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Macrolactone compounds or salts of macrolactone compounds, as well as synthesis method, pharmaceutical composition and application of macrolactone compound or salts

A technology of macrolides and compounds, applied in macrolide compounds or their salts, synthesis, pharmaceutical compositions and their application fields, and can solve problems such as defects

Active Publication Date: 2015-02-11
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the defect that clinical methicillin-resistant Staphylococcus aureus produces drug resistance to β-lactam antibiotics, and provides macrolide compounds or their salts, synthetic methods, and pharmaceuticals Composition and its application

Method used

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  • Macrolactone compounds or salts of macrolactone compounds, as well as synthesis method, pharmaceutical composition and application of macrolactone compound or salts
  • Macrolactone compounds or salts of macrolactone compounds, as well as synthesis method, pharmaceutical composition and application of macrolactone compound or salts
  • Macrolactone compounds or salts of macrolactone compounds, as well as synthesis method, pharmaceutical composition and application of macrolactone compound or salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0259] Example 1 Preparation of 9-hydrazone clarithromycin (SIPI8901)

[0260] Clarithromycin (10g, 13.37mmol) was dissolved in methanol (80mL), hydrazine acetate (36.9g, 0.4mol) was added, and heated at reflux at 70°C for 48h. After removing part of the methanol by rotary evaporation, water (200 mL) was added, the pH was adjusted to 9-10 with 3N NaOH aqueous solution, filtered, the filter cake was washed with water, and dried to obtain 10.7 g of crude white solid. 1 g of the crude product was separated by FLASH column chromatography to obtain 0.68 g of the product (yield 72.8%, HPLC purity 85%).

Embodiment 2

[0261] Example 2 Preparation of 3-desclardinose-3-hydroxyl-9-hydrazone clarithromycin (SIPI8903)

[0262] 9-hydrazone clarithromycin (1.5g, 2mmol) was dissolved in 10mL of 1N hydrochloric acid aqueous solution, stirred at 25°C for 4h. Add 10mL of dichloromethane, adjust the pH to 9-10 with 3N sodium hydroxide, separate the layers, extract the water layer with 5mL of dichloromethane, combine the dichloromethane layers, wash with 10mL of water, dry with saturated sodium chloride, add silica gel to mix the sample Afterwards, 0.85 g of the product was obtained by separation by FLASH column chromatography. (Yield 71.4%, HPLC purity 85%).

Embodiment 3

[0263] Example 3 Preparation of 3-desclardinose-3-hydroxyl-9-isopropylidene hydrazone clarithromycin (SIPI8904)

[0264] 3-desclardinose-3-hydroxy-9-hydrazone clarithromycin (1.2g, 2mmol) was dissolved in 5mL of acetone, heated to reflux at 56°C for 4h, evaporated to dryness to obtain a crude product, mixed with silica gel, followed by FLASH column chromatography The product was isolated 0.5 g. (Yield 42.4%, HPLC purity 89.6%).

[0265] MS (ESI + ,m / e):644.85[M+H] +

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Abstract

The invention discloses macrolactone compounds or salts of the macrolactone compounds, as well as a synthesis method, a pharmaceutical composition and application of the macrolactone compounds or salts. The invention provides a macrolactone compound 1, a macrolactone compound 1' or salts of the macrolactone compound 1 and the macrolactone compound 1', a pharmaceutical composition containing the macrolactone compound 1, the macrolactone compound 1' or the salts of the macrolactone compound 1 and the macrolactone compound 1' and application of the pharmaceutical composition in preparing a drug for inhibiting methicillin-resistant staphylococcus aureus. When one or more of the macrolactone compound 1, the macrolactone compound 1', the salt of the macrolactone compound 1 and the salt of the macrolactone compound 1' are jointly used in combination with beta-lactam antibiotics, the inhibiting effect of the beta-lactam antibiotics on the methicillin-resistant staphylococcus aureus can be obviously increased. The macrolactone compounds and the salts thereof are novel synergists having good in-vitro synergistic effect, can alleviate the drug resistance of the methicillin-resistant staphylococcus aureus to the beta-lactam antibiotic and are drug having good market development prospects.

Description

technical field [0001] The present invention relates to a macrocyclic lactone compound or a salt thereof, a synthesis method, a pharmaceutical composition and an application thereof. Background technique [0002] In recent years, the research and development of the third-generation macrolide antibiotics has entered a new climax. With the target of macrolide antibiotics—ribosome 50S subunit structure, and the relationship between macrolide antibiotics and ribosomes The continuous deepening of the research on the 50S subunit binding site and different binding modes will provide more theoretical basis and support for the research and development of macrolide antibiotics with novel structures. In addition, the diversity of the binding sites and binding modes of macrolide compounds and ribosomes provides some basis for their pharmacological effects other than antibacterial effects and new clinical uses. [0003] It is of great significance to overcome the defects of clinical res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/04C07H1/00A61K31/7042A61K31/7048A61K31/706A61K31/7056A61P31/04
CPCA61K31/43A61K31/431A61K31/545A61K31/546A61K31/7048A61K31/7052A61K31/7056C07H1/00C07H17/08A61K2300/00
Inventor 沈舜义陈代杰张志宏任岩松李继安李忠磊张芸徐屹军樊钱永葛涵
Owner SHANGHAI INST OF PHARMA IND
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