Quinoline, preparation method and application of quinoline

A compound and unsaturated technology, applied in the field of preparation of quinoline derivatives, can solve problems such as interactions, difficulty in patient adherence, and few types

Inactive Publication Date: 2014-03-26
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs have obvious deficiencies in the treatment of tuberculosis: (1) serious drug resistance, leading to multi-drug resistance and even extensively drug-resistant tuberculosis strains; (2) the treatment cycle is too long, at least half a year of regular medication is required It is difficult for patients to adhere to the above; (3) it has the inhibitory or inducing effect of liver drug enzymes, and it is easy to cause interaction when combined drugs, so it is often not combined with antiviral drugs (such as drugs for the treatment of AIDS); (4) side effects are relatively Many, such as gastrointestinal dysfunction and liver damage
However, there are still relatively few types of new anti-tuberculosis drugs, and there is an urgent need to develop more new anti-tuberculosis drugs to facilitate the prevention and treatment of tuberculosis

Method used

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  • Quinoline, preparation method and application of quinoline
  • Quinoline, preparation method and application of quinoline
  • Quinoline, preparation method and application of quinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Embodiment 1 Preparation of compound shown in formula II

[0143] Step 1 Preparation of compound shown in formula XII

[0144] Take 220g (1.47mol) of phenylpropionic acid and add it to 400mL of dichloromethane, add 165mL of thionyl chloride under stirring at room temperature, then add 2mL of DMF, stir at room temperature for 1 hour, reflux for 2 hours, concentrate to dryness under reduced pressure, and use 300mL of dichloromethane Methyl chloride was dissolved, and added dropwise at room temperature to a solution of 500 mL of dichloromethane containing 230 g (1.34 mol) of p-bromoaniline and 250 mL of triethylamine. After the dropwise addition was completed, the mixture was stirred overnight at room temperature. Add 400mL of 20% potassium carbonate solution to the reaction solution, stir vigorously for 10 minutes to separate the organic layer, extract the aqueous layer with 400mL of dichloromethane, combine the dichloromethane extracts, wash with 400mL of 20% potassium ...

Embodiment 2

[0152] Embodiment 2 Preparation of compound shown in formula III

[0153] Step 1 Preparation of the compound shown in formula XI (A)

[0154] Take 36.6 g (0.2 mol) of diphenylmethylamine and 26 g (0.2 mol) of epichlorohydrin in 200 mL of isopropanol, and stir at room temperature for 16 hours. The reaction solution was concentrated, 100 mL of acetonitrile and 30 mL of triethylamine were added, heated to 65° C. and stirred for 24 hours. After concentrating, it was dissolved with 400mL of 2N hydrochloric acid, and the obtained solution was washed once with 200mL of ethyl acetate, adjusted to pH=10 with aqueous sodium hydroxide solution, and extracted three times with 500mL of ethyl acetate, and the ethyl acetate extract was washed with saturated brine, anhydrous After drying over sodium sulfate, concentrate, and when the residue is viscous, add 250 mL of petroleum ether and stir vigorously. The eluted solid was collected by filtration and dried to obtain 26 g of the solid compo...

Embodiment 3

[0166] Embodiment 3 Preparation of compound shown in formula III

[0167] Under nitrogen protection, in a 250mL three-necked flask, 6g (24.19mmol) of the compound shown in Formula IV (A) obtained in Step 3 of Example 2 was dissolved in 50mL of anhydrous tetrahydrofuran, and the solution was added dropwise to 3, 5 Difluorobromobenzene 23g (178mmol) and 4.0g magnesium chips were added to the Grignard reagent prepared in 100mL tetrahydrofuran, and after the drop was completed, the temperature was raised to 50°C and stirred for 2.5h. After cooling to room temperature, 100 mL of saturated ammonium chloride aqueous solution was added to terminate the reaction, extracted three times with 50 mL of ethyl acetate each time, and the organic layers were combined. It was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, separated and purified by column chromatography (developing solvent: a mixed solution of petroleum ether and dichloromethane in a vo...

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PUM

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry and discloses a quinoline, and a preparation method and an application of the quinoline. The quinoline is a chemical compound shown as Formula I as shown in the specification, or an optical isomer, racemate, a diastereoisomer, pharmaceutically acceptable salt or solvate of the chemical compound. The quinoline has a significant killing effect on mycobacterium tuberculosis, is applicable to preparing drugs for treating or preventing diseases or symptoms caused by mycobacterium tuberculosis infection.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a quinoline derivative, its preparation method and application. Background technique [0002] In the statistics of global infectious diseases, tuberculosis is the second deadliest infectious disease after AIDS. Although there are many anti-tuberculosis drugs currently in clinical use, the first-line anti-tuberculosis drugs are still isoniazid, rifampicin (rifamycins), pyrazinamide and ethambutol, which have been used for decades. These drugs have obvious deficiencies in the treatment of tuberculosis: (1) serious drug resistance, leading to multi-drug resistance and even extensively drug-resistant tuberculosis strains; (2) the treatment cycle is too long, at least half a year of regular medication is required It is difficult for patients to adhere to the above; (3) it has the inhibitory or inducing effect of liver drug enzymes, and it is easy to cause interactions whe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06A61K31/4709A61P31/06C07D205/04C07D207/08C07D213/50C07D211/32
CPCC07D401/06A61P31/06C07D215/227
Inventor 邓杰雷皇书王为波刘才平叶文润徐立炎周昌兵张国尧邹艳冶何志琴
Owner CHONGQING PHARMA RES INST
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