A new application of pyridine compounds

A compound and pyridine technology, applied in the field of pyridine compounds, can solve the problems of poor patient compliance, large toxic and side effects, and high infection risk, and achieve the effects of low dosage, low toxic and side effects, and convenient use.

Active Publication Date: 2021-01-05
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the standard drug therapy recommended by WHO, streptomycin needs to be injected daily for a long period of time, which is inconvenient for patients. The route of administration has a high risk of infection due to incomplete disinfection of equipment, and poor patient compliance
In addition, rifampicin and streptomycin have relatively large toxic and side effects, long-term administration, and poor patient compliance
There are few available drugs, all of which need to be combined with rifamycin drugs, so if the patient is resistant to this type of drug, the therapeutic effect of all therapies will be significantly reduced, and rifampicin and other drugs will significantly Decrease the efficacy of other disease treatment drugs, such as the AIDS drug Kaletra, and the use of the two together will make the antiviral effect of Kaletra ineffective
The long-term treatment effect of clarithromycin combined with rifampicin is poor, and it is still necessary to use streptomycin and rifampicin for consolidation therapy at a later stage
Bedaquiline, a new anti-tuberculosis drug, has relatively high toxicity and side effects. The FDA has added a black box to restrict its use. It is often recommended for the treatment of drug-resistant tuberculosis patients only when other drugs are ineffective. It has not yet been recommended for the treatment of Buruli necrosis.

Method used

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  • A new application of pyridine compounds
  • A new application of pyridine compounds
  • A new application of pyridine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] This example studies the effect of pyrazolopyridine compounds and imidazopyridine compounds of the present invention on inhibiting Mycobacterium bruli's necrosis in vitro.

[0040] (1) Experimental grouping

[0041] Solvent group: give an equal volume of drug solvent as a control;

[0042] Pyrazolopyridine compound group: With the skeleton shown in formula (I), the structures of R1, R2 and R3 of each compound are shown in Table 1:

[0043] Table 1 Structural formula of pyrazolopyridine compounds

[0044] Compound number R1 R2 R3 1 5-Me Me CF 3

2 5-Me Me Formula (a) 3 5-Me Me Formula (b) 4 5-Me Me Formula (c) 5 5-Me Me Formula (d) 6 5-Me Me Formula (e) 7 5-Me Me Formula (f) 8 4-Me Me Formula (f) 9 6-Me Me Formula (f) 10 7-Me Me Formula (f) 11 5-OMe Me Formula (f) 12 5-Cl Me Formula (f) 13 5-Et Me Formula (f) 14 5-i-Pr ...

Embodiment 2

[0064] This example studies the effect of COMX and Q203 on inhibiting Mycobacterium brulii necrosis in vitro.

[0065] (1) Experimental grouping

[0066] Solvent group: give an equal volume of drug solvent as a control;

[0067] COMX group: concentrations of 1 μg / mL, 0.2 μg / mL, 0.04 μg / mL, 0.008 μg / mL, 0.0016 μg / mL, 0.00032 μg / mL;

[0068] Group Q203: concentration of 4μg / mL, 0.8μg / mL, 0.16μg / mL, 0.03μg / mL, 0.005μg / mL; 0.001μg / mL

[0069] The COMX and Q203 used above were dissolved in DMSO for use.

[0070] (2) Experimental steps

[0071] 1. For the cultivation of self-luminescent Mycobacterium bruley necrosis, the experimental steps are the same as in Example 1.

[0072] 2. Adding drugs and co-incubating for continuous detection

[0073] Add 198 μL of bacterial solution and 2 μL of the prepared drug to each EP tube, and at the same time, use a pipette to mix the drug and the bacterial solution evenly. Test the bactericidal or antibacterial effect of the drug: put the EP...

Embodiment 3

[0078] This example studies the inhibitory effect of COMX and Q203 on Mycobacterium brulii necrosis in mice.

[0079] (1) Grouping and administration of animals

[0080] Select Balb / C mice about 6 weeks old, inject the mice with self-luminous Mycobacterium brullii necrosis infection into the hind feet, and start the drug treatment 10 days after the infection. The drug groups are as follows, with 10 mice in each group:

[0081] Untreated group: given an equal volume of deionized water after infection as a negative control;

[0082] uninfected group: uninfected bacteria group, as the background baseline of the detected luminescence;

[0083] Rifampicin + streptomycin group: Rifampicin 10mg / kg by intragastric administration and streptomycin 150mg / kg by subcutaneous injection;

[0084] COMX group: COMX oral administration doses were 50mg / kg, 25mg / kg, 12.5mg / kg, 6.25mg / kg, 3.2mg / kg, 1.6mg / kg, 0.8mg / kg, 0.4mg / kg;

[0085] Q203 group: Q203 intragastric administration doses were 25...

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Abstract

Disclosed is a use of a pyridine compound in the preparation of a medicament for treating mycobacterial infectious diseases. The pyridine compound comprises a pyrazolopyridine compound and an imidazopyridine compound. The structural formula of the pyrazolopyridine compound is represented by formula (I), and the structural formula of the imidazopyridine compound is represented by formula (II). The present inventors have found that pyrazolopyridines and imidazopyridines are effective in the treatment of mycobacterial infectious diseases, especially diseases caused by infection with Mycobacterium ulcerans, Mycobacterium marinum, and Mycobacterium leprae, and said compounds also have the advantages of convenient use, quick effect, low dosage, low toxic side effects, etc.

Description

technical field [0001] The present invention relates to a new use of a pyridine compound, in particular to a use of a pyridine compound in preparing a medicine for treating mycobacterial infectious diseases. Background technique [0002] Mycobacterium ulcerans can cause severe skin ulcers, necrosis, and even blindness and death. It is often called Buruli Ulcer and has been found in Africa, Australia, Southeast Asia and South America , Japan and other regions found the disease. The treatment method for this disease is mainly to perform skin grafting after excision of the patient's tissue by surgical operation, but its cure rate is only between 16% and 28%, and it must be supplemented by drug treatment. The drug recommended by the World Health Organization for the treatment of this disease is a combination of rifampicin and streptomycin for about 8 weeks as adjuvant therapy. The therapy is based on previous experiments in mouse models. Other therapies (which have not entere...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4545A61P31/04A61P31/08
CPCA61K31/4545A61P31/04A61P31/08
Inventor 张天宇刘洋
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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