MXPA99009965A - Anti-viral pyrimidine nucleoside analogues - Google Patents

Abstract

A compound having formula (I), wherein R is selected from the group comprising C5 to C20 alkyl, C5 to C20 cycloalkyl, halogens, aryl and alkylaryl;R'is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, amino, alkylamino, dialkylamino, nitro, cyano, alkyoxy, aryloxy, thiol, alkylthiol, arythiol, alkyl;R''is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, alkyloxy, aryloxy and aryl;Q is selected from the group comprising O, S and CY2, where Y may be the same or different and is selected from H, alkyl and halogens;X is selected from the group comprising O, NH, S, N- alkyl, (CH2)n where n is 1 to 10, and CY2 where Y may be the same or different and is selected from hydrogen, alkyl and halogens;Z is selected from the group comprising O, S, NH, and N alkyl;U''is H and U'is selected from H and CH2T, or U'and U''are joined so as to form a ring moiety including Q wherein U'-U''together is respectively selected from the group comprising -CTH-CT'T''- and -CT=CT- and -CT'=CT'-, so as to provide ring moieties selected from the group comprising formula (II) and (III) wherein T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH2 and N3;T'is selected from the group comprising H and halogens and where more than one T'is present they may be the same or different;T''is selected from the group comprising H and halogens, and W is selected from the group comprising H, a phosphate group and a pharmacologically acceptable salt, derivative or prodrug thereof shows potent anti-viral activity against, for example, varicella zoster virus and cytomegalovirus.

Description

ANALOGS OF NULLOSIDES OF PIRIMTDIN ANTIVIRAL Field of the Invention The present invention relates to a new class of nucleoside analogs and their therapeutic use in the prophylaxis and treatment of viral infections caused for example by varicella zoster virus (VZV). The varicella zoster virus is the etiological agent in varicella and herpes zoster, which causes considerable diseases and diseases in humans.

Background of the Invention There is considerable interest in the development of 5-substituted pyrimidine deoxynucleosides as putative antiviral agents. In Tetrahedron Letters, 22, 421, 1981, MJ Robins and PJ Barr describe a method of binding terminal alkynes with 5-iodouracil nucleotides protected in the presence of a catalyst to give the nucleosides of 5- (alkyn-1-yl) corresponding uracil. In J. Med. Chem. 26, 661, 1983, E. de Clercq, J. Ref.031921 Descamps, J. Balzarini, J. Giziewicz, PJ Barr and MJ Robins describe a catalytic process for linking terminal alkynes with 5- ( iodine-1- (2, 3, 5, -tri-Op-toluyl-ß-D-arabinofuranosyl) uracil and 5-iodo-3'-5 '-di-0-p-toluyl-2'-deoxyuridine. cyclized by-product having methyl substituted at position 6 was isolated and characterized spectroscopically In J. Org. Chem. 48, 1854, 1983, MJ Robins and PJ Barr describes the catalytic binding of terminal alkynes with 5-iodo-1 nucleotides -methyluracil and 5-iodouracil protected as their p-toluyl esters The article also describes the conversion of 5-hexinyl-2'-deoxyuridine to 6-n-butyl-3- (2-deoxy-β-D-erythro- pentofuranosyl) furan [2, 3-d] pyrimidin-2-one, in Tetrahedron Letters 29, 5221, 1988, KA Cruickshank and D.L. Stockwell describe the catalytic condensation of 5'-dimethoxytrityl-5-iodo-2'-deoxyuridine with N-trifluoroacetylpropargylamine and the subsequent conversion to 3'-phosphoramidite. In J. Heterocyclic Chem. 28, 1917, 1991, R.

Kumar, EE Knaus and LI iebe describe a reaction employing 5- (1-fluoro-2-bromoethyl) -3 ', 5'-di-O-acetyl-2'-deoxyuridine and the production of a compound having the formula: In J. Org. Chem. 1993, 58, 6614, G. T. Crisp and B. L. Flynn describe palladium-catalyzed connections of terminal alkynes with a variety of oxyuridines. One described linkage is that between 5-ethynyl-2'-deoxyuridine and a range of fluorinated aryl compounds. In Nucleic Acids Research 1996, 24, 2470, J. Woo, R. B. Meyer and H. B. Gamper describe a process for the preparation of 3- (2'-deoxy-β-D-ribofuranosyl) -pyrrolo-. { 2, 3-d] -pyrimidin-2 (3H) -one. In Can. J. Chem. 74, 1609, 1996, R. Kumar, L.

I. Wiebe, E. E. Knaus describe a range of deoxyuridine compounds and their various antiviral activities. A compound of the formula: It was found that it will be inactive in the in vitro tests against HSV-1, HSV-2, VZV and VMC. In JP 62255499 (Teijin Ltd) describes the preparation of fluorescent nucleosides or nucleotides and their use for DNA hybridization probes. The disclosed compounds have the general formula: where Xi and Yi are HO [P (0) (0H) 0] n, Zj. is H or H0 [P (0) (0H) 0] m, with m and n = 0 to 3, Wl is H or HO and Ri and R2 are H or alkyl with Ci to C? 0. In Nippon Kagaku Kaishi 7, 1214, 1987 describes the synthesis of fluorescent dodecadeoxy ribonucleotides having the general formula: wherein R can be H or butyl.

Detailed description of the invention It is an object of the present invention to provide a novel class of nucleoside analogs.

It is a further object of the present invention to provide a novel class of nucleoside analogs for therapeutic use in the prophylaxis and treatment of viral infection for example by the varicella zoster virus. According to a first aspect of the present invention there is provided a compound having the formula I as follows: wherein R is selected from the group comprising alkyl with C5 to C20, cycloalkyl with C5 to C20, halogens, aryl and alkylaryl; R 'is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogen, amino, alkylamino, dialkylamino, nitro, cyano, alkyloxy, aryloxy, thiol, alkylthiol, arylthiol, and aryl; R "is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, alkyloxy, aryloxy and aryl; Q is selected from the group comprising 0, S and CY2, wherein Y may be the same or different and is selected from H, alkyl and halogens; • X is selected from the group comprising 0, NH, S, N-alkyl, (CH2) n wherein n is 1 to 10, and CY2 wherein Y may be the same or different and is selected from hydrogen, alkyl and halogens; Z is selected from the group comprising 0, S, NH and N-alkyl; U "is H and U 'is selected from H and CH2T, or U' and U" are linked to provide a ring portion that includes Q wherein U '-U "together are respectively selected from the group comprising -CTH-CT 'T' - and -CT '= CT'-, to provide ring portions selected from the group comprising s wherein T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH2 and NH3; T 'is selected from the group comprising H and halogens and wherein more than one T' is present, they may be the same or different; T "is selected from the group comprising H and halogens, and W is selected from the group comprising H, a phosphate group and a phosphonate group It is to be understood that the present invention extends to the compounds according to formula I in wherein the group W is modified to any salt or derivative of pharmacologically acceptable -H, phosphates or phosphonates The present invention also includes any compound which is a prodrug of the compound according to formula I, any such prodrug is provided by the modification of the portion W, wherein W is selected from the phosphates and derivatives thereof, and the phosphonates and derivatives thereof Each of R, R 'and R "may be substituted or unsubstituted and may be branched or unbranched. When any of R, R 'and R "are alkyl or cycloalkyl they may be saturated or unsaturated The nature, position and number of any substituents and unsaturations present may be varied R may contain aryl or heteroaryl groups which they may vary in their nature, position or number A preferred position is the terminal position in R. Examples of suitable substituents include OH, halogens, amino, CN, CHOH, C02alkyl, CONH2, CONHalkyl, SH, S-alkyl and N02 wherein alkyl is suitably Ci to C5 Suitably any substituent on R when R is alkyl or cycloalkyl is non-polar, more suitably any such substituent is further hydrophobic Preferably R is an alkyl group More preferably, R is an alkyl group with C to C20, which may optionally carry substituents such as halogens, Still more preferably R is a group with C8 to C14, it is particularly preferred If R is C? oH2? straight chain. When R is aryl or alkylaryl, it may be substituted. The alkylaryl can be aryl with one or more groups with attached or fixed Ci to C? 0 which can themselves be substituted or unsubstituted. The alkyl groups may include benzyl groups and rings 5, 6 or 7 numbered, heterosubstituted. Either an aryl or an alkyl portion of an alkylaryl group can be attached or attached to the ring structure. If desired R, optionally substituted as previously mentioned, may be for example - (CH2) n-aryl- (CH2) mH, where n and m are each more than l and n + m < 10 and the aryl is preferably C6H. R can not be any radical equivalent to 4-FC6H5, C6F5, 4 MeOC6H5, 3.5- (CF3) 2C6H4, 3.5-F2C6H4, 4-CF3C6H5 or C6H5. Suitably R 'is selected from the group comprising alkyl with Ci to Cio, cycloalkyl with C3 to Cio, alkylamino with? a Cι, dialkylamino with C 1 to C 0, alkyloxy with Ci to Cι, aryloxy with C 6 to Cι, alkyl thiol with Ci to C α or aryl thiol with a Cι and aryl with C 6 to Cι. R "is suitably selected from the group comprising alkyl with Ci a Cío, cycloalkyl with C3 to Cio, alkyloxy with Ci to Cio, aryloxy with e to Cio and aryl with Ce to Cio. Preferably, each of R 'and R "is a small alkyl that is an alkyl group with Ci to C2 or H. More preferably each of R' and R" is H. Throughout the present specification "halogen" is meant to mean that includes any of F, Cl, Br and I. Preferably Q is CH2, S or O. More preferably Q is O. Where Q is CY2 and includes a halogen, the halogen is preferably fluorine. And it is preferably H. Preferably X is O, S or NH. More preferably X is O. Where X is (CH2) n, n is preferably 1 or 2, more preferably 1. X can not be NH or N-alkyl when R is an alkyl group with C5 to Cio, unless Q is different from 0. Suitably when X is an N-alkyl, the alkyl is alkyl with Ci to C5 and when X is CY2 at least one Y is alkyl with Ci to C5. Preferably Z is 0. When Z is N-alkyl, suitably the alkyl is Ci-C5 alkyl. Preferably U 'and U "are linked to provide the saturated ring portion including T, T' and T". Preferably T, T 'and T "in such portion of the ring are respectively OH, H and H. Preferably T is OH When T is a halogen it is preferably F. Preferably each of T' and T" is H. When either or both of T 'and T "are halogen, they are preferably fluorine When W is a portion which makes the compound a prodrug of the compound according to formula I, it is to be understood that the term prodrug includes the base The free base may also have a direct antiviral action not dependent on the metabolism with respect to the corresponding nucleoside analogue It is also understood that "phosphate" includes diphosphates and triphosphates and "phosphonate" includes diphosphonates and Thus, W includes the pharmacologically acceptable salts and derivatives of the phosphates, diphosphates and triphosphates and of the phosphonates, diphosphonates and triphosphonates. includes any portion which provides a compound which is a prodrug of the compound according to formula I, wherein W is selected from phosphates, diphosphates and triphosphates and derivatives thereof, and phosphonates, diphosphonates and triphosphonates and the derivatives thereof. Each compound may be the pure stereoisomer coupled or attached at each of its chiral centers or it may be inverted at one or more of its chiral centers. It may be a single stereoisomer or a mixture of two or more of the stereoisomers. If the same is a mixture, the proportion may or may not be equimolar. Preferably, the compound is a single stereoisomer. The compound may be in any enantiomeric form ie it may be any of the D or L enantiomers, any of the unique stereoisomers or as a mixture of the two enantiomers. More preferably the compound has a stereochemistry that resembles that of the natural deoxy nucleosides derived from β-D-2-deoxyribose. However, other enantiomers, particularly the L-enantiomers, may be employed. It is to be understood that the present invention extends to compounds wherein the sugar and phosphate moiety, if present, have been modified either together or separately as described above. it tastes good to a person skilled in the art. It is also possible for a compound in which the present invention is incorporated which is in a sugar form as for example modified and derived from a D-xyl sugar system. The preferred compounds, particularly in which the present invention takes shape, have the following formulas: According to a further aspect of the present invention, there is provided a method for preparing the compounds having the above Formula I wherein a 5-halo nucleoside analogue is contacted with a terminal alkyne in the presence of a catalyst. Alternatively, the 5-alkynyl nucleoside can be cyclized in the presence of a catalyst. Suitably the catalyst is a copper catalyst. The 5-alkynyl nucleoside has the general formula: The compounds in which the present invention takes shape can show an antiviral activity. In particular, it has surprisingly been found that the compounds in which the invention takes place can show antiviral activity against for example the virus and / or the varicella zoster cytomegalovirus. According to a further aspect of the present invention there is provided a compound according to the present invention for use in a method of treatment, suitably in the prophylaxis or treatment of a viral infection. In this aspect of the present invention, when X is NH or N-alkyl, R can be alkyl with C7 to C2o. According to a further aspect of the present invention there is provided the use of a compound according to the present invention in the manufacture of a medicament for the prophylaxis or treatment of a viral infection. In this aspect of the present invention, when X is NH or N alkyl, R can be alkyl with C to C20. According to a further aspect of the present invention there is provided a method of prophylaxis or treatment of viral infection, comprising administering to a patient in need of such treatment, an effective dose of a compound according to the present invention. . In this aspect of the present invention, when X is NH or N alkyl, R can be alkyl with C7 to C20.

In accordance with a further aspect of the present invention, there is provided the use of a compound of the present invention in the manufacture of a medicament for use in the prophylaxis or treatment of a viral infection, particularly an infection with the varicella virus. zoster or an infection with cytomegalovirus. In this aspect of the present invention, when X is NH or N alkyl, R can be alkyl with C7 to C2o. When the virus or varicella zoster virus or cytomegalovirus is the cause of the infection, also in this aspect of the invention R can be aryl or aralkyl, without the exclusion that R is not a radical equivalent to 4-FC6H5, C6H5, 4 MeOC6H5, 3, 5 (CF3) 2C6H, 3,5-F2CeH, 4-CF3CeH5 or CßHs. In accordance with a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable excipient. In this aspect of the invention when X is NH or N alkyl, R can be alkyl with C7 to C20. According to a further aspect of the present invention there is provided a method of preparing a pharmaceutical composition comprising the step of combining a compound of the present invention with a pharmaceutically acceptable excipient. In this aspect of the invention when X is NH or N alkyl, R can be alkyl with C to C2o. The medicaments employed in the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, although corn starch and alginic acid are suitable disintegrating agents. The binding or binding agents may include starch and gelatin, although the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, carriers such as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous or intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered at an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention can include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth gum, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl. The compounds of the invention can also be presented as liposome formulations. In general, a suitable dose will be in the range of 0.1 to 300 mg per kilogram of body weight of the receptor per day, preferably in the range of 1 to 25 mg per kilogram of body weight per day and even more preferably in the range of 5 to 10 mg per kilogram of body weight per day. The desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and even more preferably 50 to 700 mg of the active ingredient per unit dosage form. The embodiments of the present invention will now be described by way of example only. It will be appreciated that modifications to the details can be made as long as they are considered within the scope of the invention.

Experimental In the following examples the bicyclic rings of the compounds are numbered following the recommended IUPAC guidelines or rules. Accordingly, 3- (2'-Deoxy-β-D-ribofuranosyl) -6-octyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one has the structure and is numbered as follows: Preparation of 5- (1-Decinyl) -2'-deoxyuridine To a stirred solution of 5-iodo-2'-deoxyuridine (800 mg, 2.26 mmol) in dry dimethylformamide (8 ml), at room temperature under a nitrogen atmosphere, dry diisopropylethylamine (584 mg, 0.80 ml, 4.52 mg) is added. mmoles), 1-decino (937 mg, 1.22 ml, 6.78 mmol), tetrakis (triphenylphosphine) palladium (0) (261 mg, 0.226 mmol) and copper iodide (I) (86 mg, 0.452 mmol). The reaction mixture is stirred at room temperature for 19 hours, after which time the reaction mixture is concentrated in vacuo. The resulting residue is dissolved in dichloromethane / methanol (1: 1) (6 ml) and an excess of Amberlite IRA-400 (form HC03") is added and the mixture is stirred for 30 minutes, then the resin is filtered, washed with methanol and the combined filtrate is evaporated to dryness The crude product is purified by silica gel column chromatography using an initial eluent of ethyl acetate, then it is changed to ethyl acetate / methanol (9: 1) by a gradient The appropriate fractions were combined and the solvent was removed in vacuo to give the product as a creamy solid (490 mg, 60%). Recrystallization of the product from the hot dichloromethane gave the crude product as fine white crystals (376). mg, 46%).

MHz): 11.56 (1H, s amp., NH-3), 8.11 (1H, s, H-6), 6.12 (1H, dd, 3J = 6.6 Hz, H-l '), 5.25 (1H, d, 3J = .2 Hz, 3 '-OH), 5.09UH, t, 5'-OH), 4.24 (1H, m, H-3'), 3.79 (1H,, H-4 '), 3.59 (2H, , H-5 '), 2.36 (2H, t, 3J = 6.8Hz, a-CH2), 2.12 (2H, m, H-2'and H-2'b), 1.47 (2H, m, ß-CH2 ), 1.38-1.26 (10H, m, 5xCH2), 0.87 (3H, t, CH3). 13C-rmn (d6-DMSO; 75 MHz): 16.2 (CH3), 21.0, 24.3, 30.4, 30.5, 30.8, 30.9 (6xCH2), 33.5 (a-CH2), 41.7 (C-2 '), 63.2 (C -5 '), 72.4 (C-3'), 75.1, 86.8, 89.8, 95.5IC-4 ', C-β, C-1', Ca), 101.3 (C-5), 144.9 (C- 6), 151.7 (C-2), 164.0 (C-4). Mass spectrum (ES-MS (+ ve)): 387 [M + Na] +, 365 [M + HJ +.

All XH and 13C-NMR spectra were recorded on a Bruker Avance DPX300 spectrometer at 300 MHz and 75 MHz respectively. Chemical shifts were recorded in parts per million (ppm) downfield from tetramethylsilane. The low resolution mass spectra were recorded during a run of the mass spectrometer Fisons Instruments VG Platform Electrospray in an ionic mode either positive or negative, with acetonitrile / water as the mobile phase.

Examples 1 to 6 Examples 1 to 6 each take body in the present invention and illustrate the effect of chain length on the alkyl group R. In terms of the Formula I above each compound had the following components X = 0, Z = 0, Q = 0, W = H, R "= R '= H, T = OH and T' = T" = H.

Example 1 3- (2'-Deoxy-β-D-ribofuranosyl) -6-dodecyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5- (1-tetradecinyl) -2'-deoxyuridine (382 mg, 0.91 mmol) in methanol / triethylamine (7: 3) (30 mL), at room temperature under a nitrogen atmosphere, is added copper iodide (I) (45 mg, 0.225 mmol). The reaction mixture is then heated to reflux and stirred for 5 hours. The solvent is removed in vacuo and the crude product is purified by silica gel column chromatography, using an initial eluent of dichloromethane / methanol (9: 1), followed by an eluent of dichloromethane / methanol (8: 2). The appropriate fractions were combined and the solvent was removed in vacuo, yielding the pure product as a white solid. (188 mg, 49%). ^ -rmn (d6-DMS0; 300 MHz): 8.70 (1H, s, H-4), 6.27 (1H, s, H-5), 6.18 (lH, dd, 3J = 5.7Hz, 6.0 Hz, H- l '), 5.19 (1H, d, 3J = 4.2 Hz, 3'-OH), 5.05 (1H, t, 3J = 4.9 Hz, 5' -OH), 4.25 (1H, m, H-3 '), 3.91 (1H, m, H-4 '), 3.66 (2H, m, H-5'), 2.60 (2H, t a -CH2), 2.42 and 2.03 (2H, m, H-2'and H-2 'b), 1.61 (2H, m, ß-CH2), 1.21 (18H, m amp., 9? CH2), 0.83 (3H, m, CH3). 13C- rmn (d6-DMSO; 75 MHz: 14.7 (CH3), 23.0, 27.2, 28.4, 29.3, 2x29.6, 2x29.8, 2x29.9 (10xCH2), 32.2 (-CH2), 42.3 (C-2 '), 61.5 (C-5) '), 70.3 (C-3'), 88.2, 88.9 (C-1 'and C-4'), 100.2 (C-5), 107.6 (C-4a), 137.3 (C-4), 154.8 (C -2), 159.1 (C-6), 172.0 (C-7a). Mass spectrum (ES-MS (+ ve)); m / z 484 (15%, [M + Cu] +), 459 (20%, [M + K] +), 443 (40%, [M + Na] +), 421 (40%, [M + H] +, 305 (100%, [base + H] +). Elemental analysis (found: C, 65.62%; H, 8.82%; N, 6.90%. C23H36N2? 5 requires: C, 65.69%; H, 8. 63%; N, 6.66%).

Example 2 3- (2'-Deoxy-β-D-ribofuranosyl) -6-decyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a solution of 5- (1-dodecyl) -2'-deoxyuridine (130 mg, 0.33 mmol) in 10 ml of triethylamine / methanol (7: 3) is added copper iodide (I) (8 mg) and the solution is refluxed for 3 hours. The volatiles were evaporated and the residue is taken up in 20 ml of chloroform and washed with a 2% aqueous solution of sodium ethylenediaminetetraacetate (2x10 ml) and water (10 ml). The combined aqueous layers are extracted with chloroform (2x250 ml). The combined organic layers are dried (MgSO4) and the solvent is removed in vacuo to give a solid (59 mg, 45%) which is recrystallized from ethanol and diisopropyl ether (27 mg, 21%).

P.f. 164-165 ° C. Rf 0.05 (EtOAc). XH-rmn (d6-DMSO; 300 MHz): 8.67 (1H, s, H-4), 6.43 (1H, s, H-5), 6.16 (1H, t, 3J = 6.1 Hz, H-l1), 5.28 (1 H, d, 3 J = 4.2 Hz, 3 * -OH), 5.12 (1 H, t, 3 J = 5.1 Hz, 5 '-OH), 4.22 (1 H, m, H-3'), 3.89 (1 H, m, H- '), 3.63 (2H,, H-5 '), 2.64 (2H, t, 3 J = 7.2 Hz, a-CH2), 2.33 and 2.04 (2H, m, H-2'a and H-2'b), 1.60 (2H,, ß -CH2), 1.28-1.23 (14H, m, 7xCH2), 0.85, (3H, t, J = 6.9Hz, CH3). 13C-rmn (d6-DMSO; 75 MHz): 14.2 (CH3), 22.3, 26.6, 27.6, 28.6, 28.9, 28.9, 29.1, 29.2, 31.5 (9xCH2), 41.4 (C-2 '), 61.0 (0-5') / 69.7 (0-3 '), 87.6, 88.3 (C-1', C-4 '), 106.6, 100.0 (C-4a, C-5), 137.0 (C-4), 154.0 (C-6), 158.5 (C-2) ), 171.4 (C-7a). Mass spectrum (ES-MS (+ ve)): 415 [M + Ma] +.

Example 3 3- (2'-Deoxy-β-D-ribofuranosyl) -6-octyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5- (1-decinyl) -2'-deoxyuridine (216 mg, 0.59 mmol) in methanol / triethylamine (7: 3) (20 mL), at room temperature under a nitrogen atmosphere, iodide is added of copper (I) (20 mg, 0.10 mmol). The reaction mixture is then heated to reflux and stirred for 5 hours. The solvent is removed in vacuo and the crude product is purified by silica gel column chromatography, using an initial eluent of dichloromethane / methanol (9: 1), followed by an eluent of dichloromethane / methanol (8: 2). The appropriate fractions were combined and the solvent was removed in vacuo, yielding an orange / brown solid. The crude product is triturated and washed with acetone, followed by drying, giving the crude product as a fine white powder (118 mg, 55%).

XH-rmn (d6-DMSO; 300MHz): 8.63 (1H, s, H-4), 6.39 (1H, s, H-5), 6.12 (1H, dd, 3J = 6.0 Hz, 6.4 Hz, H-l) '), 5.25 (1H, d, 3J = 4.5 Hz, 3 * -OH), 5.09 (1H, t, 5'-OH), 4.19UH, m, H-3'), 3.86 (1H, m, H -4 '), 3.60 (2H, m, H-5'), 2.60 (2H, t, 3 J = 7.2 Hz, a-CH2), 2.33 and 2.00 (2H, m, H-2'ß and H- 2'b), 1.57 (2H, m, ß-CH2), 1.2K10H, m amp., 5xCH2), 0.8K3H, t, CH3). 13C-rmn (d6-DMSO; 75 MHz): 14.4 (CH3), 22.5, 26.8, 27.8, 28.8, 29.1 (5xCH2), 31.7 (ß-CH2), 39.1 (a-CH2), 41.6 (C-2 ' ), 61.2 (C-5 '), 70.KC-3'), 87.8, 88.5 (0-1 'and C-4'), 100.2 (0-5), 106.8 (C-4a), 137.2 (0 -4), 154.2 (0-2, 158.7 (0-6), 171. & (C-7a). Mass spectrum (ES-MS (+ ve)): 387 [M + Na] +, 365 [ M + H] +.

Example 4 3- (2'-Deoxy-β-D-ribofuranosyl) -6-hexyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5-iodo-2'-deoxyuridine (800 mg, 2.26 mmol) in dry dimethylformamide (8 ml), at room temperature under a nitrogen atmosphere, dry diisopropylethylamine (584 mg, 0.80 ml, 4.52 mmol) is added. ), 1-octino (747 mg, 1.00 ml, 6.78 mmol), tetrakis (triphenylphosin) palladium (O) (261 mg, 0.226 mmol) and copper iodide (I) (86 mg, 0.452 mmol). The reaction mixture is stirred at room temperature for 19 hours, after which time thin layer chromatography (ethyl acetate / methanol (95: 5)) of the reaction mixture showed complete conversion of the starting material . Copper (I) iodide (80 mg, 0.40 mmol) and triethylamine (15 ml) were then added to the reaction mixture, which was subsequently heated at 70-80 ° C for 4 hours. The reaction mixture is then concentrated in vacuo and the resulting residue is dissolved in dichloromethane / methanol (1: 1) (8 ml) and an excess of Amberlite IRA-400 (form HC03 ~) is added and the mixture is stirred for 30 minutes. Then the resin is filtered, it is washed with methanol and the combined filtrates are evaporated to dryness. The crude product was initially triturated with acetone and then purified by silica gel column chromatography using an initial eluent of dichloromethane / methanol (95: 5), followed by an eluent of dichloromethane / methanol (9: 1). The appropriate fractions were combined and the solvent was removed in vacuo to give the title product as a creamy solid (196 mg, 26%). Trituration of the product with petroleum ether gave the pure product as a fine white solid (176 mg, 23%). iH-rmn (d6-DMSO; 300 MHz): 8.64 (1H, s, H-4), 6.40 (1H, s, H-5), 6.13UH, dd, 3J = 6.0 Hz, 6.4 Hz, H-l '), 5.25 (1H, d, 3J = 4.1 Hz, 3' -OH), 5.10 (1H, t, 5 '- OH), 4.19 (1H, m, H-3 '), 3.87 (1H, m, H-'), 3.60 (2H, m, H-5 '), 2.61 (2H, t, 3J = 7.2 Hz, - CH2), 2.33 and 2.01 (2H,, H-2'and H-2'b), 1.57 (2H,, ß-CH2), 1.25 (6H, m amp., 3xCH2), 0.82 (3H, m, CH3 ). 13C-nm (de-DMSO, 75 MHz): 16.2 (CH3), 24.2, 28.6, 29.6 (3xCH2), 30.3 (ß-CH2), 33.1 (a-CH2), 43.4 (0-2 '), 63.0 ( C-5 '), 71.9 (C-3'), 89.6, 90.3 (0-1 'and C-4'), 102.0 (C-5), 108.6 (C-4a), 139.0 (C-4), 156.0 (0-2), 161.7 (0-6), 173.4. { C-7a). Mass spectrum (ES-MS (+ ve)): 359 [M + Na] +, 337 [M + H] \ Each of the products of Examples 1, 2, 3 and 4 were tested in vitro in tissue culture assays to verify a potent antiviral action with respect to varicella zoster virus (VZV). Acyclovir was included in the test procedure as a control. The results are given in Table I below. VZV (OKa and YS strains) induced a cytopathogenicity in fibroblast cells of the human embryonic lung (HEL) 7 days after infection. The EC50 was defined as the concentration of the drug (in μM) required to reduce the cytopathogenicity induced by the virus in 50%.

Table I Compound ECso / VZV / μM CCso / μM Example 1 < 1.2 > 200 Example 2 0.005 > 50 Example 3 0.003 > 50 Example 4 1.3 > 200 Acyclovir 0.2 > 100 Accordingly, in terms of the general formula I wherein R is a straight chain alkyl group having 10 or 8 carbon atoms and X is O, ie equivalent to Examples 2 and 3 respectively, an extremely strong antiviral activity was exhibited potent with respect to varicella zoster virus. Where R is a straight chain alkyl group having 12 or 6 carbon atoms and X is O, ie equivalent to Examples 1 and 3 respectively, an antiviral activity comparable to acyclovir was exhibited.

Example 5 3- (2'-Deoxy-β-D-ribofuranosyl) -6-pentyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5- (1-heptinyl) -2'-deoxyuridine (125 mg, 0.39 mmol) in methanol / triethylamine (7: 3) (14 mL), at room temperature under a nitrogen atmosphere, iodide is added of copper (I) (15 mg, 0.075 mmol). The reaction mixture was then heated to reflux and stirred for 8 hours. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography, using an initial eluent of ethyl acetate, followed by an eluent of ethyl acetate / methanol (9: 1). The appropriate fractions were combined and the solvent was removed in vacuo, yielding the product as a colorless white solid (85 mg, 68%). The product was isolated by trituration with diethyl ether, followed by drying, giving the crude product as a fine white powder (55 mg, 44%).

: H-rmn (d6-DMSO, 300 MHz): 8.67 (1H, s, H-4), 6.43 (1H, s, H-5), 6.16 (lH, dd, 3J = 6.0 Hz, H-l ' ), 5.29 (1H, d, 3J = 4.1 Hz, 3'-OH), 5.13 (1H, m, 5 '-OH), 4.22 (1H, m, H-3'), 3.89 (1H, m, H -4 '), 3.63 (2H, m, H-5'), 2.64 (2H, t, o-CH2), 2.35 and 2.06 (2H, m, H-2 ', and H-2'b), 1.61 (2H, m, ß-CH2), 1.30 (4H, m, 2xCH3), 0.87 (3H, m, CH3). 13C- rmn (d6-DMSO; 75 MHz): 14.1 (CH3), 22.0, 26.3 (2xCH2), 27.5 (ß-CH2), 30.8 (a-CH2), 41.4 (C-2 '), 60.9 (C-) 5 '), 69.8 (C-3'), 87.6, 88.3 (C-1 'and C-4'), 100.0 (C-5), 106.6 (C-4a), 137.0 (C-4), 154.0 ( C-2), 158.5 (C-6), 171.4 (C-7a).

Example 6 3- (2'-Deoxy-β-D-ribofuranosyl) -6-heptyl-2,3-dihydrofuro [2,3-d]? Irimidin-2-one To a stirred solution of 5-iodo-2'-deoxyuridine (800 mg, 2.26 mmol) in dry dimethylformamide (8 ml), at room temperature under a nitrogen atmosphere, dry diisopropylethylamine (584 mg, 0.80 ml, 4.52 mg) is added. mmoles), 1-nonino (842 mg, 1.11 ml, 6.78 mmol), tetrakis (triphenylphosphine) palladium (O) (261 mg, 0.226 mmol) and copper iodide (I) (86 mg, 0.452 mmol). The reaction mixture is stirred at room temperature for 20 hours, after such time the c.c.d. (thin layer chromatography) (ethyl acetate / methanol) (95: 9) of the reaction mixture, showed the complete conversion of the starting material. Then the copper (I) iodide (80 mg, 0.40 mmol) and triethylamine (15 ml) and methanol (20 ml) were added to the reaction mixture which was subsequently heated to reflux for 8 hours. The reaction mixture is then concentrated in vacuo and the resulting residue is dissolved in dichloromethane / methanol (1: 3) (20 ml) and an excess of Amberlite IRA-400 (form HC03") and solid sodium thiosulfate and the mixture is stirred for 30 minutes, then the mixture is filtered through silica which was subsequently washed with dichloromethane / methanol (6: 4) and the combined filtrates are evaporated to dryness.The crude product was initially triturated with hexane and then it was purified by silica gel column chromatography using an initial eluent of ethyl acetate, followed by an eluent of ethyl acetate / methanol (9: 1) .The appropriate fractions were combined and the solvent was removed in vacuo to give the product as a yellow solid (660 mg, 84%). Trituration of the product with dichloromethane yielded the pure product as a creamy solid (484 mg, 61%).

: H-rmn (d6-DMSO; 300MHz): 8.67 (lH, s, H-4), 6.43 (lH, s, H-5), 6.16 (1H, dd, 3J = 5.3 Hz, 6.0 Hz, H- l '), 5.29 (1H, d, 3J = 4.0 Hz, 3'-OH), 5.13 (1H, t, 5'-OH), 4.22 (1H, m, H-3'), 3.90 (1H, m , H-4 '), 3.63 (2H, m, H-5'), 2.63 (2H, t, 3J = 7.2 Hz, a-CH2), 2.35 and 2.06 (2H, m, H-2'and H- 2'b), 1.60 (2H, m, ß-CH2), 1.25 (8H, m amp., 4xCH2) 0.85 (3H,, CH3). 13C-nm (de-DMSO; 75MHz): 16.3 (CH3), 24.5, 28.8, 29.8, 30.8 (5xCH2), 33.6 (a-CH2), 43.6 (C-2 '), 63.2 (C-5'), 72.1 • (C-3 '), 89.8, 90.5 (C-1' and 04 '), 102.2 (C-5), 108.8 (C04a), 139.2 (C-4), 156.2 (C-2), 160.7 ( C-6), 173.6 (C-7a) Each of the products of Examples 5 and 6 in which R is respectively C5 and C7 was tested in vitro in tissue culture assays to verify a potent antiviral action with respect to Varicella zoster virus (VZV). The results in terms of the EC50 which was defined as the concentration of the drug (in μM) required to reduce the cytopathogenicity induced by the virus in 50% are given in Table II below. Equivalent figures for measurements on the equivalent compounds in which the present invention takes shape where R is C6, C8, CIO or C12, and for acyclovir are also given in the table.

TABLE II Compound: X = 0 EC50 / VZV / μM R: C5 3 C6 1.3 C7 0.17 C8 0.03 CIO 0.005 C12 < 1.2 Acyclovir 0.2 Each of the compounds in which the present invention takes shape show an antiviral activity greater than or comparable to that of acyclovir, which shows increasing efficacy throughout the series C5 to CÍO.

Examples 7, 8 and 9 Examples 7, 8 and 9 demonstrate the preparation of the compounds having a substituted R alkyl group and their efficacy as antiviral agents. In each case the alkyl group is nC9 and the substituent is terminal. With respect to formula I above, in each case, X is 0, Z is 0, R 'and R "are each H, Q is 0, W is H, T is OH and T' and T" is H.

Example 7 3- (2'-Deoxy-β-D-ribofuranosyl) -6- (9-hydroxynonyl) -2,3-dihydrofuro [2,3-dyrimidin-2-one] To a stirred solution of 5- (11-hydroxy-l-undecinyl) -2'-deoxyuridine (200 mg, 0.51 mmol) in methanol / triethylamine (7: 3) (20 ml), at room temperature under an atmosphere of nitrogen, copper (I) iodide (20 mg, 0.10 mmol) is added. The reaction mixture is then heated to reflux and stirred for 4 hours. The solvent is removed in vacuo and the crude product is purified by column chromatography on silica gel, using an initial eluent of ethyl acetate, followed by an eluent of ethyl acetate / methanol (95: 5). The appropriate fractions were combined and the solvent was removed in vacuo to give the product (147 mg, 74%) as a faint yellow solid. The product was triturated with dichloromethane, followed by drying, giving the pure product as a fine white powder suitable for biological testing and elemental analysis.

: H-rmn (d6-DMSO; 300 MHz): 8.67 (lH, s, H-4), 6.43. (1H, s, H-5), 6.16 (lH, dd, 3J = 6.0 Hz, H-l '), 5.28 (lH, d, 3J = 4.2 Hz, 3'-OH), 5.12 (lH, t, 3J = 5.3Hz, 5'-OH), 4.33 (lH, t, 3J = 4.9Hz, 5.3Hz, alkyl-OH), 4.22 (lH, m, H-3 '), 3.90 (lH, m, H- 4 '), 3.64 (2H, m, H-5'), 2.64 (2H, t, 3J = 7.2Hz, a-CH2), 2.35 and 2.04 (2H, m, H-2 'and H2'b), 1. 61 (2H, m, ß-CH2), 1.39-1.25 (14H, m, 7xCH2). 13C-rmn (from DMSO; 75MHz): 27.2, 28.1.29.1,30.1,30.4, 30.7 (x2), 34.3 (8xCH2), 42.9 (C-2 '), 62.4, 62.5 (C-5', CH2CH2OH), 71.4 (C-3 '), 89.1, 89.8 (C-' 1 'and C-4'), 101.5 (C-5), 108.1 (C-4a), 138.5 (C-4), 155.5 ( C-2), 160.1 (C-6), 172.9 (C-7a). Mass spectrum (ES-MS (+ ve)); m / z 433 (20%, [M + K] +), 417 (100%, [M + Na] *), 395 (20%, [M + H] +), 279 (100%, [base + H] *).

Example 6- (9-Chlorononyl) -3- (4-hydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl) -2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of the Crude 5- (11-chloro-l-undecinyl) -1- (4-hydroxy-5-hydroxymethyl) tetrahydro-2-furanyl) 1,2,3,4-tetrahydro-2,4-pyrimidinedione (280 mg) in methanol / triethylamine (7: 3) (20 ml), at room temperature under a nitrogen atmosphere, copper iodide (15.2 mg, 0.08 mmol) is added. The reaction mixture is then heated to reflux and stirred for 5 hours. The solvent is removed in vacuo and the crude product is purified twice by column chromatography on silica gel, using ethyl acetate / methanol. (9: 1) as the eluent. The appropriate fractions were combined and the solvent was removed in vacuo to give a yellow solid, the crude product (230 mg, 71%). The crude product was then triturated and crystallized with acetone and dried to give the pure product as a fine white solid. 1 H-NMR (d6-DMSO; 300MHz): 8.67 (1H, s, H-4), 642 (1H, s, H-4), 642 (lH, s, H-5), 6.16 (lH, t, 3J = 6.0 Hz, H-l '), 5.28 (lH, d, 3J = 4.2 Hz, 3'-OH), 5.12 (lH, t, 3J = 5.1 Hz, 5'-OH), 4.21 (lH, m , H-3 '), 3.94 (lH, m, H-4'), 3.56 (4H, m, H-5 'and CH2C1), 2.64 (2H, t, 3J - 7.2 Hz, a-CH2), 2.34 , 2.05 (2H, m, H-2'and H-2'b), 1.75 (2H, m, b-CH2), 1.61, 1.44, 1.25 (12H, m, 6xCH2).

- NMR (d6-DMSO; 75MHz): 172.0 (C-7a), 159.1 (C-6), 154.6 (C-2), 137.6 (C-4), 107.2 (C-4a), 100.6 (C-) 5), 88.9, 88.2 (C-1 'and C-4'), 70.5 (C-3 '), 61.6 (C-5'), 46.2 (CH2C1), 42.0 (C-2 '), 30.0, 29.6 , 29.4, 29.2, 29.2, 28.2, 27.4 26.5, (8xCH2).

Mass spectrum (ES-MS (+ ve)): m / z 450 (20% [M + K] +), 435 (45% [M + Na] +), 412 (30% [M + H] + ), 297 (10% [Base + H] +).

Each of the products of Examples 7 and 8 were tested in vitro in tissue culture assays to verify a potent antiviral action with respect to varicella zoster virus (VZV). Acyclovir was included in the test procedure as a control. The EC50 and CC50 values were measured as described under Examples 1 to 6 above. The results are given in Table III below.

Table III Example R ECso / VZV / μM CC5o / μM 7 -C9H 8 8OH 0.4 > 200 8 - C9H18CI 0.006 > 200 Acyclovir 0.2 > 100 The product of Example 8 was further tested in vitro in tissue culture assays to verify a potent antiviral action with respect to cytomegalovirus (CMV). The cytopathogenicity induced by CMV in fibroblast cells of the human embryonic lung (HEL) was measured after infection. The EC50 and the CC50 were defined as above for VZV. Equivalent data for the known CMV active agent, dihydroxypropyl guanine (DHPG) are included in Table IV as a control. The results are given in Table IV below.

Table IV Example R EC5o / VZV / μM CCso / μM 8 -CGHisCÍ 7. 2 200 DHPG 3. 1 > 200 The product of Example 8 with R equal to -CgHißCl shows the antiviral activity with respect to CMV comparable with DHPG.

Examples 9 and 10 Examples 9 and 10 are both Comparative Examples. They are each equivalent to the compounds of Examples 1 to 8 with the exception that the R group is respectively -C3H6OH and -C4H8OH.

Example 9 3- (2'-Deoxy-β-D-ribofuranosyl) -6- (3-hydroxypropyl) -2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5- (5-hydroxy-l-pentynyl) -2'-deoxyuridine (200 mg, 0.64 mmol) in methanol / triethylamine (7: 3) (20 ml), at room temperature under an atmosphere of nitrogen, copper (I) iodide (20 mg, 0.10 mmol) is added. The reaction mixture is then heated to reflux and stirred for 4 hours. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography, using an initial eluent of ethyl acetate, changing to an eluent of ethyl acetate / methanol (7: 3) by means of a gradient. . The appropriate fractions were combined and the solvent was removed in vacuo to give the product (102 mg, 51%) as a faint yellow solid. The product was further purified by recrystallization from ethanol. ^ -rmn (dg-DMSO; 300 MHz): 8.67 (lH, s, H-4), 6.44 (lH, s, H-5), 6. 16 (lH, dd, 3J = 6.0 Hz, H-l '), 5.29 (lH, d, 3J = 4.2 Hz, 3'-OH), 5.13 (lH, m, 5'-OH), 4.59 (lH, m, alkyl-OH), 4.21 (lH, m, H-3 '), 3.90 (lH, m, H-4'), 3.64 (2H, m, H-5 '), 3.45 (2H, m, CH2CH2OH), 2.69 (2H, m, a-CH2), 2.35 and 2.06 (2H, m, H-2'a and H-2'b), 1.75 (2H, m, CH2). 13C- rmn (d6-DMSO; 75 MHz): 25.0 (CH2CH2OH), 42.0 (C-2 '), 60.5, 61.6 (C-5', CH2CH2OH), 70.5 (C-3 '), 88.2, 88.9 (C-1' and C-4 '), 100.5 (C -5), 107.2 (C-4a), 137. 6 (C-4), 154.6 (C-2), 159.1 (C-6), 172.0 (C-7a). Mass spectrum (ES-MS (+ ve)); m / z 374 (15%, [M + Cu] *), 349 (10%, [M + K] +), 333 (25%, [M + Na] *), 311 (20%, [M + H] +), 195 (100%, [base + H] *) . Elemental analysis (encont.:C, 54.23%; H . 98%; N, 8.84 :. CnH? 8 206 requires: c, 54.19%; H, 5.8%; N, 9.03%).

Example 10 3- (2'-Deoxy-β-D-ribofuranosyl) -6- (4-hydroxybutyl) -2,3-dihydrofuro [2,3-d] pyrimidin-2-one To a stirred solution of 5- (6-hydroxy-1-hexinyl) -2'-deoxyuridine (300 mg, 0.92 mmol) in methanol / triethylamine (7: 3) (20 ml), at room temperature under an atmosphere of nitrogen, copper (I) iodide (20 mg, 0.10 mmol) is added. The reaction mixture is then heated to reflux and stirred for 3 hours. The solvent is removed in vacuo and the crude product is purified by column chromatography on silica gel, using an initial eluent of ethyl acetate, changing to an eluent of ethyl acetate / methanol (8: 2) by means of a gradient. . The appropriate fractions were combined and the solvent was removed in vacuo to give the product (162 mg, 54%) as a faint yellow solid. The product was further purified by recrystallization from ethanol. ^ -rmn (d6-DMSO; 300 MHz): 8.67 (lH, s, H-4), 6.43 (lH, s, H-5), 6.16 (lH, dd, 3J = 6.0 Hz, H-l ') , 5.29 (lH, d, 3J = 4.1 Hz, 3'-OH), 5.14 (lH, t, 3J = 5 Hz, 5'-OH), 4.44 (lH, t, 3J = 5 Hz, alkyl-OH) , 4.21 (lH, m, H-3 '), 3.90 (lH, m, H-4'), 3.63 (2H, m, H-5 '), 3.41 (2H, m, CH2CH2OH), 2.65 (2H, t, 3J = 7.2 Hz, a-CH2), 2.35 and 2.04 (2H, m, H-2'and H-2'b), 1.64 and 1.46 (4H, m, 2xCH2). 13C- rmn (d6-DMSO; 75 MHz): 23.3, 27.4 (2xCH2), 31.9 (a-CH2), 41.4 (C-2 '), 60.4, 61.0 (C-5', CH2CH2OH), 69.9 (C-) 3 '), 87.6, 88.3 (C-1' and C-4 '). 100.0 (C-5), 106.6 (C-4a), 137.0 (C-4), 153.5 (C-2), 158.5 (C-6), 171.4 (C-7a). Mass spectrum (ES-MS (+ ve)); m / z 388 (10%, [M + Cu] +), 363 (10%, [M + K] +), 347 (20%, [M + Na] +), 325 (20%, [M + H] +), 209 (100%, [base + H] +). Elemental analysis (found: C, 55.34%; H, 6. 41%; N, 8.84%. C? 5H20N2O6 requires: C, 55.55%; H, 6.22%; N, 8.64%).

The products of Examples 9 and 10 were each tested in tissue culture assays in vitro to verify a potent antiviral action with respect to Varicella zoster virus (VZV). The EC50 and CC50 values were measured as above. The results are given in Table V below and include those for acyclovir as the control.

Table V Example R ECso / VZV / μM CCso 9 -C3H6OH 9. 7 > 200-C4H8OH 29 > 200 Acyclovir 0. 2 > 100 Neither the product of Example 9 nor the product of Example 10 demonstrated an antiviral activity useful against VZV with respect to the control. The low activity is attributed to the short chain length of the alkyl.

Example 11 The present example investigated the effect of altering Q in the general formula prior to sulfur. The compound prepared in terms of the above formula had R = -C9H? 9, X = 0, R '= R "= H, Q = S, Z = 0, W = H, T = 0H and T' = T" = H. The compound was prepared by analogous reactions to Example 2, using the 4'-thio nucleoside. The compound was evaluated by an in vitro tissue culture assay to verify the potent antiviral action with respect to varicella zoster virus (VZV) as described above. The results are given in Table VI below.

Table VT Example R T T 'T "Q EC5o / VZV / μM CC5o / μM eleven - . 11 -C9H19 OH H H S 0.006 93 The product of example 16 shows an extremely potent antiviral activity with respect to the varicella zoster virus.

Examples 12 to 15 Each of Examples 12 to 15 describes compounds according to the above general formula wherein X is NH. In Examples 12 to 15 according to the above general formula Z = 0, Q = 0, W = H, T = OH, T '= T "= H, R' = R" = H and R is respectively -C6Hn , -C8H? 7 and -C? 2H25.

Example 12 3- (2'-Deoxy-β-D-ribofuranosyl) -6-hexyl-3,7-dihydro-2H-pyrrolo [2,3-d] pyrimidin-2-one To a solution of the 3- (2 ') Deoxy-β-D-ribofuranosyl) -6-hexyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one in methanol (5 ml) is added 33% aqueous ammonia (5 ml). The reaction vessel is sealed and the reaction mixture is heated to about 50 ° C for 20 hours. The solvent is removed in vacuo and the crude product is purified by column chromatography using an eluent of dichloromethane / methanol (9: 1). The appropriate fractions are combined and the solvent is removed in vacuo to give the pure product as a glassy solid (48 mg, 60%). The product is then collected as a white powder by trituration with diethyl ether.

XH-rmn (d6-DMS0; 300MHz): 11.04 (lH, s, NH-7, 8.48 (lH, s, H-4), 6.24 (1H, dd, 3J = 6.4 Hz, H-l '), 5.90 (1 H, s, H-5, 5.25 (1 H, d, 3 J = 4.1 Hz, 3 '-OH), 5.10 (1 H, t, 5' -OH), 4.22 (1 H, m, H-3 '), 3.86 (1H, m, H-4 '), 3.63 (2H, m, H-5'), 2.28 and 1.99 (2H,., H-2'ß and H-2'b), 1.59 (2H, m , a-CH2), 1.27 (8H, m amp., 4? cH2), 0.85 (3H, t, CH3). 13C- rmn (d6-DMSO: 75MHz): 14.7 (CH3), 22.8, 2x28.3, 29.0 (4xCH2), 31.8 (a-CH2), 42.1 (C-2 '), 61.8 (C-5'), 70.7 (C-3 '), 87.4, 88.5 (C-1' and C-4 ') , 97.0 (C-5), 109.6 (C-4a), 135.2 (C-4), 143.2 (C-6), 154.6 (C-2), peak for 7a too small for identification.

Example 13 3- (2'-Deoxy-β-D-ribofuranosyl) -6-octyl-3,7-dihydro-2H-pyrrolo [2,3-d] pyrimidin-2-one To a solution of the 3- (2'-deoxy-β-D-ribofuranosyl) -6-octyl-2,3-dihydrofuro [2,3-d] pyrimidin-2-one in methanol (5 ml) is added ammonia. aqueous to 33% (5 ml). The reaction vessel is sealed and the reaction mixture is heated to ca. 50 ° C for 20 hours. The solvent is removed in vacuo and the crude product is purified by column chromatography using an eluent of dichloromethane / methanol (9: 1). The appropriate fractions are combined and the solvent is removed in vacuo and the product (79 mg, 79%) is isolated as a creamy powder by trituration with diethyl ether.

'H-rmn (d6-DMSO; 300 MHz): 11.13 (lH,' s, NH-7), 8.51 (1H, s, H-4), 6.26 (1H, dd, 3J = 6.4 Hz, H-1) '), 5.91 (1H, s, H-5), 5.29 (1H, m, 3' -OH), 5.14 (1H,, 5'-OH), 4.24 (1H, m, H-3 '), 3.88 (1H, m, H-4 '), 3.65 (2H, m, H-5'), 2.30 and 2.00 (2H, m, H-2'a and H-2'b), 1.60 (2H,, a-CH2), 1.24 (12H, m amp., 6xCH2), 0.85 (3H, m, CH3). 13C- rmn (d6-DMSO; 75 MHz: 16.5 (CH3), 24.6, 30.0 30.1, 31.0, 31.1, 13.2, (6xCH2), 33.8 (a-CH2), 43.9 (C-2 '), 63.5 (C-) 5 '), 72.4 (C-3'), 89.2, 90.2 (C-1 'and C-4'), 98.8 (C-5), 111.3 (C-4a), 136.9 (C-4), 144.9 ( C-6), 156.4 (C-2), 161.7 (C-7a).

Example 14 3- (2'-Deoxy-β-D-ribofuranosyl) -6-dodecyl-3,7-dihydro-2H-pyrrolo [2,3-d] pyrimidin-2-one The above compound is prepared by a method analogous to that described under Examples 12 and 13 above.

Example 15 In a compound where X is N, the effect of varying Q to S was investigated. With respect to the previous general formula, other components were R = -C8Hi9, R '= R "= H, W = H, T = 0H , Z = 0 and T '= T "= H. The compound was prepared by the analogous reactions to Example 13 using the 4'-thionucleoside. Each of the products of Examples 12 to 15 was tested in vitro in tissue culture assays to verify a potent antiviral action with respect to varicella zoster virus (VZV) as described above under Examples 1 to 4. results are given in Table VII below.

VTI Table Example R X Q ECso / VZV / μM CC50 / μM 12 -. 12 -C6H15 -NH 0 > 50 13 -C8Hi5 -NH 0 0. 15 14 -C-C 2 H 25 -NH 0 3. 7 > 200 15 -C9H19 -NH s 0. 21 200 Each of the products of Examples 13 to 15 exhibited an antiviral effect with respect to the varicella zoster virus.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (17)

2. A compound that has the formula: characterized in that: R is selected from the group comprising alkyl with C5 to
3. C20, cycloalkyl with C5 to C2o, halogens, aryl and alkylaryl, except that R is not a radical equivalent to
4. 4-FC6H5, C6F5, 4MeOC6H5, 3,
5. 5- (CF3) 2C6H4, 3.5-F2C6H4, 4- CF3C6H5 or C6H5; R 'is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogen, amino, alkylamino, dialkylamino, nitro, cyano, alkyloxy, aryloxy, thiol, alkylthiol, arylthiol, alkyl; R "is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, alkyloxy, aryloxy and aryl; Q is selected from the group comprising 0, S and CY2, wherein Y may be the same or different and is selected from H, alkyl and halogens; X is selected from the group comprising 0, NH, S, N-alkyl, (CH2) n wherein n is 1 to 10, and CY2 wherein Y may be the same or different and is selected from hydrogen, alkyl and halogens; Z is selected from the group comprising 0, S, NH, and N alkyl; U "is H and U 'is selected from H and CH2T, or U' and U" are joined to form a ring portion including Q where U '-U "together are respectively selected from the group comprising -CTH-CT 'T' - and -CT = CT y-CT '= CT'-, to provide ring portions selected from the group comprising where: T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH2 and NH3; T 'is selected from the group comprising H and halogens and wherein more than one T' is present, they may be the same or different; T "is selected from the group comprising H and halogens; W is selected from the group comprising H, a phosphate group and a pharmaceutically acceptable salt, derivative or prodrug thereof. 2. A compound according to claim 1, characterized in that R is an alkyl group with C to C2o. 3. A compound according to claim 2, characterized in that R is an alkyl group with C8 to C? 4. Four . A compound according to any of the preceding claims, characterized in that R 'and R "are each H. 5. A compound according to any of the preceding claims, characterized in that Q is O.
6. 6. A compound according to any of the preceding claims, characterized in that X is 0.
7. 7. A compound according to any of the preceding claims, characterized in that Z is 0.
8. 8. A compound according to any of the preceding claims, characterized in that U 'and U "are joined to provide the saturated ring portion including T, T' and T".
9. 9. A compound according to any of the preceding claims, characterized in that T is OH.
10. 10. A compound according to any of the preceding claims, characterized in that each of T 'and T "is H.
11. 11. A method for preparing the compounds according to any of claims 1 to 10, characterized by a 5-halo nucleoside analogue is contacted with a terminal alkyne in the presence of a catalyst, or a 5-alkynyl nucleoside is cyclized in the presence of a catalyst.
12. 12. A compound according to any of claims 1 to 10, characterized in that it is used in a treatment method.
13. 13. The use of a compound according to any of claims 1 to 9 in the manufacture of a medicament for the prophylaxis or treatment of a viral infection.
14. 14. A method of prophylaxis or treatment of viral infection, characterized in that it comprises the administration to a patient in need of such treatment, of an effective dose of a compound according to any of claims 1 to 10.
15. 15. A compound according to any of claims 1 to 10, characterized in that it is used for the manufacture of a medicament for use in the prophylaxis or treatment of a viral infection.
16. 16. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 10 in combination with a pharmaceutically acceptable excipient.
17. 17. A method of preparing a pharmaceutical composition, characterized in that it comprises the step of combining a compound according to any of claims 1 to 10 with a pharmaceutically acceptable excipient. SUMMARY OF THE INVENTION The present invention relates to a compound having the formula (I) wherein R is selected from the group comprising alkyl with C5 to C20, cycloalkyl with C5 to C20, halogen, aryl and alkylaryl; R 'is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogen, amino, alkylamino, dialkylamino, nitro, cyano, alkyloxy, aryloxy, thiol, alkylthiol, arylthiol, alkyl; R "is selected from the group comprising hydrogen, alkyl, cycloalkyl, halogens, alkyloxy, aryloxy and aryl; Q is selected from the group comprising O, S and CY2, wherein Y may be the same or different and is selected from H, alkyl and halogens; X is selected from the group comprising O, NH, S, N-alkyl, (CH2) n wherein n is 1 to 10, and CY2 wherein Y may be the same or different and is selected from hydrogen, alkyl and halogens; Z is selected from the group consisting of 0, S, NH and N-alkyl, U "is H and U 'is selected from H and CH2T, or U' and U" are bonded to form a ring portion that includes Q wherein U '-U "together are respectively selected from the group comprising -CTH-CT'T" - and -CT = CT- and -CT' = CT'-, to provide ring portions selected from the group comprising the formulas (II) and (III) wherein T is selected from the group consisting of OH, H, halogens, O-alkyl, O-acyl, -aryl, CN, NH2 and NH3; T 'is selected from the group comprising H and halogens and where more than one T 'is present, they may be the same or different; T "is selected from the group comprising H and halogens, and W is selected from the group comprising H, a phosphate group and a pharmaceutically acceptable salt, derivative or prodrug thereof shows potent antiviral activity against, for example, varicella virus zoster and cytomegalovirus.