EP0369001A1 - Glucosylphosphotriester von thymidin-derivaten, die aktiv gegen retroviren sind - Google Patents
Glucosylphosphotriester von thymidin-derivaten, die aktiv gegen retroviren sindInfo
- Publication number
- EP0369001A1 EP0369001A1 EP89907766A EP89907766A EP0369001A1 EP 0369001 A1 EP0369001 A1 EP 0369001A1 EP 89907766 A EP89907766 A EP 89907766A EP 89907766 A EP89907766 A EP 89907766A EP 0369001 A1 EP0369001 A1 EP 0369001A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- derivative
- glucosyl
- formula
- treated
- lymphocytes
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
-
- 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
Definitions
- the subject of the invention is glucosyl phosphotriesters of thymidine derivatives having activity against retroviruses, in particular against HIV-1 and HIV-2.
- antiviral nucleosides constituted by derivatives of 3'-azido 3 '-deoxythyaidine (AU) are described in EP 0196175.
- the invention therefore aims to provide new glucosyl phosphotriesters of thymidine derivatives and a process for the synthesis of these derivatives.
- the invention further aims to provide compositions with antiretroviral effect.
- - R ' represents a hydrogen atom or an azido group
- - -alk represents a saturated or unsaturated hydrocarbon radical of 5 to 30 carbon atoms, optionally substituted.
- substitution groups of the -alk radical advantageously represent an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, an amino group.
- Glucosyl phosphodiesters respond to structure (II):
- a glucose-6-phosphate derivative of formula (III) is reacted: in which the radicals R, which are identical or different from each other, represent protective groups of hydroxyl function, this derivative advantageously being in the form of a salt, with a thymidine derivative of formula (IV):
- R 'and cop presenting in the formulas above the meanings given in relation to the structure (I).
- the foregoing arrangements make it possible to obtain liposoluble derivatives of nucleotides capable of crossing a membrane, for example the envelope of a cell or the meningeal barrier, endowed with an anti-viral effect with regard to retroviruses.
- the coupling reaction between derivatives (III) and (IV) is carried out at a temperature above ambient, more particularly from 30 to 100 ° C in an organic solvent medium.
- Suitable solvents include pyridine, trichloroethane.
- the desired coupling is obtained by operating at a temperature of 60 to 80oC, in particular close to 70oC.
- the reaction is carried out under an atmosphere of inert gas such as nitrogen or argon.
- an excess of derivative (III) is used.
- An excess in moles of 1.5 to 2 makes it possible to carry out the coupling under satisfactory conditions.
- the derivative of formula (III) used in the coupling reaction is in the form of a salt whose reactivity promotes coupling.
- the protective groups are removed prior to the attachment of an alkyl chain.
- groups suitable for the implementation of the invention mention will be made of acyl groups, in particular acetyl, substituted alkyl such as benzyl, benzoyl.
- acyl groups in particular acetyl, substituted alkyl such as benzyl, benzoyl.
- the elimination of these groups is carried out according to conventional techniques of organic chemistry, operating under conditions which do not alter the structure of the phosphodiester (V) and its substituents.
- the acyl groups in a mixture are removed, for example using sodium hydroxide solutions or a NH 3 / OH 3 OH mixture.
- the reactive derivative containing the alk group is advantageously a halide, in particular a bromide or an iodide, or also a tosylate, or a sulfonium salt.
- the reaction is advantageously carried out in an organic solvent medium, at a temperature above ambient, in particular from 50 to 100oC.
- the phosphodiester is preferably in the form of a high reactivity salt and used in excess of at least about 10 times more, in moles. oar compared to the reactive derivative containing the group -alc.
- R is as defined in relation to formula (III), this derivative advantageously being in the form of a salt, with a thyoidine derivative of formula (IV) above, then the hydroxyl blocking groups are removed.
- the coupling reaction is advantageously carried out in an organic solvent, at room temperature in the presence of TPSNT.
- the derivative of formula (VII) is advantageously obtained by reaction of the corresponding glucose derivative with cyanoethylphosphate in the form of reactive salt.
- compositions are characterized in that they comprise an effective amount of at least one derivative of formula (I) or (II) in combination with a pharmacological vehicle.
- compositions are particularly useful for treating AIDS and related diseases.
- compositions are in forms suitable for oral, nasal, topical, rectal, vaginal, subcutaneous, intravenous, intramuscular or intradermal administration.
- compositions which can be administered orally include tablets, tablets, granules, solutions or suspensions in an aqueous or non-aqueous medium.
- suppositories and vaginal creams or foams are used.
- formulations used for parenteral administration are advantageously formed by sterile, isotomic, aqueous or non-aqueous solutions or suspensions.
- 1,2,3,4-tetra-0-acetyl 6-D-glucose phosphate is prepared according to Whistler RL, Doner LW and Kosik M. (1972) Methods in Carbohyd Chem. Flight. VI, 711-712 Académie Press NY or Lardy HA and Fischer HOL (1946) J. Biol. Chem. 164 513-519. 5 g (16.44 mmol) of sodium salt of 6-D-glucose phosphate and 18 ml (190.4 mmol) of acetic anhydride distilled in 20 ml of pyridine are stirred for 16 h at room temperature.
- aqueous phase is then reduced in volume before being passed over a column of Dowex 50WX8 resin previously exchanged in pyridinium form.
- Co-evaporation is carried out three times, with anhydrous pyridine, 200 g (0.75 mmol) of azido-3 'thymidine (A2T) and 656 g (0.75 mmol ⁇ 1.5 excess) of 1,2,3,4-tetra 0-acetyl 6-D-glucose phosphate in pyridinium form. About 15 ml of anhydrous pyridine and 2.56 ml of trichloroacetonitrile (0.75 mmol ⁇ 35 excess) are added. The mixture is heated to 70oC with good stirring and maintaining under a nitrogen atmosphere for 16 h.
- the barium salt of cyanoethyl phosphate is exchanged to the pyridinium salt by passing it through a Dowex H + ® column and collecting the product in pyridine.
- the exchange relates to 2.5 g of cyanoethyl phosphate. Evaporated to dryness after passing over the column. 7.75 mM of pyridinium salt is obtained which is co-evaporated three times with pyridine. 2.58 mM of 1,2,3,4 tetracetyl glucose is added, ie 900 mg. Coevaporate 2 times with pyridine. It is taken up in 20 al of anhydrous pyridine, then 7 al (58 mM) of freshly distilled trichloroacetonitrile are added. It is degassed with nitrogen and left at 75oC under nitrogen for 14 hours approximately.
- the purification is carried out: 1) on a column of Merck 9385® silica, 2) on a column of Sephadex LH 20® eluted with the THF / MeOH 95/5 mixture. 312 mg (55%) of the phosphotriester are obtained, the acetyl groups of which are eliminated with 1% sodium aethylate for 15 minutes, at room temperature. The aéae treatment that previously, after neutralization with a Dowex® resin gives the compound 2 (165 ag) identical to that obtained under 3.
- a column of Dowex 50WX8 ® resin is prepared, which has been balanced in tetrabutylammonium form by exchanging Dowex 50WX8 H + ® resin with stirring for two hours in concentrated tetrabutylammoniua hydroxide and then washing it until at neutral pH of washing water. The 283 mg of 2 obtained previously have passed on this column. The absorbent fractions at 254 nm are collected which are lyophilized.
- Example 3 Study of products with retrovirus action.
- the virus used is a recombinant murine retrovirus (MoMLV) into which a reporter gene (LacZ) has been introduced. It is produced in transcrementing lines which do not produce wild viruses.
- MoMLV murine retrovirus
- LacZ reporter gene
- Hua T lyaphocytes are kept in RPMI 1640 medium containing 10% fetal calf serua (Seroaed), 1% glutamine (Gibco), 1% antibiotics (PSN, Gibco), 10 % interleukin II (Biotest), 2 ⁇ g / ml polybrene (Sigma) and a 1/2500 dilution of human ⁇ -interferon ⁇ . This place is called coaplet medium.
- the MT4 cell line is cultured at a rate of 3 ⁇ 10 5 cells / ml in an RPMI 1640 medium containing 10% fetal calf serum, 1% antibiotics and 1% glutamine. c) Cells
- the cytotoxicity of the products was studied on human T lymphocytes obtained from the peripheral blood of a sero-negative donor. Before treatment, these lymphocytes are stimulated by phytohemagglutinin p (pHAp) (Difco) for 3 days.
- pHAp phytohemagglutinin p
- the effect of the products on the aultiplication of the HIV1 virus was studied on human T lymphocytes obtained from the peripheral blood of a seronegative donor, the lymphocytes were isolated by Ficoll gradient (Pharmacia) and then stimulated for 3 days by phytohemagglutinin p (pHAp) (Difco) before being used for treatment and infection with the HIV1 virus.
- pHAp phytohemagglutinin p
- the action of the products on the cytopathogenic effect of the HIV1 virus was studied using the MT4 cell line.
- This line is a human T cell line transformed by the HTLV1 virus. These cells are particularly sensitive to the HIV1 virus since 6
- cytopathogenic effect leading 10 4 + 80% of cells to death.
- the cytopathogenic effect is directly correlated to the infection of cells by the virus, 4 its intracellular replication and 4 the expression of viral antigens by cells. An inhibition of this effect therefore corresponds to an inhibition of the multiplication of the virus.
- lymphoblastoid T cell supernatants (CEM line) infected with the HIV1 virus.
- LAV strain LAV strain
- the activity of the undiluted viral preparation used for human lymphocytes was 200.00 cpa / ml.
- the production of the HIV1 virus by human T cells treated or not treated with each product was regularly monitored by measuring the reverse transcriptase activity present in 1 ml of culture supernatant. This method is described by Rey et al in BBRC (1984), 121, 121-133.
- 1 ml of supernatant is concentrated 100 times by ultracentrifugation, then the enzymatic activity of this sample is determined in 50 ⁇ l of a reaction mixture containing 50 mM Tris PH 7.9, 20 mM KCl, 5 mM MgCl 2 , 1 mM dithiotreitol, 0.05 OD / ml Poly A, 0.05 OD / ml oligodt 12-18.5 ⁇ Ci 3 HTTP and 0.1% triton X100.
- MT4 cells were infected with 100 ⁇ l of HIV1 virus for 3.10 cells in a 1 ml volume. After 30 minutes of viral adsorption at 37oC, the cells were washed and then resuspended at a rate of 3.10 cells / ml in medium containing each product at the following concentrations: 10 M; 45 ⁇ 10 -6 M and 10 -6 M.
- FIG. 1 shows that the variation in cell growth ( ⁇ 10 6 cells / ml) is reported as a function of time, in days.
- the representations used have the following meanings: ⁇ cell witness; cells treated with the products obtained in the invention 4 concentrations of 10 -3 M 5 ⁇ 10 -6 M and 10 -6 M
- a 10-day treatment with lt product 6651 has no significant effect on the growth of T cells in vitro at the dosets used.
- the cells are treated with product 6714 at the same dose for 3 days, no effect is observed on cell multiplication.
- FIG. 2 also shows that product 6651 at a dose of 10 -5 M causes total inhibition of the multiplication of the virus.
- the product 665 1 inhibits this ef f and cytopathogen 4 10 -6 M in a first experiment and 4 10 -5 M in a second experience.
- the product 6714 at 10 -5 has been shown to inhibit the cytopathogenic power of the virus during an experiment.
- the activity RT ⁇ 10 4 (cpm ⁇ 10 6 cells) is reported as a function of time, in days.
- the curve • _ • represents the results with the control virus; the results obtained using the products tested 4 at concentrations of 10 -5 M respectively,
- the HIV-1 virus used is derived from a CEM-LAV 1 cell culture supernatant; these are maintained by adding each pass (every 3 or 4 days) of uninfected CEM cells.
- the titer of the virus in the clarified culture supernatant is greater than 10 6 cpra / ml in reverse transcriptase activity and of 103 infectious units / ml on lymphocytes of seronegative donors. c) Cells and lymphocytes
- the lymphocytes were isolated from the peripheral blood of seronegative donors on a FicollR gradient (MSL, Eurobio). The lymphocytes thus obtained were stimulated with phytohemaglutinin p (PHA-p) for 3 days before their use.
- PHA-p phytohemaglutinin p
- lymphocytes are cultured in RPMI 1640 medium, supplemented with 10% fetal calf serum. 10% interleukin 2, 2 ⁇ g / ml polybrene, 1% glutamine, 1% antibiotics. cl Macrophages
- Macrophages were obtained from a leukocyte pocket. Mononuclear cells were separated on a gradient of
- Ficoll R The cells were adjusted to 50.108 cells / ml in RPMI 1640 medium (MBA) containing
- HIV-1 by macrophages infected in the presence or not of drugs 6714 or ddT and 6651 or AZT - was followed, either in continuous culture for at least 30 days, or after lysis of the macrophages on day +14 and infection of lymphocytes with this lysate .
- the quantity of cells cultured and the infection conditions are identical to those previously described.
- the macrophages were lyzed by two freezes at -20 ° C and thawing at 37 ° C successive.
- the recovered lysate was used as an inoculum to infect 3.10 6 activated lymphocytes from a seronegative donor. After 1 h of adsorption, the lymphocytes were adjusted to 10 6 cells per ml and the drugs were added at concentrations corresponding to those of the lysate.
- lymphocytes were subcultured every 3 or 4 days and an assay of the reverse transcriptase was carried out using the culture supernatant on each passage.
- the reverse transcriptase activity is assayed from 1 ml of culture supernatant concentrated 100 times by ultracentrifugation for 5 min at 95,000 rpm (Rotor
- the pellet is resuspended in 10ul of NTE
- the enzymatic activity is revealed by the addition of 40 ⁇ l of the following reaction mixture: Tris 50 mM pH 7.9; 20 mM KCl; 5 mM MgCl 2 ; 1 mM dithiotreithol; polyrA 0.05 0.D./ml; oligodT 12-18 0.05 0.D./ml and 3 HTTP 5 ⁇ Ci.
- FIGS. 3a, 3b, 3c, 3d show the viral production obtained with macrophages in continuous culture, infected or not, treated or not, respectively with the drug 6714, ddT, 6651 and AZT for 42 days, at different concentrations.
- the symbols used in the figures are as follows: Figures 3a and 3b; infected macrophages treated with 5.10 -5 M 6714 or ddT, respectively, infected macrophages treated with 10 -5 M of
- Figures 3c and 3d infected macrophages treated with 10 -6 M of
- FIGS. 4a, 4b, 4c, 4d show the infectious power on activated lymphocytes of lysates of macrophages infected or not, treated or not, respectively with the drugs 6714, ddT, 6651 and AZT.
- Figure 4a Lysate of infected macrophages treated with
- Figure 4b Lysate of infected macrophages treated with 5.10 -5 M ddT + lymphocytes treated with 5.10 -5 M ddT. Lysate of infected macrophages treated with 10 -5 M ddT + lymphocytes treated with 10 -5 M ddT, Lysate of infected macrophages untreated + untreated lymphocytes, Lysate of uninfected macrophages treated with 5.10 -5 M ddT + lymphocytes treated with 5.10 -5 M ddT, Lysate of uninfected macrophages treated with 10 -5 ddT + lymphocytes treated with 10 -5 M ddT, Untreated uninfected macrophage lysate + untreated lymphocytes.
- Figure 4c Lysate of infected macrophages treated with 10 -5 M of 6651 - lymphocytes treated with 10 -5 M of 6651, Lysate of infected macrophages treated with
- Lysates of infected macrophages treated with drugs 6714 and ddT make it possible to obtain viral production by activated lymphocytes. This production is comparable to the untreated lysate for the drug 6714, whatever the concentration tested and for the drug ddT at the concentration of 10 - 5 M. The viral production seems lower for the concentration 5.10 -5 M of ddT. On the other hand, no viral production is obtained on the lymphocytes with the lysates of macrophages treated with AZT and treated with 10 -5 M and 10 -6 M of 6651. A low viral production is observed with the concentration of 10 - 7 M of drug 6651.
- tests carried out on continuous cultures of macrophages show that drugs 6651 and AZT at concentrations 10 -5 M, 10 -6 M and 10 -7 M and the drugs
- tests carried out on continuous cultures of macrophages show that the drugs 6651 and AZT at concentrations 10 -5 M, 10 -6 M and 10 -7 M and the drugs 6714 and ddT at concentrations 5.10 -5 M and 10 - 5 M block the proliferation of HIV-1 virus in macrophages.
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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)
- Saccharide Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8807252A FR2631964B1 (fr) | 1988-05-31 | 1988-05-31 | Glucosyl phosphotriesters de derives de thymidine ayant une activite contre les retrovirus |
FR8807252 | 1988-05-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0369001A1 true EP0369001A1 (de) | 1990-05-23 |
Family
ID=9366796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89907766A Withdrawn EP0369001A1 (de) | 1988-05-31 | 1989-05-31 | Glucosylphosphotriester von thymidin-derivaten, die aktiv gegen retroviren sind |
Country Status (4)
Country | Link |
---|---|
US (1) | US5393744A (de) |
EP (1) | EP0369001A1 (de) |
FR (1) | FR2631964B1 (de) |
WO (1) | WO1989012062A1 (de) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5159067A (en) * | 1987-01-28 | 1992-10-27 | University Of Georgia Research Foundation Inc. | 5'-Diphosphohexose nucleoside pharmaceutical compositions |
US5358937A (en) * | 1989-01-30 | 1994-10-25 | Institut Pasteur | Glycosyl phospholipid derivatives of nucleosides and their use as medicines |
FR2642428A1 (fr) * | 1989-01-30 | 1990-08-03 | Pasteur Institut | Derives glycosyl phospholipidiques de nucleosides et leur application en tant que medicaments |
WO1994013686A1 (fr) * | 1992-12-16 | 1994-06-23 | Institut Pasteur | Derives glycosyl phosphotriesters et leur utilisation au niveau du systeme nerveux central |
FR2699178B1 (fr) * | 1992-12-16 | 1995-02-10 | Pasteur Institut | Dérivés glycosyl phosphotriesters et leur utilisation au niveau du système nerveux central. |
US5760013A (en) * | 1996-08-21 | 1998-06-02 | National Science Council | Thymidylate analogs and the use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4837311A (en) * | 1987-06-22 | 1989-06-06 | Hoffman-La Roche Inc. | Anti-retroviral compounds |
-
1988
- 1988-05-31 FR FR8807252A patent/FR2631964B1/fr not_active Expired - Lifetime
-
1989
- 1989-05-31 EP EP89907766A patent/EP0369001A1/de not_active Withdrawn
- 1989-05-31 WO PCT/FR1989/000269 patent/WO1989012062A1/fr not_active Application Discontinuation
-
1990
- 1990-01-29 US US07/460,959 patent/US5393744A/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO8912062A1 * |
Also Published As
Publication number | Publication date |
---|---|
US5393744A (en) | 1995-02-28 |
WO1989012062A1 (fr) | 1989-12-14 |
FR2631964A1 (fr) | 1989-12-01 |
FR2631964B1 (fr) | 1990-09-07 |
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