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Pleuromutilin derivative containing 1, 2, 4-triazole acrylamide side chain as well as preparation method and application of pleuromutilin derivative

A technology of triazole acrylamide and pleuromutilin, which is applied in the field of pleuromutilin derivatives and its preparation, can solve the problem of low drug resistance, and achieve the effects of high safety, convenient operation and low cost

Pending Publication Date: 2022-06-07
西安康远晟生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the high conservation of PTC, its drug resistance is low

Method used

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  • Pleuromutilin derivative containing 1, 2, 4-triazole acrylamide side chain as well as preparation method and application of pleuromutilin derivative
  • Pleuromutilin derivative containing 1, 2, 4-triazole acrylamide side chain as well as preparation method and application of pleuromutilin derivative
  • Pleuromutilin derivative containing 1, 2, 4-triazole acrylamide side chain as well as preparation method and application of pleuromutilin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] (1) Preparation of Intermediate I

[0072]

[0073] Pleuromutilin (757.0 mg, 2 mmol) and p-toluenesulfonyl chloride (418.0 mg, 2.2 mmol) were dissolved in dichloromethane (30 mL), placed in a reactor, TEA (0.8 mL, 6 mmol) and DMAP (24.4 mg, 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) in a yield of 95.0%. The prepared intermediate I was used as the starting material for intermediate II.

[0074] (2) Preparation of Intermediate II

[0075]

[0076] To a solution of 3-mercapto-1,2,4-triazole (242.7 mg, 2.4 mmol) in dichloromethane (10 mL) was added 1,8-diazabicycloundec-7-ene dropwise (DBU) (1.3 mL, 9 mmol), and the mixture was stirred at room temperature for 30 min, and then a solution of intermediate I (1065.4 mg, 2.0 mmol) in dichloromethane (10 mL) wa...

Embodiment 2

[0084] Compound 2: (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4 ,9a-propylcyclopent[8]cycloalken-5-yl 2-((1-((E)-3-(4-(trifluoromethyl)phenyl)acryloyl)-1H-1,2 Preparation of ,4-triazol-3-yl)thio)acetate

[0085]

[0086] The preparation process of intermediate I and intermediate II was the same as that of Example 1. 4-Trifluorocinnamic acid (23.9 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), placed in a reactor, and DCC was added to the reaction solution. (41.2 mg, 0.2 mmol) and NMM (0.019 mL, 0.17 mmol), activated for 30 min, added Intermediate II (64.6 mg, 0.14 mmol), reacted at room temperature for 7 h, concentrated the reaction solution under reduced pressure, and the residue was subjected to column chromatography (200 -300-mesh silica gel powder was used as the stationary phase, and the mobile phase was petroleum ether:ethyl acetate (V:V)=1:1), and dried to obtain the final product compound 2 (51.632 mg, 0.112 ...

Embodiment 3

[0090] Compound 3: (3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4 ,9a-Propcyclopenta[8]cycloalken-5-yl 2-((1-((E)-3-(thiophen-3-yl)acryloyl)-1H-1,2,4-triazole- Preparation of 3-yl)thio)acetate

[0091]

[0092] The preparation process of intermediate I and intermediate II was the same as that of Example 1. Trans-3-(3-thienyl)acrylic acid (24.7 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL), placed in a reactor, and added to the reaction solution. Add EDCI (38.4 mg, 0.2 mmol), HOBT (27 mg, 0.2 mmol) and TEA (0.023 mL, 0.17 mmol), activate for 30 min, add intermediate II (64.6 mg, 0.14 mmol), react at room temperature for 9 h, and concentrate under reduced pressure The reaction solution and the residue were separated and purified by column chromatography (200-300 mesh silica gel powder was the stationary phase, and the mobile phase was dichloromethane:methanol (V:V)=30:1), and dried to obtain the final product compound 3 (50....

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Abstract

The invention discloses a pleuromutilin derivative containing a 1, 2, 4-triazole acrylamide side chain as well as a preparation method and application of the pleuromutilin derivative, and belongs to the field of medical chemistry. According to the compound, pleuromutilin and different substituted acrylic acid are used as raw materials, 3-sulfydryl-1, 2, 4-triazole is used as a connector under the action of a catalyst, and the pleuromutilin derivative which is not reported, has the activity of resisting drug-resistant bacteria and contains a 1, 2, 4-triazole acrylamide side chain is synthesized. The synthesis method is high in operation safety, mild in reaction condition and suitable for industrial production. Preliminary biological activity tests and safety evaluation show that the pleuromutilin derivative containing the 1, 2, 4-triazole acrylamide side chain and having the drug-resistant bacterium resisting activity has good drug-resistant bacterium resisting activity and safety, so that the pleuromutilin derivative can be applied to treatment of infectious diseases, especially infectious diseases caused by drug-resistant bacteria, and has good application prospects. The medicine development value is very good.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative containing a 1,2,4-triazole acrylamide side chain and a preparation method and application thereof. Background technique [0002] Pleuromutilin is a white crystal isolated from the fermentation broth of Basidiomycetes Pleurotus mutilus. and Pleurotus Passeckerianus. It is a tricyclic diterpenoid with a molecular formula of C 22 H 34 O 5 . According to research, it has a good inhibitory effect on Gram-positive bacteria. Pleuromutilin antibacterial drugs are different from other marketed antibacterial drugs. It acts on the bacterial ribosomal peptidyl transfer center (PTC), interfering with the binding of tRNA to P-site and A-site, thereby inhibiting protein synthesis. However, due to the high conservation of PTC, its drug resistance is low. Therefore, pleuromutilin antibiotics are resistant to resistant Gram-positive bacteria, such as ...

Claims

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Application Information

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IPC IPC(8): C07D249/12C07D409/06C07D401/06A61K31/4196A61K31/4439A61P31/00A61P31/04
CPCC07D249/12C07D409/06C07D401/06A61P31/00A61P31/04Y02P20/55
Inventor 张少军万佳孔纯纯梁承远辛亮武康雄韩俊杰彭兆瑞
Owner 西安康远晟生物医药科技有限公司
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