Pleuromutilin derivative containing thiazole-picolyl heteroaromatic quaternary ammonium salt side chain as well as preparation method and application of pleuromutilin derivative

A technology of pleuromutilin and picolylmethylaron, which is applied in the field of pleuromutilin derivatives and its preparation, can solve problems such as untreatable, multi-drug resistance, adverse reactions that cannot be widely used, etc., to improve poor water solubility, The effect of excellent antibacterial activity

Pending Publication Date: 2022-05-27
SHAANXI UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Due to the widespread use and even abuse of antibiotics, many bacteria have developed increasingly serious multidrug resistance, which has become a huge threat to global human health and a public health crisis. Existing antibiotics such as cephalosporins, aminoglycosides, macrocyclic endogenous Esters and even polymyxins have been unable to treat infections caused by some "super bacteria", or cannot be widely used due to serious adverse reactions. Explore antibiotics with new antibacterial mechanisms, good bioavailability and low toxicity key to drug development

Method used

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  • Pleuromutilin derivative containing thiazole-picolyl heteroaromatic quaternary ammonium salt side chain as well as preparation method and application of pleuromutilin derivative
  • Pleuromutilin derivative containing thiazole-picolyl heteroaromatic quaternary ammonium salt side chain as well as preparation method and application of pleuromutilin derivative
  • Pleuromutilin derivative containing thiazole-picolyl heteroaromatic quaternary ammonium salt side chain as well as preparation method and application of pleuromutilin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] (1) Preparation of Intermediate I

[0061]

[0062] Pleuromutilin (757mg, 2mmol) and p-toluenesulfonyl chloride (456mg, 2.4mmol) were dissolved in dichloromethane (80mL), placed in a reactor, TEA (0.8mL, 6mmol) and DMAP (24.4mg, 0.2 mmol), stirred at room temperature for 5 h. The reaction solution was concentrated under reduced pressure, and the concentrated product was washed with saturated aqueous sodium bicarbonate solution (50 mL) to obtain Intermediate I (1012.1 mg, 1.9 mmol) with a yield of 95.0%. The prepared intermediate I was used as the starting material for intermediate II.

[0063] (2) Preparation of Intermediate II

[0064]

[0065] Intermediate I (1012.1 mg, 1.9 mmol) and 2-mercapto-4-(4-pyridyl)thiazole (388 mg, 2 mmol) were dissolved in N,N-dimethylformamide (40 mL) and placed in a reactor , potassium carbonate (524.4 mg, 3.8 mmol) and potassium iodide (31.54 mg, 0.19 mmol) were added, and the reaction was heated at 60 °C for 6 h. After the rea...

Embodiment 2

[0073] Compound 2: 4-(2-((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7- Vinyldecahydro-4,9a-propacyclopent[8]cycloalken-5-yl)oxy)-2-oxoethyl)thiazol-4-yl)-1-((5-nitrofuran- Preparation of 2-yl)methyl)pyridyl bromide salt

[0074]

[0075] The preparation process of intermediate I and intermediate II was the same as that of Example 1. Intermediate II (166 mg, 0.3 mmol) and 2-bromomethyl-5-nitrofuran (247.2 mg, 1.2 mmol) were dissolved in dichloromethane ( 10 mL), placed in a reactor, reacted at room temperature for 9 h, concentrated the solvent under reduced pressure, and separated and purified the residue by column chromatography (200-300 mesh silica gel powder was the stationary phase, and the mobile phase was dichloromethane: methanol (V: V) =20:1), dried to give compound 2 (108.68 mg, 0.143 mmol) in 47.7% yield. figure 1 is the hydrogen NMR spectrum of compound 2 in deuterated DMSO, figure 2 C NMR spectrum of compound 2 in deuterated DMSO...

Embodiment 3

[0079]Compound 3: 4-(2-((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7- Vinyldecahydro-4,9a-propacyclopent[8]cycloalken-5-yl)oxy)-2-oxoethyl)thiazol-4-yl)-1-(thiophen-3-ylmethyl) ) Preparation of pyridyl bromide salt

[0080]

[0081] The preparation process of intermediate I and intermediate II was the same as that of Example 1. Intermediate II (166 mg, 0.3 mmol) and 3-bromomethylthiophene (212.4 mg, 1.2 mmol) were dissolved in acetonitrile (10 mL) and placed in a reactor. , react at room temperature for 8 hours, concentrate the solvent under reduced pressure, and separate and purify the residue by column chromatography (200-300 mesh silica gel powder is the stationary phase, and the mobile phase is dichloromethane:methanol (V:V)=20:1), dry Compound 8 (125.73 mg, 0.172 mmol) was obtained in 57.3% yield.

[0082] 1 H NMR(600MHz, DMSO)δ9.35(d,J=6.5Hz,2H),9.21(s,1H),8.88(d,J=6.4Hz,2H),7.67(d,J=4.2Hz,1H) ), 7.31(d, J=4.2Hz, 1H), 6.21(s, 2H), 6.1...

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Abstract

The invention discloses a pleuromutilin derivative containing a thiazole-picolyl heteroaromatic quaternary ammonium salt side chain as well as a synthesis method and application of the pleuromutilin derivative, and belongs to the field of medical chemistry. The pleuromutilin derivative is prepared by taking pleuromutilin and different substituted aromatic heterocyclic ring bromides as raw materials and taking thiazole-pyridine as a connector under the action of a catalyst, and the prepared pleuromutilin derivative containing the thiazole-picolyl aromatic heterocyclic ring quaternary ammonium salt side chain is not reported yet. Preliminary biological activity test evaluation shows that the pleuromutilin derivative containing the thiazole-picolyl heteroaromatic quaternary ammonium salt side chain has good antibacterial activity, and especially for drug-resistant bacteria, the drug effect of the pleuromutilin derivative is significantly superior to that of three commercially available pleuromutilin antibiotics; the results show that the gene has important value in the development of drugs for resisting drug-resistant bacteria.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a pleuromutilin derivative containing a side chain of a thiazole-pyridylmethyl aromatic heterocyclic quaternary ammonium salt, and a preparation method and application thereof. Background technique [0002] Due to the widespread use and even abuse of antibiotics, many bacteria have developed increasingly serious multi-drug resistance, which has become a huge threat to global human health and a public health crisis. Existing antibiotics such as cephalosporins, aminoglycosides, macrocyclic Esters and even polymyxins are no longer untreatable for infections caused by some "superbugs", or they cannot be widely used due to severe adverse reactions. Explore antibiotics with novel mechanisms of antibacterial action, good bioavailability and less toxicity is now the key to drug development. [0003] Pleuromutilin is a white crystal isolated from the fermentation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/4439A61P31/04
CPCC07D417/14A61P31/04Y02A50/30
Inventor 梁承远范明明辛亮李京忆田蕾张洁赵宇晴张少军武康雄彭兆瑞
Owner SHAANXI UNIV OF SCI & TECH
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