PT98545A - Processo para a preparacao de novos conjugados de antraciclinas utilizados como ligantes de agentes bioactivos - Google Patents

Processo para a preparacao de novos conjugados de antraciclinas utilizados como ligantes de agentes bioactivos

Info

Publication number
PT98545A
PT98545A PT98545A PT9854591A PT98545A PT 98545 A PT98545 A PT 98545A PT 98545 A PT98545 A PT 98545A PT 9854591 A PT9854591 A PT 9854591A PT 98545 A PT98545 A PT 98545A
Authority
PT
Portugal
Prior art keywords
anthraciclin
ligants
preparation
new
bioactive agents
Prior art date
Application number
PT98545A
Other languages
English (en)
Other versions
PT98545B (pt
Inventor
Francesco Angelucci
Laura Bersani
Michele Caruso
Marina Ripamonti
Daniela Ruggieri
Antonio Suarato
Original Assignee
Erba Farmitalia
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 Erba Farmitalia filed Critical Erba Farmitalia
Publication of PT98545A publication Critical patent/PT98545A/pt
Publication of PT98545B publication Critical patent/PT98545B/pt

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • External Artificial Organs (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
PT98545A 1990-08-03 1991-08-01 Processo para a preparacao de novos conjugados de antraciclinas utilizados como ligantes de agentes bioactivos PT98545B (pt)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB909017024A GB9017024D0 (en) 1990-08-03 1990-08-03 New linker for bioactive agents

Publications (2)

Publication Number Publication Date
PT98545A true PT98545A (pt) 1992-06-30
PT98545B PT98545B (pt) 1999-01-29

Family

ID=10680097

Family Applications (1)

Application Number Title Priority Date Filing Date
PT98545A PT98545B (pt) 1990-08-03 1991-08-01 Processo para a preparacao de novos conjugados de antraciclinas utilizados como ligantes de agentes bioactivos

Country Status (28)

Country Link
US (2) US5387578A (pt)
EP (1) EP0495053B1 (pt)
JP (1) JP3169222B2 (pt)
KR (1) KR920702234A (pt)
CN (1) CN1058598A (pt)
AT (1) ATE135919T1 (pt)
AU (1) AU650900B2 (pt)
CA (1) CA2067184C (pt)
CS (1) CS241491A3 (pt)
DE (1) DE69118350T2 (pt)
DK (1) DK0495053T3 (pt)
ES (1) ES2088013T3 (pt)
FI (1) FI100697B (pt)
GB (1) GB9017024D0 (pt)
GR (1) GR3019449T3 (pt)
HU (1) HUT61898A (pt)
IE (1) IE76467B1 (pt)
IL (2) IL98986A (pt)
MY (1) MY106526A (pt)
NO (1) NO921287L (pt)
NZ (1) NZ239165A (pt)
PH (1) PH31048A (pt)
PT (1) PT98545B (pt)
RU (1) RU2116087C1 (pt)
TW (1) TW211572B (pt)
WO (1) WO1992002255A1 (pt)
YU (1) YU48441B (pt)
ZA (1) ZA916025B (pt)

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US5439936A (en) * 1989-10-03 1995-08-08 The Regents Of The University Of California Method of treating certain tumors using illudin analogs
GB9017024D0 (en) * 1990-08-03 1990-09-19 Erba Carlo Spa New linker for bioactive agents
DE4236237A1 (de) * 1992-10-27 1994-04-28 Behringwerke Ag Prodrugs, ihre Herstellung und Verwendung als Arzneimittel
GB9309663D0 (en) * 1993-05-11 1993-06-23 Erba Carlo Spa Biologically active compounds
GB9416007D0 (en) * 1994-08-08 1994-09-28 Erba Carlo Spa Anthracyclinone derivatives
US5783178A (en) * 1994-11-18 1998-07-21 Supratek Pharma. Inc. Polymer linked biological agents
US6030941A (en) * 1996-05-01 2000-02-29 Avi Biopharma, Inc. Polymer composition for delivering substances in living organisms
AU729643B2 (en) * 1996-05-01 2001-02-08 Antivirals Inc. Polypeptide conjugates for transporting substances across cell membranes
US5932553A (en) * 1996-07-18 1999-08-03 The Regents Of The University Of California Illudin analogs useful as antitumor agents
US5723632A (en) 1996-08-08 1998-03-03 Mgi Pharma, Inc. Total synthesis of antitumor acylfulvenes
DE19636889A1 (de) 1996-09-11 1998-03-12 Felix Dr Kratz Antineoplastisch wirkende Transferrin- und Albuminkonjugate zytostatischer Verbindungen aus der Gruppe der Anthrazykline, Alkylantien, Antimetabolite und Cisplatin-Analoga und diese enthaltende Arzneimittel
AU7124598A (en) * 1997-04-18 1998-11-13 Access Pharmaceuticals, Inc. Polymer-platinum compounds
US5965118A (en) * 1997-04-18 1999-10-12 Access Pharmaceuticals, Inc. Polymer-platinum compounds
CA2291074C (en) * 1997-05-21 2008-04-01 The Board Of Trustees Of The Leland Stanford Junior University Composition and method for enhancing transport across biological membranes
US6531230B1 (en) * 1998-01-13 2003-03-11 3M Innovative Properties Company Color shifting film
US6025328A (en) 1998-02-20 2000-02-15 The Regents Of The University Of California Antitumor agents
US7141603B2 (en) * 1999-02-19 2006-11-28 The Regents Of The University California Antitumor agents
CA2336564C (en) * 1998-07-30 2011-06-28 Amdex A/S Method for preparing water-soluble cross-linked conjugates
US6706892B1 (en) * 1999-09-07 2004-03-16 Conjuchem, Inc. Pulmonary delivery for bioconjugation
AU775373B2 (en) 1999-10-01 2004-07-29 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
MXPA03003401A (es) * 2000-10-16 2004-06-30 Neopharm Inc Formulacion liposomica de mitoxantrona.
US6825166B2 (en) * 2001-03-23 2004-11-30 Tapestry Pharmaceuticals, Inc. Molecular conjugates for use in treatment of cancer
US20040234497A1 (en) * 2001-05-04 2004-11-25 Yi Luo Hyaluronic acid containing bioconjugates:targeted delivery of anti-cancer drugs to cancer cells
CN1463270A (zh) * 2001-05-31 2003-12-24 梅达莱克斯公司 细胞毒素、其有用的前体药物、连接基团和稳定剂
CA2483696A1 (en) * 2002-05-06 2003-11-20 University Of Utah Research Foundation Preblocking with non-ha gags increases effectiveness of ha conjugated anticancer agents
MXPA06013413A (es) * 2004-05-19 2007-01-23 Medarex Inc Enlazadores quimicos y conjugados de los mismos.
RU2402548C2 (ru) * 2004-05-19 2010-10-27 Медарекс, Инк. Химические линкеры и их конъюгаты
US20060105941A1 (en) * 2004-11-12 2006-05-18 Allergan, Inc. Mixed antibiotic codrugs
US7714016B2 (en) * 2005-04-08 2010-05-11 Medarex, Inc. Cytotoxic compounds and conjugates with cleavable substrates
JP4989648B2 (ja) * 2005-08-03 2012-08-01 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 抗癌剤として有用なイルジン類似体
ES2416136T3 (es) * 2005-09-26 2013-07-30 Medarex, Inc. Conjugados de anticuerpo-fármaco y su uso
ES2375843T3 (es) 2005-10-26 2012-03-06 Medarex, Inc. Procedimientos y compuestos para la preparación de an�?logos de cc-1065.
WO2007059404A2 (en) 2005-11-10 2007-05-24 Medarex, Inc. Duocarmycin derivatives as novel cytotoxic compounds and conjugates
TWI412367B (zh) 2006-12-28 2013-10-21 Medarex Llc 化學鏈接劑與可裂解基質以及其之綴合物
CN101616911A (zh) * 2007-02-21 2009-12-30 梅达莱克斯公司 具有单个氨基酸的化学连接物及其偶联物
US8742076B2 (en) * 2008-02-01 2014-06-03 Genentech, Inc. Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods
AR072804A1 (es) 2008-07-15 2010-09-22 Genentech Inc Conjugados derivados de antraciclina,proceso para su preparacion,composiciones farmaceuticas que los contienen y su uso como agentes antitumorales.
BR112013013127B1 (pt) 2010-12-02 2021-06-22 Nerviano Medical Sciences S.R.L. Processo para a preparação de derivados de morfolinil antraciclina, compostos derivados de morfolinil antraciclina e composição farmacêutica compreendendo estes compostos
WO2014067960A2 (en) 2012-10-30 2014-05-08 Nerviano Medical Sciences S.R.L. Functionalized 9-bromo-camptothecin derivatives
WO2014080251A1 (en) 2012-11-24 2014-05-30 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules
KR102178606B1 (ko) 2013-03-15 2020-11-13 자임워크스 인코포레이티드 세포독성 및 유사분열-억제 화합물, 및 이를 사용하는 방법
RU2729194C2 (ru) 2013-12-27 2020-08-05 Займворкс Инк. Сульфонамидсодержащие связывающие системы для лекарственных конъюгатов
PT3122757T (pt) 2014-02-28 2023-11-03 Hangzhou Dac Biotech Co Ltd Ligantes carregados e as suas utilizações em conjugação
RU2723651C2 (ru) 2014-09-17 2020-06-17 Займворкс Инк. Цитотоксические и антимитотические соединения и способы их применения
CN108449940B (zh) 2015-07-12 2021-06-08 杭州多禧生物科技有限公司 与细胞结合分子的共轭偶联的桥连接体
US9839687B2 (en) 2015-07-15 2017-12-12 Suzhou M-Conj Biotech Co., Ltd. Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule
CA3020864A1 (en) 2016-04-15 2017-10-19 Macrogenics, Inc. Novel b7-h3-binding molecules, antibody drug conjugates thereof and methods of use thereof
CN110099682B (zh) 2016-11-14 2023-03-31 杭州多禧生物科技有限公司 偶联连接体，含有此连接体的细胞结合分子-药物偶联物及其制备和应用
US10386338B2 (en) 2017-10-30 2019-08-20 Cynthia Rena Wright DNA/RNA PEMS microcantilever probe for detection of viral infection and detection of genetic variants
WO2022078524A2 (en) 2021-11-03 2022-04-21 Hangzhou Dac Biotech Co., Ltd. Specific conjugation of an antibody

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GB2098219A (en) * 1981-05-08 1982-11-17 Erba Farmitalia Daunorubicin-protein conjugates
JPS63241541A (ja) * 1987-03-30 1988-10-06 Konica Corp 感光性組成物および感光性平版印刷版
IL89220A (en) * 1988-02-11 1994-02-27 Bristol Myers Squibb Co Anthracycline immunoconjugates, their production and pharmaceutical compositions containing them
US5066490A (en) * 1988-06-01 1991-11-19 The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services Protein crosslinking reagents cleavable within acidified intracellular vesicles
GB9017024D0 (en) * 1990-08-03 1990-09-19 Erba Carlo Spa New linker for bioactive agents

Also Published As

Publication number Publication date
HU9201146D0 (en) 1992-07-28
FI921451A0 (fi) 1992-04-02
ATE135919T1 (de) 1996-04-15
ZA916025B (en) 1992-04-29
EP0495053A1 (en) 1992-07-22
IE76467B1 (en) 1997-10-22
PT98545B (pt) 1999-01-29
TW211572B (pt) 1993-08-21
PH31048A (en) 1998-02-03
YU134691A (sh) 1994-06-10
CA2067184C (en) 2002-11-26
IL98986A (en) 1995-12-08
US5387578A (en) 1995-02-07
HUT61898A (en) 1993-03-29
US5547667A (en) 1996-08-20
IE912757A1 (en) 1992-02-12
EP0495053B1 (en) 1996-03-27
KR920702234A (ko) 1992-09-03
ES2088013T3 (es) 1996-08-01
MY106526A (en) 1995-06-30
DE69118350T2 (de) 1996-08-22
CN1058598A (zh) 1992-02-12
AU650900B2 (en) 1994-07-07
DK0495053T3 (da) 1996-04-22
CA2067184A1 (en) 1992-02-04
IL113101A0 (en) 1995-06-29
FI100697B (fi) 1998-02-13
GR3019449T3 (en) 1996-06-30
NO921287D0 (no) 1992-04-02
NO921287L (no) 1992-04-02
RU2116087C1 (ru) 1998-07-27
FI921451L (fi) 1992-04-02
CS241491A3 (en) 1992-02-19
IL98986A0 (en) 1992-07-15
DE69118350D1 (de) 1996-05-02
GB9017024D0 (en) 1990-09-19
AU8311391A (en) 1992-03-02
JPH05501726A (ja) 1993-04-02
JP3169222B2 (ja) 2001-05-21
WO1992002255A1 (en) 1992-02-20
NZ239165A (en) 1993-09-27
YU48441B (sh) 1998-07-10

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