h, and subjected to silica gel column chromatography (CH 2 Cl 2 / CH 3 OH 100 / 3, V / V) to give a white solid (400mg, 88%).

Embodiment 2

[0041] Example 2 N-[(5,6,7,8-tetrahydro-4H-[1,2,3]triazol[1,5-a][1,4]diazepine-3-yl) Methyl]-5-chloro--1H-indole-2-carboxamide

[0042]

[0043] 3-[(5-chloro-1H-indole-2-carboxamido)methyl]-7,8-dihydro-4H-[1,2,3]triazole[1,5-a][ 1,4] Diazepine-5(6H)-tert-butyl carboxylate (400 mg, 0.90 mmol) was dissolved in 60 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added dropwise in an ice-water bath. After 30 min, the ice-water bath was removed, and the Stir for 4 h, stop the reaction, evaporate the solvent to dryness under reduced pressure, dissolve the residue with 30 mL of ethyl acetate, wash the organic phase with saturated sodium bicarbonate solution and saturated brine (15 mL×3), and dry over anhydrous magnesium sulfate for 2-3 h. Concentrate, dry the sample, and take it directly to the next step without further purification.

Embodiment 3

[0044] Example 3 (R)-N-({5-[2-(3-hydroxypyrrolidin-1-yl)acetyl]-5,6,7,8-tetrahydro-4H-[1,2,3 ]triazol[1,5-a][1,4]diazepine-3-yl}methyl)-5-chloro-1H-indole-2-carboxamide

[0045]

[0046] Dissolve (R)-2-(3-hydroxypyrrolidin-1-yl)acetic acid (145mg, 1mmol) in DMF (8mL), add EDCI (230mg, 1.2mmol) while stirring, HOBT (162mg, 1.2mmol ), DIPEA (0.52mL, 3mmol), under nitrogen protection, stirred for 30min at 0°C, added N-[(5,6,7,8-tetrahydro-4H-[1,2,3]triazole[1,5 -a][1,4]diazepine-3-yl)methyl]-5-chloro-1H-indole-2-carboxamide (150.5mg, 0.50mmol), then stirred at room temperature overnight, and the reaction solution Pour into ice water, extract with ethyl acetate (15mL×3), wash the organic phase with saturated brine (15mL×3), dry over anhydrous magnesium sulfate for 2-3h, perform silica gel column chromatography (CH 2 Cl 2 / CH 3 OH100 / 3, V / V) to obtain a white solid (117.8 mg, 50%).

[0047] HPLC analysis: 98.5%.

[0048] ESI-MS m / z:472.1(M+H)+.

[0049] 1 H-NMR(400MHz,d6...

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Abstract

The invention relates to a complex of an azepine-fused triazole ring and indole carboxylic acid, which has glycogen phosphorylase inhibitory activity and is shown in a formula (I), a salt of the complex, a preparation method of the complex and application of the complex to preparation of medicines for treating and / or preventing diseases related to abnormal glycogen metabolism.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a complex of heterozolotriazole ring and indole carboxylic acid as a glycogen phosphorylase inhibitor and a salt thereof, a preparation method and a medical application thereof. Background technique [0002] The main feature of diabetes is that the concentration of glucose in the blood is higher than the normal level for a long time, and there are two main sources of blood sugar: glycogenolysis and gluconeogenesis. According to relevant research reports, in the fasting state, about 3 / 4 of the fasting blood sugar comes from the glycogenolysis of the liver, and the rest comes from the gluconeogenesis of the liver. In patients with type 2 diabetes, the rate of hepatic glucose production is significantly increased and hepatic glucose production is high. Therefore, inhibiting hepatic glucose production has become one of the important targets for the development of new antidiabetic ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/551A61P3/10A61P3/06A61P9/10A61P9/04A61P9/00A61P5/48A61P35/00
CPCA61P3/06A61P3/10A61P5/48A61P9/00A61P9/04A61P9/10A61P35/00C07D487/04
Inventor 燕志卫张丽颖
Owner CHENGDE MEDICAL UNIV
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