WO2024258316A1 - Nouveaux agents antifongiques puissants à base de thiazolidine-2,4-dione et de triazole - Google Patents

Nouveaux agents antifongiques puissants à base de thiazolidine-2,4-dione et de triazole Download PDF

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Publication number
WO2024258316A1
WO2024258316A1 PCT/RU2024/050125 RU2024050125W WO2024258316A1 WO 2024258316 A1 WO2024258316 A1 WO 2024258316A1 RU 2024050125 W RU2024050125 W RU 2024050125W WO 2024258316 A1 WO2024258316 A1 WO 2024258316A1
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spp
compound
disease
candida
pharmaceutical composition
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Russian (ru)
Inventor
Игорь Борисович ЛЕВШИН
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Obschestvo S Ogranichennoi Otvetstvennostyu "l Bio"
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Obschestvo S Ogranichennoi Otvetstvennostyu "l Bio"
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Priority claimed from RU2023115908A external-priority patent/RU2814730C1/ru
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to the chemistry of organic compounds, pharmacology and medicine and concerns a new chemical compound characterized by high antifungal activity, which, in particular, can be used for the prevention and treatment of infectious diseases in a subject.
  • WHO published a list of the most dangerous fungal pathogens posing a threat to civilization and classified the creation of new therapeutic agents for the treatment of invasive infections as the most in-demand category.
  • the first line is occupied by such fungal strains as C. auris, C. tropicalis, C. parapsilosis, Mucorales [WHO fungal priority pathogens list to guide research, development and public health action, https://www.who.
  • the pathogen is characterized by high virulence parameters, which include the ability to form biofilms with a tendency to colonize, leading to transmission in health care settings and the development of resistance to existing antifungal drugs.
  • Most isolates studied had high-level resistance to fluconazole (minimum inhibitory concentration, MIC > 64 g/mL).
  • MIC minimum inhibitory concentration
  • up to 30% of isolates showed reduced susceptibility to amphotericin B. More than 5% may be resistant to echinocandins, which are currently recommended first-line antifungals for candidemia.
  • Risk factors in intensive care unit patients include: previous antifungal use, vascular surgery, hospital stay, underlying pulmonary disease, and indwelling urinary catheterization.
  • C. auris is implicated in a minority of cases of candidemia, mortality associated with C. auris has been as high as 60% in some studies [J. Fungi, 2020, 6, 91 .doi: 10.3390/jof60091 ].
  • Candida albicans usually susceptible to fluconazole, has long been the most common species associated with invasive candidiasis.
  • the epidemiology of Candida infections is changing, leading to an increase in infections caused by species with less predictable susceptibility to antifungal drugs.
  • the SENTRY antifungal surveillance program tracks the global epidemiology of invasive Candida infections, including species distribution and antifungal resistance.
  • the program recently released its first 20 years of data, which included more than 20,000 clinical isolates collected through passive surveillance in 39 countries.
  • C. glabrata In the United States, more than 30% of candidemia cases are currently caused by C. glabrata, which is an alarming trend given the increasing rates of antifungal resistance associated with this species [Lamoth, F.; Lockhart, S.R.; Berkow, E.L.; Calandra, T. Changes in the epidemiological landscape of invasive candidiasis. J. Antimicrob. Chemother. 2018, 1 , i4-i13].
  • C. glabrata isolates In some centres, resistance to echinocandins mediated by mutations in FKS1 occurs in 10% of C. glabrata isolates, and of these echinocandin-resistant strains, resistance to current commercial azole agents occurs in 20% of strains. In contrast, in the UK, C. glabrata isolates were rarely resistant to echinocandins (0.55%). C. parapsilosis is also more common. This species accounts for 15% of candidemia cases in the USA and 20% in Russia, and in South Africa, C. parapsilosis competes with C. albicans as the leading cause of invasive disease [Friedman, & Schwartz. (2019). Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens. Journal of Fungi, 5(3), 67. doi:10.3390/jof5030067].
  • Candida species have undergone taxonomic reclassification with the emergence of new classes, genera, and species over the past decade. However, C. albicans remains the most common causative agent of candidiasis.
  • Zygomycosis is an umbrella term, previously known as mucormycosis, that includes all mycotic diseases caused by fungi of the genus Zygomycetes.
  • the major known human pathogens belong to the order Mucorales, family Mucoraceae, which includes the genera Rhizopus, Absidia, Mucor, Rhizomucor, and Apophysomyces. Most human diseases are caused by members of the genus Mucorales. Although the most common causes are Rhizopus spp. Zygomycosis due to Mucorales usually occurs in immunocompromised hosts as an opportunistic infection. Risk factors include diabetes mellitus, neutropenia, long-term immunosuppressive therapy, chronic prednisone use, iron chelation therapy, broad-spectrum antibiotic use, and a primary disruption of the skin barrier such as trauma, surgical wounds, needle sticks, or burns.
  • Mucorales are associated with angioinvasive disease, often resulting in thrombosis, infarction of involved tissues, and tissue destruction mediated by a variety of fungal proteases, lipases, and mycotoxins. If diagnosis is not made early, dissemination often occurs. Therapy, if effective, must be started early and requires a combination of antifungal drugs, surgery, and removal of underlying risk factors.
  • the objective of the present invention is to develop and create a new effective antifungal agent that is promising for use in clinical practice for the treatment and/or prevention of infectious diseases caused by fungal infection.
  • the technical result of the invention consists in the development of a new compound characterized by highly effective antifungal activity of a wide spectrum of action, including in relation to zygomycetes, and which is promising for use in the therapy of infectious diseases in a subject caused by fungal infections (including mold fungi), for example, caused by candidal and filamentous pathogens, in particular C. auris, C. albicans, C. tropicalis, C. krusei, C. parapsilosis, Cryptococcus neoformans, A. niger, A.
  • the compounds of the invention are characterized by high antimicrobial activity against fungal strains resistant to commercial azole drugs used.
  • the pathogen is a pathogen of the genus Candida spp., Rhizopus spp., Aspergillus spp., Microsporum spp., Trichophyton spp. and/or Epidermophyton spp.
  • the pathogen is Candida auris, Candida albicans, Candida non albicans (such as Candida krusei, Candida glabrata, Candida parapsilosis), Aspergillus fumigates, Aspergillus niger and/or Rhizopus stoloniferw others.
  • the achievement of the specified technical result is also ensured by using the compound according to the invention or its pharmaceutically acceptable salt to obtain a pharmaceutical composition with antifungal activity for the treatment and/or prevention of an infectious disease of microbial etiology in a subject caused by a fungal infection.
  • a pharmaceutical composition with antifungal activity for the treatment and/or prevention of an infectious disease of microbial etiology in a subject caused by a fungal infection containing an effective amount of a compound according to the invention and/or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable auxiliary substance.
  • the pharmaceutically acceptable excipient is a carrier, filler and/or solvent.
  • the subject is a human or an animal.
  • the disease is a disease of the skin, nails and/or internal organs.
  • the disease is disseminated candidiasis, disseminated zygomycosis, dermatophytosis, superficial mycosis, candidiasis of the skin and/or nails, invasive candidiasis, vaginal candidiasis, candidal stomatitis, endocarditis, or mucormycosis.
  • the present invention also relates to a method for inhibiting the growth and/or completely eliminating fungal pathogens, in particular pathogens of the genus Candida spp., Rhizopus spp., Aspergillus spp., Microsporum spp., Trichophyton spp. and/or Epidermophyton spp., comprising administering to a subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the invention also includes a method for treating and/or preventing a disease of microbial etiology in a subject caused by a fungal infection, comprising administering a therapeutically or prophylactically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, to the body of a subject in need of treatment and/or prevention of such diseases.
  • the method involves administering a compound of the invention or a pharmaceutically acceptable salt thereof as monotherapy or in combination with one or more therapeutic agents.
  • the present invention also includes the preparation of compounds and/or compositions of the invention.
  • listing numeric ranges by endpoints includes all numbers within that range.
  • the compound of the present invention may exist in radioisotope-labeled form, i.e. said compound may contain one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the most common natural isotopes.
  • Radioisotopes of hydrogen, carbon, phosphorus, chlorine include 3 H, 14 C, 32 P, 35 S, and 36 Cl, respectively.
  • a compound of the present invention that contains such radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention.
  • Tritium, i.e. 3 H, and carbon, i.e. 14 C, radioisotopes are particularly preferred due to ease of preparation and detection.
  • a radiolabeled compound of the present invention can be prepared using methods well known to those skilled in the art.
  • the labeled compound can be prepared using the procedures described herein by simply replacing the unlabeled reagents with the appropriate labeled reagents.
  • the compound 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 limits of medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and which meet a reasonable benefit-risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in the medical arts.
  • the salts may be prepared in situ during the isolation or purification of the compounds of the invention, and may also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively.
  • Examples of pharmaceutically acceptable, non-toxic acid salts include salts of the amino group formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in the art, such as ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenyl
  • Typical alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and others.
  • pharmaceutically acceptable salts may contain, if desired, non-toxic ammonium, quaternary ammonium and amine cations derived from such counterions as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • the compound of the present invention may exist as a prodrug.
  • prodrug refers to a precursor or derivative form of a compound of the invention, which may have improved properties, such as better solubility, reduced cytotoxicity or increased bioavailability, compared to the parent compound or drug, and is capable of being activated or converted into a more active parent form.
  • Prodrug group means a group that is converted by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, to produce a compound of the invention, i.e., a group that is converted to produce a compound of the invention by hydrolysis or the like caused by gastric acid or the like.
  • terapéuticaally effective amount is meant that amount of the compound administered or delivered to a patient that is most likely to produce the desired response to treatment. The exact amount required may vary from subject to subject depending on the age, weight, and general condition of the patient, the severity of the disease, the method of administration, combination therapy with other drugs, etc.
  • prophylactically effective amount is meant that amount of the compound administered or delivered to a patient that is most likely to produce the desired response to the prophylaxis of infectious diseases caused by fungal infection. The exact amount required may 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, combination therapy with other drugs, etc.
  • a therapeutically or prophylactically effective amount is that amount that will be effective in preventing fungal infection.
  • patient includes all mammalian species, preferably humans, that utilize the compounds of the invention either by self-administration or by administration to the patient by another person for the treatment and/or prevention of a disease or medical condition.
  • treatment and “therapy” 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. inducing regression of the disease.
  • prevention covers the elimination of risk factors, as well as preventive treatment of subclinical stages of the disease in humans, aimed at reducing the likelihood of the clinical stages of the disease.
  • Patients for preventive therapy are selected based on factors that, based on known data, entail an increased risk of developing clinical stages of the disease compared to the general population.
  • Preventive therapy includes a) primary prevention and b) secondary prevention.
  • Primary prevention is defined as preventive treatment in patients who have not yet reached the clinical stage of the disease.
  • Secondary prevention is the prevention of recurrence of the same or a similar clinical state of the disease.
  • risk reduction refers to therapy that reduces the incidence of clinical disease.
  • risk reduction include primary and secondary disease prevention.
  • administering includes delivering to the recipient a compound described in the present invention, a prodrug, or other pharmacologically acceptable derivative of such a compound using any acceptable preparations or routes of administration well known in the art.
  • MIC minimum inhibitory concentration
  • MIC minimum inhibitory concentration
  • the compounds of the present invention can be prepared using the following synthetic methods. The methods listed are not exhaustive and allow for reasonable modifications. The reactions should be carried out using suitable solvents and materials. It should be understood that these and all examples provided in the application materials are not limiting and are provided only to illustrate the present invention.
  • the compound according to the invention can be obtained by one of the methods presented in the diagrams below.
  • the starting materials in methods A and B are 2-(2,4-difluorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol (1) and a commercially available compound, the 3-substituted acetic acid 5-(4-chlorobenzylidene)thiazolidine-2,4-dione (CAS 423153-08-6).
  • Method B uses 4-(2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)acetyl)piperazin-1-yl (2) and a commercially available methyl-substituted oxirane (CAS 127000-90-2) as starting materials.
  • Boc-piperazine (2.5 g, 13.42 mmol, 1 equiv) was suspended in methylene chloride (40 ml), then triethylamine (4.07 g, 40.27 mmol, 3 equiv) was added.
  • the reaction mixture is cooled with ice, then a solution of 2-(5-(4-(chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid chloride, obtained in situ (5.09 g, 16.11 mmol, 1.2 equiv) in methylene chloride (20 ml) is added dropwise with stirring. After the addition of the acid chloride solution is complete, the cooling bath is removed and the reaction mixture is stirred for 16 hours at room temperature.
  • the resulting substance was transferred to a flask and dried on a rotary evaporator to constant weight.
  • the obtained salt - 4-(2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)acetyl)piperazin-1-yl hydrochloride (3.28 g) - was suspended in water (40 ml), BiOH (60 ml) was added and ArCO3 (2.0 g) was carefully added, the mixture was stirred at room temperature for 30 min, then the organic phase was separated, and the aqueous portion was re-extracted with BiOH (20 ml). The organic extracts were combined and evaporated in vacuo.
  • This salt was obtained in a similar manner to the method described above using suitable reagents.
  • the comparative antifungal activity of the compound of the invention, the prior art analogue (compound 9 from document RU2703997) and microbiological standards of fluconazole and voriconazole was studied for the spectrum of antifungal action against clinical isolates of Candida spp. and Rhizopus spp. using the micromethod of double serial dilutions in RPMI 1640 nutrient broth against clinical isolates and standard strains of Candida spp. The activity was assessed in accordance with the recommendations of the Clinical and Laboratory Standards Institute (CLSI), a global non-profit organization for the development of standards and recommendations in medicine. Methods M27-A3 (Clinical and Laboratory Standards Institute.
  • CCSI Clinical and Laboratory Standards Institute
  • the results of the conducted studies showed that the compound according to the invention is characterized by a significantly higher level of activity against the particularly dangerous pathogen of the species Rhisopus spp. compared to the known an analogue compound from the prior art, as well as compared to the antifungal drug voriconazole, namely, the MIC level of the compound according to the invention is at least 33 times lower than that of the analogue compound from RU2703997, and at least 266 times lower than voriconazole. Further, comparative studies were also carried out with respect to strains
  • Table 5 Distribution of MIC values among strains of dermatophyte fungi to the substance of compounds: 9 from RU2703997, L 363 according to the invention and commercial preparations of itraconazole and amphotericin B (Ab B).
  • the proposed compounds are of interest to medicine and can find application in the treatment and prevention of infectious diseases, in particular those caused by various fungal infections (including particularly dangerous pathogens), for example, such diseases as mucormycosis, invasive candidiasis, vaginal candidiasis, candidal stomatitis, endocarditis, and other diseases of humans and animals.
  • infectious diseases in particular those caused by various fungal infections (including particularly dangerous pathogens)
  • diseases as mucormycosis, invasive candidiasis, vaginal candidiasis, candidal stomatitis, endocarditis, and other diseases of humans and animals.
  • the invention also relates to pharmaceutical compositions that comprise a compound of the invention (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and/or excipients that can be administered to a patient along with the compound that is the essence of this invention, do not reduce the pharmacological activity of this compound and are not toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions mentioned in 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, thickening and emulsifying agents, preservatives, binders, lubricants, etc. suitable for the particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickening and emulsifying agents, preservatives, binders, lubricants, etc. suitable for the particular dosage form.
  • Materials which can serve as pharmaceutically acceptable carriers include mono- and oligosaccharides and derivatives thereof; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, sesame, olive, corn and soybean oils and others; 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; depyrogenated water; isotonic solution, Ringer's solution; alcohol and phosphate buffer solutions.
  • the composition may also contain other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release agents, film agents, sweeteners, flavors and fragrances, preservatives and antioxidants.
  • the subject of the present invention is also dosage forms - a class of pharmaceutical compositions, the structure of which is optimized for a specific method of administration into the body in a therapeutically effective dose, for example, for administration into the body intravenously, intramuscularly, orally, subcutaneously, by inhalation, intranasally, sublingually, rectally, or by other generally accepted methods in recommended dosages.
  • the dosage forms of the present invention may contain structures obtained by methods of using liposomes, microencapsulation methods, methods of obtaining nanoforms of a drug, or other methods known in pharmaceuticals.
  • the active ingredient is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, acacia, mannitol, microcrystalline cellulose, hypromellose or similar compounds.
  • pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, acacia, mannitol, microcrystalline cellulose, hypromellose or similar compounds.
  • the tablets may be coated with sucrose, cellulose derivatives or other suitable coating agents.
  • the tablets may be prepared by various methods such as direct pressing, dry or wet granulation or hot alloying in a hot state.
  • a pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active ingredient with a solvent and filling soft or hard capsules with the resulting mixture.
  • aqueous suspensions For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injections and infusions are used.
  • the compound according to the invention finely ground powders of lactose, starch, talc are thoroughly mixed in a mortar and starch paste is added to the resulting mixture as a binding ingredient and mixed. The resulting mixture is sifted through a sieve. The resulting granules are dried in an oven at a temperature of 60°C for 35 minutes.
  • Granules obtained by method A are lubricated with magnesium stearate and baked in an oven at 60°C until completely dry (P. Bhatt. Handbook of pharmaceutical technology practical. P. Bhatt, A.Kumar Eds. Pharmatech 2021). Then the dried granules are formed into tablets using an eccentric (pressing) tablet machine (Menshutina N.V., Alves S.V., Mishina Yu.V. innovative technologies and equipment for pharmaceutical production. BINOM, 2012).
  • the compound of the present invention and its pharmaceutically acceptable salts are an antifungal agent, i.e. a useful agent for the therapy and/or prevention of diseases or conditions caused by fungal infections, including pathogens of the genus Candida spp., Rhizopus spp., Aspergillus spp., Microsporum spp., Trichophyton spp. Due to its antifungal activity, the compound of the present invention can be used for the prevention, treatment and/or reduction of the risk of developing an infectious disease of microbial etiology in a subject caused by a fungal infection.
  • an antifungal agent i.e. a useful agent for the therapy and/or prevention of diseases or conditions caused by fungal infections, including pathogens of the genus Candida spp., Rhizopus spp., Aspergillus spp., Microsporum spp., Trichophyton spp. Due to its antifungal activity, the compound of the present invention can be used for the prevention, treatment
  • the compound of the invention can be administered using a pharmaceutical composition in any pharmaceutical dosage form by any route of administration.
  • Dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form selected.
  • the compound of the invention can be administered to a patient daily for a period of time necessary for the treatment and/or prevention of diseases, including a course of therapy lasting days, months, years.
  • Routes of administration include, but are not limited to: intravenously, intramuscularly, orally, subcutaneously, by inhalation, intranasally and sublingually. Preferred routes of administration are oral and intravenous.
  • the invention also relates to a pharmaceutical composition containing a daily dose of said compound in the form of a fixed dosage unit, and to a combination containing said pharmaceutical composition or said compound.
  • said composition for use according to the invention is administered one or more times a day in a dosage of 1 mg or more of the compound of the invention.
  • the preferred dosage is 1-1500 mg.
  • the most preferred dosage is 10-1000 mg.
  • One or more additional pharmacologically active agents may be administered in combination with the compound of the invention.
  • any additional single or multiple active agents other than the compound of the invention may be used in any combination with the compound of the invention in a single or separate dosage form that allows for simultaneous or sequential therapeutic action of the active agents.
  • Such additional one or more agents may be administered simultaneously, or as part of a pharmaceutical composition, or at separate times.

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Abstract

L'invention se rapporte à la chimie des composés organiques, à la pharmacologie et à la médecine, et concerne un nouveau composé chimique caractérisé par une action antifongique élevée, notamment un composé de (Z)-(5-(4-chlorobenzylidène)-3-(2-(4- ((2R,3R)-3-(2,4-difluorophényl)-hydroxy-4-(1Н-1,2,4-1-yl) butane-2-yl)pipérazine-1-yl)-2- oxoéthyl) thiazolidine-2,4-dione correspondant à a formule suivante (1), ainsi que son sel pharmaceutiquement acceptable. Les expériences réalisées ont montré que ce composé est actif en ce qui concerne de nombreuses souches de champignons, y compris ceux résistant à des compositions commerciales utilisées de la famille des azoles.
PCT/RU2024/050125 2023-06-16 2024-06-14 Nouveaux agents antifongiques puissants à base de thiazolidine-2,4-dione et de triazole Ceased WO2024258316A1 (fr)

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RU2023115908 2023-06-16
RU2023115908A RU2814730C1 (ru) 2023-06-16 Новые потенциальные противогрибковые средства на основе тиазолидин-2,4-диона и триазола

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105554B2 (en) * 2000-08-31 2006-09-12 Oxford Glycosciences (Uk) Ltd. Benzylidene thiazolidinediones and their use as antimycotic agents
RU2662153C1 (ru) * 2017-04-20 2018-07-24 Общество С Ограниченной Ответственностью "Дермавитал Групп" Гибридные эфиры на основе производных тиазолидин-2,4-диона и азолов (1н-1,3-имидазола и 1н-1,3,4-триазола) и их применение
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