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Beta- tetrahydro-carboline antifungal drug and preparation method and application thereof

A tetrahydrocarboline, antifungal technology, applied in the field of medicine, can solve the problems of no antifungal effect, limited bacteriostatic effect, unclear structure-activity relationship and the like

Active Publication Date: 2018-10-09
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compounds reported above (including the following compounds wsz-c38 and hxm-b10) have limited antibacterial effects, unclear structure-activity relationships, and no antifungal effects in animals

Method used

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  • Beta- tetrahydro-carboline antifungal drug and preparation method and application thereof
  • Beta- tetrahydro-carboline antifungal drug and preparation method and application thereof
  • Beta- tetrahydro-carboline antifungal drug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0078] 1. Preparation of compound A series

[0079] Synthetic route 1

[0080]

[0081] Reagent conditions: (a) POCl 3 , DMF, rt, yield 81-92%; (b) NH 4 OAc,CH 3 NO 2 , rf, yield 78-91%; (c) LiAlH 4 , THF, rf, yield 37-78%; (d) AcOH:MeOH=10:1, yield 45-90%; (e) THF, rt, 1h, yield 51-89%; (f) K 2 CO 3 , EtOH, yield 51-66%; (g) NaH, DMF, yield 34-54%; (h) TFA, CH 2 Cl 2 , yield 71-85%.

[0082] In the above reagent conditions, "rt" means normal temperature reaction, "yield" means yield, and "rf" means reflux, the same below.

[0083] The preparation process of compound A1-A29 is as follows:

[0084] (a1) Preparation of compound 2-6

[0085] Indole and POCl 3 React in DMF solvent at room temperature to obtain compound 2. Compound 2 was dissolved in nitromethane, and compound 3 was catalyzed by ammonium acetate. Compound 3 was dissolved in anhydrous tetrahydrofuran as a solvent, and lithium aluminum tetrahydrogen was added to react under anhydrous conditions to ob...

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PUM

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Abstract

The invention discloses a beta-tetrahydro-carboline antifungal compound and a pharmaceutically acceptable salt thereof. The structure of the compound is shown as the general formula I, wherein n is 1to 3; R1 is hydrogen or monosubstituted acetylene or polysubstituted acetylene in any optional position on the benzene ring, X is O or NH, R2 is substituted or unsubstituted aliphatic or aromatic ring; or X is NR3, R2 and R3 are individually lower alkyl and substituted or unsubstituted aliphatic or aromatic ring; or X is N, R2 and X composes substituted or unsubstituted heterocycloalkyl. The invention also discloses a preparation method of the compound and the application of the compound in preparation of antifungal drugs. The compound has the characteristic of well antifungal activity, the result of partial compound is better than that of the control drug fluconazole, and the compound can be utilized to prepare antifungal drugs. The experiment result also show that the combined usage of the partial compound and fluconazole has good synergistic effect to clinically isolated fluconazole-resistant candida albicans.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a β-tetrahydrocarboline derivative with antifungal activity and pharmaceutically acceptable salts thereof, a preparation method, and the antifungal activity of the compound, which can be used for treating fungal infections type of disease. Background technique [0002] In recent years, invasive fungal infections have continued to increase, especially in patients with HIV, tumors, organ transplantation, blood diseases, and intensive care. The morbidity and mortality of invasive fungal infections have continued to increase. Candida albicans, Cryptococcus neoformans and Aspergillus fumigates are the three most pathogenic fungi with the highest morbidity and mortality. [0003] Currently, there are only four classes of drugs clinically used to treat deep fungal infections: polyenes (amphotericin B), nucleic acids (5-fluorocytosine), and azoles (fluconazole, itraconazole,...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/4545A61K31/496A61K31/5377A61P31/10
CPCA61P31/10C07D471/04
Inventor 刘娜盛春泉姜艳娟涂杰李壮董国强武善超
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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