CA2185104A1 - Naphthalene derivatives as prostaglandin 12 agonists - Google Patents

Naphthalene derivatives as prostaglandin 12 agonists

Info

Publication number
CA2185104A1
CA2185104A1 CA002185104A CA2185104A CA2185104A1 CA 2185104 A1 CA2185104 A1 CA 2185104A1 CA 002185104 A CA002185104 A CA 002185104A CA 2185104 A CA2185104 A CA 2185104A CA 2185104 A1 CA2185104 A1 CA 2185104A1
Authority
CA
Canada
Prior art keywords
salt
compound
hydroxy
formula
hydrogen
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
CA002185104A
Other languages
English (en)
French (fr)
Inventor
Kiyoshi Taniguchi
Masanobu Nagano
Kouji Hattori
Kazunori Tsubaki
Osamu Okitsu
Seiichiro Tabuchi
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.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Individual
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
Priority claimed from GB9404734A external-priority patent/GB9404734D0/en
Priority claimed from GB9407036A external-priority patent/GB9407036D0/en
Application filed by Individual filed Critical Individual
Publication of CA2185104A1 publication Critical patent/CA2185104A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
    • C07D213/64One oxygen atom attached in position 2 or 6
    • 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
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02Compounds containing any of the groups, e.g. carbazates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D237/00Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D303/00Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02Compounds containing oxirane rings
    • C07D303/12Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00Systems containing two condensed rings
    • C07C2602/02Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Epoxy Compounds (AREA)
  • Pyridine Compounds (AREA)
CA002185104A 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin 12 agonists Abandoned CA2185104A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9404734.7 1994-03-10
GB9404734A GB9404734D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GB9407036.4 1994-04-08
GB9407036A GB9407036D0 (en) 1994-04-08 1994-04-08 Naphthalene derivatives

Publications (1)

Publication Number Publication Date
CA2185104A1 true CA2185104A1 (en) 1995-09-14

Family

ID=26304472

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002185104A Abandoned CA2185104A1 (en) 1994-03-10 1995-03-08 Naphthalene derivatives as prostaglandin 12 agonists

Country Status (17)

Country Link
US (2) US5763489A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
EP (1) EP0749424B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JP3245864B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
KR (1) KR100383305B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CN (1) CN1057522C (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AT (1) ATE205479T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AU (1) AU688871B2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
CA (1) CA2185104A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DE (1) DE69522676T2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DK (1) DK0749424T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ES (1) ES2160156T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
GR (1) GR3037080T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
HU (1) HU224822B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
PT (1) PT749424E (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
RU (1) RU2155188C2 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW282456B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1995024393A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2176640C2 (ru) * 1993-12-20 2001-12-10 Фудзисава Фармасьютикал Ко., Лтд. Гетероциклические соединения или их фармацевтически приемлемая соль, промежуточные соединения
TW401408B (en) 1995-07-21 2000-08-11 Fujisawa Pharmaceutical Co Heterocyclic compounds having prostaglandin I2 agonism
DE19537548A1 (de) * 1995-10-09 1997-04-10 Merck Patent Gmbh Endothelin-Rezeptor-Antagonisten
DE19604191A1 (de) * 1996-02-06 1997-08-07 Hoechst Schering Agrevo Gmbh 2,4-Diamino-1,3,5-triazine, Verfahren zu deren Herstellung und deren Verwendung als Herbizide und Pflanzenwachstumsregulatoren
AUPO713297A0 (en) 1997-06-02 1997-06-26 Fujisawa Pharmaceutical Co., Ltd. Oxazole compound
GB9720270D0 (en) 1997-09-25 1997-11-26 Pharmagene Lab Limited Medicaments for the treatment of migraine
AUPP003297A0 (en) 1997-10-27 1997-11-20 Fujisawa Pharmaceutical Co., Ltd. 4,5-diaryloxazole compounds
AUPP029197A0 (en) * 1997-11-10 1997-12-04 Fujisawa Pharmaceutical Co., Ltd. Benzocycloheptene derivatives
AUPP109097A0 (en) * 1997-12-22 1998-01-22 Fujisawa Pharmaceutical Co., Ltd. Napthalene derivatives
US6335459B1 (en) 1998-12-23 2002-01-01 Syntex (U.S.A.) Llc Aryl carboxylic acid and aryl tetrazole derivatives as IP receptor modulators
US20040127529A1 (en) * 1999-06-21 2004-07-01 Fujisawa Pharmaceutical Co., Ltd. Remedies for skin ulcer
EP1188447A1 (en) * 1999-06-21 2002-03-20 Fujisawa Pharmaceutical Co., Ltd. Remedies for skin ulcer
AU2002224032A1 (en) * 2000-11-21 2002-06-03 Fujisawa Pharmaceutical Co. Ltd. Processes for preparation of tetrahydronaphthalene derivatives
WO2002085412A1 (fr) * 2001-04-18 2002-10-31 Fujisawa Pharmaceutical Co., Ltd. Inhibiteurs de la fibrose des tissus
KR101187693B1 (ko) 2003-05-09 2012-10-05 도레이 카부시키가이샤 신장질환의 치료 또는 예방제
AR059898A1 (es) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2
AR064346A1 (es) 2006-12-14 2009-04-01 Astellas Pharma Inc Compuesto de oxicarbonilo
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
DE602008004794D1 (de) 2007-09-14 2011-03-10 Addex Pharmaceuticals Sa 1',3'-disubstituierte 4-phenyl-3,4,5,6-tetrahydro-2h,1'h-ä1,4'übipyridinyl-2'-one
CN103483226A (zh) 2008-03-18 2014-01-01 艾尼纳制药公司 用于治疗前列环素(pgi2)受体相关病症的pgi2受体调节剂
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
MX2011005242A (es) 2008-11-28 2011-09-06 Ortho Mcneil Janssen Pharm Derivados de indol y benzoxazina como moduladores de los receptores de glutamato metabotropicos.
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY153912A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 1, 2, 4,-triazolo[4,3-a[pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
PT2430022E (pt) 2009-05-12 2013-12-26 Janssen Pharmaceuticals Inc Derivados de 1,2,3-triazolo[4,3-a]piridina e a sua utilização para o tratamento ou prevenção de doenças neurológicas e psiquiátricas
ES2552879T3 (es) 2010-11-08 2015-12-02 Janssen Pharmaceuticals, Inc. Derivados de 1,2,4-triazolo[4,3-a]piridina y su uso como moduladores alostéricos positivos de receptores mGluR2
WO2012062750A1 (en) 2010-11-08 2012-05-18 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
EP2643320B1 (en) 2010-11-08 2015-03-04 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3368B1 (ar) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2
JO3367B1 (ar) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2
KR20220038826A (ko) 2014-01-21 2022-03-29 얀센 파마슈티카 엔.브이. 대사 조절형 글루탐산 작동성 수용체 제2아형의 양성 알로스테릭 조절제 또는 오르토스테릭 작동제를 포함하는 조합 및 그 용도
HUE053734T2 (hu) 2014-01-21 2021-07-28 Janssen Pharmaceutica Nv 2-es altípusú metabotróp glutamáterg receptor pozitív allosztérikus modulátorait tartalmazó kombinációk és alkalmazásuk
AU2018227842B2 (en) 2017-03-01 2024-05-02 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
AU2023222747A1 (en) 2022-02-15 2024-08-22 United Therapeutics Corporation Crystalline prostacyclin (ip) receptor agonist and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1366514A1 (ru) * 1986-01-28 1988-01-15 Днепропетровский химико-технологический институт им.Ф.Э.Дзержинского Способ получени производных N-арил-5-ариламидо-4,6-диметилпиридона-2
DE3837809A1 (de) * 1988-11-08 1990-05-10 Merck Patent Gmbh Tetralinderivate
US5344836A (en) * 1991-11-11 1994-09-06 Ono Pharmaceutical Co., Ltd. Fused benzeneoxyacetic acid derivatives

Also Published As

Publication number Publication date
HU9602466D0 (en) 1996-11-28
DK0749424T3 (da) 2001-11-26
ATE205479T1 (de) 2001-09-15
CN1057522C (zh) 2000-10-18
PT749424E (pt) 2002-03-28
CN1147250A (zh) 1997-04-09
WO1995024393A1 (en) 1995-09-14
JP3245864B2 (ja) 2002-01-15
AU1861895A (en) 1995-09-25
KR100383305B1 (ko) 2003-11-01
DE69522676T2 (de) 2002-04-18
TW282456B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1996-08-01
US5863918A (en) 1999-01-26
HK1013289A1 (en) 1999-08-20
ES2160156T3 (es) 2001-11-01
JPH09509958A (ja) 1997-10-07
EP0749424B1 (en) 2001-09-12
DE69522676D1 (de) 2001-10-18
AU688871B2 (en) 1998-03-19
KR970701698A (ko) 1997-04-12
EP0749424A1 (en) 1996-12-27
RU2155188C2 (ru) 2000-08-27
GR3037080T3 (en) 2002-01-31
HU224822B1 (en) 2006-02-28
US5763489A (en) 1998-06-09
HUT75226A (en) 1997-04-28

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Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued