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Pyridone derivative and application thereof in preparation of medicine for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis

A pharmacy and compound technology, applied in the direction of antibacterial drugs, active ingredients of heterocyclic compounds, pharmaceutical formulations, etc.

Active Publication Date: 2021-06-29
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the first-line anti-tuberculosis drugs mainly include isoniazid, rifampin, ethambutol, and pyrazinamide, but under the pressure of drug selection, drug-resistant strains of Mycobacterium tuberculosis appear, and one quarter of active tuberculosis patients in China Resistance to isoniazid and rifampicin

Method used

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  • Pyridone derivative and application thereof in preparation of medicine for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis
  • Pyridone derivative and application thereof in preparation of medicine for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis
  • Pyridone derivative and application thereof in preparation of medicine for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1 Preparation of 4'-fluoro-N-((1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-4-yl)methyl)-[ 1,1'-biphenyl]-4-carboxamide (Compound 1)

[0086] Compound 1 was synthesized according to the following route:

[0087]

[0088] 1.1. Synthesis of acetylcyclohexanone (i.e. intermediate 1m):

[0089] Mix cyclohexanone (29.50g) and morpholine (31.45g) and add solvent toluene (150mL), add p-toluenesulfonic acid (0.53g) while stirring, and slowly heat to 120°C. Use a water separator to separate the water produced by the reaction. When 6.00 mL of water is separated, stop the reaction, and gradually cool the reaction system to room temperature, and remove the solvent under reduced pressure to obtain a dark yellow viscous liquid. Dissolve the liquid in dichloromethane, stir and cool down to 0 °C, add 50.00 mL of triethylamine, and stir for 5 min. Dilute 24.00 mL of acetyl chloride with dichloromethane and slowly drop into the reaction system, a large amount of white sm...

Embodiment 2

[0097] Example 2 Preparation of N-((1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-4-yl)methyl)-4'-(trifluoro Methoxy)-[1,1'-biphenyl]-4-carboxamide (Compound 2)

[0098]

[0099] Synthesize intermediate 1a according to the method of Example 1, and then refer to the method of step 1.4 of Example 1, replacing the raw material with 4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-carboxylic acid , Compound 2 was obtained.

[0100] 1 H NMR (400MHz, DMSO-d 6 )δ11.51(s, 1H), 8.49(t, J=4.7Hz, 1H), 8.11(d, J=1.8Hz, 2H), 7.91-7.75(m, 4H), 7.47(d, J=8.3 Hz,2H),4.36(d,J=4.6Hz,2H),2.70(s,2H),2.38(s,2H),2.11(s,3H),1.63(s,4H).ESI-MS:m / z[M+Na] + calculated for 479.2, found 479.1.

Embodiment 3

[0101] Example 3 Preparation of 4'-(dimethylamino)-N-((1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-4-yl)methanol base)-[1,1'-biphenyl]-4-carboxamide (Compound 3)

[0102]

[0103] Synthesize intermediate 1a according to the method of Example 1, and then refer to the method of step 1.4 of Example 1, replacing the raw material with 4'-(dimethylamino)-[1,1'-biphenyl]-4-carboxylic acid to prepare Compound 3 was obtained.

[0104] 1 H NMR (400MHz, DMSO-d 6 )δ11.51(s, 1H), 8.37(t, J=4.8Hz, 1H), 7.90(d, J=8.3Hz, 2H), 7.69(d, J=8.1Hz, 2H), 7.27(t, J=8.1Hz, 1H), 7.00-6.91(m, 2H), 6.76(dd, J=8.4, 2.4Hz, 1H), 4.36(d, J=4.7Hz, 2H), 2.96(s, 6H), 2.72(s,2H),2.38(s,2H),2.12(s,3H),1.63(s,4H).ESI-MS:m / z[M+Na] + calculated for 438.2, found 438.2.

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Abstract

The invention provides a pyridone derivative and application thereof in preparation of a medicine for preventing and / or treating tuberculosis caused by mycobacterium tuberculosis, which belong to the field of pharmacy. The structure of the pyridone derivative is shown as a formula (I). Experimental results show that the pyridone derivative provided by the invention can specifically inhibit the activity of mycobacterium tuberculosis, has small toxic and side effects, can be used for preparing a medicine for resisting mycobacterium tuberculosis, can also be used for preparing a medicine for preventing and / or treating tuberculosis, and a new choice is provided for medicines for treating tuberculosis (especially drug-resistant tuberculosis).

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a pyridone derivative and its use in the preparation of medicines for preventing and / or treating tuberculosis caused by Mycobacterium tuberculosis. Background technique [0002] Tuberculosis (TB), a chronic infectious disease caused by Mycobacterium tuberculosis infection, is one of the infectious diseases with the highest morbidity and mortality in human history. Tuberculosis is mainly transmitted through the air through the respiratory tract, mainly pulmonary tuberculosis; Mycobacterium tuberculosis can cause disease in almost any part of the body, known as the white plague. The main symptoms of tuberculosis patients include cough, fever, night sweats and weight loss. If the resistance of the infected person decreases or drug resistance develops, the condition may worsen, breathing is extremely difficult, and eventually die of pulmonary hemoptysis. According to the statisti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/24C07D401/12C07D405/12C07D409/12C07D413/12C07D215/227C07D213/82C07D213/64C07D401/04A61K31/472A61K31/4725A61K31/4709A61K31/4704A61K31/506A61K31/455A61K31/444A61K31/44A61K31/443A61P31/06
CPCC07D217/24C07D401/12C07D405/12C07D409/12C07D413/12C07D215/227C07D213/82C07D213/64C07D401/04A61P31/06
Inventor 高超余洛汀
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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