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WO2019190354A1 - Dérivés de formamidine possédant une activité antimicrobienne - Google Patents

Dérivés de formamidine possédant une activité antimicrobienne Download PDF

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Publication number
WO2019190354A1
WO2019190354A1 PCT/RU2019/050017 RU2019050017W WO2019190354A1 WO 2019190354 A1 WO2019190354 A1 WO 2019190354A1 RU 2019050017 W RU2019050017 W RU 2019050017W WO 2019190354 A1 WO2019190354 A1 WO 2019190354A1
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Prior art keywords
tuberculosis
mycobacterium
methyl
pharmaceutical composition
compounds
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/RU2019/050017
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English (en)
Russian (ru)
Inventor
Алексей Валерьевич КЛЮЧЕНОВИЧ
Андрей Александрович ГИЛЕП
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.)
Mt-Medicals LLC
Original Assignee
Mt-Medicals LLC
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 Mt-Medicals LLC filed Critical Mt-Medicals LLC
Publication of WO2019190354A1 publication Critical patent/WO2019190354A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen atoms

Definitions

  • This invention relates to the chemistry of organic compounds, pharmacology, medicine, veterinary medicine and relates to the prevention and treatment of diseases caused by mycobacterial infections, in particular tuberculosis, using a new class of compounds.
  • tuberculosis is the leading infectious cause of death in the world [1]. Most deaths are associated with high sensitivity of HIV-infected patients to TB; in the presence of double HIV / TB infection, deaths are recorded in a quarter of cases.
  • pathogen features such as a low growth rate of pathogens, the ability to transition to a resting state, the presence of a highly hydrophobic cell surface of Mycobacterium tuberculosis, which serves as a kind of physical barrier, intracellular localization of pathogens, and a high concentration of M. tuberculosis cells in the affected organ.
  • pathogen features such as a low growth rate of pathogens, the ability to transition to a resting state, the presence of a highly hydrophobic cell surface of Mycobacterium tuberculosis, which serves as a kind of physical barrier, intracellular localization of pathogens, and a high concentration of M. tuberculosis cells in the affected organ.
  • the main method of treatment for TB patients is complex chemotherapy with antimicrobial agents, aimed at suppressing the multiplication of TB mycobacteria or deep damage to the function of the microbial cell, leading to its death.
  • Existing anti-TB drugs have different efficacy, toxicity and different mechanisms of action,
  • the present invention is the development and creation of new anti-infective agents with antimycobacterial activity, promising for use in clinical practice for the treatment of tuberculosis and other diseases associated with mycobacterial infections.
  • the technical result of the invention is the development and production of new chemical compounds with increased activity and effectiveness in inhibiting mycobacteria, in particular Mycobacterium tuberculosis, including resistant strains of Mycobacterium tuberculosis.
  • the compounds of the invention are promising for use in the treatment of diseases associated with mycobacterial infection, in particular in the treatment of tuberculosis, including resistant forms of tuberculosis.
  • R is independently selected and is C 4-14 methyl-branched alkyl, partially or fully halogenated C 4-14 methyl-branched alkyl, C 4-14 - methyl-branched alkenyl, partially or fully halogenated C 4-14 - methyl-branched alkenyl, wherein R is located in the para- or meta-position relative to the nitrogen atom of the hydroxyformimidamidine moiety;
  • R ' is independently selected and is C 4-14 methyl branched alkyl, partially or fully halogenated C 4-14 methyl branched alkyl, C 4-14 is methyl branched alkenyl or partially or fully halogen C 4-14 methyl branched alkenyl, with R 'is located in the para- or meta-position relative to the nitrogen atom of the hydroxyformimidamidine fragment.
  • a separate subclass of compounds of interest includes compounds of the invention selected from the group:
  • This invention also relates to the use of the compounds of the invention for the treatment and / or prevention of an infectious disease in a subject caused by a mycobacterial infection.
  • the infectious disease is caused by Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium avium, or other microorganisms included in the Mycobacterium tuberculosis complex (Mycobacterium tuberculium avob complex) or
  • the disease is tuberculosis.
  • the tuberculosis is resistant.
  • the subject is a mammal or a bird.
  • the mammal is a human.
  • This invention also relates to the use of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of an infectious disease caused by a mycobacterial infection.
  • the invention provides pharmaceutical compositions for treating and / or preventing an infectious disease caused by mycobacterial infection, comprising an effective amount of at least one compound of the invention and at least one pharmaceutically acceptable excipient.
  • the infectious disease is caused by Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium avium or other microorganisms included in the Mycobacterium tuberculosis complex (Mycobacterium tuberculium avc complex) or.
  • the disease is tuberculosis.
  • the tuberculosis is in a drug resistant form.
  • the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent.
  • the pharmaceutical composition is characterized in that it has a bacteriostatic effect.
  • the pharmaceutical composition is characterized in that it has a bactericidal effect.
  • the present invention also relates to a method for treating and / or preventing infectious diseases, comprising administering (as monotherapy or in combination with one or more agents) a therapeutically effective amount of a compound of the invention to a human or animal organism in need of treatment and / or prevention of such diseases.
  • administering as monotherapy or in combination with one or more agents
  • a therapeutically effective amount of a compound of the invention to a human or animal organism in need of treatment and / or prevention of such diseases.
  • administering includes the delivery to a recipient of a compound described in the present invention of a prodrug, or other pharmacologically acceptable derivative of such a compound, using any acceptable formulations or routes of administration to the body that are well known in the art.
  • the invention also includes the preparation of compounds of general formula I and general formula II.
  • alkyl refers to branched alkyls, namely methyl branched alkyl groups, for example 3-methylbutyl, 3-methylpentyl, 3-methylhexyl, etc., preferably 3-methylbutyl and 3,6-dimethylheptyl.
  • alkyl may be either substituted or unsubstituted.
  • alkyl as used herein also refers to groups typically having four to fourteen carbon atoms. For example, the term C 4- 14 alkyl means isobutyl isopentyl, isohexyl, isoheptyl, etc.
  • alkenyl where the position of one or more double bonds is defined on any C 4-14 carbon atom, preferably 3-methylbut-1-enyl, 3,6-dimethylhept-2-enyl , 3,6-dimethylhept-2,5-dienyl.
  • haloalkyl includes branched saturated hydrocarbon chains in which one or more hydrogen atoms are replaced by halogen.
  • haloalkyl groups include, but are not limited to, the following groups: 3-methyl-4, 4, 4-trifluorobutyl, 5,5,5-trifluoro-4- (trifluoromethyl) pentyl, 4,4,4-trifluoro-3- ( trifluoromethyl) butyl and the like.
  • halogen by itself or in part of another term refers to an atom of fluorine, chlorine, bromine or iodine.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex wherein the solvent molecule is water.
  • the compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free base of the compound of the invention with a suitable acid.
  • An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in this field, for example, by ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorite, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohexanoate heptane, heptoacetate heptoacetate, glycohexanoate heptane, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptohydrate, heptoacetate, heptoacetate, heptohydrogen
  • patient encompasses all types of mammals, preferably humans, and also includes birds.
  • treatment cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.
  • prevention covers the elimination of risk factors, as well as the preventive treatment of subclinical stages of the disease in humans, aimed at reducing the likelihood of the clinical stages of the disease.
  • Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increase in the risk of clinical stages of the disease compared with the general population.
  • Preventive therapy includes a) primary prevention and b) secondary prevention.
  • Primary prophylaxis is defined as prophylactic treatment in patients whose clinical stage of the disease has not yet begun. Secondary prophylaxis is the prevention of the repeated onset of the same or similar clinical condition of the disease.
  • risk reduction covers therapy that reduces the incidence of the clinical stage of the disease. Examples of reducing the risk of disease are primary and secondary disease prevention.
  • the subject of the invention also relates to a method for treating and / or preventing diseases caused by mycobacterial infection, comprising administering to a patient a compound of the invention.
  • a method for treating and / or preventing diseases caused by Mycobacterium tuberculosis comprising administering to a patient a compound of the invention.
  • the subject of this invention relates to a method for the treatment and / or prevention of tuberculosis, including resistant forms of tuberculosis.
  • the subject of this invention also includes the administration to a subject in need of appropriate treatment, a therapeutically effective amount of a compound of general formula (I) and / or general formula (II).
  • a therapeutically effective amount is meant an amount of one or more of the described compounds administered or delivered to a patient, in which the patient is most likely to show the desired response to treatment (prophylaxis).
  • the exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.
  • the substance or pharmaceutical composition containing the substance can be introduced into the patient's body in any quantity and by any route of administration effective for treating or preventing a disease.
  • compositions comprising the essence of the invention can be administered orally, parenterally, topically, and the like to the human or other animals.
  • the introduction can be carried out both once and several times a day, week (or any other time interval), or from time to time.
  • the compound can be introduced into the patient’s body daily for a certain period of days, and then a period follows without a substance.
  • a dose of each of the components of the combination therapy is administered during the required treatment period.
  • the compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.
  • the invention also relates to pharmaceutical compositions that contain at least one of the compounds described herein (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such that can be introduced into the patient’s body together with the compound that is the essence of this invention, and which do not destroy the pharmacological activity of this compound, and I are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc.
  • Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers.
  • excipients such as cocoa butter and suppository wax
  • oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil
  • glycols such as propylene glycol
  • esters such as ethyl oleate and ethyl laur
  • composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • dyes such as sodium lauryl sulfate and magnesium stearate
  • release fluids such as sodium lauryl sulfate and magnesium stearate
  • film-forming agents such as sodium lauryl sulfate and magnesium stearate
  • sweeteners such as sodium lauryl sulfate and magnesium stearate
  • flavors and fragrances such as sodium lauryl sulfate and magnesium stearate
  • preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate
  • the subject of this invention is also dosage forms — a class of pharmaceutical compositions whose composition is optimized for a particular route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, topically, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally , subcutaneously, intramuscularly, as well as by the infusion method, in recommended dosages.
  • a therapeutically effective dose for example, for administration to the body orally, topically, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally , subcutaneously, intramuscularly, as well as by the infusion method, in recommended dosages.
  • the dosage form of the present invention may contain a compound of the formula described herein or a pharmaceutically acceptable salt thereof, and an additional preparation, for example, selected from the following: an antitumor preparation, an antiviral drug, an anti-inflammatory drug, and any pharmaceutically acceptable carrier, adjuvant or solvent.
  • additional preparation for example, selected from the following: an antitumor preparation, an antiviral drug, an anti-inflammatory drug, and any pharmaceutically acceptable carrier, adjuvant or solvent.
  • Dosage forms of the present invention may contain formulations prepared using liposome or microencapsulation methods, methods for preparing nanoforms of the preparation, and other examples known in the pharmaceutical art.
  • the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like. Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.
  • pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
  • Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.
  • a pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.
  • the compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.
  • Scheme 1 shows the preparation of compounds of the invention.
  • 60 ml of dry toluene, 11.4 g of amine (compound 3) are placed in a round-bottom flask equipped with a reflux condenser and a magnetic stirrer. and 10.3 ml of dimethylacetal dimethylformamide.
  • the mixture was boiled for 4 hours, cooled, the solvent was evaporated, and 11.4 g of N, N-dimethylformimidamide (compound 4) were obtained, which was used in the next step without further purification.
  • the bacterial mass was removed into a sterile mortar and homogenized in a sterile 0.9% sodium chloride solution.
  • the suspension was transferred by syringe into a sterile tube and settled for 15 min to precipitate conglomerates of cells.
  • the supernatant (2-3 ml) was transferred via a syringe into a special sterile tube and, using the turbidity standard (5 units), the cell concentration was aligned to the standard (Standard Turbidity Sample named after Tarasevich OSO 42-28-10). 1.5 ml of the suspension was diluted in 13.5 ml of isotonic solution (dilution 1: 10).
  • 0.22 ml of the resulting suspension of mycobacteria was added to sterile eppendorfs K1 (control - 0.9% aqueous solution of sodium chloride) and K2 (control 0.9% aqueous solution of sodium chloride with 1% DMSO).
  • 0.22 ml of a 0.9% aqueous solution of sodium chloride was added to the selected volume of the suspension in eppendorf K 1, and 0.2 ml of a 0.9% aqueous solution of sodium chloride with DMSO was added to eppendorf K2 (so that the final DMSO concentration was 1%).
  • For experimental samples from suspension in sterile eppendorf were selected at 0, 12 ml.
  • the tubes were kept for 4 days in a horizontal position at 37 ° C, then transferred to a tripod and incubated in an upright state for 21 days at 37 ° C.
  • Mycobacteria growth was assessed visually by coating the surface of the medium with colonies of mycobacteria.
  • M1Cuo% (100% minimum inhibitory concentration) of the compounds of the invention was carried out in accordance with a previously developed and applied method [2].
  • the plates were incubated in a C0 2 iicubator for 24 hours, after which 20 ⁇ l of various concentrations of L-hydroxy-] M- (4-isopentyl-2-methylphenyl) formimidamide or 20 ⁇ l of Dubo broth (control) were added to the wells and incubated for 12 14 days.
  • the MIC of 10% was taken as the minimum concentration of the test substance, which completely suppresses the growth of mycobacteria by the 12-14th day of incubation, which manifests itself in the absence of a visible precipitate of mycobacteria at the bottom of the well.
  • M1Cuo% against both the M. tuberculosis strain H37Rv and the M. tuberculosis strain CN-40 isoniazid-resistant strain
  • M1Suo% against Mycobacterium avium in the range of 9.5 -42.7 ⁇ g / ml.
  • the MTT test was carried out, in particular, with PM'-hydroxy-] M- (4-isopentyl-2-methylphenyl) formimidamide at concentrations from 1 to 50 ⁇ M in HEK293T cell culture.
  • PM'-hydroxy-] M- (4-isopentyl-2-methylphenyl) formimidamide at concentrations from 1 to 50 ⁇ M in HEK293T cell culture.
  • One day after sieving cells were incubated with the compounds of the invention for 1 day.
  • the ability of cells to restore MTT was determined spectrophotometrically. Based on the data obtained, the nature of the relationship between the concentration of the inhibitor and the metabolic activity of the cells was revealed.
  • Methodology 1) HEK 293 T cells are seeded into a 96-well plate at a concentration of 100,000 cells / ml, 100 ⁇ l per well.
  • test substance is added to the medium.
  • concentration of the substance 50, 35, 20 and 5 ⁇ m in 2 replicates. This leaves holes for control samples:
  • H37Rv control for inclusion of uracil by extracellular H37Rv: 1561 ⁇ 211;
  • the obtained research results indicate an effective inhibition of the growth of mycobacteria in pulmonary macrophages using compounds according to the invention and, in particular, using 1hG'-hydroxy-] M- (4-isopentyl-2-methylphenyl) formimidamide.

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

Abstract

L'invention concerne la chimie des compositions organiques, la pharmacologie, la médecine humaine, la médecine vétérinaire et concerne la prévention et la thérapie des maladies infectieuses provoquées par des infections mycobactériennes, notamment de la tuberculose, au moyen d'une nouvelle classe de compositions. A cet effet, on propose également des compositions de formule générale I et/ou de formule générale II dans lesquelles R et R1 ont des valeurs indiquées dans le descriptif : formule (I), formule (II). Les composés de l'invention offrent des perspectives intéressantes en termes d'utilisation dans le traitement de maladies associées à l'infection mycobactérienne, notamment dans la thérapie de la tuberculose.
PCT/RU2019/050017 2018-03-29 2019-02-12 Dérivés de formamidine possédant une activité antimicrobienne Ceased WO2019190354A1 (fr)

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RU2018111277 2018-03-29
RU2018111277A RU2702224C2 (ru) 2018-03-29 2018-03-29 Производные фенил формамидина, обладающие антимикобактериальной активностью

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN113979893A (zh) * 2021-11-08 2022-01-28 中国药科大学 一种n-羟基甲脒衍生物、制备方法及用途

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US20150025087A1 (en) * 2013-07-17 2015-01-22 Global Alliance For Tb Drug Development Azaindole compounds, synthesis thereof, and methods of using the same

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US20150025087A1 (en) * 2013-07-17 2015-01-22 Global Alliance For Tb Drug Development Azaindole compounds, synthesis thereof, and methods of using the same

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Title
BHAT SHRIDHAR ET AL.: "Analogs of N'-hydroxy-N-(4H,5H-naphtho[l,2-d]thiazol -2-yl) methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases", BIOORG MED CHEM., vol. 20, no. 14, 2012, pages 4507 - 4513 *
KORDULAKOVA JANA ET AL.: "Isoxyl activation is required for bacteriostatic activity against Mycobacterium tuberculosis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 51, no. 11, 2007, pages 3824 - 3829, XP055639175 *
NIKONENKO BORIS V. ET AL.: "In Vitro Activity of 3-Triazeneindoles agains t Mycobacterium tuberculosis and Mycobacterium avium", ANTIMICROBIA I AGENTS AND CHEMOTHERAPY, vol. 60, no. 10, 2016, pages 6422 - 6424, XP055500931, doi:10.1128/AAC.00998-16 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113979893A (zh) * 2021-11-08 2022-01-28 中国药科大学 一种n-羟基甲脒衍生物、制备方法及用途

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RU2702224C2 (ru) 2019-10-07
RU2018111277A (ru) 2019-10-01

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