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Diaryl propionyl-N-methyl hydroxamic acid type urease inhibitor and synthesis and application thereof

A technology of diarylpropionyl and methyl hydroxamic acid, which can be used in drug combination, urinary system diseases, digestive system and other directions, can solve the problems of low activity, hindering application, large dosage and the like

Inactive Publication Date: 2013-04-03
党晓琴
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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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  • Diaryl propionyl-N-methyl hydroxamic acid type urease inhibitor and synthesis and application thereof
  • Diaryl propionyl-N-methyl hydroxamic acid type urease inhibitor and synthesis and application thereof
  • Diaryl propionyl-N-methyl hydroxamic acid type urease inhibitor and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of 3-(3-hydroxyphenyl)-3-(2,3,4-trihydroxyphenyl)-3-hydroxypropionyl-N-methylhydroxamic acid (50)

[0039] Add 2.52g pyrogallic acid to 20ml BF 3 ·Et 2 O, then add 3.31g of m-hydroxybenzoic acid, heat up to 85°C and react for 15h. After the reaction is complete, pour it into the aqueous solution of AcONa, filter with suction, wash, and EtOH-H 2 O recrystallized to obtain 3.78 g of 3-hydroxyphenyl-2,3,4-trihydroxyphenyl ketone, yield 77%;

[0040] 2.46g of 3-hydroxyphenyl-2,3,4-trihydroxyphenyl ketone, 6.5g of Zn powder, 4.82g of NH 4 Cl and 4.45mL ethyl bromoacetate were ground together until uniform. After standing at room temperature for 18 h, pour saturated NH 4 Cl solution, AcOEt extraction, anhydrous MgSO 4 Dry, evaporate the solvent, purify with silica gel column, eluent volume ratio: AcOEt:petroleum ether=1:2, get 3-hydroxyl-3-(3-hydroxyphenyl)-3-(2,3,4- Trihydroxyphenyl) ethyl propionate, 2.17g, productive rate 65%;

[0041] Dissolv...

Embodiment 2

[0043] The diaryl propionyl-N-methylhydroxamic acid series compounds 1-86 listed in Table 1 were synthesized in the same manner as in Example 1, using different substituted forms of benzoic acid and benzene as raw materials.

[0044] Each R group of diaryl propionyl-N-methyl hydroxamic acid series compound in the general formula I of table 1

[0045] serial number

[0046] serial number

[0047] serial number

[0048] serial number

[0049] Note: The initial raw materials were purchased from aldrich company

Embodiment 3

[0050] Embodiment 3: the inhibitory enzyme activity of compound

[0051] Add 25 μL of Jack bean 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. Incubate at ℃ 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), at room temperature After standing for 50 minutes, measure the OD value at 630nm with a microplate reader, and the percentage inhibition rate is calculated according to the following formula:

[0052]

[0053] All experiments were performed in solutions at pH 8.2 (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 relates to diaryl propionyl-N-methyl hydroxamic acid compounds which have a structural general formula shown in the specification. The diaryl propionyl-N-methyl hydroxamic acid compounds have a good function of inhibiting urease, and can be used for preparing medicaments for resisting gastritis, gastric ulcer, lithangiuria and the like. The invention also discloses a method for preparing the diaryl propionyl-N-methyl hydroxamic acid compounds.

Description

technical field [0001] The invention relates to a preparation method of a class of diarylpropionyl-N-methylhydroxamic acid urease inhibitors and their application in the preparation of anti-gastritis and gastric ulcer drugs. technical background [0002] Helicobacter pylari 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. py...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06A61P1/04A61P13/02
Inventor 肖竹平王旭东易利成胡小军杨盼
Owner 党晓琴
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