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Metronidazole derivatives and their preparation methods and uses

A technology of metronidazole and its derivatives, applied in the field of medicinal chemistry, can solve problems affecting physiological functions, side effects, and dependence on imports of anticancer drugs, and achieve broad-spectrum anticancer effects

Active Publication Date: 2018-10-02
XIAMEN INST OF RARE EARTH MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most cancers are found in the middle to late stages, and the overall effect of clinical treatment is poor, especially the continuous emergence of multidrug resistance, which makes cancer treatment difficult.
[0006] At present, most of the anticancer drugs clinically used in my country rely on imports, and the prices are high
In addition, most anticancer drugs still cannot achieve satisfactory specificity. When patients undergo chemotherapy, normal cells in the body are often poisoned, which seriously affects normal physiological functions and is accompanied by many side effects.

Method used

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  • Metronidazole derivatives and their preparation methods and uses
  • Metronidazole derivatives and their preparation methods and uses
  • Metronidazole derivatives and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The synthesis of the metronidazole derivative shown in embodiment 1 formula (I)

[0050] Only the reaction of nicotinic acid and metronidazole is used as an example for illustration, and the preparation process of other metronidazole derivatives is similar to the reaction process of nicotinic acid and metronidazole, and will not be illustrated one by one in the examples.

[0051] Synthesis of metronidazole derivative YJP-1:

[0052]

[0053] Add 0.123g (1mmol) of nicotinic acid and 0.206g (1mmol) of DCC into a 50mL round bottom flask, add 10mL of dry THF, stir and react in an ice bath for 30min, and dissolve 0.171g (1mmol) of metronidazole and 0.122g (1mmol) of ) 10 mL THF solution of DMAP was slowly added dropwise to the reaction system, stirred and reacted in an ice bath for 30 min, and then naturally rose to room temperature for reaction. After the completion of the TLC detection reaction, the reaction solution was concentrated in vacuo, and the residue was direc...

Embodiment 2

[0056] The synthesis of the metronidazole derivative YJP-12 shown in embodiment 2 formula (I)

[0057]

[0058] Add 0.173g (1mmol) of 2-quinolinecarboxylic acid and 0.206g (1mmol) of DCC into a 50mL round-bottomed flask, add 10mL of dry THF, and stir in an ice bath for 30min to dissolve 0.171g (1mmol) of metronidazole and 0.122 A solution of g (1 mmol) DMAP in 10 mL THF was slowly added dropwise to the reaction system, stirred in an ice bath for 30 min, and then naturally rose to room temperature for reaction. After the completion of the TLC detection reaction, the reaction solution was concentrated in vacuo, and the residue was directly separated from the column. (石油醚) :V (乙酸乙酯) =5:1~2:1), the target compound YJP-12 was obtained.

[0059] The structures of the compounds prepared in Example 1-2 are all passed 1 H NMR, ESI-MS and other analytical methods were characterized. Their physical constants and spectral data are explained in tabular form:

[0060] The structures...

Embodiment 3

[0067] Example 3 Anticancer Activity Test

[0068] MTT method was used to screen the activity against colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7. The specific screening process is as follows:

[0069] (1) Spread the lung cancer cell line A549 in a 96-well plate, add 100 μL of culture medium, and wait for the cells to grow to 90%, add 1 μL of drugs into the wells, and detect 8 different concentrations of each drug (respectively, the initial concentration of the drug Concentration, 50μM, 5μM, 500nM, 50nM, 5nM, 500pM, 50pM), for each drug concentration, do 3 replicate wells in parallel, after culturing for 24h, add 20μL of the prepared 5mg / mL MTT solution to each well for 4 hours Afterwards, the culture medium was aspirated, and 150 μL of DMSO was added to each well, and the optical density (OD) value thereof was measured at a wavelength of 595 nm. The negative control is DMSO. Calculate the inhibition rate according...

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Abstract

The invention relates to a metronidazole derivative shown in the formula (1) (please see the specific formula in the specification) and salt or solvate which can be accept by the metronidazole derivative on the pharmaceutical science. R can be the same or different and can be independently selected from hydrogen, halogen, a cyano group, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenation C1-C6 alkyl, halogenation C1-C6 alkoxy, aryl, aryloxy and the like, and n is an integer from 0 to 4. The invention further relates to a preparing method and application of the metronidazole derivative in the formula (I). The compound or the salt of the compound has the strong inhibitory activity on the colorectal cancer cell strain HCT-116, the human lung cancer cell strain A549 and the breast cancer cell strain MCF-7. The compound has broad spectrum on anti-cancer activity and can serve as candidate medicine or a lead compound for treating tumors, cancers and other diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a class of metronidazole derivatives, in particular to the preparation of the metronidazole derivatives represented by formula (I), pharmaceutical compositions containing the derivatives and their uses. The compounds have broad-spectrum anticancer activities and can be used as drugs or lead compounds for treating diseases such as tumors and cancers. Background technique [0002] Cancer has become the most important fatal disease in the world, and the mortality rate of cancer patients in developed countries is also high. Cancer can occur in various organs and tissues at any age. The main types of cancer that cause death are: lung cancer, stomach cancer, liver cancer, colon cancer and breast cancer. [0003] In recent years, lung cancer has become the malignant tumor with the highest incidence rate. According to the World Health Organization (WHO) statistics: in 2008, the number o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/4439A61K31/4709A61P35/00
CPCC07D401/12
Inventor 雍建平卢灿忠
Owner XIAMEN INST OF RARE EARTH MATERIALS
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