Benzothiazinone compound, preparation method thereof and application of benzothiazinone compound as antituberculosis drug

A technology of benzothiazinone and compounds, which is applied in the field of benzothiazinone compounds and their preparation and application as anti-tuberculosis drugs, can solve the problems of poor druggability, etc., and achieve low cLogP value, good druggability, and excellent inhibition effect of effect

Active Publication Date: 2021-02-26
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

BTZ043 (phase I) and pBTZ169 (phase II) are anti-tuberculosis drugs targeting DprE1 with benzothiazinone (BTZ) as the backbone. The MICs of the two compounds against the standard strain of tuberculosis are 0.02, respectively. μM and 0.004μM, compared with the existing clinical first-line drug isoniazid (MIC 0.5μM), it has obvious antibacterial advantages in vitro, but the existing benzothiazinone anti-tuberculosis drug has a high cLogP value and poor druggability

Method used

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  • Benzothiazinone compound, preparation method thereof and application of benzothiazinone compound as antituberculosis drug
  • Benzothiazinone compound, preparation method thereof and application of benzothiazinone compound as antituberculosis drug
  • Benzothiazinone compound, preparation method thereof and application of benzothiazinone compound as antituberculosis drug

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preparation example Construction

[0027] The preparation method of benzothiazinone compound of the present invention is as follows:

[0028] (1) Compound A5 is reacted with an amine compound to obtain a benzothiazinone compound;

[0029] (2) Reducing the benzothiazinone compound prepared in step (1) to obtain compound A7, which undergoes a substitution reaction to obtain the benzothiazinone compound;

[0030] Alternatively, the benzothiazinone compound prepared in step (1) is reduced to obtain compound A7, and the compound A7 undergoes a substitution reaction followed by an azide reaction to obtain a benzothiazinone compound;

[0031] Alternatively, the benzothiazinone compound prepared in step (1) undergoes an azide reaction to obtain the benzothiazinone compound.

[0032] Further, compound A3 is chlorinated to obtain compound A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are one-pot reactions.

[0033] Specifically, the preparation of each compound of the present invention ...

Embodiment 1

[0044] Example 1 Compound 1: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one

[0045]

[0046] Dissolve ammonium thiocyanate (46 mg, 1.2 eq.) in 5 mL of anhydrous acetone, add polyethylene glycol (0.05 eq, based on compound A3) dropwise, and stir until dissolved at room temperature to obtain isothiocyanate ammonium solution;

[0047] Compound A3 (50 mg, 1eq, R 3 is methyl) dissolved in dichloromethane (anhydrous) (5 mL), dropwise N, N -Dimethylformamide (0.05eq., based on compound A3), add dropwise oxalyl chloride (0.25 mL, 2.5eq.), stir at room temperature for 0.5 hours after the addition is complete, spin dry the solvent and excess oxalyl chloride to obtain the corresponding intermediate acid chloride compound (compound A4, R 3 is methyl); then dropwise add the above-mentioned ammonium isothiocyanate solution, and stir at room temperature for 20 minutes after the dropwise addition is completed, to obtain intermedia...

Embodiment 2

[0049] Example 2 2-(Benzyl(methyl)amino)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one

[0050]

[0051] Compared with Example 1, the amine used is N -Methyl-1-phenylmethylamine, the rest unchanged, to obtain compound 2 (2-(benzyl(methyl)amino)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one) as a yellow solid (52% yield).

[0052] 1 H NMR (400 MHz, CDCl 3 ) δ 9.34 (s, 1H), 9.04 (s, 1H), 7.33-7.26 (m,5H), 5.13 – 4.94 (m, 2H), 3.40-3.29 (m, 3H), 3.19 (s, 3H). 13C NMR (151 MHz, CDCl 3 ) δ 165.8, 158.7, 144.0, 140.0, 136.0, 135.0, 129.3, 129.0, 128.3, 127.6, 127.1, 126.9, 54.6, 44.2, 30.0. MS-ESI (m / z): 405.7 [M+H] + .

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Abstract

The invention discloses a benzothiazinone compound and a preparation method and application of the benzothiazinone compound as an antituberculosis drug, and particularly relates to a novel compound with a benzothiazinone skeleton. The compound has an inhibition effect on tubercle bacillus, especially tubercle bacillus with clinical drug resistance. Results show that the compound shows an obvious antibacterial effect, the antibacterial effect far exceeds that of a positive control isoniazide, and particularly, compared with a positive control pBTZ169, the compound has an obvious and good cLogPvalue.

Description

technical field [0001] The invention relates to a new class of compounds with a benzothiazinone skeleton, which exhibits inhibitory effect on mycobacterium tuberculosis, especially the same inhibitory effect on mycobacterium tuberculosis with clinical drug resistance. Background technique [0002] As a developing country, China currently has about 4.5 million tuberculosis patients, the second largest number of tuberculosis patients in the world, and about 450,000 people die of tuberculosis every year. Tuberculosis has become a serious public health problem. The main problem with existing clinical medications is that they cannot effectively control multidrug-resistant and broad-spectrum drug-resistant bacteria. The application of new anti-tuberculosis drugs with novel structure and different mechanism of action from existing clinical drugs is the way to effectively control tuberculosis. Clinically resistant to at least two first-line drugs (isoniazid and rifampicin) are cal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D279/08C07D417/12A61P31/06A61K31/5415
CPCC07D279/08C07D417/12A61P31/06Y02A50/30
Inventor 乔春华
Owner SUZHOU UNIV
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