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Substituted tetracycline compounds

A compound, tetracycline technology, applied in the direction of tetracycline active ingredients, preparation of organic compounds, drug combination, etc., can solve problems such as antibiotic resistance

Inactive Publication Date: 2010-10-20
PARATEK PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, widespread use of tetracyclines for severe and mild conditions and diseases has directly led to the emergence of resistance to these antibiotics, even among highly susceptible commensal and pathogenic bacteria such as pneumococci and Salmonella

Method used

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  • Substituted tetracycline compounds
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0348] Embodiment 1: Synthesis of selected compounds of the present invention

[0349]

[0350] 7-iodo-shancycline (15.0g, 22.9mmol) and Pd(dppf) 2 Cl 2 (1.7g, 2.29mmol) and DMF (300ml) were mixed in a 1L round bottom two-neck flask to prepare the above compound. Na 2 CO 3 (7.2g, 68.2mmol) was dissolved in water (15ml), and then added to the reaction solution. 2-Fluoro-pyridine-5-boronic acid (6.4 g, 45.9 mmol) was dissolved in DMF (25 ml) and then also added to the reaction solution. Under argon atmosphere, the reaction mixture was stirred at 65°C (oil bath temperature), and the reaction was monitored by HPLC and LC / MS. The reaction was shown to be complete within 3 hours. Filter through celite and evaporate the solvent in vacuo. Redissolve in MeOH (30ml) and precipitate in MTBE (3L) to give a yellow precipitate. Filtration and vacuum drying overnight yielded 15 g of a yellow powder. The crude product (9 g, 17.8 mmol) was dissolved in TFA / trifluoromethanesulfonic ...

Embodiment 2

[0427] Embodiment 2: In vitro minimum inhibitory concentration (MIC) determination

[0428] The following experiments were used to determine the effect of tetracycline compounds on common bacteria. 2 mg of each compound was dissolved in 100 μl DMSO. This solution was then added to cation-adjusted Mueller Hinton Broth (CAMHB) at a final compound concentration of 200 μg / ml. The tetracycline compound solution was diluted to a volume of 50 µl and the test compound concentration was 0.098 µg / ml. Optical density (OD) measurements were performed on log-phase fresh broth cultures of the test strains. Dilute to a final cell density of 1 x 10 6 CFU / ml. When OD=1, the bacterial cell density of different genera should be approximately:

[0429] Escherichia coli (E.coli) 1×10 9 CFU / ml

[0430] Staphylococcus aureus (S.aureus) 5×10 8 CFU / ml

[0431] Enterococcus sp. 2.5×10 9 CFU / ml

[0432] Add 50 μl of bacterial cell suspension to each well of the microtiter plate. The final de...

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Abstract

The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.

Description

[0001] This application is a divisional application of the following applications: filing date: June 25, 2004; application number: 200480025635.1; invention title: same as above. [0002] related application [0003] This application claims priority to the following patent applications: U.S. Provisional Patent Application Serial No. 60 / 530,123, filed December 16, 2003, U.S. Provisional Patent Application Serial No. 60 / 525,287, filed November 25, 2003, and U.S. Provisional Patent Application Serial No. 60 / 486,017, filed July 9, all of which are titled "Substituted Tetracycline Compounds." The entire contents of each of the aforementioned patent applications are hereby incorporated by reference. Background of the invention [0004] Systematic screening of soil samples collected from around the world for evidence of microbes capable of producing bactericidal and / or bacteriostatic compositions led directly to the development of tetracycline antibiotics. The first of these new co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/26C07D213/56C07D211/38C07D211/70C07D231/12C07D211/58C07D233/61C07D233/84C07D235/18C07C237/26C07C251/82A61K31/65A61P31/04A61P31/12A61P33/06C07C271/22C07C271/54C07C275/28C07C275/30
CPCC07C2103/46C07C237/26C07C271/22C07C2101/14C07C2101/02C07C275/30C07C271/54C07C275/28C07C2101/16C07C2601/02C07C2601/14C07C2601/16C07C2603/46A61K31/65A61P11/00A61P19/00A61P19/08A61P29/00A61P31/00A61P31/04A61P31/12A61P33/00A61P33/06A61P35/00Y02A50/30C07C237/48
Inventor M·L·纳尔逊K·奥赫蒙V·阿莫O·K·金P·阿巴托H·阿塞法J·贝尔尼亚克B·巴蒂亚T·鲍塞尔J·陈M·格里尔L·亨尼曼M·Y·伊斯迈尔R·梅希歇J·马修斯
Owner PARATEK PHARM INC