FR2677026A1 - Nucleosides containing a modified base - Google Patents

Abstract

The present invention relates to new derivatives of nucleosides which are therapeutically active in particular against the AIDS virus, in which the purine or pyrimidine base is modified, and to processes for preparing them.

Description

 The present invention relates to novel chemical compounds consisting of modified nucleoside derivatives, the present invention also relates to a process for the preparation of these compounds as well as their use as medicaments, in particular anti-viral drugs.

 Currently, the azido 3 'tymidine (AZT) is used against the fight against AIDS. However, the occurrence of side effects makes AZT treatment truly beneficial only in combination with anti-viral agents and / or immune system stimulants.

Therefore, today, it is imperative to develop other compounds with improved safety that may be associated with or substituted for AIT.

 More generally, the object of the present invention is to provide novel therapeutically active derivatives of known therapeutically active nucleoside derivatives. It is generally desirable to have new molecules related to a known drug so as to vary the spectrum of activity or toxicity and thus have a range of substitution products that may appear necessary depending on the disease or of the patient to be treated.

 In particular, an object of the present invention is to provide derivatives of AZT or of the compound called CS87 (3'-azido didesoxy uridine) active against the HIV virus or, in general, of all the nucleosides known to present a activity on the HIV virus.

 Another aim is to provide more active or less toxic derivatives and thus having a better therapeutic index than known therapeutically active nucleoside derivatives.

 To do this, the present invention provides novel chemical compounds consisting of therapeutically active nucleosides modified in their base, purine or purimide, maintaining the unchanged sugar portion.

- X représente S, N-OR1 avec R1 qui représente un alkyl en C1-C5 éventuellement substitué notamment par un ou plusieurs hydroxy, halogène ou méthoxy, au quel cas la ligne brisée --- représente une simple liaison et la ligne pointillée ... représente une double liaison, ou - X représente -SR2 avec R2 qui représente un alkyl en C1-C5 éventuellement substitué notamment par un ou plusieurs hydroxy un halogène ou méthoxy, au quel cas la ligne brisée --- représente une double liaison et la ligne pointillé ... représente une simple liaison, ou - X représente=O, au quel cas Z représente S - Y représente H, un halogène, un radical alkyl ou un radical alcoxy en C1-C7, éventuellement substitués notamment par un ou plusieurs hydroxy, halogène ou méthoxy - C représente le cycle glycosidique d'un dérivé de nucléoside thérapeutiquement actif, notamment d'un dérivé nucléoside antiviral en particulier actif contre le virus du sida, et - Lorsque X représente S, Y représente CH3 et Z = O, alors C est substitué par un groupe N3, CN ou halogène notamment F, de préférence en position 3' du cycle glycosidique.More specifically, the subject of the present invention is a chemical compound, characterized in that they are represented by the following general formula I in which - Z represents O or S

X represents S, N-OR 1 with R 1 which represents a C 1 -C 5 alkyl optionally substituted in particular with one or more hydroxy, halogen or methoxy, in which case the broken line represents a single bond and the dotted line. represents a double bond, or - X represents -SR 2 with R 2 which represents a C 1 -C 5 alkyl optionally substituted in particular with one or more hydroxyl, halogen or methoxy, in which case the broken line represents a double bond and the dotted line ... represents a single bond, or - X represents = O, in which case Z represents S - Y represents H, a halogen, an alkyl radical or a C 1 -C 7 alkoxy radical, optionally substituted in particular by one or more hydroxy, halogen or methoxy-C represents the glycoside ring of a therapeutically active nucleoside derivative, especially an antiviral nucleoside derivative particularly active against the AIDS virus, and - when X represents S, Y rep wherein CH3 and Z = O, then C is substituted by N3, CN or halogen, especially F, preferably at the 3 'position of the glycosidic ring.

Among these compounds, mention is made more particularly of the uridine or thymidine derivatives for which Y is H or Y respectively.
CH3, and Z represents O.

formule dans laquelle - R3 représente H,-R'3CO, avec R'3 qui représente un radical hydrocarboné en C1-C20 tel qu'un alkyl ou alcoxy, éventuellement substitué notamment par une fonction polaire telle que OH, NH2 ou COOH, en une ou plusieurs positions, - R4 représente N3, CN, un halogène tel que F au quel cas R5 = H, ou - R4 représente un radical méthylidène au quel cas R5 représente N3,
NH-CHO, CN, SCN, un halogène tel que F ou - R4 et R5 forment ensemble une double liaison entre les carbones en position 3' et 2' du cycle glycosidique au quel cas le carbone en position 3' peut éventuellement être substitué par un radical CH2-Nu avec Nu = N3,
NH-CHO, CN, SCN, halogène notamment F.The glycosidic ring of certain nucleoside derivatives known for their activity against the HIV virus can be represented by formula II

formula in which - R3 represents H, -R'3CO, with R'3 which represents a hydrocarbon radical C1-C20 such as an alkyl or alkoxy, optionally substituted in particular by a polar function such as OH, NH2 or COOH, in one or more positions, - R4 represents N3, CN, a halogen such as F in which case R5 = H, or - R4 represents a methylidene radical in which case R5 represents N3,
NH-CHO, CN, SCN, a halogen such as F or - R4 and R5 together form a double bond between the carbons at the 3 'and 2' position of the glycosidic ring in which case the carbon at the 3 'position may optionally be substituted by a CH2-Nu radical with Nu = N3,
NH-CHO, CN, SCN, halogen including F.

 Some of the derivatives with such a sugar portion have been described in the patent application FR 90 06 251 in the name of the applicant.

 The compounds most studied to date, however, are those for which R3 and R5 represent H and R4 represents N3, CN or F, preferably N3.

 The preferred compounds according to the present invention are those for which a) X = S, Y = H and Z = O or b) X = N-OCH3, Y = H or CH3, and Z = O or c) X = S- CH3, Y = H or CH3, and Z = O.

 By way of illustration of these compounds, mention may be made of the following compounds: 3'-azido-2 ', 3'-dideoxy-beta-D-4-thiouridine 3'-azido-2', 3'-dideoxybeta DN-4-methoxy-5-methylcytidine 3'-azido-2 ', 3'-dideoxy-beta-DN-4-methoxycytidine 3'-azido-2', 3'-dideoxy-beta-D-4 méthylthiouridine.

 In general, the compounds according to the invention may be prepared by conventional methods known to those skilled in the art.

 Thus, most conveniently, the compounds according to the invention can be prepared by a process in which the product of formula I is prepared whose function at the 5 'position of the glycoside ring C is a hydroxyl function protected by a protecting group such as a benzoyl group optionally substituted, in particular with a methoxy group, or the Trityl group, and is deprotected or reacted, if necessary, with a carboxylic acid of formula R'3COOH or a chloride of this acid.

* [2,4-bis(4-méthoxyphényl)-l ,3-dithia-2,4-diphosphétane-2,4-disulfurej
Les composés pour lequels Y représente H ou CH3 pourront être obtenus si on le souhaite à partir respectivement de l'uridine ou la thymidine

avec U = Uracyle pour l'uridine et T = Thymine pour la Thymidine
Certains exemples de ces procédés sont fournis dans la description détaillée qui suivra pour préparer les composés 100, 104, 105 et 114.More particularly, the compounds according to the invention may be prepared according to one of the following processes A to E in which, where appropriate, the reactive functions of Y, Z and C are initially protected and then deprotected after the reaction of the X = function.

* [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide]
The compounds for which Y represents H or CH 3 may be obtained, if desired, from uridine or thymidine, respectively.

with U = Uracyl for uridine and T = Thymine for Thymidine
Some examples of these methods are provided in the following detailed description for preparing compounds 100, 104, 105 and 114.

 Finally, the subject of the present invention is the use as a medicament of the compounds according to the invention.

 The compounds are particularly interesting for their anti-viral, anti-tumor, and / or immunostimulant activity according to the case, and in particular for their activity vis-à-vis retroviruses including the HIV-I virus.

 Other advantages and features of the present invention will become apparent in light of the examples which follow.

Scheme 1 below shows the synthesis routes followed in the following examples, if it is desired to prepare the compounds from the unmodified deoxynucleosides on the basis or the sugar part as mentioned above.

mince (acétate d'éthyle). Le milieu réactionnel est ensuite hydrolysé dans 150 mL d'un mélange eau et glace, puis le nucléoside est extrait avec 3 x 50 mL de chloroforme. - Les extraits sont regroupés et lavés à l'eau jusqu'à neutralité, séchés sur sulfate de magnésium, et concentrés à sec. On obtient 4,3 g (100 %) d'un solide jaune qui est purifié par chromatographie éclair (éther de pétrole, acétate d'éthyle). Après évaporation de la fraction appropriée on isole 2,35 g (4,8 mmoles, 65 %), de cristaux jaunes caractérisés comme suit:
F = 98-100 C; [α]D20= 71,4 (c=0,5, chloroforme);
UV (anol): A(max) = 331 nm (16.900), 242 nm (4.800), 209 nm (26.500)
Spectre de masse (IC, NH): miz = 486, 504 (0,5, M+18), 487 (8,1, M+1), 243 (100, (Ph)3C), 129 (3, B+2H);
R.M.N. 'H (CDCl3):: 5 = 9,4 (signal large, 1 H, N-H), 7,6 (d, 1 H, H-6,
JH-5,H-6= 7,6 Hz), 7,4-7,2 (m, 15 H, H aromatiques), 6,2 (t, 1 H, H-1', J1',2'= 6,1 Hz, J1',2"= 6,0 Hz), 6,1 (dd, 1 H, H-5), 4,6 (m, 1 H, H-3'), 4,0 (m, 1 H, H-4'), 3,6-3,4 (m, 2 H, H-5', H-5"), 2,6-2,4 (m, 1 H, H-2', 12,3 123 Hz) 2,3-2,2 (m, 1 H, H-2"). Example 1 2'-Deoxy-5'-O-triphenylmethyl-ss-D-4-thiouridine (101)
To a solution of 1.8 g (7.3 mmol) of 2'-deoxy-ss-D-4-thiuridine 57 in 32 mL of anhydrous pyridine containing 29 mg of 4-dimethylaminopyridine (DMAP) was added 1.25 equivalents. molar 2.54 g (9.12 mmol) of triphenylethyl chloride, and the whole is heated for 1 hour and 30 minutes at reflux 87. The reaction is monitored by chromatography on a layer

thin (ethyl acetate). The reaction medium is then hydrolysed in 150 ml of a mixture of water and ice, and the nucleoside is then extracted with 3 × 50 ml of chloroform. The extracts are combined and washed with water until neutral, dried over magnesium sulphate and concentrated to dryness. 4.3 g (100%) of a yellow solid are obtained which is purified by flash chromatography (petroleum ether, ethyl acetate). After evaporation of the appropriate fraction, 2.35 g (4.8 mmol, 65%) are isolated of yellow crystals characterized as follows:
Mp 98-100 ° C; [α] D20 = 71.4 (c = 0.5, chloroform);
UV (anol): A (max) = 331 nm (16,900), 242 nm (4,800), 209 nm (26,500)
Mass Spectrum (IC, NH): miz = 486, 504 (0.5, M + 18), 487 (8.1, M + 1), 243 (100, (Ph) 3 C), 129 (3, B + 2H);
1 H NMR (CDCl 3): δ = 9.4 (broad signal, 1H, NH), 7.6 (d, 1H, H-6,
JH-5, H-6 = 7.6 Hz), 7.4-7.2 (m, 15H, aromatic H), 6.2 (t, 1H, H-1 ', J1', 2 ' = 6.1 Hz, J1 ', 2 "= 6.0 Hz), 6.1 (dd, 1H, H-5), 4.6 (m, 1H, H-3'), 4.0 (m, 1H, H-4 '), 3.6-3.4 (m, 2H, H-5', H-5 "), 2.6-2.4 (m, 1H, H) -2 ', 12.3323 Hz) 2.3-2.2 (m, 1H, H-2 ").

Calc. for C28H26O4N2S: C, 69.13; H, 5.35; N, 5.76.

Found: C, 69.43; H, 5.56; N, 5.35.

(pEAD) en solution dans 20 mL de THF. L'ensemble est agité 10 minutes après la fin de l'addition à température ambiantel05. La réaction est suivie par chromatographie sur couche mince (acétate d'éthyle).Le milien réactionnel est ensuite concentré à sec par distillation du solvant sous pression réduite et le résidu est directement purifié par une chromatographie sur colonne de gel de silice (éther de pétrole, acétate d'éthyle). On obtient après évaporation de la fraction appropriée 1,59 g (3,39 mmoles, 78,6 %) d'un dérivé cristallin caractérisé comme suit: F= 135-138SC; [α]D20 = 40 (c=0,5, chloroforme);
UV (éthanol): (maux) = 327 nm (24.840), 265 nm (3.060), 212 nm (31.350), 207 nm (28.850);
Spectre de masse (IC, NH3): m/z= 468, 469 (5,6, M+1), 243 (100, (Ph3)C);
R.M.N. 1H (CDCI3): 8 = 7,67,2 (m, 15 H, H aromatiques), 6,83 (d, 1 H,
H-6, JH-5,H-6= 7,1 Hz), 6,76 (d, 1 H, H-5), 5,54 (d, 1 H, H-1' 3,77 Hz), 5,2 (signal large, 1 H, H-3'), 4,3-4,1 (m, 1 H, H-4'), 3,5-3,3 (m, 2 H, H-5', H-5", J5,= = 10,4 Hz), 2,9 (m, 1 H, H-2'), 2,4 (m, 1 H,
H-2", J2',2"= 13,2 Hz). Example 2 2,3'-Anhydro-2'-deoxy-5'-O-triphenylmethyl-> D-4-thiouridine (102)
To a solution of 2.1 g (4.3 mmol) of 2'-deoxy-5'-O-triphenylmethyl-D-4-thiouridine in 20 mL of tetrahydrofuran (THF) was added 1.5 molar equivalents. 1.69 g (6.45 mmol) of triphenylphosphine (PPh 3). When the solution becomes homogeneous, 1.5 molar equivalents 1.02 ml (6.45 mmol) of diethylazodicarboxylate are added very slowly.

(pEAD) in solution in 20 mL of THF. The whole is stirred 10 minutes after the end of the addition at ambient temperature el05. The reaction is followed by thin layer chromatography (ethyl acetate). The reaction mixture is then concentrated to dryness by distillation of the solvent under reduced pressure and the residue is directly purified by chromatography on a column of silica gel (petroleum ether , ethyl acetate). After evaporation of the appropriate fraction, 1.59 g (3.39 mmol, 78.6%) of a crystalline derivative are obtained, characterized as follows: F = 135-138 ° C; [α] D20 = 40 (c = 0.5, chloroform);
UV (ethanol): (sore) = 327 nm (24,840), 265 nm (3,060), 212 nm (31,350), 207 nm (28,850);
Mass Spectrum (Cl, NH 3): m / z = 468, 469 (5.6, M + 1), 243 (100, (Ph 3) C);
1H NMR (CDCl3): δ = 7.67.2 (m, 15H, aromatic H), 6.83 (d, 1H,
H-6, JH-5, H-6 = 7.1 Hz), 6.76 (d, 1H, H-5), 5.54 (d, 1H, H-1, 3.77 Hz) 5.2 (broad signal, 1H, H-3 '), 4.3-4.1 (m, 1H, H-4'), 3.5-3.3 (m, 2H, H) -5 ', H-5 ", J5, = = 10.4 Hz), 2.9 (m, 1H, H-2'), 2.4 (m, 1H,
H 2 ", J 2 ', 2" = 13.2 Hz).

réactionnel est ensuite hydrolysé dans 5 volumes 40 mL d'eau acidulée avec 1 mmole d'acide chlorhydrique. Le nucléoside est alors extrait avec 2 x 50 mL d'acétate d'éthyle, les extraits sont combinés, lavés à l'eau jusqu'à neutralité, séchés sur sulfate dc magnésium, filtrés et
concentrés à sec.On obtient 0,485 g (95 %) d'un dérivé non cristallin
impur en CCM purifié par chromatographie sur colonne de gel de silice
(éther de pétrole, acétate d'éthyle). Après évaporation de la fraction
appropriée on isole 0,135 g (0,26 mmole, 26,5 %) d'un dérivé qui est caractérisé comme suit:
IR: 2100 (N3), 1680-1620 (C=0),3050 et 710 (C-H aromatiques);
Spectre de masse (IC, NH3) = m/z = 511, 530 (0,5,M+18), 512 (2,2, M+1), 243 (100, (Ph3)C), 129 (5,1, B+2H);
R.M.N. 1H (CDCl3): 8 = 9,4 (signal large, 1 H, N-H), 7,8 (d, 1 H, H-6, JH-5,H-6= 7,9 Hz), 7,4-7,2(m, 15 H, H aromatiques), 6,1 (dd, 1 H, H-1',
J1',2'= 6,6 Hz, J1',2"= 6,5 Hz) 6,05 (d, 1 H, H-5), 4,4 (m, 1 H, H-3'), 4,0-3,9 (m, 1 H, H-4'), 3,6-3,3 (m, 2 H, H-5', H-5", J5.= 11,0 Hz), 2,7-2,2 (m, 2 H, H-2', H-2", J2',2"= 13,7 Hz).Example 3 3'-Azido-2 ', 3'-dideoxy-5'-O-triphenylmethyl-ss-D-4-thiouridine (31)
To a solution of 0.468 g (1 mmol) of 2,3'-anhydro-5'-O-triphenylmethyl-ss-D-4-thiouridine 102 in 8 mL of dimethylformamide (DMF), 5 molar equivalents of 0.325 g are added. (5 mmol) sodium azide (NaN 3) and the whole is stirred for 1 hour and 30 minutes at 140 ° C. 105. The reaction is monitored by thin layer chromatography (ethyl acetate). The environment

The reaction mixture is then hydrolysed in 5 volumes with 40 ml of acidulated water and 1 mmol of hydrochloric acid. The nucleoside is then extracted with 2 x 50 mL of ethyl acetate, the extracts are combined, washed with water until neutral, dried over magnesium sulfate, filtered and dried.
concentrated to dry. 0.485 g (95%) of a non-crystalline derivative
impure in TLC purified by silica gel column chromatography
(petroleum ether, ethyl acetate). After evaporation of the fraction
0.135 g (0.26 mmol, 26.5%) of a derivative which is characterized as follows is isolated:
IR: 2100 (N3), 1680-1620 (C = O), 3050 and 710 (aromatic CH);
Mass Spectrum (Cl, NH 3) = m / z = 511, 530 (0.5, M + 18), 512 (2.2, M + 1), 243 (100, (Ph 3) C), 129 (5 , 1, B + 2H);
1 H NMR (CDCl 3): δ = 9.4 (broad signal, 1H, NH), 7.8 (d, 1H, H-6, JH-5, H-6 = 7.9 Hz), 7, 4-7.2 (m, 15H, aromatic H), 6.1 (dd, 1H, H-1 ',
J1 ', 2' = 6.6 Hz, J1 ', 2 "= 6.5 Hz) 6.05 (d, 1H, H-5), 4.4 (m, 1H, H-3') , 4.0-3.9 (m, 1H, H-4 '), 3.6-3.3 (m, 2H, H-5', H-5 ", J5 = 11.0 Hz) 2.7-2.2 (m, 2H, H-2 ', H-2 ", J2', 2" = 13.7 Hz).

Example 4 3'-azido-2 ', 3'-dideoxy-ss-D-4-thiouridine (100)
In 10 ml of an 80% acetic acid solution, 0.135 g (0.26 mmol) of 3'-azido-2 ', 3'-dideoxy-5'-O-triphenylmethyl-ss-D-4 are introduced. Thiouridine 103.

Ic résidu est purifié par chromatographie éclair sur gel de silice (éther de pétrole, acétate d'éthyle), on isole après évaporation de la fraction appropriée 35,5 mg (0,13 mmoles, 50 %) d'un dérivé cristallin qui est caractérisé comme suit:
F = 110-112 C; [α]D20 = 100 (c=0,4, chloroforme);
UV (éthanol): #(max) = 329 nm (19.400), 247 nm (4.400) 202 nm (13.500);
Spectre de masse (IC, NH):: miz = 269, 287 (7,6, M+18), 270 (100, M+1), 129 (6,6, B+2H);
R.M.N. 'H (CDCl3): 3 = 9,4 (signal large, 1 H, N-H), 7,6 (d, 1 H, H-6, JH-5,H-6= 7.5 Hz), 6,4 (d, 1 H, H-5), 6,1 ( 1 H, H-1', J1',2'= 6,2 Hz,
J1',2"= 6,0 Hz), 4,4 (m, 1 H, H-3'), 4,2-3,8 (m, 3 H, H-4', H-5', H-5"), 2,6-2,2 (m, 2 H, H-2', H-2").The whole is brought to reflux 10 minutes $ 7. The reaction is monitored by thin layer chromatography (petroleum ether, ethyl acetate, 2: 1). The reaction medium is then concentrated to dryness and

This residue is purified by flash chromatography on silica gel (petroleum ether, ethyl acetate), the appropriate fraction is isolated after evaporation 35.5 mg (0.13 mmol, 50%) of a crystalline derivative which is characterized as follows:
M.p. 110-112 ° C; [α] D20 = 100 (c = 0.4, chloroform);
UV (ethanol): # (max) = 329 nm (19,400), 247 nm (4,400) 202 nm (13,500);
Mass Spectrum (IC, NH): miz = 269, 287 (7.6, M + 18), 270 (100, M + 1), 129 (6.6, B + 2H);
1 H NMR (CDCl 3): 3 = 9.4 (broad signal, 1H, NH), 7.6 (d, 1H, H-6, JH-5, H-6 = 7.5 Hz), 6.4 (d, 1H, H-5), 6.1 (1H, H-1 ', J1', 2 '= 6.2 Hz,
J1 ', 2 "= 6.0 Hz), 4.4 (m, 1H, H-3'), 4.2-3.8 (m, 3H, H-4 ', H-5', H-5 "), 2.6-2.2 (m, 2H, H-2 ', H-2").

est suivie par chromatographie sur couche mince (acétate d'éthyle). Example 5 3'-Azido-2 ', 3'-dideoxy-ss-D-4-methylthiouridine (104)
To a solution of 60 mg (0.22 mmol), 3'-azido-2 ', 3'-dideoxy-ss-D -4-thiouridine 100 in 5 mL of anhydrous acetone was added 1.3 molar equivalents. 40.5 mg (0.29 mmol), potassium carbonate (K2CO3). The mixture is stirred for 30 minutes at room temperature and then 2.7 molar equivalents of 38 L (0.6 mmol) of methyl iodide are added. The reaction

is followed by thin layer chromatography (ethyl acetate).

After 1 hour at room temperature, the reaction medium is
concentrated to dryness and the residue is purified by plate chromatography
Preparations of silica gel (ethyl acetate, petroleum ether, 2: 1).

After extraction of the appropriate band, 38 mg (0.13 mmol,
60%) of a crystalline derivative characterized as follows:
Mp 95-97 ° C;
[α] D20 = 94.2 * (c = 0.35, chloroform);
UV (ethanol): k (max) = 300 nm (17,300), 278 nm (12,200), 202 nm (15,300)
Mass Spectrum (Cl, NH 3): m / z = 283, 301 (0.3, M + 18), 284 (100, M + 1),
143 (19.3, B + 2H);
Example 6
3'-azido-2 ', 3'-dideoxy-ss-DN-4-methoxycytidine (105)
22 mg (77 μmol) of 3'-azido-2 ', 3'-dideoxy-s-D-4-methylthiouridine were dissolved in 3 mL of anhydrous pyridine.

When the solution is homogeneous, 20 molar equivalents (0.129 g, 1.54 mmol) of methoxyamine hydrochloride (CEI3ONH3 + Cl) are added and the mixture is stirred overnight at room temperature25.

sur couche mince (acétate d'éthyle, éther de pétrole, 3:1 double élu -tion). Le milieu réactionnel est ensuite concentré à petit volume et le résidu est traité par une partition de 2 x 30 mL de chloroforme, 20 mL d'eau. Les extraits sont regroupés, lavés à l'eau jusqu'à neutralité, séchés sur sulfate de magnésium et finalement concentrés à sec.On obtient 13 mg (46,8 llmoles, 60 %) d' un dérivé cristallin qui est caractérisé comme suit:
F = 121-123 C; [α]D20= 53.8 (c=0,5, chloroforme);
IR (KBr): 3500 (O-H), 2100 (N3), 1750-1600 (C=O);
UV (ethanol): X(max) = 276 nm (7.900), 236 nm (13.470), 200 nm (8.520);
Spectre de masse (IC, NH3): m/z = 282, 283 (100, M+1), 141 (27,4, B+2H);
R.M.N. 1H (D2O): 8 = 6,95 (d, 1 H, H-6, JH-5,H-6= 8,3 Hz) 6,0 (t, 1 H,
H-1', J1',2'= 6,8 Hz, J1',2"= 6,7 Hz). 5,55 (d, 1 H, H-5), 4,2-4,1 (m, 1
H, H-3'), 3,8 (m, 1 H, H-4'), 3,7-3,4 (m, 5 H, O-CH3, H-5', H-5",
J5',5"= 12,5 Hz), 2,4-2,2 (m, 2 H, H-2', H-2").The reaction is followed by chromatography

thin layer (ethyl acetate, petroleum ether, 3: 1 double elution). The reaction medium is then concentrated to a small volume and the residue is treated with a partition of 2 × 30 ml of chloroform, 20 ml of water. The extracts are combined, washed with water until neutral, dried over magnesium sulphate and finally concentrated to dryness. 13 mg (46.8 μmol, 60%) of a crystalline derivative is obtained which is characterized as follows:
Mp 121-123 ° C; [α] D20 = 53.8 (c = 0.5, chloroform);
IR (KBr): 3500 (OH), 2100 (N3), 1750-1600 (C = O);
UV (ethanol): X (max) = 276 nm (7,900), 236 nm (13,470), 200 nm (8.520);
Mass spectrum (1H, NH 3): m / z = 282, 283 (100, M + 1), 141 (27.4, B + 2H);
NMR 1H (D 2 O): δ = 6.95 (d, 1H, H-6, JH-5, H-6 = 8.3 Hz) 6.0 (t, 1H,
H-1 ', J1', 2 '= 6.8 Hz, J1', 2 "= 6.7 Hz) 5.55 (d, 1H, H-5), 4.2-4.1 ( m, 1
H, H-3 '), 3.8 (m, 1H, H-4'), 3.7-3.4 (m, 5H, O-CH 3, H-5 ', H-5 ",
J5 ', 5 "= 12.5 Hz), 2.4-2.2 (m, 2H, H-2', H-2").

Calc. for C10 H14 O4 N6 C, 42.55; H, 4.96; N, 29.78.

Found: C, 42.8; H, 4.70; N, 29.95.

[α]D20 = 53,3 (c=1, chloroforme);
IR (KBr): 2100 (N3), 1680-1620 (C=O) 3050 et 710 C-H aromatiques);
UV (éthanol): (maux) = 260 nm (11.800), 230 nm (17.400);
R.M.N. H (CDCl3): a = 9,6 (signal large, 1 H, N-H), 8,0-7,4 (m, 6 H, H aromatiques, H-6), 6,2 (t, 1 H, H-i', J 5,9 Hz, J1',2"= 5,7 Hz), 5,6 (d, 1 H, H-5, JH-5,H-6= 8,0 Hz), 4,7 (m, 2 H, H-S', H-5"), 4,4-4,0 (m, 2 H, H-3', H-4'), 2,8-2,3 (m, 2 H, H-2', H-2").Example 7 3'-azido-2 ', 3'-dideoxy-5'-O-benzoyl-ss-D-uridine (ion)
This derivative was prepared from 6 g (26.3 mmol) of 2'-deoxyuridine according to the method described by Dr. JM
Valéry105. 5.24 g (14.6 immoles, 92%) of a solid are obtained which is characterized as follows:
M.p. 53-57 ° C;

[α] D20 = 53.3 (c = 1, chloroform);
IR (KBr): 2100 (N3), 1680-1620 (C = O) 3050 and 710 aromatic CH);
UV (ethanol): (evils) = 260 nm (11,800), 230 nm (17,400);
1 H NMR (CDCl 3): a = 9.6 (broad signal, 1H, NH), 8.0-7.4 (m, 6H, aromatic H, 6), 6.2 (t, 1H); , 5.9 Hz, J1 ', 2 "= 5.7 Hz), 5.6 (d, 1H, H-5, JH-5, H-6 = 8.0 Hz) 4.7 (m, 2H, H-S ', H-5 "), 4.4-4.0 (m, 2H, H-3', H-4 '), 2.8-2 , 3 (m, 2H, H-2 ', H-2 ").

Calc. for C16 H15 O5 N5: C, 53.78; H, 4.2; N, 19.6.

Found: C, 53.39; H, 4.17; N, 19.67.

chromatographie sur couche mince (acétate d'éthyle, toluène, 4:1).Le milieu réactionnel est ensuite concentré à sec puis on ajoute directement 20 équivalents molaires, 4,68 g (56 mmoles) de chlorhydrate de méthoxyamlne en solution dans 50 ml de pyridine préalablement préparée, sans isoler l'intermAiaire tosylé 109 très instable.Example 8 3'-Azido-5'-O-benzoyl-2 ', 3'-dideoxy-ss-DN-4-methoxycytidine (110)
To a solution of 1 g (2.8 mmol) of 3'-azido-2 ', 3'-dideoxy-5'-O-benzoyl-B-D-uridine in 50 mL of anhydrous acetonitrile is added 1, 7 molar equivalents 570 mg (4.8 mmol) of potassium carbonate and 1.2 molar equivalents 641 mg (3.36 mmol) of p-toluenesulphonyl chloride. The mixture is stirred for 2 hours at 85-90 ° C. The reaction is followed by

thin layer chromatography (ethyl acetate, toluene, 4: 1). The reaction medium is then concentrated to dryness and then 20 molar equivalents, 4.68 g (56 mmol) of methoxyamine hydrochloride in solution in 50 ml are added directly. previously prepared pyridine, without isolating the highly unstable tosylated intermary.

The whole is stirred for 15 minutes at room temperature. The reaction is monitored by thin layer chromatography (ethyl acetate, petroleum ether, 4: 1). The reaction medium is then concentrated to dryness by distillation of the solvent under reduced pressure and the residue is treated with a partition of 2 × 50 mL of ethyl acetate and 30 mL of water. The extracts are then combined, washed with 2 x 30 mL of water until neutral, dried over magnesium sulfate, filtered and concentrated to dryness. 1.026 g of an oil is obtained which is directly purified by flash chromatography (petroleum ether, ethyl acetate). 0.594 g (1.27 mmol, 55%) of a crystalline derivative are isolated after evaporation of the appropriate fraction. which is characterized as follows:
Mp 68-70 ° C; [α] D20 = 22 (c = 0.5, chloroform);
IR (KBr): 3050 (aromatic CH), 2100 (N3), 1710-1600 (C = O);
UV (ethanol): k (max) = 275 nm (8,200), 230 (21,000);
Mass Spectrum (IC, NH): mp = 386, 387 (100, M + 1), 246 (1.5, MB), 141 (60.2, B + 2H);
1H NMR (CDCl 3): δ = 9.5 (broad signal, 1H, NH), 8.0-7.6 (m, 5H, aromatic H), 6.8 (d, 1H, H- 6, JH-6, H-5 = 8.3 Hz), 6.2 (t, 1H, H-1 ', J = 6.5 Hz, J1', 2 "= 6.4 Hz) 5, 45 (dd, 1H, H-5), 4.6 (m, 2H, H-5 ', HS "), 4.4-4.2 (m, 1H, H-3'), 4 , 2-4.1 (m, 1H, H-4 '), 3.8 (s, 3H, O-CH) 2.6-2.2 (m, 2H, H-2', H -2 ").

Calc. for C17H18O5N6: C, 52.8; H, 4.66; N, 21.76.

Found: C, 52.55; H, 4.6; N, 21.5.

d'éthyle, éther de pétrole, 3:1). Le milieu réactionnel est ensuite concentré à sec et le benzoate de méthyle formé est extrait avec 2 x 40 mL de toluène. La phase aqueuse est neutralisée à la résine échangeuse d'ions (H+) et concentrée à sec.On obtient 81 mg (0,29 mmole, 74 %) d'un dérivé cristallin qui est caractérisé comme suit:
F = 120-125'C Une purification par chromatographie sur plaques préparatives de silice (acétate d'éthyle, éther de pétrole, 3:1) génère après évaporation de la fraction appropriée 60 mg (0,21 mmole, 54,8 %) d'un dérivé cristallin qui est caractérisé comme suit:
F = 121-123 C; [α]D20= 54 (c=0,5, chloroforme); m (KBr): 3500 (O-H), 2100 (N), 1710-1600 (C=O);
Spectre de masse (IC, NH): mtz = 282, 283 (100, M+1), 141 (2714, B+2H);
R.M.N. H (D2O): # = 7,0 (d, 1 H, H-6, JH-5,H-6= 8,3 Hz), 6,0 (t, 1 H,
H-1', J1',2'= J1',2"= 6,7 Hz), 5,6 (d, 1 H, H-5), 4,2 (m, 1 H, H-3'), 3,8 (m, 1 H, H-4'), 3,7-3,5 ( m, 5 H, O-CH3, H-5', H-5", J5',5" = 12,4
Hz), 2,4-2,2 (m, 2 H, H-2', H-2").Example 9 3'-azido-2 ', 3'-dideoxy-s-DN-4-methoxycytidine (105)
The treatment of 0.15 g (0.38 mmol) of 3'-azido-5'-O-benzoyl-2 ', 3'-dideoxy-ss-
D-uridine 110 under the conditions described by Höly45 in solution in 10 mL methanol in the presence of 1.1 molar equivalents of sodium methoxide generates the debenzoyl derivative in 1 hour at room temperature. The reaction is monitored by thin layer chromatography (acetate

ethyl, petroleum ether, 3: 1). The reaction medium is then concentrated to dryness and the methyl benzoate formed is extracted with 2 × 40 mL of toluene. The aqueous phase is neutralized with the ion exchange resin (H +) and concentrated to dryness. 81 mg (0.29 mmol, 74%) of a crystalline derivative is obtained which is characterized as follows:
Mp = 120 ° -125 ° C. Purification by chromatography on preparative silica plates (ethyl acetate, petroleum ether, 3: 1) after evaporation of the appropriate fraction 60 mg (0.21 mmol, 54.8%) of a crystalline derivative which is characterized as follows:
Mp 121-123 ° C; [α] D20 = 54 (c = 0.5, chloroform); m (KBr): 3500 (OH), 2100 (N), 1710-1600 (C = O);
Mass Spectrum (IC, NH): mtz = 282, 283 (100, M + 1), 141 (2714, B + 2H);
H-NMR (D2O): # = 7.0 (d, 1H, H-6, JH-5, H-6 = 8.3 Hz), 6.0 (t, 1H,
H-1 ', J1', 2 '= J1', 2 "= 6.7 Hz), 5.6 (d, 1H, H-5), 4.2 (m, 1H, H-3 ' ), 3.8 (m, 1H, H-4 '), 3.7-3.5 (m, 5H, O-CH3, H-5', H-5 ", J5 ', 5" = 12.4
Hz), 2.4-2.2 (m, 2H, H-2 ', H-2 ").

Calc. for C10H14O4N6: C, 42.55; H, 4.96; N, 29.78.

Found: C, 42.75; H, 4.85; N, 29.90.

Example 10 3'-Azido-5'-Op-methoxybenzoyl-ss-D-thymidine (111)
This derivative was prepared from 0.484 g (2 mmol) of thymidine 1 according to the protocol described by Dr. JM Valery105
0.59 g (1.49 mmol, 90%) of a solid is obtained which is characterized as follows:
Mp 58-60 ° C;

UV (ethanol): # (max) = 257 nm (22,840), 208 (21,600);
IR (KBr): 2100 (N,), 1700 (C = O);
1 H NMR (CDCl 3): s = 9.36 (broad signal, 1H, NH), 7.22 (s, 1H,
H-6), 7.98 and 6.95 (AB, 4H, J 8.7 Hz), 6.18 (t, 1H, H-1 ', 6.5, 6.5 Hz), 4, 65-4.53 (m, 2H, H-5 ', H-5 ", J5', 5" = 12.3 Hz, J5 ', 4' = 3.3 Hz, J5 ", 4 '= 3 , 65 Hz), 4.35 (m, 1H, H-3 '), 4.21 (m, 1H, H4'), 3.87 (s, 3H, Ph-OMe), 2.54. -2.35 (m, 2H, H-2 ', H-2 ", J2', 2" = 13.9 Hz), 1.71 (s, 3H, CH3-C-5).

Calc. for C18H196N5: C, 53.87; H, 4.77; N, 17.44.

Found: C, 53.68; H, 4.81; N, 17.22.

équivalents molaires de chlorhydrate de méthoxyamine dans la pyridine.Example 3 3'-azido-2 ', 3'-dideoxy-5'-op-methoxybenzoyl-DN-4-methoxy-5-methylcytidine (113)
Treatment of 0.2 g (0.5 mmol) of 3'-azido-5'-op-methoxybenzoyl-ss-D-thymidine 111 under the conditions described for the preparation of 110, with 1.7 molar equivalents of carbonate of potassium and 1.4 molar equivalents of p-toluenesulphonyl chloride for 2 hours at 85-90 ° C., generates the tosylated derivative 112 which is directly treated with a solution of 20 ml.

molar equivalents of methoxyamine hydrochloride in pyridine.

The reaction is monitored by thin layer chromatography (ethyl acetate, petroleum ether, 1: 1, double elution). After treatment, 0.18 g (0.42 mmol, 84.2%) of a solid which is purified by flash chromatography (petroleum ether, ethyl acetate) is obtained. The appropriate fraction is isolated after evaporation. 0.143 g (0.33 mmol, 66.5%) of a crystalline derivative which is characterized as follows:
Mp 99-101 ° C; [α] D20 = 7.2 (c = 0.5, chloroform);
IR (KBr): 2100 (N3), 1690 and 1625 (C = O);
UV (ethanol): k (max) = 257 nm (24,300), 252 nm (23,840), 208 nm (21,600), and a shoulder at 272 nm;
Mass spectrum (1H, NH 3): m / z = 430, 431 (100, M + 1), 276 (6.0, MB), 155 (52.6, B + H), 124 (5.6, B-OMe);
1 H NMR (CDCl 3): s = 8.1 (broad signal, 1H, NH), 8.0 and 6.95 (2 X ID, 2 X 2 H, aromatic H, Jortho = 8.5 Hz), 6.5 (s, 1H, H-6), 6.2 (t, 1H, H-1 ', J, = J, = 6.5Hz), 4.7-4.5 ( m, 2H, H-5 ', H-5 ", 12.2 Hz, J5', 4 '= 2.85 Hz, J5", 4' = 3.1 Hz), 4.3 (m, 1 H, H-3 '), 4.2-4.1 (m, 1H, H-4'), 4.0-3.8 (2 x 1 s, 2 x 3H, N-OMe, Ph -OMe), 2.5-2.2 (m, 2
H, H-2 ', H-2 ", J2', r '= 13.9 Hz), 1.65 (s, 3H, CH, -C-5).

Calc.for C19 H22 6 N6: C, 53.02; H, 5.11; N, 19.53.

Found: C, 53.21; H, 5.16; N, 19.45.

[α]D20= 39,5 (c=0,6, chloroforme);
UV (éthanol): # (max) = 272 nm (7.700), 238 nm (10.800);
JR (KBr): 3500 (O-H), 2100 (N3);
Spectre de masse (IC, NH): m/z = 296, 297 (100, M+1), 155 (20,7, B+H), 124 (4,5, B - MeO);
R.M.N. 1H a)2O): s = 6,8 (d, 1 H, H-6), 6,05 (t, 1 H, H-1', J1',2'= 6,7
Hz, J1',2"= 6,6 Hz), 4,8-4,6 (m, i H, H-3'), 4,2 (m, 1 H, H-4'), 3,8-3,6 (m, S H, H-5', H-5", N-OMe), 2,4-2,2 (m, 2 H, H-2', H-2"), 1,7 (d, 3 H, CH3-C-S, JCH3,H-6=1,05 Hz).Example 12 3'-Azido-2 ', 3'-dideoxy-ss-DN-4-methoxy-5-methylcytidine (114)
The treatment of 0.143 g (0.33 mmol) of 3'-azido-2 ', 3'-dideoxy-5'-O-p-methoxybenzoyl-ss-DN-4-methoxy-5-methylcytidine 113 under the conditions described for the preparation of 10S generates after treatment 57 mg (0.19 moles, 58.2%) of a crystalline derivative which is characterized as follows: F = 134-136 ° C;

[α] D20 = 39.5 (c = 0.6, chloroform);
UV (ethanol): # (max) = 272 nm (7,700), 238 nm (10,800);
JR (KBr): 3500 (OH), 2100 (N3);
Mass Spectrum (IC, NH): m / z = 296, 297 (100, M + 1), 155 (20.7, B + H), 124 (4.5, B-MeO);
1H NMR a) 20): s = 6.8 (d, 1H, H-6), 6.05 (t, 1H, H-1 ', J1', 2 '= 6.7
Hz, J1 ', 2 "= 6.6 Hz), 4.8-4.6 (m, 1H, H-3'), 4.2 (m, 1H, H-4 '), 3, 8-3.6 (m, SH, H-5 ', H-5 ", N-OMe), 2.4-2.2 (m, 2H, H-2', H-2"), 1 , 7 (d, 3H, CH3-CS, JCH3, H-6 = 1.05 Hz).

Calc. for C11 H16 O4 N6: C, 44.59; H, 5.45; N, 28.37.

Found: C, 44.77; H, 5.45; N, 28.19.

Example 13
Anti-HIV activity
The compound 3'-azido-2 ', 3'-dideoxy-beta-DN-4-ylouridine (hereinafter compound TL 892) was tested, the data of which are given in the table below.
Conc. OD 540 nm Percentages of CPM [3H1
(g / ml) CEM13 cells incorporated protection viability inhibited
foul. replicating RT lysis

<tb><SEP> 0 <SEP> 648 <SEP> 891 <SEP> 100% <SEP> 27% <SEP> on <SEP> 31349 <SE> 0% <SEP>
<tb><SEP> 0.03 <SEP> 825 <SEP> 917 <SEP> 103% <SEP> 10% <SEP> 66K <SEP> 34017 <SEP> -9%
<tb><SEP> 0.10 <SEP> 829 <SEP> 911 <SEP> 102% <SEP> 9% <SEP> 69n <SEQ> 17439 <SEP> 44% <SEP>
<tb><SEP> 0.30 <SEP> 824 <SEP> 918 <SEP> 103X <SEP> 10% <SEP> 65% <SEW> 15815 <SEP> 50% <SEP>
<tb><SEP> 1 <SEP> 889 <SEP> 969 <SEP> 109% <SEP> 8K <SEP> 75% <SEP> 10461 <SEP> 67%
<tb><SEP> 3 <SEP> 883 <SEP> 968 <SEP> 109% <SEP> 9% <SEP> 73% <SEK> 8666 <SEP> 72%
<tb><SEP> 10 <SEP> 944 <SEP> 1006 <SEP> 113X <SEP> 6% <SEP> 83X <SEP> 6064 <SEP> 81X <SEP>
<tb><SEP> 30 <SEP> 1004 <SEP> 999 <SEP> 112K <SEP> - <SEP> 1X <SEP> 101% <SEP> 4019 <SEQ> 87%
<tb><SEP> 100 <SEP> 1131 <SEP> 1179 <SEP> 132X <SEP> 4% <SEP> 91X <SEQ> 1759 <SE> 94%
<tb> AZT <SEP> 1M <SEP> 1046 <SEP> 1062 <SEP> 119% <SEP> 2% <SEP> 96K <SEP> 2854 <SEP> 91%
<Tb>
Legend
Col 1: concentration of the product.

Col 2 and 3: OD 540 nm (MTT method for measuring cell viability)
the lower the OD, the more cell lysis there is.

Col 4:% viability of cells treated with a product dose but not
infected (measurement of tox of the test compound).

Col 5:% lysis (cytopathic effect) induced by the virus.

Col 6:% of protection conferred by the tested product.

Col 7: reverse transcriptase activity measured in the nicknames of
treated and infected cells, 7 days after infection (marker)
viral replication.

Col 8: report (treated sample vs. control sample) indicating
inhibition of replication.

 A compound is considered active when it inhibits at least 50% reverse transcriptase production while giving at least 50% protection against the cytopathic effect and vice versa.

CC50: dose of a product giving 50% cytostatic or cytotoxic effect.

EC50: dose of a product giving 50% efficiency with respect to a given marker (in this case the inhibition of viral replication measured in production of reverse transcriptase).

IS: selectivity index of a compound; report CC50 / EC50.

The following values are obtained for the compound TL 892: CC50> 100
EC50 = 0.315> 300
By comparison, the corresponding values for AZT are
CC50 = 25
EC50 = 0.005
IS = 5000
This compound TL 892 therefore has a very interesting anti-HIV activity.

Claims (12)

1 / Chemical compounds characterized in that they are represented by the general formula in which - Z represents O or S

 X represents S, N-OR1 with R1 which represents an optionally substituted C1-C5 alkyl, in which case the broken line represents a single bond and the dotted line represents a double bond, or - X represents -SR2 with R2 which represents a C1-C5 alkyl optionally substituted in which case the broken line --- represents a double bond and the dotted line ... represents a single bond or - X represents = O, in which case Z represents S - Y represents H, a halogen, an alkyl radical or an optionally substituted C 1 -C 7 alkoxy radical; C represents the glycoside ring of a therapeutically active nucleoside derivative, in particular an antiviral nucleoside derivative, in particular an active against the AIDS virus, and - When X is S, Y is CH3 and Z is O, then C is substituted by N3, CN or halogen including F, preferably 3 'of the glycosidic ring.  2 / A compound according to claim 1, characterized in that Y represents H or CH3 and Z represents O  3 / A compound according to claim 1 or 2, characterized in that C is represented by formula II

  which - R3 represents H, -COR'3, with R'3 which represents an optionally substituted C1-C20 hydrocarbon radical, - R4 represents N3, CN, a halogen such as F in which case R5 = H - R4 represents a methylidene radical in which case R5 represents N3, NH-CHO, CN, SCN, a halogen such as F or - R4 and R5 together form a double bond between the carbons at the 3 'and 2' position of the glycosidic ring in which case the carbon at the 3 'position may optionally be substituted by a CH2-Nu radical with Nu = N3, NH-CHO, CN, SCN, halogen including F  4 / A compound according to claim 3, characterized in that R3 and R5 represent H and R4 represents N3 CN or F, preferably N3  5 / compound according to one of claims 1 to 4, characterized in that X = S, Y = H, Z = O  6 / A compound according to one of claims 1 to 4, characterized in that. X = N-OCH3 Y Y = H or CH3 and .Z = O  7 / compound according to one of claims l to 4, characterized in that X X = S-CH3. Y = H or CH3 and .Z = O  8 / Compounds according to one of claims 1 to 7, characterized in that it is: 3'-azido-2 ', 3'-dideoxy-beta-D-4-thiouridine 3' -azido 2 ', 3'-dideoxy-beta-DN-4-methoxy-5-methylcytidine, 3'-azido-2', 3'-dideoxy-beta-DN-4-methoxycytidine, and 3'-azido; 2 ', 3'-dideoxy-beta-D-4-methylthiouridine.  9 / Process for the preparation of a compound according to one of claims 1 to 8, characterized in that the product of formula I is prepared in which the OH function at the 5 'position of the glycoside ring C is a protected hydroxy function by a protecting group such as the benzoyl group optionally substituted in particular by a methoxy group, or the Trityl group, and is deprotected or reacted, optionally with a carboxylic acid of formula R'3COOH  10 / Process for the preparation of a compound according to one of claims 1 to 8, characterized in that it is prepared from one of the following processes, if appropriate, the reactive functions in Z, C and Y being initially protected and then deprotected

 11 / Use as a medicament of the compounds according to one of claims 1 to 8  12 / The use according to claim 11, as an anti-viral drug especially against the AIDS virus.