DE69528005D1 - Prolineamid-Derivate - Google Patents

Prolineamid-Derivate

Info

Publication number
DE69528005D1
DE69528005D1 DE69528005T DE69528005T DE69528005D1 DE 69528005 D1 DE69528005 D1 DE 69528005D1 DE 69528005 T DE69528005 T DE 69528005T DE 69528005 T DE69528005 T DE 69528005T DE 69528005 D1 DE69528005 D1 DE 69528005D1
Authority
DE
Germany
Prior art keywords
prolineamid
derivatives
salt
usuful
hydrate
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 - Lifetime
Application number
DE69528005T
Other languages
English (en)
Other versions
DE69528005T2 (de
Inventor
Masahiro Ohshima
Norimichi Iwase
Shigeo Sugiyama
Koichi Sugawara
Misao Okitsu
Yoshikuni Tamao
Yasuhiro Morinaka
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.)
Mitsubishi Chemical Corp
Original Assignee
Mitsubishi Chemical Corp
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 Mitsubishi Chemical Corp filed Critical Mitsubishi Chemical Corp
Application granted granted Critical
Publication of DE69528005D1 publication Critical patent/DE69528005D1/de
Publication of DE69528005T2 publication Critical patent/DE69528005T2/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/04Heterocyclic 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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic 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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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 chain containing hetero atoms as chain links
    • 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
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/04Heterocyclic 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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic 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 no 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
    • C07D207/16Carbon 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
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60Carbon 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
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C07K5/06069Ser-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06078Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06104Dipeptides with the first amino acid being acidic
    • C07K5/06113Asp- or Asn-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Plural Heterocyclic Compounds (AREA)
DE69528005T 1994-01-27 1995-01-26 Prolineamid-Derivate Expired - Lifetime DE69528005T2 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP773394 1994-01-27

Publications (2)

Publication Number Publication Date
DE69528005D1 true DE69528005D1 (de) 2002-10-10
DE69528005T2 DE69528005T2 (de) 2003-04-17

Family

ID=11673914

Family Applications (1)

Application Number Title Priority Date Filing Date
DE69528005T Expired - Lifetime DE69528005T2 (de) 1994-01-27 1995-01-26 Prolineamid-Derivate

Country Status (16)

Country Link
US (1) US5744487A (de)
EP (1) EP0669317B1 (de)
KR (1) KR950032114A (de)
CN (1) CN1066712C (de)
AT (1) ATE223378T1 (de)
AU (1) AU1025795A (de)
CA (1) CA2140598C (de)
DE (1) DE69528005T2 (de)
ES (1) ES2182852T3 (de)
FI (1) FI950309A (de)
HU (1) HUT72062A (de)
NO (1) NO950297L (de)
NZ (1) NZ270395A (de)
RU (1) RU95101048A (de)
TW (1) TW306917B (de)
ZA (1) ZA95631B (de)

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US5583146A (en) * 1992-12-02 1996-12-10 Bristol-Myers Squibb Company Heterocyclic thrombin inhibitors
US6984627B1 (en) 1993-06-03 2006-01-10 Astrazeneca Ab Peptide derivatives
SE9301916D0 (sv) * 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
IL112795A (en) 1994-03-04 2001-01-28 Astrazeneca Ab Derivatives of peptides as antithrombotic drugs, their preparation, and pharmaceutical preparations containing them
US5561146A (en) * 1994-06-10 1996-10-01 Bristol-Myers Squibb Company Modified guanidino and amidino thrombin inhibitors
DE4421052A1 (de) 1994-06-17 1995-12-21 Basf Ag Neue Thrombininhibitoren, ihre Herstellung und Verwendung
DE4443390A1 (de) * 1994-12-06 1996-06-13 Basf Ag Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten
WO1996024609A1 (de) * 1995-02-10 1996-08-15 Basf Aktiengesellschaft Thrombininhibitoren
KR100388185B1 (ko) * 1995-02-17 2003-11-28 애보트 게엠베하 운트 콤파니 카게 트롬빈 억제제로서의 신규 디펩티드 아미딘
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
CA2176414A1 (en) * 1995-05-18 1996-11-19 S. David Kimball Acyl guanidine and amidine prodrugs
SA96170106A (ar) * 1995-07-06 2005-12-03 أسترا أكتيبولاج مشتقات حامض أميني جديدة
HUP9802291A3 (en) * 1995-07-26 1999-06-28 Mitsubishi Chem Corp Penicillaminamide derivatives and pharmaceutical compositions containing them
AR005245A1 (es) 1995-12-21 1999-04-28 Astrazeneca Ab Prodrogas de inhibidores de trombina, una formulación farmaceutica que las comprende, el uso de dichas prodrogas para la manufactura de un medicamento y un procedimiento para su preparacion
AU1990197A (en) * 1996-03-12 1997-10-01 Bristol-Myers Squibb Company Carbamyl guanidine and amidine prodrugs
US5811402A (en) * 1996-03-22 1998-09-22 Eli Lilly And Company Antithrombotic diamides
SE9602263D0 (sv) 1996-06-07 1996-06-07 Astra Ab New amino acid derivatives
US6200967B1 (en) 1996-06-25 2001-03-13 Eli Lilly And Company Anticoagulant agents
US5863929A (en) * 1996-06-25 1999-01-26 Eli Lilly And Company Anticoagulant agents
SE9602646D0 (sv) 1996-07-04 1996-07-04 Astra Ab Pharmaceutically-useful compounds
AR013084A1 (es) 1997-06-19 2000-12-13 Astrazeneca Ab Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados
DE69805592T2 (de) * 1997-11-19 2003-01-09 Mitsubishi Chem Corp Ein 1/2-Sulfat des ((S)-1-((S)-2-((Trans-4-aminocyclohexylmethyl)carbamoyl)-pyrrolidine-1-carbonyl)-2-iso-propylthio-2-methylpropyl)-carbamidsäurepropylesters
SE9704543D0 (sv) 1997-12-05 1997-12-05 Astra Ab New compounds
SE9802939D0 (sv) 1998-09-01 1998-09-01 Astra Ab New process
SE9804313D0 (sv) * 1998-12-14 1998-12-14 Astra Ab New compounds
BR0007453A (pt) 1999-01-13 2001-10-30 Astrazeneca Ab Composto, formulação farmacêutica, uso de umcomposto, método de tratamento de uma condiçãoonde a inibição da trombina é requerida e,processo de preparação de um composto
FR2791683A1 (fr) * 1999-03-30 2000-10-06 Synthelabo Derives de n-sulfonyl-dipeptides, leur preparation et leur application en therapeutique
AR023510A1 (es) 1999-04-21 2002-09-04 Astrazeneca Ab Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina.
US6316488B1 (en) * 1999-06-17 2001-11-13 Merck & Co., Inc. Antibiotic compound
SE0001803D0 (sv) 2000-05-16 2000-05-16 Astrazeneca Ab New compounds i
EP1808440B1 (de) * 2000-08-11 2011-07-27 Wilex AG Nicht-kovalente Inhibitoren von Urokinase und Blutgefäßbildung
JP2004506648A (ja) * 2000-08-11 2004-03-04 コーバス インターナショナル, インコーポレイテッド ウロキナーゼおよび血管形成の非共有結合性インヒビター
US6433186B1 (en) 2000-08-16 2002-08-13 Astrazeneca Ab Amidino derivatives and their use as thormbin inhibitors
AR035216A1 (es) * 2000-12-01 2004-05-05 Astrazeneca Ab Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios
US7129233B2 (en) * 2000-12-01 2006-10-31 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
JP4179878B2 (ja) * 2001-02-02 2008-11-12 中外製薬株式会社 ペプチド誘導体
US7195759B2 (en) * 2001-06-06 2007-03-27 The University Of Manitoba Therapeutic uses of glandular kallikrein
US20090162342A1 (en) * 2001-06-07 2009-06-25 Sanomune Inc. Therapeutic uses of glandular kallikrein
AR034517A1 (es) 2001-06-21 2004-02-25 Astrazeneca Ab Formulacion farmaceutica
US7838560B2 (en) 2002-03-11 2010-11-23 The Medicines Company (Leipzig) Gmbh Urokinase inhibitors, production and use thereof
SE0201659D0 (sv) 2002-05-31 2002-05-31 Astrazeneca Ab Modified release pharmaceutical formulation
SE0201661D0 (sv) * 2002-05-31 2002-05-31 Astrazeneca Ab New salts
DE10234058A1 (de) * 2002-07-26 2004-02-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Benzoesäureamide, deren Herstellung und deren Verwendung als Arzneimittel
DE10301300B4 (de) 2003-01-15 2009-07-16 Curacyte Chemistry Gmbh Verwendung von acylierten 4-Amidino- und 4-Guanidinobenzylaminen zur Inhibierung von Plasmakallikrein
US7781424B2 (en) * 2003-05-27 2010-08-24 Astrazeneca Ab Modified release pharmaceutical formulation
DE10342108A1 (de) * 2003-09-11 2005-04-14 Curacyte Chemistry Gmbh Basisch-substituierte Benzylaminanaloga als Inhibitoren des Gerinnungsfaktors Xa, ihre Herstellung und Verwendung
US7795205B2 (en) 2004-04-12 2010-09-14 Canyon Pharmaceuticals, Inc. Methods for effecting regression of tumor mass and size in a metastasized pancreatic tumor
US7524354B2 (en) * 2005-07-07 2009-04-28 Research Foundation Of State University Of New York Controlled synthesis of highly monodispersed gold nanoparticles
DE102005044319A1 (de) 2005-09-16 2007-03-22 Curacyte Chemistry Gmbh 2-(Aminomethyl)-5-Chlor-Benzylamid-Derivate und ihre Verwendung als Hemmstoffe des Gerinnungsfaktors Xa
CN101033209B (zh) * 2006-03-09 2014-08-27 上海医药工业研究院 药物中间体(2s,4r)-4-羟基-n,n-二甲基-2-吡咯烷甲酰胺的制备方法
DE102006050672A1 (de) 2006-10-24 2008-04-30 Curacyte Discovery Gmbh Hemmstoffe des Plasmins und des Plasmakallikreins
TW200827336A (en) 2006-12-06 2008-07-01 Astrazeneca Ab New crystalline forms
US20090061000A1 (en) * 2007-08-31 2009-03-05 Astrazeneca Ab Pharmaceutical formulation use 030
CN102464701B (zh) * 2010-11-08 2015-10-21 上海医药工业研究院 一类新型化合物、其制备方法及用途
US8497245B2 (en) * 2010-12-21 2013-07-30 The Medicines Company (Leipzig) Gmbh Trypsin-like serine protease inhibitors, their preparation and use as selective inhibitors of the clotting factors IIa and Xa
WO2013173923A1 (en) 2012-05-25 2013-11-28 Diamedica, Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
SI2854841T1 (sl) 2012-06-04 2017-06-30 Diamedica Inc. Glikozilacijske izooblike humanega tkivnega kalikreina-1
US11857608B2 (en) 2017-03-09 2024-01-02 Diamedica Inc. Dosage forms of tissue kallikrein 1

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JPH0813834B2 (ja) * 1990-08-01 1996-02-14 日東紡績株式会社 トリペプチド誘導体及びそれを有効成分とする蛋白分解酵素阻害剤
CA2075154A1 (en) * 1991-08-06 1993-02-07 Neelakantan Balasubramanian Peptide aldehydes as antithrombotic agents
CA2129339C (en) * 1992-02-14 2002-09-10 George P. Vlasuk Inhibitors of thrombosis
AU675981B2 (en) * 1992-12-02 1997-02-27 Bristol-Myers Squibb Company Guanidinyl-substituted heterocyclic thrombin inhibitors

Also Published As

Publication number Publication date
AU1025795A (en) 1995-08-03
EP0669317A1 (de) 1995-08-30
CN1066712C (zh) 2001-06-06
RU95101048A (ru) 1996-10-27
FI950309A0 (fi) 1995-01-24
CA2140598C (en) 2010-03-09
CN1121068A (zh) 1996-04-24
ATE223378T1 (de) 2002-09-15
ZA95631B (en) 1995-10-05
FI950309A (fi) 1995-07-28
TW306917B (de) 1997-06-01
CA2140598A1 (en) 1995-07-28
US5744487A (en) 1998-04-28
ES2182852T3 (es) 2003-03-16
NO950297D0 (no) 1995-01-26
HUT72062A (en) 1996-03-28
NZ270395A (en) 1997-06-24
KR950032114A (ko) 1995-12-20
NO950297L (no) 1995-07-28
DE69528005T2 (de) 2003-04-17
EP0669317B1 (de) 2002-09-04
HU9500240D0 (en) 1995-03-28

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