WO1984000759A1 - Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals - Google Patents
Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals Download PDFInfo
- Publication number
- WO1984000759A1 WO1984000759A1 PCT/EP1983/000219 EP8300219W WO8400759A1 WO 1984000759 A1 WO1984000759 A1 WO 1984000759A1 EP 8300219 W EP8300219 W EP 8300219W WO 8400759 A1 WO8400759 A1 WO 8400759A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- acid addition
- addition salt
- formula
- free form
- Prior art date
Links
- 0 CC*C(*)C(C(C1C=N)=*)=CN(C(C2C)OC(CO)C2O)C1=O Chemical compound CC*C(*)C(C(C1C=N)=*)=CN(C(C2C)OC(CO)C2O)C1=O 0.000 description 2
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Definitions
- Desoxyuridine derivatives processes for their preparation and their use as pharmaceuticals
- the present invention concerns desoxyuridine derivatives, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals in particular as viricides in particular against herpes viruses.
- R 1 and R 2 represent independently hydrogen or tower alkyl
- R 3 represents halogen, CHF 2 or CF 3 ,
- R 4 represents hydrogen, hydroxy or fluorine
- X represents oxygen or imino, and n is 0 or 1, whereby the sugar radical is ⁇ - or ß-glycosically bound to the pyrimidine ring; in free form or acid addition salt form.
- the compounds of the invention can be prepared according to the invention a) by reacting a compound of formula II
- R 3 group whereby in the formulas Ia, II and III, R 1 , R 2 , R 3 ,
- R 4 , X and n are as defined above, R 5 represents halogen or acyloxy,
- R 3 ' represents hydroxy in free or protected form and any hydroxy group present in the sugar radical may be protected; and when requi red removing any protecting group from the compound thus obtained; and recovering the compound thus obtained in free form or in aci d additi on sal t form.
- Process a) can be carried out for example by converti ng a compound of formula II in conventional manner into i ts trimethylsilyl derivative and reacting this with a compound of formula III whose hydroxy groups are protected in a sol vent eg a halogenated hydrocarbon or acetoni trile.
- a compound of formula Ia in unprotected or protected form can be dissolved in a solvent inert under the reaction conditions eg a Tower alkyl carboxylic acid amide such as di methylformamide.
- R 3 'to halogen can be carried out either with free or with protected OH-groups in the sugar moiety.
- R 3 represents halogen
- the reaction can be carried out using a conventional halogenation method eg employing carbon tetrachloride or bromosuccinimide.
- R 3 represents CHF 2 or CF 3
- the reaction can be carried out using conventional fluorination methods eg from a compound of formula Ia after oxidation to an aldehyde with a dialkylsulfurtrifluoride or after oxidation to a carboxylic acid, with a sulfur tetrafluoride.
- protecting groups are those conventionally employed in reactions of this nature such as p-toluyl, benzyl, p-nitrobenzoyl, trimethylsilyl. These can be introduced and removed using conventional procedures.
- Salt forms can be prepared in conventional manner from free forms and vice versa.
- the compounds of formula I and Ia can be in ⁇ - or ⁇ -configuration with respect to bonding of the sugar radical.
- the compound of formula I is shown in ß-form.
- the pyrimidine radical in the compounds of formula I and Ia can exist in tautorneric forms such as
- the invention is intended to cover all tautorneric forms of the compounds.
- the compounds of formula I and Ia can also exist in the form of optical isomers or mixtures which isomers can be separated in conven tional manner.
- the invention is intended to cover isomer! c forms and mixtures thereof, whereby the compounds are present in the latter form unless otherwise mentioned.
- Lower alkyl groups contain 1 to 4 preferably 1 or 2 carbon atoras.
- the starting materials of formula Ia are also new and form part of the invention. They can be prepared by reacting a compound of formula II a
- R 1 , R 2 , R 3 '.X and n are as defined above analogously to process a) with a compound of formula III
- the compounds of formula II, Ila and III are either known or can be prepared analogously to known methods eg as illustrated hereinafter in the examples.
- End products and intermediates can be isolated and purified in conventional manner.
- the compounds of formula I exhibit chemotherapeutic, in particular anti-viral agents as indicated in particular by their effect against Herpes viruses which can be demonstrated in vitro and in vivo, for example by the reduction of cytopathogenic effects (CPE) of various viruses eg Herpes simplex I and II in vitro from concentration of approx. 0.003 ug / ml to approx. 300 ⁇ g / ml and in vivo in tests carried out in mice and guinea pig using systemic, topical and encephalitis-infection models (of. HE Renis et al. J. Med. Chem. 16 (7) 754 [1973]).
- CPE cytopathogenic effects
- the compounds are therefore useful as chemo therapeutics in particular as agents for combating herpes diseases and infections.
- a suitable daily dosage is from about 200 to 1200 mg suitably given in divided doses two to four times a day containing about 50 to 600 mg of the compounds or in retard form.
- Compounds can be employed in free form or, when the compound is sufficiently basic, also in the form of a chemotherapeutically acceptable acid addition salt thereof, especially when X is imino, which forms have the same Order of activity as the free forms.
- Suitable salt forms include hydrochloride, hydrogen fumarate and naphthalene-1,5-disulfonate.
- Compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and administered in such forms as tablets or capsules or parenterally. Such compositions also form part of the invention.
- the invention therefore also concerns a method of combating herpes diseases or infections comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof and such compounds for use as chemotherapeutic agents, in particular as anti-viral agents especially against herpes viruses.
- R 1 , R 2 a) H b) tower alkyl preferably methyl or ethyl
- R 4 a) H, OH, F b) H, OH, especially H and combinations of these.
- Examples of particular compound groups are thus those of formula I a) wherein R 1 and R 2 represent hydrogen, R 3 represents halogen, R 4 represents hydrogen, hydroxy or fluorine, X represents oxygen or imino and n is 1; b) wherein R 1 and R 2 are as defined above, R 3 represents halogen, X represents oxygen, R 4 represents hydrogen, hydroxy or fluorine and n is 1.
- a particularly preferred individual compound is 1- (2-deoxy- ⁇ -D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione in free form or acid addition salt shape.
- Example 1 1- (2-deoxy- ⁇ -D-erythro-pentofuranosyl) -5 (2-chloroethyl) -
- Example 8 1- ( ⁇ -D-arabinofuranosyl) -5- (2-bromoethyl) - (1H, 3H) - pyrimidine-2,4-dione
- Example 10 4-amino-5- (2-chloroethyl) -1- (2-deoxy- ⁇ -D-erythropento furanosyl) -1H-pyrimidine-2-one 3.12 g of a 4-amino-5- (2- hydroxyethyl) -1H-pyrimidine-2-one are silated analogously to Example 6 and reacted with 7.76 g of 2-deoxy-3,5-di-Op-toluoyl-D-erythro-pentofuranosyl-chloride.
- the required starting materials may be prepared for example as follows:
- the methanol ic residue of the hydrogenation is neutral ised with ion exchanger Merck II (strongly basic), filtered over active carbon, concentrated and the crystalline residue recrystallized from water.
- the title product is obtained as colorless needles mp212-15 °.
- KH-1 ' ⁇ , KH-1' ß proton on C-1 of deoxyribose moiety, the bondi ng properties of whi ch al low assi gnment of anomers.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT904183A ATA904183A (de) | 1982-08-17 | 1983-08-12 | Verfahren zur herstellung von neuen desoxyuridinderivaten |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH492282 | 1982-08-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1984000759A1 true WO1984000759A1 (en) | 1984-03-01 |
Family
ID=4284858
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1983/000219 WO1984000759A1 (en) | 1982-08-17 | 1983-08-12 | Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS5953499A (da) |
AU (1) | AU1800483A (da) |
BE (1) | BE897516A (da) |
DE (1) | DE3390162T1 (da) |
DK (1) | DK372283A (da) |
ES (1) | ES8604943A1 (da) |
FI (1) | FI832884A (da) |
FR (1) | FR2531962B1 (da) |
GB (1) | GB2125401B (da) |
IL (1) | IL69497A0 (da) |
IT (1) | IT1169765B (da) |
NL (1) | NL8302859A (da) |
PT (1) | PT77209B (da) |
SE (1) | SE8304408L (da) |
WO (1) | WO1984000759A1 (da) |
ZA (1) | ZA836072B (da) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0211354A2 (en) * | 1985-07-29 | 1987-02-25 | Merrell Dow Pharmaceuticals Inc. | Nucleosides and their use as antineoplastic agents |
WO1988004662A1 (en) * | 1986-12-19 | 1988-06-30 | Astra Läkemedel Aktiebolag | Use of nucleosides for the manufacture of medicament for treatment of diseases caused by retrovirus or hepatitis b virus |
EP0291230A2 (en) * | 1987-05-11 | 1988-11-17 | Merck & Co. Inc. | 1-(2-(Hydroxymethyl)-cycloalkylmethyl)-5-substituted uracils |
US5215971A (en) * | 1986-12-19 | 1993-06-01 | Medivir Ab | Antiviral pharmaceutical composition comprising 5-substituted pyrimidine nucleosides |
US5409906A (en) * | 1987-04-16 | 1995-04-25 | Medivir Ab | α nucleoside compounds and a method for treating HBV using said compounds |
WO1998045309A1 (en) * | 1997-04-04 | 1998-10-15 | Astra Pharmaceuticals Ltd. | Novel phosphate compounds and their use as medicaments |
EP1425022A1 (en) * | 2001-08-24 | 2004-06-09 | Koronis Pharmaceuticals, Inc. | Mutagenic nucleoside analogs for the treatment of viral disease |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4526988A (en) * | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
US5401838A (en) * | 1992-06-22 | 1995-03-28 | Eli Lilly And Company | Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
MX9303708A (es) * | 1992-06-22 | 1994-05-31 | Lilly Co Eli | Proceso de glucosilacion anionica estereoselectiva para preparar 2'-desoxifluoro-beta nucleosidos. |
US5821357A (en) * | 1992-06-22 | 1998-10-13 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoropurine and triazole nucleosides |
US5426183A (en) * | 1992-06-22 | 1995-06-20 | Eli Lilly And Company | Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
US5594124A (en) * | 1992-06-22 | 1997-01-14 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-Deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides and intermediates thereof |
US5606048A (en) * | 1992-06-22 | 1997-02-25 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
US5371210A (en) * | 1992-06-22 | 1994-12-06 | Eli Lilly And Company | Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
US5424416A (en) * | 1993-08-25 | 1995-06-13 | Eli Lilly And Company | Process for preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonates and their use in preparation of 2',2'-difluoro-2'-deoxy nucleosides |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2915254A1 (de) * | 1978-04-24 | 1979-11-15 | Stichting Rega V Z W | Neue chemische verbindungen, verfahren zu deren herstellung und deren verwendung als arzneimittel mit antiviraler wirkung |
DE3002197A1 (de) * | 1980-01-22 | 1981-07-23 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-alkylsubstituierte pyrimidin-nukleoside, verfahren zu deren herstellung und daraus hergestellte virostatische und cytostatische mittel |
DE3010399A1 (de) * | 1980-03-18 | 1981-09-24 | Kailash Kumar Dr. 2359 Lentföhrden Gauri | Verwendung von 5-haloalkyl-pyrimidin-nukleosiden als virostatika und cytostatika |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3709874A (en) * | 1970-03-19 | 1973-01-09 | Syntex Corp | 1-beta-d-arabinofuranosyl cytosine derivatives and methods of preparing |
GB2060604B (en) * | 1979-10-03 | 1983-11-23 | Univ Birmingham And Stichting | E15-(2-halogenovinyl)-2'-deoxycytidines |
HU183567B (en) * | 1981-09-07 | 1984-05-28 | Mta Koezponti Kemiai Kutato In | Process for preparing /e/-5-/2-bromo-vinyl/-uridine and derivatives thereof |
-
1983
- 1983-08-10 FI FI832884A patent/FI832884A/fi not_active Application Discontinuation
- 1983-08-10 FR FR8313242A patent/FR2531962B1/fr not_active Expired
- 1983-08-11 BE BE0/108521A patent/BE897516A/fr not_active IP Right Cessation
- 1983-08-12 WO PCT/EP1983/000219 patent/WO1984000759A1/de active Application Filing
- 1983-08-12 DE DE19833390162 patent/DE3390162T1/de not_active Withdrawn
- 1983-08-15 DK DK372283A patent/DK372283A/da not_active Application Discontinuation
- 1983-08-15 AU AU18004/83A patent/AU1800483A/en not_active Abandoned
- 1983-08-15 SE SE8304408A patent/SE8304408L/xx not_active Application Discontinuation
- 1983-08-15 IL IL69497A patent/IL69497A0/xx unknown
- 1983-08-15 GB GB08321880A patent/GB2125401B/en not_active Expired
- 1983-08-15 NL NL8302859A patent/NL8302859A/nl not_active Application Discontinuation
- 1983-08-16 IT IT22565/83A patent/IT1169765B/it active
- 1983-08-16 JP JP58150111A patent/JPS5953499A/ja active Pending
- 1983-08-16 PT PT77209A patent/PT77209B/pt unknown
- 1983-08-17 ZA ZA836072A patent/ZA836072B/xx unknown
- 1983-08-17 ES ES524997A patent/ES8604943A1/es not_active Expired
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2915254A1 (de) * | 1978-04-24 | 1979-11-15 | Stichting Rega V Z W | Neue chemische verbindungen, verfahren zu deren herstellung und deren verwendung als arzneimittel mit antiviraler wirkung |
DE3002197A1 (de) * | 1980-01-22 | 1981-07-23 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-alkylsubstituierte pyrimidin-nukleoside, verfahren zu deren herstellung und daraus hergestellte virostatische und cytostatische mittel |
DE3010399A1 (de) * | 1980-03-18 | 1981-09-24 | Kailash Kumar Dr. 2359 Lentföhrden Gauri | Verwendung von 5-haloalkyl-pyrimidin-nukleosiden als virostatika und cytostatika |
Non-Patent Citations (9)
Title |
---|
BIOCHEMISTRY, vol. 21, 20 juillet 1982, Am. Chemical Society, pages 3698-3703; E. LIVNEH et al.: "Light-induced free-radical reactions of purines and pyrimidines in deoxyribonucleic acid. Effect of structure and base sequence on reactivity" * |
CHEMICAL ABSTRACTS, vol. 74, no. 19, 10 mai 1971, page 540, no. 100336k, Columbus, Ohio, US; V.S. GUPTA et al.: "Synthesis and properties of 5-hydroxymethyl-2'-deoxyuridine and its alpha-anomer" & CAN. J. CHEM. 1971, 49(5), 719-24 * |
CHEMICAL ABSTRACTS, vol. 86, no. 15, 11 avril 1977, page 546, no. 106946d, Columbus, Ohio, US; S. YA. MEL'NIK et al.: "Transformation of 5-(polyfluoroalkyl)- and 5-(polyfluoroalkoxymethyl)uridines" & BIOORG. KHIM. 1976, 2(11), 1520-5 * |
CHEMICAL ABSTRACTS, vol. 90, no. 23, 4 june 1979, page 696, no. 187266q, Columbus, Ohio, US; S.YA. MEL'NIK et al.: "Synthesis and study of 5-(polyfluoroalkyl)- and 5-(polyfluoroalkoxymethyl)-2'-deoxypyrimidine nucleosides" & BIOORG. KHIM. 1979, 5(1), 41-6 * |
CHEMICAL ABSTRACTS, vol. 92, no. 25, 23 june 1980, page 31, no. 208903d, Columbus, Ohio, US; T.A. BEKTEMIROV et al.: "Study of the antiviral activity of anomeric 5-substituted 2'-deoxyuridines"& VOPR. VIRUSOL. 1979, (6), 603-6 * |
CHEMICAL ABSTRACTS, vol. 97, no. 23, 6 décembre 1982, page 608, no. 198501h, Columbus, Ohio, US; S.Y. MEL'NIK et al.: "Synthesis of thymidine analogs with branched substitutions at the 5 position of the pyrimidine ring" & BIOORG. KHIM. 1982, 8(8), 1102-7 * |
EIGHTH SYMPOSIUM ON NUCLEIC ACIDS CHEMISTRY, held in Sapporo, 21-23 août 1980, Nucleic Acids Symposium Series no. 8, Information Retrieval Ltd., 1980 (londres, GB), pages S39-S42; S. SHINJI et al.: "Synthesis and antiherpesviral activity of 5-C-substituted uracil nucleosides" * |
J. CARBOHYDRATES-NUCLEOSIDES-NUCLEOTIDES, vol. 5, no. 3, 1978, pages 187-224; MARCEL DEKKER, INC.; E. DE CLERCQ et al.: "Nucleoside analogs with selective antiviral activity" * |
THE VTH SYMPOSIUM ON THE CHEMISTRY OF NUCLEIC ACID COMPONENTS held at Bechyne Castle Czechoslovakia, 6-11 septembre 1981, Nucleic Acids Symposium Series no. 9, pages 53-55, Information Retrieval Ltd., 1981 (londres, GB); S.YA. MELNIK et al.: "Synthesis and investigation * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0211354A2 (en) * | 1985-07-29 | 1987-02-25 | Merrell Dow Pharmaceuticals Inc. | Nucleosides and their use as antineoplastic agents |
EP0211354A3 (en) * | 1985-07-29 | 1988-02-10 | Merrell Dow Pharmaceuticals Inc. | Nucleosides and their use as antineoplastic agents |
WO1988004662A1 (en) * | 1986-12-19 | 1988-06-30 | Astra Läkemedel Aktiebolag | Use of nucleosides for the manufacture of medicament for treatment of diseases caused by retrovirus or hepatitis b virus |
US5215971A (en) * | 1986-12-19 | 1993-06-01 | Medivir Ab | Antiviral pharmaceutical composition comprising 5-substituted pyrimidine nucleosides |
US5409906A (en) * | 1987-04-16 | 1995-04-25 | Medivir Ab | α nucleoside compounds and a method for treating HBV using said compounds |
EP0291230A2 (en) * | 1987-05-11 | 1988-11-17 | Merck & Co. Inc. | 1-(2-(Hydroxymethyl)-cycloalkylmethyl)-5-substituted uracils |
EP0291230A3 (en) * | 1987-05-11 | 1990-06-13 | Merck & Co. Inc. | 1-(2-(hydroxymethyl)-cycloalkylmethyl)-5-substituted uracils |
WO1998045309A1 (en) * | 1997-04-04 | 1998-10-15 | Astra Pharmaceuticals Ltd. | Novel phosphate compounds and their use as medicaments |
EP1425022A1 (en) * | 2001-08-24 | 2004-06-09 | Koronis Pharmaceuticals, Inc. | Mutagenic nucleoside analogs for the treatment of viral disease |
EP1425022A4 (en) * | 2001-08-24 | 2009-04-29 | Koronis Pharmaceuticals Inc | MUTAGENIC NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF VIRAL DISEASE |
Also Published As
Publication number | Publication date |
---|---|
NL8302859A (nl) | 1984-03-16 |
GB2125401A (en) | 1984-03-07 |
IT1169765B (it) | 1987-06-03 |
ES8604943A1 (es) | 1986-02-16 |
GB2125401B (en) | 1985-10-16 |
PT77209A (en) | 1983-09-01 |
SE8304408L (sv) | 1984-02-18 |
ES524997A0 (es) | 1986-02-16 |
BE897516A (fr) | 1984-02-13 |
ZA836072B (en) | 1985-03-27 |
FI832884A (fi) | 1984-02-18 |
DE3390162T1 (de) | 1985-02-21 |
SE8304408D0 (sv) | 1983-08-15 |
IT8322565A0 (it) | 1983-08-16 |
AU1800483A (en) | 1984-02-23 |
DK372283D0 (da) | 1983-08-15 |
FR2531962A1 (fr) | 1984-02-24 |
GB8321880D0 (en) | 1983-09-14 |
FR2531962B1 (fr) | 1986-11-14 |
DK372283A (da) | 1984-02-18 |
IL69497A0 (en) | 1983-11-30 |
JPS5953499A (ja) | 1984-03-28 |
PT77209B (en) | 1986-03-18 |
FI832884A0 (fi) | 1983-08-10 |
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