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Salt of benzo-thiopyrone compound as well as preparation method and application of salt

A kind of technology of benzothiopyran and compound, applied in the field of medicine, can solve the problems such as undisclosed specific embodiment and experimental result

Active Publication Date: 2021-03-09
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Patent 201810092333.X and PCT / CN2018 / 080787 disclose 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyr Examples of pyran-4-one and its hydrochloride, but did not disclose specific examples and experimental results of other pharmaceutically acceptable salts

Method used

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  • Salt of benzo-thiopyrone compound as well as preparation method and application of salt
  • Salt of benzo-thiopyrone compound as well as preparation method and application of salt
  • Salt of benzo-thiopyrone compound as well as preparation method and application of salt

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specific Embodiment approach

[0045] The present invention can be described in detail by the following examples, but it does not imply any adverse limitation on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, it is necessary to make various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Obvious.

[0046] For all of the following examples, standard manipulations and purification methods known to those skilled in the art can be used. All temperatures are in °C (degrees Celsius) unless otherwise indicated. The structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR).

[0047] Preparation of the Example section

[0048] The structure of the compound was obtained by H NMR spectroscopy ( 1 H NMR) to determine. Proton NMR chemical shifts (δ) are given in parts ...

Embodiment 1

[0072]

[0073]2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one 1 maleate ( Compound 1)

[0074] synthetic route:

[0075]

[0076] Add compound (I) (1.14g, 2.5mmol) into a 100mL three-neck flask, add 21mL of anhydrous methanol, stir well at room temperature, slowly add maleic acid (0.348g, 3.0mmol) at room temperature, and after 2-3min after the addition, the solution A yellow solid started to precipitate, kept stirring at room temperature for 3 hours, then suction filtered, the filter cake was rinsed with 5 mL of methanol, and dried to obtain 1.23 g of a yellow powdery solid, yield: 86%.

[0077] 1 H NMR (400MHz, CD 3 OD)δ:9.02(d,J=2.2Hz,1H),8.90(d,J=2.2Hz,1H),6.40(s,1H),6.27(s,2H),3.98(brs,4H),3.32 (brs,4H),2.94-2.92(m,2H),1.86-1.79(m,5H),1.76-1.72(m,1H),1.39-1.21(m,3H),1.12-1.03(m,2H) .

Embodiment 2

[0079]

[0080] 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one·3 / 2 fumaric acid Salt (compound 2)

[0081] synthetic route:

[0082]

[0083] Add compound (I) (0.228g, 0.5mmol) into a 25mL single-necked bottle, add 6mL of anhydrous methanol, stir at room temperature, add fumaric acid (0.232g, 2.0mmol), after the addition, keep stirring at 80°C for 3 After 1 hour, it was naturally cooled to room temperature, ice-bathed for 10 min, and suction filtered. The filter cake was rinsed with 1 mL of methanol, and dried to obtain 0.25 g of a yellow powdery solid, yield: 79%.

[0084] 1 H NMR (400MHz, DMSO-d 6 )δ:13.08(brs,2H),8.85-8.83(m,2H),6.62(s,3H),6.30(s,1H),3.66-3.64(m,4H),2.48(brs,4H),2.16 -2.14(m,2H),1.76-1.65(m,5H),1.54-1.48(m,1H),1.27-1.12(m,3H),0.90-0.82(m,2H).

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Abstract

The invention discloses a salt of a benzo-thiopyrone compound, and particularly relates to a salt of 2-(4-(cyclohexylmethyl)piperazine-1-yl)-6-(trifluoromethyl)-8-nitro-benzo-thiopyrone-4-one shown asa formula (I), a preparation method of the salt and an application of the salt in medicines for treating and / or preventing infectious diseases caused by mycobacterium tuberculosis. In particular, thepresent invention relates to pharmaceutically acceptable salts of formula (I) and pharmaceutical compositions comprising the compounds of the invention. The invention aims to prepare a salt of 2-(4-(cyclohexylmethyl)piperazine-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one with remarkably improved pharmacokinetic properties and physicochemical properties and strong mycobacterium tuberculosis resisting activity, and the salt can be used as a potential new drug and can be used for treating infectious diseases caused by bacteria, and especially used for treatment or prophylactic treatment of pulmonary tuberculosis (TB) diseases caused by Mycobacterium tuberculosis, in particular Mycobacterium tuberculosis, while at the same time being useful for overcoming problems associated with drug resistance of Mycobacterium tuberculosis.

Description

technical field [0001] The invention belongs to the technical field of medicine. Particularly related to the salt of benzothiopyrone compounds: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 shown in formula (I) -Salts of nitro-benzothiopyran-4-ones, preparation methods thereof, pharmaceutical compositions using the salts as active ingredients, and their use in the treatment and / or prevention of infectious diseases caused by Mycobacterium tuberculosis in the application. Background technique [0002] Tuberculosis (Tuberculosis, TB) is a chronic fatal disease caused by Mycobacterium tuberculosis, and it is a major infectious disease that endangers human health and causes human death. According to WHO estimates, in 2017, there were about 1.7 billion latent tuberculosis infected people in the world, and the latent infection rate was 23%. There are about 10 million new tuberculosis patients in the world, about 1.4 million deaths, and the incidence rate of tuberc...

Claims

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Application Information

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IPC IPC(8): C07D335/04A61K31/496A61P31/06
CPCC07D335/04A61P31/06A61K31/496A61K31/4535
Inventor 李刚黄海洪李鹏马辰张婷婷王宝莲李燕
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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