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Macrolide compound and synthesis method, pharmaceutical composition and application of compound

A macrolide and compound technology, applied in the field of macrolide compounds, can solve the problems of the lack of structural diversity of antibiotics, the development and spread of drug resistance, etc., and achieve good in vitro synergy effect and good market. Development prospects, effects of alleviating drug resistance

Active Publication Date: 2021-07-16
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, although the clinically used glycopeptide antibiotics vancomycin and teicoplanin, lipopeptide antibiotics daptomycin, oxazolidinone antibiotic linezolid, and tetracyclic antibiotic tigecycline etc. The control of MRSA infection plays an important role, however, due to the lack of structural class diversity of these antibiotics, the development and spread of MRSA resistance to these commonly used antibiotics is becoming more and more serious

Method used

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  • Macrolide compound and synthesis method, pharmaceutical composition and application of compound
  • Macrolide compound and synthesis method, pharmaceutical composition and application of compound
  • Macrolide compound and synthesis method, pharmaceutical composition and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19

[0174] Example 1 9-hydrazone clarithromycin (intermediate 2)

[0175] Step 1: Preparation of hydrazine acetate

[0176] Glacial acetic acid (168ml, 2.94mol) was added dropwise into 85% hydrazine hydrate (140ml, 2.45mol) under stirring in an ice bath, during which mechanical stirring was used and the reaction temperature was controlled not to exceed 10°C. Remove the ice bath after the addition of glacial acetic acid is completed, turn to room temperature and stir for 40 minutes, during which solids will precipitate out, filter with suction, wash the solids with 50ml of ethanol, then continue to add the solids to 100ml of absolute ethanol and stir for 10 minutes, filter with suction, and Repeat the above operation. The solid obtained by suction filtration was put into a 500ml eggplant-shaped bottle and vacuum-dried to obtain 198g of white crystals, with a yield of 87.90%.

[0177] Step 2: Preparation of pyridinium trifluoroacetate

[0178] Pyridine (16ml, 0.2mol) was dissolve...

Embodiment 2

[0182] Example 2 3-hydroxyl 9-hydrazone clarithromycin (intermediate 3)

[0183]

[0184] Add 9-hydrazone clarithromycin (10 g, 13.1 mmol) and 50 ml of 1 N aqueous HCl into a 100 ml round bottom flask, and stir at room temperature for 4 h. Add 30ml of dichloromethane, adjust the pH to 9-10 with 3 equivalents of NaOH solution, separate the layers, extract the aqueous layer twice with 10ml of DCM, wash the organic phase with water and saturated brine successively, spin dry, and dry in vacuo to obtain a white Solid 8.61g, yield 86%.

Embodiment 3

[0185] Example 3 2'-O-acetyl-3-hydroxyl-9-isopropylidene hydrazone clarithromycin (intermediate 4)

[0186]

[0187]Dissolve 8.61 g of 3-hydroxy 9-hydrazone clarithromycin in 50 ml of acetone, stir at room temperature for 4 h, monitor the reaction by TLC, add 0.17 ml of acetic anhydride after completion, stir at room temperature for 3 h, spin dry and add 40 ml of dichloromethane, and then wash the organic phase with distilled water , washed with saturated brine, spin-dried, and vacuum-dried to obtain 8.55 g of a white solid with a yield of 85%.

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PUM

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Abstract

The invention discloses a macrolide compound and a synthesis method, a pharmaceutical composition and application of the compound. When the macrolide compound or the pharmaceutically acceptable salt thereof provided by the invention is used together with beta-lactam antibiotics, the effect of the beta-lactam antibiotics on inhibiting methicillin-resistant staphylococcus aureus can be obviously improved. A test result shows that the in-vitro synergistic effect is good, and the compound is a novel synergist, can relieve the drug resistance of methicillin-resistant staphylococcus aureus (MRSA) to oxacillin, and has a good market development prospect.

Description

technical field [0001] The present invention relates to a macrocyclic lactone compound, its synthesis method, pharmaceutical composition and application. Background technique [0002] The problem of bacterial drug resistance is becoming more and more severe, and the prevalence of drug-resistant bacteria is becoming wider and wider, especially Staphylococcus aureus (MRSA). MRSA is defined as: staphylococcus aureus resistant to methicillin, oxacillin, cephradine or mec gene positive. Since MRSA was first isolated in 1961, its infection rate and isolation rate have gradually increased around the world. Grundmann et al. believe that as many as 53 million people around the world may carry MRSA. my country is an area with high prevalence of MRSA, and the prevention and control situation is very severe. The survey on the current situation of MRSA infection in general hospitals in Shanghai showed that the MRSA infection rate of inpatients in 2008 was 2.68%, accounting for 81.85% o...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00A61K31/7048A61P31/04
CPCC07H17/08C07H1/00A61P31/04Y02A50/30
Inventor 沈舜义樊钱永李湘刘珊徐屹军张芸
Owner SHANGHAI INST OF PHARMA IND
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