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

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

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

AI Technical Summary

Problems solved by technology

[0004]Anti-tuberculosis drugs targeting DprE1 with benzothiazinone (BTZ) as the backbone, currently under development are BTZ043 (phase I) and pBTZ169 (phase II ), the MICs of the two compounds against the standard strain of Mycobacterium tuberculosis were 0.02 μM and 0.004 μM, respectively. Azinonone anti-tuberculosis drugs have high cLogP value and poor druggability

Method used

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

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preparation example Construction

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

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

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

[0030] Further, compound A3 is chlorinated to obtain acid chloride A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are one-pot reactions.

[0031] Specifically, the preparation of each compound of the present invention can refer to the following schematic route:

[0032]

[0033] The chemical structural formula of the amine compound is as follows:

[0034]

[0035] Wherein, the definition of the substituent is the same as above.

[0036] More specifically, the above reaction pathway can be exemplified as follows:

[0037] The steps of A1→A3 are: compound A1 is...

Embodiment 1

[0042] Example 1 Compound 1: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one

[0043]

[0044] 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 acid solution;

[0045] 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, stir at room temperature for 20 minutes after the dropwise addition is completed, and the reactio...

Embodiment 2

[0047] Example 2 Compound 3: 2-(3-(methoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro-4 H -Benzo[ e ][1,3]thiazin-4-one

[0048]

[0049] The operation was the same as in Example 1, except that the amine used was azetidine-3-oxo-methyloxime, and the rest remained unchanged to obtain compound 3 as a white solid (yield 46%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 9.08 (s, 1H), 5.05 – 5.04 (m, 4H), 3.93 (s, 3H), 3.19 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.3, 162.0, 146.0, 144.1, 139.8, 135.6, 134.3, 128.3, 126.1, 62.5, 60.2, 43.52. MS-ESI (m / z): 384.6 [M+H] + .

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Abstract

The invention discloses a benzothiazinone derivative as well as a preparation method and application thereof as an antituberculosis drug, and particularly relates to a novel compound with a benzothiazinone skeleton, and the compound has an inhibition effect on tubercle bacillus, particularly tubercle bacillus with clinical drug resistance. The benzothiazinone skeleton benzene ring is creatively changed, especially the substituent group is creatively changed to obtain a series of compounds, and an unexpected technical effect is achieved; the compound has an excellent tubercle bacillus inhibition effect, the reported compound activity has great advantages compared with the existing clinical first-line drug isoniazide (MIC 0.5[mu]M), and more importantly, compared with the benzothiazinone antitubercular drug pBTZ 169 in the existing research stage, the compound has a lower cLogP value and better druggability.

Description

technical field [0001] The technical field of the present invention relates to the application of antibacterial drugs, mainly for the research and development of drugs for bacilli, such as Mycobacterium tuberculosis or Bacillus leprae, after infecting the human body; specifically, it relates to a new class of compounds with a benzothiazinone skeleton. It has been shown to have an inhibitory effect on Mycobacterium tuberculosis, especially it also has an inhibitory effect on Mycobacterium tuberculosis with clinical drug resistance. Background technique [0002] Tuberculosis is one of the infectious diseases and remains one of the leading causes of death in developing countries. There are many carriers of Mycobacterium tuberculosis, and one out of every three people is a carrier of Mycobacterium tuberculosis, that is, there are nearly 2 billion Mycobacterium tuberculosis carriers in the world. In addition, due to the slow growth and reproduction of tuberculosis, it usually ta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D279/08C07D417/04C07D417/12C07D491/113C07D417/14C07D471/10A61K31/5415A61P31/06
CPCC07D279/08C07D417/04C07D417/12C07D491/113C07D417/14C07D471/10A61P31/06
Inventor 乔春华
Owner SUZHOU UNIV
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