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2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyranyl-4-one compound

A trifluoromethoxyl compound technology, applied in the field of medicine, can solve problems such as adverse reactions of patients and difficulty in regular drug use

Active Publication Date: 2018-12-04
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, long-term drug combination therapy causes adverse reactions in patients, and it is difficult to adhere to regular drug use. In addition, most of the drugs used were born in the 1950s and 1960s. Long-term, widespread and irregular use made the development of drug-resistant bacteria increasingly serious, and the emergence of multi-drug Drug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug-resistant TB (TDR-TB)

Method used

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  • 2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyranyl-4-one compound

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Experimental program
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specific Embodiment approach

[0116] 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.

[0117] 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).

[0118] Preparation of the Example section

[0119] The structure of the compound was obtained by H NMR spectroscopy ( 1 H NMR) to determine. Proton and Carbon NMR shifts (δ) are given in part...

Embodiment 1

[0133]

[0134] (S)-2-(2-Methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-benzo Pyran-4-one

[0135] route:

[0136]

[0137] Experimental steps:

[0138] The first step (S)-1-(2-chloro-3-nitro-5-(trifluoromethyl)phenyl)-3-(2-methyl-1,4-dioxa-8-nitrogen Preparation of heterospiro[4.5]decane-8-yl)propane-1,3-dione B-1

[0139] In a 25mL reaction bottle, the compound 3-(2-chloro-3-nitro-5-(trifluoromethyl)phenyl)-3-oxopropionic acid A (311mg, 1.0mmol), DCC (201mg, 1.0mmol) was dissolved in dry dichloromethane (5mL), under Ar protection, (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane (157mg, 1.0 mmol), stirred at room temperature for 12 hours. The insoluble solids were filtered off, concentrated, and separated by silica gel (200-300 mesh) column chromatography, using ethyl acetate-petroleum ether (V:V=5-15:100) mixture as the eluent. Intermediate B-1 was obtained, 250 mg of light yellow solid, yield 55.5%.

[0140] 1 H NMR (400MHz, CDCl 3 )δ:15....

Embodiment 2

[0145]

[0146] 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-trifluoromethyl-8-nitro-benzopyran-4-one

[0147] route:

[0148]

[0149] Experimental steps:

[0150] The first step 1-(2-chloro-3-nitro-5-trifluoromethylphenyl)-3-(4-(cyclohexylmethyl)piperazin-1-yl)propane-1,3-di Preparation of Ketone B-2

[0151] Using 1-(cyclohexylmethyl)piperazine (182mg, 1.0mmol) as the raw material, the procedure similar to the first step in Example 1 was used to obtain intermediate B-2, 272mg of light yellow solid, with a yield of 57.1%.

[0152] 1 H NMR (400MHz, CDCl 3 )δ:15.62(brs,1H),8.01(s,1H),8.00(s,1H),5.67(s,1H),3.73-3.49(m,4H),2.45(m,4H),2.17(m ,2H),1.79-1.71(m,5H),1.26-1.20(m,4H),0.90-0.87(m,2H).

[0153] The second step of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-trifluoromethyl-8-nitro-benzopyran-4-one II-2 (compound 2) preparation

[0154] With 1-(2-chloro-3-nitro-5-trifluoromethylphenyl)-3-(4-(cyclohexylmethyl)piperazin-1-yl)propane-1,3-dione ( 95mg, 0.2mmol) as raw ...

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Abstract

The invention discloses a 2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyranyl-4-one compound, a preparation method thereof, and an application of the compound in a medicine for preventing and / or treating infectious diseases caused by mycobacterium tuberculosis. Specifically, the invention relates to a compound shown in the formula (I), an isomer of the compound, a pharmaceutically acceptable salt of the compound, and a pharmaceutical composition containing the compound, wherein X, Y, R<1>, R<2> and n are as described in the specification. The invention aims to prepare the novel compound with anti-mycobacterium tuberculosis activity, and the novel compound is used as a potential new medicine, can be used for treating or prophylactically treating infectious diseases caused by bacteria, especially tuberculosis (TB) caused by mycobacterium, and can also be used for overcoming the problems related to drug resistance of mycobacterium tuberculosis.

Description

technical field [0001] The invention belongs to the technical field of medicine. In particular, it relates to 2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compounds represented by the general formula (I), and its preparation method uses the compound as Pharmaceutical compositions of active ingredients, and their use in the treatment and / or prophylaxis of infectious diseases caused by Mycobacterium tuberculosis. Background technique [0002] Tuberculosis (TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. Like AIDS, tuberculosis has become one of the leading causes of death in the world. According to the World Health Organization (WHO) estimate (Global tuberculosis report 2016), the number of new tuberculosis cases in the world in 2015 was approximately 10.4 million, of which 5.9 million were males (56%), 3.5 million were females (34%), and 100 million for ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/113C07D311/22C07D405/04C07D495/10C07D497/10C07D335/06C07D417/12C07D409/04C07D409/12A61K31/438A61K31/496A61K31/4535A61P31/06
CPCC07D311/22C07D335/06C07D405/04C07D409/04C07D409/12C07D417/12C07D491/113C07D495/10C07D497/10A61K31/38A61K31/382A61K31/435A61K31/438A61K31/4535A61K31/496A61P31/06C07D311/58
Inventor 黄海洪李鹏李刚马辰张婷婷
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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