[go: up one dir, main page]

WO2023227123A1 - Utilisation d'un dérivé de pyridine - Google Patents

Utilisation d'un dérivé de pyridine Download PDF

Info

Publication number
WO2023227123A1
WO2023227123A1 PCT/CN2023/096638 CN2023096638W WO2023227123A1 WO 2023227123 A1 WO2023227123 A1 WO 2023227123A1 CN 2023096638 W CN2023096638 W CN 2023096638W WO 2023227123 A1 WO2023227123 A1 WO 2023227123A1
Authority
WO
WIPO (PCT)
Prior art keywords
mycobacterium
substance
tuberculous
formula
tuberculous mycobacteria
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/096638
Other languages
English (en)
Chinese (zh)
Inventor
黄海荣
朱芮
尚园园
初乃惠
聂文娟
李永国
李磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Chest Hospital Affiliated Of Capital Medical University
Shanghai Jia Tan Pharmatech Co Ltd
Guangzhou Joyo Pharmatech Co Ltd
Original Assignee
Beijing Chest Hospital Affiliated Of Capital Medical University
Shanghai Jia Tan Pharmatech Co Ltd
Guangzhou Joyo Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Chest Hospital Affiliated Of Capital Medical University, Shanghai Jia Tan Pharmatech Co Ltd, Guangzhou Joyo Pharmatech Co Ltd filed Critical Beijing Chest Hospital Affiliated Of Capital Medical University
Publication of WO2023227123A1 publication Critical patent/WO2023227123A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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

Definitions

  • the present invention relates to the use of a pyridine derivative.
  • Non-tuberculous mycobacterial (NTM) lung disease is more common in patients with underlying lung diseases such as bronchiectasis and COPD (chronic obstructive pulmonary disease) and is an important cause of increased mortality in these patients.
  • NTM species or subspecies More than 200 NTM species or subspecies have been reported, among which Mycobacterium avium complex (MAC, mainly including Mycobacterium avium and Mycobacterium intracellulare), Mycobacterium abscessus (Mab) and Mycobacterium kansasii are The most common bacterial species causing NTM lung disease (NTM-PD). Treatment of NTM infections is often challenging as different NTM species are generally naturally resistant to most antibiotics.
  • MAC Mycobacterium avium complex
  • Mob Mycobacterium abscessus
  • NTM kansasii Mycobacterium kansasii
  • Bedaquiline is a novel antibiotic that targets drug-resistant tuberculosis by inhibiting ATP synthesis.
  • BDQ not only showed potent efficacy against multidrug-resistant tuberculosis in vitro and in vivo, but also showed potent activity against many different NTM strains in vitro.
  • the multiple serious side effects of BDQ such as unexplained mortality, QT interval prolongation, hepatotoxicity, and phospholipidosis, limit the promotion of BDQ. Therefore, finding highly active anti-NTM drugs is the primary task to establish effective NTM infection treatment regimens.
  • the technical problem to be solved by the present invention is to provide the use of a pyridine derivative in order to overcome the lack of drugs for inhibiting non-tuberculous mycobacterial diseases in the prior art.
  • the pyridine derivative of the invention has good inhibitory effect on non-tuberculous mycobacteria, has low cytotoxicity and good safety.
  • the present invention provides the use of substance X in the preparation of drugs for inhibiting non-tuberculous mycobacteria; the substance Acceptable salt solvates;
  • the substance X is preferably a compound represented by formula I-1;
  • the substance X may be one of the active ingredients or the only active ingredient of the drug.
  • the non-tuberculous mycobacteria may be selected from one or more of fast-growing non-tuberculous mycobacteria and slow-growing non-tuberculous mycobacteria.
  • the fast-growing non-tuberculous mycobacteria can be selected from the group consisting of Mycobacterium abscessus, Mycobacterium field, Mycobacterium aichi, Mycobacterium aureus, Mycobacterium South Africa, Mycobacterium chelonae, Mycobacterium Chida, Mycobacterium trubucus, Mycobacterium cosmetics, Mycobacterium dieli, Mycobacterium fortuitum, Mycobacterium mucogenes, Mycobacterium orbu, Mycobacterium parafortuitum, Mycobacterium exogenous , Mycobacterium dust, Mycobacterium senegal, Mycobacterium septicemia, Mycobacterium smegmatis, Mycobacterium heat-resistant, Mycobacterium eastsea, Mycobacterium fortuitum subgenus fortuitum, Mycobacterium new orleans, Mycobacterium winter bacilli, Mycobacterium absces
  • the fast-growing non-tuberculous mycobacteria is preferably Mycobacterium New Jersey.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of ATCC19977, ATCC27406, ATCC27280, ATCC23366, ATCC33464, ATCC14472, ATCC19627, ATCC27278, DSM44829, ATCC19340, ATCC6841, DSM44124, ATCC27023, AT CC19686, DSM43271, ATCC35154 , one or more of ATCC35796, ATCC700731, ATCC19420, ATCC19527, ATCC27282, DSM46621, DSM44679, DSM44177, DSM45103 and DSM44017.
  • the rapidly growing non-tuberculous mycobacterium is preferably DSM44679.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of Mycobacterium asiatica, Mycobacterium avium, Mycobacterium cryptica, Mycobacterium chimera, Mycobacterium gastricus, Mycobacterium gordonii , Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium vole, chromogenic Mycobacterium, Mycobacterium parascrofulaceus, Mycobacterium rhodesia, Mycobacterium scrofula, Mycobacterium sulgaris , Mycobacterium terrestrialis, Mycobacterium minora, Mycobacterium xenoides, Mycobacterium caddis bacilli, Mycobacterium aarhusii, Mycobacterium kubica, Mycobacterium intermedius, Mycobacterium sphagnum, Mycobacterium stutzeri, and Mycobacterium marinum.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of ATCC25276, ATCC25291, DSM44243, DSM44622, ATCC15754, ATCC14470, ATCC13950, ATCC12478, ATCC19422, ATCC19530, DSM44648, ATCC27024, ATCC19981, ATCC35799, ATCC15755, ATCC23292 , one or more of ATCC19250, ATCC27726, DSM45069, DSM44627, DSM44064, ATCC33027, ATCC27962 and ATCC927.
  • the medicament may include pharmaceutical excipients.
  • the administration method of the drug can be a conventional administration method in the art, such as oral administration.
  • the substance X is a therapeutically and/or prophylactically effective amount.
  • the present invention also provides a pharmaceutical composition for inhibiting non-tuberculous mycobacteria, which includes: substance X as described above, and pharmaceutical excipients.
  • the present invention also provides the use of substance X in the preparation of drugs for treating and/or preventing non-tuberculous mycobacterial infections; the substance salts or solvates of pharmaceutically acceptable salts thereof;
  • the above-mentioned substance X is preferably a compound represented by formula I-1;
  • the substance X may be one of the active ingredients or the only active ingredient of the drug.
  • the non-tuberculous mycobacteria may be selected from one or more of fast-growing non-tuberculous mycobacteria and slow-growing non-tuberculous mycobacteria.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of Mycobacterium abscessus, Mycobacterium bacilli, Mycobacterium aichi, Mycobacterium aureus, Mycobacterium South Africa, Mycobacterium chelonae, Mycobacterium Chida, Mycobacterium trubucus, Mycobacterium cosmetics, Mycobacterium dieli, Mycobacterium fortuitum , Mycobacterium mucogenes, Mycobacterium obdu, Mycobacterium parafortuitum, Mycobacterium exogenous, Mycobacterium dust, Mycobacterium senegal, Mycobacterium septicemia, Mycobacterium smegmatis, Mycobacterium heat-resistant , Mycobacterium donghaiense, Mycobacterium fortuitum subgenus fortuitum, Mycobacterium new orleans, Mycobacterium winter, Mycobacterium abscess
  • the fast-growing non-tuberculous mycobacteria is preferably Mycobacterium New Jersey.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of ATCC19977, ATCC27406, ATCC27280, ATCC23366, ATCC33464, ATCC14472, ATCC19627, ATCC27278, DSM44829, ATCC19340, ATCC6841, DSM44124, ATCC27023, AT CC19686, DSM43271, ATCC35154 , one or more of ATCC35796, ATCC700731, ATCC19420, ATCC19527, ATCC27282, DSM46621, DSM44679, DSM44177, DSM45103 and DSM44017.
  • the rapidly growing non-tuberculous mycobacterium is preferably DSM44679.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of Mycobacterium asiatica, Mycobacterium avium, Mycobacterium cryptica, Mycobacterium chimera, Mycobacterium gastricus, Mycobacterium gordonii , Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium vole, chromogenic Mycobacterium, Mycobacterium parascrofulaceus, Mycobacterium rhodesia, Mycobacterium scrofula, Mycobacterium sulgaris , Mycobacterium terrestrialis, Mycobacterium minora, Mycobacterium xenoides, Mycobacterium caddis, Mycobacterium aarhusii, Mycobacterium kubica, Mycobacterium intermedius, Mycobacterium sphagnum, One or more species of Mycobacterium marinum and Mycobacterium marinum.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of ATCC25276, ATCC25291, DSM44243, DSM44622, ATCC15754, ATCC14470, ATCC13950, ATCC12478, ATCC19422, ATCC19530, DSM44648, ATCC27024, ATCC19981, ATCC35799, ATCC15755, ATCC23292 , one or more of ATCC19250, ATCC27726, DSM45069, DSM44627, DSM44064, ATCC33027, ATCC27962 and ATCC927.
  • the non-tuberculous mycobacterial infection is preferably NTM lung disease and/or disseminated NTM disease.
  • the medicament may include pharmaceutical excipients.
  • the administration method of the drug can be any method conventional in the art, such as oral administration.
  • the substance X may be in a therapeutically and/or prophylactically effective amount.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing non-tuberculous mycobacterial infection, which includes: substance X as described above, and pharmaceutical excipients.
  • the non-tuberculous mycobacterial infection is preferably NTM lung disease and/or disseminated NTM disease.
  • the present invention also provides the use of substance X in the preparation of non-tuberculous mycobacteria inhibitors; the substance Acceptable salt solvates;
  • the substance X is preferably a compound represented by formula I-1;
  • the substance X may be one of the active ingredients or the only active ingredient of the drug.
  • the non-tuberculous mycobacteria may be selected from one or more of fast-growing non-tuberculous mycobacteria and slow-growing non-tuberculous mycobacteria.
  • the fast-growing non-tuberculous mycobacteria can be selected from the group consisting of Mycobacterium abscessus, Mycobacterium field, Mycobacterium aichi, Mycobacterium aureus, Mycobacterium South Africa, Mycobacterium chelonae, Mycobacterium Chida, Mycobacterium trubucus, Mycobacterium cosmetics, Mycobacterium dieli, Mycobacterium fortuitum, Mycobacterium mucogenes, Mycobacterium orbu, Mycobacterium parafortuitum, Mycobacterium exogenous , Mycobacterium dust, Mycobacterium senegal, Mycobacterium septicemia, Mycobacterium smegmatis, Mycobacterium heat-resistant, Mycobacterium eastsea, Mycobacterium fortuitum subgenus fortuitum, Mycobacterium new orleans, Mycobacterium winter bacilli, Mycobacterium absces
  • the fast-growing non-tuberculous mycobacteria is preferably Mycobacterium New Jersey.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of ATCC19977, ATCC27406, ATCC27280, ATCC23366, ATCC33464, ATCC14472, ATCC19627, ATCC27278, DSM44829, ATCC19340, ATCC6841, DSM44124, ATCC27023, AT CC19686, DSM43271, ATCC35154 , one or more of ATCC35796, ATCC700731, ATCC19420, ATCC19527, ATCC27282, DSM46621, DSM44679, DSM44177, DSM45103 and DSM44017.
  • the rapidly growing non-tuberculous mycobacterium is preferably DSM44679.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of Mycobacterium asiatica, Mycobacterium avium bacteria, Mycobacterium cryptica, Mycobacterium chimera, Mycobacterium gastricus, Mycobacterium gordonii, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium vole, Chromogenous Mycobacterium, Parascrofula Mycobacterium, Mycobacterium rhodesia, Mycobacterium scrofula, Mycobacterium sulgaris, Mycobacterium terrestrialis, Mycobacterium minora, Mycobacterium xenoides, Mycobacterium caddis, Aarhus One or more of Mycobacterium spp., Mycobacterium kubica, Mycobacterium intermedius, Mycobacterium sphagnum, Mycobacterium stutzeri, and Mycobacterium marinum.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of ATCC25276, ATCC25291, DSM44243, DSM44622, ATCC15754, ATCC14470, ATCC13950, ATCC12478, ATCC19422, ATCC19530, DSM44648, ATCC27024, ATCC19981, ATCC35799, ATCC15755, ATCC23292 , one or more of ATCC19250, ATCC27726, DSM45069, DSM44627, DSM44064, ATCC33027, ATCC27962 and ATCC927.
  • the medicament may include pharmaceutical excipients.
  • the administration method of the drug can be a conventional administration method in the art, such as oral administration.
  • the substance X is a therapeutically and/or prophylactically effective amount.
  • the present invention also provides the use of substance X in the preparation of non-tuberculous mycobacteria inhibitors; the substance Acceptable salt solvates;
  • the substance X is preferably a compound represented by formula I-1;
  • the substance X may be one of the active ingredients or the only active ingredient of the drug.
  • the non-tuberculous mycobacteria may be selected from one or more of fast-growing non-tuberculous mycobacteria and slow-growing non-tuberculous mycobacteria.
  • the fast-growing non-tuberculous mycobacteria can be selected from the group consisting of Mycobacterium abscessus, Mycobacterium field, Mycobacterium aichi, Mycobacterium aureus, Mycobacterium South Africa, Mycobacterium chelonae, Mycobacterium Chida, Mycobacterium trubucus, Mycobacterium cosmetics, Mycobacterium dieli, Mycobacterium fortuitum, Mycobacterium mucogenes, Mycobacterium orbu, Mycobacterium parafortuitum, Mycobacterium exogenous , Mycobacterium dust, Mycobacterium senegal, Mycobacterium septicemia, Mycobacterium smegmatis, Mycobacterium heat-resistant, Mycobacterium eastsea, Mycobacterium fortuitum subgenus fortuitum, Mycobacterium new orleans, Mycobacterium winter bacilli, Mycobacterium absces
  • the fast-growing non-tuberculous mycobacteria is preferably Mycobacterium New Jersey.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of ATCC19977, ATCC27406, ATCC27280, ATCC23366, ATCC33464, ATCC14472, ATCC19627, ATCC27278, DSM44829, ATCC19340, ATCC6841, DSM44124, ATCC27023, AT CC19686, DSM43271, ATCC35154 , one or more of ATCC35796, ATCC700731, ATCC19420, ATCC19527, ATCC27282, DSM46621, DSM44679, DSM44177, DSM45103 and DSM44017.
  • the rapidly growing non-tuberculous mycobacterium is preferably DSM44679.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of Mycobacterium asiatica, Mycobacterium avium, Mycobacterium cryptica, Mycobacterium chimera, Mycobacterium gastricus, Mycobacterium gordonii , Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium vole, chromogenic Mycobacterium, Mycobacterium parascrofulaceus, Mycobacterium rhodesia, Mycobacterium scrofula, Mycobacterium sulgaris , Mycobacterium terrestrialis, Mycobacterium minora, Mycobacterium xenoides, Mycobacterium caddis, Mycobacterium aarhusii, Mycobacterium kubica, Mycobacterium intermedius, Mycobacterium sphagnum, One or more species of Mycobacterium marinum and Mycobacterium marinum.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of ATCC25276, ATCC25291, DSM44243, DSM44622, ATCC15754, ATCC14470, ATCC13950, ATCC12478, ATCC19422, ATCC19530, DSM44648, ATCC27024, ATCC19981, ATCC35799, ATCC15755, ATCC23292 , one or more of ATCC19250, ATCC27726, DSM45069, DSM44627, DSM44064, ATCC33027, ATCC27962 and ATCC927.
  • the medicament may include pharmaceutical excipients.
  • the administration method of the drug can be a conventional administration method in the art, such as oral administration.
  • the substance X is a therapeutically and/or prophylactically effective amount.
  • the present invention also provides the use of substance X in the preparation of non-tuberculous mycobacterial antibacterial agents; the substance Acceptable salt solvates;
  • the substance X is preferably a compound represented by formula I-1;
  • the substance X may be one of the active ingredients or the only active ingredient of the drug.
  • the non-tuberculous mycobacteria may be selected from one or more of fast-growing non-tuberculous mycobacteria and slow-growing non-tuberculous mycobacteria.
  • the fast-growing non-tuberculous mycobacteria can be selected from the group consisting of Mycobacterium abscessus, Mycobacterium field, Mycobacterium aichi, Mycobacterium aureus, Mycobacterium South Africa, Mycobacterium chelonae, Mycobacterium Chida, Mycobacterium trubucus, Mycobacterium cosmetics, Mycobacterium dieli, Mycobacterium fortuitum, Mycobacterium mucogenes, Mycobacterium orbu, Mycobacterium parafortuitum, Mycobacterium exogenous , Mycobacterium dust, Mycobacterium senegal, Mycobacterium septicemia, Mycobacterium smegmatis, Mycobacterium heat-resistant, Mycobacterium eastsea, Mycobacterium fortuitum subgenus fortuitum, Mycobacterium new orleans, Mycobacterium winter bacilli, Mycobacterium absces
  • the fast-growing non-tuberculous mycobacteria is preferably Mycobacterium New Jersey.
  • the rapidly growing non-tuberculous mycobacteria can be selected from the group consisting of ATCC19977, ATCC27406, ATCC27280, ATCC23366, ATCC33464, ATCC14472, ATCC19627, ATCC27278, DSM44829, ATCC19340, ATCC6841, DSM44124, ATCC27023, AT CC19686, DSM43271, ATCC35154 , one or more of ATCC35796, ATCC700731, ATCC19420, ATCC19527, ATCC27282, DSM46621, DSM44679, DSM44177, DSM45103 and DSM44017.
  • the rapidly growing non-tuberculous mycobacterium is preferably DSM44679.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of Mycobacterium asiatica, Mycobacterium avium, Mycobacterium cryptica, Mycobacterium chimera, Mycobacterium gastricus, Mycobacterium gordonii , Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium vole, chromogenic Mycobacterium, Mycobacterium parascrofulaceus, Mycobacterium rhodesia, Mycobacterium scrofula, Mycobacterium sulgaris , Mycobacterium terrestrialis, Mycobacterium minora, Mycobacterium xenoides, Mycobacterium caddis bacilli, Mycobacterium aarhusii, Mycobacterium kubica, Mycobacterium intermedius, Mycobacterium sphagnum, Mycobacterium stutzeri, and Mycobacterium marinum.
  • the slow-growing nontuberculous mycobacteria can be selected from the group consisting of ATCC25276, ATCC25291, DSM44243, DSM44622, ATCC15754, ATCC14470, ATCC13950, ATCC12478, ATCC19422, ATCC19530, DSM44648, ATCC27024, ATCC19981, ATCC35799, ATCC15755, ATCC23292 , one or more of ATCC19250, ATCC27726, DSM45069, DSM44627, DSM44064, ATCC33027, ATCC27962 and ATCC927.
  • the medicament may include pharmaceutical excipients.
  • the administration method of the drug can be a conventional administration method in the art, such as oral administration.
  • the substance X is a therapeutically and/or prophylactically effective amount.
  • the present invention also provides a method for treating and/or preventing non-tuberculous mycobacterial infection, which includes: administering a therapeutically effective amount and/or a preventive effective amount of the substance X or the above-mentioned medicine to a subject in need. combination.
  • the non-tuberculous mycobacterial infection is preferably NTM lung disease and/or disseminated NTM disease.
  • the medicine for treating and/or preventing related diseases caused by non-tuberculous mycobacteria can be in conventional dosage forms in the art, such as tablets, capsules, intravenous injections, intraperitoneal injections, inhalants, and aerosols. , lyophilized agent, patch, gel, spray or suppository, etc.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and preparation of prescriptions. They can be all substances included in pharmaceutical preparations except active ingredients. Please refer to the fourth volume of the Pharmacopoeia of the People's Republic of China (2020 Edition) Or Handbook of Pharmaceutical Excipients (Raymond CRowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment means: (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) the biological cascade that causes or causes the condition. one or more points or (b) one or more biological manifestations of a condition, (3) amelioration of one or more symptoms, effects, or side effects associated with a condition, or one or more symptoms associated with a condition or its treatment or a variety of symptoms, effects or side effects, or (4) slow the progression of a condition or one or more biological manifestations of a condition.
  • prevention refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject
  • the amount of a substance, a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by one skilled in the art.
  • prophylactically effective amount refers to an amount sufficient to prevent a disease or disorder, or an amount sufficient to prevent one or more symptoms associated with a disease or disorder, or to prevent recurrence of a disease or disorder.
  • subject refers to any animal that is to be or has been administered the compound according to the embodiments of the present invention, preferably mammals, and most preferably humans.
  • mammal includes any mammal, mammalian Examples include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the pyridine derivative of the present invention has strong antibacterial activity against different non-tuberculous mycobacteria, has low cytotoxicity, good safety, and has the ability to treat and/or prevent diseases caused by non-tuberculous mycobacteria. potential for related diseases.
  • Figure 1 shows the cytotoxicity test results of BDQ and the compound represented by formula I-1 in THP-1 cells.
  • NTM non-tuberculous mycobacteria
  • RGM rapidly growing non-tuberculous mycobacteria
  • SGM chronically growing non-tuberculous mycobacteria
  • BDQ bedaquiline, purchased from Congliye Pharmaceutical (Nanjing, China)
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • CAMHB Cation-adjusted Mueller-Hinton broth
  • OADC oleic acid-calf serum albumin-glucose-catalase
  • the broth microdilution form is set to a 2-fold concentration gradient dilution, and the concentration range of BDQ and the compound shown in Formula I-1 is 0.0039-2.0 mg/L.
  • the growth of RGM can be observed after 3 days, and the growth of SGM can be observed after 7-10 days.
  • the MIC value is defined as the lowest antibiotic drug concentration at which no color change from blue to pink occurs.
  • the MIC50 and MIC90 of the drug against different strains were calculated respectively.
  • MIC50 and MIC90 refer to the MIC required to inhibit the growth of 50% and 90% of the test bacteria in a batch of tests.
  • ECOFF is determined based on the distribution characteristics of MIC values. ECOFF is defined as the concentration that can inhibit >95% of bacterial flora for a unimodal MIC distribution curve, while for a bimodal MIC distribution curve, ECOFF is set between the two peaks.
  • MBC colony forming units
  • the broth (CAMHB) was cultured with or without 5% OADC.
  • Count CFU after 7-10 days of RGM or 28 days of SGM.
  • MBC is defined as the lowest effective drug concentration in CFU that is at least 3 log10 below the initial CFU.
  • THP-1 cells were used to evaluate the cytotoxicity of BDQ and the compounds shown in formula I-1.
  • the cells were seeded into 96-well plates and induced to differentiate into macrophages with 100 nMPMA. After 48 hours, cells were washed once and cultured in fresh RPMI medium (purchased from Gibco) containing 10% fetal calf serum (RPMI complete medium). Drug solutions were added to the wells at final concentrations ranging from 1 to 16 ⁇ g/mL and incubated for an additional 24 h and 48 h.
  • CCK-8 cell proliferation and cytotoxicity assay kit purchased from Solarbio, Beijing, China was used to monitor the cytotoxicity of different concentrations of BDQ and the compound represented by Formula I-1.
  • Cell viability ((Abs450 of treated cells/Abs450 of control cells)/(Abs450 of untreated cells/Abs450 of control cells)) ⁇ 100%.
  • the MICs of BDQ and the compounds represented by formula I-1 against 51 standard strains are shown in Tables 3 and 4.
  • the antibacterial activity of the compound represented by formula I-1 is similar to that of BDQ, or the MIC of some standard strains is doubled.
  • the compound represented by Formula I-1 showed strong antibacterial activity against almost all tested SGM strains, with MICs usually lower than 0.25 ⁇ g/mL.
  • the compound represented by formula I-1 also showed very effective in vitro activity against the included RGM standard strain.
  • the MIC of all 26 RGM standard strains is ⁇ 0.5 ⁇ g/ml
  • the MIC of 25 SGM standard strains is ⁇ 0.25 ⁇ g/ml.
  • the MIC distributions of the four most common NTM strains to BDQ and the compounds shown in Formula I-1 are shown in Table 5.
  • the sensitivity distribution of clinical isolates to BDQ and the compounds shown in Formula I-1 is consistent with the standard strains, that is Only most SGM isolates had strong antibacterial activity against all included strains. It also has similar activity against Mycobacterium abscessus, but the MIC value is higher than that of SGM.
  • BDQ and the compound shown in Formula I-1 showed the strongest activity against Mycobacterium kansasii and Mycobacterium intracellulare, with ECOFF both being 0.0156 ⁇ g/mL and MIC50 both being 0.0078 ⁇ g/mL. , MIC90 are both 0.0156 ⁇ g/mL. The vast majority of isolates of both strains included had MICs below 0.008 ⁇ g/mL. BDQ and the compound shown in Formula I-1 have good activity against Mycobacterium abscessus, with MIC50 of 0.125 ⁇ g/mL and 0.25 ⁇ g/mL respectively.
  • the MIC90 of BDQ and the compound shown in Formula I-1 against Mycobacterium abscessus are 0.25 ⁇ g/mL and 0.5 ⁇ g/mL respectively.
  • the ECOFF of Mycobacterium abscessus for BDQ and the compound represented by Formula I-1 is 0.25 ⁇ g/mL or 0.5 ⁇ g/mL respectively.
  • the MBCs of the compound represented by formula I-1 and BDQ against the five NTM standard strains were both greater than 32 ⁇ MIC. Therefore, the MBC/MIC ratio of the compound represented by formula I-1 or BDQ against the five NTM standard strains is much higher than 4, indicating that both drugs are effective against Mycobacterium abscessus (Mycobacterium abscessus), Mycobacterium fortuitum (Mycobacterium) fortuitum), Mycobacterium intracellulare, Mycobacterium avium and Mycobacterium kansasii all have bacteriostatic effects (Table 6).
  • the THP-1 cell survival rate reached more than 75% when the concentration was 16 ⁇ g/mL, and the THP-1 cell survival rate reached more than 90% when the concentration was 8 ⁇ g/mL.
  • the concentration was 4 ⁇ g/mL, At 2 ⁇ g/mL and 1 ⁇ g/mL, the survival rate of THP-1 cells was close to 100%.
  • the cell survival rate dropped to less than 75% at the concentration of 16 ⁇ g/mL, the cell survival rate reached more than 75% at the concentration of 8 ⁇ g/mL, and the cell survival rate reached more than 80% at the concentration of 4 ⁇ g/mL and 2 ⁇ g/mL.
  • the cell survival rate at 1 ⁇ g/mL was close to 100%, and there was no statistical difference between BDQ and the compound represented by Formula I-1 ( Figure 1).
  • the compounds represented by formula I-1 of the present application all have good antibacterial activity against strains of different NTM species, and it is proved that the tested standard strains and clinical isolates are sensitive to it, and all tested standard strains of RGM or SGM strains
  • the MICs were all below 0.5 ⁇ g/mL, and most of them had MICs well below 0.1 ⁇ g/mL (Tables 3 and 4). with BDQ In comparison, the activity is similar.
  • the inhibitory activity of the compound represented by formula I-1 against clinical isolates of the four most isolated strains is consistent with the results of standard strains.
  • the MIC50 and MIC90 of Mycobacterium intracellulare, Mycobacterium avium and Mycobacterium kansasii are ⁇ 0.0625 ⁇ g respectively.
  • the ECOFF value of the compound represented by formula I-1 of the present application against NTM bacterial species which is very important for setting breakpoints for drug susceptibility testing in the future, Mycobacterium abscessus, Mycobacterium intracellulare, Mycobacterium avium and Mycobacterium kansasii
  • the ECOFFs of Bacilli are generally low, ranging from 0.0156 ⁇ g/mL to 0.5 ⁇ g/mL.
  • THP-1 cells have a survival rate of nearly 100% when exposed to compounds of formula I-1 below 4 ⁇ g/mL for 24 hours.
  • This concentration is the concentration of the three most commonly isolated bacterial species (Mycobacterium intracellulare, Mycobacterium avium).
  • Mycobacterium and Mycobacterium kansasii) 200-300 times the MIC obtained by testing with standard strains.
  • 4 ⁇ g/mL is 16 times the MIC obtained by the standard strain of Mycobacterium abscessus tested in this study.
  • the macrophage assay shows that the compound represented by Formula I-1 is safe at an effective therapeutic concentration.
  • AZM azithromycin, purchased from Shanghai Modern Pharmaceutical Co., Ltd.
  • BDQ bedaquiline, purchased from Congliye Pharmaceutical (Nanjing, China)
  • formula I-1 provided by Shanghai Jiatan Pharmaceutical Technology Co., Ltd.
  • Wild-type AB zebrafish were selected for natural pair fertilization and cultured in a water temperature of 28°C. Formulated with Middlebrook 7H9 (Becton Dickinson) broth enriched with 10% OADC (oleic acid-calf serum albumin-glucose-catalase) and containing 0.05% Tween 80 (Sigma-Aldrich), it will have a smooth (S ) morphology of Mycobacterium abscessus ATCC19977 was incubated in a 37°C incubator for 5 to 7 days, and then the moderate to logarithmic growth of Mycobacterium abscessus was centrifuged, washed and placed in phosphate buffered saline containing 0.05% Tween 80 ( The bacterial suspension was homogenized and sonicated in PBS), and the bacterial colonies were allowed to settle for 5 to 10 minutes.
  • Middlebrook 7H9 Becton Dickinson
  • OADC oleic acid-calf serum albumin-glu
  • the bacteria were then enriched in phosphate buffered saline (PBS), and DIO (green fluorescence) was used to label Mycobacterium abscessus.
  • PBS phosphate buffered saline
  • DIO green fluorescence
  • the AZM concentrations were 62.5 ⁇ g/mL, 125 ⁇ g/mL, 250 ⁇ g/mL, 500 ⁇ g/mL and 1000 ⁇ g/mL; the BDQ concentrations were 3.91 ⁇ g/mL, 7.81 ⁇ g/mL, 15.6 ⁇ g/mL, 31.2 ⁇ g/mL and 62.5 ⁇ g/mL; the concentrations of the compounds shown in Formula I-1 are 15.7 ⁇ g/mL, 31.3 ⁇ g/mL, 62.5 ⁇ g/mL, 125 ⁇ g/mL, 250 ⁇ g/mL, 500 ⁇ g/mL, and 1000 ⁇ g/mL.
  • zebrafish 3 days after fertilization were randomly distributed into six-well plates, with 30 fish in each well.
  • DMSO Dishanghai Aladdin Biochemical Technology Co., Ltd., China
  • AZM concentration of AZM
  • the concentration of AZM is 62.5 ⁇ g/mL
  • the concentration of BDQ is 15.6 ⁇ g/mL
  • the concentration of the compound shown in Formula I-1 is 1.95 ⁇ g/mL, 3.91 ⁇ g/mL, 7.81 ⁇ g/mL, 15.6 ⁇ g/mL, and 31.2 ⁇ g/mL.
  • mL and 62.5 ⁇ g/mL were set up. Each cup had a capacity of 20 mL and was treated at 35°C. The number of zebrafish deaths was recorded every day and dead zebrafish were removed. Perform statistical analysis on the data after the experiment to calculate the survival rate of zebrafish in each experimental group.
  • MTC maximum tolerated concentration
  • Table 7 shows the MTC effects of different concentrations of AZM (azithromycin), BDQ, and the compound represented by Formula I-1 in zebrafish.
  • AZM azithromycin
  • BDQ azithromycin
  • Formula I-1 the compound represented by Formula I-1 in zebrafish.
  • Table 8 Compared with the negative control group, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001. Compared with the compound of formula I-1 at 62.5 ⁇ g/mL, a1 p ⁇ 0.001, a2 p ⁇ 0.05, a3 p ⁇ 0.01.
  • the fluorescence intensity in the zebrafish model represents Mycobacterium abscessus infection.
  • Table 8 shows the fluorescence of the MTC concentration of azithromycin, the MTC concentration of bedaquiline and the MTC concentration of the compound shown in Formula I-1 for the whole body and head of zebrafish respectively. strength.
  • the whole body fluorescence intensity distribution of zebrafish in the azithromycin group and the bedaquiline group was lower than that in the negative control group (433684 ⁇ 11910 vs. 671089 ⁇ 22305, p ⁇ 0.01; 438648 ⁇ 8280 vs. 671089 ⁇ 22305, p ⁇ 0.01)).
  • the whole body fluorescence intensity of the 62.5 ⁇ g/mL azithromycin group and the 15.6 ⁇ g/mL bedaquiline group was higher (433684 ⁇ 11910 vs. 375347 ⁇ 11359, p ⁇ 0.001; 433684 ⁇ 11910 vs. 375347 ⁇ 11359, p ⁇ 0.001); in In the analysis of head fluorescence intensity, compared with the 62.5 ⁇ g/mL azithromycin group and the 15.6 ⁇ g/mL bedaquiline group, the head fluorescence intensity was higher than that of the compound MTC group shown in Formula I-1 (78397 ⁇ 4815 vs. 70976 ⁇ 5726 , p>0.05. 79664 ⁇ 5809 vs. 70976 ⁇ 5726, p>0.05). There was no statistical difference between the compound MTC group shown in I-1 and the 62.5 ⁇ g/mL azithromycin group and the 15.6 ⁇ g/mL bedaquiline group.
  • Table 9 Compared with the negative control group, a1 p ⁇ 0.05, b2 p ⁇ 0.01, b3 p ⁇ 0.001. Compared with the concentration of the compound shown in formula I-1 which is 62.5 ⁇ g/mL, c1 p ⁇ 0.05, c2 p ⁇ 0.001.
  • Table 9 shows that when the concentration of the compound shown in Formula I-1 is 62.5 ⁇ g/mL, the survival rate of zebrafish is 38.33%, and the survival rate of zebrafish 7 days after fertilization dropped from 90% to 38.33%; when Formula I-1 When the concentrations of the indicated compounds and BDQ were 15.6 ⁇ g/mL, the survival rates of zebrafish were 48.33% and 75%, respectively. This shows that compared with BDQ, the compound represented by Formula I-1 has a higher survival rate in treating zebrafish infected by Mycobacterium abscessus and has better antibacterial activity against Mycobacterium abscessus in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne l'utilisation d'un dérivé de pyridine. La divulgation concerne en particulier l'utilisation d'une substance X dans la préparation d'un médicament permettant d'inhiber des mycobactéries non tuberculeuses, un médicament permettant de traiter et/ou de prévenir une infection mycobactérienne non tuberculeuse, un inhibiteur de mycobactéries non tuberculeuses ou un agent antibactérien contre les mycobactéries non tuberculeuses. La substance X est un composé représenté par la formule (I), un solvate de celui-ci, un sel pharmaceutiquement acceptable de celui-ci ou un solvate d'un sel pharmaceutiquement acceptable de celui-ci. Le dérivé de pyridine de la présente invention présente un effet d'inhibition des mycobactéries non tuberculeuses satisfaisant, ainsi qu'une faible cytotoxicité et une sécurité satisfaisante.
PCT/CN2023/096638 2022-05-27 2023-05-26 Utilisation d'un dérivé de pyridine Ceased WO2023227123A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210600329 2022-05-27
CN202210600329.6 2022-05-27

Publications (1)

Publication Number Publication Date
WO2023227123A1 true WO2023227123A1 (fr) 2023-11-30

Family

ID=88849840

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/096638 Ceased WO2023227123A1 (fr) 2022-05-27 2023-05-26 Utilisation d'un dérivé de pyridine

Country Status (2)

Country Link
CN (1) CN117122595A (fr)
WO (1) WO2023227123A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119033788A (zh) * 2024-08-27 2024-11-29 南京中医药大学 分枝杆菌硫醇二硫还原酶抑制剂在制备抗分枝杆菌药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117875A1 (fr) * 2004-05-28 2005-12-15 Janssen Pharmaceutica N.V. Utilisation de derives quinoline substitues destines aux traitements de maladies mycobacteriennes resistant aux medicaments
CN105330595A (zh) * 2014-07-14 2016-02-17 南京明德新药研发股份有限公司 吡啶衍生物及其作为抗分支杆菌的应用
WO2017121323A1 (fr) * 2016-01-13 2017-07-20 辰欣药业股份有限公司 Procédé de préparation d'un composé dérivé de pyridine, intermédiaire et forme cristalline dudit composé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117875A1 (fr) * 2004-05-28 2005-12-15 Janssen Pharmaceutica N.V. Utilisation de derives quinoline substitues destines aux traitements de maladies mycobacteriennes resistant aux medicaments
CN105330595A (zh) * 2014-07-14 2016-02-17 南京明德新药研发股份有限公司 吡啶衍生物及其作为抗分支杆菌的应用
WO2017121323A1 (fr) * 2016-01-13 2017-07-20 辰欣药业股份有限公司 Procédé de préparation d'un composé dérivé de pyridine, intermédiaire et forme cristalline dudit composé

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARBARO LISA, NAGALINGAM GAYATHRI, TRICCAS JAMES A., TAN LENDL, WEST NICHOLAS P., BAELL JONATHAN B., PRIEBBENOW DANIEL L.: "Synthesis and evaluation of pyridine-derived bedaquiline analogues containing modifications at the A-ring subunit", RSC MEDICINAL CHEMISTRY, vol. 12, no. 6, 23 June 2021 (2021-06-23), pages 943 - 959, XP093111255, ISSN: 2632-8682, DOI: 10.1039/D1MD00063B *
HUANG, Z.G. ET AL.: "Discovery and Preclinical Profile of Sudapyridine (WX-081), a Novel Anti-tuberculosis Agent", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 71, 27 May 2022 (2022-05-27), XP087100304, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2022.128824 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119033788A (zh) * 2024-08-27 2024-11-29 南京中医药大学 分枝杆菌硫醇二硫还原酶抑制剂在制备抗分枝杆菌药物中的应用

Also Published As

Publication number Publication date
CN117122595A (zh) 2023-11-28

Similar Documents

Publication Publication Date Title
Ingham et al. Bacteriological study of otogenic cerebral abscesses: chemotherapeutic role of metronidazole.
Amaral et al. Antimicrobial activity of phenothiazines
Wang et al. Treatment of typhoid fever with ofloxacin
Pasquali et al. Mutant prevention concentration of ciprofloxacin and enrofloxacin against Escherichia coli, Salmonella Typhimurium and Pseudomonas aeruginosa
Nicolle et al. Prospective, randomized, placebo-controlled trial of norfloxacin for the prophylaxis of recurrent urinary tract infection in women
CN106620649A (zh) 使用单剂量奥利万星的治疗方法
AU2017259960A1 (en) 9-aminomethyl minocycline compounds and methods of use thereof in urinary tract infection (UTI) treatment
JP6179844B2 (ja) フルオロキノロン類を用いた細菌性肺感染症の治療方法。
US20220062319A1 (en) Combination in the treatment of nontuberculous mycobacterial diseases
Calcagno et al. Drugs for treating infections caused by non-tubercular mycobacteria: A narrative review from the study group on mycobacteria of the Italian Society of Infectious Diseases and Tropical Medicine
Naber et al. Gatifloxacin 200 mg or 400 mg once daily is as effective as ciprofloxacin 500 mg twice daily for the treatment of patients with acute pyelonephritis or complicated urinary tract infections
Byrne et al. Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients
Yendewa et al. A two-part phase 1 study to establish and compare the safety and local tolerability of two nasal formulations of XF-73 for decolonisation of Staphylococcus aureus: A previously investigated 0.5 mg/g viscosified gel formulation versus a modified formulation
Soimala et al. Occurrence and molecular composition of methicillin-resistant Staphylococcus aureus isolated from ocular surfaces of horses presented with ophthalmologic disease
Raoof et al. Treatment of respiratory tract infections with ciprofloxacin
WO2023227123A1 (fr) Utilisation d'un dérivé de pyridine
US20250121013A1 (en) Use of bacillus amyloliquefaciens for preventing and treating parkinson's disease
Huang et al. Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem
Ganière et al. In vitro antimicrobial activity of orbifloxacin against Staphylococcus intermedius isolates from canine skin and ear infections
Peters Comparison of intravenous ciprofloxacin and mezlocillin in treatment of complicated urinary tract infection
Bach et al. Rufloxacin once daily versus ciprofloxacin twice daily in the treatment of patients with acute uncomplicated pyelonephritis
Abdulabbas et al. Determination of Fractional Inhibitory Concentration (FIC) Index as A Measure of Synergy of Antibiotics in E. coli O157: H7
Mohammed et al. Antibiotic sensitivity of high vaginal swabs from asymptomatic pregnant women
US20240316068A1 (en) Methods for treating hypervirulent klebsiella pneumoniae infection
Carter et al. Besifloxacin ophthalmic suspension 0.6%

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23811193

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23811193

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 07/05/2025)

122 Ep: pct application non-entry in european phase

Ref document number: 23811193

Country of ref document: EP

Kind code of ref document: A1