CA2362390A1 - Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases - Google Patents

Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases Download PDF

Info

Publication number
CA2362390A1
CA2362390A1 CA002362390A CA2362390A CA2362390A1 CA 2362390 A1 CA2362390 A1 CA 2362390A1 CA 002362390 A CA002362390 A CA 002362390A CA 2362390 A CA2362390 A CA 2362390A CA 2362390 A1 CA2362390 A1 CA 2362390A1
Authority
CA
Canada
Prior art keywords
carboxamidine
methylthiothiophene
amino
thiazol
methylthio
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
CA002362390A
Other languages
English (en)
Inventor
Carl R. Illig
Nalin L. Subasinghe
James B. Hoffman
Kenneth J. Wilson
M. Jonathan Rudolph
Juan Jose Marugan
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.)
3 Dimensional Pharmaceuticals Inc
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
Application filed by Individual filed Critical Individual
Publication of CA2362390A1 publication Critical patent/CA2362390A1/fr
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (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)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Reproductive Health (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés correspondant à la formule (I) dans laquelle X représente O, S ou NR?7¿ et R?1¿-R?7¿, Y et Z possèdent les notifications données dans la description. Elle concerne également des hydrates ou solvates de ces composés, ou des sels de ceux-ci acceptables sur le plan pharmacologique. L'invention concerne encore des procédés de préparation des composés correspondant à la formule (I). Ces nouveaux composés constituent des puissants inhibiteurs des protéases, notamment des sérines protéases du type trypsine, telles que la chymotrypsine, la trypsine, la plasmine et l'urokinase. Certains de ces composés démontrent une inhibition directe et sélective de l'urokinase, ou ils constituent des intermédiaires utiles pour former des composés possédant une telle activité.
CA002362390A 1999-02-09 1999-08-11 Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases Abandoned CA2362390A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US24706299A 1999-02-09 1999-02-09
US09/247,062 1999-02-09
PCT/US1999/018065 WO2000047578A1 (fr) 1999-02-09 1999-08-11 Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases

Publications (1)

Publication Number Publication Date
CA2362390A1 true CA2362390A1 (fr) 2000-08-17

Family

ID=22933398

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002362390A Abandoned CA2362390A1 (fr) 1999-02-09 1999-08-11 Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases

Country Status (19)

Country Link
EP (1) EP1150979A1 (fr)
JP (1) JP2002536446A (fr)
KR (1) KR20010098982A (fr)
CN (1) CN1337961A (fr)
AU (1) AU5671799A (fr)
BG (1) BG105866A (fr)
BR (1) BR9917036A (fr)
CA (1) CA2362390A1 (fr)
CZ (1) CZ20012858A3 (fr)
EA (1) EA200100882A1 (fr)
HU (1) HUP0201475A2 (fr)
IL (1) IL144560A0 (fr)
MX (1) MXPA01008084A (fr)
NO (1) NO324887B1 (fr)
NZ (1) NZ513701A (fr)
PL (1) PL351767A1 (fr)
SK (1) SK11422001A3 (fr)
WO (1) WO2000047578A1 (fr)
ZA (1) ZA200106849B (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003529536A (ja) * 1999-02-09 2003-10-07 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド Ｃ１ｓ介在疾患および状態の処置法、およびそれのための化合物および組成物
JP2005538953A (ja) * 2002-05-28 2005-12-22 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド 新規チオフェンアミジン、それらの組成物、および補体媒介疾患および病気を治療する方法
DK1569912T3 (en) 2002-12-03 2015-06-29 Pharmacyclics Inc 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors.
US7482376B2 (en) 2003-07-03 2009-01-27 3-Dimensional Pharmaceuticals, Inc. Conjugated complement cascade inhibitors
OA13187A (en) * 2003-07-10 2006-12-13 Achillion Pharmaceuticals Inc Substituted arylthiourea derivatives useful as inhibitors of viral replication.
WO2005079865A1 (fr) 2004-02-12 2005-09-01 Molecular Insight Pharmaceuticals Complexes de technetium- et rhenium-bis(heteroaryle), et leurs procedes d'utilisation
WO2010042867A2 (fr) 2008-10-09 2010-04-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activateurs de la pyruvate kinase humaine
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
AU2011245441B2 (en) 2010-04-29 2014-12-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activators of human pyruvate kinase
CA2825306C (fr) * 2011-01-25 2019-02-26 The Regents Of The University Of Michigan Inhibiteurs de bcl-2/bcl-xl et methodes therapeutiques les utilisant
AR086744A1 (es) * 2011-06-28 2014-01-22 Nippon Soda Co Compuesto heterociclico conteniendo nitrogeno y fungicida para el uso en agricultura y jardineria
EP2606726A1 (fr) * 2011-12-21 2013-06-26 Bayer CropScience AG Dérivés de trifluoroéthylsulfure substitués par du N-arylamidine en tant qu'acaricides et insecticides
TWI644899B (zh) 2013-02-04 2018-12-21 健生藥品公司 Ｆｌａｐ調節劑
EP3070085B1 (fr) 2013-02-04 2019-01-09 Janssen Pharmaceutica NV Modulateurs à volet
US11779018B2 (en) * 2018-03-30 2023-10-10 Sumitomo Chemical Company, Limited Heterocyclic compound and arthropod pest control composition containing same
CN109020837A (zh) * 2018-07-27 2018-12-18 广东省石油与精细化工研究院 一种2-取代苯基-乙脒盐酸盐的制备方法

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4220654A (en) * 1979-06-04 1980-09-02 Merck & Co., Inc. Cyclic imidazole cyanoguanidines
US4424367A (en) * 1982-08-19 1984-01-03 Norwich Eaton Pharmaceuticals, Inc. 5-(4-Aminophenyl)-2-thiophenecarboximidamide hydrochloride hemihydrate
JPS59139357A (ja) * 1983-01-28 1984-08-10 Torii Yakuhin Kk アミジン誘導体
DE3427865A1 (de) * 1984-07-27 1986-02-06 Torii & Co., Tokio/Tokyo Amidinoverbindungen, verfahren zu deren herstellung und diese verbindungen enthaltende pharmazeutische mittel
US5084466A (en) * 1989-01-31 1992-01-28 Hoffmann-La Roche Inc. Novel carboxamide pyridine compounds which have useful pharmaceutical utility
US5340833A (en) * 1992-05-01 1994-08-23 Eisai Co., Ltd. Urokinase inhibitors
GB9312761D0 (en) * 1993-06-21 1993-08-04 Wellcome Found Amino acid derivatives
US5821267A (en) * 1993-10-21 1998-10-13 G.D. Searle & Co. Amidino derivatives useful as nitric oxide synthase inhibitors
ZA951617B (en) * 1994-03-04 1997-02-27 Lilly Co Eli Antithrombotic agents.
US5612353A (en) * 1995-06-07 1997-03-18 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
TW414795B (en) * 1996-07-01 2000-12-11 Yamanouchi Pharma Co Ltd A thiophene derivative and the pharmaceutical composition
DE19632773A1 (de) * 1996-08-14 1998-02-19 Basf Ag Neue Thrombininhibitoren
PE121699A1 (es) * 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
JP2002501081A (ja) * 1998-01-26 2002-01-15 ビーエーエスエフ アクチェンゲゼルシャフト トロンビンインヒビター
EP1049673A1 (fr) * 1998-01-26 2000-11-08 Basf Aktiengesellschaft Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine
JP2002502852A (ja) * 1998-02-09 2002-01-29 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド プロテアーゼ阻害剤、特にウロキナーゼ阻害剤としてのヘテロアリールアミジン、メチルアミジンおよびグアニジン
PL343317A1 (en) * 1998-03-31 2001-08-13 Warner Lambert Co Benzoxazinones/benzothiazinones as serine protease inhibitors
IL136605A0 (en) * 1998-03-31 2001-06-14 Warner Lambert Co Quinolones as serine protease inhibitors
HUP0101470A3 (en) * 1998-03-31 2002-09-30 Warner Lambert Co Quinoxalinones as serine protease inhibitors such as factor xa and thrombin and medicaments containing the compounds

Also Published As

Publication number Publication date
NO20013853D0 (no) 2001-08-07
BR9917036A (pt) 2002-07-30
CZ20012858A3 (cs) 2002-05-15
MXPA01008084A (es) 2004-09-10
IL144560A0 (en) 2002-05-23
CN1337961A (zh) 2002-02-27
NZ513701A (en) 2001-09-28
ZA200106849B (en) 2002-11-20
EA200100882A1 (ru) 2002-04-25
AU5671799A (en) 2000-08-29
BG105866A (en) 2002-06-28
HUP0201475A2 (hu) 2003-10-28
NO324887B1 (no) 2007-12-27
PL351767A1 (en) 2003-06-16
EP1150979A1 (fr) 2001-11-07
WO2000047578A1 (fr) 2000-08-17
SK11422001A3 (sk) 2002-04-04
NO20013853L (no) 2001-10-09
JP2002536446A (ja) 2002-10-29
KR20010098982A (ko) 2001-11-08

Similar Documents

Publication Publication Date Title
US6403633B2 (en) Heteroaryl amidines, methylamidines and guanidines, and use thereof as protease inhibitors
US6492403B1 (en) Methods of treating C1s-mediated diseases and conditions and compositions thereof
EP1054886B1 (fr) Heteroaryl amidines, methylamidines et guanidines utiles en tant qu'inhibiteurs de protease et plus particulierement en tant qu'inhibiteurs d'urokinase
CA2362390A1 (fr) Amidines, methylamidines et guanidines, heteroaryles, en tant qu'inhibiteurs de proteases
EP2314593B1 (fr) Inhibiteurs du recepteur de l'adp plaquettaire
AU2001287991B2 (en) Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein junkinases
AU2005230867A1 (en) Certain triazole-based compounds, compositions, and uses thereof
JP2002502852A5 (fr)
FR2993563A1 (fr) Derives de thiophenes utiles dans le traitement du diabete
JP2002536446A5 (fr)
CA2859024C (fr) Derives de benzisothiazol-3(1h)-one-5-sulfonyle en tant que modulateurs de recepteur de chimiokine
US9603834B2 (en) 1,2- bis-sulfonamide derivatives as chemokine receptor modulators

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued