WO2015020556A1 - Composé de xénomycine ayant des propriétés antifongiques - Google Patents

Composé de xénomycine ayant des propriétés antifongiques Download PDF

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Publication number
WO2015020556A1
WO2015020556A1 PCT/RU2013/000689 RU2013000689W WO2015020556A1 WO 2015020556 A1 WO2015020556 A1 WO 2015020556A1 RU 2013000689 W RU2013000689 W RU 2013000689W WO 2015020556 A1 WO2015020556 A1 WO 2015020556A1
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group
antifungal agent
ring
compound according
hydrogen atom
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PCT/RU2013/000689
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English (en)
Russian (ru)
Inventor
Катерина ГУРОВА
Елена Борисовна РЫДКИНА
Варрен ВЕЙД
Андрей ГУДКОВ
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Общество С Ограниченной Ответственностью "Панацела Лабс"
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Priority to PCT/RU2013/000689 priority Critical patent/WO2015020556A1/fr
Publication of WO2015020556A1 publication Critical patent/WO2015020556A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the use of xenocimine compounds as an antifungal agent.
  • Xenomycin has a powerful unique antifungal activity against a wide range of pathogenic fungi, and they are effective in concentrations that are pharmacologically achievable in blood and tissues.
  • the present invention describes, in particular:
  • R b 1 ; R 4 is absent, a hydrogen atom, a C b unsubstituted or substituted alkyl group, a C 7 -C 12 alkylaryl group, or together with Z and R 4 when Z is a nitrogen atom form a 4-7 membered unsubstituted or substituted heterocyclic ring ;
  • R 5 represents a hydrogen atom or a C b unsubstituted or substituted alkyl group;
  • W is absent, CH 2 , C (O) or CH (CH 3 );
  • X is absent, CH 2 , C (O), CH (CH 3 ), CH (OH) or CH (F);
  • Y is absent, CH 2 or C (O); optionally taken together, the structure of YZR 5 forms a 4-5-membered unsubstituted or substituted heterocyclic ring;
  • Z is an oxygen atom, a nitrogen atom or a CH group;
  • the A ring is a 5-7 membere
  • ring is and ring A is where U and / or V is a carbon substituent or heteroatom to form a 5-6 membered carbocyclic or heterocyclic R4 ⁇ HC-R A
  • R 1 , R 2 , R 3 , R 4 , R 5 , W is absent, X is absent, Y is absent, Z is an oxygen atom, a nitrogen atom or a CH group as an antifungal agent.
  • R ° represents a hydrogen atom or CpC b -substituted or unsubstituted alkyl group as an antifungal agent.
  • R 6 represents a hydrogen atom or a CgC 6 -substituted or unsubstituted alkyl group as an antifungal agent.
  • an alkyl group as an antifungal agent.
  • R 6 represents a hydrogen atom or CgC 6 -substituted or unsubstituted alkyl group, as an antifungal agent.
  • FIG. 1 Growth of C. albicans 24433 upon incubation in the presence of increasing concentrations of fluconazole (FLK), and xenomycin CBL0100 and PLX01 107, starting with a concentration of 1 L of the minimum inhibitory concentration of each study drug.
  • FLK fluconazole
  • xenomycin CBL0100 and PLX01 107 starting with a concentration of 1 L of the minimum inhibitory concentration of each study drug.
  • the yeast cells were transferred to a medium with a concentration two times higher than the previous one when the cell concentration reached 108 cells / ml (dashed line).
  • C. albicans 24433 One colony of C. albicans 24433 was used for inoculation in 10 ml of RPMI-G medium with incubation overnight at 30 ° C. An aliquot containing 106 cells was transferred to 10 ml of medium containing X A part the minimum inhibitory concentration of the tested antifungal drug (fluconazole (PLA), CBL0100 and PLX01107) and incubated at 30 ° C. Yeast cell counts were performed daily. When the culture reached a density of at least 108 cells / ml, aliquots containing 106 cells were transferred to fresh medium containing a concentration of antifungal drug exceeding the previous 2 times, and re-incubated.
  • the growth of C. albicans culture with a concentration of compound PLX01107 equal to 4 ⁇ MIC (MIC 0.5 mmol / L) was achieved within 35 days and completed by the 44th day.
  • the growth of C. albicans culture with a 2-fold MIC of compound CBL0100 (MIC 1 mmol / L) was achieved on the 49th day of incubation and is still ongoing.
  • C. albicans is least affected by a progressive increase in the concentration of fluconazole, while CBL0100 significantly reduces its growth rate, while PLX01 107 has an intermediate effect.
  • C. albicans takes approximately twice as long to acquire the ability to grow in the presence of PLX01107 (4-fold excess MIC) compared with fluconazole.
  • CBL0100 was still less potent in stimulating the production of resistance in yeast.
  • the selectivity indicator is the ratio of the 50% inhibitory dose (ID50) for MT2 cells to the minimum inhibitory concentration (MIC) for Candida PLX compounds with high activity against C. albicans. For four PLX compounds, this ratio was similar to that of CBL0100 (PLX01001, 1002, 1012, 1 126), and for two compounds - PLX01008 and PLX01138 - the ID50 / MIC ratio was even better than that of CBL0100.
  • Our leader is PLX01008 because he has better solubility-metabolic stability characteristics than PLX01138.
  • mice with reduced immunity animal model, imitating systemic mycosis in humans, as a complication of immunodeficiency
  • mice were used, which were injected with cyclophosphamide 3 days before infection (200 mg / kg) and one day after infection (100 mg / kg). Animals aged 8 weeks, 7 animals in each group, were infected with C. albicans by injection into the tail vein of a dose of 4x103 CFU / mouse. Six hours after infection, treatment with xenomycin was started, which continued for 3 days (the goal of the experiment is survival).
  • Xenomycin CBL0100 was administered orally (dissolved in HPMC), PLX01008 and PLX01107 were administered by intravenous injection (dissolved in captisol).
  • Xenomycin was used at a dose of 80% of the maximum tolerated dose with repeated administration.
  • Amphotericin B at a dose of 1 mg / kg, administered intraperitoneally, was included in these experiments as a standard of treatment (control). Animals were checked daily for signs of illness and weight loss.
  • the initial screening included toxicity testing of a 20 ⁇ M solution of a compound from the PLX group against C. albicans after 24 hours of incubation with low molecular weight compounds.
  • the experiment was conducted in 96-well plates in which 105 CFU / ml of C. alibicans was placed in 100 ⁇ l of sterile water, then a 100 ⁇ M solution of compounds diluted in x2 RPMI 1640 medium with 3- (T ⁇ -morpholino) propanesulfonic acid and glucose was added.
  • the optical density was measured for 24 hours using a spectrophotometer at a wavelength of 450 nm.
  • a 20 ⁇ M CBL0100 solution and 1 mg / ml amphotericin B solution were used as a positive control.
  • a 0.2% DMSO solution was a negative control.
  • the experiments were carried out in four replicates and repeated at least twice. PLX compounds with an average growth inhibition of C. albicans> 50% were taken for secondary screening.
  • Connection PLX 1008 was obtained as follows
  • TLC ethyl acetate (aluminum plate, UV manifestation).
  • TLC ethyl acetate / triethylamine 10/1 (aluminum plate, manifestation
  • TLC methanol / chloroform / triethylamine 1/12 / 0.25 (aluminum plate, UV manifestation).
  • the melting temperature is determined in a sealed capillary in inert.
  • the substance decomposes at 300 ° C.
  • the applied volume 40 ⁇ l.

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

Abstract

L'invention concerne l'utilisation de composés de xénomycine en qualité d'agent antifongique, notamment à un représentant des xénomycines correspondant à la formule générale (I), et à son utilisation en qualité d'agent antifongique. L'invention concerne un composé ayant la formule structurelle (I). Les propriétés biologiques du composé correspondant à la formule générale (I) ont été démontrées.
PCT/RU2013/000689 2013-08-08 2013-08-08 Composé de xénomycine ayant des propriétés antifongiques WO2015020556A1 (fr)

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PCT/RU2013/000689 WO2015020556A1 (fr) 2013-08-08 2013-08-08 Composé de xénomycine ayant des propriétés antifongiques

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PCT/RU2013/000689 WO2015020556A1 (fr) 2013-08-08 2013-08-08 Composé de xénomycine ayant des propriétés antifongiques

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2803571C1 (ru) * 2023-03-22 2023-09-15 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" ПРИМЕНЕНИЕ 5-[(1H-ИНДОЛ-3-ИЛ)МЕТИЛ]-7-МЕТИЛ-2,3-ДИГИДРО-1H-ПИРРОЛО[1,2-d][1,4]ДИАЗЕПИН-4(5H)-ОНА В КАЧЕСТВЕ ПРОТИВОГРИБКОВОГО СРЕДСТВА В ОТНОШЕНИИ ДРОЖЖЕВЫХ ГРИБОВ

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042445A1 (fr) * 2008-10-06 2010-04-15 Cleveland Biolabs, Inc. Composés carbazole et utilisations thérapeutiques desdits composés

Patent Citations (1)

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WO2010042445A1 (fr) * 2008-10-06 2010-04-15 Cleveland Biolabs, Inc. Composés carbazole et utilisations thérapeutiques desdits composés

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KHOSHTARIYA T.E. ET AL.: "Issledovanie nekotorykh proizvodnykh ZN-pirrolo [2,3-s]karbazola.", SOOBSCHENIYA AKADEMII NAUK GRUZINSKOI SSR, vol. 109, no. 2, 1983, pages 325 - 328 *
MUTASEM O. TANA ET AL.: "Discovery of New Antifungal Leads via Pharmacophore Modeling and SQAR Analysis of Fungal N-Myristoyl Transferase Inhibitors Followed by In Silico Screening.", CHEM. BIOL. DRAG DES., vol. 78, 2011, pages 391 - 407 *
WICHAPONG, KANIN ET AL.: "Postprocessing of Protein-Ligand Docking Poses Using Linear Response MMM-PB/SA Application to Wee 1 Kinase Inhibitors.", J. CHEM. INF. MODEL., vol. 50, 2010, pages 1574 - 1588 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2803571C1 (ru) * 2023-03-22 2023-09-15 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" ПРИМЕНЕНИЕ 5-[(1H-ИНДОЛ-3-ИЛ)МЕТИЛ]-7-МЕТИЛ-2,3-ДИГИДРО-1H-ПИРРОЛО[1,2-d][1,4]ДИАЗЕПИН-4(5H)-ОНА В КАЧЕСТВЕ ПРОТИВОГРИБКОВОГО СРЕДСТВА В ОТНОШЕНИИ ДРОЖЖЕВЫХ ГРИБОВ
RU2803600C1 (ru) * 2023-03-22 2023-09-18 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" ПРИМЕНЕНИЕ 10-МЕТИЛ-6,7-ДИГИДРО-5H-ПИРИДО[2,3-b]-ПИРРОЛО[1,2-d][1,4]ДИАЗЕПИНА В КАЧЕСТВЕ ПРОТИВОГРИБКОВОГО СРЕДСТВА В ОТНОШЕНИИ ДРОЖЖЕВЫХ ГРИБОВ
RU2803747C1 (ru) * 2023-03-22 2023-09-19 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Применение (z)-2-(2-оксопропилиден)индолин-3-она в качестве противогрибкового средства в отношении дрожжевых грибов
RU2806192C1 (ru) * 2023-03-28 2023-10-27 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Применение 3-арилспиро[фуро[3',4':2,3]пирроло[1,2-a]хиноксалин-5,3'-индолин]-1,2,2',6(7H)-тетраонов в качестве средств, обладающих антибактериальной и противогрибковой активностями
RU2808981C1 (ru) * 2023-04-27 2023-12-05 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" ПРИМЕНЕНИЕ 7-МЕТИЛ-5-[4-(ТРИФТОРМЕТИЛ)ФЕНИЛ]-1,2,4,5-ТЕТРАГИДРО-3H-ПИРРОЛО[1,2-a][1,4]ДИАЗЕПИН-3-ОНА В КАЧЕСТВЕ ПРОТИВОГРИБКОВОГО СРЕДСТВА В ОТНОШЕНИИ ДРОЖЖЕВЫХ ГРИБОВ
RU2810715C1 (ru) * 2023-04-27 2023-12-28 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" ПРИМЕНЕНИЕ 5-(4-МЕТОКСИФЕНИЛ)-7-МЕТИЛ-1,2,4,5-ТЕТРАГИДРО-3H-ПИРРОЛО[1,2-a][1,4]ДИАЗЕПИН-3-ОНА В КАЧЕСТВЕ ПРОТИВОГРИБКОВОГО СРЕДСТВА В ОТНОШЕНИИ ДРОЖЖЕВЫХ ГРИБОВ

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