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US20140323763A1 - Antibacterial and antifungal substances biphenylyl compounds - Google Patents

Antibacterial and antifungal substances biphenylyl compounds Download PDF

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Publication number
US20140323763A1
US20140323763A1 US13/995,261 US201113995261A US2014323763A1 US 20140323763 A1 US20140323763 A1 US 20140323763A1 US 201113995261 A US201113995261 A US 201113995261A US 2014323763 A1 US2014323763 A1 US 2014323763A1
Authority
US
United States
Prior art keywords
substance
group
chain length
carbon atoms
antibacterial
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/995,261
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English (en)
Inventor
Franz Furkert
Bernd Clement
Britta Gerig
Dieter Heber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Christian Albrechts Universitaet Kiel
Original Assignee
Christian Albrechts Universitaet Kiel
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Christian Albrechts Universitaet Kiel filed Critical Christian Albrechts Universitaet Kiel
Assigned to CHRISTIAN-ALBRECHTS-UNIVERSITY OF KIEL reassignment CHRISTIAN-ALBRECHTS-UNIVERSITY OF KIEL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CLEMENT, BERND, GERIG, Britta, HEBER, DIETER, FURKERT, Franz
Publication of US20140323763A1 publication Critical patent/US20140323763A1/en
Abandoned legal-status Critical Current

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • the invention relates to antibacterial and antimycotic active substances and their use for production of pharmaceutical compositions.
  • Methicillin-resistant germs represent a specific problem; if a Staphylococcus aureus is methicillin-resistant (so-called MRSA) often resistances against antibiotics of other groups (quinolones, tetracyclines, aminoglycosides, erythromycins, sulfonamides) are displayed.
  • MRSA methicillin-resistant
  • the problem underlying the present invention is to provide new compounds which are effective against various bacteria and fungi, especially against those which are already showing multidrug resistance and in this context are suitable as pharmaceutical agents.
  • R 1 , R 2 and R 3 are hydrogen, an alkyl group having a chain length of 1-4 carbon atoms, (e.g. methyl (CH 3 )—, ethyl (CH 2 CH 3 )—, propyl (CH 2 CH 2 CH 3 )—, isopropyl (CHCH 3 CH 3 )—, butyl (CH 2 CH 2 CH 2 CH 3 )—, isobutyl (CHCH 3 CH 2 CH 3 )— or tert-butyl (CCH 3 CH 3 CH 3 )— group), an alkoxy group having a chain length of 1-3 carbon atoms (e.g.
  • R 4 and R 5 are hydrogen or an alkyl group having a chain length of 1-4 carbon atoms (e.g.
  • Table 1 shows the values of the minimum inhibitory concentration (MIC) of the substances of the present invention.
  • the minimum inhibitory concentration is the lowest concentration of the tested substance which completely inhibits the growth of each test organism, i.e. wherein after incubation the turbidity is not measurable.
  • the relevant determination is valid if the growth control (DMSO and medium) a distinct turbidity is shown.
  • Staphylococcus aureus S. a. methicillin-resistent Staphylococcus aureus MRSA, Escherichia coli E. c., Pseudomonas aeroginosa P. a., Staphylococcus epidermis S. e., Candida albicans C. a., Enterococcus hirae E. h., Aspergillus niger A. n., Aspergillus fumigatus A. f., n. b. not defined.
  • GG20-4 4 11 (5) 16 64 8 GG20-5 8 n. b. n. b. n. b. GG 28 8 (2) n. b. n. b. n. b. *for identification of multiple testings: Representation of rounded average values of logarithmic endpoints, number of tests in brackets.
  • a particular advantage of the compounds of the present invention is their high solubility in water. This is a major benefit in the use of the substances as a drug because on the one hand, the oral bioavailability of the drug is increased, on the other hand the administration by injection of aqueous solutions is possible.
  • 100 mg of the compound GG20-4 (see Table 1) could be dissolved in 10 ml of distilled water, wherein the person skilled in art knows that pharmaceuticals are typically administered in combination with pharmaceutically acceptable excipients.
  • Another example for substances according to the present invention is the compound 4-bromo-4′-(4-dimethylaminobutyl)biphenylhydrochloride 2 (GG28). This substance is not known in the literature and also has both antibacterial and antifungal activity.
  • the synthesis of the antimicrobial and antifungal active substances of the present invention are shown in Scheme 1 and 2. They can be produced by conventional methods.
  • the compound 2 was obtained based on the compound 1 in the sense of a Wolff-Kishner-Reduction following by the Huang-Minlon-Variant:
  • the basic biphenyls of the present invention represent high effective inhibitors of the growth of bacteria and fungi. They can be easily and economically synthesized by standard methods with high purity. Accordingly, the present invention provides compounds for inhibiting the growth of bacteria and/or fungi and, consequently, drugs for the treatment of infections of bacteria and/or fungi.
  • the substances of the present invention can also be used as laboratory reagents for inhibiting the growth of bacteria and/or fungi in cell culture, similar as described for the selection marker system neomycin and neomycin-phosphotransferase system.
  • the melting points of the synthesized substances were measured with the melting point apparatus Büchi 510 device and microhotplate Thermovar (Company Reichert).
  • the NMR spectra were measured with the nuclearmagneticresonancespectrometer Bruker ARX 300 and the IR spectra (as KBr-Presslinge) with a Perkin-Elmer FT-IR 16 PC spectrometer.
  • the mass spectra were measured with a device of type Hewlett-Packard 5989.
  • Elementary analysis was perfomed in the Institute of Inorganic Chemistry, of the CAU Kiel using a CHNS-analyzator of the company Hekatech GmbH. Unless otherwise stated, the chemicals including vancomycin-HCl and tetracycline-HCl at the highest purity were purchased at the company Sigma-Aldrich GmbH.
  • the minimum inhibitory concentrations of the substances of the present inventions against various infectious germs i.a. against methicillin-resistant Staphylococcus aureus were determined with the Bouillon-microdilutionmethod in accordance with the procedure M07-A8 of the Clinical and Laboratory Standards Institute (Pennsylvania, USA).
  • the long-term cultures of the test organisms are incubated at titled agar at 22° C. and each inoculated after 4 weeks on fresh medium. After every fifth culture passage or ascertainment of impurities to the correspondent culture is discarded and newly grown from the lyophilized.
  • Suspensions are produced on titled agar by floating with 0.9% sterile NaCl solution.
  • the turbidity is adjusted photometrically by dilution according to the turbidity of the Mc Farland-standard 0.5.
  • the bacterial suspensions are diluted in the ratio of 1:10, the Pi-suspension of the fungi remains undiluted.
  • the number of the germs in the inocula is adjusted so that there are approximately 5 ⁇ 10 5 colony forming units per milliliter after inoculation of the test wells.
  • the amount of a substance to be tested in a trial is weighed out on a microbalance with an Eppendorf reaction vessel and dissolved in an appropiate volume of dimethyl sulfoxide so that the concentration of the resulting solution corresponds to the 21 times highest final test concentration.
  • the stock solution is subsequently diluted in a serial in a ratio respectively 1 ad 2 with DMSO resulting in seven different concentrations in the wells of a predilutionplate. In the eighth well only DMSO is pipetted.
  • the inocula are pipetted in the test wells using an eight-channel pipette.
  • the concentrations of the test substance are each 128 ⁇ g/mL to 2 ⁇ g/mL.
  • the prepared plates are converted to a microtiter plate reader (Anthos htlll) which is connected to a printer.
  • the plates are shaken for 60 seconds with high frequency before each measurement and the absorption of the probes is measured at the wavelength of light of 590 nm.
  • the plates are incubated at 34° C. for 16 to 20 h for bacteria and Candida albicans , and 68 to 72 h at 34° C. for mould fungis.
  • microtiterplates are measured again as described above.
  • the minimum inhibitory concentration is the lowest concentration of the tested substance which is able to inhibit the complete growth of the particular test organism, i.e. where after incubation no turbidity is measurable.
  • the particular determination is valid whether in the growth control (DMSO and medium) a distinct turbidity is observed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US13/995,261 2010-12-21 2011-12-21 Antibacterial and antifungal substances biphenylyl compounds Abandoned US20140323763A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102010055322A DE102010055322A1 (de) 2010-12-21 2010-12-21 Antibakteriell und antimykotisch wirkende Substanzen
DE102010055322.0 2010-12-21
PCT/EP2011/073601 WO2012085092A1 (fr) 2010-12-21 2011-12-21 Composés biphénylyle substances à action antibactérienne et antimycotique

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/073601 A-371-Of-International WO2012085092A1 (fr) 2010-12-21 2011-12-21 Composés biphénylyle substances à action antibactérienne et antimycotique

Related Child Applications (1)

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US14/738,221 Division US9693974B2 (en) 2010-12-21 2015-06-12 Antibacterial and antifungal biphenylyl compounds

Publications (1)

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US20140323763A1 true US20140323763A1 (en) 2014-10-30

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US13/995,261 Abandoned US20140323763A1 (en) 2010-12-21 2011-12-21 Antibacterial and antifungal substances biphenylyl compounds
US14/738,221 Expired - Fee Related US9693974B2 (en) 2010-12-21 2015-06-12 Antibacterial and antifungal biphenylyl compounds

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Country Status (4)

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US (2) US20140323763A1 (fr)
EP (1) EP2654740B1 (fr)
DE (1) DE102010055322A1 (fr)
WO (1) WO2012085092A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4289272A4 (fr) * 2021-02-02 2024-07-17 Korea Research Institute of Bioscience and Biotechnology Adjuvant antimicrobien contenant un composé dérivé du biphényle en tant que principe actif, et utilisations de celui-ci

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994365B2 (en) * 2006-07-07 2011-08-09 Christian-Albrechts-Universitaet Zu Kiel Basic acetophenones as inhibitors of NO-synthases

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1523655A (en) * 1975-02-10 1978-09-06 Armour Pharma 4-(4-biphenylyl) butylamines and treatment of the animal organism therewith
US4055664A (en) * 1975-02-10 1977-10-25 Armour Pharmaceutical Company Pharmaceutical preparations containing 4-(4-biphenylyl) butylamines and treatment of the animal organism therewith
CA2044533A1 (fr) * 1990-06-29 1991-12-30 Philippe Guerry Derives aminoalkylbiphenyliques substitues
US5527780A (en) * 1992-11-05 1996-06-18 Roussel Uclaf Erythromycin derivatives
AU3012699A (en) * 1998-03-26 1999-10-18 Department Of The Army, U.S. Government Substituted aromatic compounds for treatment of antibiotic resistant infections
GB9810299D0 (en) * 1998-05-15 1998-07-15 Glaxo Group Ltd Use of nitric oxide synthase inhibitors
CA2247675C (fr) * 1998-09-17 2009-05-05 Pola Chemical Industries, Inc. Antifongiques
DE19937537A1 (de) * 1999-08-09 2001-03-08 Gruenenthal Gmbh Substituierte 2-Dialkylaminoalkylbiphenyl-Derivate
WO2009079549A2 (fr) 2007-12-17 2009-06-25 Massachusetts Institute Of Technology Inhibiteurs de l'oxyde nitrique synthase bactérienne et procédés de criblage apparentés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994365B2 (en) * 2006-07-07 2011-08-09 Christian-Albrechts-Universitaet Zu Kiel Basic acetophenones as inhibitors of NO-synthases

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAS No. 34762-69-1 (Entered in STN Registry on November 16, 1984). *
Klein et al., "Snthese, Pharmacological and Biophysical Characterization, and Membrane-Interaction QSAR Analysis of Cationic Amphiphilic Model Compounds," J. Med. Chem., 1999, 42, 3874-3888. *
Patani et al., "Bioisoterism: A Rational Approach in Drug Design," Chem. Rev. 1996, 96, 3147-3176. *

Also Published As

Publication number Publication date
DE102010055322A1 (de) 2012-06-21
EP2654740A1 (fr) 2013-10-30
US9693974B2 (en) 2017-07-04
WO2012085092A1 (fr) 2012-06-28
EP2654740B1 (fr) 2015-02-11
US20150272910A1 (en) 2015-10-01

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Owner name: CHRISTIAN-ALBRECHTS-UNIVERSITY OF KIEL, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLEMENT, BERND;FURKERT, FRANZ;GERIG, BRITTA;AND OTHERS;SIGNING DATES FROM 20130731 TO 20130821;REEL/FRAME:031108/0292

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION