WO2017069661A1 - Pyrimidyl-di(diazaspiro-alcanes) présentant une activité antivirale - Google Patents

Pyrimidyl-di(diazaspiro-alcanes) présentant une activité antivirale Download PDF

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Publication number
WO2017069661A1
WO2017069661A1 PCT/RU2016/050040 RU2016050040W WO2017069661A1 WO 2017069661 A1 WO2017069661 A1 WO 2017069661A1 RU 2016050040 W RU2016050040 W RU 2016050040W WO 2017069661 A1 WO2017069661 A1 WO 2017069661A1
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diyl
compound
compounds
mol
added
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PCT/RU2016/050040
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Vadim Albertovich MAKAROV
Vladimir Georgievich Nesterenko
Roman Nikolaevich BOLGARIN
Elena Alexandrovna NOVOSELOVA
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Limited Liability Company “Nearmedic Plus”
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Publication of WO2017069661A1 publication Critical patent/WO2017069661A1/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
    • C07D487/12—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 three hetero rings
    • C07D487/20—Spiro-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
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to novel biologically active py ri mi dyl -di ( di azaspi ro- alkane) derivatives of general formula (I), a pharmaceutically acceptable salt thereof, which exhibit activity against various viruses, a method for preparing and use thereof as antiviral agents.
  • the problem of searching for novel antiviral agents is due to a significant spread of viral infections in humans and animals. This is associated with a decrease in the immune protection in the human population, and with broad-scale development of viral resistance to commercially available drugs.
  • the problem of rapid development of resistance is determined by the fact that in general, many used, known antiviral drugs are derivatives of one class of compounds, and by insufficient efficacy and toxicity of drugs.
  • H PV Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J Clin Invest. 2001, 108(4), 503-10 H PV (Selinka HC, Giroglou T, Sapp M. A nalysis of the infectious entry pathway of human papillomavirus type 33 pseudovirions, Virology, 2002, 1, 279- 287; Selinka HC, Giroglou T, Nowak T, Christensen ND, Sapp M.
  • H CMV Hetereschke R., Woskobojnik I., Makarov V ., Schmidtke M., Bogner E . DST P-27 prevents entry of human cytomegalovirus. Antimicrob Agents Chemother. 2014, 58(4): 1963-1971
  • H IV strains Patel V, Ferguson M, Minor PD. Antigenic sites on type 2 poliovirus, V irology, 1993, 192, 361-4
  • RSV Hallak L K, Spillmann D, Collins PL, Peeples M E .
  • the target for diazoniadispiro-alkanes is two sulfate groups located on adjacent sugar residues, thus, for example, for GlcA2S-GlcNS6S, GlcA2S-GlcNS3S, IdoA2S-GlcNAc6S, IdoA2S-GlcNH23SS6S, IdoA2S-GlcNS6S, and IdoA2SGIcNS3S, and a good electrostatic interaction is observed between negative charges on the sulfate groups and positively charged nitrogen atoms of diazoniadispiro-alkanes.
  • the object of the present invention is to provide novel pharmacologically active compounds against viral infections, including strains resistant to currently available drugs, which would have a low toxicity, would not cause adverse effects in warm- blooded organisms, and would have mechanism of action that affect the process of viral invasion into a host cell by means of blocking heparan sulfate receptors of the target cell.
  • X and Y are ⁇ £3 ⁇ 4, or X is ⁇ S3 ⁇ 4 and Y is orX is ⁇ 3 ⁇ 4 ⁇ S3 ⁇ 4 and Y is ⁇ £3 ⁇ 4;
  • A represents pyri mi di ne-4,6-diyl or pyrimidine-2,4-diyl that can comprise H, N0 2 , CHO, OH, OAlk, halogen, NHAlk, or NA Ik 2 as a substituent; wherein Alk is a linear or branched substituent having 1 to 4 carbon atoms; and
  • Hal is a halogen atom.
  • Preferred compounds are compounds of formula (I), wherein
  • X and Y are ⁇ £3 ⁇ 4, or X is ⁇ S3 ⁇ 4 and Y is orX is ⁇ 3 ⁇ 4 ⁇ S3 ⁇ 4 and Y is CH 2 ;
  • A represents pyri mi di ne-4,6-diyl or pyri mi di ne-2,4-diyl that comprises CI, Br,
  • Hal is a halogen atom, chlorine or bromine.
  • Samples of such compounds are compounds of formula (I), wherein X is Y is ⁇ 3 ⁇ 4; A is py ri mi di ne-4, 6- di y I that can comprise H, N0 2 , or Alk as a substituenf Hal is a chlorine or bromine atom, and Alk is methyl,
  • X is ⁇ 3 ⁇ 4, Y is ⁇ is pyrimidine- 4,6-diyl that can comprise (3 ⁇ 4 N0 2 , or A lk as a substituent; Hal is a chlorine or bromine atom, and Alk is methyl.
  • the invention also relates to a pharmaceutically acceptable acid addition salt of said compounds.
  • the compounds can be prepared and used in a crystalline form.
  • Synthesized compounds of general formula I and their pharmaceutically acceptable acid or base addition salts have been studied against pathogenic viruses and can be used in the manufacture of medicaments for the treatment or prevention of viral diseases, for example, caused by human immunodeficiency virus, cytomegalovirus, hepatitis C or B virus, herpes virus type 1 and 2, and papillomatosis virus.
  • Fig.1 Compounds 3 and 11 were studied in PsV experiment with HeLaT cells. Two concentrations of each compound were added simultaneously with H PV 16-PsVs virus and were compared with untreated cells. The luciferase activity was measured at 48 hpi.
  • salts of compounds of formula (I) means any salts of an inorganic or organic acid or base, which have a required pharmacological activity of the initial compound. These salts can be prepared in situ during the synthesis, isolation or purification of a compound of formula (I) or can be specially prepared.
  • compositions of formula I are characterized by that they comprise therapeutically active non-toxic addition salt forms with acids which are able to form compounds of formula I.
  • Said addition salts with acids can be prepared by the treatment of compounds, in base form, represented by general formula I by suitable acids, for example, inorganic acids: a hidrohalic acid, in particular, hydrochloric acid, hydrobromic acid; sulfuric acid, nitric acid, or phosphoric acid; and organic acids, for example: acetic acid, hydroxyacetic acid, propionic acid, lactic acid, piruvic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid, or citric acid.
  • suitable acids for example, inorganic acids: a hidrohalic acid, in particular, hydrochloric acid, hydrobromic acid; sulfuric acid, nitric acid, or phosphoric acid; and organic acids, for example: acetic acid, hydroxyacetic acid, propionic acid,
  • the invention also relates to use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, optionally, in a crystalline form, or a pharmaceutical composition based thereon in the manufactory of a medicament for the preventi on or treatment of vi ral i nf ecti ons.
  • Another subject matter of the invention is a method for preventing or treating a viral infection, comprising administering or applying to a subject a compound of formula (I), a pharmaceutically acceptable acid addition salt or a pharmaceutical composition based thereon, in an effective amount.
  • a method for treating with the claimed compounds, a pharmaceutical composition or a medicament based thereon also is effective against strains resistant to currently available medicaments.
  • Benzoyl-piperazine hydrochloride in an amount of 18 g (0.0795 mol) was added to a solution of 5.34 g (0.0954 mol) of KOH in 55 mL of ethanol and stirred at 20-22eC for 0.5 h. Then, 13.3 mL (0.199 mol) of ethylene chlorohydrin was added thereto, and a solution of 11.6 g (0.207 mol) of K OH in 98 mL of ethanol (rectificate) was added by drops for one hour, avoiding an increase in temperature higher than 20eC. After 20 hours, the formed KCI was filtered off, washed with 25 mL of absolute ethanol.
  • the yield of a white crystalline compound was 37%.
  • 1-Benzoylpiperazine hydrochloride 3 (0.014 mol) was suspended in 5 mL of ethanol, and a solution of NaOH (0.017 mol) in 15 mL of ethanol was added thereto. The mixture was stirred for 1 h. NaCI was filtered off, the stock solution was evaporated, chloroform was added, NaCI was filtered off once more, and chloroform was evaporated.
  • 1-Benzoylpiperazine was obtained in the form of oil with a yield of 95%.
  • a mixture of 1 -benzoyl pi perazine 4 (0.035 mol), 1,3-dibromopropane (0.0175 mol), and sodium bicarbonate (0.056 mol) was boiled in 60 mL of ethanol for 16 h.
  • the precipitated residue was filtered and washed with methanol, tetrahydrofuran, and acetone.
  • the product was obtai ned i n an amount of 0.16 g.
  • T he product was dri ed at 100e ⁇ f or 20 h.
  • the yield of a white crystalline compound was 23%.
  • the solution was decanted, 15 mL of methanol and 5 mL of acetone were added to the remaining oil, and the precipitated residue was filtered off and washed with methanol, tetrahydrofuran, and acetone.
  • the product was obtai ned i n an amount of 0.15 g. T he product was dri ed at 100e ⁇ f or 20 h.
  • Glacial acetic acid in an amount of 25 mL was added to 5.37 g (0.0537 mol) of homopiperazine under cooling with iced water, while the temperature increased up to 40-50eC. When the temperature decreased to 20e(3 ⁇ 4 the cooling was stopped. The suspension was stirred to complete dissolution of homopiperazine (about 2 h). Then the solution was cooled to 51C (ice bath), and 6.27 mL (0.0537) of benzoyl chloride were slowly dropped (45 min) so that the temperature of the mass was not higher than 10tC. Then, the solution was stirred at room temperature for 3 h. Acetic acid was evaporated in a rotary evaporator at 80tC.
  • the volume of distillation was 15-16 mL, which corresponded to the 2/3 volume of acetic acid used in the reaction.
  • the residue which was viscous oil, was diluted with 50 mL of water, cooled in ice bath to 151C under stirring, and alkalized with a 40% solution of NaOH (20 mL) to pH 8-8.5.
  • the precipitated by-product of 1,4-dibenzoyldiazepine was filtered off, and the stock solution was extracted with chloroform (3x40 mL).
  • the pH value of the aqueous layer was checked. If the pH value was lower than 7, it was alkalized once more to pH of 8- 8.5 and extracted with chloroform (2x40 mL). Combined chloroform extracts were dried over Na 2 S04. Chloroform was evaporated to obtain 7.13 g (65%) of 1 -benzoyl - 1,4-diazepine in the form of oil.
  • the yield a fawn-colored crystalline compound was 40%.
  • the yield a fawn-colored crystalline compound was 6%.
  • 2x1 ⁇ 4 GMK cells were cultured in a 96- well flat- bottom microtiter plate (Falcon 3075).
  • the cytotoxicity of the studied compositions was determined by confluent monol ayers of G M K eel I s, formed i n 60 wel I s ( 5% C 0 2 , 37eC ) .
  • W hen monol ayers were removed from the nutrient medium, 100 mL of the nutrient medium were added to nine twice-diluted compositions, and the latter were incubated for 72 h at 371C in 5% C0 2 .
  • the cells from six wells were used as control without treatment.
  • a Dynex immunoassay system (DIAS, Guernsey, Great Britain), which had been developed for an automated E L ISA method, was used for careful purification, staining, measurement, and evaluation of the viability of the cell monolayers in a cytotoxic preparation, and in an antiviral assay.
  • the staining to evaluate T NF cytotoxical activity was carried out by using crystal violet as disclosed in Nain et al. (1990). At first, the supernatant was aspirated, and the cell monolayers were washed three times with 300 mL of a physiological sodium chloride solution to remove dead cells.
  • the cells were fixed and washed one time with 50 mL of a 0.003% solution of crystal violet (w/v) in 20% methanol for 10 min. After six subsequent washings with 100 mL of water, the monolayers were treated with a lysis buffer (a solution of 0.8979 of sodium citrate and 1.25 mL of 1 N HCI in 98.05 mL of 47.5% ethanol) for 20 min to eluate crystal violet.
  • a lysis buffer a solution of 0.8979 of sodium citrate and 1.25 mL of 1 N HCI in 98.05 mL of 47.5% ethanol
  • the viability of the cells was measured as a percentage ratio to the mean optical density based on the results of measuring six wells, which was taken as 100%.
  • the cytotoxic concentration decreasing the cell viability by 50% was calculated from a dose-effect curve of the mean values of two paral I el probes i n three sharp es.
  • the antiviral activity was studied according to the method disclosed earlier ( ⁇ . Schmidtke, U. Thomasler, CD J ahn, H.-M. Dahse, A. Stelzner, A rapid assay for evaluation of antiviral activity against coxsackie virus B3, influenza virus A, and herpes simplex virus type 1, J ournal of V irological Methods 95 (2001) 133-143).
  • the confluent monolayers of cells formed for two days in 6-well plates were inoculated with 1 mL of a viral suspension of a corresponding virus in a nutrient medium on GM K cells, which comprises about 100 mL of plaque-forming units (PFU) in the absence and presence of the studied compositions twice diluted.
  • PFU plaque-forming units
  • the seed material was aspirated and mixed with 2 mL of a corresponding growth solution comprising 0.4% agar and a drug at a corresponding concentration.
  • Three untreated control probes of viruses and one non-infected untreated control cell were also studied. The concentrations of the components were determined by duplicating measurements.
  • the probes were incubated at 371C for 72 h until platelets were detected and then fixed and washed with a 0.4% solution of crystal violet in a mixture of formalin (3% of v/v) and ethanol (1.67% v/v) in water.
  • the platelets were counted by using a negatoscope after their removal from agar application.
  • a dependence curve of the mean platelet count in two comparative treated wells at each concentration versus the platelet counts in three untreated virus-infected wells was plotted.
  • the concentration at which the platelet count reduces by 50% (IC50) was calculated from a dose-effect curve for the latest values in three tests of platelet reduction.
  • E C 50 is a concentration of the compounds, providing 50% protection of cells against death
  • CC50 is a concentration resulting in 50% death of cells
  • MDBK cells against death caused by BV DV virus as defined by the MTT assay.
  • 6-Aza-uridine >100 >100 1.4 >0.3
  • the antiviral activity of pyrimidyl-di(diazadispiro-alkanes) of formula (I) against papillomavirus infection was studied by the method based on Pseudovirus-based neutralization Assay (PsV Assay) with H PV 16-PsVs virus that delivers a plasmid encoding Gaussia L uciferase in HeLaT cells in DME M. This method is described in (Selinka et al., J V irol, 2007, 81(20): 10970-80, Inhibition of transfer to secondary receptors by heparan sulfate- binding drug or antibody induces noninfectious uptake of human papillomavirus).
  • Both studied compounds significantly reduced luciferase activity that characterizes PsV infection. They inhibit completely the viral penetration at a concentration of 5 ⁇ g/mL when compounds were added together with the virus (p ⁇ 0.001).
  • compound 3 was used at a concentration of 0.5 ⁇ g/mL, the inhibition of papillomavirus penetration into a cell was more significant than for compound 11, but, in any case, at a concentration of 0.5 ⁇ g/mL, both compounds significantly reduced the infection of a cell with the virus as compared with the cells untreated with a preparation (p ⁇ 0.0001).

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  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne de nouveaux dérivés de pyrimidyl-di(diazaspiro-alcane) de formule (I) ou leur sel d'addition d'acide pharmaceutiquement acceptable. Les composés présentent un large spectre d'activité antivirale contre le virus de l'herpès, le virus de l'immunodéficience humaine, le papillomavirus et le virus de l'hépatite. L'invention concerne également l'utilisation des composés de formule (I), leur procédé de préparation et une méthode de traitement utilisant les composés revendiqués. La formule générale est : (I) A représente un groupe pyrimidine-4,6-diyle ou pyrimidine-2,4-15-diyle qui peut comprendre un atome H, NO2, CHO, OH, OAlk, un atome d'halogène, NH (Alk) ou N(Alk)2 comme substituant ; Hal représente un atome de chlore ou de brome ; Alk représente un substituant linéaire ou ramifié comportant de 1 à 4 atomes de carbone.
PCT/RU2016/050040 2015-10-20 2016-09-21 Pyrimidyl-di(diazaspiro-alcanes) présentant une activité antivirale WO2017069661A1 (fr)

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RU2015144872A RU2633699C2 (ru) 2015-10-20 2015-10-20 Пиримидил-ди(диазадиспироалкан)ы с противовирусной активностью

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308960A1 (fr) * 2008-06-18 2011-04-13 Kyoto University Agent promoteur de l adhésion cellulaire et procédé destiné à promouvoir l adhésion cellulaire
WO2013168807A1 (fr) * 2012-05-11 2013-11-14 国立大学法人京都大学 Additif pour suspension de cellule de greffon et composition thérapeutique
WO2015167368A1 (fr) * 2014-04-30 2015-11-05 Limited Liability Company "Nearmedic Plus" Hexahydrate de dichlorhydrate de tétrachlorure de 4,6-di(3,12-diaza-6,9-diazoniadispiro[5.2.5.2]hexadécan-1-yl)-2-méthyl-5-nitropyrimidine utilisé pour pour le traitement de l'infection herpétique et composition pharmaceutique topique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH502760A (de) * 1967-01-04 1971-02-15 Basf Ag Mittel zur Hemmung des Pflanzenwachstums und zur Änderung des Pflanzenhabitus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308960A1 (fr) * 2008-06-18 2011-04-13 Kyoto University Agent promoteur de l adhésion cellulaire et procédé destiné à promouvoir l adhésion cellulaire
WO2013168807A1 (fr) * 2012-05-11 2013-11-14 国立大学法人京都大学 Additif pour suspension de cellule de greffon et composition thérapeutique
WO2015167368A1 (fr) * 2014-04-30 2015-11-05 Limited Liability Company "Nearmedic Plus" Hexahydrate de dichlorhydrate de tétrachlorure de 4,6-di(3,12-diaza-6,9-diazoniadispiro[5.2.5.2]hexadécan-1-yl)-2-méthyl-5-nitropyrimidine utilisé pour pour le traitement de l'infection herpétique et composition pharmaceutique topique

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ARTEMENKO I A.G.; MURATOV E.N.; KUZ'MIN V.E.; KOVDIENKO N.A.; HROMOV A.I.; MAKAROV V.A.; RIABOVA O.B.; WUTZLER P.; SCHMIDTKE M: "Identification of individual structural fragments of N,N'-(bis-5-nitropyrimidyl)dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds.", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 60, no. 1, 2007, pages 68 - 77
ARTEMENKO, A.G.; MURATOV, E.N.; KUZ'MIN, V.E.; KOVDIENKO, N.A.; HROMOV, A.I.; MAKAROV, V.A.; RIABOVA, O.B.; WUTZLER, P.; SCHMIDTKE: "Identification of individual structural fragments of NN'-(bis-5-nitropyrimidyl)dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 60, 2007, pages 68 - 77
DONALISIO M; RUSNATI M; CAGNO V; CIVRA A; BUGATTI A; GIULIANI A; PIRRI G; VOLANTE M; PAPOTTI M; LANDOLFO S: "Inhibition of human respiratory syncytial virus infectivity by a dendrimeric heparan sulfate-binding peptide", ANTIMICROB AGENTS CHEMOTHER., vol. 56, 2012, pages 5278 - 88
HALLAK LK; SPILLMANN D; COLLINS PL; PEEPLES ME.: "Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection", J VIROL, vol. 74, 2000, pages 10508 - 13
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M. SCHMIDTKE; U. SCHNITTLER; B. JAHN; H.-M. DAHSE; A. STELZNER: "A rapid assay for evaluation of antiviral activity against coxsackie virus B3, influenza virus A, and herpes simplex virus type 1", JOURNAL OF VIROLOGICAL METHODS, vol. 95, 2001, pages 133 - 143
PAESCHKE R.; WOSKOBOJNIK I.; MAKAROV V.; SCHMIDTKE M.; BOGNER E.: "DSTP-27 prevents entry of human cytomegalovirus.", ANTIMICROB AGENTS CHEMOTHER., vol. 58, no. 4, 2014, pages 1963 - 1971
PAESCHKE R.; WOSKOBOJNIK L; MAKAROV V.; SCHMIDTKE M.; BOGNER E.: "DSTP-27 prevents entry of human cytomegalovirus", ANTIMICROB AGENTS CHEMOTHER., vol. 58, 2014, pages 1963 - 1971
PATEL V; FERGUSON M; MINOR PD.: "Antigenic. sites on type 2 poliovirus", VIROLOGY, vol. 192, 1993, pages 361 - 4
SCHMIDTKE M ET AL: "Synthesis, cytotoxicity and antiviral activity of N,N'-bis-5- nitropyrimidyl derivatives of dispirotripiperazine", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 55, no. 1, 1 July 2002 (2002-07-01), pages 117 - 127, XP008141707, ISSN: 0166-3542, [retrieved on 20020219], DOI: 10.1016/S0166-3542(02)00014-1 *
SCHMIDTKE M.; RIABOVA O.; DAHSE H.-M.; STELZNER A.; MAKAROV V.: "Synthesis, Cytotoxicity and Antiviral Activity of N,N'-bis-5-nitropyrimidyl Derivatives of Dispirotripiperazine", ANTIVIRAL RESEARCH, vol. 55, 2002, pages 117 - 127
SCHMIDTKE, M.; WUTZLER, P.; MAKAROV, V.: "Novel opportunities to study and block interactions between viruses and cell surface heparan sulfates", LETT. DRUG DESIGN DISCOV., vol. 1, 2004, pages 35 - 44
SELINKA ET AL., J VIROL, vol. 81, no. 20, 2007, pages 10970 - 80
SELINKA HC; GIROGLOU T; NOWAK T; CHRISTENSEN ND; SAPP M.: "Further evidence that papillomavirus capsids exist in two distinct conformations", J VIROL., vol. 77, 2003, pages 12961 - 7
SELINKA HC; GIROGLOU T; SAPP M.: "Analysis of the infectious entry pathway of human papillomavirus type 33 pseudovirions", VIROLOGY, vol. 1, 2002, pages 279 - 287
SHUKLA D.; SPEAR P.G.: "Herpesviruses and heparan . sulfate: an intimate relationship in aid of viral entry", J CLIN INVEST, vol. 108, no. 4, 2001, pages 503 - 10
TAN CW; CHAN YF.: "Enterovirus 71 receptors: promising drug targets?", EXPERT REV ANTI INFECT THER., vol. 11, 2013, pages 547 - 9

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