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DPP-4 inhibitor, preparation method thereof and application of DPP-4 inhibitor in diabetes mellitus

A DPP-4, inhibitor technology, applied in metabolic diseases, medical preparations containing active ingredients, organic active ingredients, etc., can solve problems such as inactivation and short half-life

Active Publication Date: 2018-10-26
中昱医学检验(广州)有限公司
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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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  • DPP-4 inhibitor, preparation method thereof and application of DPP-4 inhibitor in diabetes mellitus
  • DPP-4 inhibitor, preparation method thereof and application of DPP-4 inhibitor in diabetes mellitus
  • DPP-4 inhibitor, preparation method thereof and application of DPP-4 inhibitor in diabetes mellitus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Synthesis of 4-(8-(thiophen-2-yl)-quinolin-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylic acid diethyl ester

[0031]

[0032] 1. Synthesis of (Z)-2-((8-bromo-quinolin-2-yl)methylene)-4-methyl-3-oxopentanoic acid ethyl ester

[0033]

[0034] In a 150 mL round bottom flask equipped with a magnetic stirrer, 8-bromo-quinoline-4-carbaldehyde (compound 1) (8.50 g, 36.00 mmol), ethyl 4-methyl-3-oxopentanoate ( 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-((8-bromo-qui...

Embodiment 2

[0044] Example 2: Diethyl 4-(8-(5-methoxy-thiophen-2-yl)-quinolin-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylate Synthesis

[0045]

[0046] 5-Methoxy-thiophene-2-boronic acid (19.60mmol), compound 5 (9.69g, 18.87mmol), 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-(8-(5-methoxy-thiophen-2-yl)-quinoline-2- as an off-white solid Base)-2,6-diisopropylpyridine-3,5-dicarboxylate, 8.56g, yield 83%. LC-MS (ESI, pos, ion) m / z: 547 [M+H].

Embodiment 3

[0047] Example 3: Diethyl 4-(8-(3-methoxy-thiophen-2-yl)-quinolin-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylate Synthesis

[0048]

[0049] 3-Methoxy-thiophene-2-boronic acid (19.60mmol), compound 5 (9.69g, 18.87mmol), 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-(8-(3-methoxy-thiophen-2-yl)-quinoline-2- as an off-white solid Base)-2,6-diisopropylpyridine-3,5-dicarboxylate, 8.67g, yield 84%. LC-MS (ESI, pos, ion) m / z: 547 [M+H].

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PUM

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Abstract

The invention discloses a compound or pharmaceutically acceptable salt thereof shown as a formula I (the formula l is shown in the following description), wherein R1, R2 and R3 are each independentlyselected from H or OCH3. In an in-vitro DDP-4 enzyme inhibition test, IC50 values of listed compounds to DDP-4 are all smaller than omarigliptin and Sitagliptin. The test shows that the compound provided by the invention has better DDP-4 inhibition activity and can be used for deeper study as a drug for treating and / or preventing non-insulin-dependent diabetes mellitus, hyperglycemia or insulin resistance.

Description

technical field [0001] The invention relates to a DPP-4 inhibitor, its preparation and 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 functi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14A61K31/4709A61P3/10
CPCA61P3/10C07D409/14
Inventor 孟晓旭
Owner 中昱医学检验(广州)有限公司
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