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 PDF

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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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adenine
group
xylofurannosyl
acetyl
cytosine
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PCT/FR1992/001182
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French (fr)
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Jean-Louis Imbach
Gilles Gosselin
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Centre National De La Recherche Scientifique (Cnrs)
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    • 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

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)
Figure imgf000003_0003
Figure imgf000003_0003
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
Figure imgf000003_0001
or
Figure imgf000003_0001
Figure imgf000003_0002
Figure imgf000003_0002
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.
Figure imgf000009_0001
Tableau (suite)
Figure imgf000009_0001
Table (continued)
Figure imgf000010_0001
Figure imgf000010_0001
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.
Figure imgf000014_0001
Figure imgf000014_0001
A = Adénine A = Adenine
R = C1-C4 alkyle ou aryle TBDMS = tertiofautylméthylsilyle
Figure imgf000015_0001
R = C 1 -C 4 alkyl or aryl TBDMS = tertiofautylmethylsilyl
Figure imgf000015_0001
NH2-NH2,H2O NH 2 -NH 2 , H 2 O
----------------------------→ puis séparation par chromatographie ---------------------------- → then separation by chromatography
Figure imgf000015_0002
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000015_0003
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)
Figure imgf000016_0001
dans laquelle
Figure imgf000016_0001
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
Figure imgf000016_0002
dans lequel R' représente un atome d'hydrogène ou un groupe (C2-4)alcanoyle,
Figure imgf000016_0002
in which R 'represents a hydrogen atom or a (C 2-4 ) alkanoyl group,
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.
PCT/FR1992/001182 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 WO1993012128A1 (en)

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Cited By (17)

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EP0624372A2 (en) * 1993-03-18 1994-11-17 Nippon Chemiphar Co., Ltd. Medicament for treating human immunodeficiency virus
EP0624372A3 (en) * 1993-03-18 1995-02-01 Nippon Chemiphar Co Medicament for treating human immunodeficiency virus.
US5990093A (en) * 1993-09-10 1999-11-23 Emory University Treating HBV with phospholipid prodrugs of β-L-2',3'-dideoxyadenosine 5'-monophosphate
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
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
US6992072B2 (en) 2001-03-03 2006-01-31 Pharma Nord Aps Combating side-effects
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
WO2002069943A2 (en) * 2001-03-03 2002-09-12 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
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
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USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

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