FR2688003A1 - Nucleoside derivatives, their preparation and their biological applications - Google Patents

Abstract

These derivatives correspond to the formula in which X represents an oxygen or sulphur atom, one of Y1 or Y2 represents NR'' and the other represents C=X or CH2, Z represents NH or CR'R''; R, R' and R'' each represent a hydrogen atom, an optionally halogenated alkyl or cycloalkyl group, and R1, R2 and R3 each represent a hydrogen atom or a hydroxy, acyloxy, benzoyloxy, N3, SCN or CN group or alternatively the symbols R1 and R2 represent together a second bond, with the proviso that R1, R2 and R3 are not simultaneously H.

Description

 The present invention relates to novel nucleoside derivatives, their preparation and their biological applications including antiviral.

 A natural nucleoside is a compound formed of a carbohydrate (ribose or deoxyribose) on which a purine or pyrimidine base is grafted.

The development of new nucleosides is currently one of the major developments in the field of fine chemicals. These compounds possess antiviral properties and some are used as an anti-herpes substance (eg 5- (2-bromovinyl) arabinouridine and 5-methoxymethyl-2'-deoxyuridine).
HIV (anti-AIDS) (eg, 3'-azido-3'-deoxythymidine, referred to as AZT, 2'-3-didehydro-2 ', 3'-dideoxythymidine and 2', 3'-dideoxycytidine), or as anticancer substances Examples thereof (e.g., 3- (3-oxoprop-1-enyl) -thymidine are, for example, the following documents: - LJJ HRONOWSKI and WA SZAREK, J. Chem Soc., Chem.

Commun., 1990, 21, 1547; - P. KUMAR and L.I. WIEBE, Nucleoside Nucleotides, 1990, 9 (6), 847 and 861; A.A. Van Aerschot et al. Nucleoside Nucleotides, 1990, i (4), 557; - SHARMA and BOBEK, Tetrahedron Lett., 1990, 31 (41), 5839; B.V. JOSHI and C. B. REESE, Tetrahedron Lett., 1990, 31 (51), 7483; A. MATUSDA, M. SATOH and T. UEDA, Nucleoside Nucleotides, 1990, 9 (4), 587.

 The search for new molecules, if possible more active and more selective (that is to say, less toxic for the patient) is actively pursued.

In the absence of an exact knowledge of the modes of action of these compounds, the strategy consists of preparing new modified nucleosides by inducing changes on either the carbohydrate moiety, or on the purine or pyrimidine moiety and to evaluate posteriori biological activities.

 We have now prepared new nucleosides comprising a ribosic unit attached to a triazine or nonaromatic piperazine base, which have biological activities, including antiviral interesting.

dans laquelle
X représente un atome d'oxygène ou de soufre, l'un des Y1 ou Y2 représente NR" et l'autre représente
C = X ou CH2,
Z représente NH ou CR'R"
R, R' et R" représentent chacun un atome d'hydrogène, un groupe alkyle droit ou ramifié de 1 à 12 atomes de carbone ou cycloalkyle en C3 à C12 atomes de carbone, chacun pouvant porter un ou plusieurs atomes d'halogène, et
R1, R2 et R3 représentent chacun un atome d'hydrogène ou un groupe hydroxy ou acyloxy de 2 à 7 atomes de carbone, benzoyloxy, ou un autre groupe nucléophile tel que Na, SCN ou CN, ou bien les symboles R1 et R2 représentent ensemble une seconde liaison, sous réserve que R1, R2 et
R3 ne soient pas H simultanément.The subject of the invention is therefore nucleoside derivatives corresponding to the formula

in which
X represents an oxygen or sulfur atom, one of Y1 or Y2 represents NR "and the other represents
C = X or CH2,
Z represents NH or CR'R "
R, R 'and R "each represents a hydrogen atom, a straight or branched alkyl group of 1 to 12 carbon atoms or C3 to C12 cycloalkyl carbon atoms, each of which may carry one or more halogen atoms, and
R1, R2 and R3 each represent a hydrogen atom or a hydroxy or acyloxy group of 2 to 7 carbon atoms, benzoyloxy, or another nucleophilic group such as Na, SCN or CN, or the symbols R1 and R2 together represent a second link, provided that R1, R2 and
R3 are not H simultaneously.

Compounds (I) in which R1,
R2 and R3 are each C2-C7 hydroxy or acyloxy, especially acetoxy, or benzoyloxy.

Compounds (I) in which R is (C1-C12) alkyl or cycloalkyl are preferred.
C3 to C12 and R 'and R "are each H. Cycloalkyl or mono-, di- or tricyclic alkyl group such as adamantyl.

 The invention relates more particularly to the compounds (I) in which X is 0.

dans laquelle X, Y1, Y2, Z, R, R' et R" ont la même signification que dans la formule I, avec un dérivé glucidique de formule

dans laquelle R'1, R' 2 et R'3 ont respectivement la même signification que R1, R2 et R3 dans la formule I à l'exception de hydroxy, et le cas échéant on déacyle le composé (I) ainsi obtenu dans lequel l'un au moins de R1, R2 et R3 est un groupe acyloxy, pour obtenir le composé hydroxylé correspondant.The compounds of the invention may be prepared by coupling a triazine or piperazine derivative of formula

in which X, Y 1, Y 2, Z, R, R 'and R "have the same meaning as in formula I, with a carbohydrate derivative of formula

in which R'1, R '2 and R'3 respectively have the same meaning as R1, R2 and R3 in formula I with the exception of hydroxy, and where appropriate the compound (I) thus obtained is deacylated in which at least one of R 1, R 2 and R 3 is an acyloxy group, to obtain the corresponding hydroxylated compound.

In one of the preferred cases where R1, R2 and R3 each represent OH, Y1 is C = X, Y2 is NR ", Z is NH,
R 'and R "each represent H and X is 0, the process can be represented by the following scheme

<tb><SEP> 0
<tb><SEP> O <SEP> Ç <SEP> CER
<tb> AcOO <SEP> OAc <SEP> 02
<tb><SEP> t <SEP> HNI1ae <SEP> AcOO
<tb><SEP> OAc
<tb><SEP> H
<tb><SEP> o
<tb><SEP> O
<tb><SEP> HNzC <SEP> t
<tb><SEP> O <SEP> = <SEP> Cs <SEP> / <SEP> H <SEP> (R '<SEP> = <SEP> H
<tb><SEP> N
<tb><SEP> X = O
<tb> deacetylationY, <SEP> = <SEP> CO
<tb><SEP> HOCH <SEP><SEP> = <SEP> Z <SEP> = <SEP> = 0
<tb><SEP> Y1 <SEP> = <SEP> CO
<tb><SEP> HH <SEP> Y <SEP> Y2 <SEP> = <SEP> Z <SEP> = <SEP> NH)
<tb><SEP> H <SEP> Hz <SEP> H
<tb><SEP> HO <SEP> OH
<tb><SEP> HO <SEP> OH
<Tb>
Ac being an acetyl group.

 a) Coupling. The coupling reaction of peracetylated ribose with the above triazine derivative can be carried out regio- and stereo-selectively.

 Among the many systems that can be used for this type of coupling, the method described by Vorbrüggen and Bennua, Chem. Ber. 1981, 114, 1234, 1256 and 1279. It combines the carbohydrate-purine or pyrimidine pair with trimethylsilane chloride (TMSCl), hexamethyldisilazane (HMDS) and trimethylsilyltrifluoromethanesulfonate (TMSTf). It has the triple advantage of leading to the coupling product in a single operation, being very selective and minimizing the amount of by-products. The optimization of the reaction conditions showed that the compounds according to the invention could be obtained with a yield of about 20% operating under argon at 0 C with molar ratios of carbohydrates / base TMSCl / HMDS / TMSTf = 1. / 1 / O, 8 / 0.8 / 2.2.

b) Deacetylation
It is best to use a gentle deacylation method. It consists in placing the triacetylated nucleoside in a reaction medium comprising a weak base such as an amine, for example a medium consisting of methanol / water / triethylamine.

The triazine derivatives of formula II (Y1 =
CX; Y2 = NR ", Z = NH) can be synthesized in the following manner.

1) Synthesis of Brominated Esters
The starting point of this multi-step synthesis is the elaboration of the α-brominated esters. The diagram is the following
5 10 15 20 25 30 35

 The acid chlorides corresponding to the acid pass through the addition of phosphorus trichloride (dissolved in hexane) and heating at 40-50 ° C with stirring for 1 to 2 days. This reaction is rapid (approximately 1 hour) and exothermic, followed by methanol esterification.

2) Synthesis of Triazinic Bases
From the previously synthesized α-brominated esters and semicarbazide hydrochloride, the triazine bases can be obtained according to the following scheme:

 Carbohydrate derivatives of formula III are generally known. Paracetylated ribose is especially available from Aldrich, Sigma, etc.

x = o
II Y1 = NH
Y2 = CH2
Z = CRR'
Le couplage entre le dérivé pipérazinique (II) et le dérivé glucidique (III) est effectué selon le même processus que pour les dérivés triaziniques.The piperazine bases of formula II (Y1 =
NR ", Y2 = CH2, Z = CRR ') can be elaborated according to the reaction

x = o
II Y1 = NH
Y2 = CH2
Z = CRR '
The coupling between the piperazine derivative (II) and the carbohydrate derivative (III) is carried out according to the same process as for the triazine derivatives.

 The following examples illustrate the invention.

The structures of these compounds have been confirmed by conventional means of spectroscopy:
NMR, IR, Mass.

 1H NMR spectra are recorded on VARIAN EM 360 spectrometers (60 MHz) or BRUCKER AC 200 (200 MHz) with tetramethylsilane as an internal standard in DMSO d6 or DCCl3. The chemical shifts are denoted in ppm (6), the couplings in Hz and the signals are expressed in the following way: singlet (s), doublet (d), triplet (t), multiplet (m). Any mobile proton is confirmed by the addition of D2O.

 The IR spectra are recorded on a PERKIN ELMER 1310 device. The sample is in the form of KBr pellets or in solution in carbon tetrachloride between two KBr windows.

 The W spectra are recorded on a WIKON 930 instrument (KONTRON INSTRUMENT) in absorbance between 200 and 400 nm on products in solution in ethanol in 1cm quartz vessels of optical path.

 The mass spectra are made on a SHIMADZU QP 1000 spectrometer in E.I.

Melting points are determined on a bench
KOFLER.

Thin-layer analytical chromatography (TLC) is performed
or on MERCK 60F254 silica gel (0.20 mm thick) deposited on aluminum foil.

 - In inverse phase on silica gel RP 18F254 MERCK deposited on glass plate (3x5 cm).

 The preparative plate chromatographies are carried out on a MERCK 60PF254 gel deposited on a glass plate (20 × 20 cm, 2 mm thick).

 Column chromatography is carried out on LICHROPREP Si 60 MERCK gel (15-25 μm). The 2 cm diameter column has an approximate height of 15 cm.

 PREPARATION OF THE COMPOUNDS OF FORMULA II.

Preparation 1 a) methyl 2-bromopropanoate
The 2-bromopropanoic acid (90 ml, 1 mol, 1 eq.) Is brought into contact with phosphorus trichloride (52.2 ml, 0.6 mol, 1.8 eq.) For 2 days with stirring at 40 °. C. 2-bromopropanoic acid chloride is recovered after decantation of orthophosphorous acid Excess methanol (50 ml) is added dropwise over one hour (the reaction is exothermic and the evolution of hydrochloric acid is Methyl propanoate neutralized was extracted with ether (1 × 50 ml) and the medium was neutralized with potassium hydroxide or washed with distilled water (1 × 50 ml). The organic phase was separated, dried for one hour on magnesium sulfate, filtered through celite, the ether is evaporated to give a yellowish liquid which is distilled under reduced pressure (o 40 mm Hg) obtaining two levels: 59 "C and 69-70" C. The second level (69-70 ° C) is assigned to methyl 2-bromopropanoate: Eb = 144 ° C, reverse phase TLC: Rf = 0.76 (methanol) / water = 70:30).

b) 1,6-Dihydro-3,5-dioxo-6-methyl-1,2,4-triazine (II
R = CH3; R '= H; X = O; Y1 = CO; Y2 = Z = NH)
This synthesis was carried out according to 2 different protocols
Methyl 2-bromopropanoate (I: 10.5 g 0.069 mol, II: 16.7 g - 0.1 mol) and semicarbazide hydrochloride (I: 6.8 g - 0.06 mol; II: 15.6 g - 0 14 mol) are placed in absolute ethanol (30 ml) with stirring at 70 ° C. under an argon atmosphere. A first equivalent of triethylamine (I: 8.6 ml - 0.06 mol; II: 19, 5 ml - 0.14 mol) is added dropwise to release the primary amine function of the semicarbazide semicarbazide dissolves After 12 hours, a second equivalent of triethylamine (I: 8.6 ml-0.06 mol; 14 ml-0.1 mol) is added in several fractions to remove the hydrobromide.After 5 days, the medium is neutral.The separation of triethylamine hydrochloride and hydrobromide can be carried out according to the following 2 methods (method
A for I - method B for II)
Method A (I): Filtration of triethylamine hydrochlorides and hydrobromides. Evaporation of ethanol. Addition of a chloroform / water (1: 1) mixture to the filtrate. The remaining triethylamine salts are dissolved in the aqueous phase. The methyl 2-semicarbazidopropanoate is extracted and decanted into the organic phase.

The organic phase is dried over magnesium sulfate for one hour, filtered through Celite, and the chloroform is evaporated.

 Method B (II): Acetone is added to the medium to crystallize the hydrochlorides and triethylamine hydrobromides and then filtered and the solvents evaporated (ethanol and acetone).

After separation of the hydrochloride and triethylamine hydrobromide, treated with sodium ethanoate in absolute methanol (1: 111 mg of sodium, 4.8 mmol / 30 ml of ethanol, II: 9g of sodium; mol / 30 ml of ethanol) for cyclization. Hydrochloric acid solution (12%) is added until neutralization of the medium. The salts (mainly NaCl) are removed by filtration in hot ethanol. 1,6-Dihydro-3,5-dioxo-6-methyl-1,2,4-triazine crystallizes in cold methanol in the form of white crystals:
Yield: 1: 78mg (1%); II: 1.9g (15%); Mp = 214 ° C. 1H NMR 60 MHz (DMSO d6): δ 1.3 (d, 3H, H6 '), 3.3 (m, 1H, H6), 5.5 (m, 1H, H), 8 , 9 (s, 1H, disappears in D2O, H2 or H5), 10.4 (s, 1H, disappears in D2O, H4 or H3); Mass: 129 (M +), 114 (M + CH 3), 86 and 71 (skeletal fragmentation);
IR: 3240 (vNH: -CO-NH-CO-), 3050 (vNH triazine ring), 1755, 1711 (vC = O); TLC: Rf = 0.16 (vchloroform / ethanol = 95: 5).

Preparation 2 a) Methyl 2-bromoadamantane-ethanoate
The ethanoic acid adamantane acid (2 g, 0.01 mol, 1 eq.) Is dissolved in hexane (10 ml) and the phosphorus trichloride (0.52 ml, 6 mmol, 1.8 eq.) Is added to 50 ml. With stirring for 18 hours. After decantation (4 hours) of orthophosphorous acid and evaporation of hexane, the chloride of adamantane ethanoic acid is obtained in the form of a colorless liquid which is subjected to the action of bromine (0, 6 ml, 0.011 mol, 1.1 eq.) With stirring at room temperature for 3 weeks. (The hydrobromic acid released and the excess bromine are removed in a potash trap.) The chloride of 2-bromo adamantane ethanoic acid is obtained in the form of a translucent brown liquid which is added an excess of methanol (1 ml) dropwise for 30 minutes (the reaction is exothermic with evolution of hydrochloric acid). Methyl 2-bromo-adamantane ethanoate and excess methanol are immiscible.

After cooling, the product obtained is extracted with ether (1 × 20 ml). The medium is neutralized with potassium hydroxide (which discolors the organic phase) and then washed with distilled water (1 × 20 ml). The organic phase is decanted, dried for one hour over magnesium sulfate, filtered through celite and the ether is evaporated to give the title compound as a thick yellowish liquid crystallizing in air.

Yield: 2.506g (87.2%); Mp = 46 ° C, 1H NMR 60 MHz (CDCl 3): 61.7 (m, 12H, 6 CH 2 AD), 2.1 (m, 3H, 3 CHad), 3.8 (s, 3H, CH 3 O-), 4 (s). , 1H, -CH-Br); IR: 2925 (vasCH2Ad), 2890 (vCHAd), 2850 (VCH2Ad), 1735 (vC = O), 1160 (vC-O); TLC reverse phase: Rf = 0.28 (methanol / water = 70:30).

b) 6-adamantane-1,6-dihydro-3,5-dioxo-1,2,4-triazine (II: R = 1-adamantyl; R '= H; X = O; Y1 = CO; Y2 = Z; = NH)
The compound obtained in a) (2.6 g, 0.01 mol) and semicarbazide hydrochloride (1.4 g, 0.0125 mol) are placed in absolute ethanol (40 ml) with stirring at 70 ° C. A first equivalent of triethylamine (1.8 ml, 0.0125 mol) is added dropwise to release the primary amine function of semicarbazide, which dissolves, after 12 hours a second equivalent of triethylamine (1.4 ml). 0.01 mol) is added to remove the hydrobromide and, after separation of the hydrochlorides and triethylamine hydrobromides (Method B), the product is dried in a desiccator for 3 days and then treated with ethanolate in absolute ethanol. (0.345 g of sodium, 0.015 mol / 30 ml of ethanol) for the cyclization A solution of hydrochloric acid (12%) is added until neutralization of the medium.

The solvents (water and ethanol) are evaporated and distilled water (1 × 20 ml) is added to solubilize the salts (mainly NaCl). After filtration of the product and drying, the brown gum obtained is recrystallized from ethanol. The title compound crystallizes as brown crystals.

Yield: 20mg (0.8%); Mp 178 ° C; IR: 3000-3400 (VN-H), 2800-2900 (vC-H); 1690 (vu = 0) TLC: Rf = 0.37 (chloroform / ethanol = 95: 5).

Preparation 3 1,6-dihydro-3,5-dioxo-6-propyl-1,2,4-triazine (II: R = n-C3H7; R '= H; X = O; Y1 = CO; Y2 = Z) = NH)
The methyl 2-bromopentanoate obtained according to the procedure of the preparation 1a) (15.6 g, 0.08 mol) and the semicarbazide hydrochloride (13.4 g, 0.12 mol) are placed in absolute ethanol. (30 ml) with stirring at 70 ° C. under an argon atmosphere A first equivalent of triethylamine (16.7 ml, 0.12 mol) is added dropwise to release the primary amine function of semicarbazide; After 12 hours, a second equivalent of triethaylamine (11.2 ml, 0.08 mol) is added to remove the hydrobromide.

After separation of the hydrochloride and triethylamine hydrobromide (method A), treated with sodium ethanoate in absolute ethanol (1.85 g of sodium, 0.08 mol / 30 ml of ethanol) for cyclization. Hydrochloric acid solution (~ 12%) is added until neutralization of the medium. The salts (NaCl) are removed by filtration in hot methanol. 1,6-Dihydro-3,5-dioxo-6-propyl-1,2,4-triazine crystallizes in cold ethanol as white crystals.

Yield: 2.35 g (18.7%); Mp = 215 ° C; 1H NMR (DMSOd6): δ (m, 3H, H6 '' '), 1.6 (m, 4H, H6' + H6 ''), 3.3 (m, 1H, H6), 5.6 ( d, 1H, H1), 8.8 (s, 1H, disappears in D20, H2 or H5), 10, 3 (s, 1H, disappears in D2O, H4 or H3); Mass: 158 (MH +), 157 (M +), 115 (M-CH3-CH = CH2: Mac Lafferty), 114 (M1-CH3-CH2-CH2), 86 and 71 (skeletal fragmentations); IR: Main bands identical to those of Preparation lb); W (ethanol): λmax = 245 nm (E335); TLC: Rf = 0.20 (chloroform / ethanol = 95: 5).

Preparation 4 3-decyl 2-piperazinone (II: X = O, Y1 = NH, Y2 = CH2, Z = CRR 'with R = nC1OH21 and R' = H)
The hydrochloride of this compound prepared according to
S. PIEKARSKI (Oleaginous, 1962, 10, 785) (5 g) was dissolved in chloroform (40 ml) and then 1.5 g of KOH in 20 ml of water was added. After stirring and decantation, the organic phase is dried and then evaporated. We get white crystals
yield 3.1 g (73%).

Preparation 2,3-dimethyl-2-piperazinone (II: X = O; Y1 = NH; Y2 = CH2; Z = CRR 'with R = R' = CH3)
A solution of ethyl 2-bromo-2-methylpropanoate (9.05 ml, 0.062 mol) in 40 ml of benzene is added dropwise to a solution of 25 ml of ethylenediamine in 40 ml of benzene. ambient temperature. After addition of the reagent, the solution is refluxed for 2 hours. After cooling, an alcoholic potassium hydroxide solution containing 3.45 g (0.062 mol of KOH) is added to neutralize the medium. The KBr precipitate is filtered and the solution is evaporated. The residue is taken up in hot ethyl acetate. On cooling, white crystals are obtained.

Yield: 2.15 g (27%)
Mp = 134 ° C
IR spectrum vC = O: 1640 cm -1
vNH amine: 3350 cm -1
EXAMPLE 1 6-aza-5,6-dihydro-5-methyl-2 ', 3', 5'-triacetate-uridine (I: R 1 = R 2 = R 3 = CH 3 COO; R = CH 3; R '= H; X = O; Y1 = CO; Y2 = Z = NH)
Two syntheses are carried out under close conditions (I-II) and the raw products are collected before separation.

Peracetyl ribose (0.3183 g, 1 mmol) and 1,6-dihydro-3,5-dioxo-6-methyl-1,2,4-triazine (0.129 g, 1 mmol) are dissolved in the 1, 2 dichloroethane (5 ml). Thereafter trimethylsilane chloride (101 μl, 0.8 mmol), hexamethyldisilazane (169 μl) is added successively; 0.8 mmol) and trimethylsilyltrifluoromethanesulfonate (400 μl, 2.2 mmol) with stirring under an argon atmosphere at 0 ° C. The solution turns brown. After 24 hours (I) or 6 hours (II), the medium is treated with a water / saturated solution of sodium bicarbonate solution (1: 1, 16 ml). We reach then the neutrality. Dichloromethane (20 ml) is added to extract the compound formed. The organic phase is decanted and then dried over magnesium sulphate, filtered through vegetable charcoal and celite. After evaporation of the dichloromethane, the crude product is in the form of a thick yellowish syrup (306.3 mg for I + 315.3 mg for II) which is adsorbed on
Florisil to separate the title compound by column chromatography (15 cm silica) with the following eluents: chloroform (100%, 300 ml); chloroform / ethanol (99: 1, 100 ml, 98: 2, 100 ml). Further purification is carried out by plate chromatography (eluent: chloroform / ethanol = 95: 5).

 Yield: 67 mg (9.6%); TLC: Rf = 0.23 (chloroform / ethanol = 95: 5).

EXAMPLE 2 6-aza-5,6-dihydro-5-proDyl-2 ', 3', 5'-triacetate-uridine (I: R 1 = R 2 = R 3 = CH 3 COO, R = n-C 3 H 7, R '= H X = O; Y1 = CO; Y2 = Z = NH)
636.6 mg (2 mmol) of peracetylated ribose and 314 mg (2 mmol) of 1,6-dihydro-3,5-dioxo-6-propyl-1,2,4-triazine are dissolved in 10 ml of 1,2-dichloroethane. .

202 ml of trimethylsilane chloride, 338 ml of hexamethyldisilazane and 800 μl of trimethylsilyltrifluoromethane are subsequently added successively at 0 ° C. under an argon atmosphere. The solution turns brown. It is treated with 32 ml of a water / saturated solution of sodium bicarbonate (1: 1) to stop the reaction and dichloromethane (20 ml) is added to extract the compound formed. The organic phase is decanted after checking the neutrality of the medium, then dried over magnesium sulfate and filtered on charcoal and celite.After evaporation of dichloromethane, the crude product (443 mg) is in the form of a yellowish syrup . It is extracted by column chromatography (Eluents: chlorofroma 150 ml, chloroform / ethanol = 99: 1-100 ml, 98: 2 - 100 ml, 97: 3-100 ml). 135.8 mg (16.3% yield) of the title compound are obtained.

1 H NMR 200 MHz (CDCl 3): 0.69 (t, 3H, J 5 '' '- 5' '= 15.4 Hz, H 5' '), 1.3 (m, 2H, H 5,'), 1.7 (m, 2H, H5), 2.2 (several s, 9H-OAc), 3.5 (dd, 1H, J55 = 6.2 Hz, J56 = 3.5 Hz, H5), 4 , 2 (m, 3H, H4, H5a, H5b), 4.6 (d, 1H, J2 = 6.5Hz, H2,), 5.3 (m, H, H3), 5.6 (d, 1H, J65 = 4Hz, H6), 6.1 (d, 1H, J1'-2 '= 7Hz, H1'), 7.1 and 7.7 (2s, 1H, disappear in D2O, H acid); Mass: 417 (MH +), 259,240,217,167,158, 157,156,149, 145,143,140,139,128,127, 115,114,103, IR: 3100-3400 (vN-H), 2960 (CH3), 2920 (vasCH2), 2860 (vsCH3), 1750 (vC = O ester) ), 172O (vC = O base); TLC: Rf = 0.34 (chloroform / ethanol = 95: 5).

EXAMPLE 3 6-aza-5,6-dihydro-5-methyl-uridine (I: R 1 = R 2 = R 3 = OH, R = CH 3, R '= H, X = O, Y 1 = CO, Y 2 = Z = NH )
The uridine derivative obtained according to Example 1 (35.5 mg, 9.1 pmol) is placed in a reaction mixture water / methanol / triethylamine (10: 10: 1-10 ml) for 2 hours with stirring at 0 ° C. C. The reaction is followed by
TLC (eluent: chloroform / ethanol = 70:30). As the deacetylation proceeds, the product solubilizes in the solution. After evaporation of the reaction mixture and removal of traces of water by azeotropy in ethanol (2 ml); the title compound is separated by plate chromatography (eluent: chloroform / ethanol = 70: 30).

Yield: 12 mg (50t);
IR (cm-1): 3400 (vNH), 3200 (vOH), 2960 (vCH3), 1720 (vC = Obase)
TLC: Rf = 0.45 (eluent: chloroform / ethanol = 7: 3).

EXAMPLE 4 6-aza-5,6-dihydro-5-propyl-uridine (I: R 1 = R 2 = R 3 = OH, R = n-C 3 H 7, R '= H, X = O, Y 1 = CO, Y 2 = Z; = NH)
The uridine derivative obtained according to Example 2 (141 mg, 3.4 × 10 -5 mol) is placed in a water / methanol / triethylamine (10: 10: 1-30 ml) reaction mixture for 2 days while stirring at room temperature. 25 ° C. The reaction is monitored by TLC (eluent: chloroform / ethanol = 70:30) As the deacetylation proceeds, the product solubilizes in the solution After evaporation of the reaction mixture and removal of the traces of water by azeotropy in ethanol (2 ml), the title compound is separated by plate chromatography (eluent chloroform / ethanol = 70:30).

Yield: 20 mg (20.3%);
IR (cm-1) 3400 (kNH), 3200 (vOH), 2970 (VCH3), 1720 (vC = Obase)
UV (ethanol): λ max: 245 nm (E 400); TLC: Rf = 0.55 (eluent chloroform / ethanol = 70: 30).

EXAMPLE 5 1- (2,3,5-Tri-O-acetyl-ss, D-ribofuranosyl) 3-decyl-2-piperazinone (I: R 1 = R 2 = R 3 = CH 3 COO, R = R '= HX = O, Y 1 = NH; Y2 = CH2; Z = CHn-C10H21)
Peracetyl ribose (0.318 g, 1 mmol) and 3-decyl 2-piperazinone (0.240 g, 1 mmol) are dissolved in 1,2-dichloroethane (5 ml). Trimethylsilane chloride (101 μl, 0.8 mmol), hexamethyl disilazane (169 μl, 0.8 mmol) and trimethylsilyltrifluoromethanesulfonate (218 μl, 1.2 mmol) are then successively added with stirring under stirring. argon atmosphere. The reaction is continued for 5 hours at room temperature.

After extraction according to Example 1, a thick yellowish syrup is obtained: 0.667 g. The crude product is purified on a silica column with the following eluents: ether / hexane (70:30, 200 ml), ether (100%, 100 ml), chloroform (100%, 100 ml).

 Further purification is carried out by plate chromatography (eluent ether / hexane 60:40).

 0.185 g (37%) is obtained.

EXAMPLE 6 1- (2,3,5-Tri-O-acetyl-ss, D-ribofuranosyl) 3,3-dimethyl-2-piperazinone (: R 1 = R 2 = R 3 = CH 3 COO; R = R '= H: X = Y1 = NH; Y2 = CH2; Z = C (CH3) 2)
Peracetyl ribose (0.318 g, 1 mmol) and 3,3-dimethyl-2-piperazinone (0.128 g, 1 mmol) are dissolved in acetonitrile (5 ml). Trimethylsilane chloride (101 μl, 0.8 mmol), hexamethyldisilazane (169 μl, 0.8 mmol) and trimethylsilyltrifluoromethanesulfonate (400 μl, 2.2 mmol) are then successively added with stirring. under argon atmosphere. The reaction is continued for 2 hours at room temperature.

After treatment identical to that of Example 1, a thick syrup is obtained: 0.252 g.

with eluent: chloroform / ethanol 95: 5 gives 108 mg of product.

Yield: 28%
IR spectrum vC = O acetate: 1740 cm -1
vC = O amide: 1640 cm -1
vNH amine: 3450 cm -1
The compounds of the invention have been subjected to biological experimentation.

EXAMPLE OF BIOLOGICAL TESTING: ACTI IN VITRO STUDY
FAST ANTIVIRAL
The inhibitory activity of 6-aza-5,6-dihydro-5-propyl-uridine on the cytopathic effect (ECP) induced by a lentivirus: Visna virus on a primary choroid plexus cell culture was investigated. microplates, according to the protocol proposed by S. Beausoleil et al. Rev. Infect. Diseases, 1989, 11 (5), 732; and Rev. Med. Vet., 1991, 142 (7), 557. The antiviral activity studied is the curative effect on these cells pre-infected with the virus before the addition of the compounds according to the invention.

Cytotoxicity test
Before performing the antiviral test, the toxicity of the product to choroid plexus cells was determined. The study of this cytotoxicity is carried out on a microplate containing a 24-hour cell layer.

Each dilution of product is added in 8 wells, in the presence of a control cell by test. After 7 days of incubation, the evaluation of the cytotoxicity is carried out by reading under an inverted microscope. The cultures are examined after staining with
May-Grunwal-Giemsa. The minimum cytotoxic concentration (CMC) is the first dilution that does not result in a change in cell morphology.

 For the product according to Example 4, the CMC is equal to 25 μM.

Study of cytopathic inhibition
The cytopathic effect inhibition tests are carried out in a microplate on a cell pad inoculated with 0.15 TCID 50 of virus per cell for 30 minutes at 37 ° C., before addition of the product to be tested. parallel with a control cell and an untreated virus control On day 6, the formation of syncytial foci is observed under an inverted microscope after staining with May-Grunwald-Giemsa.

Results
The percentage of protective effect of the product studied on the target cells exposed to the virus is determined by the following formula
in the control virus-in the test treated 100 x syncytia number in the control virus-in the control cells
The effective 50% concentration (EC 50) obtained with 6-aza-5,6-dihydro-5-propyl-uridine is 17.5 μM. This compound therefore has an inhibitory activity detected on the Visna virus. Indeed, at the value equal to the CMC (25 μM), an inhibition of the cytopathic effect of the virus on the cells was observed, greater than 70%.

 The present study shows that the compounds of the invention and in particular 6-aza-5,6-dihydro-5-propyluridine are active on lentiviruses and can therefore be used as drugs including antiviral.

 The invention therefore also comprises pharmaceutical compositions containing as active principle a compound of formula I and a pharmaceutically acceptable vehicle or excipient, especially injectable compositions.

 In addition to their application as antiviral, the compounds (I) of the invention can be used as antibacterials, fungicides, insecticides and antiparasitics.

Claims (10)

 1. Derivatives of nucleosides corresponding to the formula

 in which X represents an oxygen or sulfur atom, one of Y1 or Y2 represents NR "and the other represents C = X or CH2, Z represents NH or CR'R " R, R 'and R "each represents a hydrogen atom, a straight or branched alkyl group of 1 to 12 carbon atoms or C3 to C12 cycloalkyl carbon atoms, each of which may carry one or more halogen atoms, and R 1, R 2 and R 3 each represent a hydrogen atom or a hydroxy, acyloxy group of 2 to 7 carbon atoms, benzoyloxy, N 3, SCN or CN, or the symbols R 1 and R 2 together represent a second bond, provided that R1, R2 and R3 are not H simultaneously.  Compounds (I) according to claim 1, wherein R1, R2 and R3 each represent a C2-C7 hydroxy or acyloxy group.  3. Compounds (I) according to claim 1, characterized in that Y1 represents C = X, Y2 represents NR "and Z represents NH.  4. Compounds (I) according to one of claims 1 to 3, wherein R represents a C 1 to C 12 alkyl or C 3 to C 12 cycloalkyl and R 'and R "each represent H.  5. Compounds (I) according to any one of claims 1 to 4, wherein X is O.  6. 6-aza-5,6-dihydro-5-propyl-uridine.  7. Process for the preparation of the compounds according to any one of Claims 1 to 6, characterized in that a triazine or piperazine derivative of formula

 in which X, Y1, Y2, Z, R and R 'have the same meaning as in formula I, with a carbohydrate derivative of formula

 in which R'1, R'2 and R'3 respectively have the same meaning as R1, R2 and R3 in formula I with the exception of hydroxy, and where appropriate the compound (I) thus obtained is deacylated in which at least one of R 1, R 2 and R 3 is an acyloxy group, to obtain the corresponding hydroxylated compound.  8. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable vehicle or excipient.  An antiviral drug comprising a compound according to any one of claims 1 to 6.  10. Use of the compounds according to any one of claims 1 to 6 as antibacterials, fungicides, insecticides and antiparasitics.