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WO1993017651A2 - Analogues nucleosidiques antiviraux, leur fabrication et leur utilisation - Google Patents

Analogues nucleosidiques antiviraux, leur fabrication et leur utilisation Download PDF

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Publication number
WO1993017651A2
WO1993017651A2 PCT/DE1993/000213 DE9300213W WO9317651A2 WO 1993017651 A2 WO1993017651 A2 WO 1993017651A2 DE 9300213 W DE9300213 W DE 9300213W WO 9317651 A2 WO9317651 A2 WO 9317651A2
Authority
WO
WIPO (PCT)
Prior art keywords
fluoro
thymine
guanine
adenine
compounds
Prior art date
Application number
PCT/DE1993/000213
Other languages
German (de)
English (en)
Other versions
WO1993017651A3 (fr
Inventor
Eckart Matthes
Martin Von Janta-Lipinski
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
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 Max-Delbrück-Centrum für Molekulare Medizin filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Publication of WO1993017651A2 publication Critical patent/WO1993017651A2/fr
Publication of WO1993017651A3 publication Critical patent/WO1993017651A3/fr

Links

Classifications

    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • Antiviral nucleoside analogues their preparation and their use
  • the invention relates to pyrimidine and purine nucleoside analogs, processes for their preparation and their use as pharmaceutical active substances or agents for the prophylaxis and / or treatment of infections, in particular those caused by the hepatitis B virus (HBV) or HIV (human immunodeficiency virus).
  • HBV hepatitis B virus
  • HIV human immunodeficiency virus
  • HBV is the triggering agent for hepatitis B, an infectious disease that affects around 200 million people worldwide and whose chronic form is associated with an increased risk of primary liver carcinoma, which in China alone has around one million new tumors leads to sick children every year.
  • nucleoside analogues point in the direction of new potentially effective agents, for which an activity against hepatitis B and / or HIV infections is claimed in the following patent applications: 1. 3 'fluomucleosides of adenine, guanine, cytosine and thymine (EP 0 277 151 and EP 0 254 268)
  • the invention has for its object to provide new pyrimidine and Purix nucleosides and their preparation, which are effective against hepatitis B and HIV infections and can be used as pharmaceutical agents for the prophylaxis and / or treatment of corresponding infections, and to show other compounds which good tolerance and low toxicity are highly effective against these infections.
  • B thymine, uracil, 5-halouracil, 5-azidouracil, 5-hydroxymethyluracil, 5-formyluracil, 5-ethyluracil, 5-chloroethyluracil,
  • Cytosine 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, 5-ethylcytosine
  • R 3 H, OH, F, N 3 , NH 2
  • R 4 OH, O-acetyl, O-palmitoyl, alkoxycarbonyl, phosphonate,
  • B thymine, uracil, cytosine, adenine or guanine
  • R H, then R is OH, O-acetyl, O-palmitoyl, 0-alkoxycarbonyl, mono-, di-, triphosphate,
  • R, R H, F, Cl, Br, NH 2 , N3, SCN, phosphonate, phosphoamide mean.
  • pyrimidine and purine nucleosides are active substances against viral infections, as are caused in particular by the hepatitis B virus (HBV) and HIV. They can be used advantageously as such and in the form of pharmaceutical agents together with suitable auxiliaries and / or carriers for the treatment and / or prophylaxis of hepatitis B and AIDS.
  • the compounds of the formula I are synthesized by oxidation of the optionally protected 5 * -deoxy-5 * -iodo-4 ⁇ - fluorine derivatives or the ( ⁇ ) 4- ⁇ -fluoro-4 ⁇ -iodomethylcyclopent-1-yl derivatives with silver (II) oxide, subsequent reduction with borohydride and removal of existing protective groups.
  • Compounds of the formula II are prepared by treating the optionally protected 3 ⁇ -hydroxycyclopent-l-yl derivatives of the corresponding heterocycles with DAST and then removing the protective groups present.
  • compounds of the formula III are prepared by nucleophilic substitution of sulfonyloxy or other groups in the corresponding, optionally protected cyclopent-1-yl derivatives of the respective heterocycles and, if appropriate, modification by subsequent reactions, for example by hydrogenolysis and removal of existing protective groups.
  • Treatment and / or prophylaxis of hepatitis B and HIV infections according to the invention consists in the administration of an effective amount of one or more compounds of the formulas I, II and / or III as such or in the form of suitable formulations.
  • the pharmaceutical preparations according to the invention which are suitable for prophylaxis and / or therapy, in particular of infections caused by the hepatitis B virus or HIV, contain at least one pyrimidine or purine nucleoside of the formulas I, II and / or III , as defined above, as an active ingredient in addition to a pharmaceutically suitable auxiliary and / or carrier or several such additives and optionally other therapeutic agents or active ingredients.
  • the agents are advantageously produced in the form of dosing units with one or more unit doses.
  • the invention further relates to the use of compounds of the following general formulas IV, V and VI against infections, in particular by the hepatitis B virus (IV and V) or by the hepatitis B virus and HIV (VI).
  • IV and V hepatitis B virus
  • VI hepatitis B virus and HIV
  • B thymine, uracil, cytosine, adenine, guanine
  • R 8 , R 9 and R 10 H or
  • R 11 OH, O-acetyl, O-palmitoyl, alkoxycarbonyl, mono-, di-,
  • B 1 thymine, uracil, cytosine, adenine, guanine and
  • B 1 adenine
  • R 1 H
  • R 2 OH
  • R 6 F
  • R 7 NH.
  • the compounds of the formulas IV and V are particularly effective compounds for the treatment and / or prophylaxis of hepatitis B infections.
  • Compounds of the formula VI with the stated restriction are also effective against HIV infections. They are used for the production of corresponding pharmaceutical agents.
  • the pharmaceutical compositions are produced in the form of dosage units or multiples thereof.
  • the auxiliaries and carriers used must be compatible, compatible with the other components of the agent and harmless to the patient.
  • the pharmaceutical formulations or application forms of the pharmaceutical compositions according to the invention include those which are suitable for oral, rectal, nasal, topical, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • One or more active ingredients are combined with the carrier, which consists of several Accompanying components can be composed, brought into contact and, if necessary, converted into a corresponding pharmaceutical form.
  • compositions for oral administration are produced in the form of coated tablets, tablets, capsules, as a powder or as granules, each of which contains a certain amount of the active ingredient. They can also be formulated as solutions or as suspensions. If necessary, flavoring agents and / or other customary additives are added. Means for rectal administration are made as suppositories with a suitable basis. Medicines for vaginal administration are e.g. Formulated as pessaries, tampons, creams, gels, pastes, foams or spray products.
  • the agents for parenteral administration can contain one dosage unit of the active ingredient or a multiple thereof and can be stored, for example, in ampoules, vials or in a freeze-dried state. Injection solutions and suspensions prepared immediately before use can be obtained from sterile powders, granules and tablets, e.g. B. by dissolving the substance in physiological saline, glucose or other media suitable for IV injection or infusion.
  • ( ⁇ ) -Iß- (3ß-hydroxy-4ß-trityloxymethylcyclopent-l-yl) 5-methylcytosine are in 30 ml Dissolved dichloromethane and mixed with 3.5 mmol of DAST with stirring. The reaction mixture remains at room temperature for 2 hours. It is then neutralized with bicarbonate and the solvent removed in vacuo. The residue is heated in 50 ml of 80% acetic acid for 3 hours at 90 ° C. After the solvent has been removed in vacuo, the residue is purified by column chromatography on silica gel 40 (0.063-0.2 mm, Merck) with chloroform (5% methanol). 47 mg of the title compound are isolated.
  • the starting nucleoside is completely converted within 90 minutes.
  • Reaction solution is neutralized with sodium bicarbonate and i. Vac. evaporated to dryness. The residue is i. Vac.
  • Reaction solution becomes the solvent i. Vac. away.
  • the remaining residue is on silica gel G (0.063 - 0.2 mm,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des analogues nucléosidiques connus, ainsi que des nouveaux, qui sont particulièrement actifs dans le traitement contre l'hépatite B et les infections à VIH. L'invention concerne également leur fabrication et leur utilisation.
PCT/DE1993/000213 1992-03-04 1993-03-03 Analogues nucleosidiques antiviraux, leur fabrication et leur utilisation WO1993017651A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4207363.4 1992-03-04
DE19924207363 DE4207363A1 (de) 1992-03-04 1992-03-04 Antivirale nucleosidanaloga, ihre herstellung und ihre pharmazeutische verwendung

Publications (2)

Publication Number Publication Date
WO1993017651A2 true WO1993017651A2 (fr) 1993-09-16
WO1993017651A3 WO1993017651A3 (fr) 1993-11-25

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DE (1) DE4207363A1 (fr)
WO (1) WO1993017651A2 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995022330A1 (fr) * 1994-02-17 1995-08-24 Commonwealth Scientific And Industrial Research Organisation Agents antiviraux
WO2004046159A1 (fr) * 2002-11-19 2004-06-03 F. Hoffmann-La-Roche Ag Derives nucleosidiques antiviraux
CN100351264C (zh) * 2002-11-19 2007-11-28 霍夫曼-拉罗奇有限公司 抗病毒核苷衍生物
JP2009510075A (ja) * 2005-09-26 2009-03-12 ファーマセット，インコーポレイティド 抗ウイルス剤としての修飾４’−ヌクレオシド
US7608601B2 (en) 2001-06-12 2009-10-27 Roche Palo Alto Llc 4′-Substituted nucleoside derivatives as inhibitors of HCV RNA replication
CN104193801A (zh) * 2014-08-12 2014-12-10 苏州维泰生物技术有限公司 一种鸟嘌呤肽核酸单体及其合成方法
US9249173B2 (en) 2006-12-28 2016-02-02 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
CN107254539A (zh) * 2011-07-29 2017-10-17 剑桥表现遗传学有限公司 用于检测核苷酸修饰的方法
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
US10202411B2 (en) 2014-04-16 2019-02-12 Idenix Pharmaceuticals Llc 3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV
US10231986B2 (en) 2013-03-13 2019-03-19 Idenix Pharmaceuticals Llc Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV
US10238680B2 (en) 2013-08-01 2019-03-26 Idenix Pharmaceuticals Llc D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
US10513534B2 (en) 2012-10-08 2019-12-24 Idenix Pharmaceuticals Llc 2′-chloro nucleoside analogs for HCV infection
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
US10717758B2 (en) 2012-05-22 2020-07-21 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
EP3762372A4 (fr) * 2018-03-07 2021-12-08 Emory University Compositions thérapeutiques à base de nucléosides et de nucléotides contenant 4-halogène et utilisations associées
RU2819040C2 (ru) * 2018-03-07 2024-05-13 Эмори Юниверсити Терапевтические композиции 4’-галогенсодержащих нуклеотидов и нуклеозидов и их применение

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2691409B1 (fr) 2011-03-31 2018-02-21 Idenix Pharmaceuticals LLC. Composés et compositions pharmaceutiques pour le traitement d'infections virales
TW201329096A (zh) 2011-09-12 2013-07-16 Idenix Pharmaceuticals Inc 經取代羰氧基甲基磷酸醯胺化合物及用於治療病毒感染之藥學組成物
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
EP2852604B1 (fr) 2012-05-22 2017-04-12 Idenix Pharmaceuticals LLC Promédicaments de 3',5'-phosphoramidate cyclique pour traiter une infection par le virus de l'hépatite c
EP2900682A1 (fr) 2012-09-27 2015-08-05 IDENIX Pharmaceuticals, Inc. Esters et malonates de promédicaments à base de s-acyl-2-thioéthyle (sate)
WO2014099941A1 (fr) 2012-12-19 2014-06-26 Idenix Pharmaceuticals, Inc. 4'-fluoro-nucléosides pour le traitement du vhc
US9309275B2 (en) 2013-03-04 2016-04-12 Idenix Pharmaceuticals Llc 3′-deoxy nucleosides for the treatment of HCV
EP2981542B1 (fr) 2013-04-01 2021-09-15 Idenix Pharmaceuticals LLC 2',4'-fluoronucléosides pour le traitement du vhc

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EP0277599A3 (fr) * 1987-01-30 1990-05-09 Asahi Glass Company Ltd. Dérivés de cyclopentane contenant du fluor et procédés pour leur préparation
CA1327000C (fr) * 1987-08-07 1994-02-15 David L.J. Tyrrell Therapie antivirale pour l'hepatite b
SE8704298D0 (sv) * 1987-11-03 1987-11-03 Astra Ab Compounds for use in therapy
EP0375183A1 (fr) * 1988-12-05 1990-06-27 Schering Corporation Dimers et trimers antiviraux
WO1991019727A1 (fr) * 1990-06-19 1991-12-26 Sloan-Kettering Institute For Cancer Research 5-hydrogenophosphonates et 5'-methylphosphonates de nucleosides modifies du sucre, compositions et utilisations de ces produits pour traiter des infections virales
DE4021006A1 (de) * 1990-07-02 1992-01-09 Hoechst Ag Pyrimidin-derivate, deren herstellung und verwendung sowie diese enthaltende arzneimittel

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995022330A1 (fr) * 1994-02-17 1995-08-24 Commonwealth Scientific And Industrial Research Organisation Agents antiviraux
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US7608601B2 (en) 2001-06-12 2009-10-27 Roche Palo Alto Llc 4′-Substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
HRP20050417B1 (hr) * 2002-11-19 2013-11-08 F. Hoffmann - La Roche Ag Antiviralni derivati nukleozida
WO2004046159A1 (fr) * 2002-11-19 2004-06-03 F. Hoffmann-La-Roche Ag Derives nucleosidiques antiviraux
CN100351264C (zh) * 2002-11-19 2007-11-28 霍夫曼-拉罗奇有限公司 抗病毒核苷衍生物
US8569478B2 (en) 2005-09-26 2013-10-29 Gilead Pharmasset Llc Modified 4′-nucleosides as antiviral agents
AU2006294807B2 (en) * 2005-09-26 2013-01-17 Gilead Pharmasset Llc Modified 4'-nucleosides as antiviral agents
JP2009510075A (ja) * 2005-09-26 2009-03-12 ファーマセット，インコーポレイティド 抗ウイルス剤としての修飾４’−ヌクレオシド
US9249173B2 (en) 2006-12-28 2016-02-02 Idenix Pharmaceuticals, Llc Compounds and pharmaceutical compositions for the treatment of viral infections
CN107254539A (zh) * 2011-07-29 2017-10-17 剑桥表现遗传学有限公司 用于检测核苷酸修饰的方法
US10717758B2 (en) 2012-05-22 2020-07-21 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
US10040814B2 (en) 2012-05-25 2018-08-07 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US10774106B2 (en) 2012-05-25 2020-09-15 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US10544184B2 (en) 2012-05-25 2020-01-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US9845336B2 (en) 2012-05-25 2017-12-19 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US10301347B2 (en) 2012-05-25 2019-05-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US10513534B2 (en) 2012-10-08 2019-12-24 Idenix Pharmaceuticals Llc 2′-chloro nucleoside analogs for HCV infection
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
US10231986B2 (en) 2013-03-13 2019-03-19 Idenix Pharmaceuticals Llc Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
US10238680B2 (en) 2013-08-01 2019-03-26 Idenix Pharmaceuticals Llc D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
US10202411B2 (en) 2014-04-16 2019-02-12 Idenix Pharmaceuticals Llc 3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV
CN104193801A (zh) * 2014-08-12 2014-12-10 苏州维泰生物技术有限公司 一种鸟嘌呤肽核酸单体及其合成方法
EP3762372A4 (fr) * 2018-03-07 2021-12-08 Emory University Compositions thérapeutiques à base de nucléosides et de nucléotides contenant 4-halogène et utilisations associées
GB2611644A (en) * 2018-03-07 2023-04-12 Univ Emory 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto
GB2589205B (en) * 2018-03-07 2023-05-24 Univ Emory 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto
GB2611644B (en) * 2018-03-07 2023-07-26 Univ Emory 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto
RU2819040C2 (ru) * 2018-03-07 2024-05-13 Эмори Юниверсити Терапевтические композиции 4’-галогенсодержащих нуклеотидов и нуклеозидов и их применение
IL277160B1 (en) * 2018-03-07 2024-06-01 Univ Emory 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto
IL277160B2 (en) * 2018-03-07 2024-10-01 Univ Emory 4'-halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Also Published As

Publication number Publication date
DE4207363A1 (de) 1993-09-09
WO1993017651A3 (fr) 1993-11-25

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