Aloe-emodin nitrogen-heterocyclic derivative as well as preparation method and application thereof

A heterocyclic group and heteroatom technology, applied in the field of aloe-emodin nitrogen heterocyclic derivatives and its preparation, can solve problems such as low bioavailability, poor intestinal absorption, and limitations in clinical development and application

Active Publication Date: 2020-08-28
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, aloe-emodin has the characteristics of intestinal malabsorption, short half-life, and low bioavailability, so its clinical development and ap...

Method used

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  • Aloe-emodin nitrogen-heterocyclic derivative as well as preparation method and application thereof
  • Aloe-emodin nitrogen-heterocyclic derivative as well as preparation method and application thereof
  • Aloe-emodin nitrogen-heterocyclic derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Embodiment 1, the preparation of intermediate 3-(hydroxymethyl)-1,8-dimethoxyanthracene-9,10-dione

[0156]

[0157] Dissolve aloe-emodin (10.8g, 40mmol) in 300mL acetone, add dimethyl sulfate (9.5mL, 100mmol), potassium carbonate (22.1g, 160mmol), and reflux at 60°C for 12h. After the reaction, the mixture was cooled to room temperature and filtered. The residue was washed with water and dried in air to obtain compound 2 as a yellow solid (yield: 78%). 1 H NMR (400MHz, DMSO-d 6 )δ7.78–7.73(m,1H),7.71–7.66(m,2H),7.54(dd,J=8.2,1.3Hz,1H),7.46(d,J=1.5Hz,1H),5.54(s ,1H),4.64(s,2H),3.92(s,6H).

Embodiment 2

[0158] Embodiment 2, the preparation of intermediate 3-(chloromethyl)-1,8-dimethoxyanthracene-9,10-dione

[0159]

[0160]Compound 2 (3 g, 10 mmol) was added to 100 mL of thionyl chloride, and refluxed at 90° C. for 8 h. After the reaction, the solvent was spin-dried, the residue was quenched with ice water, and extracted three times with ethyl acetate, 50 mL each time. Combine the organic phases and wash with NaHCO 3 solution, followed by anhydrous Na 2 SO 4 dry. Purification by silica gel column chromatography (DCM:MeOH volume ratio 95:5, gradient elution) gave bright yellow solid compound 3 (yield: 65%). 1 H NMR (400MHz, DMSO-d 6 )δ7.78–7.72(m,2H),7.69(dd,J=7.6,1.2Hz,1H),7.60(d,J=1.6Hz,1H),7.54(dd,J=8.3,1.3Hz,1H ),4.90(s,2H),3.92(d,J=6.5Hz,6H).

Embodiment 3

[0161] Example 3, Preparation of 3-((3-fluorobutyridin-1-yl)methyl)-1,8-dimethoxyanthracene-9,10-dione (4a)

[0162]

[0163] Compound 3 (158 mg, 0.5 mmol), 3-fluoroazetidine hydrochloride (126 mg, 0.5 mmol), potassium iodide (catalytic amount) and potassium carbonate (138 mg, 1 mmol) were dissolved in 15 mL of DMF / MeCN mixed solution Medium (the volume ratio of DMF and MeCN is 1:4), heated at 70°C for 8h. After the completion of the reaction monitored by TLC, it was diluted with 20 mL of ethyl acetate, and extracted twice with 15 mL of water each time. The organic phase was washed with saturated brine, followed by anhydrous Na 2 SO 4 dry. Compound 4a was obtained by column chromatography (DCM:MeOH volume ratio 97:3, gradient elution). Compound 4a is a yellow solid with a yield of 63%; m.p: 143-144°C; 1 H NMR (400MHz, Chloroform-d) δ7.83 (dd, J = 7.7, 1.2Hz, 1H), 7.71 (d, J = 1.5Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 7.33 –7.27(m,2H),5.17(dp,J=57.3,5.4Hz,1H),4.01(d,J=3.9Hz...

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Abstract

The invention provides an aloe-emodin nitrogen-heterocyclic derivative as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound shown as a formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof. The compound provided by the invention can effectively inhibit macrophages from generating NO and inflammatory factors, and can also effectively inhibit the expression of iNOS and COX-2, so that the activation of an NF-kappa B signal path is inhibited, the inflammatory reaction is alleviated or the occurrence of the inflammatory reaction is inhibited; meanwhile, the compound has a good treatment effect on colitis, especially acute ulcerative colitis; thebiological activity of the compound 5r is remarkably superior to that of aloe-emodin. In addition, the compound is good in safety and stable in metabolism, and has important application value in research and development of anti-inflammatory drugs.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to an aloe-emodin nitrogen heterocyclic derivative and its preparation method and application. Background technique [0002] Inflammation is a basic pathological process in which living tissues with vascular system respond mainly to defense responses to the stimulation of various injury factors. The typical symptoms of acute inflammation are redness, swelling, heat, pain, and dysfunction. It is also accompanied by systemic reactions such as fever and changes in the number of white blood cells in peripheral blood. In the development of inflammation, NF-κB signaling pathway plays an important role. In dormant cells, NF-κB locally binds to the cytoplasm and inhibitors to form IκB. In contrast, proinflammatory cytokines, such as IL-1 and TNF-α, can trigger activation of the NF-κB signaling pathway, which in turn leads to phosphorylation and subsequent proteasome-mediat...

Claims

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Application Information

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IPC IPC(8): C07D205/04C07D209/44C07D209/08C07D295/116C07D265/30C07D211/46C07D211/62C07D211/14C07D215/06C07D217/04C07D491/113C07D471/10C07D211/78C07D211/26C07D211/56C07D295/205C07D295/185C07D213/74C07D239/42A61P29/00A61P1/04A61K31/397A61K31/40A61K31/4035A61K31/404A61K31/5375A61K31/4453A61K31/445A61K31/47A61K31/472A61K31/438A61K31/4412A61K31/44A61K31/495A61K31/496A61K31/506
CPCA61P1/04A61P29/00C07D205/04C07D209/08C07D209/44C07D211/14C07D211/26C07D211/46C07D211/56C07D211/62C07D211/78C07D213/74C07D215/06C07D217/04C07D239/42C07D265/30C07D295/116C07D295/185C07D295/205C07D471/10C07D491/113
Inventor 黎勇
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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