Site specific delivery of therapeutic agents has been a goal of the pharmaceutical industry for many years. The idea of improving the safety and efficacy of therapeutic agents by such a mechanism is very attractive. Many drug-design approaches have been taken toward this end. One broad class of such targeted drugs has relied upon obtaining specific delivery by complexing cell-binding proteins or macromolecules with therapeutic agents. For example, a wide variety of reports have described the preparation of drugs conjugated with cell-targeted monoclonal antibodies, protein/liposome aggregates or viruses. An alternative approach for targeted drug delivery employs the fact that many cells themselves possess unique binding receptors on their surfaces.

Thus, targeted therapeutic agents may be designed to incorporate ligand molecules which can be bound by these cell-specific receptors. Carbohydrate binding proteins represent one important class of cell-surface receptors that pharmaceutical scientists have designed drugs to target. The first cell-surface carbohydrate binding protein was characterized about twenty years ago by Ashwell and co-workers (Ashwell, G., and Morell, A.G. (1974) Adv. Enrymol. Relat. Areas Mol. Biol. 41:99-128; Pricer, W.E., and Ashwell, G. (1971) J. Biol. Chem., 246: 4825-4833). These researchers showed that glycoproteins treated to remove terminal sialic acids on attached oligosaccharides were specifically taken up by liver cells when injected into animals. Subsequent work demonstrated that this liver-specific ligand retention is mediated by a carbohydrate-recognizing receptor, now commonly referred to as the asialoglycoprotein receptor, that occurs on the surface of hepatocytes (Lodish, H.F. (1991) Trends Biochem. Sci., 16, 374-377; Weiss, P.,

and Ashwell, G. (1989) Prog. Clin. Biol. Res. 300, 169-184).

More recently, other carbohydrate receptors have also been characterized. For example, mannose /N-acetyl-glucosamine and fucose receptors are found on cells such as macrophages and monocytes (Haltiwanger, R.S., and Hill, R.L. (1986) J.

Biol. Chem. 261:7440-7444; Ezekowitz, R.A. and Stahl, P.D. (1988) J. Cell Sci.

Suppl. 9:121-133; Haltiwanger, R.S., Lehrman, M.A., Eckhardt, A.E. and Hill, R.L. (1986), J. Biol. Chem. 261: 7433-7439). Selectin receptors, carbohydrate-binding proteins specific for Lewis or sialyl-Lewis blood group oligosaccharide structures, occur on endothelial cells, neutrophils and platelets (Munro, J. M. (1993) Eur. Heart. J. 14 suppl K:72-77).

A further class of endocytosing receptor is the cation independent mannosyl-6-phosphate (CI Man-6-P) receptor which is responsible for internalisation of exogenous molecules containing mannose 6-phosphate (Stein, M., Zjiderhand-Bleekemolen, J.E., Geuze, H., Hasilik, A., and von Figura, K. (1987) EMBO J. 6:2677-2681). cDNA cloning revealed that the CI Man-6-P and the human insulin-like growth factor II receptor are identical (Kiess, W., Blickenstaff, G.D., Sklar, M.M., Thomas, C.L., Nissley, S.P., and Sahagian, G.G. (1988) J.

Biol. Chem. 263: 9339-9344). Although the physiological role of this receptor (IGFII/Man-6-P) is incompletely understood, it is found at the site of metastatic prostate tumour growth thus making it an attractive target for anti-cancer therapy (Sehgal, Baley, P.A., and Thompson T.C. (1996) Cancer Res. 56:3359-3365). It has also been shown that breast cancer tumours express more of the IGFII/Man-6-P receptor mRNA than fibroblasts in the same tumours (Zhao Y; Escot C; Maudelonde T; Puech C; Rouanet P; Rochefort H (1993) Cancer Res.

53:2901-2905). Furthermore, IGFII/Man-6-P receptor mRNA was significantly higher in lymph node positive tumours suggesting a correlation with aggressive breast cancers (Zhu, Z., Gershon, M.D., Ambron, R., Gabel, C., and Gershon, A.A (1995) P.N.A.S. 92: 3546-3550). In the case of breast cancer there is hardly

any therapy for the more aggressively growing tumours and this receptor may provide a vehicle to deliver chemotherapy to these tumours. Envelope glycoproteins of varicella zoster virus (VZV) contain Man-6-P residues and the importance of the IGFII/Man-6-P receptor for viral entry is underscored by the observation that Man-6-P competitively and selectively inhibits infection of cells in vitro by VZV (Zhu et al, supra). Thus, an anti-VZV drug coupled to, for example, a Man-6-P receptor ligand may target it specifically to the infected cell.

In addition to their particular carbohydrate specificity, carbohydrate binding proteins can be further classified by whether or not they participate in receptor mediated endocytosis. Receptors which do not mediate endocytosis remain on the cell surface, with or without bound ligands, for comparatively long time periods, while receptors mediating endocytosis are rapidly internalized from the cell-surface via clatherin coated pits, delivering bound ligands to endocytic vesicles which in turn quickly merge with lysosomes (Trowbridge, I.S. (1991) Curr. Opin. Cell Biol.

3, 634-641; Schwartz, A.L. (1991) Targeted. Diagn. Ther., 4:3-39; Stoorvogel, W., Strous, G.J., Geuze, H.J., Oorschot, B., and Schwartz, A.L. (1991) Cell, 65:417-427; DeCourcy, K., and Storrie, B. (1991) Exp. Cell Res., 192:52-60; Haylett, T., and Thilo, L. (1991) J. Biol. Chem., 266:8322-8327).

The asialoglycoprotein, mannose/N-acetylglucosamine and mannose-6-phosphate receptors described above mediate endocytosis, whereas current evidence indicates the selectin receptors do not (Dini, L., Lentini, A., Mantile, G., Massimi, M., and Devirgiliis, L.C. (1992) Biol. Cell, 74:217-224; Munro, J. M. (1993) Eur. Heart.

J. 14 suppl K:72-77).

Many reports have described the design of therapeutic agents conjugated with carbohydrates to target receptors mediating endocytosis on specific cells. Adding glycolipids to liposomes can greatly improve the targeting of these large aggregates to specific cells (Mumtaz, S., Ghosh, P.C., and Bachhawat, B.K. (1991)

Glycobiology, 1:505-510; Barratt, G., Tenu, J.P., Yapo, A., and Petit, J.F. (1986) Biochim. Biophys. Acta, 862: 153-164). Drugs and carbohydrates have been combined on dextran scaffolds for targeting, as with AraC-dextran -galactose complexes used to deliver drugs to liver cells (Nishikawa et al. (1993) Pharmaceutical Research, 10:).

Similarly, carbohydrate-modified chitosan microspheres improve the cell targeting of encapsulated therapeutic agents to some cell types (Ohya, Y., Takei, T., Kobayashi, H., and Ouchi, T. (1993) J. Microencapsul. 10: 1-9). Antimony complexes with yeast mannan derivatives provide a therapy for Leishmania-infected macrophages (Cantos, G., Barbieri, C.L., Iacomini, M., Gorin, P.A., and Travassos, L.R. (1993) Biochem. J., 289:155-160).

Poly-lysine is employed in a range of drug designs as a scaffold for the combination of therapeutic agents and carbohydrates. For example, poly-lysine-based complexes are used for applications ranging from the targeting of DNA carriers for gene therapy (Wu, G.Y., Zhan, P., Sze, L.L., Rosenberg, A.R., and Wu, C.H.

(1994) J. Biol. Chem., 269:11542-11546s; McKee, T.D., DeRome, M.E., Wu, G.Y., and Findeis, M.A. (1994) Bioconjug. Chem., 5:306-311; Midoux, P., Mendes, C., Legrand, A., Raimond, J., Mayer, R., Monsigny, M., and Roche, A.C. (1993) Nucleic Acids Res., 21:871-878) to the selective delivery of anti-viral agents to liver cells (Fiume, L., Bassi, B., Busi, C, Mattioli, A., Spinosa, G., and Faulstich, H. (1986) FEBSLett, 203:203-206).

Finally a wide variety of glycoproteins (native, as well as ones modified to manipulate the attached carbohydrate structures), neoglycoproteins, and glycopeptides have been coupled to therapeutic agents to improve their cell targeting characteristics (Fiume, L., Di Stefano, G., Busi, C., Mattioli, A. (1994) Biochem. Phannacol., 47: 643-650; Cristiano, R.J., Smith, L.C., Kay, M.A., Brinkley, B.R., Woo, S.L. (1993) Proc. Natl. Acad. Sci. U.S.A., 90:11548-11552;

Sett, R., Sarkar, K., and Das, P.K. (1993) J. Infect. Dis., 168:994-999; Fiume, L., Busi, C., Mattioli, A., and Spinosa, G. (1988) Crit. Rev. Ther. Drug Carrier Syst., 4:265-284; Bonfils, E., Depierreux, C., Midoux, P., Thuong, N.T., Monsigny, M., and Roche, A.C. (1992) Nucleic Acids Res., 20:4621-4629; Steer, C.J., and Ashwell, G. (1986) Prog. Liver Dis., 8: 99-123; Grabowski, G.A., Barton, N.W., Pastores, G., Dambrosia, J.M., Banerjee, T.K., McKee, M.A., Parker, C., Schiffmann, R., Hill, S.C. and Brady, R.O. (1995) Ann. Inter. Med., 122:33-39; Bonfils, E., Mendes, C., Roche, A.C., Monsigny, M., and Midoux, P.

(1992) Bioconj. Chem., 3:277-284).

Another class of binding proteins of possible importance to the field of targeted therapeutics are the plasma membrane carbohydrate transporters. These proteins bind carbohydrates, usually monosaccharides, present in the fluids around the cell and transfer them directly into the cell's cytoplasm (Bell, G.I., Burant, C.F., Tekeda, J., and Gould, G.W. (1993) J. Biol. Chem., 268: 19161-19164; Gould, G.W., and Holman, G.D. (1993) Biochem. J., 295:329-341). For example, one or more types of glucose transporters occur on the surfaces of all cells (Marrall, N.W., Plevin, R., and Gould, G.W. (1993) Cell Signal., 5:667-675; Pardridge, W.M. (1993) Ann. N. Y. Acad. Sci., 27:692, 126-137; Gould, G.W., and Holman, G.D. (1993) Biochem. J., 295:329-341; Pardridge, W.M. (1991) Adv. Exp. Med.

Biol., 291:43-53; Mueckler, M. (1994) Eur. J. Biochem., 219:713-725; Yang, J., and Holman, G.D. (1993) J. Biol. Chem., 268:4600-4603). More recently there has been a suggestion that this type of enhanced pharmacology with neuropeptides may be due in part to additional cell uptake through interaction with monosaccharide transporters in the endothelium of the blood brain barrier (Polt, R., Porreca, F., Szabo, L.Z., Bilsky, E.J., Davies, P., Abbruscato, T.J., Davis, T.P., Harvath, R., Yamamura, H.I., and Hruby, V.J. (1994) Proc. Natl. Acad.

Sci. U.S.A., 91:7114-7118).

Several drug-conjugates utilising carbohydrate mediated targeting have been

investigated over the past few years. Previous inventions have involved macromolecular carriers incorporating sugar moieties such as neoglycoproteins and glycosylated polymers. These examples have successfully shown the advantages of glycotargeting, particularly for the targeting to the asialoglycoprotein receptor via complexes of galactose containing residues and for targeting to macrophages via complexes of mannose containing residues.

However, all attempts so far have not resulted in a therapeutically viable product.

The main problems associated with these products relate to their complex nature, cost, immunogenicity, difficulty in conjugation and undesirable specific tissue interaction of the carrier proteins.

In an earlier application, International Patent Application No. PCT/GB96/01519, we provided compounds specifically designed to target certain therapeutic moieties, including 5-fluorouracil, to certain cells. We have now extended this work and have now developed simple, efficient methodologies for conjugating active drug substances to enable them to be targeted to carbohydrate-specific binding proteins.

Conjugation utilises monosaccharides or other simple low molecular weight carbohydrates. The resulting glycoconjugates are metabolised in target tissues to generate the bioactive species.

Thus, according to a first aspect the present invention provides a compound of the general formula I: B-CHO (I) wherein CHO represents an optionally derivatised D-Galactose, D-Mannose, L- Fucose, D-Mannose-6-phosphate, D-6-azidogalactose or D-2-deoxy-2-N- Acetylgalactose moiety and B represents a biologically active moiety conjugatable to the monosaccharide, or a pharmaceutically acceptable salt thereof.

Compounds of the invention include both oc and anomers.

The biologically active moiety includes pharmaceutically active moieties and can be conjugated to the monosaccharide via either an oxygen atom or a nitrogen atom.

Certain compounds within the general formula I are the subject of International patent Application No. PCT/GB96 /01519 and are disclaimed from the present invention. These compounds fall within the scope of general formula Ia: wherein: R is halogen; Y is hydrogen, NH2, SH or OH; X is: wherein: either Rl or R2 is a bond, with the other being hydrogen;

either R3 or R4 is hydrogen, with the other being hydrogen, OH, OAc or NHAc; R5 is OH or OAc; either R7 or R8 is hydrogen, with the other being OH or OAc; R9 is hydrogen, CH2OH or CH2OAc; with the proviso that when R4 is OH, OAc or NHAc then R8 is hydrogen; and enantiomers of such compounds.

The compounds of the present invention are capable of binding to endocytosing carbohydrate binding proteins via the monosaccharide moiety and thus are able to target delivery of the biologically active moiety to cells which possess such proteins.

In the context of the present invention "optionally derivatised" includes the possibility that the monosaccharide has one or more "protecting groups" The skilled person will appreciate that a whole range of such groups are available and may be used.

The pharmaceutically active moiety is any moiety which can be conjugated to the monosaccharide and which, at least when so conjugated, is biologically active.

Conjugation may take place through an oxygen atom or a nitrogen atom.

As the basis of the present invention is the targeting of pharmaceutically active moieties by means of the interaction of the monosaccharide with the binding protein, there is in principle no limitation to the scope of the pharmaceutically active moiety. Practical considerations, however, may mean that certain pharmaceutically active moieties, or structurally or funtionally defined classes of pharmaceutically active moieties, will be preferred for use in the invention.

Functionally defined classes of drugs from which pharmaceutically active moieties may be derived include cytotoxic agents, antimicrobial agents, including antiviral,

antibacterial (which term includes antibiotic and antituberculosis compounds), antifungal and antiparasitic agents (which term includes antiprotozoal agents such as antimalarials).

Examples of antimicrobial agents include: antiviral agents such as zalcutabine, zidovudine, deoxynoj irimycin, penciclovir and acyclovir; antibacterial agents including pyrazinamide and isoniazid; and antiprotozoals such as pyrimethamine, sulfadiazine and sulfadoxine (for malaria and/or toxoplasmosis).

When the biologically active moiety is an antiviral or antimalarial agent then preferably CHO represents D-Mannose.

Preferred compounds within the scope of the present invention include: 6-azido-6-deoxy-1 -(5 -fluorouracil)- -D-galactopyranose; 2-pyrimethamine- 1' -D-mannopyranose; 2-Pyrimethamine-1 -D-galactopyranose; N3 -Penciclovir- 1 ' -D-mannopyranose; N3-Penciclovir-1 '-D-galactopyranose; <BR> <BR> <BR> <BR> Penciclovir-P-D-galactopyranose; <BR> <BR> <BR> <BR> <BR> Acyclovir- -D-galactopyranose; Sulfadiazine- 1 -D-galactopyranose; 1 -(5 -Fluorouracil)-6-Monophosphate-D-(x-mannopyranose; 3' -Azido-3 '-deoxy-5 ' - -D-galactopyranosylthymidine; 3'-Azido-3'-deoxy-5'-oe-D-mannopyranosylthymidine; and 3' -Azido-3 '-deoxy-5 ' - -D-(2 'deoxy-2' '-N-acetyl-galactosaminopyranosyl)- thymidine; Pyrazinamide- 1 -D-galactopyranose; 6-Deoxynoj irimycin)-1 -D-galactopyranose; and 3' -Azido-3 '-deoxy-5 ' - -L-fucopyranosylthymidine .

A particularly preferred antimalarial compound of the invention is a novel galactosyl conjugate of pyrimethamine [4-amino-5-(2-chlorophenyl)-6-ethyl-2-(l D-galactosyl)amino-pyrimidine] which is designed for preferential uptake to the liver where it can be degraded by hydrolases to the parent drug pyrimethamine.

Through this mechanism of site specific delivery, and thence site specific activation, significant (but not systemically toxic) concentrations of pyrimethamine are targeted to act against the liver stage of the parasite, thereby overcoming the significant limitation of the parent drug.

Approximately 500 million people annually become infected by malaria worldwide and about 2.7 million people die from this infection each year.

Malaria induced deaths occur mostly in children. However, immunologically 'naive' travellers (e.g. tourists, military personnel) in endemic areas are also highly susceptible to life-threatening malaria infections. Infection rates continue to increase throughout the world, mainly due to the emergence of drug-resistant variants of the parasite. Higher rates of travel across the globe also threaten to expose entirely new territories to malaria infection. For example, more than one thousand malaria cases are reported each year in the United States, approximately 1 % of which are contracted within the country's borders. Of the four malaria strains that infect humans, Plasmodium falciparum is the most common and deadly form, with a mortality rate of 1-3% and causing about 95% of malaria deaths worldwide.

Pyrimethamine is a potent inhibitor of malaria parasite dihydrofolate reductase (DHFR) an enzyme which plays a critical role in the synthesis of the thymidine used for parasite DNA synthesis. Since pyrimethamine only weakly inhibits human DHFR it can provide a parasite specific protection against malaria infection. However, the utility of pyrimethamine is now somewhat limited since resistance to this drug is emerging throughout the world, requiring it to be

formulated in combination with other antimalarial agents to be maximally effective. In addition, pyrimethamine effectively blocks the reproduction of the erythrocyte stage of the malaria parasite but is not known to have activity against liver stage malaria in vivo. Thus, pyrimethamine must be taken long after leaving a malaria-endemic area so that all liver stage parasites have matured to the pyrimethamine-sensitve blood stage.

This galactosyl conjugate, will have use in the treatment or prophylaxis of parasitic infections such as those caused by Plasmodium species and by Toxoplasma species. It will be understood that the aforementioned compound can be administered in combination with other medicaments used in the treatment of these infections, e.g. sulphonamides such as sulfadoxine or other antimalarials.

The conjugation of a carbohydrate derivative with either an amine, amide or alcohol group may be carried out by any suitable method known in the art and/or by the processes described below. The carbohydrate derivative may be either activated at the anomeric centre to allow reaction with an acceptor atom (0 or N) or may react as a free sugar. There have of course been many examples of glycosylation reactions in the chemical literature and therefore the variety of carbohydrate donor/leaving groups that would be possible to utilise is enormous (K.J. Hale and A.C. Richardson, Carbohydrates, Chapter 1 in The Chemistry of Natural Products, 1991). The choice of conditions and the selection of leaving group are determined for each case individually using modifications known in the art. The carbohydrate may be conjugated to an amino group without prior derivatisation of the anomeric centre under a variety of conditions. Simply heating the amino compound and the sugar in methanol or ethanol (with or without an acid catalyst e.g. sulphuric acid) or heating the same compounds in dimethyl sulfoxide and acetic acid will yield the desired product in many examples (D.J. Nelson et al (1985) J. Carbohydr. Chem. 4: 91-7; M.S. Shengeliya et al (1986) Zh. Org. Khim.

22: 1868-73; G. Sosnovsky and N.U.M. Rao. (1989) Carbohydr. Res. 190:c1-c2).

The product of the reaction may be separated by standard techniques including ion exchange and reverse phase column chromatography and HPLC. Alternatively the carbohydrate may be conjugated to a free alcohol group using enzymatic means. A carbohydrate derivatised at the anomeric centre with an appropriate donor group (or another carbohydrate) may be conjugated to the alcohol using a glycosidase in reverse (G. Vic and D.H.G. Crout. (1994) Tetrahedron. Asymmetry 5: 2513-2516) or alternatively the carbohydrate may be transferred to the free alcohol using a glycosyl transferase (V. Kren et al (1994) J. Chem. Soc. Perkin Trans. I:2481).

Over and above these methods of conjugation via the free carbohydrate it may be desirable to carry out the conjugation reaction using a protected sugar activated at the anomeric centre. For example, the sugar may be protected with any hydroxyl protecting group (e.g. benzyl ether, silyl ether, acetate, benzoate etc.) with a donor at the anomeric centre (e.g. halogen, thioalkyl, phenyl sulfoxide, trichloroacetimidate, n-pentenyl etc.) this donor may then require activation (e.g.

NIS/triflic acid, Lewis acid) to react with the biologically active target compound (K.J. Hale and A.C. Richardson, Carbohydrates, Chapter 1 in The Chemistry of Natural Products, 1991; M.A. Salekh et al (1989) Zh. Org. Khim. 25:2613-19) The protecting groups on the conjugated carbohydrate may then be removed by methods known in the art. When the pharmacologically active molecule is an amide it may be possible to activate it by formation of a trimethylsilyl derivative (G.

Snatzke et al (1985) Liebigs Ann. Chem. 3: 439-47), a method commonly used in nucleoside synthesis (J.B. Hobbs, (1985) Nucleosides, nucleotides and nucleic acids, Chapter 8 in The Chemistry of Natural Products (R.H. Thomson, ed.) Blackie, Glasgow). Subsequent reaction with an activated carbohydrate derivative can then afford the glycoconjugate.

As well as the methods described above where the group on the target compound to be conjugated is a primary amide [H2N(O=)C-R], the conjugation may be

undertaken by reacting the glycosyl amine derivative of the sugar with the carboxylic acid derivative of the target compound (if available), in the presence of a suitable coupling agent, e.g. DCC. This would result in the same conjugate as if the primary amide was reacted with the free sugar. E.g. Glycosyl-NH2 + HO(O = )C-R < Glycosyl-NH(O=)C-R Alternatively, to form the glycoconjugate of a drug which is a primary amide of structure [H2N(O=)C-R], the glycosyl azide derivative of the sugar can be reacted with the carboxylic acid derivative of the target compound (if available), in the presence of a trialkylphosphine. E.g. Glycosyl-N3 + Et3P + HO(O = )C-R < Glycosyl-NH(O=)C-R As described herein the compounds of the present invention are useful as therapeutic agents in view of their ability to target specific carbohydrate binding receptors. Thus, according to a second aspect of the invention there is provided a compound of the invention for use in medicine.

Usually, the compounds of the invention when so used will provided in the form of a pharmaceutical formulation, Thus, according to a third aspect the present invention provides pharmaceutical formulations comprising one or more compounds of the invention, together with one or more pharmaceutically acceptable carriers or excipients.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per dose. Such a unit may contain for example 50mg/kg to 300mg/kg, preferably 50mg/kg to 150mg/kg depending on the condition being treated, the route of administration and the age, weight and condition of the patient.

For example, in the case of the novel galactosyl conjugate of pyrimethamine [4-

amino-5 -(2-chlorophenyl)-6-ethyl-2-(1 '-D-galactosyl)amino-pyrimidine], the preferred dosage of the compound will be in the range normally used for Pyrimethamine itself. Thus, daily dosages in the range 1-25mg would be useful.

In general terms, however, the usual dose range will be 0.1-50mg per day, preferably 1-10mg per day. It is believed that due to the "targeting" effect provided by this derivative, lower dosages than are conventionally used with Pyrimethamine will be effective in the prevention and/or treatment of malaria.

Pharmaceutical compositions within the scope of the present invention may include one or more of the following; preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odourants, salts, buffers, coating agents or antioxidants. They may also contain therapeutically active agents.

Pharmaceutical compositions within the scope of the present invention may be adapted for a administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual. or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such a composition may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a carrier under sterile conditions.

Various routes of administration will now be considered in greater detail: (I) Oral Administration Pharmaceutical compositions adapted for oral administration may be provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions.

Tablets or hard gelatine capsules may comprise lactose, maize starch or

derivatives thereof, stearic acid or salts thereof.

Soft gelatine capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.

Solutions and syrups may comprise water, polyols and sugars. For the preparation of suspensions oils (e.g. vegetable oils) may be used to provide oil- in-water or water-in-oil suspensions.

(ii) Transdermal Administration Pharmaceutical compositions adapted for transdermal administration may be provided as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis (Iontophoresis is described in Pharmaceutical Research, 3(6):318 (1986)).

(iii) Topical Administration Pharmaceutical compositions adapted for topical administration may be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For infections of the eye or other external tissues, for example mouth and skin, a topical ointment or cream is preferably used. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administration to the eye include eye drops. Here the active ingredient can be dissolved or suspended in a suitable carrier, e.g. in an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouthwashes.

(iv) Rectal Administration Pharmaceutical compositions adapted for rectal administration may be provided as suppositories or enemas.

(v) Nasal Administration Pharmaceutical compositions adapted for nasal administration which use solid carriers include a coarse powder (e.g. having a particle size in the range of 20 to 500 microns). This can be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nose from a container of powder held close to the nose.

Compositions adopted for nasal administration which use liquid carriers include nasal sprays or nasal drops. These may comprise aqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of apparatus, e.g. pressurised aerosols, nebulizers or insufflators. Such apparatus can be constructed so as to provide predetermined dosages of the active ingredient.

(vi) Vaginal Administration Pharmaceutical compositions adapted for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

(vii) Parenteral Administration Pharmaceutical compositions adapted for parenteral administrations include

aqueous and non-aqueous sterile injectable solutions or suspensions. These may contain antioxidants, buffers, bacteriostats and solutes which render the compositions substantially isotonic with the blood of an intended recipient. Other components which may be present in such compositions include water, alcohols, polyols, glycerine and vegetable oils, for example. Compositions adapted for parenteral administration may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, e.g.

sterile water form injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

In other aspects the present invention provides: a) a method for the treatment of a viral infection which comprises administering to a subject an effective amount of a compound of the invention; b) a method for the treatment of cancer which comprises administering to a subject an effective amount of a compound of the invention; c) a method for the treatment of malaria which comprises administering to a subject an effective amount of a compound of the invention; d) the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of a viral infection; and e) the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of malaria.

Preferred features of each aspect of the invention are equally prferred for each other aspect mutatis mutandis.

The following examples illustrate the synthetic methods described herein. For each compound the methodologies available have been evaluated to allow the most efficient route to the target. These examples should not be construed as in any way limiting the invention.

EXAMPLE 1 Preparation of 6-azido-6-deoxv- 1 -(5-fluorouracil) - B-D-aalactonvranose a) Preparation of 6-Azido-D-galactose To commercial Zinc12 (4.0 g) in acetone (50 mL) was added conc. H2SO4 (0.14 mL) in one portion, and the mixture stirred until it became clear. D-galactose (4.0 g) was then added and the suspension stirred for 4 hours, whereupon it became a yellow coloured solution. After 4 hours at room temperature, Na2CO3 (7.0 g) was added followed by H20 (5.0 mL) and the reaction mixture stirred for a further 30 min. The resulting mixture was then extracted with ether (3x100 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 1,2:3,4-di-O-isopropylidene-oc-D- galactopyranose (5.0 g, 87%) as a pale yellow

oil.

To a stirred solution of crude 1,2:3 ,4-di-O -isopropylidene-ce-D-galactopyranose (5.0 g, 0.019 mol) in pyridine (20.0 mL) was added TsCl (4.39 g, 0.023 mol) in one portion. After 24 hours at room temperature, the reaction mixture was diluted with dichloromethane (50.0 mL) and quenched with brine (50.0 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3x200 mL). The combined organic extracts were dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude residue was purified by column chromatography using dichloromethane as eluant to give 1,2:3,4-di-O-isopropylidine-6-tosyl-a-D- galactopyranose (7.4 g, 93%) as a white solid.

To a stirred solution of 1 ,2:3,4-di-O-isopropylidene-6 -tosyl-(x-D-galactopyranose (1.7 g, 4.102 mmol) in DMF (15.0 mL) was added NaN3 (4.67 g, 0.072 mol). The reaction mixture was heated at 900C for 3 days and then cooled to room temperature. Water (10.0 mL) was added and the mixture extracted with ether (3x100 mL). The combined ethereal layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography, with EtOAc Hexanes (20:1) as eluant, to give 6-azido-6-deoxy-1 ,2:3,4-di-O-isopropylidene -a-D-galactopyranose (0.9 g, 77%) as a pale yellow oil. 'H NMR (CDCl3) 8 5.74 (1H, d, CH), 4.61 (1H, dd, CH), 4.33 (1H, dd, CH), 4.19 (1H, m, CH), 3.88 (1H, m, CH), 3.48 (1H, m, CH), 3.36 (1H, m, CH), 1.55 (3H, s, CH3), 1.44 (3H, s, CH3), 1.34 (6H, s, CH3, CH3).

b) Preparation of 12.3 .4-tetra-O-acetvl-6-azido- 6Zeoxy-D-alactopvranose 6-Azido-6-deoxy- 1,2:3 ,4-di-O-isopropylidene-oc-D-galactopyranose (0.85 g, 2.979 mmol) was treated with AcOH (90%, 25.0 mL). After 1 hour stirring at room temperature, the reaction mixture was heated at 90"C for 4 days. The reaction

mixture was then co-evaporated from toluene (3x100 mL) to obtain crude 6-azido-6-deoxy- D-galactopyranoside (0.59 g, 97%) as a colourless and viscous oil.

The crude residue (0.59 g, 2.876 mmol) was dissolved in pyridine (5.0 mL) and Ac2O (5.0 mL). After 3.5 hours at room temperature, the solvent was removed in vacuo and the residue co-evaporated from toluene (3x100 mL). The residue was purified by column chromatography, with CH2Cl2 : MeOH (50:1 < 30:1) as eluant, to give 1,2,3,4-tetra- O-acetyl-6-azido-6-deoxy-D-galactopyranose (0.98 g, 91%) as a white solid.

'H NMR (CDCl3) 6 5.69 (1H, dd, CH), 5.05 (1H, dd, CH), 4.20 (1H, m, CH), 3.88 (1H, m, CH), 3.48 (1H, m, CH), 3.36 (1H, m, CH), 3.19 (1H, m, CH), 1.93-2.15 (12H, s, (CH3)4).

c) Preparation of 6-azido-6-deoxy-1-(5-fluorouracil) -o-D-valactopyranose To a solution of 5-fluorouracil (0.34 g, 2.625 mmol) and 1,2,3,4-tetra-O-acetyl-6-azido-6-deoxy-α- D-galactopyranose (0.98 g, 2.625 mmol) in MeCN (30.0 mL) at 0°C under argon was added HMDS (0.44 mL, 2.10 mmol) followed by TMSCl (0.27 mL, 2.10 mmol) in one portion. After 5 min, SnCl4 (0.37 mL, 3.15 mmol) was added dropwise to the above mixture at 0°C over a 3 min. period. The reaction mixture was stirred at room temperature for 4 days and quenched with saturated aqueous NaHCO3 and extracted with EtOAc (4x100 mL). The organic layers were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using CH2Cl2 : MeOH (150:1 -> 75:1) as eluant to give 2,3 ,4-tri-O-acetyl-6-azido- 6-deoxy-1-(5-fluorouracil)- -D-galactopyranose (1.0 g, 84%) as a pale yellow oil.

'H NMR (CDCl3) 6 8.23 (1H, s, CH), 7.41 (1H, d, NH), 5.78 (1H, dd, CH), 5.49 (1H, d, CH), 5.20 (2H, m, CH2), 4.00 (1H, dd, CH), 3.49 (1H, ddd, CH), 3.31 (1H, ddd, CH), 2.23 (3H, s, CH3), 2.00 (6H, s, CH3, CH3).

To a solution of 2,3,4-tri-O-acetyl-6-azido-6-deoxy- 1-(5-fluorouracìl)- - D-galactopyranose (0.10 g) in MeOH (20.0 mL) was added NaOMe (1.OM in MeOH, 1.0 mL) at room temperature. After 1 hour the reaction mixture was neutralised with Dowex 50X8-400 ion exchange resin, filtered, and concentrated to dryness. Purification on a C18 column and eluting with water afforded 6-azido-6-deoxy-1-(5-fluorouracil)- -D-galactopyranose (24.0 mg, 34%) as a white solid. mp: 106-109°C; MS (FAB) calcd. for CloHl2No6F + Na 340.1, found 339.693 (MNa+); 'H NMR (D20) 6 8.08 (1H, d, CH), 5.68 (1H, dd, CH), 4.09 (2H, m, CH, CH), 3.90 (2H, m, CH2), 3.68 (1H, m, CH), 3.57 (1H, m, CH).

EXAMPLE 2 Preparation of 4-Amino-5-(2-chlorophenvl)-6-ethyl-2-( 1 '-D-mannosvl)- aminopvrimidine To a suspension of pyrimethamine (1.0 g, 4.021 mmol) and D(+)-mannose (1.52 g, 8.444 mmol) in toluene (5.0 mL) was added acetic acid (0.1 mL, 2.051 mmol) and DMSO (1.2 mL) at room temperature. The reaction mixture was then heated at 80-90°C for 7 days, whereupon the solvent was removed in vacuo. The residue

was co-evaporated from toluene (3x100 mL), and purified by column chromatography using CH2Cl2 : MeOH (20:1 < 15:1 -> 10:1 -> 5:1) as eluant to give the title compound along with unreacted D(+)-mannose. The mixture was further purified on a C18 column eluting with water to remove the unreacted D(+)-mannose. Further elution with MeOH : H2O 1:1 -> 4:1 -> 10:1 gave 2-pyrimethamine-1'-D-mannopyranose (0.202 g, 12%) as a cream solid.

mp: 140-143°C; MS (FAB) calcd. for C,8H24N405Cl + Na 434.1, found 433.655 (MNa+); 'H NMR, (CD3OD) 6 7.43 (2H, dd, Ar-CH2), 7.23 (2H, dd, Ar-CH2), 5.40 (1H, d, CH), 3.82-3.40 (6H, M, CH, CH2), 3.25 (2H,d, NH2), 2.24 (1H, M, NH), 1.00 (5H, m, C2H5).

EXAMPLE 3 Preparation of 4-Amino-5-(2-chlorophenvl)-6-ethyl-2-(1 '-D-alactosvl)- aminopvrimidine To a suspension of pyrimethamine (1.0 g, 4.021 mmol) and D-galactose (1.52 g, 8.444 mmol) in acetic acid (0.1 mL, 2.051 mmol) was added DMSO (1.2 mL) at room temperature. The reaction mixture was heated at 90-100°C for 7 days after

which the solvent was removed in vacuo. The residue was co-evaporated from toluene (3x100 mL), and purified by column chromatography using CH2Cl2 MeOH (8:1 -> 6:1) as eluant to give the crude product. This material was further purified on a prep TLC eluting with CH2Cl2 : MeOH (20:1) (8 elution) to give 2-pyrimethamine-1 '-D -galactopyranose (0.218 g, 13%) as an off-white solid. mp: 138-141°C; MS (FAB) calcd. for C,8H24N405CI 411.132, found 411.168 (MH+) EXAMPLE 4 Preparation of N3-Penciclovir-1'-D-mannopyranose To a suspension of penciclovir (1.0 g, 3.949 mmol) and mannose (1.49 g, 8.292 mmol) in toluene (5.0 mL) was added acetic acid (0.1 mL, 1.97 mmol) and DMSO (1.2 mL) at room temperature. The reaction mixture was heated at 90-100°C for 7 days after which the solvent was removed in vacuo. The residue was co-evaporated from toluene (3x100 mL) and purified by column chromatography, using CH2Cl2 MeOH (30:1 o 20:1 -> 10:1 -> 5:1) as eluant, to give the title compound along with unreacted D(+)-mannose. The mixture was further purified on a C18 column eluting with water to remove the unreacted D(+)-mannose. Further elution with H2O : MeOH (5:1 o 3:1 -> 1:1) gave 3-penciclovir-1'-mannopyranose (0.584 g, 36%) as a pale yellow solid. mp: 112-115°C MS (FAB) calcd. for C,6H25N508 415.4, found 415.785 (M+) and also calcd. for

C,6H25N508 + Na 438.4, found 439.785 (MNa+); 'H NMR (D2O) 6 7.92 (1H, d, Ar-CH), 5.55 (1H, d, CH), 4.37-3.60 (12H, m, CH, N-CH2, (CH2OH)2), 2.10-1.99 (3H, m, CH2, CH).

EXAMPLE 5 Preparation of N3-Penciclovir-1'-D-galactopyranose To a suspension of penciclovir (1.0 g, 3.949 mmol) and D-galactose (2.85 g, 15.8 mmol) in acetic acid (5.0 mL) was added DMSO (5.0 mL) at room temperature.

The reaction mixture was then heated at 80-90°C for 7 days after which the solvent was removed in vacuo. The residue was co-evaporated from toluene (3x100 mL), <BR> <BR> <BR> <BR> and purified by column chromatography using CH2Cl2 : MeOH (30:1 < 20:1 -> - 10:1 -> 5:1) as eluant to give the title compound along with the unreacted D-galactose. The mixture was further purified on a C18 column eluting with water to remove the unreacted D-galactose. Further elution with H2O : MeOH (5:1 -> 3:1 -> 1:1) gave 3-penciclovir-1' -D-galactopyranose (0.483 g, 30%) as a pale yellow solid. mp: 108-110°C MS (FAB) calcd. for C,6H25N5O8 + Na 438.4, found 438.891 (MNa+); 'H NMR (D2O) 6 7.92 (1H, d, Ar-CH), 4.38-3.60 (12H, m, CH, N-CH2, (CH2OH)2), 2.08-1.95 (3H, m, CH2, CH).

EXAMPLE 6 Preparation of Penciclovir-D-D-9alactopvranose A solution of penciclovir (10mug, 39.5pmol) and 1-p-nitrnphenol--D- galactopyranoside (60mg, 0.197mmol) in dimethylformamide (DMF) (0.4ml) was added to a mixture of -galactosidase (30mg, 132U; from aspergillus oryzae) and sodium phosphate buffer (0.4ml; 0.1M, pH5.0). After standing at rt for 18h the DMF and water were evaporated under reduced pressure (coevaporating with water to remove excess DMF), purified on a C18 reverse phase column (unreacted galactose eluting in water followed by product in 20% methanol/water) and then on

reverse phase HPLC (product eluting in 20% methanol/water). Freeze dried to give the desired product (2mg, 12%).

'H NMR (D2O): 6 1.8-1.90 (1H, m, CH), 1.90-2.0 (2H, m, CH2), 3.5-3.58 (1H, m, CH), 3.60-3.7 (5H, m, CH or CH2), 3.7-3.8 (2H, m, CH), 3.9-4.0 (2H, m, CH), 4.154.22 (2H, m, CH), 4.34.38 (1H, d, CH), 7.85 (1H, s, =CH).

EXAMPLE 7 Preparation of Acyclovir- -D-galactopyranose A solution of acyclovir (lOmg, 39.6mol) and 1-p-nitrophenol- -D- galactopyranoside (60mg, 0.19mmol) in dimethylformamide (DMF) (0.4ml) was added to a mixture of -galactosidase (30mg, 132U; from Aspergillus oryzae) and sodium phosphate buffer (0.4ml; 0.1M, pH5.0). After standing at rt for 18h the DMF and water were evaporated under reduced pressure (coevaporating with water to remove excess DMF), purified on reverse phase HPLC (eluting unreacted galactose in water then product eluting in 20% methanol/water). Freeze dried to give the desired product (lmg, 8%).

'H NMR (D2O): 6 3.45-3.5 (1H, m, CH), 3.6-3.65 (2H, m, CH), 3.75-3.8 (2H, m, CH), 3.8-3.85 (2H, m, CH), 3.9 (1H, m, CH), 4.0-4.05 (2H, m, CH), 4.38 (1H, d, CH), 5.55 (2H, s, CH), 7.95 (1H, s, =CH).

EXAMPLE 8 Preparation of Sulfadiazine- 1 -Daalactotyranose To a suspension of sulfadiazine (4.0 g, 15.9 mmol) and D-galactose (2.80 g, 15.9 mmol) in acetic acid (15.0 mL) was added DMSO (15.0 mL) at room temperature. The reaction mixture was heated at 800C for 24 hours, after which the solvent was removed in vacuo. The residue was co-evaporated from toluene (2x200 mL), and purified by column chromatography, using CH2Cl2 : MeOH (20: 1 10:1 3:1) as eluant, to give the title compound along with the unreacted D-galactose.

The mixture was further purified on a C18 column eluting with water to remove the unreacted D-galactose. Further elution with H2O : MeOH (5:1 3:1) gave sulfadiazine-1-D-galactopyranose (0.400 g, 6%) as a white solid. mp: 143-145 "C MS (FAB) calcd. for C,6H20N4O7S 412.4, found 412.915 (M+) 'H NMR, D2O 6 8.40-8.35 (2H, d, Ar-H), 7.80-7.78 (2H, d, Ar-H), 6.90-6.88 (1H, dd, Ar-H), 6.80-6.78 (2H, d, Ar-H), 4.514.48 (1H, d, CH), 3.85 (1H, d, CH), 3.70-3.58 (4H, m, CH), 3.54-3.50 (1H, dd, CH).

EXAMPLE 9 Preparation of 1-(5-Fluorouracil)-6-Monophosphate-D-α-mannopvranose Pyrophosphoryl chloride (2.62 mL, 0.0188 mol) was added dropwise over 1 min to a cooled (0-5°C), stirred solution of 1-(5-fluorouracil)-a-D-mannopyranose (1.1 g, 3.76 mmol) in m-cresol (40.0 mL). After stirring for 5 hours at OOC, the reaction mixture was allowed to stand at 4°C for 16 hours. The resulting clear yellow solution was then poured onto ice water (200 mL) and extracted with ether (4x100 mL). The aqueous layer was separated and concentrated in vacuo. The residue was purified on an activated charcoal column eluting with water to remove by-products and then eluting with EtOH/NH3/H20 (30:2:68) to obtain the crude product. The latter material was further purified by passage through Sephadex [water NH4HC03 (0. iM)] to give 1-(5-fluorouracil)-6- monophosphate-D-a-mannopyranose (0.93 g, 61%) as a white solid. mp: 110-112"C MS (FAB) calcd. for CloHl4N2OloFP + Na 429.3, found 428.863 (MNa+); 'H NMR (D2O) 6 8.05 (1H, d, CH), 5.98 (1H, dd, CH), 4.53 (1H, m, CH), 4.28-4.20 (3H, m, CH), 4.11 (1H, m, CH), 4.00 (1H, t, CH).

EXAMPLE 10 Preparation of 3'-Azido-3'-deoxv-5 ' -8-D-galactopvranosvlthymidine (a) A mixture of 3'-azido-3'-deoxythymidine (50mg, 0.187mmol), methyl- 2,3,4,6-tetra-O-acetyl-1-thio- -D-galactopyranoside (92mg, 0.243 mmol) and molecular sieves was stirred in acetonitrile/propionitrile (4ml, 50:50), under argon for 20 min. The mixture was cooled to -70°C and N-iodosuccinamide (59mg, 0.262mmol) added followed by triflic acid (1 drop). The reaction was slowly warmed to -20°C over 2h, quenched with triethylamine and warmed to rt.

The reaction mixture was diluted with ethyl acetate (30ml) filtered through celite and then washed successively with sodium bicarbonate (25ml, saturated), citric acid (25ml,saturated) and brine (25ml). The organic layer was dried (sodium sulphate), evaporated under reduced pressure and the crude product purified by flash chromatography (5 % methanol/dichloromethane).

The above product was dissolved in methanol and sodium methoxide (5 drops, 1 .0M solution in methanol) added. After 1h the methanol was evaporated under reduced pressure and the product purified on a C18 column, eluting (water) to give a product that was further purified using reverse phase HPLC and freeze dried to give the desired product (15mg, 20%).

Mp llO"C (dec) 'H NMR (D2O): 6 1.98-2.0(3H, s, CH3), 2.50-2.62(2H, m, CH2), 3.6-4.0(7H, m, CH or CH2), 4.22-4.3(2H, m, CH or CH2), 4.5-4.55(2H, m, CH or CH2), 6.22-6.3(1H, t, CH), 7.85(1H, s, =CH).

(b) A solution of 3'-azido-3'-deoxythymidine (10mug, 0.037mmol) and 1-p- nitrophenol- -D-galactopyranoside (56mg, 0.187mmol) in dimethylforamide (DMF) (0.4ml) was added to a mixture of -galactosidase (30mg, 132U; from Aspergillus oryzae) and sodium phosphate buffer (0.4ml; 0. IM, pH5.0). After standing at rt for 18h the DMF and water were evaporated under reduced pressure (co-evaporating with water to remove excess DMF), purified on reverse phase HPLC (product eluting in 20% methanol/water) and freeze dried to give the desired product (2mg, 12%).

'H NMR (D2O): 6 1.98-2.0(3H, s, CH3), 2.50-2.62(2H, m, CH2), 3.6-4.0(7H, m, CH or CH2), 4.22-4.3(2H, m, CH or CH2), 4.5-4.55(2H, m, CH or CH,), 6.22-6.3(1H, t, CH), 7.85(1H, s, =CH).

EXAMPLE 11 Preparation of 3' -Azido-3 '-deoxy-5' --D-mannoovranosvlthvmidine A mixture of 3' -azido-3 '-deoxythymidine (50mg, 0.1 87mmol), methyl-2,3,4,6- tetra-O-acetyl-1-thio- -D-mannopyranoside (92mg, 0.243 mmol) and molecular sieves was stirred in acetonitrile/propionitrile (4ml, 50:50), under argon for 20 min. The mixture was cooled to -700C and N-iodosuccinamide (59mg, 0.262mmol) added followed by triflic acid (1 drop). The reaction was slowly warmed to -20°C over lh, quenched with triethylamine and warmed to rt.

The reaction mixture was diluted with ethyl acetate (30ml) filtered through celite and then washed successively with sodium bicarbonate (25ml, saturated), citric acid (25ml,saturated) and brine (25ml). The organic layer was dried (sodium

sulphate), evaporated under reduced pressure and the crude product purified by flash chromatography (5 % methanol/dichloromethane).

The above product was dissolved in methanol and sodium methoxide (5 drops, 1 .0M solution in methanol) added. After 1h the reaction was neutralised with Dowex H+ resin, filtered and evaporated under reduced pressure and the product purified on a C18 column, eluting (water) to give a product that was further purified using reverse phase HPLC and freeze dried to give the desired product (28mg, 35%).

Mp. 145"C (dec) 'H NMR (D2O): 6 1.85-1.98(3H, s, CH3), 2.45-2.62(2H, m, CH2), 3.6-4.0(8H, m, CH or CH2), 4.2-4.22(1H, m, CH or CH2), 4.45-4.55(1H, m, CH or CH2), 5.95(1H, s, CH), 6.22-6.3(1H, t, CH), 7.8(1H, s, =CH).

EXAMPLE 12 Preparation of 3'-Azido-3'-deoxv-5 '-13-D-(3''deoxv-2' '-N-acetvl- aalacto sam inopvranosvl) -thvmidine A mixture of 3'-Azido-3'-deoxythymidine (22mg, 0.082mmol) and 2-deoxy-N- (tetra-chlorophthalamido)- 1,2,4,6-tetra-acetyl- -D-galactopyranoside (76mg, 0.123mmol) and molecular sieves in dichlrormethane (DCM) (2ml) was stirred for 15min, under argon. The reaction was cooled in an ice bath and boron

trifluoroetherate (BF3.Et2O) (0.02ml, 0.123mmol) added. After 2h a further 0.05ml of BF3.Et2O was added and the reaction stirred at rt for 18h.

The reaction mixture was filtered (celite) and poured onto ice water (20ml).

DCM (30ml) was added and the organic layer separated and washed with sodium bicarbonate (20ml, saturated) and brine (20ml). The organic layer was dried (sodium sulphate) and evaporated under reduced pressure and purified by flash chromatography (60% ethyl acetate/pet.ether) to give the intermediate (12mg).

The above intermediate was dissolved in methanol (2ml) and ethylenediamine (1 drop, 4 equiv.) added at rt. Warmed to 35"C for 1h and then evaporated under reduced pressure. This product was dissolved in pyridine (1 ml), acetic anhydride added (1 ml) at rt and stirred for 18h.

After evaporation of the pyridine and acetic anhydride (co-evaporation with toluene) the product was dissolved in methanol and treated with sodium methoxide (5 drops, 1 .0M solution) at rt for 1.5h. The reaction was neutralised with Dowex H+ resin, filtered and evaporated under reduced pressure.

Purification on reverse phase HPLC (30% methanol/water) and freeze drying gave the desired product (4mg, 58%) Mp. 145"C (dec) lH NMR (D2O): 6 2.0(3H, s, CH3), 2.2(3H, s, CH3), 2.4-2.45(1H, m, CH), 2.45-2.5(1H, m, CH), 3.7-3.9(6H, m, CH or CH2), 4.0(1H, d, CH), 4.2(1H, m, CH), 4.25(1H, d, CH), 4.4(1H, m, CH), 4.5(1H, d, CH), 6.3(1H, t, CH), 7.88(1H, s, =CH).

EXAMPLE 13 Preparation of Pyrazinamide-1-D-alactopvranose To a solution of 2-pyrazinecarboxylic acid (37.0mg, 0.295 mmol) and 2,3,4,6- tetra-O-acetyl-1-azido-1-deoxy-D-galactopyranose (0. lOg, 0.268mmol) in

dichloromethane (1.owl) was added triethylphosphine (1.OM solution in THF, 0.3ml, 0.295mmol) under an argon atmosphere at room temperature. The reaction mixture was stirred at rt for 30h. After addition of water (10.Oml) the reaction mixture was extracted with ethyl acetate (3x50ml). The organic extracts were washed with water (1x50ml) and brine (1x50ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography using CH2Cl2:MeOH (90:1 < 75:1) as eluant, to give pure 2,3,4, 6-tetra-O-acetyl- 1 -pyrazinamide- 1 -deoxy-D-galactopyranose (57mg, 47 %) as a colourless oil.

'H NMR, (500 MHz, CDCl3) 6 11.72 (lah, d, NH), 9.50 (1H, d, CH), 8.86 (1H, d, CH), 8.58 (1H, d, CH), 5.50 (2H, dd, CH), 5.20 (1H, dd, CH), 4.92 (1H, dd, CH), 4.10-4.05 (3H, m, CH, CH2), 2.00-2.10 (12H, s, CH3).

To a solution of 2,3,4, 6-tetra-O-acetyl-l -pyrazinamide-l -deoxy-D- galactopyranose (15mg, 0.033mmol) in MeOH (5.0ml) was added NaOMe (1.OM solution in MeOH, 2 drops) at room temperature. After 1 hour the reaction mixture was neutralised with Dowex 50X8-400 ion exchange resin, filtered and concentrated to dryness. Purification on a C18 column and eluting with water afforded pyrazinamide-1-D-galactopyranose (1.Omg, 11 %) as a white solid.

EXAMPLE 14 Preparation of (6 or other derivative-Deoxvnoiirimvcin) -1-D-aalactopvranose To a solution of N-Fmoc deoxynojirimycin (0.25g, 0.649mmol), 2,3,4,6-tetra-0- acety l- 1 -thiomethyl-1 -deoxy-D-galactopyranose (0 .246g, 0.649mmol) and molecular sieves (4A, 0.2g) in MeCN (10ml) was added N-iodosuccinimide (0. 146g, 0.649mmol) and trifluoromethanesulfonic acid (i drop) at -400C under argon. The reaction mixture was gradually allowed to warm to -20°C and then quenched with saturated aqueous sodium thiosulphate. The resulting mixture was extracted with dichloromethane (3x100ml). The combined organic layers were washed with brine (50.0ml) and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, using CH2CI2:MeOH (150:1 < 140:1 < 120:1 < 100:1 -> 90:1 -> 80:1 -> 60:1 -> 50: 1) as eluant, to give four different 2,3,4,6-tetra-O-acetyl-1-D-galactopyranosyl derivatives of N-Fmoc-deoxynojirimycin as a white solid.

To a solution of any of the above 2,3,4,6-tetra-O-acetyl-1-D-galactopyranosyl derivatives of N-Fmoc-deoxynojirimycin (9mg) in MeOH (5.Oml) was added NaOMe (1.OM solution in MeOH, 0.2ml) at room temperature. After 1 hour the reaction mixture was neutralised with Dowex 50X8-400 ion exchange resin, filtered and concentrated to dryness. Purification on a C18 column and eluting with water afforded the 1-D-galactopyranosyl derivative of deoxynojirimycin (1.Omg) as a white solid.

EXAMPLE 15 Preparation of 3'-Azido-3'-deoxy-5'-( -L-fucopyranosylthymidine A mixture of 3' -azido-3 '-deoxythymidine (50mg, 0.1 87mmol), methyl-2,3,4,6- tetra-O-acetyl-1-thio- -L-fucopyranoside (78mg, 0.243 mmol) and molecular sieves was stirred in acetonitrile/propionitrile (4ml, 50:50), under argon for 20 min. The mixture was cooled to -70°C and N-iodosuccinamide (59mg, 0.262mmol) added followed by triflic acid (1 drop). The reaction was slowly

warmed to -20°C over 2h, quenched with triethylamine and warmed to rt.

The reaction mixture was diluted with ethyl acetate (30ml) filtered through celite and then washed successively with sodium bicarbonate (25ml, saturated), citric acid (25ml,saturated) and brine (25ml). The organic layer was dried (sodium sulphate), evaporated under reduced pressure and the crude product purified by flash chromatography (5 % methanol/dichloromethane).

The above product was dissolved in methanol and sodium methoxide (5 drops, 1 .0M solution in methanol) added. After 1h the methanol was evaporated under reduced pressure and the product purified on a C18 column, eluting (water) to give a product that was further purified using reverse phase HPLC and freeze dried to give the desired product (8mg, 10% ; 5mg ~anomer/ 3mg a~anomer) Mp. 140"C (dec) (a) p-anomer 'H NMR (D2O): 6 1.2(3H, s, CH3), 1.85(3H, s, CH3), 2.4-2.5(2H, m, CH2), 3.5(1H, m, CH), 3.6(1H, m, CH), 3.7-3.8(2H, m, CH), 3.95(1H, m, CH), 4.05(1H, m, CH), 4.15(1H, m, CH), 4.2-4.25(2H, m, CH), 6.2-6.25(1H, t, CH), 7.58(1H, s, =CH).

(b) a-anomer 'H NMR (D2O): 6 1.2(3H, s, CH3), 1.9(3H, s, CH3), 2.2-2.3(2H, m, CH2), 2.35-2.4(2H, m, CH), 3.5(1H, t, CH), 3.6(2H, m, CH), 3.7-3.8(2H, m, CH), 3.9-4.0(2H, m, CH), 4.15(1H, m, CH), 4.2(1H, d, CH), 6.2(1H, m, CH), 7.6(1H, s, =CH).

EXAMPLE 16 4-Amino-5-(2-chlorophenvl)-6-ethyl-2-(1'-D-galactoSvl)- aminopvrimidine A solution of pyrimethamine (1.0 g, 4.021 mmol) and D-galactose (1.45 g, 8.042

mmol) in DMSO (5.0 mL) was heated with acetic acid (1.5 mL) at 800C for 4 days. After this time the reaction mixture was concentrated in vacuo. Column chromatography (silica gel, CH2C12-MeOH 20:1 10:1) removed excess DMSO and unreacted pyrimethamine leaving the product contaminated with unreacted D- galactose. This was further purified by reverse phase chromatography (cm 8, water water-methanol 1:1) to give 4-amino-5-(4-chlorophenyl)-6-ethyl-2-(l '-D- galactosyl)-aminopyrimidine (0.84 g, 51%) as a colourless solid after freeze drying.

mp: 137-1390C; 1H NMR, CD30D 7.48 (2H, dd, Ar-CH2), 7.20 (2H, dd, Ar-CH2), 5.16 (1H, d, CH), 4.00-3.50 (6H, multiplets, CH, CH2), 2.24 (1H, q, CH2CH3), 1.00 (3H, t, CH2CH3).

EXAMPLE 17 In vitro efficacy Freshly extracted mouse livers were digested with collagenase to free the cells from the tissue matrix. The cells were subjected to a low speed centrifugation and then spread on a percoll gradient to yield essentially pure, viable hepatocytes. The hepatocytes were dispensed into welled microscope slides at a density of 100,000 cells per well. The cells were cultured for 24 hours in EMEM media with 10% fetal calf serum. At the end of the incubation the hepatocytes were essentially confluent. The hepatocytes were overlayed in fresh media containing the test compound. After 5 hours P. yoelii sporozoites were isolated from mosquitoes and then overlayed on the monolayer of hepatocytes in media still containing the test compound. The sporozoite-overlayed hepatocytes were re-cultured for an additional 3 hours. Dexamethasone was added in the media for the remainder of the experiment.

Next the cells were washed to remove non-internalised sporozoites. The cells were incubated for 24 hours and then incubated for an additional 24 hours in the presence of the test compound. Finally, the cells were fixed and then overlayed with NYLS-3, a monoclonal antibody which recognises an antigen on the liver stage malaria schizonts. A fluorescinated secondary antibody was added and excess was washed to remove unbound material. The wells were scored via fluorescence microscopy for the number of schizonts visible in the hepatocytes in each well. The results obtained with pyrimethamine and the compound of Example 16 are shown in the following table.

Compound Conc., pM No. Of Schizonts Mean % Inhibition Control 0 32, 45, 34 37 0 Pyrimethamine 50 31, 20, 24 25 32 Example 16 50 5, 6, 6 5.6 84 Example 18 Preparation of 9- -D-Galactopyranosyl-6-thiopurine 6-Chloropurine (1.0g, 6.47 mmol) was suspended in a solution of a, -D- galactose pentaacetate (2.5 g, 6.47 mmol) under argon in 40 mL of anhydrous acetonitrile. After 3 min, SnC14 (1.5 mL, 13.0 mmol) was added and the resulting clear solution allowed to stir at room temperature for 18 hours before heating to 800C for 5 hours. The reaction mixture was then concentrated to a small volume (ca. 15 mL), and NaHCO3 (3.8 g, 45 mmol) and distilled H20 (14 mL) were added. When the vigorous evolution of CO2 had ceased, the mixture was extracted with CH2C12 (9 x 100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using CH2C12: MeOH (100:1 < 80:1) as the eluant. 6- Chloropurine 9- -D-galactopyranosyl-tetra-O-acetate (2.17 g, 69%) was obtained

as a white foam.

To a stirred solution of 6-chloropurine 9- -D-galactopyranosyl-tetra-O-acetate (2.17 g, 4.47 mmol) in EtOH (100 mL) was added thiourea (580 mg, 7.62 mmol) in one portion. The reaction mixture was heated at 100"C for 42 hours and then cooled to room temperature. Evaporation in vacuo at 30"C (bath temperature), allowed a white solid to separate from the reaction mixture. The solid was then collected by filtration and washed with EtOH to give 9- -D-galactopyranosyl- tetra-O-acetate 6-thiopurine (1.59 g, 74%) as colourless crystals.

Melting Point: 214-215°C; 'H NMR (300 MHz, DMSO) 6 13.82 (1H, br s, NH), 8.44 (1H, s, CH), 8.22 (1H, s, CH), 6.05 (1H, s, CH), 5.64 (1H, s, CH), 5.49 (1H, s, CH), 5.36 (1H, s, CH), 4.57 (1H, s, CH), 3.98-4.07 (2H, m, CH2), 2.17 (3H, s, CH3), 1.92 (6H, s, CH3, CH3), 1.73 (3H, s, CH3).

To a solution of 9- -D-galactopyranosyl-tetra-O-acetate 6-thiopurine (400 mg, 0.83 mmol) in MeOH (5.0 mL) was added NaOMe (1.OM solution in MeOH, 1.5 mL) at room temperature. After 2 hours the reaction mixture was neutralised with Dowex 50X8-400 ion exchange resin, filtered, and concentrated to dryness.

Purification by C18 chromatography eluting with water afforded 9- -D- galactopyranosyl-6-thiopurine (185 mg, 71%) as a white solid.

Melting Point: 190-191°C; 'H NMR (300 MHz, D2O) 6 8.47 (1H, s, CH), 8.27 (1H, s, CH), 5.47 (1H, d, CH), 4.12 (1H, t, CH), 3.93 (1H, d, CH), 3.85 (1H, t, CH), 3.72 (1H, dd, CH), 3.65 (2H, d, CH2).