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Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof

A technology of pleuromutilin and antibacterial activity, applied in the direction of organic active ingredients, medical preparations containing active ingredients, antibacterial drugs, etc., can solve the problem of the generation of drug-resistant strains, the screening and discovery of new drug molecules, and the time-consuming, human and financial issues

Active Publication Date: 2014-07-09
SOUTH CHINA AGRI UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As the problem of bacterial drug resistance becomes more and more serious, the discovery of new antibacterial drug molecules is becoming more and more urgent, but the screening and discovery of new drug molecules requires a lot of time, manpower and financial resources, and often new drugs have developed drug resistance before they are on the market. strain

Method used

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  • Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof
  • Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof
  • Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Synthesis of 4-mercaptobenzyl alcohol [formula (1)]

[0066] 4gLiAlH 4 Added to 50ml tetrahydrofuran to form a suspension, N 2 For protection, dissolve 8.5 g of 4-mercaptobenzoic acid into 100 ml of tetrahydrofuran, and slowly add it dropwise to the above suspension under ice-cooling. After the addition, continue to stir for 30 minutes, then raise the temperature to reflux, and stir for 16 hours. After the reaction, add 40ml ethyl acetate and 50ml15%H2O respectively. 2 SO 4 solution, filtered, the aqueous phase was extracted 3 times with 50ml ethyl acetate, the organic phases were combined, washed with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 7.5 g of light yellow or colorless liquid. Purified by silica gel column chromatography (ethyl acetate:petroleum ether=75:25) to obtain 7.1 g of white solid with a yield of 93% and a melting point of 51-53°C. MS-ESI (M+1): 141.2. The H NMR spectrum results are as follows:

[...

Embodiment 2

[0069] Synthesis of (4-hydroxymethyl-phenylmercapto)-acetyl-14-oxo-miaolin [formula (3)]

[0070] Add 11.0g of pleuromutilin formula (b) and 5.5g of p-toluenesulfonyl chloride to 50ml of ethyl acetate in sequence, wash in an ice bath, and adjust the pH value to strong with 20ml of 1mol / L potassium hydroxide solution Alkaline, heat up to 35°C, stir vigorously for 2.5 hours, and monitor the end of the reaction by thin-layer chromatography. After the reaction was complete, the organic solvent was distilled off under reduced pressure, and the residue was diluted 10 times with water, and the white solid was washed out, filtered with suction, washed with water until neutral, dried, and recrystallized from acetone to obtain 14.8 g of a white solid. The yield is 92%, MS-ESI (M+1): 533.1.

[0071] Dissolve 1.5g of sodium methoxide in 250ml of methanol, cool down to 15°C, add 4.8g of the product 4-mercaptobenzyl alcohol formula (1) of Example 1, and 17.6g of the product of step 1) succ...

Embodiment 3

[0074] Synthesis of (4-chloromethyl-phenylmercapto)-acetyl-14-oxo-miaolin [formula (5)]

[0075] 5g of the product formula (3) of Example 2 was dissolved in 100ml of dichloromethane, then 1.5g of triethylamine and 0.75ml of DMF were added, the temperature was lowered to 0°C, and 2.1g of SOCl was added dropwise under vigorous stirring 2 After adding 10 ml of dichloromethane solution, the temperature was naturally raised to room temperature, and stirring was continued for 1.5 h. After the reaction was completed, the reaction solution was poured into 80ml of ice water, extracted with ethyl acetate, separated, and the organic phase was washed with water until neutral, anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure, and separate by silica gel column chromatography to obtain 5.8 g of a solid of formula (5). Yield 70.5%, melting point: 121.1-123.8 MS-ESI (M+1): 519.5. The proton nuclear magnetic resonance spectrum results are as follows:

[0076] 1 HNMR(DMSO)δ: 7.70...

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Abstract

The invention discloses pleuromutilin derivatives with the structure as shown in a formula (I) in the specification and the antibacterial activity, salts, solvates, optical isomers and polymorphism compounds thereof acceptable in pharmacy and / or veterinary medicines as well as a preparation method and an application of the pleuromutilin derivatives and the salts, solvates, optical isomers and polymorphism compounds thereof in antibacterial compositions. The preparation method has the beneficial effects that two different lead compounds are connected together by covalent bonds so as to generate a synergistic effect, an additive effect or new pharmacological activity in vivo; sulfonamides are spliced into side chains of pleuromutilin so as to generate new pleuromutilin derivatives, the antibacterial activity of the obtained new compounds can be enhanced, the obtained new compounds have obvious antibacterial activity for gram-positive bacterium, gram-negative bacterium and mycoplasma and an obvious inhibiting effect on drug-resistance bacteria such as MRSA, and the antibacterial spectrums of the obtained new compounds are effectively expanded.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to an antibacterially active pleuromutilin derivative and its preparation method and application. Background technique [0002] In recent years, drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), multidrug-resistant Pseudomonas aeruginosa (MDRPA) and vancomycin-resistant enterococci (VRE) have emerged. The number of cases is increasing day by day, and there is a trend of large-scale outbreaks in some areas, which poses a huge threat to public health security. Bacterial drug resistance has existed since the day antibiotics were produced. It is the result of natural selection of bacteria for survival. However, due to people's over-reliance on antibiotics, the emergence of drug-resistant strains is getting faster and faster, and different species have emerged. The tendency ...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07D319/20C07D239/69C07D213/76C07D261/16C07D277/52A61K31/635A61K31/63A61P31/04
Inventor 方炳虎刘雅红陈良柱杨德学曹贺龙潘志坤
Owner SOUTH CHINA AGRI UNIV
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