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C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative

A technology of -13-, triple deoxygenation, applied in the field of medicine

Active Publication Date: 2013-03-27
LUOYANG HUIZHONG ANIMAL MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the development of macrolide antibiotics faces many difficulties. So far, no macrolide antibiotics can well inhibit the high-level constitutive MLS isolated clinically. B Drug-resistant Staphylococcus aureus and Streptococcus pyogenes, and the drug resistance of bacteria will penetrate from macrolide to ketolide, and the problem of multi-drug resistance is inevitable

Method used

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  • C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative
  • C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative
  • C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] The purpose of this example is to prepare the compound of the above-mentioned general formula 2, which is called: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy -3-C-methyl-3-O-methyl-α-L-hexapyranosyl-oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10 , 12,14-Hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-[(phenylmethoxy)carbonyl]-β-hexylpyridine Xylanosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

[0268] Add 800mL of dichloromethane into a 2L three-neck reaction flask, cool to 0-5°C, stir, add 50g (0.068moL) of compound 1 (manufactured by Guobang Import and Export Company, batch number: 20091101), and stir until dissolved. Dissolve 28.8g (24mL; 0.1688moL) of benzyl chloroformate (Xinyi Huili Fine Chemical Co., Ltd., batch number: 20111008) into 60mL of dichloromethane, drop it in at constant pressure, and control the temperature at 0-5°C. After dropping, stir at this temperature for 1 h. After the reaction is completed, 50° C. is rotary evaporated under re...

Embodiment 2

[0274] The purpose of this example is to prepare the compound of the above general formula 3, which is named: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10 , 13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O[(benzene methoxy)carbonyl]-β-hexylopyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15-one.

[0275] Add 1 L of 95% ethanol to a 5 L three-necked flask, heat and stir in a water bath at 50° C., weigh 300 g (0.345 moL) of compound 2 prepared by the method in Example 1, and then add 1 L of 95% ethanol to the reaction flask. Stir to dissolve; take 750mL (9.0moL) of concentrated hydrochloric acid in 1800mL water, stir and mix, and add to the reaction solution in batches. Reaction at 50°C for 22h. After the reaction is complete, cool to room temperature, extract with tert-butyl methyl ether (4000mL×3) in sequence to obtain the lower aqueous phase, then take 610g of sodium carbonate and dissolve it in 4000mL of water, stir to dissolve...

Embodiment 3

[0281] The purpose of this example is to prepare the compound of the above general formula 4, which is named: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10 -Trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-[(phenyl Methoxy)carbonyl]-β-hexylopyranosyl]oxy]-1-oxa-6-azacyclopentadecane-13,15dione.

[0282] method 1

[0283] Dimethyl sulfoxide / trifluoroacetic anhydride oxidation

[0284] Add 10g (0.014moL) of compound 3 into 60mL of dichloromethane under nitrogen protection, stir, cool to about 0°C, add 22.0mL of dimethyl sulfoxide (Chengdu Kelong Chemical Company, batch number: 20100708), and then take 4.6mL Trifluoroacetic anhydride (Jiangsu Shiyan Chemical Company, batch number: 20101008) was added dropwise, and after the dropwise addition was completed, it was reacted for 30 min, and 9.8 mL of triethylamine (Chengdu Kelong Chemical Company, batch number: 20100708) was added dropwise, and the inner temperature was controlled at -...

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PUM

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Abstract

The invention provides a C-3 substituted-9-deoxidized-9A-aza-9A-high erythromycin A derivative which has a structure shown as formula (I), wherein R1 is H, hydroxyl or methoxyl; R2 is hydroxyl; R3 is an organic matter substituted or unsubstituted by a heteroatom. The heteroatom is one or more of halogen, N, O and S. R4 is H, carboxybenzyl, benzoyl or acetyl. The compound shown by formula (I) is an antibacterial agent and can be used to treat various bacterial and protozoon infections. The invention further relates to an application and a preparation method of the compound, and a composition formed by the compound.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to new C-3 substituted-9-deoxy-9A-aza-9A-homoerythromycin A derivatives, their preparation method and the pharmaceutical composition of the compound. The present invention also relates to the use of the derivative in the preparation of medicines for treating and / or preventing bacterial infections and protozoan infections. Background technique [0002] Macrolides are an important class of anti-infective drugs. Since the discovery of erythromycin in 1952, after 60 years of development, they have become the second largest category after β-lactam antibiotics in clinical application. Anti-infective drugs have made great contributions to the treatment of human and animal diseases. [0003] However, the development of macrolide antibiotics faces many difficulties. So far, no macrolide antibiotics can well inhibit the high-level constitutive MLS isolated clinically. B Drug-resistant Staphy...

Claims

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Application Information

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IPC IPC(8): C07H17/08A61K31/7048A61P31/04
CPCC07H17/00C07H17/08A61P31/04A61P33/02
Inventor 刘兴金张许科
Owner LUOYANG HUIZHONG ANIMAL MEDICINE
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