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Indole derivative and application of indole derivative in diabetes mellitus

A derivative, indole technology, applied in the field of indole derivatives and their application in diabetes, can solve the problems of short half-life, inactivation, etc.

Inactive Publication Date: 2018-09-04
王先化
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as the substrate of DPP-4, GLP-1 has a very short half-life and will be rapidly cut and inactivated by DPP-4 within 1-2 minutes after secretion.

Method used

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  • Indole derivative and application of indole derivative in diabetes mellitus
  • Indole derivative and application of indole derivative in diabetes mellitus
  • Indole derivative and application of indole derivative in diabetes mellitus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Synthesis of 4-(6-(naphthalene-2-yl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylic acid diethyl ester

[0032]

[0033] 1. Synthesis of (Z)-2-((6-bromo-1H-indol-2-yl)methylene)-4-methyl-3-oxopentanoic acid ethyl ester

[0034]

[0035] In a 150 mL round bottom flask equipped with a magnetic stirrer, put 6-bromo-1H-indole-2-carbaldehyde (compound 1) (8.07 g, 36.00 mmol), ethyl 4-methyl-3-oxopentanoate Ester (compound 2) (5.70 g, 36.03 mmol), isopropanol (21.1 mL), piperidine (2.2 mL) and glacial acetic acid (1.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved with dichloromethane (13.88 mL) and washed with saturated NaHCO 3 (3*30mL) solution washed with anhydrous MgSO 4 After drying, remove MgSO by filtration 4 , after concentrating the solvent under reduced pressure, flash column chromatography to obtain off-white solid (Z)-2-(...

Embodiment 2

[0045] Example 2: 4-(6-(4-methyl-naphthalen-2-yl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylic acid diethyl Synthesis of esters

[0046]

[0047] 4-methyl-naphthalene-2-boronic acid (19.60mmol), compound 5 (9.83g, 19.60mmol), Na 2 CO 3 (6.23g, 58.8mmol), DME (31.75mL) and H 2 O (7.83 mL) was added to a 100 mL microwave vial. vial with N 2 Degas for 1 h, then add PdCl 2 (dppf)CH 2 Cl 2 (1.73 g, 2.35 mmol) adduct. The reaction mixture was heated at 120 °C for 2 hours by microwave irradiation. The resulting mixture was diluted with ethyl acetate and filtered through celite, then concentrated in vacuo. Purification by flash chromatography using 0-100% ethyl acetate / heptane as eluent afforded 4-(6-(4-methyl-naphthalen-2-yl)-1H-indole-2 as an off-white solid -Diethyl)-2,6-diisopropylpyridine-3,5-dicarboxylate, 8.93 g, yield 81%. LC-MS (ESI, pos, ion) m / z: 563 [M+H].

Embodiment 3

[0048] Example 3: 4-(6-(4,5 Dimethyl-naphthalen-2-yl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylic acid Synthesis of Diethyl Ester

[0049]

[0050] 4,5 dimethyl-naphthalene-2-boronic acid (19.60mmol), compound 5 (9.83g, 19.60mmol), Na 2 CO 3 (6.23g, 58.8mmol), DME (31.75mL) and H 2 O (7.83 mL) was added to a 100 mL microwave vial. vial with N 2 Degas for 1 h, then add PdCl 2 (dppf)CH 2 Cl 2 (1.73 g, 2.35 mmol) adduct. The reaction mixture was heated at 120 °C for 2 hours by microwave irradiation. The resulting mixture was diluted with ethyl acetate and filtered through celite, then concentrated in vacuo. Purification by flash chromatography using 0-100% ethyl acetate / heptane as eluent afforded 4-(6-(4,5-dimethyl-naphthalen-2-yl)-1H-indole as an off-white solid Diethyl -2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylate, 8.70 g, yield 77%. LC-MS (ESI, pos, ion) m / z: 577 [M+H].

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PUM

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Abstract

The invention discloses an indole derivative represented by a formula I (as shown in the description) or a pharmaceutically acceptable salt of indole derivative, wherein R1, R2, R3 and R4 are respectively selected from H or CH3. The inhibition activity of a compound listed in an in-vitro DPP-4 enzyme inhibition test to DPP-4 is between the inhibition activities of Sitagliptin and omarigliptin. Theindole derivative represented by the formula I is a novel-structure DPP-4 inhibitor, the features of the indole derivative in pharmacology toxicology and pharmacokinetics are worthy of being relatively deeply researched, and a drug for treating and / or preventing non-insulin-dependent diabetes mellitus, hyperglycemia or insulin resistance can be obtained.

Description

technical field [0001] The invention relates to an indole derivative and its application in diabetes. Background technique [0002] Diabetes is a disease that seriously threatens human health due to absolute or relative insufficiency of insulin, resulting in elevated blood sugar, which can lead to serious complications and eventually disability or death. There are many kinds of traditional hypoglycemic drugs, mainly divided into insulin sensitizers (such as biguanides, thiazolidinediones, etc.) and insulin secretagogues (such as sulfonylureas and non-sulfonylureas), and so on. But these drugs do not prevent the progression of diabetes, and there are toxic side effects such as weight gain, hypoglycemia, and eventual loss of efficacy. Therefore, it is an urgent task to develop new antidiabetic drugs to prevent or even reverse the deterioration of the disease. [0003] Dipeptidyl peptidase IV (DPP-4) is a glycoprotein widely distributed in the human body. Its function is simi...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4439A61P3/10A61P5/50
CPCA61P3/10A61P5/50C07D401/04
Inventor 孟晓旭
Owner 王先化
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