WO2019148575A1 - Nouvelle utilisation d'un composé à base de pyridine - Google Patents

Nouvelle utilisation d'un composé à base de pyridine Download PDF

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WO2019148575A1
WO2019148575A1 PCT/CN2018/077992 CN2018077992W WO2019148575A1 WO 2019148575 A1 WO2019148575 A1 WO 2019148575A1 CN 2018077992 W CN2018077992 W CN 2018077992W WO 2019148575 A1 WO2019148575 A1 WO 2019148575A1
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formula
mycobacterium
compound
medicament
pyridine compound
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PCT/CN2018/077992
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English (en)
Chinese (zh)
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张天宇
刘洋
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中国科学院广州生物医药与健康研究院
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Publication of WO2019148575A1 publication Critical patent/WO2019148575A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/08—Antibacterial agents for leprosy

Definitions

  • the present invention relates to a novel use of a pyridine compound, and in particular to the use of a pyridine compound for the preparation of a medicament for treating a mycobacterial infectious disease.
  • Mycobacterium ulcerans can cause severe skin ulcers, necrosis, and even blindness and death. It is often called Buruli Ulcer and is currently in Africa, Australia, Southeast Asia, and South America. The disease was found in various regions such as Japan. The treatment of this disease is mainly through surgical resection of the patient's tissue and then skin grafting, however, the cure rate is only between 16% and 28%, and must be supplemented with medication.
  • the World Health Organization's recommended treatment for this disease is adjuvant therapy with rifampicin and streptomycin for about 8 weeks. The therapy is based on experimental results in previous mouse models. Other therapies (not yet in clinical practice, mainly in 2016), mainly using clarithromycin, betaxazoline instead of streptomycin and rifampicin (or similar drug rifapentine) Need to be treated for about 8 weeks.
  • Surgical treatment of the disease is costly and has a low cure rate and must be supplemented with medication.
  • streptomycin requires long-term daily injections, which is inconvenient for patients. The route of administration is not completely sterilized due to equipment sterilization, and patient compliance is poor.
  • rifampicin and streptomycin have large toxic side effects, and long-term administration has poor patient compliance.
  • Kelizhi's anti-virus Reducing the efficacy of other disease treatment drugs, such as the AIDS drug Kelizhi, the use of the two will cause Kelizhi's anti-virus to be 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 treatment later.
  • the new anti-tuberculosis drug betaxazoline has a large side effect.
  • the FDA has added a black box to limit the use. It is often recommended for the treatment of drug-resistant tuberculosis patients when other drugs are not effective. It has not been recommended to treat Brucella necrosis. .
  • pyridine compound for the preparation of a medicament for treating a mycobacterial infectious disease by overcoming the above-mentioned deficiencies of the prior art, the pyridine compound having the following structural formula:
  • R1 represents 5-Me, 4-Me, 6-Me, 7-Me, 5-OMe, 5-Cl, 5-Et, 5-i-Pr or 5-t-Butyl;
  • R2 stands for Me
  • R3 represents CF 3 , formula (a), formula (b), formula (c), formula (d), formula (e) or formula (f):
  • the pyridine compound has the following structural formula:
  • the mycobacterium is Brucella necroticum.
  • the mycobacterium is Mycobacterium marinum or Mycobacterium leprae.
  • the drug is an oral dosage form or an external dosage form.
  • the oral dosage form comprises tablets, capsules, granules and oral liquids;
  • the topical dosage forms include ointments, gels, band-aids and patches.
  • Another object of the present invention is to provide a medicament for treating a mycobacterial infectious disease, the medicament comprising a pyridine compound and a pharmaceutically acceptable carrier, the pyridine compound having the following structural formula:
  • R1 represents 5-Me, 4-Me, 6-Me, 7-Me, 5-OMe, 5-Cl, 5-Et, 5-i-Pr or 5-t-Butyl;
  • R2 stands for Me
  • R3 represents CF 3 , formula (a), formula (b), formula (c), formula (d), formula (e) or formula (f):
  • the pyridine compound has the following structural formula:
  • the compound represented by the formula (III) in the present invention is abbreviated as COMX; the compound represented by the formula (IV) is abbreviated as Q203.
  • the mycobacterial infectious disease is Brucella necrosis, Mycobacterium tuberculosis infectious disease or leprosy.
  • the drug is an oral dosage form or an external dosage form.
  • the oral dosage form comprises tablets, capsules, granules and oral liquids; the topical dosage forms include ointments, gels, band-aids and patches.
  • the pyridine compound of the present invention comprises a pyrazolopyridine compound and an imidazopyridine compound; the pyrazolopyridine compound has a structural formula of the formula (I), and the imidazopyridine compound has a structural formula As shown in formula (II).
  • the beneficial effects of the present invention are as follows: the inventors of the present invention are the first to use pyrazolopyridines and imidazopyridines to effectively treat mycobacterial infectious diseases, especially by Brucella necrotic It is a disease caused by Mycobacterium marinum and Mycobacterium leprae infection, and has the advantages of convenient use, quick effect, low dosage and low side effects.
  • Figure 1 is a graph showing the dynamic inhibition of luminescence values of Mycobacterium breve in vitro by COMX and Q203.
  • Figure 2 is a graph showing the dynamic changes in foot luminescence values of mice infected with Brilliant Nebulous Mycobacterium tuberculosis after COMX treatment.
  • Figure 3 is a graph showing the results of luminescence detection of the foot tissue of mice infected with Brilliant Nebulous Mycobacterium tuberculosis after COMX treatment.
  • Figure 4 is a photograph of the foot of a self-illuminating Brucella necrotic Mice mouse infected on day 7 of COMX treatment (5 days after treatment, every other day).
  • Figure 5 is a graph showing the dynamic changes in the luminescence value of the foot of mice infected with Brilliant Nebulous Mycobacterium tuberculosis after Q203 treatment.
  • Figure 6 shows the relative bacterial load of the mice infected with M. leprae mice after 4 weeks of treatment with COMX and Q203 (4 weeks after treatment, 4 weeks apart).
  • Solvent group give an equal volume of drug solvent as a control
  • Pyrazolopyridine compound group The skeleton represented by the formula (I), and the structures of R1, R2 and R3 of each compound are shown in Table 1:
  • Imidazopyridine compound group The skeleton represented by the formula (II), and the structures of R1, R2 and R3 of each compound are shown in Table 2:
  • pyrazolopyridines and imidazopyridines used above were dissolved in DMSO for use.
  • Self-illuminating Brucella necroticum was added to 7H11 solid medium and cultured at 30 ° C for 58 days; single colonies were picked from the plate to detect relative light units (RLU) using a luminescence detector, and single colonies that confirmed luminescence were connected.
  • 50 mL of 7H9 liquid medium was cultured for about 7 days, resuspended in sterile physiological saline, filtered through a 300-mesh cell sieve, and filtered to form a single existing bacterial suspension for detection experiments.
  • a 96-well plate Take a 96-well plate, add the prepared compound to the first vertical row on the left side, mix the drug with the bacterial solution using a pipetting gun, and then perform a 2-fold gradient dilution from left to right using a lance. Detecting the bactericidal or bacteriostatic effect of the drug: After the fifth day of incubation, the 96-well plate was placed in a microplate reader, and the luminescence values of each group were detected.
  • the minimum inhibitory concentration is the lowest concentration at which the compound inhibition rate is higher than 90%.
  • the pyrazolopyridine and imidazopyridine series compounds have good inhibitory activity against Brucella necroticum.
  • the pyrazolopyridine compound of No. 11 i.e., COMX
  • the imidazopyridine compound of No. 27 i.e., Q203
  • Solvent group give an equal volume of drug solvent as a control
  • COMX group concentration of 1 ⁇ g / mL, 0.2 ⁇ g / mL, 0.04 ⁇ g / mL, 0.008 ⁇ g / mL, 0.0016 ⁇ g / mL, 0.00032 ⁇ g / mL;
  • Group Q203 concentration 4 ⁇ g/mL, 0.8 ⁇ g/mL, 0.16 ⁇ g/mL, 0.03 ⁇ g/mL, 0.005 ⁇ g/mL; 0.001 ⁇ g/mL
  • mice were selected for about 6 weeks, and the infected mice were injected with self-illuminating Brucella necroticus, and the treatment was started 10 days after infection.
  • the administration groups were as follows: 10 mice per group:
  • Untreated group give an equal volume of deionized water after infection as a negative control
  • Uninfected group uninfected bacterial group, as a background baseline for the detected luminescence
  • Rifampicin + streptomycin group rifampicin 10mg/kg and subcutaneous injection of streptomycin 150mg/kg;
  • COMX intragastric administration amount is 50mg/kg, 25mg/kg, 12.5mg/kg, 6.25mg/kg, 3.2mg/kg, 1.6mg/kg, 0.8mg/kg, 0.4mg/kg;
  • Q203 administered by intragastric administration were 25mg/kg, 6.25mg/kg, 1.6mg/kg;
  • the perfusion volume of each drug was 0.2 mL/time/time, and it was administered only once a day for 5 consecutive days.
  • the in vivo luminescence value of the mice was detected according to the design time point. After the anesthetized mice on the seventh day, the cervical spine was dissected and sacrificed. The tissue of the foot was ground and the tissue luminescence value was measured. The smaller the luminescence value, the better the drug treatment effect, and vice versa. .
  • COMX as low as 0.4 mg/kg has exhibited significant activity against Mycobacterium breve. Only 0.8mg/kg of COMX was better than 10mg/kg of rifampicin and 150mg/kg of streptomycin, indicating that COMX has good activity against Mycobacterium bryogenes and is in vivo. The effect is faster than the drugs currently used. Two days after discontinuation of the drug, the first-line therapy (RIF10+STR150) mice showed a rebound in in vivo luminescence, while COMX did not rebound above 3.1 mg/kg.
  • Fig. 3 The results of luminescence detection of the foot tissue of infected mice are shown in Fig. 3. As can be seen from Fig. 3, after 5 days of treatment, the standard first-line therapy (RIF10+STR150) treatment group can still detect higher luminescence value, and 12.5 mg. The COMX treatment group above /kg has even reached the background value (the same value as the uninfected group), indicating that COMX can significantly shorten the course of treatment.
  • the standard first-line therapy (RIF10+STR150) treatment group can still detect higher luminescence value, and 12.5 mg.
  • the COMX treatment group above /kg has even reached the background value (the same value as the uninfected group), indicating that COMX can significantly shorten the course of treatment.
  • mice Female C57BL/6 mice were selected and infected with M. leprae in the foot of the mice. The drug was administered 12 weeks after infection. The drug administration was as follows, 20 mice per group:
  • Untreated group give an equal volume of deionized water as a negative control
  • Rifampicin group the amount of intragastric administration is rifampicin 10 mg/kg;
  • COMX group COMX was administered and administered by intragastric administration at a dose of 25 mg/kg;
  • Group Q203 Q203 was administered and administered by intragastric administration at a dose of 25 mg/kg;
  • the perfusion amount of each drug was 0.2 mL/time/time, and it was administered only once a day for 4 weeks for continuous treatment and 5 days for weekly treatment.
  • mice After the end of treatment in all groups, wait for 4 weeks, the mice were sacrificed by anesthesia for cervical dislocation, and the soft tissue of the infected foot was taken out with scissors. The tissue genome was extracted and purified by quantitative PCR.
  • the upstream detection primer sequence was: 5 '-GCAGTATCGTGTTAGTGAACAGTGCA-3', the downstream detection primer sequence is 5'-CGCTAGAAGGTTGCCGTATGTGC-3'.
  • the amount of Mycobacterium leprae suspension was determined as a standard control, and the amount of bacteria in the tissues of each group of mice was converted according to the fluorescence quantitative PCR result curve.
  • the test results are shown in Fig. 6.
  • the mouse bacterial load of the pyrazolopyridine compound (represented by COMX) and the imidazopyridine compound (represented by SQ203) was lower than that of the control group and 10 mg/kg.
  • Ming COMX and SQ203 have very good therapeutic effects on leprosy.
  • Solvent group give an equal volume of drug solvent as a control
  • COMX group concentration of 0.1 ⁇ g / mL, 0.01 ⁇ g / mL, 0.001 ⁇ g / mL;
  • Group Q203 concentration of 0.1 ⁇ g/mL, 0.01 ⁇ g/mL, 0.001 ⁇ g/mL
  • the self-illuminating Mycobacterium marinum was connected to 7H11 solid medium and cultured at 30 ° C for 7 days; single colonies were picked from the plate and the relative light unit (RLU) was detected using a luminescence detector. The single colony that confirmed the luminescence was incubated in 50 mL of 7H9 liquid medium for about 3 days, resuspended in sterile physiological saline, filtered through a 300-mesh cell sieve, and filtered to form a single existing bacterial suspension for detection. experiment.
  • each EP tube 198 ⁇ L of the bacterial solution and 2 ⁇ L of the drug prepared drug were separately added, and the pipetting drug was mixed with the bacterial liquid using a pipetting gun. After incubation for 24 hours, detect the bactericidal or bacteriostatic effect of the drug: After placing the EP tube into the luminescence detector, wait for 1-2 seconds, wait until the outside light is quenched, and press the detection button to record the RLUs of each EP tube.
  • the method for calculating the growth inhibition rate and the minimum inhibitory concentration of the compound against the bacteria was the same as in Example 1.
  • Mycobacterium marinum and Brucella necrotica are highly related, and the genomic similarity rate of the two is 99%.
  • the results showed that both COMX group and Q203 could significantly inhibit Mycobacterium marinum, and the minimum inhibitory concentration of both was 0.01 ⁇ g/mL, and the antibacterial activity was very good.

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Abstract

L'invention concerne l'utilisation d'un composé à base de pyridine dans la préparation d'un médicament pour le traitement de maladies infectieuses à mycobactéries. Le composé à base de pyridine comprend un composé pyrazolopyridine et un composé imidazopyridine. La formule structurale du composé pyrazolopyridine est représentée par la formule (I), et la formule structurale du composé imidazopyridine est représentée par la formule (II). Les présents inventeurs ont découvert que les pyrazolopyridines et les imidazopyridines sont efficaces dans le traitement de maladies infectieuses à mycobactéries, en particulier de maladies provoquées par une infection à Mycobacterium ulcerans, Mycobacterium marinum et Mycobacterium leprae, lesdits composés ayant également l'avantage d'une utilisation pratique, d'un effet rapide, d'un faible dosage, de faibles effets indésirables toxiques, etc.
PCT/CN2018/077992 2018-02-01 2018-03-05 Nouvelle utilisation d'un composé à base de pyridine WO2019148575A1 (fr)

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Cited By (2)

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WO2021050708A1 (fr) * 2019-09-10 2021-03-18 Shionogi & Co., Ltd. Composés 5,6-hétéroaromatiques contenant de la benzylamine utiles contre une infection mycobactérienne
US11820767B2 (en) 2015-09-17 2023-11-21 University Of Notre Dame Du Lac Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection

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CN112089713B (zh) * 2020-09-18 2022-02-22 中国科学院广州生物医药与健康研究院 一种基于吡唑并[1,5-a]吡啶类化合物的治疗结核分枝杆菌感染的药物组合物

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Publication number Priority date Publication date Assignee Title
US11820767B2 (en) 2015-09-17 2023-11-21 University Of Notre Dame Du Lac Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection
WO2021050708A1 (fr) * 2019-09-10 2021-03-18 Shionogi & Co., Ltd. Composés 5,6-hétéroaromatiques contenant de la benzylamine utiles contre une infection mycobactérienne
EP4028130A4 (fr) * 2019-09-10 2023-08-30 Shionogi & Co., Ltd Composés 5,6-hétéroaromatiques contenant de la benzylamine utiles contre une infection mycobactérienne

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