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Novel nitroimidazole compound and application thereof in pharmacy

A compound, nitro technology, applied in the fields of pharmacology, medicinal chemistry and pharmacology, can solve the problems of low oral bioavailability, serious adverse reactions, poor effect, etc., to improve the activity of anti-mycobacterium tuberculosis, strong anti- Mycobacterium tuberculosis effect, effect of excellent pharmacokinetic properties

Active Publication Date: 2013-12-18
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 relatively serious, such as the combination of rifampicin and isoniazid may cause severe liver toxicity, and ethambutol can cause optic nerve damage; Drug-resistant Mycobacterium tuberculosis, especially multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is not 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.]
[0006] Japan's Otsuka Pharmaceutical Co., Ltd (Otsuka Pharmaceutical Co., Ltd) also synthesized many nitroimidazole compounds, especially OPC-67683 [J.Med.Chem., 2006, 49 (26), 7854-7860.], the role The mechanism is similar to PA-824, which is used to treat tuberculosis. This compound has strong activity, but has the same problem as PA-824. The compound has low solubility in water, resulting in low oral bioavailability, so there is room for further improvement

Method used

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  • Novel nitroimidazole compound and application thereof in pharmacy
  • Novel nitroimidazole compound and application thereof in pharmacy
  • Novel nitroimidazole compound and application thereof in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0093] Preparation Example 1 5-(4-(Trifluoromethoxy)phenoxy)isoindole (TH-1)

[0094]

[0095] tert-butyl 5-hydroxyisoindole-2-carboxylate (470 mg, 2.0 mmol, synthesized by reference Bioorg.Med.Chem.Lett., 2001, 11(5), 685-688) and 1-bromo 4-tri Fluoromethoxybenzene (481mg, 2.0mmol) was dissolved in 1,4-dioxane (10mL), copper iodide (38mg, 0.2mmol), N,N-dimethylglycine (62mg, 0.6 mmol), cesium carbonate (977mg, 3.0mmol), heated to reflux for 24h under the protection of argon, the reaction was completed, filtered, concentrated, column chromatography (CH 2 Cl 2 / CH 3 OH=100 / 1), the resulting product is directly put into the next step reaction.

[0096] The intermediate obtained in the previous step was dissolved in dichloromethane (10 mL), and the mixture was cooled with ice salt, and trifluoroacetic acid (10 mL) was added. After the addition was complete, the mixture was reacted at room temperature for 3 hours, stopped the reaction, and concentrated. The residue was dissol...

preparation example 2

[0098] Preparation 2 5-(4-(trifluoromethyl)phenoxy)isoindole (TH-2)

[0099]

[0100] Using tert-butyl 5-hydroxyisoindole-2-carboxylate (470 mg, 2.0 mmol) and 1-bromo-4-trifluoromethylbenzene (450 mg, 2.0 mmol) as starting materials, the intermediate product was obtained similarly to the synthesis of TH-1 TH-2 (340 mg, 61%).

[0101] MS(ESI / LR):280.1[M+1] + .

preparation example 3

[0102] Preparation 3 7-(4-(trifluoromethoxy)phenoxy)-1,2,3,4-tetrahydroisoquinoline (TH-3)

[0103]

[0104] With tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (498mg, 2.0mmol, reference Bioorg.Med.Chem.,2009,17(23),7850-7860 Synthesis) and 1-bromo-4-trifluoromethoxybenzene (481mg, 2.0mmol) as raw materials, similar to the synthesis of TH-1, the intermediate product TH-3 (402mg, 65%) was obtained.

[0105] MS(ESI / LR):310.1[M+1] + .

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Abstract

The invention relates to a novel nitroimidazole compound as well as a preparation method and an application thereof. The invention in particular relates to nitroimidazole compounds shown in a formula (I) and a preparation method thereof as well as an application of the compounds shown in the formula (I) and pharmaceutically acceptable salts of the compounds shown in the formula (I) in preparation of medicines used for treating diseases related to infection caused by mycobacterium tuberculosis.

Description

Technical field [0001] The present invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and more specifically, relates to a new class of nitroimidazole compounds, methods for preparing the compounds, and the use of such compounds for the treatment of diseases related to infections caused by Mycobacterium tuberculosis. . 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 treatment ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/5383A61P31/06
Inventor 樊后兴王天才贺礼东
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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