WO1993012128A1 - DERIVATIVES OF 9-(β-D-XYLOFURANNOSYL)ADENINE AND OF 1-(β-D-XYLOFURANNOSYL)CYTOSINE, PREPARATION THEREOF AND APPLICATION IN THERAPEUTICS - Google Patents
DERIVATIVES OF 9-(β-D-XYLOFURANNOSYL)ADENINE AND OF 1-(β-D-XYLOFURANNOSYL)CYTOSINE, PREPARATION THEREOF AND APPLICATION IN THERAPEUTICS Download PDFInfo
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- WO1993012128A1 WO1993012128A1 PCT/FR1992/001182 FR9201182W WO9312128A1 WO 1993012128 A1 WO1993012128 A1 WO 1993012128A1 FR 9201182 W FR9201182 W FR 9201182W WO 9312128 A1 WO9312128 A1 WO 9312128A1
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- Prior art keywords
- adenine
- group
- xylofurannosyl
- acetyl
- cytosine
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 title claims description 32
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 title claims description 26
- 229930024421 Adenine Natural products 0.000 title claims description 25
- 229960000643 adenine Drugs 0.000 title claims description 25
- 229940104302 cytosine Drugs 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003435 aroyl group Chemical group 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 230000000840 anti-viral effect Effects 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 4
- 241000450599 DNA viruses Species 0.000 claims 1
- 230000003602 anti-herpes Effects 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract 3
- 210000004027 cell Anatomy 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 5
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000000120 cytopathologic effect Effects 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- LLKFNPUXQZHIAE-UHFFFAOYSA-N 5-(3-aminopropyl)-8-bromo-3-methyl-2h-pyrazolo[4,3-c]quinolin-4-one Chemical compound O=C1N(CCCN)C2=CC=C(Br)C=C2C2=C1C(C)=NN2 LLKFNPUXQZHIAE-UHFFFAOYSA-N 0.000 description 1
- OIRDTQYFTABQOQ-GAWUUDPSSA-N 9-β-D-XYLOFURANOSYL-ADENINE Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O OIRDTQYFTABQOQ-GAWUUDPSSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
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
-
- 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
Definitions
- the present invention relates to derivatives of 9- ( ⁇ -D-xylofurannosyl) adenine and 1- ( ⁇ -D-xylofurannosyl) cytosine, their preparation and their therapeutic application.
- R 1 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
- R 2 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
- R 3 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
- R ' represents a hydrogen atom or a (C 2-4 ) alkanoyl group.
- R 1 acetyl
- B adenine
- the preferred compounds of the invention are those for which the (C 2-4 ) alkanoyl group is the acetyl group and the aroyl group is the benzoyl group.
- the compounds of the examples are prepared according to the diagrams given in the appendix.
- R 1 , R 2 and R 3 represent an NO 2 group are prepared from the corresponding compounds in which R 1 , R 2 and R 3 represent a hydrogen atom by reaction with nitric acid in the presence acetic anhydride and urea.
- 9- (2,5-di-acetyl- ⁇ -D-xylofurannosyl) adenine adenine.
- the reaction mixture is stirred away from moisture for 14 hours, then diluted with 200 ml of chloroform.
- the resulting solution is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and with water (twice 100 ml for each wash).
- reaction mixture is stirred at room temperature for 40 hours, then diluted with 200 ml of chloroform.
- the resulting solution is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water (twice 100 ml for each wash).
- 9- (3-O-nitro- ⁇ -D-xylofurannosyl) adenine To 6 ml (143 mmol) of fuming nitric acid cooled to -30 ° C., 218 mg (3.63 mmol) of urea are added per portion with vigorous stirring. The temperature is gradually allowed to rise to 10 ° C in order to remove the nitrous acid, then it is cooled again to -30 ° C. 0.55 ml (5.82 mmol) of acetic anhydride is then added dropwise, then, in portions, 0.5 g (1.42 mmol) of 9- (2,5-di-O-acetyl- ⁇ -D-xylofurannosyl) adenine.
- the temperature is gradually allowed to rise to 20 ° C and stirring is continued for 40 minutes.
- the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
- HIV 1 strain HTLV III B
- MT4 cells T4 cells transformed by HTLV-1
- the test compounds are added, after adsorption of the virus, into the culture medium at different concentrations.
- the viability of the cells is measured by a colorimetric reaction based on their capacity to reduce the 3- (4,5 dimethylthiazol-2-yl) -2,5 diphenyl-tetrazolium bromide to formazan, property due to mitochondrial dehydrogenases.
- the quantity of formazan produced (D.O. at 540 nm) is proportional to the number of living cells.
- the percentage of protection of infected cells by treatment with the compounds is calculated by applying the formula proposed by Pauwels et al.
- the limiting concentrations giving an anti-HIV 1 effect range from 10 -3 M to 10 -5 M.
- viruses used are herpes simplex type 1 (HSV1), strain F, herpes simplex type 2 (HSV2), strain G, and vaccinia virus, strain Copenhagen.
- the tests are carried out in 96-well microplates on cells aged 48 hours.
- the final concentration of the substances is therefore 10 -3 M, 10 -4 M, 10 -5 m and from 10 -6 M.
- the dilutions of virus and substances are carried out in Dulbecco medium containing 2% of fetal calf serum (SVF).
- microplates are centrifuged at 3000 g for 45 minutes at room temperature.
- 0.2 ml of culture medium (MBE + 10% FCS) containing the substances to be tested is added at concentrations of 10 -3 M, 10 -4 M, 10 -5 M and of
- microplates are incubated at 37 ° C in an atmosphere containing 5% CO 2 .
- the antiviral effect of the substances is measured by comparing the cytopathogenic effect observed in the wells containing the products with that observed in the virus control wells.
- the antiviral effect is obtained for concentrations ranging from 10 -4 M to 10 -5 M.
- the products having shown antiviral activity are taken up according to the same protocol, but using final dilutions of
- the results of the pharmacological tests show that the compounds of the invention are active with respect to the HIV1, HSV1, HSV2 and vaccinia viruses. They have also been tested by way of example on the following viruses: human cytomegalovirus (CMV) strain AD 169, Sindbis virus, coxsackie B 3 virus
- the compounds of the invention can therefore be used for their antiproliferative and herpetic activity and in the topical treatment of skin infections with HSV1 and HSV2.
- R C 1 -C 4 alkyl
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Saccharide Compounds (AREA)
Abstract
Compounds having the general formula (I) wherein R1? is a hydrogen atom, a (C2-4?)alkanyl group, an aryl group or a nitro group, R2? is a hydrogen atom, a (C2-4?)alkanyl group, an aryl group or a nitro group, R3? is a hydrogen atom, a (C2-4?)alkanyl group, an aryl group or a nitro group, B is a radical having the formula (a) or (b) wherein R' is a hydrogen atom or a (C2-4?)alkanyl group. Application in therapeutics.
Description
DERIVES DE LA 9-(β-D-XYLOFURANNOSYL) ADENINE 9- (β-D-XYLOFURANNOSYL) ADENINE DERIVATIVES
ET DE LA 1-(β-D-XYLOFURANNOSYL)CYTOSINE, AND 1- (β-D-XYLOFURANNOSYL) CYTOSINE,
LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE. La présente invention a pour objet des dérivés de la 9-(β-D- xylofurannosyl)adenine et de la 1-(β-D-xylofurannosyl)cytosine, leur préparation et leur application en thérapeutique. THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS. The present invention relates to derivatives of 9- (β-D-xylofurannosyl) adenine and 1- (β-D-xylofurannosyl) cytosine, their preparation and their therapeutic application.
Les composés de l'invention répondent à la formule générale (I) The compounds of the invention correspond to the general formula (I)
dans laquelle in which
R1 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 1 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
R2 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 2 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
R3 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 3 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
B représente un radical de formule B represents a radical of formula
ou
or
dans lequel R' représente un atome d'hydrogène ou un groupe (C2-4)alcanoyle. wherein R 'represents a hydrogen atom or a (C 2-4 ) alkanoyl group.
Les composés dans lesquels Compounds in which
- R1 = acétyle, R2 = R3 = acétyle et B = adénine, - R 1 = acetyl, R 2 = R 3 = acetyl and B = adenine,
- R1 = H, R2 = R3 = benzoyle et B = adénine, - R 1 = H, R 2 = R 3 = benzoyl and B = adenine,
- R1 = H, R2 = R3 = acétyle et B = adénine, - R 1 = H, R 2 = R 3 = acetyl and B = adenine,
- R1 = acétyle, R2 = R3 = benzoyle et B = adénine ou - R 1 = acetyl, R 2 = R 3 = benzoyl and B = adenine or
cytosine, cytosine,
- R1 = R2 = R3 = H et B = adénine ou cytosine - R 1 = R 2 = R 3 = H and B = adenine or cytosine
ne font toutefois pas partie de l'invention.
Les composés préférés de l'invention sont ceux pour lesquels le groupe (C2-4) alcanoyle est le groupe acétyle et le groupe aroyle est le groupe benzoyle. Les composés des exemples sont préparés selon les schémas donnés en annexe. are not, however, part of the invention. The preferred compounds of the invention are those for which the (C 2-4 ) alkanoyl group is the acetyl group and the aroyl group is the benzoyl group. The compounds of the examples are prepared according to the diagrams given in the appendix.
Les composés pour lesquels R1, R2 et R3 représentent un groupe NO2 sont préparés à partir des composés correspondants dans lesquels R1, R2 et R3 représentent un atome d'hydrogène par réaction avec de l'acide nitrique en présence d'anhydride acétique et d'urée.
The compounds for which R 1 , R 2 and R 3 represent an NO 2 group are prepared from the corresponding compounds in which R 1 , R 2 and R 3 represent a hydrogen atom by reaction with nitric acid in the presence acetic anhydride and urea.
Les exemples suivants illustrent en détail la préparation de quelques composés selon l'invention. Les numéros indiqués entre parenthèses dans les titres des exemples correspondent à ceux du tableau donné plus loin. The following examples illustrate in detail the preparation of some compounds according to the invention. The numbers indicated in parentheses in the titles of the examples correspond to those in the table given below.
Les microanalyses élémentaires et les spectres U.V., RMN et de masse confirment les structures des produits obtenus. Elementary microanalyses and U.V., NMR and mass spectra confirm the structures of the products obtained.
Exemple 1 (composé n° 1). Example 1 (compound # 1).
9-(2,5-di-acétyl-β-D-xylofurannosyl)adénine. a) 9-(5-0-tert-butyldiméthylsilyl-β-D-xylofurannosyl)adénine. A une suspension de 3,2 g (11,97 mmoles) de 9-(β-D-xylofuran- nosyl)adénine dans 24 ml de pyridine anhydre, on ajoute 2,3 g (15,26 mmoles) de chlorure de tert-butyldiméthylsilyle. Le mélange reactionnel est agité à l'abri de l'humidité durant 14 heures, puis dilué avec 200 ml de chloroforme. La solution résultante est lavée successivement avec une solution aqueuse saturée d'hydrogénocarbonate de sodium et avec de l'eau (deux fois 100 ml pour chaque lavage). 9- (2,5-di-acetyl-β-D-xylofurannosyl) adenine. a) 9- (5-0-tert-butyldimethylsilyl-β-D-xylofurannosyl) adenine. To a suspension of 3.2 g (11.97 mmol) of 9- (β-D-xylofuranosyl) adenine in 24 ml of anhydrous pyridine, 2.3 g (15.26 mmol) of tertiary chloride are added -butyldimethylsilyl. The reaction mixture is stirred away from moisture for 14 hours, then diluted with 200 ml of chloroform. The resulting solution is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and with water (twice 100 ml for each wash).
La phase organique est ensuite séchée sur sulfate de sodium, filtrée et évaporée à sec et coévaporée avec du toluène. Le résidu est purifié par chromatographie sur colonne de gel de silice. On obtient 3 g de 9-(5-0-tert-butyldiméthylsilyl-β-D- xylofurannosyl)adénine pur. F = 201-202°C (cristallisé dans le méthanol). b) 9-(2,3-di-0-acétyl-5-0-tert-butyldiméthylsilyl-β-D-xylofu- rannosyl)adénine. The organic phase is then dried over sodium sulfate, filtered and evaporated to dryness and coevaporated with toluene. The residue is purified by chromatography on a column of silica gel. 3 g of pure 9- (5-0-tert-butyldimethylsilyl-β-D-xylofurannosyl) adenine are obtained. Mp 201-202 ° C (crystallized from methanol). b) 9- (2,3-di-0-acetyl-5-0-tert-butyldimethylsilyl-β-D-xylofuranosyl) adenine.
A une solution de 2,9 g (7,6 mmoles) de 9-(5-0-tert-butyl- diméthylsilyl-β-D-xylofurannosyl-)adénine dans 38 ml de pyridine anhydre, on ajoute, à 0°C, 1,58 ml (16,76 mmoles) d'anhydride acétique. To a solution of 2.9 g (7.6 mmol) of 9- (5-0-tert-butyl-dimethylsilyl-β-D-xylofurannosyl-) adenine in 38 ml of anhydrous pyridine, the following is added at 0 ° C , 1.58 ml (16.76 mmol) of acetic anhydride.
Le mélange reactionnel est agité à température ambiante durant 40 heures, puis dilué avec 200 ml de chloroforme. La solution résultante est lavée successivement avec une solution aqueuse saturée d'hydrogénocarbonate de sodium et de l'eau (deux fois 100 ml pour chaque lavage). The reaction mixture is stirred at room temperature for 40 hours, then diluted with 200 ml of chloroform. The resulting solution is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water (twice 100 ml for each wash).
La phase organique est ensuite séchée sur sulfate de sodium, filtrée et évaporée à sec et coévaporée avec du toluène. Le
résidu est purifié sur colonne de gel de silice. On obtient 1,8 g de composé pur. F = 133-134°C (cristallisé dans un mélange chloroforme - éther isopropylique). c) 9-(2,5-di-O-acétyl-β-D-xylofurannosyl)adénine. The organic phase is then dried over sodium sulfate, filtered and evaporated to dryness and coevaporated with toluene. The residue is purified on a column of silica gel. 1.8 g of pure compound are obtained. Mp 133-134 ° C (crystallized from a chloroform-isopropyl ether mixture). c) 9- (2,5-di-O-acetyl-β-D-xylofurannosyl) adenine.
A une solution de 1,7 g (3,65 mmoles) de 9-(2,3-di-O-acétyl- 5-0-tert-butyldiméthylsilyl-β-D-xylofurannosyl)adénine dans 44 ml de tetrahydrofuranne, on ajoute 0,31 ml (5,4 mmoles) d'acide acétique et 11,2 ml d'une solution 1N de fluorure de tetrabutylammonium dans le tetrahydrofuranne. Après 3 heures d'agitation à température ambiante, le mélange reactionnel est évaporé sous pression réduite, puis coévaporé avec du toluène. Le résidu est purifié sur colonne de gel de silice. On obtient 1,1 g de composé pur. F = 117-119°C (cristallisé dans l'acétate d'éthyle). To a solution of 1.7 g (3.65 mmol) of 9- (2,3-di-O-acetyl-5-0-tert-butyldimethylsilyl-β-D-xylofurannosyl) adenine in 44 ml of tetrahydrofuran, we add 0.31 ml (5.4 mmol) of acetic acid and 11.2 ml of a 1N solution of tetrabutylammonium fluoride in tetrahydrofuran. After 3 hours of stirring at room temperature, the reaction mixture is evaporated under reduced pressure, then coevaporated with toluene. The residue is purified on a column of silica gel. 1.1 g of pure compound are obtained. Mp 117-119 ° C (crystallized from ethyl acetate).
Exemple 2 (composé n° 6). Example 2 (compound n ° 6).
9-(3-O-nitro-β-D-xylofurannosyl)adénine. A 6 ml (143 mmoles) d'acide nitrique fumant refroidi à -30°C, on ajoute, par portion et sous forte agitation 218 mg (3,63 mmoles) d'urée. On laisse la température progressivement remonter jusqu'à 10°C afin d'éliminer l'acide nitreux, puis on refroidit à nouveau à -30°C. On ajoute alors goutte à goutte 0,55 ml (5,82 mmoles) d'anhydride acétique puis, par portions, 0,5 g (1,42 mmole) de 9-(2,5-di-O-acétyl-β-D-xylo- furannosyl)adénine. On laisse la température progressivement remonter jusqu'à 20°C et l'agitation est poursuivie pendant 40 minutes. Le mélange reactionnel est refroidi à -20°C, puis versé goutte à goutte et sous agitation sur 200 ml d'une solution aqueuse saturée de sulfate d'ammonium, mélangée à de la glace (pH = 6,7). On vérifie que le pH est supérieur ou égal à 1 et on ajoute rapidement une solution aqueuse saturée d'hydrogénocarbonate de sodium, jusqu'à ce que le pH soit égal à 6,5. 9- (3-O-nitro-β-D-xylofurannosyl) adenine. To 6 ml (143 mmol) of fuming nitric acid cooled to -30 ° C., 218 mg (3.63 mmol) of urea are added per portion with vigorous stirring. The temperature is gradually allowed to rise to 10 ° C in order to remove the nitrous acid, then it is cooled again to -30 ° C. 0.55 ml (5.82 mmol) of acetic anhydride is then added dropwise, then, in portions, 0.5 g (1.42 mmol) of 9- (2,5-di-O-acetyl-β -D-xylofurannosyl) adenine. The temperature is gradually allowed to rise to 20 ° C and stirring is continued for 40 minutes. The reaction mixture is cooled to -20 ° C., then poured dropwise and with stirring onto 200 ml of a saturated aqueous solution of ammonium sulfate, mixed with ice (pH = 6.7). It is checked that the pH is greater than or equal to 1 and a saturated aqueous solution of sodium hydrogencarbonate is rapidly added, until the pH is equal to 6.5.
La phase aqueuse est extraite avec du chloroforme et les phases organiques, rassemblées, sont lavées trois fois avec de l'eau, puis séchées sur sulfate de sodium et évaporées à sec. Le résidu est dissout sous agitation dans 45 ml de
méthanol ammoniacal (préalablement saturé à -10°C et hermétiquement fermé), et l'agitation est poursuivie pendant 6 heures, à température ambiante. Le mélange reactionnel est évaporé à sec et coevapore trois fois avec de l'éthanol absolu. On obtient directement 0,27 g de 9-(3-0-nitro-β-D-xylofurannosyl)adénine pur par cristallisation dans l'éthanol. F = 220-223°C. Exemple 3 (composé n° 18). The aqueous phase is extracted with chloroform and the organic phases, combined, are washed three times with water, then dried over sodium sulfate and evaporated to dryness. The residue is dissolved with stirring in 45 ml of ammoniacal methanol (previously saturated at -10 ° C and hermetically closed), and stirring is continued for 6 hours, at room temperature. The reaction mixture is evaporated to dryness and coevaporated three times with absolute ethanol. 0.27 g of pure 9- (3-0-nitro-β-D-xylofurannosyl) adenine is obtained directly by crystallization from ethanol. Mp 220-223 ° C. Example 3 (compound # 18).
N4-acétyl-1-(2,3,5-tri-O-acétyl-β-D-xylofurannosyl)cytosine. N 4 -acetyl-1- (2,3,5-tri-O-acetyl-β-D-xylofurannosyl) cytosine.
A une suspension de 0,5 g (2,06 mmoles) de 1-(β-D-xylofurannosyl)cytosine dans 6,5 ml de pyridine anhydre, on ajoute goutte à goutte, à 0°C et sous agitation, 1,2 ml (12,7 mmoles) d'anhydride acétique. Le mélange reactionnel est agité durant 1 heure à 0°C, puis durant 48 heures à température ambiante. 100 ml d'eau et 100 ml de chloroforme sont ensuite ajoutés. La phase organique est séparée, séchée sur sulfate de sodium, évaporée à sec et coévaporée avec du dioxanne. Le résidu est dissout dans du dioxanne et lyophilisé pour donner 0,64 g de N4-acétyl-1-(2,3,5-tri-O-acétyl-β-D- xylofurannosyl)cytosine pur. F = 94-97°C. Exemple 4 (composés n° 10 et n° 11). To a suspension of 0.5 g (2.06 mmol) of 1- (β-D-xylofurannosyl) cytosine in 6.5 ml of anhydrous pyridine, is added dropwise, at 0 ° C. and with stirring, 1, 2 ml (12.7 mmol) of acetic anhydride. The reaction mixture is stirred for 1 hour at 0 ° C, then for 48 hours at room temperature. 100 ml of water and 100 ml of chloroform are then added. The organic phase is separated, dried over sodium sulfate, evaporated to dryness and coevaporated with dioxane. The residue is dissolved in dioxane and lyophilized to give 0.64 g of pure N 4 -acetyl-1- (2,3,5-tri-O-acetyl-β-D-xylofurannosyl) cytosine. Mp 94-97 ° C. Example 4 (compounds 10 and 11).
1-(3,5-di-O-acétyl-β-D-xylofurannosyl)cytosine 1- (3,5-di-O-acetyl-β-D-xylofurannosyl) cytosine
et 1-(5-O-acétyl-β-D-xylofurannosyl)cytosine. and 1- (5-O-acetyl-β-D-xylofurannosyl) cytosine.
A une solution de 1,3 g (3,16 mmoles) de N4-acétyl-1-(2,3,5- tri-O-acétyl-β-D-xylofurannosyl)cytosine (composé n° 18) dans 100 ml de pyridine, on ajoute 0,65 ml (13,1 mmoles) d'hydrate d'hydrazine. Le mélange reactionnel est agité durant 1 heure à température ambiante et 0,65 ml (13,1 mmoles) d'hydrate d'hydrazine est à nouveau ajouté. On poursuit l'agitation durant 5 heures et ajoute 20 ml d'acétone. Après 2 heures d'agitation, le mélange est évaporé à sec, et coevapore trois fois avec du toluène. Le résidu est purifié par chromatographie sur colonne de gel de silice et donne, par ordre d'élution, 0,50 g de composé n° 10 et 0,30 g de composé n° 11
n° 10 : F = 144-146°C (cristallisé dans l'acétate d'éthyle) nº 11 : F = 103-106°C (lyophilisé dans l'eau). To a solution of 1.3 g (3.16 mmol) of N 4 -acetyl-1- (2,3,5-tri-O-acetyl-β-D-xylofurannosyl) cytosine (compound No. 18) in 100 ml of pyridine, 0.65 ml (13.1 mmol) of hydrazine hydrate is added. The reaction mixture is stirred for 1 hour at room temperature and 0.65 ml (13.1 mmol) of hydrazine hydrate is again added. Stirring is continued for 5 hours and 20 ml of acetone are added. After 2 hours of stirring, the mixture is evaporated to dryness, and coevaporated three times with toluene. The residue is purified by chromatography on a column of silica gel and gives, in order of elution, 0.50 g of compound No. 10 and 0.30 g of compound No. 11 # 10: M = 144-146 ° C (crystallized from ethyl acetate) # 11: M = 103-106 ° C (lyophilized in water).
Le tableau ci-après illustre les structures et propriétés physiques de quelques composés de l'invention.
The table below illustrates the structures and physical properties of some compounds of the invention.
A = adénine A = adenine
C = cytosine C = cytosine
Ac = acétyle = CH3CO Ac = acetyl = CH 3 CO
Bz = benzoyle = C6H5CO
Bz = benzoyl = C 6 H 5 CO
Les composés de l'invention ont été soumis à une série d'essais pharmacologiques qui ont mis en évidence leur intérêt comme substances à activités thérapeutiques. The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
1) Etude de l'activité anti VIH 1. 1) Study of anti-HIV activity 1.
La multiplication du VIH 1 (souche HTLV III B) dans les cellules MT4 (cellules T4 transformées par HTLV-1) est suivie par l'effet cytopathogène induit par le virus. Les cellules sont infectées avec une dose de VIH 1 produisant après 4 jours une diminution de 90 % du nombre de cellules vivantes. Les composés testés sont ajoutés, après l'adsorption du virus, dans le milieu de culture à différentes concentrations. The multiplication of HIV 1 (strain HTLV III B) in MT4 cells (T4 cells transformed by HTLV-1) is followed by the cytopathic effect induced by the virus. The cells are infected with a dose of HIV 1 producing, after 4 days, a 90% decrease in the number of living cells. The test compounds are added, after adsorption of the virus, into the culture medium at different concentrations.
La viabilité des cellules est mesurée par une réaction colorimétrique basée sur leur capacité à réduire le 3-(4,5 diméthylthiazol-2-yl)-2,5 diphényl-tétrazolium bromide en formazan, propriété due aux deshydrogenases mitochondriales. La quantité de formazan produite (D.O. à 540 nm) est proportionnelle au nombre de cellules vivantes. The viability of the cells is measured by a colorimetric reaction based on their capacity to reduce the 3- (4,5 dimethylthiazol-2-yl) -2,5 diphenyl-tetrazolium bromide to formazan, property due to mitochondrial dehydrogenases. The quantity of formazan produced (D.O. at 540 nm) is proportional to the number of living cells.
Le pourcentage de protection des cellules infectées par le traitement avec les composés est calculé en appliquant la formule proposée par Pauwels et col. The percentage of protection of infected cells by treatment with the compounds is calculated by applying the formula proposed by Pauwels et al.
D.O. 540 des cellules infectées traitées - D.O. 540 des cellules infectées D.O. 540 of the infected cells treated - D.O. 540 of the infected cells
D.O. 540 des cellules non infectées - D.O. 540 des cellules infectées D.O. 540 of uninfected cells - D.O. 540 of infected cells
Par cette méthode, on met en évidence que les concentrations limites donnant un effet anti VIH 1 vont de 10-3M à 10-5M. By this method, it is demonstrated that the limiting concentrations giving an anti-HIV 1 effect range from 10 -3 M to 10 -5 M.
2) Etude des activités anti HSV1, anti HSV2 et antivaccine. Sur des cellules de singe lignée Vero, on teste l'activité antivirale des composés de l'invention, en mesurant l'inhibition de l'effet cytopathogène induit par 100 TICD 50 2) Study of anti HSV1, anti HSV2 and antivaccine activities. On Vero lineage monkey cells, the antiviral activity of the compounds of the invention is tested, by measuring the inhibition of the cytopathogenic effect induced by 100 TICD 50.
(quantité de virus capable de nécroser 50 % des cellules). Les virus utilisés sont l'herpès simplex type 1 (HSV1),
souche F, l'herpès simplex type 2 (HSV2), souche G, et le virus de la vaccine, souche Copenhague. (amount of virus capable of necrosis 50% of cells). The viruses used are herpes simplex type 1 (HSV1), strain F, herpes simplex type 2 (HSV2), strain G, and vaccinia virus, strain Copenhagen.
Les essais sont effectués en microplaques de 96 godets sur des cellules âgées de 48 heures. The tests are carried out in 96-well microplates on cells aged 48 hours.
Pour tous les virus, on ajoute successivement : For all viruses, we successively add:
- 100 TCID 50* de virus dans un volume de 0.1 ml - 100 TCID 50 * of virus in a volume of 0.1 ml
- et 0,1 ml de chaque substance à une concentration de - and 0.1 ml of each substance at a concentration of
2 10-3M, de 2 10-4M, de 2 10-5M et de 2 10-6M. La concentration finale des substances est donc de 10-3M, de 10-4M, de 10-5m et de 10-6M. Les dilutions de virus et des substances sont effectuées dans du milieu Dulbecco contenant 2 % de sérum de veau foetal ( SVF ) . 2 10 -3 M, 2 10 -4 M, 2 10 -5 M and 2 10 -6 M. The final concentration of the substances is therefore 10 -3 M, 10 -4 M, 10 -5 m and from 10 -6 M. The dilutions of virus and substances are carried out in Dulbecco medium containing 2% of fetal calf serum (SVF).
Chaque concentration de substance est testée en quadruple. Les microplaques sont centrifugées à 3000 g pendant 45 minutes à température ambiante. Each concentration of substance is tested in quadruple. The microplates are centrifuged at 3000 g for 45 minutes at room temperature.
Après avoir éliminé le virus, on rajoute 0,2 ml de milieu de culture (MBE + 10 % de SVF) contenant les substances à tester à des concentrations de 10-3M, de 10-4M, de 10-5M et de After eliminating the virus, 0.2 ml of culture medium (MBE + 10% FCS) containing the substances to be tested is added at concentrations of 10 -3 M, 10 -4 M, 10 -5 M and of
10-6M. 10 -6 M.
Les microplaques sont incubées à 37°C dans une atmosphère contenant 5 % de CO2. The microplates are incubated at 37 ° C in an atmosphere containing 5% CO 2 .
L'effet antiviral des substances est mesuré en comparant 1 ' effet cytopathogène observé dans les cupules contenant les produits à celui observé dans les cupules témoin virus. The antiviral effect of the substances is measured by comparing the cytopathogenic effect observed in the wells containing the products with that observed in the virus control wells.
L'effet antiviral est obtenu pour des concentrations allant de 10-4M à 10-5M. Dans un deuxième temps, les produits ayant montré une activité antivirale sont repris selon le même protocole, mais en utilisant des dilutions finales de The antiviral effect is obtained for concentrations ranging from 10 -4 M to 10 -5 M. In a second step, the products having shown antiviral activity are taken up according to the same protocol, but using final dilutions of
10- 4 , 5.10-5, 2,5.10-5, 1.105, 5.10-6, 2,5.10-6 et 10-6. 10 - 4 , 5.10 -5 , 2.5.10 -5 , 1.10 5 , 5.10 -6 , 2.5.10 -6 and 10 -6 .
Les résultats des essais pharmacologiques montrent que les composés de l'invention sont actifs vis-à-vis des virus HIV1, HSV1, HSV2 et vaccine. Ils ont également été testés à titre d'exemple sur les virus suivants : cytomégalovirus humain (CMV) souche AD 169, virus Sindbis, virus coxsackie B3 The results of the pharmacological tests show that the compounds of the invention are active with respect to the HIV1, HSV1, HSV2 and vaccinia viruses. They have also been tested by way of example on the following viruses: human cytomegalovirus (CMV) strain AD 169, Sindbis virus, coxsackie B 3 virus
(CoxB3), poliovirus type I (Polio I), souche Mahoney, virus respiratoire syncytial (RSV), souche A2, paramyxovirus type III (Para III).
Les composés de l'invention peuvent donc être utilisés pour leur activité antiproliferative et herpétique et dans le traitement topique d'infections cutanées à HSV1 et HSV2.
(CoxB 3 ), poliovirus type I (Polio I), Mahoney strain, respiratory syncytial virus (RSV), strain A2, paramyxovirus type III (Para III). The compounds of the invention can therefore be used for their antiproliferative and herpetic activity and in the topical treatment of skin infections with HSV1 and HSV2.
A = Adénine A = Adenine
R = C1-C4 alkyle ou aryle TBDMS = tertiofautylméthylsilyle
R = C 1 -C 4 alkyl or aryl TBDMS = tertiofautylmethylsilyl
NH2-NH2,H2O NH 2 -NH 2 , H 2 O
----------------------------→ puis séparation par chromatographie ---------------------------- → then separation by chromatography
C = cytosine C = cytosine
R = C1-C4 alkyle
R = C 1 -C 4 alkyl
Claims
Revendications 1. Composés répondant à la formule générale (I) Claims 1. Compounds corresponding to the general formula (I)
R1 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 1 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
R2 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 2 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
R3 représente un atome d'hydrogène, un groupe (C2-4)alcanoyle, un groupe aroyle ou un groupe nitro, R 3 represents a hydrogen atom, a (C 2-4 ) alkanoyl group, an aroyl group or a nitro group,
B représente un radical de formule B represents a radical of formula
à l'exception des composés pour lesquels with the exception of compounds for which
- R1 = acétyle, R2 = R3 = acétyle et B = adénine, - R 1 = acetyl, R 2 = R 3 = acetyl and B = adenine,
- R1 = H, R2 = R3 = benzoyle et B = adénine, - R 1 = H, R 2 = R 3 = benzoyl and B = adenine,
- R1 = H, R2 = R3 = acétyle et B = adénine, - R 1 = H, R 2 = R 3 = acetyl and B = adenine,
- R1 = acétyle, R2 = R3 = benzoyle et B adénine ou - R 1 = acetyl, R 2 = R 3 = benzoyl and B adenine or
cytosine, cytosine,
- R1 = R2 = R3 = H et B = adénine ou cytosine. - R 1 = R 2 = R 3 = H and B = adenine or cytosine.
2. Composés selon la revendication 1, caractérisés par le fait que B représente l'adénine. 2. Compounds according to claim 1, characterized in that B represents adenine.
3. Composés selon la revendication 1, caractérisés par le fait que B représente la cytosine. 3. Compounds according to claim 1, characterized in that B represents cytosine.
4. Composé selon la revendication 2, caractérisé en ce que R2 représente un atome d'hydrogène et R 1 et R3 représentent chacun un groupe acétyle. 4. Compound according to claim 2, characterized in that R 2 represents a hydrogen atom and R 1 and R 3 each represent an acetyl group.
5. Composé selon la revendication 2 , caractérisé en ce que R1 et R3 sont des atomes d'hydrogène et R2 est NO2. 5. Compound according to claim 2, characterized in that R 1 and R 3 are hydrogen atoms and R 2 is NO 2 .
6. Composé selon la revendication 3, caractérisé en ce que R1 est un atome d'hydrogène et R2 et R3 représentent chacun un groupe acétyle . 6. Compound according to claim 3, characterized in that R 1 is a hydrogen atom and R 2 and R 3 each represent an acetyl group.
7. Médicament caractérisé en ce qu'il contient un composé selon l'une quelconque des revendications 1 à 6. 7. Medicament, characterized in that it contains a compound according to any one of claims 1 to 6.
8. Composition pharmaceutique caractérisée en ce qu'elle contient un composé selon l'une quelconque des revendications 1 à 6 en association avec tout excipient approprié. 8. Pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 to 6 in combination with any suitable excipient.
9. Composition pharmaceutique antivirale caractérisée en ce qu'elle contient un composé selon l'une quelconque des revendications 1 à 6 en association avec tout excipient approprié. 9. An antiviral pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 to 6 in combination with any suitable excipient.
10. Composition pharmaceutique ayant une activité à l'égard des virus à ADN, caractérisée en ce qu'elle contient un composé selon l'une quelconque des revendications 1 à 6 en association avec tout excipient approprié. 10. Pharmaceutical composition having activity with regard to DNA viruses, characterized in that it contains a compound according to any one of claims 1 to 6 in association with any suitable excipient.
11. Composition pharmaceutique à activité antiherpétique caractérisée en ce qu'elle contient un composé selon l'une quelconque des revendications 1 à 6 en association avec tout excipient approprié. 11. Pharmaceutical composition with antiherpetic activity characterized in that it contains a compound according to any one of claims 1 to 6 in association with any suitable excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5510676A JPH06505510A (en) | 1991-12-12 | 1992-12-14 | Derivatives of 9-(β-D-xylofuranosyl)adenine and 1-(β-D-xylofuranosyl)cytosine, their preparation and application as therapeutic agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR91/15420 | 1991-12-12 | ||
| FR9115420A FR2684997A1 (en) | 1991-12-12 | 1991-12-12 | DERIVATIVES OF 9- (BETA-D-XYLOFURANNOSYL) ADENINE AND 1- (BETA-D-XYLOFURANNOSYL) CYTOSINE, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993012128A1 true WO1993012128A1 (en) | 1993-06-24 |
Family
ID=9419960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR1992/001182 WO1993012128A1 (en) | 1991-12-12 | 1992-12-14 | DERIVATIVES OF 9-(β-D-XYLOFURANNOSYL)ADENINE AND OF 1-(β-D-XYLOFURANNOSYL)CYTOSINE, PREPARATION THEREOF AND APPLICATION IN THERAPEUTICS |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0572644A1 (en) |
| JP (1) | JPH06505510A (en) |
| CA (1) | CA2103884A1 (en) |
| FR (1) | FR2684997A1 (en) |
| WO (1) | WO1993012128A1 (en) |
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| EP0624372A2 (en) * | 1993-03-18 | 1994-11-17 | Nippon Chemiphar Co., Ltd. | Medicament for treating human immunodeficiency virus |
| US5808047A (en) * | 1995-03-24 | 1998-09-15 | Eli Lilly And Company | Process for the preparation of 2,2'-anhydro- and 2'-keto-1-(3',5'-di-O-protected-β-D-arabinofuranosyl) nucleosides |
| US5990093A (en) * | 1993-09-10 | 1999-11-23 | Emory University | Treating HBV with phospholipid prodrugs of β-L-2',3'-dideoxyadenosine 5'-monophosphate |
| US6245749B1 (en) | 1994-10-07 | 2001-06-12 | Emory University | Nucleosides with anti-hepatitis B virus activity |
| WO2002069943A3 (en) * | 2001-03-03 | 2003-04-17 | Ulrich Walker | Use of pyrimidine nucleosides and/or the prodrugs thereof for combating the side-effects of haart (highly active anti-retroviral therapy) and other anti-viral therapies |
| US7439351B2 (en) | 1993-09-10 | 2008-10-21 | The Uab Research Foundation | 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents |
| US9073960B2 (en) | 2011-12-22 | 2015-07-07 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
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| FR6164M (en) * | 1966-10-13 | 1968-07-08 | ||
| DE2105560A1 (en) * | 1971-02-06 | 1972-09-07 | Boehringer Mannheim Gmbh, 6800 Mannheim | Purine ribonucleoside derivatives and processes for making the same |
| EP0098186A1 (en) * | 1982-06-14 | 1984-01-11 | Synthelabo | Pharmaceutical compositions containing purine or pyrimidine xylosides and lyxosides |
| EP0317728A2 (en) * | 1987-09-22 | 1989-05-31 | Warner-Lambert Company | Use of 9-(beta-D-arabinofuranosyl) adenine derivatives for the preparation of pharmaceutical compositions for the treatment of aids |
| EP0322384A1 (en) * | 1987-11-03 | 1989-06-28 | Medivir Aktiebolag | Nucleosides for use in therapy |
-
1991
- 1991-12-12 FR FR9115420A patent/FR2684997A1/en not_active Withdrawn
-
1992
- 1992-12-14 JP JP5510676A patent/JPH06505510A/en active Pending
- 1992-12-14 CA CA002103884A patent/CA2103884A1/en not_active Abandoned
- 1992-12-14 WO PCT/FR1992/001182 patent/WO1993012128A1/en not_active Application Discontinuation
- 1992-12-14 EP EP93902329A patent/EP0572644A1/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6164M (en) * | 1966-10-13 | 1968-07-08 | ||
| DE2105560A1 (en) * | 1971-02-06 | 1972-09-07 | Boehringer Mannheim Gmbh, 6800 Mannheim | Purine ribonucleoside derivatives and processes for making the same |
| EP0098186A1 (en) * | 1982-06-14 | 1984-01-11 | Synthelabo | Pharmaceutical compositions containing purine or pyrimidine xylosides and lyxosides |
| EP0317728A2 (en) * | 1987-09-22 | 1989-05-31 | Warner-Lambert Company | Use of 9-(beta-D-arabinofuranosyl) adenine derivatives for the preparation of pharmaceutical compositions for the treatment of aids |
| EP0322384A1 (en) * | 1987-11-03 | 1989-06-28 | Medivir Aktiebolag | Nucleosides for use in therapy |
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| CANADIAN JOURNAL OF CHEMISTRY. vol. 66, no. 5, 1988, OTTAWA CA pages 1258 - 1262 M.J.ROBBINS ET AL. 'Nucleic Acid Related Compounds. 53. Synthesis and Biological Evaluation of 2'-deoxy-beta-threo-pentofuranosyl Nucleosides. ' * |
| CHEMICAL ABSTRACTS, vol. 101, no. 23, 1984, Columbus, Ohio, US; abstract no. 207519, B.B.GOSWAMI ET AL. 'Mechanism of Inhibition of Herpesvirus Growth by 2'-5'-Linked Trimer of 9-B-D-Xylofuranosyladenine' page 345 ;colonne 2 ; * |
| CHEMICAL ABSTRACTS, vol. 103, no. 25, 1985, Columbus, Ohio, US; abstract no. 215691g, G.GOSSELIN ET AL. 'Synthesis of Arabinofuranonucleosides from Certain Xylofuranonucleosides' page 934 ;colonne 2 ; * |
| CHEMICAL ABSTRACTS, vol. 112, 1990, Columbus, Ohio, US; abstract no. 151297j, V.M.SHOBUKHOV ET AL. 'A Comparative Study of Antiherpetic Effects of 9-B-D-Xylofuranosyladenine and 9-B-D-arabinofuranosyladenine and their Inhibitory Effect for HSV-1 with Abnormal Genome in Cell Culture' page 21 ;colonne 2 ; * |
| CHEMICAL ABSTRACTS, vol. 112, no. 11, 1990, Columbus, Ohio, US; abstract no. 99118k, A.NEUMANN ET AL. 'Facile Synthesis of Anomerical Pure 9-(beta-D-xylofuranosyl) adenine.' page 809 ;colonne 2 ; * |
| CHEMICAL ABSTRACTS, vol. 66, 1967, Columbus, Ohio, US; abstract no. 83226q, J.DE RUDDER ET AL. 'Inhibitory Activity of 9-B-D-Xylofuranosyladenine on Herpes virus Multiplication in Cell Cultures' page 7782 ;colonne 2 ; * |
| CHEMICAL ABSTRACTS, vol. 75, no. 3, 1971, Columbus, Ohio, US; abstract no. 20873p, M.IKEHARA ET AL. 'Nucleosides and Nucleotides. L. Purine Cyclonucleosides. 14. Synthesis and Properties of Cyclonucleosides Derived from 9-D-Xylofuranosyladenine' page 503 ;colonne 1 ; * |
| CHEMICAL ABSTRACTS, vol. 93, no. 1, 1980, Columbus, Ohio, US; abstract no. 10y, R.I.GLAZER 'Potentiation by 2'-Deoxycoformycin of the Inhibitory Effects of Cordycepin and Xylosyladenine on Nuclear RNA Synthesis in L1210 Cells' page 1 ;colonne 2 ; * |
| JOURNAL OF MEDICINAL CHEMISTRY. vol. 29, no. 2, 1986, WASHINGTON US pages 203 - 213 G.GOSSELIN ET AL. 'Systematic Synthesis and Biological Evaluation of alpha- and beta-D-Xylofuranosyl Nucleosides of the Five Naturally Occurring Bases in Nucleic Acids and Related Analogues' * |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0624372A3 (en) * | 1993-03-18 | 1995-02-01 | Nippon Chemiphar Co | Medicament for treating human immunodeficiency virus. |
| EP0624372A2 (en) * | 1993-03-18 | 1994-11-17 | Nippon Chemiphar Co., Ltd. | Medicament for treating human immunodeficiency virus |
| US6525033B1 (en) | 1993-09-10 | 2003-02-25 | Emory University | Nucleosides with anti-hepatitis B virus activity |
| US7439351B2 (en) | 1993-09-10 | 2008-10-21 | The Uab Research Foundation | 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents |
| US5990093A (en) * | 1993-09-10 | 1999-11-23 | Emory University | Treating HBV with phospholipid prodrugs of β-L-2',3'-dideoxyadenosine 5'-monophosphate |
| US6245749B1 (en) | 1994-10-07 | 2001-06-12 | Emory University | Nucleosides with anti-hepatitis B virus activity |
| US7468357B2 (en) | 1994-10-07 | 2008-12-23 | Emory University | Nucleosides with anti-hepatitis B virus activity |
| US5808047A (en) * | 1995-03-24 | 1998-09-15 | Eli Lilly And Company | Process for the preparation of 2,2'-anhydro- and 2'-keto-1-(3',5'-di-O-protected-β-D-arabinofuranosyl) nucleosides |
| WO2002069943A3 (en) * | 2001-03-03 | 2003-04-17 | Ulrich Walker | Use of pyrimidine nucleosides and/or the prodrugs thereof for combating the side-effects of haart (highly active anti-retroviral therapy) and other anti-viral therapies |
| US6992072B2 (en) | 2001-03-03 | 2006-01-31 | Pharma Nord Aps | Combating side-effects |
| US9073960B2 (en) | 2011-12-22 | 2015-07-07 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US10464965B2 (en) | 2011-12-22 | 2019-11-05 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US11021509B2 (en) | 2011-12-22 | 2021-06-01 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US10485815B2 (en) | 2012-03-21 | 2019-11-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2103884A1 (en) | 1993-06-13 |
| JPH06505510A (en) | 1994-06-23 |
| EP0572644A1 (en) | 1993-12-08 |
| FR2684997A1 (en) | 1993-06-18 |
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