WO2015076684A1 - Dérivés de 4-amino-3,5-diméthyl-4h-1,2,4-triazole, leur procédé de préparation, composé pharmaceutique les contenant et leur utilisation - Google Patents

Dérivés de 4-amino-3,5-diméthyl-4h-1,2,4-triazole, leur procédé de préparation, composé pharmaceutique les contenant et leur utilisation Download PDF

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Publication number
WO2015076684A1
WO2015076684A1 PCT/PL2014/000132 PL2014000132W WO2015076684A1 WO 2015076684 A1 WO2015076684 A1 WO 2015076684A1 PL 2014000132 W PL2014000132 W PL 2014000132W WO 2015076684 A1 WO2015076684 A1 WO 2015076684A1
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WO
WIPO (PCT)
Prior art keywords
formula
dimethyl
amino
methanol
triazol
Prior art date
Application number
PCT/PL2014/000132
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English (en)
Inventor
Leszek CIUNIK
Damian PIENĄŹCZAK
Bogumiła SZPONAR.
Katarzyna WAJDA-HERMANOWICZ
Aleksandra ZATAJSKA
Original Assignee
Wrocławskie Centrum Badań Eit + Sp. Z O.O.
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Publication of WO2015076684A1 publication Critical patent/WO2015076684A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • 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
    • A61P31/10—Antimycotics

Definitions

  • the invention relates to new chemical compounds - chiral triazole derivatives, a method of preparation thereof, a pharmaceutical agent containing the new compounds and use thereof.
  • the new compounds exhibit bactericidal and fungicidal activity, finding potential use as effective broad-spectrum antibiotics.
  • Triazoles represent heterocyclic five-membered aromatic compounds containing three nitrogen atoms. Their beneficial properties have found numerous medical applications. Triazole derivatives are used as bacterial enzyme inhibitors that support antibiotics, e.g. a ⁇ -lactamase inhibitor, medicaments inhibiting development of estrogen-dependent cancers, ergosterol synthesis inhibiting medicaments, medicaments inhibiting RNA and DNA replication of some viruses, psychotropic medicaments (such as benzo-l,4-diazepine triazole derivatives) and many others.
  • antibiotics e.g. a ⁇ -lactamase inhibitor
  • medicaments inhibiting development of estrogen-dependent cancers e.g. a ⁇ -lactamase inhibitor
  • medicaments inhibiting RNA and DNA replication of some viruses e.g. a ⁇ -lactamase inhibitor
  • medicaments inhibiting RNA and DNA replication of some viruses e.g. a ⁇ -lactamase inhibitor
  • medicaments inhibiting RNA and DNA replication of some viruses e.
  • Patents US 4,251,512, 4,147,791, 4,038,406 and 4,048,318 disclose fungicidal compounds and compositions with synergistic activity containing triazole derivatives.
  • published international application WO 2006/109933 shows a use of triazole based compounds, their salts and pharmaceutical compositions with fungicidal activity in therapy.
  • Publication WO03/065807 discusses a use of alkoxylated amines for activity enhancement of fungicidal preparations containing fungicidal triazoles.
  • Patent PL214249 disclosed medically beneficial, antibacterial and antifungal activity of hemiaminals obtained on the basis of 4-amino-4H-l,2,4-triazole. Studies have shown differences in antibacterial and antifungal activity depending on the type of substituents in the phenyl ring. In particular, compounds showing bactericidal activity against Escherichia Coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus Aureus and Candida albicans strains have been disclosed. Nevertheless, the 2bald, 3nbald, 4nbald compounds act selectively only against specific strains and the inhibition of fungal growth takes place only for the maximal concentration (MIC 1 mg/1 ml).
  • the compounds disclosed in the PL214249 are conformationally variable, which diminishes their stability.
  • a need identified in the prior art is also to provide compounds with improved stability while maintaining their effective cidal activity.
  • the object of the invention is therefore providing stable and biologically active substances used in medicine.
  • the object has been realized by the present invention.
  • the object of the invention is a compound of a general formula:
  • Rl denotes: N0 2 , CI or H
  • R2 denotes: N0 2 or H
  • R3 denotes: N0 2 , CI, CN, CH 3 or H,
  • R4 denotes: N0 2 or H
  • R5 denotes: N0 2 , CI or H
  • R6 denotes: CH 3 ,
  • R7 denotes: CH 3 .
  • the compound is selected from the group comprising: a) [(3,5-dimethyl-4H-l,2,4-triazol-4-yl)-amino](2-nitrophenyl)methanol (Formula 1); b) [(3,5-dimethyl-4H-l,2,4-triazol-4-yl)amino](3-nitrophenyl)methanol (Formula 2); c) [(3,5-dimethyl-4H-l,2,4-triazol-4-yl)amino](4-nitrophenyl)methanol (Formula 3); d) [(3,5-dimethyl-4H-l,2,4-triazol-4-yl)amino](2,4-dinitrophenyl)methanol (Formula 4); e) [(3,5-dimethyl-4H-l,2,4-triazol-4-yl)amino](4-chloro-3-nitrophenyl)methanol (Formula) [For
  • the object of the invention is also the new triazole derivative [(3,5-dimethyl-4H-l,2,4-triazol-4- yl)amino](2,4-dinitrophenyl)methanol (Formula 4) or a pharmaceutically acceptable salt thereof.
  • the compound of the general formula described above is in a conformation referred to as extended.
  • a further object of the invention is a pharmaceutical agent containing the compound defined by the general formula above as an active principle, as well as particular embodiments thereof, or a pharmaceutically acceptable salt thereof.
  • the agent is made in the form of an ointment, gel, tablet, capsule, powder, granules, syrup, injection or suppositories.
  • a further object of the invention is the compound defined by the general formula above, as well as particular embodiments thereof, or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a further object of the invention is the compound defined by the general formula above, as well as particular embodiments thereof, or a pharmaceutically acceptable salt thereof for preventing and/or treating infections caused by bacteria and fungi.
  • the compounds of formula 2, 3, 4, 6, 7 are used.
  • the compounds of formula 3 or 5 are used.
  • the compounds are used in concentrations of 500 and 1000 ⁇ g/ml.
  • the compound of formula 7 is used for preventing and/or treating infections caused by Staphylococcus aureus and E. coli.
  • the compound of formula 7 is used for preventing and/or treating infections caused by Staphylococcus aureus and E. coli.
  • the compound is used in concentrations of 250 ⁇ for S. aureus and 125 ⁇ / ⁇ 1 for E. coli respectively.
  • a further object of the invention is a method of preparation of the new triazole derivatives according to the invention, wherein a benzaldehyde derivative is reacted with 4-amino-3,5- dimethyl-4H-l,2,4-triazole, with equimolar amounts of the two substances dissolved in a solvent, followed by separation of the obtained compounds.
  • the solvent used in the reaction of preparation of the new triazole derivatives is an organic solvent, such as methanol, ethanol, acetonitrile, propanol, isopropanol, DMF, DMSO, butanol, acetone, phenol, diethyl ether, chloroform, n-hexane and cyclohexane.
  • organic solvent such as methanol, ethanol, acetonitrile, propanol, isopropanol, DMF, DMSO, butanol, acetone, phenol, diethyl ether, chloroform, n-hexane and cyclohexane.
  • the solvent is diethyl ether, chloroform, n-hexane and cyclohexane, more preferably n-hexane.
  • the new derivatives are compounds obtained as a result of reacting 4-amino-3,5-dimethyl-4H- 1,2,4-triazole with benzaldehyde derivative. They belong to a group of hemiaminals, known as considerably unstable and difficult to separate intermediate compounds in the Schiff bases synthesis. Preferably they are characterized by having two chiral centers and specifically selected substituents. Due to their properties they may be employed as active principles in prophylactic medicaments and those used in treating infections caused by the presence of bacteria and fungi.
  • the new compounds according to the invention may be used for the preparation of a medicament intended for prevention or treating infections caused by bacteria and fungi.
  • Figure 1 shows the activity of the compounds against Bacilus subtilis bacteria. Designations: line with "x" - formula 3, line with squares - formula 4, line with triangles - formula 5.
  • Figure 2 shows the activity of the compounds against Staphylococcus aureus bacteria. Designations: line with squares - formula 1, line with stars - formula 3, line with triangles - formula 4, line with diamonds - formula 5, line with x - formula 7.
  • Figure 3 shows the activity of the compounds against Escherichia coli bacteria. Designations: line with squares - formula 4, line with triangles - formula 7.
  • Figure 4 shows the activity of the compounds against Proteus sp. bacteria. Designations: line with x - formula 3, line with squares - formula 4, line with triangles - formula 5.
  • Example 1 Chiral triazole compounds.
  • the course of the reaction of hemiaminals synthesis involves nucleophilic addition of an amine to the carbonyl group of the aldehyde.
  • the presence of an acid in the reaction mix catalyzes separation of a water molecule, which results in the final end product being undesirable imines or, with large excess thereof - in inhibition of the reaction through blocking the amino group.
  • the preferred reaction conditions are promoted by the absence of an acid in the reaction mix, adequate selection of the properties of donor-acceptor substituents in the phenyl ring and the specific properties of the amino residue. The latter is confirmed by the course of the synthesis of benzaldehyde derivatives and aniline leading to obtaining only a Schiff base.
  • n-hexane is comparable to acetonitrile.
  • the reagents were heated and mixed under reflux in 50°C for 9 hours. Then the reaction mix was washed with two small portions of acetonitrile and methanol and air-dried.
  • the 1H NMR, 13 C NMR spectra as well as COSY and HMBC correlation spectra for characterization of the synthesized compounds were obtained with the following spectrometers: the Bruker Avance III 600 MHz spectrometer, the Bruker Avance 500 MHz spectrometer and the 300 MHz AMX Bruker NMR spectrometer.
  • the studies were performed in the Nuclear Magnetic Resonance Laboratory of the Faculty of Chemistry, University of Wroclaw.
  • the applied solvent was The signals in the NMR spectrum were calibrated on the solvent signal - 2.51 ppm in the 1H NMR spectrum and 39.91 ppm in the 13 C NMR spectra.
  • ESI-MS spectra were obtained with the micrOTOF-Q-Bruker Dalonic device for the mass spectrum (m/z) 400-4000 in the Mass Spectrometry Laboratory of the Faculty of Chemistry, University of Wroclaw.
  • the solvent was methanol and the ion source was electrospray (ESI).
  • the IR studies were performed with the Bruker 66/s FTIR (Bruker IFS66) spectrometer in the Infrared Spectroscopy Laboratory of the Faculty of Chemistry, University of Wroclaw. The measurements were performed in KBr. The spectra were measured in the 4000-400 cm "1 range.
  • IR abbreviations: vw - very weak, w - weak, m - medium, s - strong, vs - very strong
  • KBr 1. wavenumber [cm 1 ] 429 - vw; 504 - w; 540 - vw; 569 - m; 615 - w; 666 - w; 682 - m; 731 - m; 754 - m; 762 - w; 777 - m; 810 - m; 846 - vw; 862 - m; 912 - w; 952 - w; 978 - vw; 1024 - w; 1065 - s; 1080 - s; 1165 - vw; 1198 - m; 1246 - w; 1331 - vs; 1346 - vs; 1382 - m; 1419 - m; 1454
  • the Microplate Alamar Blue® Assay (MABA) was conducted for a series of concentrations of the tested compounds. To the so prepared material bacterial suspension of a determined optical density was added and 24 hour incubation was conducted during which the bacteria are exposed to a potentially bactericidal chemical compound. Subsequently the Alamar Blue® dye is added, which distinguishes between living bacteria having metabolic activity and dead ones. The activity was measured with a fluorimeter.
  • the Minimal Inhibitory Concentration was determined by calculating the inhibition of bacterial growth after plotting inhibition curves.
  • Negative 'no growth' and positive 'growth' controls were prepared.
  • Reagents and materials for the MABA test a) Alamar Blue® dye (Biosource, USA) - marker for bacteria for fluorescence measurements, b) dimethyl sulfoxide (DMSO, Merck) - solvent for the tested compounds, c) sterile PBS.
  • Alamar Blue® dye Biosource, USA
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • Bacteria stored on agar slants (inoculum - 3 rd passage), were each time seeded to a liquid medium and cultured for 24 hours in 37°C. Optical density measurement of bacterial suspension was performed for the wavelength 550 nm. In order to standardize the measurement the suspension was diluted as needed to absorbance of 0.5. Preparation of compounds for determination of bactericidal activity using the MABA test
  • test portions of 10 mg were dissolved in 100 ⁇ DMSO and then diluted to the volume of 10 ml in sterile PBS (1 mg/ml).
  • the tested compounds were diluted in an exponential series in the liquid bacterial medium on a sterile 96-well plate for cell culture (Nunc), the first dilution being 1 mg/1 ml, the next 0.5 mg/1 ml, 0.25 mg/1 ml etc.
  • 100 ⁇ of sterile PBS was added to each well (excluding the first), followed by addition of 200 ⁇ of the tested compound to the first well in line. 100 ⁇ of each was taken and transferred (diluting it) to the consecutive wells.
  • the controls for the test were:
  • the bacterial growth inhibitory activity of the compounds was determined using MIC (Minimal Inhibitory Concentration), being the minimal concentration [ ⁇ g/ml] exhibiting bacterial growth inhibition.
  • the compound of formula 4 shows the most effective activity against all studied microorganisms. The result demonstrates a substantial bactericidal potential, both against gram-positive and gram-negative bacteria.
  • the compounds defined by formula 2, formula 3, formula 4, formula 6 and formula 7 have fungicidal activity (Candida albicans) in concentrations of 500 and 1000 ⁇ g/ml.
  • the compound defined by formula 7 also showed activity against Staphylococcus aureus (250 ⁇ g ml) and E. coli (125 ⁇ g/ml).
  • the compounds defined by formula 3 and formula 5 yere active against Bacillus subtilis, Staphylococcus aureus and Proteus sp. in concentrations of 500 and 1000 ⁇ g/ml.

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

L'invention concerne de nouveaux dérivés de 4-amino-3,5-diméthyl-4H-1,2,4-triazole, leur procédé de préparation, un composé pharmaceutique contenant les nouveaux composés et leur utilisation. Il s'agit de nouveaux composés obtenus dans une réaction de 4-amino-3,5-diméthyl-4H-1,2,4-triazole avec des dérivés de benzaldéhyde. Les composés sont caractérisés par des centres de chiralité et les propriétés chimiques et biologiques avantageuses qui s'ensuivent. Les nouveaux dérivés de triazole peuvent être utilisés en tant que principes actifs de médicaments pour prévenir et/ou traiter des infections causées par la présence de champignons ou de bactéries.
PCT/PL2014/000132 2013-11-20 2014-11-18 Dérivés de 4-amino-3,5-diméthyl-4h-1,2,4-triazole, leur procédé de préparation, composé pharmaceutique les contenant et leur utilisation WO2015076684A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL406149A PL406149A1 (pl) 2013-11-20 2013-11-20 Pochodne 4-amino-3, 5-dimetylo-4H-1, 2,4-triazoli, sposób ich otrzymywania, środek farmaceutyczny zawierający te związki oraz ich zastosowanie
PLP.406149 2013-11-20

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WO2015076684A1 true WO2015076684A1 (fr) 2015-05-28

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4038406A (en) 1972-09-26 1977-07-26 Bayer Aktiengesellschaft 1,2,4-triazole antimycotic compositions and use thereof
US4048318A (en) 1972-01-11 1977-09-13 Bayer Aktiengesellschaft 1-Substituted-1,2,4-triazole fungicides
US4147791A (en) 1972-01-11 1979-04-03 Bayer Aktiengesellschaft 1-Substituted-1,2,4-triazole fungicidal compositions and methods for combatting fungi that infect or attack plants
PL214249A1 (fr) 1979-03-20 1980-10-06 Polska Akademia Nauk Instytut
US4251512A (en) 1975-11-26 1981-02-17 Bayer Aktiengesellschaft Synergistic fungicidal compositions containing 1,2,4-triazole derivatives
WO2003065807A1 (fr) 2002-02-05 2003-08-14 Janssen Pharmaceutica N.V. Formulations comprenant des triazoles et des amines alcoxylees
US20050113347A1 (en) 2002-01-18 2005-05-26 Dr. Reddy's Laboratories Limited Novel antibacterial compounds: process for their preparation and pharmaceutical compositions containing them
WO2006109933A1 (fr) 2005-03-30 2006-10-19 Daewoong Pharmaceutical Co., Ltd. Derives de triazole antifongiques
US20060270628A1 (en) 2003-04-29 2006-11-30 Jagattaran Das Antiinfective 1,2,3-triazole derivatives, process for their preparation and pharmaceutical compositions containing them
WO2009005381A1 (fr) * 2007-06-29 2009-01-08 Uniwersytet Wroclawski Nouveaux dérivés chiraux de triazole, leur synthèse et leur application

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4048318A (en) 1972-01-11 1977-09-13 Bayer Aktiengesellschaft 1-Substituted-1,2,4-triazole fungicides
US4147791A (en) 1972-01-11 1979-04-03 Bayer Aktiengesellschaft 1-Substituted-1,2,4-triazole fungicidal compositions and methods for combatting fungi that infect or attack plants
US4038406A (en) 1972-09-26 1977-07-26 Bayer Aktiengesellschaft 1,2,4-triazole antimycotic compositions and use thereof
US4251512A (en) 1975-11-26 1981-02-17 Bayer Aktiengesellschaft Synergistic fungicidal compositions containing 1,2,4-triazole derivatives
PL214249A1 (fr) 1979-03-20 1980-10-06 Polska Akademia Nauk Instytut
US20050113347A1 (en) 2002-01-18 2005-05-26 Dr. Reddy's Laboratories Limited Novel antibacterial compounds: process for their preparation and pharmaceutical compositions containing them
WO2003065807A1 (fr) 2002-02-05 2003-08-14 Janssen Pharmaceutica N.V. Formulations comprenant des triazoles et des amines alcoxylees
US20060270628A1 (en) 2003-04-29 2006-11-30 Jagattaran Das Antiinfective 1,2,3-triazole derivatives, process for their preparation and pharmaceutical compositions containing them
WO2006109933A1 (fr) 2005-03-30 2006-10-19 Daewoong Pharmaceutical Co., Ltd. Derives de triazole antifongiques
WO2009005381A1 (fr) * 2007-06-29 2009-01-08 Uniwersytet Wroclawski Nouveaux dérivés chiraux de triazole, leur synthèse et leur application

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