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Novel ketolide derivatives, and preparation method and medicinal compositions thereof

A compound and general formula technology, applied in the field of novel ketolactone and its preparation, can solve the problems of less than ideal activity against drug-resistant bacteria, and achieve the effect of simple synthesis

Inactive Publication Date: 2011-11-09
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, the introduction of oxime ethers has also been used to find ketolides with anti-drug-resistant bacteria activity (Agouridas, C., etc., J.Med.Chem.1998, 41: 4080-4100; ChenS.X., etc., J. Antibiot.2001, 54:506-509; Ma Z. et al., US2002 / 0019355; Searle X.B., WO03 / 090761; Akritopoulou-Zanze I. et al., Bioorg.Med.Chem.Lett.2004, 14:3809-3813; T. et al., Bioorg.Med.Chem.2005, 13:6615-6628; Nomura T. et al., Bioorg.Med.Chem.2006, 14:3697-3711; Nam, G. et al., Bioorg.Med.Chem.Lett .2010, 20:2671-2674), however, the anti-drug-resistant bacteria activity of the disclosed 9-oxime ether ketone lactone is not ideal yet

Method used

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  • Novel ketolide derivatives, and preparation method and medicinal compositions thereof
  • Novel ketolide derivatives, and preparation method and medicinal compositions thereof
  • Novel ketolide derivatives, and preparation method and medicinal compositions thereof

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preparation example Construction

[0044] The preparation method of the compound with the above general formula is briefly described below.

[0045] The preparation process of the present invention is as follows:

[0046] 1. Starting from erythromycin oxime, the intermediate compound 1,2′,4″-O-bis(trimethylsilyl)-6-O of the clarithromycin synthesis process was obtained through etherification, silanization, and methylation - Methylerythromycin A 9-O-(isopropoxycyclohexyl) oxime;

[0047] 2. Then hydrolyze to obtain the key compound 2: 3-OH-6-O-methylerythromycin oxime;

[0048] 3. Furthermore, under the action of acetic anhydride, 2′-OH and 9-oxime hydroxyl diacetylation to obtain compound 3: 2′-O-acetyl-3-hydroxy-6-O-methylerythromycin A 9 -O-acetyl oxime. The process of the above three steps has been mentioned in the open literature and will not be described in detail here. For similar processes, see Liang Jianhua et al., Organic Chemistry, 2005, 438-441; Zhou Baige et al., Fine Chemical Industry, 2005, 31...

Embodiment 1

[0073] Embodiment 1 (generates compound 2)

[0074] 3-Hydroxy-6-O-methylerythromycin oxime

[0075] Dissolve 13.2g of compound 1 in 40ml of ethanol, dilute 5ml of 36% concentrated HCl into 50ml of water and add dropwise to the reaction solution, react at 40°C for one hour, add ammonia water after the reaction to adjust the pH value to about 9, white precipitates precipitate out , and filter the white precipitate. This precipitate was recrystallized in ethanol and water to obtain 3-OH clarithromycin oxime (5.42g, yield 71%)

Embodiment 2

[0076] Embodiment 2 (generates compound 3)

[0077]2′-O-acetyl-3-hydroxy-6-O-methylerythromycin A 9-O-acetyl oxime

[0078] Add 50ml of dichloromethane into the flask containing 5.42g (8.96mmol) of 3-hydroxy clarithromycin oxime, add dropwise 2.6ml (24.88mmol) of acetic anhydride, and finish the reaction for one hour. , water, washed with saturated brine and filtered, and the solvent was removed under reduced pressure to obtain 5.60 g (8.13 mmol, yield 90.7%) of a white foamy compound.

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Abstract

The invention provides compounds with a general formula (I) or (II), and acceptable salts or esters prepared from the compounds and inorganic acid or organic acid. In the general formula (I) or (II), Ar refers to aromatic heterocyclic hydrocarbyl or substituted aromatic heterocyclic hydrocarbyl; and X refers to hydrogen or fluorine. The compounds have a novel structure; 9-oxime hydroxyl of ketolide is connected with an aromatic heterocyclic hydrocarbon through a propargyl side chain; and the compounds are easy and convenient to synthesize and are suitable for industrial production. Moreover, the compounds have outstanding antibacterial activity on clinically common sensitive bacteria and drugfast bacteria, such as staphylococcus aureus, streptococcus pneumonia, streptococcus pyogenes, staphylococcus epidermidis and the like, can be independently used or serve as one of active ingredients to be mixed with other medicines to treat bacterial infection and the like in various formulations or medication ways. Correspondingly, the invention also provides a preparation method for the compounds, use of the compounds as anti-infective agents and corresponding medicinal compositions.

Description

technical field [0001] The present invention relates to the field of chemical synthesis and pharmacy, and relates to a novel ketolide (9-O-aryl propynyl ketolide derivative) and a preparation method thereof, the use of this type of compound as an anti-infective drug and corresponding pharmaceutical compositions. Background technique [0002] The fourteen-membered macrolide antibiotic-erythromycin has been widely used clinically for more than 50 years, especially for those who are allergic to penicillin. The second-generation erythromycin, such as clarithromycin, azithromycin, and roxithromycin, has overcome the acid intolerance problem of erythromycin. At present, more and more strains of respiratory pathogens isolated clinically show drug resistance, such as Streptococcus pneumoniae (S.pneumoniae), Staphylococcus aureus (S.aureus) and Streptococcus pyogenes (S.pyogenes). A survey from 1997 to 1999 at the end of the last century (Hoban, D.J. et al., Clin. Infect. Dis. 2001...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00A61K31/7064A61K31/706A61P31/04
CPCC07H17/08A61P31/04
Inventor 梁建华安堃
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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