ATE85334T1 - Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung. - Google Patents

Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung.

Info

Publication number
ATE85334T1
ATE85334T1 AT88903427T AT88903427T ATE85334T1 AT E85334 T1 ATE85334 T1 AT E85334T1 AT 88903427 T AT88903427 T AT 88903427T AT 88903427 T AT88903427 T AT 88903427T AT E85334 T1 ATE85334 T1 AT E85334T1
Authority
AT
Austria
Prior art keywords
pct
bisphenylalkylpiperazine
derivatives
manufacture
drug preparation
Prior art date
Application number
AT88903427T
Other languages
English (en)
Inventor
Tomas Fex
Knut Gunnar Olsson
Aina Lisbeth Abramo
Erik Gunnar Christensson
Torbjoern Erik Lundstedt
Original Assignee
Kabi Pharmacia Ab
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 Kabi Pharmacia Ab filed Critical Kabi Pharmacia Ab
Application granted granted Critical
Publication of ATE85334T1 publication Critical patent/ATE85334T1/de

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
AT88903427T 1987-04-02 1988-03-25 Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung. ATE85334T1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE8701375A SE8701375D0 (sv) 1987-04-02 1987-04-02 Novel pyridyl- and pyrimidyl derivatives
EP88903427A EP0308476B1 (de) 1987-04-02 1988-03-25 Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung
PCT/SE1988/000144 WO1988007528A1 (en) 1987-04-02 1988-03-25 Bisphenylalkylpiperazine derivatives, a method of their preparation and a pharmaceutical preparation

Publications (1)

Publication Number Publication Date
ATE85334T1 true ATE85334T1 (de) 1993-02-15

Family

ID=20368077

Family Applications (1)

Application Number Title Priority Date Filing Date
AT88903427T ATE85334T1 (de) 1987-04-02 1988-03-25 Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung.

Country Status (18)

Country Link
US (1) US4937245A (de)
EP (1) EP0308476B1 (de)
JP (1) JPH0819104B2 (de)
KR (1) KR920003062B1 (de)
AT (1) ATE85334T1 (de)
AU (1) AU611147B2 (de)
CA (1) CA1321997C (de)
DE (1) DE3878111T2 (de)
DK (1) DK161313C (de)
ES (1) ES2006619A6 (de)
FI (1) FI92320C (de)
HU (1) HU201051B (de)
IE (1) IE61165B1 (de)
IL (1) IL85932A (de)
NO (1) NO172640C (de)
NZ (1) NZ224005A (de)
SE (1) SE8701375D0 (de)
WO (1) WO1988007528A1 (de)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8701375D0 (sv) * 1987-04-02 1987-04-02 Leo Ab Novel pyridyl- and pyrimidyl derivatives
US5219855A (en) * 1988-01-29 1993-06-15 Mitsubishi Kasei Corporation Anxiolytic drug
JP2664238B2 (ja) * 1989-03-01 1997-10-15 日清製粉株式会社 ニコチン酸またはそのエステル誘導体
US4994460A (en) * 1989-06-01 1991-02-19 Bristol-Myers Squibb Co. Agents for treatment of brain ischemia
SE9201239D0 (sv) * 1992-04-21 1992-04-21 Kabi Pharmacia Ab Agents for treating substance abuse disorders
EP0580465A1 (de) * 1992-06-25 1994-01-26 Sanofi Neue therapeutische Verwendung von heterocyclischen Piperazinen als 5-HT3-Agonisten und neue Derivaten
JPH0665203A (ja) * 1992-06-25 1994-03-08 Elf Sanofi ピペラジンのヘテロ環誘導体
SE9201956D0 (sv) * 1992-06-25 1992-06-25 Kabi Pharmacia Ab Novel nicotinicacid esters
SE9202265D0 (sv) * 1992-07-31 1992-07-31 Kabi Pharmacia Ab Novel- pyridyl and pyrimidylpiperazine derivatives
DK139593D0 (da) * 1993-12-16 1993-12-16 Lundbeck & Co As H Compounds
ATE278670T1 (de) 1997-10-27 2004-10-15 Neurosearch As Heteroaryl diazacycloalkane als cholinergische ligande für nikotin-acetylcholin-rezeptoren
US6632823B1 (en) * 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
AU779550B2 (en) 1999-04-09 2005-01-27 Meiji Seika Kaisha Ltd. Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2958694A (en) * 1959-06-22 1960-11-01 Janssen Paul Adriaan Jan 1-(aroylalkyl)-4-(2'-pyridyl) piperazines
US2985657A (en) * 1959-10-12 1961-05-23 Paul A J Janssen 1-(aroylalkyl)-4-heterocyclylpiperazines
US2979508A (en) * 1959-10-12 1961-04-11 Paul A J Janssen Heterocyclic derivatives of 1-phenyl-omega-(piperazine) alkanols
JPS6081167A (ja) * 1983-10-11 1985-05-09 Sumitomo Chem Co Ltd フエニルアセトン誘導体およびその製造法
US4605655A (en) * 1984-03-06 1986-08-12 Bristol-Myers Company Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives
JPS6175A (ja) * 1984-03-06 1986-01-06 ブリストル−マイア−ズ　コムパニ− 神経弛緩剤、１‐フルオロフェニルブチル‐４‐（５‐ハロ‐２‐ピリミジニル）ピペラジン誘導体
GB8603120D0 (en) * 1986-02-07 1986-03-12 Pfizer Ltd Anti-dysrhythmia agents
JPS63146872A (ja) * 1986-07-08 1988-06-18 Yoshitomi Pharmaceut Ind Ltd ピリミジニルピペラジン化合物
US4766215A (en) * 1987-02-27 1988-08-23 American Home Products Corporation Histamine H1 -receptor antagonists
SE8701375D0 (sv) * 1987-04-02 1987-04-02 Leo Ab Novel pyridyl- and pyrimidyl derivatives

Also Published As

Publication number Publication date
US4937245A (en) 1990-06-26
IE880869L (en) 1988-10-02
HUT50325A (en) 1990-01-29
NO172640B (no) 1993-05-10
EP0308476A1 (de) 1989-03-29
AU1579688A (en) 1988-11-02
EP0308476B1 (de) 1993-02-03
DE3878111T2 (de) 1993-07-01
KR920003062B1 (ko) 1992-04-13
NO885386L (no) 1988-12-02
KR880012586A (ko) 1988-11-28
DE3878111D1 (de) 1993-03-18
HU201051B (en) 1990-09-28
IL85932A0 (en) 1988-09-30
NZ224005A (en) 1991-03-26
FI92320C (fi) 1994-10-25
DK161313C (da) 1991-12-30
WO1988007528A1 (en) 1988-10-06
FI92320B (fi) 1994-07-15
DK671588A (da) 1988-12-01
DK671588D0 (da) 1988-12-01
IE61165B1 (en) 1994-10-05
FI885560A0 (fi) 1988-11-30
SE8701375D0 (sv) 1987-04-02
ES2006619A6 (es) 1989-05-01
NO885386D0 (no) 1988-12-02
CA1321997C (en) 1993-09-07
FI885560A7 (fi) 1988-11-30
DK161313B (da) 1991-06-24
AU611147B2 (en) 1991-06-06
NO172640C (no) 1993-08-18
JPH0819104B2 (ja) 1996-02-28
IL85932A (en) 1993-05-13
JPH01502832A (ja) 1989-09-28

Similar Documents

Publication Publication Date Title
DZ1794A1 (fr) Nouvelle formule pharmaceutique.
UA66825C2 (uk) Азаполіциклічні сполуки, конденсовані з арилом, фармацевтична композиція, спосіб лікування та спосіб зниження нікотинової залежності
ATE283047T1 (de) Verwendung von ibudilast zur herstellung eines arzneimittels zur behandlung multiple sklerose
NO933200L (no) Substituerte cykloheksanderivater, fremgangsmåte til fremstilling derav og anvendelsen av forbindelsene til behandling av sykdommer
ATE85334T1 (de) Bisphenylalkylpiperazin-derivate, verfahren zur herstellung und arzneimittelzubereitung.
ATE191849T1 (de) Verwendung von (s)-(-)-alpha-ethyl-2-oxo-1- pyrrolidinacetamid zur herstellung eines medikaments zur behandlung von angst
DE69501359D1 (de) Verwendung von Phosphatdiestern zur Behandlung von Erkrankungen der Retina
ATE223721T1 (de) Edelfosin zur behandlung von hirntumoren
EP0354568A3 (de) Catechol-Derivate
ATE135681T1 (de) Diclofenac-cholinsalz, verfahren zur herstellung und pharmazeutische zusammensetzungen, die es enthalten
ATE169635T1 (de) Therapeutische verbindungen für die behandlung von krankheiten, die mit einem glutathion-defizit assoziiert sind, herstellungsprozess und diese enthaltene pharmazeutische zusammensetzungen
DE69619868D1 (de) Piperazinylalkylthiopyrimidin derivate, diese enthaltende pharmazeutische zusammensetzungen und verfahren zu deren herstellung
DE60231054D1 (de) Piperidinderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzung zur behandlung von alzheimer-krankheit, die diese derivate enthält
ZA9480B (en) Pyrrolidine derivatives their preparation and medicaments containing them
ATE119149T1 (de) Pyrrolidonderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel.
ATE100102T1 (de) Substituierte derivate von 20,21dinoreburnamenin, verfahren zur herstellung und so hergestellte zwischenprodukte, ihre verwendung als arzneimittel und diese enthaltende pharmazeutische zusammenstellungen.
ATE200277T1 (de) Substituierte phenylamidine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
ES2137665T3 (es) Nuevos derivados de piridina o piridazina, procedimientos para su preparacion, y medicamentos que contienen estos compuestos.
ATE192650T1 (de) Verwendung von efaroxan und dessen derivaten zur herstellung eines arzneimittels zur behandlung parkinsonscher krankheit
ATE69809T1 (de) Leukotrienantagonisten, verfahren zu ihrer herstellung, ihre anwendung zur behandlung von krankheiten.
DE69533833D1 (de) Verfahren zur Herstellung von Indolopyrrolocarbazol-Derivaten
ATE66468T1 (de) Leukotrienantagonisten, verfahren zu ihrer herstellung und ihre anwendung zur behandlung von krankheiten.
DE69614838D1 (de) Verfahren zur herstellung von anhydroecgonin-estern
DE3777270D1 (de) Verwendung von l-carnitin zur herstellung eines arzneimittels zur behandlung von toxischen effekten, induziert durch die inhalation von halotan und anderen halogen enthaltenden allgemeinen anaesthetika.
ATE32514T1 (de) 3-(4'-aminobutylamino)-propylamino-bleomycinderivate, verfahren zur ihrer herstellung und diese enthaltende pharmazeutische zusammensetzungen.

Legal Events

Date Code Title Description
UEP Publication of translation of european patent specification
EEIH Change in the person of patent owner
EEIH Change in the person of patent owner
REN Ceased due to non-payment of the annual fee