A kind of dpp-4 inhibitor and its preparation and application in diabetes

A technology of DPP-4 and inhibitors, applied in the fields of metabolic diseases, endocrine system diseases, organic chemistry, etc., can solve the problems of short half-life and inactivation

Active Publication Date: 2020-04-03
张爱芳
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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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  • A kind of dpp-4 inhibitor and its preparation and application in diabetes
  • A kind of dpp-4 inhibitor and its preparation and application in diabetes
  • A kind of dpp-4 inhibitor and its preparation and application in diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Synthesis of 4-(6-(1-cyclohexylvinyl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylic acid diethyl ester

[0031]

[0032] 1. Synthesis of (Z)-2-((6-bromo-1H-indol-2-yl)methylene)-4-methyl-3-oxopentanoic acid ethyl ester

[0033]

[0034] 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 gave off-white solid (Z)-2-((6-br...

Embodiment 2

[0044] Example 2: 4-(6-(1-(2-trifluoromethylcyclohexyl)vinyl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5- Synthesis of Diethyl Diformate

[0045]

[0046] (1-(2-trifluoromethylcyclohexyl) vinyl) 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-(1-(2-trifluoromethylcyclohexyl)vinyl)-1H- as an off-white solid Diethyl indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylate, 10.09 g, yield 86%. LC-MS (ESI, pos, ion) m / z: 599 [M+H].

Embodiment 3

[0047] Example 3: 4-(6-(1-(4-trifluoromethylcyclohexyl)vinyl)-1H-indol-2-yl)-2,6-diisopropylpyridine-3,5- Synthesis of Diethyl Diformate

[0048]

[0049] (1-(4-trifluoromethylcyclohexyl) vinyl) 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-(1-(4-trifluoromethylcyclohexyl)vinyl)-1H- as an off-white solid Diethyl indol-2-yl)-2,6-diisopropylpyridine-3,5-dicarboxylate, 9.15 g, yield 78%. LC-MS (ESI, pos, ion) m / z: 599 [M+H].

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PUM

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Abstract

The invention discloses a compound shown in a formula I or pharmaceutically acceptable salts of the compound; the formula I is described in the description, wherein R1, R2, R3, R4 and R5 are independently selected from H or CF3. The IC50 values, for the dipeptidyl peptidase-IV (DPP-4), of compounds listed in in-vitro DPP-4 enzyme inhibition tests are less than those of omarigliptin and Sitagliptin. The compound provided by the invention is proved to have better DPP-4 inhibitory activity, thus being used as a medicine for treating and / or preventing non-insulin-dependent diabetes, hyperglycemiaor insulin resistance for further study.

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 Patents(China)
IPC IPC(8): C07D401/04A61P3/10A61P5/50
CPCA61P3/10A61P5/50C07D401/04
Inventor 张爱芳孟晓旭
Owner 张爱芳
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