DE69818255D1 - Arylsubstituierte piperazine die bei der behandlung von gutartiger prostatischer hyperlasie nützlich sind - Google Patents
Arylsubstituierte piperazine die bei der behandlung von gutartiger prostatischer hyperlasie nützlich sindInfo
- Publication number
- DE69818255D1 DE69818255D1 DE69818255T DE69818255T DE69818255D1 DE 69818255 D1 DE69818255 D1 DE 69818255D1 DE 69818255 T DE69818255 T DE 69818255T DE 69818255 T DE69818255 T DE 69818255T DE 69818255 D1 DE69818255 D1 DE 69818255D1
- Authority
- DE
- Germany
- Prior art keywords
- aryl
- substituted piperazines
- piperazines useful
- hyperlasia
- prostatic
- 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.)
- Expired - Fee Related
Links
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
- A61K31/33—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4623697P | 1997-05-12 | 1997-05-12 | |
US46236 | 1997-05-12 | ||
PCT/US1998/009023 WO1998051298A1 (en) | 1997-05-12 | 1998-05-08 | Arylsubstituted piperazines useful in the treatement of benign prostatic hyperlasia |
Publications (2)
Publication Number | Publication Date |
---|---|
DE69818255D1 true DE69818255D1 (de) | 2003-10-23 |
DE69818255T2 DE69818255T2 (de) | 2004-12-23 |
Family
ID=21942353
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE69818255T Expired - Fee Related DE69818255T2 (de) | 1997-05-12 | 1998-05-08 | Arylsubstituierte piperazine die bei der behandlung von gutartiger prostatischer hyperlasie nützlich sind |
Country Status (28)
Country | Link |
---|---|
US (4) | US6071915A (de) |
EP (1) | EP0984777B1 (de) |
JP (1) | JP4189867B2 (de) |
KR (1) | KR100440755B1 (de) |
CN (3) | CN1515556A (de) |
AP (1) | AP1349A (de) |
AR (1) | AR012686A1 (de) |
AT (1) | ATE250033T1 (de) |
AU (1) | AU7366998A (de) |
BR (1) | BR9809804A (de) |
CA (1) | CA2289987C (de) |
CZ (1) | CZ298217B6 (de) |
DE (1) | DE69818255T2 (de) |
DK (1) | DK0984777T3 (de) |
EA (1) | EA001904B1 (de) |
ES (1) | ES2206928T3 (de) |
HK (1) | HK1024630A1 (de) |
HU (1) | HUP0100048A3 (de) |
IL (1) | IL132836A0 (de) |
MY (2) | MY127385A (de) |
NO (1) | NO314144B1 (de) |
NZ (1) | NZ500992A (de) |
PL (1) | PL192596B1 (de) |
PT (1) | PT984777E (de) |
TR (1) | TR199902971T2 (de) |
TW (1) | TW512146B (de) |
WO (1) | WO1998051298A1 (de) |
ZA (1) | ZA983968B (de) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2768055A1 (fr) * | 1997-09-11 | 1999-03-12 | Synthelabo | Utilisation de derives de sulfonanilide pour obtenir un medicament destine au traitement de l'ejaculation retrograde ou de l'aspermie |
TW536538B (en) | 1998-02-20 | 2003-06-11 | Ortho Mcneil Pharm Inc | Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia |
ZA991319B (en) * | 1998-02-20 | 2000-11-20 | Ortho Mcneil Pharm Inc | Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia. |
EP1346983A3 (de) * | 1998-02-20 | 2003-12-03 | Ortho-Mcneil Pharmaceutical, Inc. | Phthalimido-arylpiperazine als alpha 1A Rezeptor Antagonisten nützlich zur Behandlung von gutartiger Prostatahyperplasie |
WO2002022582A2 (en) * | 2000-09-14 | 2002-03-21 | Ortho-Mcneil Pharmaceutical, Inc. | Solid salt forms of n-[2-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]ethyl]-2-oxo-1-piperidineacetamide |
MXPA03004850A (es) | 2000-11-30 | 2004-01-26 | Ranbaxy Lab Ltd | Derivados de piperazina 1,4-disustituida utiles como bloqueadores de alfa1 adrenoceptores uro-selectivos. |
WO2005118537A2 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Arylpiperazine derivatives as adrenergic receptor antagonists |
WO2006092710A1 (en) * | 2005-03-02 | 2006-09-08 | Ranbaxy Laboratories Limited | Metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a-tetrahydro-1h-isoindole-1,3-(2h)-dione |
WO2007029156A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | Isoindoledione derivatives as adrenergic receptor antagonists |
CN102391169B (zh) * | 2011-10-17 | 2015-10-28 | 上海化学试剂研究所 | N-(5-甲氧基-3-吲哚乙基)-4-取代苯基哌嗪-1-乙酰胺的制备方法 |
CN103387531A (zh) * | 2012-05-10 | 2013-11-13 | 广州医学院 | 酰胺类芳基哌嗪衍生物及其制备方法和在抗良性前列腺增生中的应用 |
CN103980195A (zh) * | 2014-04-28 | 2014-08-13 | 广州医科大学 | 酰胺类苯基哌嗪衍生物及其盐与在制备治疗良性前列腺增生症药物中的应用 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4069336A (en) * | 1976-02-25 | 1978-01-17 | Chemisches Laboratorium Fritz-Walter Lange Gmbh & Co Kg | (2-oxo-pyrrolidines)-acetic hydrazides |
JPS5955878A (ja) | 1982-09-24 | 1984-03-31 | Chugai Pharmaceut Co Ltd | 新規なフエニルピペラジン誘導体 |
AU1475583A (en) * | 1983-04-27 | 1984-11-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Substituted picolinic acids, processes for their preparation,their use and medicaments containing them |
JPS62135464A (ja) * | 1985-12-10 | 1987-06-18 | Nippon Kayaku Co Ltd | フエニルピペラジン誘導体 |
GB8703749D0 (en) | 1987-02-18 | 1987-03-25 | Sandoz Ltd | Piperazinecarboxylic acid |
US5254552A (en) * | 1988-05-24 | 1993-10-19 | American Home Products Corporation | Aryl-and heteroaryl piperazinyl carboxamides having central nervous system activity |
EP0558245A1 (de) * | 1992-02-25 | 1993-09-01 | RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY | Heterobicyclische Verbindungen als Alpha-1-Adrenergene und 5HT1A-Rezeptor-Antagonisten |
FR2692894B1 (fr) * | 1992-06-24 | 1994-10-14 | Irceba | Aryl-1-(o-alcoxy-phényl-4-pipérazinyl-1)-2, 3- ou 4-alcanols, leur procédé de préparation et leur utilisation pour la préparation de médicaments. |
US5403847A (en) * | 1992-11-13 | 1995-04-04 | Synaptic Pharmaceutical Corporation | Use of α1C specific compounds to treat benign prostatic hyperlasia |
IT1266582B1 (it) * | 1993-07-30 | 1997-01-09 | Recordati Chem Pharm | Derivati (di)azacicloesanici e diazacicloeptanici |
US5688795A (en) * | 1994-11-08 | 1997-11-18 | Syntex (U.S.A.) Inc. | 3-(4-phenylpiperazin-1-yl)propyl-amino, thio and oxy!-pyridine, pyrimidine and benzene derivatives as α1 -adrenoceptor antagonists |
US5807856A (en) * | 1995-11-15 | 1998-09-15 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonist |
EP0881235A1 (de) * | 1997-05-26 | 1998-12-02 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Phosphor Ylide, Herstellung und Verwendung zu schwachnukleophilen starkbasischen Verbindungen |
TW536538B (en) * | 1998-02-20 | 2003-06-11 | Ortho Mcneil Pharm Inc | Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia |
US6218396B1 (en) * | 1998-02-20 | 2001-04-17 | Orth-Mcneil Pharmaceutical, Inc. | Substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia |
US6063785A (en) * | 1999-02-17 | 2000-05-16 | Ortho-Mcneil Pharmaceutical Inc. | Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia |
-
1998
- 1998-05-08 PT PT98920950T patent/PT984777E/pt unknown
- 1998-05-08 EP EP98920950A patent/EP0984777B1/de not_active Expired - Lifetime
- 1998-05-08 KR KR10-1999-7010460A patent/KR100440755B1/ko not_active IP Right Cessation
- 1998-05-08 CN CNA031070485A patent/CN1515556A/zh active Pending
- 1998-05-08 AU AU73669/98A patent/AU7366998A/en not_active Abandoned
- 1998-05-08 HU HU0100048A patent/HUP0100048A3/hu unknown
- 1998-05-08 DE DE69818255T patent/DE69818255T2/de not_active Expired - Fee Related
- 1998-05-08 IL IL13283698A patent/IL132836A0/xx not_active IP Right Cessation
- 1998-05-08 AP APAP/P/1999/001684A patent/AP1349A/en active
- 1998-05-08 CZ CZ0399799A patent/CZ298217B6/cs not_active IP Right Cessation
- 1998-05-08 CA CA002289987A patent/CA2289987C/en not_active Expired - Fee Related
- 1998-05-08 PL PL342518A patent/PL192596B1/pl not_active IP Right Cessation
- 1998-05-08 NZ NZ500992A patent/NZ500992A/xx unknown
- 1998-05-08 WO PCT/US1998/009023 patent/WO1998051298A1/en active IP Right Grant
- 1998-05-08 BR BR9809804-7A patent/BR9809804A/pt active Search and Examination
- 1998-05-08 ES ES98920950T patent/ES2206928T3/es not_active Expired - Lifetime
- 1998-05-08 CN CNB988049112A patent/CN1149081C/zh not_active Expired - Fee Related
- 1998-05-08 EA EA199900928A patent/EA001904B1/ru not_active IP Right Cessation
- 1998-05-08 DK DK98920950T patent/DK0984777T3/da active
- 1998-05-08 TR TR1999/02971T patent/TR199902971T2/xx unknown
- 1998-05-08 US US09/074,789 patent/US6071915A/en not_active Expired - Lifetime
- 1998-05-08 AT AT98920950T patent/ATE250033T1/de not_active IP Right Cessation
- 1998-05-08 JP JP54927698A patent/JP4189867B2/ja not_active Expired - Fee Related
- 1998-05-08 CN CNB2003101029013A patent/CN1269807C/zh not_active Expired - Fee Related
- 1998-05-09 MY MYPI20041438A patent/MY127385A/en unknown
- 1998-05-09 MY MYPI98002108A patent/MY122095A/en unknown
- 1998-05-11 ZA ZA9803968A patent/ZA983968B/xx unknown
- 1998-05-11 AR ARP980102181A patent/AR012686A1/es active IP Right Grant
- 1998-08-12 TW TW087107253A patent/TW512146B/zh not_active IP Right Cessation
-
1999
- 1999-11-11 NO NO19995518A patent/NO314144B1/no not_active IP Right Cessation
-
2000
- 2000-03-15 US US09/526,224 patent/US6890921B1/en not_active Expired - Lifetime
- 2000-06-12 US US09/591,814 patent/US6593474B1/en not_active Expired - Lifetime
- 2000-06-29 HK HK00103972A patent/HK1024630A1/xx not_active IP Right Cessation
-
2003
- 2003-06-02 US US10/452,255 patent/US20030220493A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE69807476D1 (de) | Behandlung von schweren aromaten | |
DE69008048D1 (de) | Duftzusammensetzungen und ihre Verwendung in Reinigungsmitteln. | |
ID18993A (id) | Pakaian dalam harum | |
DE59506473D1 (de) | Tensidgemische | |
ID24663A (id) | Turunan-turunan piperazin | |
DE69839775D1 (de) | Kondensatoren in integrierten schaltkreisen | |
DE59508648D1 (de) | Milde detergensgemische | |
DE69522117D1 (de) | Waschmittelzusammensetzung und waschverfahren | |
DE69530815D1 (de) | Viskosimeter | |
DE69818255D1 (de) | Arylsubstituierte piperazine die bei der behandlung von gutartiger prostatischer hyperlasie nützlich sind | |
DE69528621D1 (de) | Multifokallinse | |
FR2717684B1 (fr) | Compositions cosmétiques détergentes et utilisations. | |
DE59810482D1 (de) | Schleifen von garnituren | |
DE59503545D1 (de) | Computergestützte umwandlung von tabellen | |
DE59707351D1 (de) | Schleifen von Garnituren | |
DE59505049D1 (de) | Milde detergensgemische | |
DE69508894D1 (de) | Reinigung von propofol | |
DE69821636D1 (de) | Alkoxylierte amine und ihre verwendung in reinigungsmitteln | |
KR960003763U (ko) | 가방밑판 | |
DE59908316D1 (de) | Schleifen von garnituren | |
DE59505462D1 (de) | Recyclefähige schleifkörperzonen | |
DE59505312D1 (de) | Milde detergensgemische | |
DE59500653D1 (de) | Gleichstrom-Sparschaltung | |
DE59507095D1 (de) | Verwendung von detergensgemischen | |
KR960013064U (ko) | 구멍뚫린 두부 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
8364 | No opposition during term of opposition | ||
8328 | Change in the person/name/address of the agent |
Representative=s name: BOEHMERT & BOEHMERT, 28209 BREMEN |
|
8339 | Ceased/non-payment of the annual fee |