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Quinolizine derivatives having antibacterial activity

A compound, methoxyl technology, applied in the field of medicine, can solve the problems of difficult clinical treatment, multi-drug resistance, increased mutation rate, etc.

Active Publication Date: 2008-04-16
吉林津升制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After antibiotics are widely used in clinic, due to the non-standard use of antibiotics, bacteria have created opportunities for frequent contact with antibiotics. In the repeated competition with antibiotics, bacteria gradually become familiar with the characteristics of antibiotics, resulting in genetic mutations, leading to bacteria resistance. Drug resistance, under the selective pressure of antibiotics, the mutation rate can increase hundreds of times, and it is easy to develop into multi-drug resistance, causing serious difficulties in clinical treatment

Method used

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  • Quinolizine derivatives having antibacterial activity
  • Quinolizine derivatives having antibacterial activity
  • Quinolizine derivatives having antibacterial activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1 Compound 1 (R 1 -R 2 Methylenedioxy (-O-CH 2 -O-), R 3 is methoxy, R 4 for hydrogen, R 5 is bromine, R 8 is methyl, r 6 、R 7 is methoxy, A - Chloride ion, namely 1-methoxy-8-methyl-12-bromo-berberine chloride) preparation of

[0109] Reaction equation:

[0110]

[0111] Reaction steps:

[0112] (1) 37.2g (100mmol) of berberine hydrochloride and 200ml of anhydrous tetrahydrofuran (THF moisture is less than 0.03%) are added in the dry reaction flask, heated and stirred to reflux, and anhydrous tetrahydrofuran solution of 15g of methyl iodide is added dropwise. After reflux for 5 hours, the reaction solution was concentrated and purified by silica gel chromatography (eluted with chloroform / ethyl acetate (15:1)) to obtain 8-methylberberine iodide.

[0113] (2) Dissolve 8-methylberberine iodide in 100ml of ice water, stir to dissolve, add bromine 16g (200mmol) dropwise at 20°C, after the drop is complete, stir...

Embodiment 2

[0121] Example 2 Compound 7 (R 1 -R 2 Methylenedioxy (-O-CH 2 -O-), R 3 is methoxy, R 4 is methyl, R 5 is bromine, R 8 is n-hexyl, R 6 、R 7 is methoxy, A - Chloride ion, namely 1-methoxy-8-n-hexyl-12-bromo-berberine chloride compound) preparation

[0122]

[0123] Reaction steps: (1) In a dry reaction flask, add 0.5 grams of magnesium powder, 50 ml of anhydrous tetrahydrofuran (THF moisture is less than 0.03%), under stirring, add a little iodine, dropwise add 1-bromo-n-hexane in anhydrous tetrahydrofuran A few drops until the color of iodine completely fades, add 3.3g of 1-bromo-n-hexane (0.02mol) in anhydrous tetrahydrofuran solution dropwise at a rate that keeps the reaction solution slowly refluxed, after the addition, reflux for 1 hour, and add 7.5g of berberine hydrochloride (0.02mol), and then reflux for 2h, the reaction solution was concentrated, and purified by silica gel chromatography (eluted with chloroform / ethy...

Embodiment 3

[0132] Example 3 Compound 21 (R1-R2 is methylenedioxy (-O-CH2-O-), R3 is hydrogen, R4 is methyl, R5 be hydrogen, R8 is methyl, R6, R7 are methoxy, A- is chloride ion, i.e. 8, the preparation of 13-dimethylberberine chloride)

[0133] Reaction equation:

[0134]

[0135] Reaction steps:

[0136] (1) Add 15g (40mmol) of berberine hydrochloride and 80ml of 20% acetone aqueous solution into the reaction flask, stir and dissolve, then slowly add 40ml of 50% aqueous sodium hydroxide solution dropwise, after adding, stir vigorously for 1h, and a large amount of orange yellow is precipitated solid. Filter and wash with 20% acetone. After the filter cake is dried, dissolve it with 100ml of dry acetonitrile, add 15ml of 1-iodomethane (d=2.29), and react the mixture under reflux for 3 hours, then concentrate to obtain 13-methylberberine iodide, which can be directly carried out to the next step without purification .

[0137] (2) In a dry reaction bottle, add 50ml of anhydrous...

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Abstract

The present invention relates to novel quinolizidine derivatives with antibiotic activity, the preparation method thereof, and medicine combination containing the compounds, as well as the application of the compounds to the fields of treatment / prevention on contagious diseases. The present invention belongs to the medicine technology field. Based on research, the quinolizidine derivatives with antibiotic activity provided by the present invention has the advantages of antibiotic effect with extended spectrum, high efficiency and low risk of drug tolerance, thereby being excellent in clinical applicable value, and capable of being used widely in clinic.

Description

1. Technical field [0001] The present invention relates to novel quinozine derivatives with antibacterial activity, their preparation methods, pharmaceutical compositions containing these compounds, and the use of these compounds in the preparation of drugs for the treatment and / or prevention of infectious diseases, belonging to the pharmaceutical technology field. 2. Background technology [0002] Infectious diseases are diseases caused by bacteria, viruses, fungi, etc. It is one of the major clinical diseases and seriously endangers human life and health. Antibiotics are chemical substances synthesized by some microorganisms that inhibit or kill certain pathogens. Antibiotics are secondary metabolites of microorganisms, which can inhibit or kill the growth and metabolism of another microorganism when used in a small amount and at low concentrations, and are widely used in infectious diseases caused by bacteria, viruses, fungi, etc. After antibiotics are widely used in cl...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P31/04A61P31/00
Inventor 黄振华
Owner 吉林津升制药有限公司
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