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Vancomycin derivative as well as intermediate, preparation method, composition and application thereof

A compound and solvate technology, applied in the field of vancomycin derivatives, can solve the problem of single types of vancomycin derivatives

Pending Publication Date: 2020-12-15
中宏鑫投资控股(深圳)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the single defect of the existing vancomycin derivatives, and provide a vancomycin derivative, its intermediate, preparation method, composition and use

Method used

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  • Vancomycin derivative as well as intermediate, preparation method, composition and application thereof
  • Vancomycin derivative as well as intermediate, preparation method, composition and application thereof
  • Vancomycin derivative as well as intermediate, preparation method, composition and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0177] The synthesis of embodiment 1 vancomycin azide compound

[0178]

[0179]In a 20ml glass bottle, vancomycin hydrochloride (compound 3, 742mg, 0.5mmol; 90% purity) was dissolved in dimethyl sulfoxide (5ml), followed by aqueous potassium bicarbonate (3M, 0.67ml) and fluorosulfonyl Azide solution (500mM, 1.5ml, containing 0.75mmol fluorosulfonyl azide, solvent is methyl tert-butyl ether). The reaction solution was stirred at room temperature for 90 minutes, during which it was detected by LC-MS. After the reaction was completed, the reaction solution was washed with n-hexane (8ml×3). The washed reaction solution was slowly added to vigorously stirred acetone (125 ml) at room temperature. The precipitated insoluble pink solid (992 mg) was isolated by suction filtration, left in air at room temperature for 20 minutes to dry and lightly crushed into powder using a mortar. Distilled water (4 ml) was added to the powder, stirred at room temperature for 20 minutes, and the...

Embodiment 2

[0182]

[0183] Add dimethyl sulfoxide (18 μL), water (7 μL), vancomycin-derived azide compound (compound 1, 50 mM solution, solvent is dimethyl sulfoxide, 10 μL, containing 0.5 μmol compound to a 1.5 ml reaction tube in sequence 1), the corresponding terminal alkyne substrate (compound 4, 100mM, the solvent is dimethyl sulfoxide, 5 μL, containing 0.5 μmol terminal alkyne), copper sulfate and tris[(1-(3-hydroxypropyl)-1H- Mixed aqueous solution of 1,2,3-triazol-4-yl)methyl]amine (THPTA) (5 μL, containing 0.1 μmol copper sulfate and 0.2 μmol THPTA) and sodium ascorbate aqueous solution (500 mM, 5 μL, containing 2.5 μmol sodium ascorbate) , reacted on a shaking table at room temperature for 12 hours. After the reaction, the reaction solution was directly diluted to obtain the corresponding vancomycin-derived 1,2,3-triazole compound (ie, compound 2-1~2-4, 2-7 ~2-17) solution (as shown in Table 1 and Table 2), used for biological activity test.

[0184] Table 1

[0185]

...

Embodiment 3

[0189] Embodiment 3 biological activity test

[0190] Dilute MRSA USA300 bacteria with MH medium to a concentration of 1*10 5 CFU / mL, 120 μL of bacterial suspension was added to each well of a 96-well plate, and then different concentrations of compounds were added (the compound concentration was diluted downward with a 2-fold gradient starting from 100 μM), and each compound was set up in three replicates at different concentrations. hole. After culturing in a 37°C incubator for 18 hours, the absorbance value was measured with a microplate reader. The concentration at which bacteria do not proliferate significantly is the minimum inhibitory concentration (MIC).

[0191] The MIC data of compounds 1, 2-1~2-4, 2-7~2-17 obtained in Examples 1 and 2 are as follows, and the blank control item is prepared according to Example 2 but does not contain compound 1 and terminal Reaction solution of alkyne substrate. The test results are shown in Table 3.

[0192] The minimum inhibito...

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Abstract

The invention discloses a vancomycin derivative as well as an intermediate, a preparation method, a composition and application thereof. The invention discloses a compound shown as a formula I as wellas pharmaceutically acceptable salt, enantiomer, solvate or solvate of the pharmaceutically acceptable salt of the compound, wherein R is one or more R1 substituted C6-20 aryls, C6-20 aryls, one or more R2 substituted 3-20 membered heterocyclic alkenyls, 5-20 membered heteroaryl, one or more R3 substituted C1-10 alkyls, C1-10 alkyl or C3-10 cycloalkyl; and heteroatoms in the 5-20 membered heteroaryl and the one or more R2 substituted 3-20 membered heterocyclic alkenyls are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4. The vancomycin derivative has a good antibacterial effect.

Description

technical field [0001] The present invention relates to a vancomycin derivative, its intermediate, preparation method, composition and application. Background technique [0002] Vancomycin is a glycopeptide antibiotic against Gram-positive bacteria. It was isolated from the fermentation broth of Amycolatopsis orientalis by McCormick in 1956. It is currently used clinically to treat methicillin-resistant gold. The drug of choice for severe infections caused by Staphylococcus aureus (MRSA), has been praised by international antibiotic experts as "human's last line of defense against stubborn drug-resistant strains" and "ace antibiotics". [0003] [0004] In 2005, Fu et al. applied biosynthetic methods to introduce amino sugar on the vancomycin core with the sugar group removed to obtain vancomycin derivatives, and then introduced an azide group on the glycoside, and used this group to derivate Obtain a series of compounds, but unfortunately the alkynyl compound structural...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00A61K38/14A61P11/00A61P31/00A61P9/00
CPCC07K9/008A61P11/00A61P31/00A61P9/00A61K38/00
Inventor 董佳家孟根屹张煚马天成
Owner 中宏鑫投资控股(深圳)有限公司
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