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Benzo aliphatic ring derivatives, and applications thereof

A technology of benzoaliphatic and cyclic derivatives, which is applied in the field of benzoalicyclic derivatives, can solve the problems of invasive fungal infections that cannot quickly exert a significant curative effect, large drug-resistant bacteria, and the emergence of a good synergistic inhibitory effect

Active Publication Date: 2019-02-26
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these drugs have made great progress in the prevention and treatment of fungal infections, they still cannot quickly exert a significant effect on some invasive fungal infections (such as cryptococcal meningitis, etc.), and sometimes the course of administration lasts for several months or even longer. long
What's more serious is that all the above drugs have serious side effects except echinocandins, especially amphotericin B, but echinocandins are ineffective against Cryptococcus
At the same time, the repeated use of only these antifungal drugs for a long time has led to the emergence of a large number of drug-resistant bacteria.

Method used

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  • Benzo aliphatic ring derivatives, and applications thereof
  • Benzo aliphatic ring derivatives, and applications thereof
  • Benzo aliphatic ring derivatives, and applications thereof

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0039] The method for preparing the compound shown in formula I provided by the invention specifically comprises the following steps:

[0040](1) Under ice bath conditions, the compound represented by formula II is reacted with the compound represented by formula III or IV in a dried organic solvent (such as dichloromethane (abbreviated as "DCM"), etc.), and saturated sodium chloride is used. The solution was quenched and the reaction was separated, the aqueous phase was extracted with halogenated hydrocarbons (such as DCM, etc.), the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure , the residue (crude product) is subjected to silica gel column chromatography to obtain the compound represented by formula Va or Vb;

[0041] The compound shown in formula Vb and lithium hydroxide monohydrate carry out a hydrolysis reacti...

Embodiment 1～43

[0053] Examples 1-43 are compound synthesis examples

Embodiment 1

[0055] 4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(2,3-dihydrobenzofuran-5-yl)butan-1-one (formula I A Preparation of the compound shown in -1):

[0056]

[0057] (1) Weigh 2,3-dihydrobenzofuran (200 mg, 1.67 mmol, compound represented by formula II-1) and 4-chlorobutyryl chloride (259 mg, 1.84 mmol, compound represented by formula III-1) in the reaction To the bottle, add 10 mL of dry DCM. Under the condition of ice bath, slowly add aluminum trichloride (245mg, 1.84mmol), maintain the ice bath and stir for 1.5h, slowly add an appropriate amount of saturated sodium chloride solution to quench the reaction, separate the layers, extract the aqueous phase with dichloromethane, The organic phases were combined, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ethe...

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Abstract

The invention discloses benzo aliphatic ring derivatives, and applications thereof. The benzo aliphatic ring derivatives are prepared through substation of benzo aliphatic ring compounds with nitrogenheterocyclic ring containing substituent groups. Most of the substituted benzo aliphatic ring compounds possess fungi inhibition activity, and the fungi inhibition activity is better than that of conventional anti-fungi medicines. When the partially substituted benzo aliphatic ring compounds are combined with conventional anti-fungi medicines, excellent synergistic inhibition effect on fungi withdrug resistance is achieved, so that the benzo aliphatic ring derivatives are capable of providing excellent base for development and invention of novel anti-fungi medicines or anti-fungi medicine synergists.

Description

technical field [0001] The present invention relates to a benzoaliphatic (aliphatic) ring derivative and use thereof; in particular, it relates to a benzoaliphatic (aliphatic) ring compound substituted by a nitrogen-containing heterocyclic group and use thereof. Background technique [0002] In recent years, invasive fungal infections have continued to increase, especially in HIV infection, organ transplantation, malignant tumors, burns, diabetes, tuberculosis, cystic fibrosis, internal catheters, trauma, tumor chemotherapy, long-term use of antibiotics and hormonal drugs. in patients. Among them, the main types of pathogenic fungi such as Candida, Cryptococcus, Aspergillus and Pneumocystis cause about 2 million illnesses and 1 million deaths each year. [0003] The incidence of invasive fungal infections is increasing year by year, and the mortality rate has remained high, but the development of corresponding antifungal drugs is relatively lagging behind. Since the succes...

Claims

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Application Information

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IPC IPC(8): C07D211/52C07D401/04C07D265/30A61K31/451A61K31/4545A61K31/5375A61P31/10
CPCA61P31/10C07D211/52C07D265/30C07D401/04
Inventor 朱进盛春泉姬长进李剑毛斐李晓康
Owner EAST CHINA UNIV OF SCI & TECH