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Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof

A technology of metronidazole and aryl, applied in the field of preparation of anti-gastritis and gastric ulcer drugs, can solve the problems of hindering application, low activity, large dosage, etc., and achieve a good effect of inhibiting activity

Inactive Publication Date: 2016-03-16
JISHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are some shortcomings in the existing urease inhibitors. For example, acetohydroxamic acid has some side effects due to its low activity and large dosage, while the highly active phosphodiamide urease inhibitors are unstable in acidic environments, hindering its clinical application

Method used

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  • Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof
  • Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof
  • Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Preparation of 2-(5-(O-metronidazol-2'-yl)-3-hydroxyphenylthio)acetohydroxamic acid (5)

[0022] Put 28.5g of 3,5-dihydroxythiophenol, 10g of NaOH, and 15mL of ethyl bromoacetate into a 100mL round-bottomed flask, add 50mL of DMSO, stir at 60°C for 16h, pour 20mL of distilled water into it, extract it with AcOEt, and wash the organic layer with Washed 3 times with saturated brine, anhydrous MgSO 4 Dry, evaporate the solvent, purify by silica gel column chromatography, volume ratio of eluent: AcOEt:petroleum ether=1:6, and obtain 21.5 g of ethyl 2-(3,5-dihydroxyphenylthio)acetate in yellow oily liquid. Dissolve 10.5g of ethyl 2-(3,5-dihydroxyphenylthio)acetate and 10g of metronidazole chloride in 50mL of absolute ethanol, 8g of anhydrous potassium carbonate, stir at room temperature for 0.5h, and heat to 60°C for 5h , add 30mL distilled water after distilling off ethanol, extract with AcOEt, combine organic layers, anhydrous MgSO 4 Dry, evaporate the solvent...

Embodiment 2

[0024] The aryl-linked metronidazole-amide derivative series compounds 1-72 listed in Table 1 were synthesized in the same manner as in Example 1, using different substituted forms of benzaldehyde as raw materials.

[0025] Each X, Y, Z group of aryl-linked metronidazole-amide derivative series compound in the general formula I of table 1

[0026]

[0027]

[0028]

[0029]

[0030] Note: The initial raw materials were purchased from aldrich company

Embodiment 3

[0031] Embodiment 3: the inhibitory enzyme activity of compound

[0032] Add 25 μL of Jackbean urease (4U) and 25 μL (1 mM) of the test compound solution to the 96-well plate, incubate at 37 °C for 2 h, then add 55 μL of phosphate buffer containing 100 mM urea and 100 mM, and incubate at 30 °C After incubating for 15 min, add 45 μL of phenol reagent (mixed solution containing 1% phenol and 0.005% sodium nitroprusside) and 70 μL alkali reagent (mixed solution of NaOCl containing 0.5% NaOH and 0.1% active chlorine), and place at room temperature After 50 minutes, measure the OD value at 630nm with a microplate reader, and the percentage inhibition rate is calculated according to the following formula:

[0033]

[0034] All experiments were carried out in solutions at pH 7.8 (0.01M K 2 HPO 4 , 1mM EDTA, 0.01M LiCl), the level of activity is measured by the half-inhibition rate IC 50 to indicate that the IC 50 The smaller the value, the higher the activity of the compound. ...

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Abstract

The invention provides an aryl connected metronidazole-amide derivative series compound. The compound has a structural general formula as shown in the specification, has a relatively good inhibition effect on urease, and can be used for preparing medicines for resisting gastritis, gastric ulcer, lithangiuria and the like. The invention further discloses a preparation method and application of the compound.

Description

technical field [0001] The invention relates to a preparation method of a class of aryl-linked metronidazole-amide type urease inhibitors and their application in the preparation of anti-gastritis and gastric ulcer drugs. technical background [0002] Helicobacter pylori can cause gastritis, gastric ulcer, duodenal ulcer, gastric atrophy, intestinal metaplasia, gastric cancer, gastric lymphoma and other diseases. In 1994, the World Health Organization and the International Cancer Research Center listed H. pylori as the first type of carcinogen. According to statistics, about half of the world's population is infected with H. pylori, and the infection rate is as high as 80-90% in developing countries. The infection rate in our country is about 60%. The detection rate of H.pylori in patients with gastritis is 80-90%, and it is higher in patients with peptic ulcer, reaching more than 95%. More than 90% of duodenal ulcers and about 80% of gastric ulcers are caused by H. pylor...

Claims

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Application Information

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IPC IPC(8): C07D233/94A61P1/04A61P13/02
CPCC07D233/94
Inventor 肖竹平师维康李玲霞吴浪舟罗兴祝璇
Owner JISHOU UNIVERSITY
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