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6,7,8,9-tetrahydro-5h-benzo[7]annulene-2-alkylamine compounds and their uses

A compound, alkylamine technology, applied in the field of medicinal chemistry and drug therapy, can solve the problems of increasing bacterial resistance, increasing bacterial virulence, etc.

Active Publication Date: 2019-05-14
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are also some research reports that the golden yellow pigment can increase the resistance of bacteria to oleic acid. In the mouse subcutaneous infection model experiment, the abscess area caused by the mutant strain that cannot produce pigment is significantly smaller than that of the wild-type strain, suggesting that the pigment can increase the resistance of bacteria to oleic acid. Antioxidant ability to increase bacterial virulence

Method used

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  • 6,7,8,9-tetrahydro-5h-benzo[7]annulene-2-alkylamine compounds and their uses
  • 6,7,8,9-tetrahydro-5h-benzo[7]annulene-2-alkylamine compounds and their uses
  • 6,7,8,9-tetrahydro-5h-benzo[7]annulene-2-alkylamine compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 16

[0095] Example 1 Preparation of 6,7,8,9-tetrahydro-5H-benzo[7]rotaxene (Intermediate II)

[0096]

[0097] 1 g of 1-benzocycloheptanone was dissolved in 7.2 ml of trifluoroacetic acid, 1.5 ml of triethylsilane was added, and the mixture was stirred at 60°C overnight. After the reaction was completed, part of the trifluoroacetic acid was removed by rotary evaporation, then the reaction solution was poured into ice water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was subjected to column chromatography The title compound was isolated as 0.91 g of a colorless oil in 90% yield.

[0098] 1 H-NMR (400MHz, CDCl 3 ) δ 7.17-6.96 (m, 4H), 2.79 (dd, J=7.0, 4.1 Hz, 4H), 1.95-1.73 (m, 2H), 1.65 (dd, J=10.0, 4.8 Hz, 4H).

Embodiment 2

[0099] Example 2 Preparation of 2-iodo-6,7,8,9-tetrahydro-5H-benzo[7]rotaxene (Intermediate III)

[0100]

[0101] 675 mg of intermediate II and 1.14 g of N-iodosuccinimide were dissolved in 20 ml of acetic acid, and the reaction was heated at 70° C. for 7 hours under nitrogen protection. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated sodium thiosulfate solution at 0 °C, saturated sodium bicarbonate solution was added, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue The compound was separated by column chromatography to give the title compound, 867 mg as a colorless oil, the yield was 69%.

[0102] 1 H-NMR (400MHz, acetone) δ 7.68 (d, J=6.9Hz, 1H), 7.42 (d, J=7.9Hz, 1H), 6.91 (d, J=7.8Hz, 1H), 2.74 (t, J = 10.2 Hz, 4H), 1.83 (s, 2H), 1.60 (s, 4H).

Embodiment 36

[0103] Example 3 Preparation of 6,7,8,9-tetrahydro-5H-benzo[7]rotaxene-2-carbonitrile (Intermediate IV)

[0104]

[0105]272 mg of intermediate III and 179 mg of cuprous cyanide were added to 10 ml of N,N-dimethylformamide and heated to reflux overnight. After the reaction of intermediate III was completed, it was cooled to room temperature, and concentrated ammonia water was added to the system until the solution became clear, extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was separated by column chromatography. , the title compound was obtained as 122 mg of a pale yellow solid with a yield of 71%.

[0106] 1 H-NMR (400MHz, CDCl 3 )δ7.47-7.28(m, 2H), 7.16(t, J=9.9Hz, 1H), 2.82(t, J=9.4Hz, 4H), 1.86(s, 2H), 1.65(s, 4H).

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Abstract

Provided are a 6,7,8,9-tetrahydro-5H-benzo[7] annulene-2-alkylamine compound represented by formula I and or a pharmaceutically acceptable salt thereforeof, and a use thereof. The compound exhibits strong inhibitory activity foragainst the synthesis of thea golden -colored pigment ofby Staphylococcus aureus (S. aureus). The golden -colored pigment of Staphylococcus aureus can help assist S.taphylococcus aureus escape from to avoid being killed by the reactive oxygen produced by the human innate immune system, and is a key virulence factor determining the pathogenic abilitypathogenicity of bacteria. The golden- colored pigment can also increase the resistance of bacteria to oleic acid, and can increase the virulence of bacteriathereof by improving the antioxidative capabilities performance of bacteriathereof. Inhibiting synthesis of the golden -colored pigment, a the virulence factor of S.taphylococcus aureus, is a new and effective antibacterial agent strategy. By targeted inhibition of synthesis of the golden -colored pigment, the compound of the present invention is expected to be developed into a novel antibacterial agent in single administrationfor monotherapy, and can also be developed into an antibacterial agent for in combined administrationcombination therapy together with existing antibiotics.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and drug therapy, and specifically relates to 6,7,8,9-tetrahydro-5H-benzo[7]rotaxene-2-alkylamine compounds and uses thereof. Background technique [0002] Staphylococcus aureus is an important pathogen that seriously endangers human life and health. As a representative of Gram-positive bacteria, it is the most common pathogen causing purulent infection in humans, which can directly lead to local purulent infection, pneumonia, pseudomembranous colitis, pericarditis, etc., and even systemic infections such as sepsis and sepsis. Staphylococcus aureus infection can be divided into hospital-acquired infection and community-acquired infection, and the discovery of the latter increases the potential biohazard of this pathogen and the possibility of causing infection outbreaks. MRSA (Methicillin-resistant staphylococcus aureus) is a methicillin-resistant Staphylococcus aureus and is recognized as a "s...

Claims

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Application Information

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IPC IPC(8): C07C211/30A61K31/137A61P31/04
CPCA61K31/137C07C211/30
Inventor 李剑蓝乐夫王友鑫陈菲菲孔庆雅蒋华良
Owner EAST CHINA UNIV OF SCI & TECH