HUP0102607A2 - Szulfonilcsoporttal szubsztituált bifenil-metil-imidazol-származékok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk - Google Patents

Szulfonilcsoporttal szubsztituált bifenil-metil-imidazol-származékok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk

Info

Publication number
HUP0102607A2
HUP0102607A2 HU0102607A HUP0102607A HUP0102607A2 HU P0102607 A2 HUP0102607 A2 HU P0102607A2 HU 0102607 A HU0102607 A HU 0102607A HU P0102607 A HUP0102607 A HU P0102607A HU P0102607 A2 HUP0102607 A2 HU P0102607A2
Authority
HU
Hungary
Prior art keywords
group
hydrogen atom
alkyl group
phenyl
atom
Prior art date
Application number
HU0102607A
Other languages
English (en)
Inventor
Heinz-Werner Kleemann
Hans Jochen Lang
Stefan Petry
Jan-Robert Schwark
Andreas Weichert
Original Assignee
Aventis Pharma Deutschland Gmbh.
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 Aventis Pharma Deutschland Gmbh. filed Critical Aventis Pharma Deutschland Gmbh.
Publication of HUP0102607A2 publication Critical patent/HUP0102607A2/hu
Publication of HUP0102607A3 publication Critical patent/HUP0102607A3/hu

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/64Heterocyclic 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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/66Heterocyclic 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
    • C07D233/70One oxygen atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/06Antiarrhythmics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/66Heterocyclic 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
    • C07D233/68Halogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/66Heterocyclic 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
    • C07D233/88Nitrogen atoms, e.g. allantoin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/66Heterocyclic 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
    • C07D233/90Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/66Heterocyclic 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
    • C07D233/91Nitro radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A találmány szerinti antiaritmiás hatású vegyületek (I) általánosképletében R(1) jelentése hidrogénatom, alkilcsoport vagy -CaH2a-fenilképletű csoport, amely fenilrészében adott esetben szubsztituálvalehet, ahol a értéke 0, 1 vagy 2, vagy R(1) jelentése -CbH2b-heteroaril képletű csoport, amely heteroarilrészében adott esetbenszubsztituálva lehet, ahol b értéke 0, 1 vagy 2, vagy R(1) jelentése -CdH2d-cikloalkil képletű csoport, ahol d értéke 0, 1 vagy 2, R(2) ésR(3) jelentése egymástól függetlenül hidrogénatom, fluoratom,klóratom, brómatom, jódatom, trifluor-metil-csoport, cianocsoport,nitrocsoport, -CH2OR(17), -CO-R(6), -O-R(7), -O-(alkilén)-O-R(17) vagy-NR(50)R(51) általános képletű csoport, ahol R(17) jelentésehidrogénatom vagy alkilcsoport, R(6) jelentése hidrogénatom,alkilcsoport, -OR(30) általános képletű csoport vagy fenilcsoport,amely adott esetben szubsztituálva lehet, ahol R(30) jelentésehidrogénatom vagy alkilcsoport, R(50) és R(51) jelentése egymástólfüggetlenül -(alkilén)-O-R(52) általános képletű csoport, ahol R(52)jelentése hidrogénatom vagy alkilcsoport, R(7) jelentése hidrogénatom,alkilcsoport vagy fenilcsoport, amely adott esetben szubsztituálvalehet, vagy R(7) jelentése heteroarilcsoport, amely adott esetbenszubsztituálva lehet, vagy R(2) és R(3) jelentése egymástólfüggetlenül alkilcsoport, cikloalkilcsoport vagy -CgH2g-fenil képletűcsoport, amely fenilrészében adott esetben szubsztituálva lehet, aholg értéke 0, 1 vagy 2, vagy R(2) és R(3) jelentése egymástólfüggetlenül -ClH2l-heteroaril képletű csoport, amelyheteroarilrészében adott esetben szubsztituálva lehet, ahol l értéke0, 1 vagy 2, vagy R(2) és R(3)jelentése egymástól függetlenül -SOn-R(22) általános képletű csoport, ahol n értéke 0, 1 vagy 2, R(22)jelentése alkilcsoport, cikloalkilcsoport vagy -CsH2s-fenil képletűcsoport, amely fenilrészében adott esetben szubsztituálva lehet, ahols értéke 0, 1 vagy 2, R(4) és R(5)jelentése egymástól függetlenülhidrogénatom, alkilcsoport, fluoratom, klóratom, brómatom, jódatom,trifluor-metil-csoport, cianocsoport, nitrocsoport, -SOp-R(16), -CO-R(23), -O-R(24) vagy -O-(alkilén)-O-R(33) általános képletű csoport,ahol p értéke 0, 1 vagy 2, R(16) jelentése alkilcsoport vagyfenilcsoport, amely adott esetben szubsztituálva lehet, ahol R(23)jelentése hidrogénatom, alkilcsoport vagy -OR(25) általános képletűcsoport, ahol R(25) jelentése hidrogénatom vagy alkilcsoport, R(24)jelentése hidrogénatom, alkilcsoport vagy fenilcsoport, amely adottesetben szubsztituálva lehet, R(33) jelentése hidrogénatom vagyalkilcsoport, azzal a megszorítással, hogy R(2) és R(3) közül legalábbaz egyik jelentése -O-(2, 3 vagy 4 szénatomos alkilén)-O-R(17) vagy -NR(50)R(51) általános képletű csoport. A találmány kiterjed a fentivegyületek fiziológiailag alkalmazható sóira és a fenti
HU0102607A 1998-07-18 1999-07-10 Imidazole derivatives with sulfonyl biphenyl methyl pharmautical compositions containing them and their use HUP0102607A3 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19832428A DE19832428A1 (de) 1998-07-18 1998-07-18 Imidazolderivate mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
PCT/EP1999/004887 WO2000003996A1 (de) 1998-07-18 1999-07-10 Imidazolderivate mit biphenylsulfonylsubstitution, verfahren zu ihrer herstellung, ihre verwendung als medikament oder diagnostikum

Publications (2)

Publication Number Publication Date
HUP0102607A2 true HUP0102607A2 (hu) 2002-03-28
HUP0102607A3 HUP0102607A3 (en) 2002-05-28

Family

ID=7874574

Family Applications (1)

Application Number Title Priority Date Filing Date
HU0102607A HUP0102607A3 (en) 1998-07-18 1999-07-10 Imidazole derivatives with sulfonyl biphenyl methyl pharmautical compositions containing them and their use

Country Status (19)

Country Link
US (1) US6369236B1 (hu)
EP (1) EP1097141B1 (hu)
JP (1) JP4567885B2 (hu)
KR (1) KR20010071957A (hu)
CN (1) CN1211370C (hu)
AR (1) AR019405A1 (hu)
AT (1) ATE362920T1 (hu)
AU (1) AU764438B2 (hu)
BR (1) BR9912241A (hu)
CA (1) CA2338059A1 (hu)
DE (2) DE19832428A1 (hu)
HK (1) HK1038743A1 (hu)
HU (1) HUP0102607A3 (hu)
ID (1) ID27774A (hu)
PL (1) PL345585A1 (hu)
RU (1) RU2246488C2 (hu)
TR (1) TR200100134T2 (hu)
WO (1) WO2000003996A1 (hu)
ZA (1) ZA200100278B (hu)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19832428A1 (de) 1998-07-18 2000-01-20 Hoechst Marion Roussel De Gmbh Imidazolderivate mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
DE19832429A1 (de) 1998-07-18 2000-01-20 Hoechst Marion Roussel De Gmbh Imidazolderivate mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
DE10206354A1 (de) * 2002-02-14 2003-08-28 Aventis Pharma Gmbh Verwendung von Inhibitoren des Natrium-abhängigen Chlorid-Bicarbonat-Austauschers zur Behandlung von thrombotischen und inflammatorischer Erkrankungen
US20030220383A1 (en) * 2002-02-14 2003-11-27 Aventis Pharma Deutschland Gmbh Use of inhibitors of the sodium-dependent chloride/bicarbonate exchanger for the treatment of thrombotic and inflammatory disorders
CA2691662A1 (en) 2007-07-02 2009-01-08 F. Hoffmann-La Roche Ag Imidazole derivatives as ccr2 receptor antagonists
JP5395905B2 (ja) 2008-09-02 2014-01-22 エルダー・ファーマシューティカルズ・リミテッド 抗炎症化合物
KR101044953B1 (ko) * 2009-01-07 2011-06-29 (주) 인우 코퍼레이션 이중분사노즐을 이용한 악취제거 시스템
CN106459105B (zh) * 2014-06-23 2021-05-07 日产化学工业株式会社 包含磺酰基键的硅烷化合物的制造方法
WO2018002673A1 (en) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Novel formulations of angiotensin ii receptor antagonists

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126342A (en) * 1990-10-01 1992-06-30 Merck & Co., Inc. Imidazole angiotensin ii antagonists incorporating acidic functional groups
CA2058198A1 (en) * 1991-01-04 1992-07-05 Adalbert Wagner Azole derivatives, process for their preparation, and their use
CA2109524A1 (en) * 1991-05-10 1992-11-11 Prasun K. Chakravarty Acidic aralkyl triazole derivatives active as angiotensin ii antagonists
TW215434B (hu) * 1992-03-07 1993-11-01 Hoechst Ag
US5310929A (en) * 1992-08-06 1994-05-10 E. I. Du Pont De Nemours And Company Prodrugs of imidazole carboxylic acids as angiotensin II receptor antagonists
FR2711367B1 (fr) * 1993-10-19 1995-12-01 Roussel Uclaf Nouveau procédé de préparation de dérivés soufrés de l'imidazole et les nouveaux intermédiaires obtenus.
FR2711368B1 (fr) * 1993-09-16 1996-01-05 Roussel Uclaf Nouveau procédé de préparation de dérivés soufrés de l'imidazole et les nouveaux intermédiaires obtenus.
FR2716882B1 (fr) 1994-03-04 1996-04-05 Roussel Uclaf Utilisation de dérivés de l'imidazole au traitement d'affections impliquant les récepteurs AT1 et AT2 de l'Angiotensine, certains de ces produits, leur préparation, compositions pharmaceutiques.
FR2716883B1 (fr) * 1994-03-04 1996-04-26 Roussel Uclaf Nouveaux dérivés tétrasubstitués de l'imidazole, leur préparation, nouveaux intermédiaires obtenus, leur application à titre de médicaments, compositions pharmaceutiques les renfermant.
DE19540995A1 (de) * 1995-11-03 1997-05-07 Hoechst Ag Substituierte Sulfonimidamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
EP0855392A3 (de) * 1997-01-22 2000-01-05 Hoechst Aktiengesellschaft Fünfgliedrige Heterocyclen mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
DE19832428A1 (de) 1998-07-18 2000-01-20 Hoechst Marion Roussel De Gmbh Imidazolderivate mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
DE19832429A1 (de) 1998-07-18 2000-01-20 Hoechst Marion Roussel De Gmbh Imidazolderivate mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament

Also Published As

Publication number Publication date
CN1309645A (zh) 2001-08-22
BR9912241A (pt) 2001-04-10
EP1097141A1 (de) 2001-05-09
KR20010071957A (ko) 2001-07-31
AU5280799A (en) 2000-02-07
CN1211370C (zh) 2005-07-20
RU2246488C2 (ru) 2005-02-20
JP4567885B2 (ja) 2010-10-20
CA2338059A1 (en) 2000-01-27
ID27774A (id) 2001-04-26
AR019405A1 (es) 2002-02-20
PL345585A1 (en) 2001-12-17
HUP0102607A3 (en) 2002-05-28
JP2002520399A (ja) 2002-07-09
ATE362920T1 (de) 2007-06-15
WO2000003996A1 (de) 2000-01-27
EP1097141B1 (de) 2007-05-23
ZA200100278B (en) 2001-08-06
US6369236B1 (en) 2002-04-09
HK1038743A1 (en) 2002-03-28
DE19832428A1 (de) 2000-01-20
AU764438B2 (en) 2003-08-21
DE59914347D1 (de) 2007-07-05
TR200100134T2 (tr) 2001-07-23

Similar Documents

Publication Publication Date Title
IL104614A (en) 4-benzoylisoxazole derivatives and herbicidal compositions comprising them
YU74792A (sh) Herbicidi
HUP0102607A2 (hu) Szulfonilcsoporttal szubsztituált bifenil-metil-imidazol-származékok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk
SE8503415D0 (sv) Novel isoindolinyl-alkyl-piperazines
TR200100603T2 (tr) Pirazin bileşikleri
GB2104890B (en) Pyridinecarbinols, their preparation and fungicides containing them
EP0078450A3 (en) Pyridazinone derivatives, process for their preparation and their use as fungicides
PL227048A2 (hu)
TR200401433T4 (tr) Yeni karışımlar.
IE45556L (en) 2-[n-(cycloalkylmethyl)-n-(phenyl)-amino]-2- imidazoline¹derivatives
ATE152442T1 (de) Substituierte arylalkylaminobenzyl- aminopropanamide, ihre herstellung und verwendung als antiepileptische, neuroprotektive und antidepressive mittel
SE8006668L (sv) 2-amino-3-bensoyl-fenylacetamider och cykliska homologer
ES8201962A1 (es) Un procedimiento para la preparacion de un compuesto de biu-ret 1,1,3,5-sustituido
AU539870B2 (en) 2-phenylamino-imidazolines-(2)
ATE19068T1 (de) Pyridinderivate, ihre herstellung und verwendung.
IE782050L (en) Thieno-piperidines
DK428087A (da) Dihydropyridin-5-phosphonsyre-cyclopropylenester
AP9801328A0 (en) Azole compounds endowed with antimycotic activity for human and veterinary use.
ES472537A1 (es) Un procedimiento para la preparacion de nuevas tiadiazolil- benzamidas
ES8801542A1 (es) Procedimiento para preparar compuestos arilsulfonicos.
IE40951L (en) Preparation of 1, 4- diazepines.
AU3634489A (en) Aminomethylphenols and fungicides containing these compounds
HUP0000957A2 (hu) Szacharin-5-karbonil-ciklohexán-1,3,5-trion-származékok,ezeket tartalmazó herbicid készítmények
IE782412L (en) Benzimidazole derivatives.
TH2435EX (th) สาร 2-(2-ซับสติทิว เบนโซอิล)-1-,3-ไซโคลเฮกเซนไดโอน

Legal Events

Date Code Title Description
FD9A Lapse of provisional protection due to non-payment of fees