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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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• 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)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

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Cited By (9)

Citations (5)

• 1991
  • 1991-12-12 FR FR9115420A patent/FR2684997A1/fr not_active Withdrawn
• 1992
  • 1992-12-14 JP JP5510676A patent/JPH06505510A/ja active Pending
  • 1992-12-14 EP EP93902329A patent/EP0572644A1/de not_active Withdrawn
  • 1992-12-14 CA CA002103884A patent/CA2103884A1/fr not_active Abandoned
  • 1992-12-14 WO PCT/FR1992/001182 patent/WO1993012128A1/fr not_active Application Discontinuation

Patent Citations (5)

Non-Patent Citations (10)

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