WO2009070045A2 - Nouveaux dérivés d'imidazole, utilisation des nouveaux dérivés d'imidazole et procédé de fabrication de ces derniers - Google Patents

Nouveaux dérivés d'imidazole, utilisation des nouveaux dérivés d'imidazole et procédé de fabrication de ces derniers Download PDF

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WO2009070045A2
WO2009070045A2 PCT/PL2008/050016 PL2008050016W WO2009070045A2 WO 2009070045 A2 WO2009070045 A2 WO 2009070045A2 PL 2008050016 W PL2008050016 W PL 2008050016W WO 2009070045 A2 WO2009070045 A2 WO 2009070045A2
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Prior art keywords
phenyl
imi
acetylbenzyl
denotes
bromo
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PCT/PL2008/050016
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English (en)
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WO2009070045A3 (fr
Inventor
Stanislaw Sobiak
Marcin Wierzchowski
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Uniwersytet Medyczny Im. Karola Marcinkowskiego W Poznaniu
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Publication of WO2009070045A3 publication Critical patent/WO2009070045A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Novel derivatives of imidazole use of novel derivatives of imidazole and a method of manufacturing them
  • the subject of the present invention are novel derivatives of imidazole, a method of manufacturing them as well as their use as the active substance in medicinal products for use in human and veterinary medicine.
  • Novel derivatives of imidazole according to the present invention are compounds with the general formula 1 ,
  • R 1 denotes a Br atom when R 2 denotes a nitro group or R 1 denotes a nitro group when R 2 denotes a Br atom;
  • - n denotes a value from 1 to 4.
  • R 3 denotes 2-halophenyl, 3-halophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethyl phenyl, 3.4-dimethylphenyl, 2,5-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5- dimethylphenyl or 2,3-dimethylphenyl; or R 3 denotes 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5- dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl, in which both halide substituents are equal; or R denotes 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4- acetophenyl
  • R 3 denotes phenyl, 4-halophenyl or 4-methylphenyl when n is greater than 1
  • R 3 denotes 1-naphthyl, 2-naphthyl, 2-tiofen, 3-tiofen, 5-halo-2-tiofen, 4-halo-2-tiofen, 3- halo-2-tiofen, 4-phenyl-phenyl, 3 -phenyl-phenyl, 2-phenyl-phenyl, 4-(4-acetylbenzyl)phenyl, 4- (3-acetylbenzyl)phenyl, 4-(2-acetylbenzyl)phenyl, 3-(4-acetylbenzyl)phenyl, 2-(4- acetylbenzyl)phenyl, 3-(3-acetylbenzyl)phenyl, 3-(2-acetylbenzyl)phenyl, 2-(3- acetylbenzyl)phenyl, 2-(2-acetylbenzyl)phenyl.
  • Biological activity as a pharmacophore is particularly shown by the imidazole core, whereas the structure and properties of the substituent at the Nl site of imidazole have a significant effect on the bioavailability of the molecule as an active substance.
  • Novel compounds being the subject of the present invention exhibit a wide range of biological activity, encompassing anti-tumour, anti-bacterial, anti-mycotic and anti-protozoan activity.
  • Novel compounds according to the present invention are characterised by a high level of cytostatic activity, especially against lymphoma, colorectal cancer, myeloma and estrogen dependent and independent breast cancer cells.
  • compounds being the subject the present invention exhibit radiosensitizing activity by catalysing the formation of reactive oxygen species under the influence of ionising radiation used in tumour therapy.
  • the biological activity of compounds according to the present invention is two-pronged and depends on the partial pressure of oxygen in the cell. In the case of hypoxia, this consists of the selective accumulation of compounds being the subject the present invention in the cell interior, and then reacting the nitro group of these compounds in the presence of reductases present there into toxic derivatives of nitroso-, hydroxylamino- and aminoimidazole responsible for their activity against tumour and anaerobic bacterial cells.
  • compounds according to the present invention catalyse the formation of reactive oxygen species responsible for activity against protozoans and bacteriocidal against aerobes.
  • Bioactivity may also be exhibited by pharmacologically permissible salts of compounds according to the present invention.
  • the subject the present invention is also a method of producing novel derivatives of 4(5)-bromo-
  • the method according to the present invention is based on synthesis in an organic solvent or a mixture of solvents selected from the following group: polychlorinated hydrocarbons containing more than 1 chlorine atom, mono- and polyhydroxyl aliphatic alcohols containing a -C 1 -C 20 alkyl, mono- and polyhydroxyl aromatic alcohols containing from 6 to 20 carbon atoms, mono- and polycyclic aromatic hydrocarbons and their homo logs containing from 6 to 20 carbon atoms; cyclic, acyclic, aromatic, aliphatic and aromatic-aliphatic ketones containing from 3 to 50 carbon atoms; acyclic, cyclic, aromatic and aromatic-aliphatic ethers; esters of aliphatic and aromatic carboxylic acids and aliphatic and aromatic alcohols containing from 2 to 50 carbon atoms; primary, secondary and tertiary amides containing from 1 to 20 carbon atoms, aliphatic and aromatic nitriles containing from 2 to 20 carbon atoms.
  • the synthesis is performed in a solvent or mixture of solvents selected from among: chloroform, dichloro methane, aliphatic alcohols containing a -C1-C5 alkyl, benzene, toluene, o-xylene, m- xylene, p-xylene, acyclic aromatic ketones containing from 3 to 6 carbon atoms, tertiary amides containing from 3 to 7 carbon atoms, N,N-dimethylformamide, or a nitrile containing from 2 to 7 carbon atoms
  • solvent or mixture of solvents selected from among: chloroform, dichloro methane, aliphatic alcohols containing a -C1-C5 alkyl, benzene, toluene, o-xylene, m- xylene, p-xylene, acyclic aromatic ketones containing from 3 to 6 carbon atoms, tertiary amides containing from 3
  • N,N-dimethylformamide is used as the solvent.
  • Synthesis according to the present invention is performed in an alkaline, neutral or slightly acidic environment.
  • the process is performed in a weakly basic environment, and to this end an alkalising agent is added, wherein preferentially it is added prior to the ⁇ -haloacyl derivatives of benzene.
  • an alkalising agent is added prior to the ⁇ -haloacyl derivatives of benzene.
  • inorganic salts, hydrate salts and hydro xyl salts preferentially carbonates and bicarbonates of metals from groups and II
  • metal hydroxides preferentially from groups and II
  • ammonia and its aqueous solutions tertiary amines, preferentially aliphatic tertiary amines; aromatic and non-aromatic heterocyclic bases possessing a tertiary nitrogen in an sp2 or sp3 configuration, preferentially imidazole or pyridine.
  • the process of producing compounds according to the present invention may also be carried out in a neutral environment, where it is preferential to use a significant excess of 5(4)-bromo-2- methyl-4(5)-nitro-lH-imidazole. Particularly preferentially, at least a twofold excess of 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole should be used.
  • Synthesis occurs at temperatures from -3O 0 C to 15O 0 C depending on the solvent used and the properties of the substrates. Preferentially, the reaction is carried out at 25-35 0 C. At lower temperatures the reaction occurs very slowly, whereas at higher temperatures the reaction products are strongly contaminated by waste and degradation products.
  • Reaction efficiency and selectivity are preferentially influenced by sonification of the reaction mixture.
  • the reaction mixture is sonificated during the initial phase for a period of 0.25 to 10 hours, preferentially 2-4 hours.
  • the sonification is performed using an ultrasound generator capable of 0.5 to 500 W, preferentially to 100 W, in ldm of reaction mixture and a frequency ranging from 16 to 90 kHz, preferentially 21.5 to 40 kHz.
  • a deleterious effect on the reaction is exerted by water.
  • agents for absorbing or binding water arising during the reaction it is preferential to use drying agents selected from the group encompassing CaCl 2 ,
  • the reaction time is dependent on reagent activity, and may last from 15 minutes to 7 days, preferentially about 48 hours.
  • a method of producing 4(5)-bromo-l-fenacylo -2-methyl-5(4)-nitro imidazole used in comparative biological analyses 30 ml of DMF was measured off into a round-bottomed 500ml flask equipped with a tube containing anhydrous calcium chloride. Next, 2.14g of 5(4)-bromo-2-methyl-4(5)-nitro-lH- imidazole and 0.87g sodium bicarbonate were added.
  • Example 5 Under identical conditions as in Example 2, a reaction was carried out between 1.6 Ig 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazo le and 1.7Og ⁇ -bromo-2-fluoroacetylphenone in the presence of 0.66g NaHCO 3 .
  • Example 14 Under identical conditions as in Example 2, a reaction was carried out between 153g 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 2.0Og ⁇ -bromo-S ⁇ -dichloroacetylphenone in the presence of 0.62g NaHCO 3 .
  • Example 16 Under identical conditions as in Example 2, a reaction was carried out between 1.04g 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 1.8Og ⁇ -bromo-2.4-dibromoacetophenone in the presence of 0.42g NaHCO 3 .
  • reaction mixture was stirred at room temperature for 15 minutes until CO 2 ceased to be emitted.
  • 1.0Og ⁇ -bromo-2-iodoacetylphenone was stirred at a temperature of 75°C for 2h.
  • the flask contents were poured into 150 ml distilled water and left at 5 0 C for
  • the resulting suspension was mixed using a magnetic stirrer at room temperature for 10 minutes.
  • Example 23 10 ml of DMF was measured off into a 50 ml round-bottomed flask equipped with a tube containing anhydrous calcium chloride. Next, 1.95g 5(4)-bromo-2-methyl-4(5)-nitro-lH- imidazole and 1.3 Ig potassium carbonate were added.
  • reaction mixture was stirred at room temperature for 15 minutes until CO 2 ceased to be emitted. Next, 1.6Og ⁇ -chloro-1-phenylpropanone were added. The mixture was transferred into a water bath set at 5O 0 C with a 150W ultrasound generator set at 21.5kHz and sonificated for 2h.
  • the cells were cultured in bottles facilitating easy gas exchange, but secured against microbial contamination from the external environment.
  • the incubation medium was Dulbecco's Modified
  • DMEM Eagle's Medium
  • the incubation was carried out for 72 hours under the following conditions: humidity 95%, CO 2 concentration 5%, temperature 37 0 C.
  • the lmg/ml solution of the tested compound was prepared ex tempore, dissolving 1 mg in 100 ⁇ l DMSO + 900 ⁇ l culture medium.
  • the culture medium was used as a solvent for further dilutions.
  • Cytotoxicity studies were performed in sterile 96-well plates, into which cells previously cultured were transferred at a rate of 5000 cells per 100 ⁇ l medium, per well. Te incubation lasted 72h and the medium was then replaced with a medium containing only 2.5% bovine serum and the 4-bromo-2-methyl -l-(2-methylphenacyl)-5-nitroimidazole in DMSO was applied next at concentrations of 50; 25; 10; 5; 2.5; 1.0; and 0.1 mM. These were incubated under the same conditions for 72h. Next, each well was supplemented with identical medium and MTT, such that the final concentration of MTT was 0.5mg/ml, and incubated for 4 hours.
  • Example 29 An MTT assay using 5-bromo-l-(4-fluoro-3-nitrophenacyl)-2-methyl-4-nitroimidazole was performed using an analogous method as in example 28.
  • Table 1 shows the IC50
  • An MTT assay for measuring the inhibitory effect on the proliferation of promyelocytotic laeukemia cells was performed using the compounds listed in Table 2.
  • HL-60 promyelocytotic laeukemia cells were used in this research.
  • the HL-60 cells were cultured in RPMI 1640 + GlutaMax medium with 10% FCS.
  • the medium contained glutamine
  • the cells were cultured in a humid atmosphere of 5% CO 2 at 37 0 C.
  • the research was performed using an MTT assay in a 96-hour in vitro culture.
  • the substance used as a standard was 5-bromo-l-(4-chlorophenacyl)-2-methyl-4-nitroimidazole.
  • Table 2 shows the cytotoxic activity of the tested compounds against HL-60 human promyelocytotic laeukemia cells.
  • Muller-Hinton agar medium prepared according to microbiological experimental procedures was inoculated with the studied strains: Staphylococcus aureus Enterococcus faecalis as well as the pathogenic fungus Candida Albicans at a rate of 1 cfu ⁇ colony forming unit).
  • the prepared medium was loaded with crystals of the studied compound. After a 48-hour incubation, at a temperature of 37 0 C and a 24-hour incubation at room temperature, the test strain growth inhibition zones were determined using a triple plus scale. Table 3 shows the results, in which individual markings correspond to:
  • H means a growth inhibition zone of 3 to 4 mm
  • H means a growth inhibition zone of 4mm.
  • Table 3 Results of microbiological analyses of selected compounds.
  • antibiotic is exhibited by 4-bromo- l-(3-bromophenacyl)-2-methyl-5- nitroimidazole both against Staphylococcus aureus bacteria and the fungus Candida albicans.
  • 5-bromo- 1 -(3.4-dichlorophenacyl)-2-methyl-4-nitroimdazol and 4-bromo- 1 -(3 A- dichlorophenacyl)-2-methyl-5-nitroimdazol both exhibit positive activity against the bacteria Enterococcus faecalis and the fungus Candida albicans.
  • the precipitate formed was filtered out and dried. This resulted in a mixture of 4-bromo-2- methyl- 1 -( 1 -nap hthylacetoyl)-5 -nitroimidazo Ie and 5 -bromo-2-methyl- 1 -( 1 -naphthylacetoyl)-4- nitroimidazole.
  • the isomer mixture was separated on a chromatography column with a silica gel with EtOAc as the mobile phase.
  • Example 60 Under identical conditions as in Example 60, a reaction was carried out between 1.2Og 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 1 .6Og ⁇ -bromo-4-phenyl-acetylphenone in the presence of 0.49g NaHCO 3 . The reaction product was isolated for crystallisation.
  • Example 60 Under identical conditions as in Example 60, a reaction was carried out between 1.2Og 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 1 .6Og ⁇ -bromo-4-phenyl-acetylphenone in the presence of 0.49g NaHCO 3 . The reaction product was isolated for crystallisation.
  • Example 60 Under identical conditions as in Example 60, a reaction was carried out between 0.97g 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 1.5Og ⁇ -bromo-4-(4-acetylbenzyl)acetylphenone in the presence of 0.4Og NaHCO 3 .
  • Example 65 Under identical conditions as in Example 65, a reaction was carried out between 1.54g 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 1.2Og 2-chloroacetylthiophen in the presence of 0.63g NaHCO 3 . The reaction product was isolated for crystallisation.
  • Muller-Hinton agar medium prepared according to microbiological experimental procedures was inoculated with the studied strains: Staphylococcus aureus Enterococcus faecalis as well as the pathogenic fungus Candida Albicans at a cfu yielding non-confluent growth.
  • the prepared medium was loaded with crystals of the studied compound. After a 48-hour incubation, at a temperature of 37 0 C and a 24-hour incubation at room temperature, the test strain growth inhibition zones were determined using a triple plus scale. Table 4 shows the results, in which individual markings correspond to:
  • 5-bromo-2-methyl-l-(l-naphthylacetoyl)-4-nitroimidazole is also characterised by strong antimycotic activity against Candida albicans.
  • tumour cells The evaluation of the viability and proliferation of the studied tumour cells was based on colorimetric analyses of the transformation of bromo-(4.5-dimethylthioazo-2-ilo)-2.5- diphenyltetrazolium (MTT), yellow, into a violet metabolite which is 4,5-dimethyl-2- ⁇ (£)-[(£)- phenyl(phenylhydrazo)methyl]diazenyl ⁇ - 1 ,3-thiazol (formazan).
  • ⁇ L-60 promyelocytotic laeukemia cells were used in this research.
  • the HL-60 cells were cultured in RPMI 1640 + GlutaMax medium with 10% FCS.
  • the medium contained glutamine
  • the cells were cultured in a humid atmosphere of 5% CO 2 at 37 0 C.
  • the research was performed using an MTT assay in a 96-hour in vitro culture.
  • Table 5 shows the cytotoxic activity of the tested compounds against HL-60 human promyelocytotic laeukemia cells.
  • the substance used as a standard was 5-bromo- 1 -(4- chlorophenacyl)-2-methyl-4-nitroimidazole.

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Abstract

L'invention porte sur de nouveaux dérivés d'imidazole, sur un procédé de fabrication de ces derniers et sur leur utilisation comme substance active dans des produits médicinaux destinés à la médecine humaine ou vétérinaire.
PCT/PL2008/050016 2007-11-27 2008-11-27 Nouveaux dérivés d'imidazole, utilisation des nouveaux dérivés d'imidazole et procédé de fabrication de ces derniers WO2009070045A2 (fr)

Applications Claiming Priority (2)

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PL383839A PL213730B1 (pl) 2007-11-27 2007-11-27 Pochodne imidazolu, sposób ich otrzymywania oraz zastosowanie pochodnych imidazolu
PLPL383839 2007-11-27

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012087115A1 (fr) * 2010-12-24 2012-06-28 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Ciblage de cancer utilisant des inhibiteurs d'isoforme ix d'anhydrase carbonique
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2020053282A1 (fr) 2018-09-13 2020-03-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012087115A1 (fr) * 2010-12-24 2012-06-28 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Ciblage de cancer utilisant des inhibiteurs d'isoforme ix d'anhydrase carbonique
US8980932B2 (en) 2010-12-24 2015-03-17 Stichting Maastricht Radiation Oncology “Maastro-Clinic” Cancer targeting using carbonic anhydrase isoform IX inhibitors
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2020053282A1 (fr) 2018-09-13 2020-03-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides

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WO2009070045A3 (fr) 2009-09-03
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