Classifications

• • 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
  • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
• • 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
• • 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

• This invention relates to new derivatives of aromatic imidazolidinones, which lower the minimum bactericidal concentration in the form of antibiotic and inhibit the growth of microorganisms (the so called 'minimum inhibitory concentration' or MIC), method of their production and use as medications, containing their pharmaceutical compositions, and new applications for imidazolidinone derivatives.
• products may thus be used in particular to prevent or treat bacterial illnesses, where antibiotics are used.
• products being compounds which lower the minimum inhibitory concentration of antibiotics, can be used, in particular to support treatment or prevention of bacterial illnesses especially such as: infections caused by Gram-negative bacilli, which prove to be a serious therapeutic problem in patients due to the increasing number of multidrug-resistant strains, including 6 caused by most dangerous pathogens named "alert pathogens" by the Infectious Diseases Society of America, ie: enterococci, MRSA, Klebsiella, Enterobacter species and strains of Pseudomonas aeruginosa and Acinetobacter baumannii [1-5].
• the compounds which are the subject of this application may increase the effectiveness of antibiotics, in particular: (1) ⁇ -lactam antibiotics, because of the mechanism of ⁇ -lactamase drug resistance of extended substrate spectrum, which often occurs in the case of Klebsiella pneumoniae bacillus, Escherichia coli, Proteus spp., Serratia spp., Enterobacter spp., Pseudomonas spp., Salmonella spp., cephalosporins, due to the mechanism of cephalosporin drug resistance most commonly occurring among bacilli of Enterobacter spp., Citrobacter spp., Serratia spp., and other antibiotics and chemotherapeutic agents, such as sparfloxacin, chloramphenicol, nalidixic acid, ansamycin antibiotics (rifamycin), oxazolidines (linezolid) [6- 12].
• ⁇ -lactam antibiotics because of the mechanism of
• the present invention relates to imidazolidinone derivatives, which are a subset of imidazoles.
• R 1 is H, halogen, alkyl, alkoxyl, aryl, carboxyl, OH or N0 2
• R 2 is H or alkyl
• R 3 is alkyl, arylalkyl or arylxyalkyl
• R 4 is H, halogen or N0 2
• X is 0 or S
• Y is H or N
• R 1 is H, halogen, alkyl, alkoxy, aryl, carboksyl, OH or N0 2 ;
• R is H, alkyl, or ester
• R 2 is H, alkyl, hydroxyalkyi, cycloalkyi, or hydroxyethylpiperazine,
• R 3 is alkyl, hydroxyalkyi, cycloalkyi or hydroxyethylpiperazine, showing antiarrhythmic and / or antihypertensive and / or antiseizure activity [21-23].
• phenylpiperazine derivatives of 5,5-diphenylhydantoin with the following formula:
• R 1 is H, alkyl, or ester or a methyl carboxyl group
• R 2 ' is H, halogen, alkoxy
• R 3 is H, hydroxy or acetoxy
• n 1, 2 or 3 showing antiarrhythmic and / or antihypertensive and / or antiseizure activity [24-28] and no inhibitory activity of bacterial drug resistance for most of the compounds in the pilot study
• Ar is a phenyl group, a phenyl group substituted by chlorine in position 2 or 3 or 4 or 2 and 4, a phenyl group substituted with nitro group in position 4, ⁇ -naphthyl group. of the tested for the ability to inhibit the mechanisms of drug resistance in cancer cells, which showed a very weak or no activity [30].
• Ri is phenyl substituted with one or more alkyl, fluoro, alkoxy substituents or naphthalene, fluorene, phenanthrene, anthracene, pyrene.
• R 2 is (un)substituted piperazine, primary amine
• i 4-chlorophenyl, 4-dimethylaminophenyl, 4-nitrophenyl, fluorene, ⁇ -naphthyl, 2-thiophene, 3-thiophene and R 2 is piperazine.
• the derivative used constitutes compounds selected from the group listed below: 2-(piperazinyl)-5-(2- thiophenylmethylidene)-lH-imidazol-4(5H)-one 2-(piperazinyl)-5-(3- thiophenylmethylidene)-lH-imidazol-4(5H)-one 5-(4-chlorobenzylidene)-2-(piperazinyl)-lH-imidazol-4(5H)-one 5-(4-nitrobenzylidene)-2-(piperazinyl)-lH-imidazol-4(5H)-one 5-(2-fluorenylmethylidene)-2-(piperazinyl)-lH-imidazol-4(5H)-one 5-(3-naphthylmethylidene)-2-(piperazinyl)-lH-imidazol-4(5H)-one 5-(4-dimethyl
• the object of the invention also relates to compounds of the invention for use as a medicament for the prevention or treatment of bacterial diseases and a therapeutic agent comprising one or more compounds described above and relating to the object of the invention.
• the object of the invention also related to the use of compounds of the invention for the manufacture of a medicament for the prevention or treatment of bacterial diseases, preferably, for the prevention or treatment of diseases caused by Gram (-), also advantageous for the preparation of medicaments for the prevention or treatment of diseases caused by E. coli bacteria of the Enterobacter genus.
• the compounds being the object of the invention are prepared by a process which is shown in Figure 1.
• the compound of formula I is obtained by 3 or 4 step synthesis according to the scheme shown in Figure 1, where in the first step as the result of Knoevenagel condensation of 2-thiohydantoin with an appropriately substituted aromatic aldehyde, carried out in an alkaline medium with the use of sodium acetate in acetic acid or sodium carbonate in water in the presence of alanine, a compound is obtained with the following formula II:
• the compound of formula I is prepared through 1-step melting reaction of the compound of formula III with the appropriate primary or secondary amine carried. Reaction is carried out without solvent in an oil bath maintained under a washer with concentrated nitric acid at the temperature of 120-160°c, controlled by a contact thermometer and followed by boiling in ethanol for 3-7 hours. In the case of a two-step reaction (3b, 4) a compound with formula IV is indirectly obtained:
• the compound of formula I is obtained by deprotection of a compound of formula IV, progressing as acid hydrolysis using hydrochloric or trifluoroacetic acid or as alkaline hydrolysis with use of concentrated sodium hydroxide. Study of the biological activity of the compounds being the object of the invention.
• the pharmacological activity of the compounds according to the invention was determined as a result of a microbiological study conducted to assess the ability to inhibit AcrAB-TolC pumps.
• the study was carried out on three strains of Enterobacter aerogenes: ATCC 13048 (reference strain), CM64 (strain overexpressing AcrAB-TolC pump) and EA27 (porin-free strain).
• the described bacterial strains were incubated with the studied compounds, administered at different concentrations: 5 mM, 2.5mM, 1.25mM, 0.6 mM, 0.3 mM, 0.15 mM, and 0.07 mM [36]:
• the value of activity parameter (A) was determined defined as the ratio of the MIC value of the antibiotic itself to the MIC value of the MIC OF THE ANTIBIOTIC
• the inhibitory capacity of F9a is the highest in relation to Rifamycin and Linezolid, for which, depending on the bacterial strain, is causes up to a 32-fold decrease of the MIC.
• antibiotics such as Levofloxacin, Tetracycline, Chloramphenicol, and Ofloxacin shows there is a lower activity in the range of 2 to 8 fold reduction in the MIC.
• the compound does not affect the activity in relation to Streptomycin in all three strains tested, and Erythromycin, Azithromycin, Ciprofloxacin and Moxifloxacin in the strain with overexpressed pump AcrAB (3AG100).
• Ethanolic solution or suspension (approx. 6 ml) of amine derivatives in the form of alkaline (0.5 - 4 mmol) was placed in a glass vial (12 ml) and saturated to pH with sour gaseous HCI which was generated by the action of concentrated sulfuric acid on NaCI.
• the vial was covered with a stopper and cooled for several hours at the temperature of 0-4 °C, the resulting precipitate was filtered off on a Biichner funnel, gently washed with ethanol and dried in an oven and / or in a vacuum oven with CaCI 2 .
• %C theor.: 52.80, act.: 52.90, %H: theor.: 5.32, act.: 5.43, %N: theor.: 16.42,act.: 16.53.
• the compound was obtained by alkaline deprotection. 0.58 mmol (0.25 g) of the hydrochloride (Z)-4-((2-(4-(2-hydroxyethyl)piperazine-l-yl)-4-oxa-lH-imidazole-5(4H)- ylidene)methyl) methyl benzoate (D7) was used. It was suspended in 2 ml of ethanol. Then added 2 ml of water and 0.4 g of potassium hydroxide, the mixture was stirred, controlled chromatographically in system V. After 24 hours, 4 ml of water, acidified with hydrochloric acid was added and the solvent was evaporated to dryness. The resulting precipitate was filtered off on a Biichner funnel, washed with ethanol and dried. 1.08 mmol, 0.45g of light yellow contaminated recipitate was yielded.
• the compound was obtained by method F.
• the blocked compound (3 mmol) was dissolved in ethanol (10 ml).
• ethanol 10 ml
• the flask was heated to about 110 ° C, water (10 ml) and sodium hydroxide (5 g) were added and then stirred overnight (16 hours) at room temperature. The next day, the mixture was heated for 0.5 hours, water was added (60 ml), then extracted four times with portions (20 ml) of methyl chloride. The combined organic fractions were dried overnight over anhydrous sodium sulfate VI.
• the aqueous phase was acidified with concentrated acetic acid to a pH of about 7.
• the precipitate was extracted three times with methylene chloride.
• the brown residue that was deposited on the walls of the separatory funnel was washed with about 10 ml of hot absolute ethanol.
• the compound was obtained by method D.
• the compound was obtained by method H.
• Ci 4 H 15 CIN 4 0 (M: 290,75)
• the compound was obtained by method F.
• %C theor.: 47.96, act.: 48.16
• %H theor.: 6.57, act.: 6.62
• %N theor.: 14.72, act.: 14.73.
• %C theor.: 57.99, act.: 58.00, %H: theor.: 6.26, act.: 6.32, %N: theor.: 12.88, act.: 12.67.
• %C theor.: 64.31, act.: 64.16, %H: theor.: 5.64, act.: 5.45, %N: theor.: 13.64, act.: 13.58.
• %C theor.: 55.56, act.: 55.58, %H: theor.: 5.83, act.: 5.65, %N: theor.: 12.96, act.: 12.93.
• Dylag T. Zygmunt M., Maciag D., Handzlik J., Bednarski M., Filipek B., Kiec-Kononowicz K. : Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives, Eur. J.

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• 2012
  • 2012-04-03 PL PL398703A patent/PL223830B1/pl unknown
• 2013
  • 2013-04-02 WO PCT/PL2013/000044 patent/WO2013151450A1/fr not_active Ceased

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