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Glycopeptide derivative and its pharmaceutically acceptable salts, and their preparation method and application

A derivative and pharmaceutical technology, applied in the field of medicinal chemical synthesis, can solve the problem of reducing the therapeutic effect of compounds and achieve good antibacterial effect

Active Publication Date: 2018-01-23
SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the enhancement of bacterial drug resistance, the therapeutic effect of compound (II) decreases, so it is very important to develop a new type of glycopeptide antibiotic with excellent antibacterial efficacy and good inhibitory effect on drug-resistant strains. Significance

Method used

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  • Glycopeptide derivative and its pharmaceutically acceptable salts, and their preparation method and application
  • Glycopeptide derivative and its pharmaceutically acceptable salts, and their preparation method and application
  • Glycopeptide derivative and its pharmaceutically acceptable salts, and their preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, the synthesis of compound LYSC-10

[0061] At room temperature, compound (II) (2.0 g, 1.2 mmol) was dissolved in 15 mL of DMSO, then DIEA (0.4 mL, 2.4 mmol) and N', N'-dimethylaminopropylenediamine (0.18 mL, 1.4 mmol) were added , stirred evenly, and then put into PyBOP (0.73g, 1.4mmol), after the addition was completed, the reaction solution was stirred at room temperature for 1h.

[0062] Add 250mL of acetone to the above reaction solution, stir to precipitate insoluble matter, let stand, filter with suction, wash the filter cake with acetone and dichloromethane successively, and remove the solvent. Purified by reverse-phase polymer filler UniPS25-300, eluted with methanol-water (volume ratio of methanol to water: 1:4) solution containing 0.04% TFA, concentrated and dried the eluate to obtain 0.66 g of white solid.

[0063] After testing, the chromatographic purity of the obtained white solid was 97.1%, and the yield was 31.8%. The mass spectrum of the...

Embodiment 2

[0065] Embodiment 2, the synthesis of compound LYSC-14

[0066] At room temperature, compound (II) (0.8g, 0.5mmol) was dissolved in 8mL DMF, then DIEA (0.25mL, 1.5mmol) and 4-cyanobenzylamine (0.1g, 0.75mmol) were added, stirred evenly, and then added TBTU (0.24 g, 0.75 mmol) was added, and the reaction solution was stirred at room temperature for 2 h.

[0067] Add 100mL of acetone to the above reaction solution, stir to precipitate insoluble matter, let stand, filter with suction, wash the filter cake with acetone and dichloromethane successively, and remove the solvent. Purified by reverse-phase polymer filler Uni PS25-300, eluted with methanol-water (volume ratio of methanol to water: 2:3) solution containing 0.03% TFA, concentrated and dried the eluate to obtain 243 mg of white solid.

[0068] After testing, the chromatographic purity of the obtained white solid was 96.3%, and the yield was 28.3%. The mass spectrum of the product and 1 H-NMR identification spectrum see ...

Embodiment 3

[0069] Embodiment 3, the synthesis of compound LYSC-38

[0070] At room temperature, compound (II) (500mg, 0.3mmol) was dissolved in 10ml of DMF-methanol (1:1 volume ratio mixing), and then 4'-chlorobiphenyl-4-carbaldehyde (85mg, 0.4mmol) was added, stirred and refluxed for 2h Then add sodium cyanoborohydride (40mg, 0.6mmol), and continue to reflux for 2h. After the reaction solution is cooled, the methanol is evaporated under reduced pressure, and the residue is poured into 50ml of acetone to precipitate insoluble matter. Washing with acetone and dichloromethane and removal of solvent gave a crude solid.

[0071] The resulting crude solid was dissolved in 5 mL of DMSO, DIEA (0.1 mL, 0.6 mmol) and N', N'-dimethylaminopropylenediamine (0.046 mL, 0.36 mmol) were added sequentially, stirred evenly, and then PyBOP (0.2 g, 0.36mmol), the addition was completed, and the reaction solution was stirred at room temperature for 1h. Add 50 mL of acetone to the reaction solution, stir to...

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Abstract

The invention discloses a glycopeptide derivative as shown in general formula (I), which is shown in the description, and its pharmaceutically acceptable salts, wherein R1 is H, 2-alkylamine-ethyl, substituted benzyl, substituted hydrocinnamoyl or linear acyl containing carbon-carbon bonds, a benzene ring on the benzyl or hydrocinnamoyl has halogen, hydroxy, amino, dimethylamino, and trifluoromethyl, or has a benzene ring substituted by halogen, hydroxy or trifluoromethyl; the linear acyl contains 1 to 6 carbon-carbon double bonds; R2 is C1-C5 linear amino, the terminal of the C1-C5 linear amino may be provided with dimethylamino or substituted benzyl, and the benzene ring of the substituted benzyl is provided with halogen, cyano group or nitro. The compound provided herein has good antibacterial activity, provides enhanced antibacterial property for glycopeptide antibiotic resistance bacteria, and is significant to the development of novel antibacterial drugs.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a class of glycopeptide derivatives and pharmaceutically acceptable salts, preparation methods and applications thereof. Background technique [0002] Glycopeptide antibiotics are the drugs of choice for the clinical treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections because they can interfere with the cross-linking of peptidoglycan on the bacterial cell wall, thereby causing bacterial cell lysis. However, a large number of empirical treatment of MRSA with glycopeptide antibiotics has led to the development of bacterial resistance, for example, the sensitivity of MRSA to vancomycin has decreased, and a large number of vancomycin-resistant enterococci ( VRE). Therefore, the efficacy of glycopeptide antibiotics in the treatment of vancomycin-resistant strains of VRE is reduced, and clinical anti-infection therapy is cons...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/02A61K38/14A61P31/04
CPCA61K38/08A61K38/14A61P31/04C07K1/113C07K7/06C07K9/00
Inventor 邵昌阮林高魏维戈梅夏兴孟庆前张芸饶敏
Owner SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT
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