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Pleuromutilin derivative with amide side chain as well as preparation and application of pleuromutilin derivative

A technology for pleuromutilin and derivatives, which is applied in the fields of pleuromutilin derivatives and their preparation and application, can solve the problems of rare pleuromutilin antibiotic-resistant bacteria and the like

Active Publication Date: 2020-08-25
SOUTH CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Compared with dozens of antibacterial drugs such as penicillins, cephalosporins, and sandacins that have been successfully developed based on the same mother core, only four antibacterial drugs have been successfully developed for pleuromutilin. resistant bacteria are rare

Method used

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  • Pleuromutilin derivative with amide side chain as well as preparation and application of pleuromutilin derivative
  • Pleuromutilin derivative with amide side chain as well as preparation and application of pleuromutilin derivative
  • Pleuromutilin derivative with amide side chain as well as preparation and application of pleuromutilin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115](1) Preparation of Intermediate I: Dissolve 10.0g (26.5mmol) pleuromutilin in 20ml pyridine and place in an ice bath; dissolve 5.6g (29.2mmol) p-toluenesulfonyl chloride in 10ml pyridine, then slowly add For the above-mentioned pleuromutilin pyridine solution, after stirring the mixture in an ice bath for 3 h, add 50 ml each of ice water and chloroform in turn, then transfer to a separatory funnel for shaking, and let it stand until it is separated; take the organic phase, Wash with 100ml of 4mol / L sulfuric acid, 100ml of saturated sodium bicarbonate solution, and 100ml of deionized water in sequence; after washing, the organic phase evaporates the organic solution under reduced pressure, adds 20ml of isopropanol to the remaining solid, heats and dissolves, and then let cool to precipitate A large amount of white powder was suction-filtered, and the filter residue was washed with isopropanol and dried to obtain intermediate I with the structure shown in formula 3, with a ...

Embodiment 2

[0119] Example 2 Synthesis of 22-O-(benzamido)acetylmurein (compound 1)

[0120] Take 1g (2.65mmol) of Intermediate III and dissolve it in 23ml of dichloromethane, get 0.73g (5.30mmol) of anhydrous potassium carbonate and add it to the reaction system; dissolve 0.41g (2.92mmol) of benzoyl chloride in a small amount of dichloromethane, Slowly add dropwise to the above reaction system under ice-bath conditions, then stir the mixture in ice-bath for 3 hours, then add 50ml each of ice water and chloroform in turn, then transfer to a separatory funnel for shaking, and let it stand for layering. The organic phase was washed twice with aqueous sodium chloride solution (15% w / v) and dried over anhydrous sodium sulfate, and the organic phase was taken; the obtained organic phase was evaporated to dryness to obtain a mixture, redissolved in dichloromethane, and added with 100- 200 mesh silica gel 2g was fully mixed, and after the solvent evaporated, the above-mentioned crude product-sil...

Embodiment 3

[0121] Example 3 Synthesis of 22-O-(3-methoxy-benzamido)acetyl muulin (compound 6)

[0122] Take 1g (2.65mmol) of Intermediate III and dissolve it in 23ml of dichloromethane, take 0.73g (5.30mmol) of anhydrous potassium carbonate and add it to the reaction system; dissolve 0.50g (2.92mmol) of 3-methoxy-benzoyl chloride in A small amount of dichloromethane was slowly added dropwise to the above reaction system under ice bath conditions, then the mixture was stirred in ice bath for 3 hours, then 50ml each of ice water and chloroform were added in turn, and then transferred to a separatory funnel for shaking, statically Leave it to separate layers, take its organic phase and wash twice with aqueous sodium chloride solution (15% w / v) and dry with anhydrous sodium sulfate, take the organic phase; the obtained organic phase is rotary evaporated to dryness to obtain the mixture, and the mixture is washed with dichloromethane Redissolve, add 2 g of 100-200 mesh silica gel and mix thor...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with an amide side chain as well as preparation and application of the pleuromutilin derivative. The pleuromutilin derivative with an amide side chain is a compound shown as a formula 2 (See the specification) or a pharmaceutically acceptable salt thereof, and a solvate, an enantiomer,a diastereoisomer, a tautomer or a mixture of the solvate, the enantiomer, the diastereoisomer and the tautomer of the compound of formula 2 or the pharmaceutically acceptable salt thereof in any proportion, including a racemic mixture. The compound not only has good in-vitro antibacterial activity and water solubility, but also has the advantage of low preparation cost compared with valnemulin and retapamulin, so that the compound is particularly suitable for being used as a novel antibacterial agent for preventing and treating human or animal bacterial infectious diseases, particularly infectious diseases caused by drug-resistant staphylococcus aureus.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative with an amide side chain and its preparation and application. Background technique [0002] Among multidrug-resistant Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE) are of major concern. Therefore, it is of great importance to the medical community to develop new antimicrobial agents with new mechanisms of action that exhibit minimal cross-resistance with existing drug treatments. [0003] Pleuromutilin (Formula 1) is an antibiotic produced by Pleurotusmutiliz (Fr.) Sacc. and Pleurotus Passeckeranius Pilat. It belongs to diterpene compounds and was first isolated and identified in 1951 by Kavanagh et al. , and its structure was determined by Birch et al. in 1966, and it was confirmed by X-ray crystallography that i...

Claims

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Application Information

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IPC IPC(8): C07C233/83C07D295/15C07C231/02A61K31/223A61K31/495A61P31/04
CPCA61P31/04C07C233/83C07D295/15C07C2603/82
Inventor 靳珍刘杰李雅军汤有志
Owner SOUTH CHINA AGRI UNIV
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