FR2746396A1 - SUBSTITUTED 1,3-THIAZOLIDIN-4-ONES AND 1,3-THIAZOLIDINES, PROCESS FOR OBTAINING THESE COMPOUNDS AND THEIR USES AS MEDICAMENTS - Google Patents

Abstract

Compounds including a thiazolidine or thiazolidone ring N-substituted by a group containing a purine or pyrimidine base, or an analogue or derivative thereof, said ring being substituted on at least one of its other constituent atoms, are disclosed. Said compounds may be used as drugs for treating viral or virus-related diseases such as AIDS or hepatitis B.

Description

 The present invention relates to substituted 1,3-thiazolidin-4-ones and 1,3-thiazolidines.

 It also relates to processes for obtaining these compounds.

 Finally, it relates to the use of these compounds as medicaments, particularly in the treatment of viral diseases.

 Retroviral infections are responsible for a large number of diseases, such as AIDS. The human immunodeficiency virus (HIV) has been identified as the etiologic agent of AIDS.

 Compounds having an inhibitory effect on the multiplication of HIV have been actively sought.

Mitsuya et al. (Proc Natl Acad Sci USA, (1985), 82, 7096-7100) describe one of these molecules, 3-azido2 ', 3'-dideoxythymidine, commonly known as AZT. This compound makes it possible to induce in patients with AIDS, a certain protection against the cytopathic effects of
HIV. 2 ', 3'-dideoxynucleosides have also been described for their protection against the cytopathogenic effects of this virus (Mitsuya et al Proc Natl Acad Sci USA, (1986), 88, 1911-1915). .

 The action of 2 ', 3'-dideoxycytidines on these retroviruses has also been demonstrated by Balzarini et al.

(Biochem Biophys Res Res (1986) 140, 735-742) .A selective inhibition of HIV replication by unsaturated derivatives at the 2 'and 3' position of 2 ', 3'-dideoxythymidine has been shown. by Baba et al. ((1987), Biochem Biophys Res.

Comm. 142, 128-134).

 Brominated or iodinated derivatives of 3'-azido-2 ', 3'-idideoxyuridine have also been reported to have inhibitory activity against Moloney murine leukemia (Lin et al., (1987), J. Med. Chem., 30, 440-441). Other derivatives such as 3'-fluoro-2 ', 3'-dideoxycytidine and 3'-fluoro 2', 3'-dideoxythymidine have been described by Herdewijn et al.

((1987) J. Med Chem 30, 1270-1278) as having potential anti-retroviral activities.

2 ', 3'-didedoxy-3'-thiacytidine, also known as 3-TC or lamivudine, has been shown to have an effect on the
HIV and hepatitis B virus (HBV) (Int.Conf.on AIDS 1989, MONTREAL, CANADA).

 3-TC was the first nucleoside containing an oxathiolane group and exhibiting activity against retroviruses to be discovered.

Another oxathiolane, 2'-deoxy-3'-thiacytidine, or
BCH-189, has been described by Soudeyns et al. ((1991)
Antimicrob. Agents Chemother., 35, N7, 1386-1390). A derivative of BCH 189, BCH-189 PFA, exhibiting less antiviral activity, was further synthesized (Charvet et al., 1994).
Antiviral Research, 25, 161-168).

 The application EP-382.526 (IAF BIOCHEM INTERNATIONAL INC.) Is also related to 1,3-oxathiolanes, having antiviral properties. These compounds may be substituted with purines or pyrimidines, or analogs or derivatives of these bases, at the 5-position of the ring.

 1,3-thiazolidines were synthesized by Faury et al. ((1994) J. Heterocyclic Chem 31, 1465-1471). These thiazolidines are substituted in position 1 and 2 of the ring, and for some of them in the 4-position. The 2-position is substituted by a methyloxybenzyl group, while the 1-position, that is to say the nitrogen of the cycle, may be substituted by various alkyl or aryl groups. In any case, the nitrogen atom is not substituted by a purine or pyrimidine group, or a derivative thereof. In addition, no use of these compounds is indicated.

More recently Graciet et al. ((1995), Nucleosides &
Nucleotides, 14 (6), 1379-1392)) have described the synthesis of 1,3thiazolidinones, substituted in position 2 by alkyloxybenzyl groups. The atom in position 1 is not substituted, but on the contrary is, in one of the processes described, protected by an acetyl group, so that it can not react during the coupling of thiazole. The carbon at the 5-position of the ring may be substituted by thymine, cytosine or one of their derivatives. In any case it is not indicated that the nitrogen in position 1 can be substituted with one of these bases.

WO-93/01 174 (Glaxo Group Limited) relates to compounds that can be used in the treatment of viral diseases, in particular virus-related diseases.
HIV. These compounds act on the HIV protease. They consist of a thiazole ring which can be substituted at the 2,4 and 5 position. The substituent at the 2-position is a CHR3NHR2 group in which R2 and R3 can be, in particular, heteroaryl groups defined as 5-membered heterocyclic groups. or 6 members containing one or more heteroatoms. Such examples of heterocycles are indicated (page 5) and are in particular 1, 2, 4triazolyl groups or pyrimidinyl groups, or imidazolyl groups. They can be merged together.

The nitrogen at the 1-position of the thiazole ring is unsubstituted.

It appears from the analysis of the state of the art that inhibitors of the replication of
HIV. Nevertheless, these molecules have many disadvantages, and in particular a significant toxicity vis-à-vis the cells of the body. Thus, AZT, which is the molecule currently the most used in the treatment of
AIDS, has some toxicity.

 In addition, viruses, and in particular HIV, are likely to acquire resistance to these inhibitors.

Consequently, there is a significant need for new molecules exhibiting viral replication inhibiting activity, and in particular replication of the virus.
HIV, while not having the disadvantages of molecules already known in the state of the art, and in particular their toxicity.

 The applicant has therefore focused on synthesizing molecules to solve this problem.

 The subject of the present invention is therefore compounds characterized in that they comprise a thiazolidine or thiazolidone nucleus, N-substituted with a group containing a purine or pyrimidine base, or an analogue or a derivative thereof, said nucleus being substituted on at least one of the other atoms composing it.

dans laquelle:
- X est S, SO, ou SO2
- Y est CH2 ou C=O
- R1 représente
* un atome d'hydrogène,
* un groupe COR8, dans lequel R8 est un atome d'hydrogène, un groupe alkyle, alcoxyalkyle, aralkyle, aryloxyalkyle, alkylcarbonyle éventuellement ramifié, substitué et/ou insaturé, ou un groupe aryle,
* un groupe dihydropyridinyle, éventuellement substitué,
* un groupe alkylsulfonyle, aralkylsulfonyle ou sulfinyle,
* un groupe aminoacyle, dérivé d'un acide aminé,
* un groupe (POZO)q Rg dans lequel Rg est un groupe alkyle ou un atome d'hydrogène, et q est compris entre 1 et 4,
* un groupe W-J dans lequel
W W est un groupe carboxyalkylcarbonyle, phospho ou sul fophospho,
J J est un nucléoside, un dérivé ou un analogue de nucléoside.It relates more particularly to compounds having the following formula I:

in which:
- X is S, SO, or SO2
Y is CH2 or C = O
- R1 represents
* a hydrogen atom,
a group COR8, in which R8 is a hydrogen atom, an optionally substituted, substituted and / or unsaturated alkyl, alkoxyalkyl, aralkyl, aryloxyalkyl or alkylcarbonyl group, or an aryl group,
a dihydropyridinyl group, optionally substituted,
an alkylsulfonyl, aralkylsulfonyl or sulfinyl group,
an aminoacyl group, derived from an amino acid,
a group (POZO) q Rg in which Rg is an alkyl group or a hydrogen atom, and q is between 1 and 4,
* a group WJ in which
WW is a carboxyalkylcarbonyl, phospho or sulphosphoric group,
JJ is a nucleoside, a derivative or a nucleoside analogue.

* a group of formula XIX following:

R2 represents a purine or pyrimidine base, or a derivative thereof or an analogue thereof, and
- m and n are independently between 0 and 10, preferably between 0 and 4 and even more preferably equal to 2.

Purine or pyrimidine base analog is understood to mean a base which exhibits a modification of at least one nitrogen in the nucleus of the base but which reproduces the general structure of a purine or pyrimidine base. Analogs may for example be molecules in which a CH 2 group has been replaced by a nitrogen atom or on the contrary a nitrogen atom has been replaced by a CH 2 group
By base derivative are meant compounds in which ring-substituent groups have been incorporated, removed or modified by substituents known to those skilled in the art, for example halogen atoms or hydroxy, amino or alkyl groups.

 R2 may be a derivatized base such as azapyrimidine, azapurine, deazapyrimidine or an optionally substituted deazapurine, and in particular 5apyrimidine, 5-azapurine, 7-deazapurine, or 7-deaaza-8-azapurine, optionally substituted .

 Preferably, the purine or pyrimidine bases, or their derivatives, or their analogues, are linked to the thiazole ring via their atoms at the 1-position or at the 9-position.

Such purine or pyrimidine groups may in particular be those represented in the annex by formulas II to XVIII in which
- R3 represents a hydrogen atom, a hydroxymethyl group, or an optionally unsaturated, branched and / or substituted C1-C6 alkyl group.

 R 4 represents a hydrogen atom, a hydroxymethyl, trifluoromethyl or optionally substituted and / or unsaturated C 1 to C 6 alkyl group, or a halogen atom, such as a bromine, chlorine, fluorine or diode.

 - R5 represents a hydrogen atom, a cyano group, carboxy, ethoxycarbamoyl or thiocarbamoyl.

 R6 and R7 independently represent a hydrogen atom, a halogen atom such as bromine, chlorine, fluorine or iodine, or an amino or hydroxy group.

 Preferably, R2 represents the group of formula II, as shown in the appendix.

Advantageously, R8 represents an alkyl group
C1 to C16, optionally unsaturated, substituted and / or branched, or a benzoyl group optionally substituted with at least one halogen atom such as bromine, chlorine, fluorine or iodine, with a C1-C4 alkyl or alkoxy group; C6 optionally unsaturated, with a nitro group or with a trifluoromethyl group. In particular R8 may be methyl, ethyl, n-propyl, t-butyl, n-butyl, methoxymethyl. It can also be a benzyl, phenoxymethyl or phenyl group substituted by a halogen atom.

 A substituted dihydropyridinyl group may be advantageously N-methyldihydropyridinyl.

 An alkyl sulfonyl group may be methanesulfonyl.

 A preferred aminoacyl group is L-valyl or Lisoleucyl. Nevertheless, it can be any other aminoacyl group derived from one of the commonly found amino acids.

 The group R 8, when it is an alkylcarbonyl group, is advantageously the CH 2pCO 2 H group, in which p is an integer between 1 and 10.

 J can be any nucleoside or nucleoside analog, or nucleoside derivative, and preferentially 3'-azido-2 ', 3'dideoxythymidine, 2', 3'-dideoxycytidine, 2 ', 3'idideoxyadenosine, 2', , 3'-dideoxyinosine, 2 ', 3'-dideoxythymidine, 2', 3'-dideoxy-2 ', 3'-didehydrothymidine, 2', 3'-dideoxy-2 ', 3'-didehydrocytidine, ribavirin, as well as nucleosides comprising bases having the formulas II to XVIII described in the appendix.

Preferably, a compound according to the invention is a homodimer of two nucleoside analogues as defined by formula I. Thus, such a compound has formula I in which R 1 represents a group of formula
Wherein X, Y, R2 and n are as defined above for Formula I.

 In the present application, the alkyl groups can be considered as advantageously having between 1 and 16 carbon atoms, preferably 1 to 4 carbon atoms, and containing one or more double bonds.

 Aryl groups present in the compounds according to the present invention advantageously comprise a phenyl group.

 Particularly preferred compounds according to the present invention are the following: 2-benzoyloxymethyl-3- (2- (cytosin-1-yl) -ethyl) -1,3-thiazolidin-4-one (compound 1), 2- benzoyloxymethyl-3- (2- (5-fluorocytosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 2), 2-benzoyloxymethyl-3- (2- (thymin-1-yl) - ethyl) -1,3-thiazolidin-4-one (Compound 3), 2-benzoyloxymethyl-3- (2- (adenin-9-yl) ethyl) -1,3-thiazolidin-4-one (Compound 4) ), 2-hydroxymethyl-3- (2- (cytosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 5), 2-hydroxymethyl-3- (2- (5-fluorocytosine) 1-yl) -ethyl) -1,3-thiazolidin-4-one (compound 6), 2-hydroxymethyl-3- (2- (thymin-1-yl) -ethyl) -1,3-thiazolidin-4-one (Compound 7), 2-hydroxymethyl-3- (2- (adenin-9-yl) ethyl) -1,3-thiazolidin-4-one (compound 8), 2-benzoyloxymethyl-3- (2- (Cytosin-1-yl) -ethyl) -1,3-thiazolidine (Compound 9), 2-benzoyloxymethyl-3- (2- (5-fluorocytosin-1-yl) -ethyl) -1,3-thiazolidine ( compound 10), 2-hydroxymethyl-3- (2- (cytosine) 1-yl) -ethyl) -1,3-thiazolidine (compound 11), 2-hydroxymethyl-3- (2- (5-fluorocytosin-1-yl) -ethyl) -1,3-thiazolidine (compound 12) .

 The present invention also relates to pharmaceutically acceptable salts of the compounds according to the present invention, and in particular salts of inorganic or organic acids and bases, such as hydrochloric, hydrobromic, sulfuric, nitric and perchloric acid salts. fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluenesulphonic, tartaric, acetyl, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzene sulphonic.

 Other acids, such as oxalic acid, although not pharmaceutically acceptable, can be used in the preparation of salts, or intermediates for the preparation of the compounds according to the invention, or of their pharmaceutically acceptable salts.

 Base salts are, for example, alkali metal salts, such as sodium, of alkaline earth metals such as magnesium, ammonium or alkylamines.

Methods for preparing the compounds according to the present invention are known to those skilled in the art, and have been described for example by Hahn et al. ((1989), Nucleotide
Analogues, 156-159) and Busso et al. ((L988), AIDS Research and
Human retroviruses, 4 (6), 449-455).

 In particular, the esters in which R 1 represents a CORs group, with R 8 being an alkyl carbonyl group, can be obtained by reaction of compounds of formula I in which R 1 is a hydrogen atom with a dicarboxylic acid, such as the acid succinic. Such esters may be used for the preparation of derivatives wherein R 1 is W 1.

dans laquelle:
- R10 est un atome d'hydrogène ou un groupe protecteur et
- R11 est un groupe (CH2)n substitué par un atome d'halogène, tel que le brome.The present invention more particularly relates to a process for the preparation of compounds of formula I in which R 1 represents a hydrogen atom, characterized in that a 1,3-thiazolidin-4-one of formula XX is reacted as follows:

in which:
R10 is a hydrogen atom or a protecting group and
- R11 is a group (CH2) n substituted by a halogen atom, such as bromine.

with a base, derivative or analog substituted with a silyl group.

 The bases, derivatives or analogs are pre-substituted by a silyl group, by reaction with a silylating agent, such as hexamethyldisilazane, in a suitable solvent, such as methylene chloride, using a Lewis acid, such as titanium tetrachloride or stannous chloride, or using as another solvent trimethylsilyltriflate or cesium carbonate.

The 1,3-thiazolidin-4-one of formula XX in which Y represents C = O can in turn be prepared by reaction of a 2-benzoyloxymethyl-1,3-thiazolidin-4-one prepared as described by Graciet et al. ((1995), Nucleosides and
Nucleotides, 14 (6), 1379-1392), with a dibromoalkane of formula Br- (CH2) n-Br in a compatible organic solvent such as dimethylformamide, in the presence of a basic catalyst, such as sodium hydroxide .

 The 1,3-thiazolidines of formula XX in which Y represents a CH 2 group can be prepared by reaction of a 2-benzoyloxymethyl-1,3-thiazolidine synthesized as described by Faury et al. ((1994) J. Heterocyclic Chem.

31, 1465) with a dibromoalkane, followed by reduction of the compound thus obtained with boron trihydride in tetrahydrofuran.

 A compound of formula I wherein R 1 represents a hydrogen atom may be esterified by reaction with a phosphorylating agent, such as POCl 3, for the manufacture of a phosphate ester, or with a suitable esterifying agent, depending on the R 1 grouping. which it is desired to substitute, such as an anhydride or an acid halide. Such an ester, or a salt, can be converted back into compounds of formula I in which R 1 is a hydrogen atom, by simple hydrolysis.

 The present invention further relates to medicaments containing one or more compounds according to the present invention, as well as to pharmaceutical compositions containing an effective amount of at least one compound according to the present invention as well as pharmaceutically compatible excipients.

 These compounds are particularly suitable for the treatment of viral diseases, and in particular the diseases for which the HIV virus is responsible.

 The present invention further relates to the manufacture of a medicament in particular for the treatment of viral or virus-related diseases, such as AIDS.

 The present invention is illustrated without being limited by the following examples.

EXAMPLE 1
Preparation of 2-benzoyloxymethyl-1-13-thiazolidin-4-one.

 1.3 ml of mercaptoacetic acid (21 mmol, 1.1 equivalents) and 1.1 g of ammonium carbonate (11 mmol, 0.6 eq) are added to a solution of 3.1 g of 2-benzoyloxyacetaldehyde (19 mmol, leg) in 80 ml of toluene.

The solution is refluxed overnight and the water formed is removed using a Dean-Stark apparatus.

The cooled solution at room temperature is washed with a 5% aqueous solution of NaHCO 3 (25 ml). The mixture is then extracted with ethyl acetate (3 x 20 ml). The butyl acetate extracts are combined and washed with brine (15 ml), dried over Na 2 SO 4 and concentrated under a gentle pressure.

 The final product is purified by flash chromatography (ethyl acetate / toluene 1: 1), and recrystallized from toluene. The yield is 47% (2.1 g). This product is a white solid m.p. = 167 C Rf (EtOAc / Toluene 1: 1) = 0.3.

1H NMR (CDCl3) 6: 7.42-8.06 (m, 5H, arom), 6.80 (bs, 1H, NH), 4.90 (dd, 1H, H-2), 4.50 (b.p. dd, 1H, C2-CH2b), 4.30 (dd, 1H, C2CH2a), 3.55 (m, 2H, CH2-5), 13C NMR (CDCl3) 6: 172.0 (CO
O), 167.0 (CO-NH), 133.5-128.6 (arom), 68.6 (CH2-O), 54.7 (C2), 31.0 (C-5); MS (FAB +): 238 (M + H) +.

EXAMPLE 2
Preparation of 2-benzovylmethyl-3- (2-bromoethyl) -1,3-thiazolidin-4-one.

 0.141 g of powdered KOH (leg, 2.53 mmol) are added to a solution of 2-benzoyloxymethyl-1,3-thiazolidin-4-one (0.6 g, 2.53 mmol, 1 eq) in anhydrous DMF. (8ml). The mixture is then stirred at room temperature for 5 minutes and then 0.220 ml of 1,2-dibromomethane is added. The solution is again stirred at room temperature overnight under a nitrogen atmosphere. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (15 ml) and then washed with distilled water (2 x 15 ml). The aqueous solution is extracted with ethyl acetate (2 x 15 ml). The organic layers are combined, dried over Na2SO4 and concentrated in vacuo until a brownish viscous mixture is obtained. After purification by flash chromatography (toluene) the final compound, in the form of a colored oil is isolated. The yield is 20% (0.250 g) Rf (EtOAc / tolene: 1/1) = 0.74.

1H NMR (CDCl3) δ: 7.95-7.30 (m, 5H, Arom), 5.03 (t, 1H, H-2), 4.60-4.30 (m, 2H, C2-CH2) ), 4.05-3.35 (m, 6H, 3CH2); 13C NMR (CDCl3) 5; 172.1 (O-CO), 166.2 (N-CO), 134.1-129.2 (Arom), 67.1 (CH2-OBz), 60.3 (C-2), 46.0 (CH2-N), 32.3 (C-5), 24.6 (CH2)
Br); MS (FAB +): 344 (M) +.

EXAMPLE 3
Preparation of 2-benzovylmethyl-3- (2- (cyclosin-1-yl) ethyl) -1,3-thiazolidin-4-one (comPosed 1).

 0.107 g of cytosin (0.96 mmol, 1.5 eq) and 0.420 g of cesium carbonate (Cs 2 CO 3, 2.0 eq, 1.3 mmol) are added in a solution of 2-benzoyloxymethyl-3- (2-bromoethyl) - 1,3-diazolidin-4-one (0.220 g, 0.64 mmol, 1 eq) in 10 ml of anhydrous DMF. The mixture is stirred at 100 ° C. under a nitrogen atmosphere for 1 hour and then allowed to cool to room temperature.

The solvent is removed and the residue is purified by flash chromatography (gradient EtOAc / MeOH 100/0 to 50/50). The final compound obtained is in the form of a white solid. The yield is 30% (0.070g). m.p = 184C Rf (EtOAc / MeOH 1: 1) = 0.50.

1H NMR (CD30D) δ: 7.95-7.30 (m, 6H, 5H Arom + H-6 '); 7.10 (bs, 2H, NH 2), 5.80 (d, 1H, H-5 '); 5.10 (t, 1H, H-2); 4.70-4.40 (m, 2H, CH2-OBz), 4.10 (t, 2H, CH2-Cyt), 3.60-3.10 (m, 4H, 2 CH2); 13C
NMR (CD30D) 6; 173.5 (O-CO), 167.0 (N-CO), 166.0 (C-4 '); 158.1 (C (O) -2 '); 146.4 (C-6 '); 133.7-125.0 (Arom), 95.0 (C-5 '): 66.0 (CH2-OBz), 60.5 (C-2), 42 (CH2-N), 31.7 (CS), 22.4 (CH2
Cyt); MS (FAB +): 375 (M + 1) +.

EXAMPLE 4
PREPARATION OF 2-benzoyloxymethyl-3- (2- (fluorocytosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 2).

 0.130 g of fluorocytosine (1.0 mmol, 1.5 eq) and 0.436 g of Cs 2 CO 3 (2.03 mmol, 2.0 eq) are added to a solution of benzoyloxymethyl-3- (2-bromoethyl) -1 3-thiazolidin-4-one (0.230 g, 0.68 mmol eq) in 10 ml of anhydrous DMF. The reaction mixture is stirred at 100 ° C for 2 hours and then allowed to cool to room temperature The solvent is removed under reduced pressure and the resulting residue is dissolved in ethyl acetate (EtOAc, 10 ml) and washed in distilled water (2 x 10 ml) The aqueous layer is extracted with ethyl acetate (2 x 10 ml) The ethyl acetate extracts are combined and dried over Na 2 SO 4 and filtered Concentrates After purification by flash chromatography (EtOAc / MeOH 9: 1) the final compound as a white solid is obtained (0.062 g) in 24% yield mp = 129 ° C. Rf (EtOAc / MeOH 9/1) = 0.1 l.

 1H NMR (CD30D) δ: 7.90-7.30 (m, 6H, 5H Arom + H-6 '); 5/10, (t, 1H, H-2); 4.70 to 4.40 (m, 2H, CH2-OBz); 4.00-3.20 (m, 6H, 3 CH 2); 13C NMR (CD30D) 6: 174.5 (N-CO); 167.1 (O-CO); 150.6 (C); 1350-129.8 (Arom + Fluorocytosin); 67.0 (CH2); 61.2 (C-2); 49.0 (CH2); 46.0 (CH2); 34.0 (CH2); MS (FAB +); 393 (M +1) +.

EXAMPLE 5
Preparation of 2-benzovylmethyl-3- (2- (thvmin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 3)

 0.120 g of thymine (0.96 mmol, 1.5 eq) and 0.420 g of Cs2CO3 (1.3 mmol, 2.0 eq) are added to 0.220 g of 2-benzoyloxymethyl-3- (2-bromoethyl) -1,3 thiazolidin-4-one (0.64 mmol, 1 eq) dissolved in 10 ml of anhydrous DMF. The reaction mixture is stirred at 100 ° C. for 1.5 hours and then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (10 ml). The white precipitate obtained is washed with 2 volumes of ethyl acetate (2 × 10 ml). The organic layers are combined, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (EtOAc / toluene 2: 1) gives 0.030 g of the final compound, in the form of a colored oil, with a yield of 12%.

 1H NMR (DMSO-d6) 6; 8.00-7.45 (m, 6H, 5H Arom + H-6 '); 5.20 (s, 1H, H-2); 4.70-4.40 (m, 2H, CH2-OBz); 4.05-3.30 (m, 6H, 3 CH 2), 1.75 (s, 3H, CH 3); 13C NMR (DMSO-d6) 6; 171.4 N-CO); 166.9 (C4 '), 165.3 (O-CO), 150.9 (C-2'), 141.3 (C-6 '), 133.7-128.6 (Arom), 108, 2 (C-5 '), 65.9 (CH 2 -BO 2), 65.0 (C-2'), 58.0, 43.0, 31.2 (3 CH 2), 13.6 (CH 3), MS (FAB +): 390 (M + 1) +.

EXAMPLE 6
Preparation of 2-benzovylmethyl-3- (2- (acienin-9-yl-ethyl) -1,3-thiazolidin-4-one (compound 4).

 0.130 g of adenine (0.96 mmol, 1.5 eq), 0.424 g of Cs 2 CO 3 (1.3 mmol 2.0 eq) and 0.127 g of 18-crown-6 (0.127 g, 0.48 mmol, 0). 75 eq) are added to 5 ml of anhydrous DMF. The mixture is stirred for 5 minutes at room temperature under a nitrogen atmosphere, then 0.120 g of 2-benzoyloxymethyl-3- (2-bromoethyl) -1,3-thiazolidin-4-one (0.64 mmol, 1 eq) is added dropwise. by drop. The reaction mixture is stirred at 100 ° C for 1 hour and then allowed to cool to room temperature. The solvent is removed under reduced pressure. Flash chromatography (EtOAc / MeOH: 9.1) gives 0.078 g of the final product, in the form of a viscous and colored solid, with a yield of 31%.

1H-NMR (DMSO-d6) δ: 8.50 (s, 1H, H-ad), 8.40 (s, 1H, H-ad), 7.80-7.40 (m, 7H, Arom + NH2); 5.10 (s, 1H, H-2); 4.60 (m, 2H, CH 2
OBz); 4.20-3.40 (m, 6H, 3 CH 2); 13C NMR (DMSO-d6) 6; 171.4 N-CO); 165-2 (O-CO); 149.9 (C-6 '), 148.8 (C-2'), 144.6 (C-4 '), 144.2 (C-8'), 133.7-129.0 (Arom) 117.7 (C-5 '), 67.8 (CH2-OBz), 60.4 (C-2), 43.0-43.1 (2 CH2), 33.0 (CH2); MS (FAB +): 399 (M + 1) +.

EXAMPLE 7
Preparation of 2-hydroxy-methyl-3- (2- (cyclosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 5).

 0.050 g of 2-benzoyloxymethyl-3- (2-cytosin-1-yl-ethyl) -1,3-thiazolidin-4-one (0.13 mmol) is dissolved in a methanolic solution of 1% sodium hydroxide solution (5 ml ). The mixture is stirred at ambient temperature for 5 minutes. The solvent is removed and the residue is purified by flash chromatography (EtOAc / MeOH: 0/1). The final compound is obtained in the form of a white solid, with a quantitative yield (0.35 g).

 m.p. = 233 C Rf (EtOAc / MeOH 1/1) = 0.33.

 1H NMR (DMSO-d6) δ: 7.45 (d, 1H, H-6 '), 6.90 (bs, 2H, NH 2); 5.60 (d, 1H, H-5 '); 4.60 (s, 1H, H-2); 3.80-3.20 (m, 8H, 4 CH 2); 13C NMR (DMSO-d6) 6; 171.4 (N-CO), 166.0 (C-4 '); 155.7 (C (O) 2 '), 145.9 (C-6'), 93.3 (C-5 '); 63.6 (CH2-OH), 62.0 (C-2), 46.1 (CH2-N), 41.1 (C-5), 31.4 (CH2-Cyt); MS (FAB +): 271 (M + 1) +.

EXAMPLE 8
Preparation of 2-hydroxy-methyl-3- (2- (5-fluorocyclosul-1-yl) ethyl) -1,3-thiazolidin-4-one (compound 6).

 0.050 g of 2-benzoyloxymethyl-3- (2- (5-fluorocytosin-1-yl) ethyl) -1,3-thiazolidin-4-one is dissolved in 5 ml of a 1% sodium hydroxide / methanol solution and stirred at room temperature for 5 minutes. After removal of the solvent, the final product is obtained in the form of a white solid by flash chromatography (EtOAc / MeOH 9: 1) with a yield of 72% (0.026 g). m.p. = 212 ° C. Rf (EtOAcMeOH: 1/1) = 0.50.

1 H NMR (DMSO-d6) δ: 7.85 (d, 1H, H-6 '), 7.40 (bs, 2H, NH 2), 5.30 (bs, 1H, OH), 4.75 (s). , 1H, H-2), 3.80-3.20 (m, 8H, 4 CH 2), 13C
NMR (DMSO-d6) 5: 171.6 (N-CO); 157.6 (C); 154.1 (C); 130.7128.3 (C); 63.6 (CH 2); 61.9 (C-2), 46.1 (CH2), 40.3 (CH2); 31.4 (CH2); MS (FAB +): 289 (M + H) +.

EXAMPLE 9
Preparation of 2-hydroxymethyl-3- (2- (thymin-1-yl) ethyl) -1,3-thiazolidin-4-one (compound 70.

 0.028 g of 2-benzoyloxymethyl-3- (2-thymin-1-yl-ethyl-1,3-thiazolidin-4-one is dissolved in 1% methanolic sodium hydroxide solution (5 ml) and stirred at room temperature for 5 minutes. The solvent is removed and the residue is purified by flash chromatography (EtOAc / MeOH: 1/1) = 0.56.

 1H N

EXAMPLE 10
Preparation of 2-hydroxymethyl-3- (2- (adenin-9-yl) ethyl) -1,3-thiazolidin-4-one (Compound 8)

 0.030 g of benzoyloxymethyl-3- (2-adenin-9-yl-ethyl) -1,3-thiazolidin-4-one is dissolved in a saturated ammoniacal methanolic solution (5 ml) and stirred at room temperature overnight. The solvent is removed, the residue is washed with ethyl acetate (2 x 5 ml) and then dried under reduced pressure. The final compound is obtained as a white solid (0.020 g) in quantitative yield.

m.p. 226 C Rf (EtOAc / MeOH: 1/1) = 0.35.

 1H NMR (DMSO-D6) δ: 8.20 (s, 1H, H-ad), 8.10 (s, 1H, H-ad), 7.10 (bs, 2H, NH 2); 4.60 (s, 1H, H-2); 4.30 (m2h, CH2); 3.90-3.20 (m, 6H, 3 CH 2); 13C NMR (DMSO-d6) 6; 171.3 (N-CO), 155.9 (C-6 '), 152.4 (C-2'), 149.6 (C-4 '), 140.7 (C-8'), , (C-5 '), 63.7 (CH2) 61.7 (C-2), 42.5 (CH2), 40.2 (CH2), 31.2 (CH2), MS (FAB +): 295 (M + 1) +.

EXAMPLE 11
Preparation of 2-benzoyloxymethyl-3- (2- (cytosin-1-yl) ethyl-1,3-thiazolidine (Compound 9)
1. Synthesis of 2-benzovloxymethyl-1,3-thiazolidine

 One equivalent of benzoyloxyacetaldehyde and one equivalent of aminoethanethiol hydrochloride are refluxed for 3 hours in a solvent such as toluene or benzene, in the presence of a base, such as N, Ndiisopropylethylamine or triethylamine.

2. N-alkylation of thiazolidine
One equivalent of 2-benzoyloxymethyl-1,3-thiazolidine and a base equivalent, such as potassium carbonate or potassium hydroxide, are reacted, and then a difunctionalized ethane equivalent, such as 1,2-dibromoethane, is added. or 1-2-ditosylethane in a solvent, such as N, N-dimethylformamide or acetonitrile, at room temperature and under a nitrogen atmosphere.

 3. Obtaining the final compound.

 One cytosine equivalent is condensed with one equivalent of 2-benzoyloxymethyl-3- (2-bromoethyl) -1,3-thiazolidine, or 2-benzoyloxymethyl-3- (2-tosylethyl) -1,3-thiazolidine obtained in step 2, in the presence of carbonate, such as potassium carbonate or cesium carbonate, as a condensation catalyst, in a solvent which may be N, N-dimethylformamide or acetonitrile. The reaction mixture is heated at 100 ° C for 1 hour under a nitrogen atmosphere.

EXAMPLE 12
Preparation of 2-benzoyloxymethyl-3- (2- (5-fluoro-cytosin-1-yl) ethyl) -1,3-thiazolidine (comPose 10)
This compound is prepared according to a protocol similar to that described in Example 11. The 5-fluorocytosine is condensed in step 3, in order to obtain the final compound, instead of cytosine.

EXAMPLE 13
PREPARATION OF 2-hydroxy-methyl-3-2-cyclos-1-yl-ethyl-1,3-thiazolidine (Compound 11)
Compound No. 9, prepared in Example 11, is dissolved in an ammonium saturated methanolic solution at room temperature overnight or in a 1% sodium methanol solution at room temperature for 10 minutes.

 The compound N 11 is recovered at the end of this step.

EXAMPLE 14
Preparation of 2-hydroxymethyl-3- (2- (5-fluorocyclosul-1-yl) ethyl) -1,3-thiazolidine (comPose 12).

 Compound No. 10, prepared in Example 12, is dissolved in a saturated ammonium methanolic solution at room temperature overnight or in a 1% sodium methanol solution at room temperature for 10 minutes. Compound 12 is recovered at the end of this step.

EXAMPLE 15
Anti-HIV activity of the compounds according to the invention.

 In vitro tests were performed on illustrative compounds of the invention to determine their inhibitory properties vis-à-vis the HIV virus. The results are summarized in Table I.

 The concentrations indicated in μM or in Hg / ml are those, in the incubation medium, that affect the ability of JC CHERMANN T cell lines developed to be infected with the HIV-1 virus (HIV-1 BRU strain) according to the experimental protocol described by REY et al (J. Virol, Methods 1987, 16, 239, 249, Virology 1991, 181, 165-171).

 When HIV-1 BRU is added to the microfilter culture system, with a multiplicity of infection of 0.1 infectious tissue culture per cell, giant multinuclear cells appear within 48 hours, and most cells merge as syncitia-like structures after 4 days. The appearance of giant cells is correlated with the detection of antigens and HIV RNA. To measure the antiviral activity, different concentrations of the test compound are added to wells in duplicate at the time of infection, then the culture is incubated at 37in.

After 5, 6 or 7 days, the number of syncitia structures per culture is counted under a microscope. The result is confirmed by five separate experiments. Controls containing infected and uninfected cells, with or without compound are made. The result is first expressed in semi-quantitative units, which take into account the growth pattern of MT-4 and the capacity of the
HIV to cause the formation of syncitia-like structures and induce cell death. In this unit system, 1 corresponds to 1 to 3 syncitia-like formations per well and no change in cell count compared to control cultures without virus. A score of 2 corresponds to 3 to 10 syncitia-like formations per well and 20 to 70% decrease in cell viability. A score of 4 corresponds to more than 30 syncitia formations per well and at least 70% drop in the number of viable cells.

 Cytotoxicity of test compounds was measured by incubating MT-4 cells at 37 ° C in 5% CO 2 alone or in the presence of the indicated compounds. After incubation, the cells are resuspended and 50 μl samples are collected and mixed with trypan blue to determine their viability.

 The concentration that results in an inhibition of cell proliferation is estimated, as compared to untreated control cultures. The results are summarized in Table I.

 2) Comparison with reference anti-HIV compounds.

 The compounds synthesized according to Examples 4, 8 and 10 were compared in vitro with the three currently used anti-HIV-1 compounds clinically used: AZT (zidovudine), ddC (stavudine) and 3TC (lamivudine).

 Comparisons were made using MT-4 cells infected with the BRU HIV-1 strain, as indicated above. The results are summarized in Table II.

 It is clear from these results that the compounds according to the invention have CC50, that is to say concentrations corresponding to 50% inhibition (in pia) comparable to those of ddC (stavudine).

EXAMPLE 16
Anti-HBV activity of the compounds according to the invention
The inhibitory properties of some of the illustrative compounds of the invention have been tested in vitro against HBV infection.

The results are shown in Table III, the protocol described by COVA et al. (J. Virol Meth 1985, 251) and
SELLS et al. (Proc Natl Acad Sci USA (1987) 84, 1005) is as follows:
1) Culture of transfected cells and treatment
The 2.2.15 cell line stably transfected with the HBV virus (Sells et al., 1987, cited above) is maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM glutamine, 1% non-essential amino acid and 300 μg / ml of G418, which is a neomycin-derived antibiotic, at 37 ° C in a humid atmosphere containing 5% CO 2. The test compounds are added to the medium after the cell cells reach confluency in 24-well plates. The cells are grown in the presence of test compounds for 6 days with change of medium every two days. The middle of the last two days is recovered and the amount of HBV DNA is determined.

Each test is done in triplicate.

 2) Ouantification of extracellular viral replication.

 The amount of vHB DNA is detected by staining hybridization as described by COVA et al. ((1985) previously cited).

800 μl of culture medium are spread as a task directly on nitrocellulose filters using the HYBRIDOT MANIFOLD equipment marketed by the Company.
GIBCO-BRL SARL (Cergy-Pontoise, France). After denaturation and neutralization, the filters are hybridized with a 32 P labeled probe (Random priming labeling kit marketed by the company Boehringer Mannheim). The intensity of the autoradiogram task is quantified using a densitometric scanner.

 The compounds as synthesized in Examples 7, 8, 9 and 10 were compared with the reference compound, FIAU (2'-fluoro-5-iodo-1ss-D-arabinofuranosyluracide), as described by FOUREL et al. (Anti-Microb Agents Chemoter (1990) 34, 473).

 The results of Table III show that the compounds according to the invention have selectivity indices comparable to those of FIAU.

 It should be noted that the compounds of Examples 8, 9 and 10 exhibit inhibitory activities against HIV and HBV.

TABLE I
In vitro HIV activity Example n IC50 μM CC50 μM SI
3 2100 100 <1
4 5 + 4 100> 20
7> 300 300 <1
8 5 + 4 100> 20
9 10 + 5 100> 10
10 5 + 4 100> 20 IC 50 represents a 50% inhibitory concentration (in μM) of the cytopathogenicity of HIV-1.

CC50 is the concentration of compound that induces 50% cell death of uninfected MT-4 cells.

SI represents the selectivity index, corresponding to the ratio CC50 / 1C50.

TABLE II
IC50 M compounds *
AZT (zidovudine) 0.01-0.1 ddC (stavudine) 1 - 10 3TC (lamivudine) 0.1 - 1
Example 4 1 - 10
Example 8 1 - 10
Example 10 1 - 10
TABLE III
Compound N extracellular DNA-CC50 (pM) - SI
EC50 (M) 7 0.5 - 2 100 50 to 200
8 0.5 - 2 150 75 to 300
9 0.5 - 2 # 200 400
10 2 200 100
FIAU 0.5 500 1000
ANNEX

Claims (12)

 A compound characterized by comprising a thiazolidine ring, or thiazolidone, N-substituted with a group containing a purine or pyrimidine base, or an analogue thereof or a derivative thereof, said ring being substituted on at least one of other atoms composing it.  2. Compound according to claim 1 having the following formula I:

 in which  - X is S, S = O or SO2  Y is CH2 or C = O  - R1 represents  * a hydrogen atom,  a CORs group, in which R8 is a hydrogen atom, an alkyl, alkoxyalkyl, aralkyl, aryloxyalkyl or alkylcarbonyl group, optionally branched, substituted and / or unsaturated, or an aryl group,  a dihydropyridinyl group, optionally substituted,  an alkylsulfonyl group, optionally substituted aralkylsulfonyl or sulfinyl,  an aminocarbonyl group, derived from an amino acid,  a group (POZ-O) q Rg in which Rg is an alkyl group or a hydrogen atom and q is between 1 and 4,  a group -W-J in which: W W is a carboxyalkylcarbonyl, phospho or sulfophospho group, and  J is a nucleoside, a derivative or a nucleoside analogue,  * a group of formula XIX following:

 -m and n are independently between 0 and 10, preferably between 0 and 4, and even more preferably are equal to 2.  R2 represents a purine or pyrimidine base, or a derivative thereof or an analogue thereof, and  3. Compound according to claim 2 characterized in that R2 is an azapyrimidine, an azapurine, a deazapyrimidine or a deazapurine, optionally substituted.  4. Compound according to one of claims 2 and 3 characterized in that R2 is a 5-azapyrimidine base, azapurine, 7-deazapurine, or 7-deaza-8-azapurine, optionally substituted.  5. Compound according to claim 2 characterized in that R2 is the group of formula II below:

 in which:  - R3 represents a hydrogen atom, a hydroxymethyl group, or C1 to C6 alkyl, optionally branched unsaturated and / or substituted,  R4 represents a hydrogen atom, a hydroxymethyl, trifluoromethyl, optionally branched C1-C6 alkyl, unsaturated and / or substituted group, or a halogen atom.  6. Compound according to claim 2, characterized in that it is 2-benzoyloxymethyl-3- (2- (cytosin-1-yl) -ethyl) -1,3-thiazolidin-4-one (compound 1), 2- Benzoyloxymethyl-3- (2- (5-fluorocytosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 2), 2-benzoyloxymethyl-3- (2- (thymin-1-yl) ) -ethyl) -1,3-thiazolidin-4-one (compound 3) 2-benzoyloxymethyl-3- (2- (adenin-9-yl) -ethyl) -1,3-thiazolidin-4-one (compound 4) 2-hydroxymethyl-3- (2- (cytosin-1-yl) ethyl) -1,3-thiazolidin-4-one (Compound 5), 2-hydroxymethyl-3- (2- (5-fluorocytosin-1) 2-hydroxymethyl-3- (2- (thymin-1-yl) -ethyl) -1,3-thiazolidin-4-one (compound 6-methyl-1,3-thiazolidin-4-one) 2-hydroxymethyl-3- (2- (adenin-9-yl) ethyl) -1,3-thiazolidin-4-one (compound 8), 2-benzoyloxymethyl-3- (2- (cytosin-1) 2-Benzoyloxymethyl-3- (2- (5-fluorocytosin-1-yl) -ethyl) -1,3-thiazolidine (Compound 10) 2- (2-benzoyloxymethyl) -3- (2- (5-fluorocytosin-1-yl) -ethyl) -1,3-thiazolidine (Compound 10) hydroxymethyl-3- (2- (cytosin-1-yl) ethyl) -1,3-thiazolidine (c 11) or 2-hydroxymethyl-3- (2- (5-fluorocytosin-1-yl) ethyl) -1,3-thiazolidine (compound 12).  7. Pharmaceutically acceptable salt of a compound according to one of claims 1 to 6.  8. Process for the preparation of the compounds according to one of claims 1 to 7 wherein R1 represents a hydrogen atom characterized in that  a 1,3-thiazolidine of the following formula XX is reacted:

 in which  R10 is a hydrogen atom or a protecting group, and  - R11 is a group (CH2) n substituted by a halogen atom, with a base, a derivative or a base analogue, previously substituted with a silyl group.  9. Medicament containing a compound according to one of claims 1 to 7.  10. Pharmaceutical composition characterized in that it contains an effective amount of a compound according to one of claims 1 to 7 and pharmaceutically compatible excipients.  11. Use of a compound according to one of claims 1 to 7 for the manufacture of a medicament for the treatment of viral diseases, or related to viruses.  12. The composition of claim 11 characterized in that said disease is AIDS or hepatitis B.