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Nitro imidazole compound, its preparation method and application

A compound and hydrate technology, applied in the fields of pharmacy, medicinal chemistry and pharmacology, can solve the problems of low water solubility, low bioavailability and poor effect

Active Publication Date: 2011-11-09
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This treatment method has the following disadvantages: the treatment cycle is long, usually more than half a year; adverse reactions are more serious, such as the combination of rifampicin and isoniazid may cause severe liver disease, ethambutol can cause optic nerve damage; Mycobacterium tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB) is less effective or even ineffective
However, due to its low water solubility and low bioavailability, PA-824 needs to be made into complex tablet formulations for oral administration, and its anti-tuberculosis activity needs to be further improved [Bioorg.Med.Chem.Lett, 2008, 18 (7), 2256-2262.]
[0005] Japan's Otsuka Pharmaceutical Co., Ltd. also synthesized many nitroimidazole compounds, especially OPC-67683 [Journal of Medicinal Chemistry 2006, 49 (26), 7854-7860], the mechanism of action is similar to that of PA -824, used to treat tuberculosis, but has the same problems as PA-824, especially water solubility, which limits its pharmacokinetic properties and has room for further improvement

Method used

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  • Nitro imidazole compound, its preparation method and application
  • Nitro imidazole compound, its preparation method and application
  • Nitro imidazole compound, its preparation method and application

Examples

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preparation example Construction

[0059] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent (usually a polar aprotic solvent) at -30°C to solvent reflux temperature (preferably -20 to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0060] Describe the preparation of structural formula (I) compound more specifically below:

[0061] Process 1

[0062]

[0063] (1) Intermediate I-1 is subjected to Mitsunobu reaction with various substituted phenols in the presence of triphenylphosphine and azo active esters to obtain intermediates. The Boc protecting group is removed under acidic conditions to obtain intermediates I-6a-I -6f. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, etc.; the azo active ester can be selected from DEAD, DIAD, etc. The optimal reaction condition is, in the presence of triphenylphosphine and DIAD, using tetrahydrofuran as a solvent, react at -10°C to room ...

specific Embodiment approach

[0105] The present invention is explained more specifically in the following examples. It should be understood, however, that these examples are given to illustrate the invention and not to limit the scope of the invention in any way. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Parts and percentages are by weight unless otherwise indicated.

[0106] In all examples, the melting point is determined with an X-4 melting point apparatus, and the thermometer is not corrected; 1 H NMR was recorded with a VarianMercury 400 or 600 nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); MS was measured with a Shimadzu LC-MS-2020 mass spectrometer. The silica gel used for separation is not specified and is 200-300 mesh, and the ratio of the eluent is the volume ratio.

preparation example 1

[0108] 4-(4-Trifluoromethoxy)phenoxy)piperidine (I-6a)

[0109] p-Trifluoromethoxyphenol (32.7g, 184mmol), N-Boc-4-hydroxypiperidine (37g, 184mmol), triphenylphosphine (48.3g, 184mmol) were dissolved in dry THF (500mL), ice DIAD (37.2 g, 184 mmol) was added dropwise under cooling in a bath, and stirred overnight at room temperature after the drop was completed. The THF was spinned off, the residue was extracted with petroleum ether, and the extract was concentrated to obtain 71.2 g of a light yellow oil. The yield of the crude product was over 100%, and it was directly put into the next reaction.

[0110] The crude product obtained in the previous step (66.5 g, 184 mmol) was dissolved in TFA (150 mL) and stirred at room temperature. After 3 hours, TFA was spinned off, water was added to the residue, the pH of NaOH solution was adjusted to above 10, and extracted with ethyl acetate. The extract was concentrated and then column chromatographed to obtain 35.3 g of white solid, w...

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Abstract

The invention relates to a nitro imidazole compound, its preparation method and use, in particular to a novel nitro imidazole compound, and its pharmaceutically acceptable salt, preparation method and application in preparing medicines for treating mycobacterium tuberculosis infectious diseases, especially infectious diseases caused by multidrug resistant mycobacterium tuberculosis. The nitro imidazole compound or the pharmaceutically acceptable salt thereof disclosed in the invention has good activity against mycobacterium tuberculosis in vitro, especially has strong activity against multidrug resistant mycobacterium tuberculosis.

Description

Technical field [0001] The invention belongs to the field of pharmacology, relates to the fields of medicinal chemistry and pharmacology, and more specifically, relates to a new class of nitroimidazole compounds and their preparation methods and drugs for treating infectious diseases, especially infectious diseases caused by Mycobacterium tuberculosis. uses in. Background technique [0002] Tuberculosis, caused by infection with Mycobacterium tuberculosis, is one of the oldest diseases in humans. To this day, tuberculosis still seriously harms human health. According to WHO statistics, about 1 / 3 of the world's population has been infected with Mycobacterium tuberculosis, and tuberculosis is the infectious disease that causes the largest number of deaths. [0003] The current treatment of tuberculosis mainly uses a combination of several first-line drugs such as isoniazid, rifampicin, ethambutol and pyrazinamide. This treatment method has the following disadvantages: the tr...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61K31/5365A61P31/06A61P11/00
CPCC07D498/04A61K31/5365A61P11/00A61P31/06
Inventor 王天才辛婷樊后兴陈义朗
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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