MXPA97010529A - Compounds therapeuti - Google Patents

Abstract

Compounds of the formula (I) are described, wherein R is halogen, Y is hydrogen, NH 2, SH or OH, X is (11) wherein either R 1 or R 2 is a bond, with the other being hydrogen; 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, Rg is hydrogen, CH2OH or CH2OAc; condition that when R4 is OH, OAc or NHAc then R8 is hydrogen, and anantiomers of said compounds. Also provided are pharmaceutical formulations comprising said compounds, their use in the treatment of various disease states and methods of treatment employing the compounds

Description

THERAPEUTIC COMPOUNDS The present invention relates to novel pyrimidine compounds, pharmaceutical formulations comprising said compounds, their use in medical treatment, particularly the treatment of cancer and pathogen infections. Pyrimidine bases are a vital component of many current therapeutic products eg, 5-fluorouracil and 5-flucytosine. 5-fluorouracil (5-FU) was introduced as an anticancer agent rationally synthesized more than 30 years ago and has still been widely used in the treatment of many cancers (Duschinsky, et al., J. Am. Chem. Soc, 79: 4559 (1957), Heidelberger, et al., Nature, 179: 663 (1957)). The utility of 5-FU however is low due to the toxic side effects, a common problem with anti-carcinogenic agents. A number of 5-FU derivatives have been synthesized for years, which are active metabolites (Heidelberger, Cancer Research, 30: 1549 (1970), Burchenal, and others, Ann. NUY, Acad. Sci., 255: 202 ( 1975), Saneyoshi et al., Chem Pharm. Bull., 26 (10): 2990 (1978)) or simple prodrugs that act as depository forms of 5-FU (Holshouser, et al., J. Med. Chem., 28: 242 (1985), Hiller, et al., Dokl Akad. Nauk, USSR, 176: 332 (1967), Ueda, et al., Chem. Pharm. Bull., 30, (1): 125 (1982)). Some of these compounds provide less toxic alternatives to 5-FU and have found a place in clinical practice. However, these less toxic compounds are absorbed by different types of tissues and consequently still exhibit side effects related to the dose, adverse, significant. Therefore, it has been a long-standing goal of the pharmaceutical industry to improve the safety and efficacy of such therapeutic agents by improving tissue selectivity and tissue direction. Many drug design approaches have been made for this purpose. A wide class of said white drugs has been supported in obtaining specific supply by complexing the cell-binding proteins or macromolecules with therapeutic agents. For example, a wide variety of reports have described the preparation of drugs conjugated with monoclonal antibodies with target cells, protein aggregates / liposomes or viruses. An alternative approach to white drug delivery employs the fact that many cells by themselves have unique binding receptors on their surfaces. Therefore, target therapeutic agents can be designed to incorporate ligand molecules that can be found by these cell-specific receptors. The carbohydrate-binding proteins represent an important class of cell-surface receptors that pharmaceutical scientists have designated drugs to be targeted. The first cell surface carbohydrate binding protein was characterized approximately twenty years ago (Ashwell and Norell, Adv., Enzymol, Relat.Areas Mol. Biol. 41: 99-128 (1974), Pricer and Ashwell, J. Biol. Chem., 246: 4825-4833 (1971)). These investigators found that glycoproteins treated to remove terminal sialic acids in bound oligosaccharides were specifically absorbed by liver cells when injected into animals (Ashwel and Morell, Adv., Enzymol, Relat.Areas Mol. Biol. 41: 99-128 ( 1974)). Subsequent work demonstrated that this liver-specific ligand retention is measured by a carbohydrate recognition receptor, now commonly referred to as the sialo-glycoprotein receptor, which occurs on the surface of hapatocytes (Lodish, Trends Biochem. ., 16: 3764-377 (1991); Weiss and Ashwell, Prog. Clin. Biol. Res. 300: 169-184 (1989)). More recently, other carbohydrate receptors have also been characterized. For example, mannose / N-acetylglucosamine and fucose receptors are found in cells such as macrophages and monocytes (Haltiwanger and Hill, J. Biol. Chem. 261: 7440-7444 (1986); Ezekowitz and Stahl, J. Cell Sci. Suppl 9: 121-133 (1988); Haltiwanger, et al., J. Biol. Chem. 261: 7433-7439 (1986)). Selectin receptors, carbohydrate-binding proteins specific for Lewis blood group oligosaccharide structures or sialyl-Lewis, occur in endothelial cells, neutrophils and platelets (Munro, Eur. Heart, J. 14 suppl K: 72-77 (1993)). In addition to their particular carbohydrate specificity, these carbohydrate-binding proteins can also be classified as to whether or not they participate in receptor-mediated endocytosis. Receptors that do not mediate endocytosis, remain on the cell surface, with or without binding ligands for comparatively long periods, while receptors that mediate endocytosis are rapidly internalized from the cell surface via claterin-coated pits, supplying ligands bound to vesicles endocytes which in turn emerge rapidly with lysosomes (Trowbridge, Curr Opin, Cefl Biol. 3: 634-641 (1991), Schwartz, Targeted, Diagn. Ther 4: 3-39 (1991), Stoorvogel, et al. , Cell, 65: 417-427 (1991), DeCourcy and Storrie, Exp. Cell Res., 192: 52-60 (1991), Haylett and Thilo, J. Biol. Chem., 266: 8322-8327 (1991). ). The asialoglycoprotein and mannose / N-acetylglucosamine receptors described above mediate adenocytosis, whereas current evidence indicates that selectin receptors do not (Dini, et al., Biol., Cell, 74: 217-224 (1992); Munro, Eur. Heart, J. 14 Suppl. K: 72-77 (1993)). Many reports have been described in the design of therapeutic agents conjugated with carbohydrates to direct them to receptors that mediate endocytosis on specific cells. The addition of glycol lipids to liposomes can greatly improve the direction of these large aggregates to specific cells (Mumtaz, et al., Glycobiology, 1: 505-510 (1991); Barratt, et al. Biochim. Biophys., Acta 862: 153 -164 (1986)). Drugs and carbohydrates have been combined on dextran scaffolds to be targeted, such as with AraC-dextran-galactose complexes used to deliver drugs to liver cells. Similarly, carbobased modified chemosan microspheres improve the targeting of encapsulated therapeutic agents for some cell types (Ohya, et al., J. mlcroencapsul 10: 1-9 (1993)). Antimony complexes with morning yeast derivatives provide a therapy for macrophages infected with Leishmania (Cantos, et al., Biochem. J., 289: 155-160 (1993)). Polylysine is used in a scale of drug designs as a scaffold for the combination of therapeutic agents and carbohydrates. For example, polylysine-based complexes are used for applications that vary from the target of DNA vehicles to gene therapy (Wu, et al., J. Biol. Chem., 269: 11542-11546 (1994); McKee, et al. , Bioconjug, Chem. 5: 306-311 (1994), Midoux, et al., Nucleic Acids Res. 21: 871-878 (1993)) for the selective delivery of antiviral agents to liver cells (Fiume, et al., FEBS Lett 203: 203-206 (1986)). Finally, a wide variety of glycoproteins (native, as well as those modified to manipulate the structures of bound carbohydrates), neoglycoproteins and glycopeptides have been coupled to therapeutic agents to improve their cell targeting characteristics (Fiume, et al., Biochem. Pharmacol. 47: 643-650 (1994); Cristiano, et al., Proc. Nati, Acad. Sci. SA 90: 11548-11552 (1993); Sett, et al., J. Infect. Dis., 168: 994-999 ( 1993); Fiume, et al., Crit. Rev. Ther. Drug Carrier St. 4: 265-284 (1988); Bonfils, et al., Nucleic Acids Res., 20: 4621-4629 (1992); Steer and Ashwell, Prog. Liver Dis. 8: 99-123 (1986); Grabowski et al., Ann., Med. 122: 33-39 (1995); Bonfils, et al., Bioconj. Chem. 3: 277-284 (1992) ). Another class of binding proteins of possible importance for the field of white therapeutics are the plasma membrane carbohydrate transporters. These proteins bind to carbohydrates, usually monosaccharides, present in the fluids around the cell and transfer them directly into the cytoplasm of cells (Bell, et al., J. Biol. Chem., 268: 19161-19164 (1993)).; Gould and Holman, Biochem. J. 295: 329-341 (1993)). For example, one or more types of glucose transporters are present on the surfaces of all cells (Marrall, et al., Cell Signal 5: 667-675 (1993); Pardridge, Ann. MY Acad. Sci. 27, 692 : 126-137 (1993), Gould and Holman, Biochem. J. 295: 329-341 (1993), Pardridge, Adv. Exp. Med. Bio 291: 43-53 (1991), Mueckeler, Eur. J. Biochem 219: 713-725 (1994), Yang and Holman, J. Biol. Chem. 268: 4600-4603 (1993)). More recently it has been suggested that it may be possible to improve the absorption of carbohydrate-containing neuropeptides by interacting with monosaccharide transporters in the endothelium of the blood brain barrier - (Polt, et al., Proc. Nati. Acad. Sci. USA 91: 7114-7118 (1994)). Several conjugates of drugs using carbohydrates mediated by signaling have been investigated in recent years (Monsigny, et al., Ann, NY, Acad. Sci., 551: 399 (1988); Monsigny, et al., Advanced Drug Delivery Reviews, 14: 1-24 (1994)). Previous work has involved macromolecular vehicles incorporating portions of sugar, such as neoglycoproteins (Sett, et al., J. Infect. Dis., 168: 994 (1993); Trouete, et al., "Targeting of Drugs", eds. ); Molema, et al., J. Med. Chem., 34: 1137 (1991); Graham, et al., Bioconjugate Chem., 5 (6): 5447 (1994); Fiume, et al., FEBS LETTS., 116 (2): 185 (1980), Enriquez, et al., WO 94/2248, Josephson, et al., US 5,336,506; Jung, et al., WO 93/252339; Josephson, et al., WO 92/17216; Josephson, and others, WO 93/11037; Menz, et al., WO 90/01295; Bijsterbosch and Van Berkel, Molecular Pharmacology, 41: 404 (1991)) and Van Berkel, Molecular Pharmacology, 41: 404 (1991)) and glycosylated polymers ( Nishikawa, et al., Pharmaceutical Research, 10 (9): 1253 (193), Kobayashi and Sumitomo, J. Macromol, Sci-Chem., A25 (5-7): 655 (1988)). Despite some success, particularly for the targeting of the asialoglycoprotein receptor via galactose complexes containing residues and for targeting macrophages via mannose complexes containing residues, these attempts have not resulted in a therapeutically viable product. These prior approaches to target targeting have concentrated on targeting large complex ligands incorporating portions of complex carbohydrates associated with the targeted pharmacoporate. The main problems associated with these products relate to their complex nature, cost, immunogenicity, difficulty in conjugation and, in some cases, the undesirable specific tissue interaction of the carrier proteins. As a result, the white strategies proposed to date have, in fact, not been practical. The belief that such ligand complexity is required in order to achieve the target has in fact departed from a consideration of an approach that uses simpler carbohydrate portions and associated chemistry to achieve direction to therapeutically useful compounds. The use of simpler carbohydrate ligands has been previously discounted on the grounds that carbohydrate-binding receptors have evolved in their nature to recognize complex carbohydrate molecules and thus exhibit poor binding with simpler sugars. However, such an approach can be expected to involve less complex synthesis and therefore lower cost as well as to produce less potentially immunogenic compounds. We have now developed a simple efficient method of targeting pyrimidine-based therapeutics to specific binding proteins for sugars. The conjugation of the carbohydrate to the pyrimidine takes place via a simpler chemical process. The sugars used are monosaccharides or other simple carbohydrates of low molecular weight. The resulting glyco-conjugates are metabolized in target tissues to generate cytotoxic species capable of destroying infectious organisms or tumor cells located therein. However, the glycoconjugates themselves have low intrinsic toxicity and therefore can provide the therapeutic benefit of pyrimidines without their toxic side effects. Therefore, in a first aspect, the invention provides a compound of the formula (I): wherein: R is halogen; And it is hydrogen, NH2, SH or OH; X is: where: any of R or R2 is a ligature, 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 with the proviso that when R4 is OH, OAc or NHAc, then R9 is hydrogen; and enantiomers of said compounds. The skilled reader will appreciate that formula I represents compounds that can be classified as α or β anomers. Therefore, both α or β-anomers are included within the scope of the invention. In addition, formula I will modalize both D and L enantiomers and therefore, both D and L enantiomers fall within the scope of the present invention. By "halogen" is meant fluorine, chlorine, bromine or iodine. In a preferred embodiment, the invention provides a compound of the formula (I) wherein: R is fluorine and is OH; and Ri and R2 are as defined in formula I, either of R3 or R4 is hydrogen with the other being OH 'R5 is OH; either R7 or R8 is hydrogen with the other being OH; R9 is hydrogen or CH2OH. Preferred compounds that fall within the scope of this embodiment include: 1 - /? - D-Galactopyranosyl-5-fluorouracil; 1-a-D-Galactopyranosyl-5-fluorouracil; 1- (> # -D-2-Deoxyglucopyranosyl) -5-fluorouracil; 1- (α-D-2-Deoxyglucopyranosyl) -5-fluorouracil; 1 -a-D-Manopyranosyl-5-f I uoro uracil; 1- (? -D-2-Deoxy-2-N-acetylagactopyranosyl) -5-fluorouracil; 1- (? -D-2-Deoxygalactopyranosyl) -5-fluorouracil; 1- (ff-D-2-Deoxygalactopyranosyl) -5-fluorouracil; 1 -? - L-Arabinopyranosyl-5-fluorouracil; 1 -a-L-Arabinopyra il-5-fl uoro uracil; 1-? -L-Galactopyranosyl-5-fluorouracil; 1-a-L-Galactopyranosyl-5-fluorouracil; 1-ß-D-2-0-Acetylgalactopyranosyl-5-fluorouracil; 1 - (? - D-2,6-Di-0-Acetylgalactopyranosyl) -5-fluorouracil; and 1- (? -D-2-deoxy-2-N-acetyl-6-0-acetylgalactopyranosyl) -5-fluorouracil. Particularly preferred compounds within this embodiment include: 1 - /? - D-Galactopyranosyl-5-fluorouracil; 1 - /? - L-Galactopyranosyl-5-fluorouracil; 1 - (/? - D-2-Deoxy-2-N-acetygalactopyranosyl) -5-fluorouracil; and 1 - /? - L-Arabinopyranosyl-5-fluorouracil, with 1-? -D-Galactopyranosyl-5-fluorouracil, 1 - /? - L-Galactopyranosyl-5-fluorouracil and 1- (? -D-2 Deoxy-2-N-acetylagalactopyranosyl) -5-fluorouracil. In a second preferred embodiment, the invention provides compounds wherein: R is fluorine; And it's NH2; R ^ and R2 are as defined in formula I; either R3 or R4 is hydrogen with the other being OH; Rs is OH; any of R or R8 is hydrogen with the other being OH; Rg is hydrogen or CH2OH. Preferred compounds that fall within the scope of this embodiment of the invention include: 1 - /? - D-Galactopyranosyl-5-f luorocytosine; 1 - (/? - D-2-Deoxyglucopyranosyl) -5-fl uoro cytosine; 1-a-D-Manopyranosyl-5-fluorocytosine; 1 - (/? - D-2-Deoxy-2-N-acetylgalactopyranosyl) -5-fluorocytosine; 1 - (? - D-2-Deoxygalactopyranosyl) -5-f luorocytosine; 1 - /? - L-Arabynopyranosyl-5-f luorocytosine; 1-a-D-Lixopyranosyl-5-fluorocytosine; and 1 -? - D-Arabinopyranosyl-5-fluorocytosine. Particularly preferred compounds within this embodiment of the invention include: 1-? -D-Galactopyranosyl-5-f luorocytosine; 1 - (? - D-2-Deoxyglucopyranosyl) -5-fluorocytosine, and 1- (? -D-2-Deoxygalactopyranosyl) -5-f luocytosine. The use of the compounds of the invention forms a second aspect of the invention.

The compounds of the general formula (I) can be prepared by any suitable method known in the art and / or by the processes described below. Therefore, according to a third aspect of the invention, there is provided a process for preparing a compound of the general formula (I), as defined above, the process comprising: (a) treating a compound of the general formula ( III): (III) with a carbohydrate derivative of the general formula (IV): (IV) wherein R1a or R2a independently represents hydrogen or any suitable donor group eg, halogen. OAc or SMe; either R3a or R4a is hydrogen with the other being hydrogen, OAc or NHAc; either R7a or R8a is hydrogen with the other being OAc; and Rga is hydrogen or CH2OAc, in the presence of a silylation reagent eg, hexamethyldisilazane and trimethylsilyl chloride and a catalyst, e.g., CF3S03H, NaBF4, SnCl4, ZnCl2, TiCl4, TmsOTf, BF3.Et20 optionally followed by the conversion of one or more OAc groups to OH groups; (b) reacting a compound of the formula (V): (V) wherein R1b and R2b are NHCONH2 or hydrogen and R3a, R4a, R7a, R8a and R9a are as defined in formula (IV), with a compound of formula (VI) or (VII): (VI) (VII) where Y represents O or S, Rio represents alkoxy, Rn represents halogen and R 2 represents hydrogen, alkyl, Na or K, in the presence of a base, e.g., sodium methoxide. The compounds of the formula (V) wherein R? By R2b are NHCONH2 or hydrogen, can be produced by treating a compound of the general formula (V), wherein R1b or R2b independently represents either hydrogen or NH2 R3a, R a, R a, R 8 a and R a are as defined in general formula (IV) above, with a carboxylation reagent e.g., ethyl chloroformate, 1,1-carbonyl di-imidazole, followed by treatment with ammonia . The compounds of the general formula (VI) or (VII) can be prepared from the appropriate acetate derivative (VIII) or nitrile derivative (IX): Rn Rio (VIII) NC. • i i (IX) respectively, by reaction with methyl formate a base, e.g., potassium methoxide wherein Y, Rio and Rn are as defined above; or (c) treating a compound of the general formula (X): (X) wherein R1c or R2c is NH2 with the other being hydrogen and R3a, R4a, R7a, Rβa and R9a are as defined in the general formula (V), with a compound of the general formula (XI): (XI) wherein R13 represents an alkyl group, and R and R12 are as defined above, optionally followed by the conversion of one or more OAc groups to OH groups. The compounds of the general formula (XI) can be prepared from the reaction of the appropriately substituted acetic acid derivative (XII): Rn H2N (XM) with an alkyl chloroformate followed by the reaction with methyl formate in the presence of base, v.br., sodium methoxide, wherein Y and R2 are as defined above. The compounds of the formula (VII) can be prepared by methods known in the art (e.g., J. Truce, J. Amer. Chem. Soc, 70: 2828 (1948)). A compound of the general formula (I) can be transformed into another compound of the general formula (I) using methods well known to those skilled in the art. Compounds of the general formula (I) wherein x represents hydrogen may be available through the usual sources, however, they may be prepared via a number of common procedures, (e.g.,) such as the reaction of urea with compounds of the general formula (VI) or (VII) as defined above; in the presence of a base eg, sodium methoxide in ethanol. The additional compounds of the general formula (I) wherein R represents halogen, can be produced by the transformation of compounds wherein R is hydrogen by reaction with an appropriate halogenation reagent, e.g., fluorination with trifluoromethyl hypofluorite and triethylamine. (e.g., M.J. Robbins and S.R. Naik, J. Amer. Chem. Soc, 93: 5272 (1971)).

The compounds of the general formula (I) wherein Y represents SH can be prepared by the reaction of the appropriate compound wherein Y represents OH with common procedures known in the art, e.g. , Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1, 3,2,4-dithiadiphosphetane-2,4-disulfide), P4S? 0 or bis-cyclohexyltin sulfide). The skilled person will appreciate that, by altering, for example, the solvent and / or catalyst in reactions as described above, the ratio of anomers to: ß can vary. Alternatively, the anomers of a can be obtained in a higher ratio using the configuration of mannose at position 2 followed by epimerization (see for example, R. U. Lemieux and A. R. Morgan, Can. J. Chem., 43 : 2190 (1965)). The methodology used in this invention is based on the published procedure of Vorbruggen and Bennua (Vorbruggen and Bennua, Tet. Lett., 1339, (1978)) for the synthesis of nucleosides. According to a fourth 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. The formulations may be presented in unit dosage forms containing a predetermined amount of active ingredient per dose. Said unit may contain for example 50 mg / kg to 600 mg / kg, preferably 50 mg / kg to 300 mg / kg and more preferably 50 mg / kg to 150 mg / kg depending on the condition being treated, the administration route and the age, weight and condition being treated, the route of administration and the age, weight and condition of the patient. The pharmaceutical formulations can be adapted for administration by any appropriate route, for example by the oral route (including buccal or sublingual), rectal, nasal, topical, (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular , intravenous or intradermal). Said formulations can be prepared by any method known in the pharmacy art, for example, by associating the active ingredient with the carrier (s) or excipient (s). Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules, solutions or suspensions in aqueous or non-aqueous liquids; foams or edible shakes; or liquid emulsions of oil in water or liquid emulsions of water in oil. Pharmaceutical formulations adapted for transdermal administration may be present as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical formulations adapted for topical administration can be formulated 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, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water or water-in-oil-based cream base. Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable vehicle, especially an aqueous solvent. Pharmaceutical formulations adapted for topical administration in the mouth include troches, lozenges and mouthwashes. Pharmaceutical formulations adapted for nasal administration in which the carrier is a solid includes a coarse powder having a particle size for example in the range of 20 to 500 microns that are administered in the way in which the aspiration is taken, i.e. for rapid inhalation through the nasal passage is from a container of dust kept enclosed to the nose. Suitable formulations wherein the vehicle is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include powders of fine particles or vapors that can be generated by means of various types of pressurized aerosols of metered doses, nebulizers or insufflators. Pharmaceutical formulations adapted for vaginal administration may be present as pessaries, tampons, creams, gels, pastes, foams or sprays formulations. Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain antioxidants, pH regulating solutions, bacteriostatic and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit dose or multiple dose containers, for example, sealed vials and vials and can be stored in a freeze-dried (lyophilized) condition that requires only the addition of the sterile liquid vehicle, eg water for injections , immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

Preferred unit dose formulations are those containing a daily dose or sub-dose, as recited above, or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients mentioned above, the formulations may also include other agents conventional in the art considering the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The compounds of the present invention are useful in that they are capable of being directed, allowing the delivery of therapeutic agents, to a desired location. Therefore, the compounds of the invention can be used in the treatment or prophylaxis of various conditions, including cancer, including metastatic liver cancer, fungal infections, etc., depending on which therapeutic agent is being targeted. In additional aspects, therefore, the present invention provides: (i) the use of a compound of the invention in the manufacture of a medicament for the treatment of cancer; (ii) the use of a compound of the invention in the manufacture of a medicament for the treatment of a fungal infection; (iii) a method for the treatment of cancer, particularly liver cancer, which comprises the step of administering to a patient an effective amount of a compound of the invention; (iv) a method for the prophylaxis or treatment of metastatic liver cancer which comprises a step of administering to a patient an effective amount of a compound of the invention; (v) a method for the treatment of a fungal infection comprising the step of administering to a patient an effective amount of a compound of the invention; (vi) the use of a compound of the invention in the manufacture of a medicament for use in the prophylaxis or treatment of psoriasis; (vii) a method for the prophylaxis or treatment of psoriasis comprising the step of administering to a patient an effective amount of a compound of the invention; (viii) the use of a compound of the invention in manufacturing or a medicament to prevent cell division; and (ix) a method for preventing cell division comprising administering to a subject an effective amount of a compound of the invention. The invention will now be described with reference to the following examples, which are not intended to in any way limit the scope of the invention. Preferred aspects of each aspect of the invention are for each other aspect mutatis mutandis.

Example 1 1-ß-D-galactopyranosyl-5-fluorouracil and 1-a-D-galactopyranosyl-5-fluorouracil A mixture of 5-fluorouracil (0.2 g, 1.54 mmol) and peracetylated galactose (0.53 g, 1.54 mmol) was stirred in acetonitrile (25 mL at 0 ° C under argon), hexamethyldisilizone (0.26 mL, 1.23 mmol) was added followed by Trimethylsilyl chloride (0.16 mL, 1.23 mmol) and the mixture was stirred for 3 minutes.A solution of tin (IV) chloride (0.22 mL, 1.84 mmol) in acetonitrile (5 mL) was added dropwise and then stirred at room temperature. 0 ° C for 30 minutes, the solution was stirred at room temperature and heated to -70 ° C until no stirring material remained.The reaction mixture was diluted with ethyl acetate (50 ml) and washed successively with solution of saturated sodium bicarbonate (40 ml), water (40 ml) and brine (40 ml) The organic layer was dried and evaporated under reduced pressure and the crude product was purified by flash chromatography (5% MeOH / DCM) give colorless crystals (0.5 g, 71%).

A sample of the above product (0.10 g) was dissolved in methanol and a solution of sodium methoxide (1M in MeOH, ~ 10 drops) was added. After stirring at room temperature for 2 hours, the reaction was neutralized with Dowex H + resin, filtered and evaporated under reduced pressure. The product was obtained as a mixture for the anomers of a and β. These can be separated by the usual methods, for example, HPLC or column chromatography. Anal. Cale. For C? 0H13FN2O7 (+ 0.5H20) Requires C 39.87 H 4.65 N 9.30 Found C 39.61 H 4.98 N 8.57 1H NMR (? -anomer): d 3.8-4.0 (5H, m, CH, CH2), 4.1 (1H, d , CH), 5.62 (1H, d, CH), 8.15 (1H, d, = CH) 1H-NMR (a-anomer): d 3.73.8 (3H, m, CH, CH2), 4.3-4.35 (1H, m, CH), 4.35-4.4 (1H, m, CH), 4.42-4.45 (1H, m, CH), 5.90 (1H, dd, CH), 8.0 (1H, d, = CH). Example 2 1-ß-L-galactopyranosyl-5-fluorouracil and 1-a-L-galactopyranosyl-5-fluorouracil The above compound was prepared using the method described in Example 1, using peracetylated L-galactose as the starting material. The product was obtained as a mixture of the a and β anomers. These can be separated by the usual methods, for example, HPLC, column chromatography. Anal. Cale. For C? 0H? 3FN2O7 (+ H20) Requires C 38.71 H 4.84 N 9.03 Found C 39.19 H 4. 89 N 8.66 1H NMR (/? - anomer): d 3.8-4.0 (5H, m, CH, CH2), 4.1 (1H, m, CH), 5.62-5.62 (1H, d, CH), 8.1 (1H, d, = CH). 1 H NMR (α-anomer): d 3.55-3.65 (3 H, m, CH, CH 2), 4.15-4.2 (1 H,, CH), 4.2-4.22 (1 H, m, CH), 4.25-4.3 (1 H, m , CH), 5.72 (1H, dd, CH), 7.85 (1H, d, = CH). Example 3 1 - (ß-D-2-Deoxyglucopyranosyl) -5-fluorouracil and 1- (a-D-3-Deoxyglucopyranosyl) -5-fluorouracil The above compound was prepared using the method described in Example 1, using peracetylated 2-deoxyglucose as the starting material. This gave a colorless product (87% yield for the second step). The product was obtained as a mixture of the α and β anomers. These can be separated by the usual methods, for example, HPLC, column chromatography. P.f. 125-130 ° C Anal. Cale. For C10H? 3FN2O6 (+ 0.5H20) Requires C 42.10 H 4.91 N 9.82 Found C 42.07 H 4.85 N 9.70 1 H NMR (ff-anomer): d 1.85-1.9 (1H, m, CH), 2.35 (1H, m, CH ) 3.45 (1H, m, CH), 3.82 (1H, m, CH), 3.9-4.0 (2H, m, CH2), 5.82 (1H, d, CH), 8.05 (1H, d, = CH) 1H-NMR (a-anomer): d 2.1-2.19 (1H, m, CH), 2.25-2.3 (1H, m, CH), 3.8-4.0 (1H, m, CH), 4.15-4.2 (1H, m, CH) , 6.10 (1H, dd, CH), 8.05 (1H, d, = CH). Example 4 1-a-D-Manopyranosyl-5-f I uoro uracil The above compound was prepared using the method described in Example 1, using peracetylated mannose as the starting material. This gave a colorless product (58% yield for the second step). Mp. 120-125 ° C Anal. Cale. For C10H13FN2O7 (+ 0.5H20) Requires C 39.87 H 4.65 N 9.30 Found C 40.25 H 4.62 N 9.24 1 H NMR: d 3.88 (1H, dd, CH), 3.99 (1H, m, CH), 4.15 (1H,, CH) , 4.2-4.3 (3H, m, CH, CH2), 6.02 (1H, d, CH), 8.1 (1H, d, = CH). Example 5 1- (ß-D-2-Deoxygalactopyranosyl) -5-fluorouracil and 1- (a-D-2-deoxygalactopyranosyl) -5-fluoro uracil The above compound was prepared using the method described in Example 1, using peracetylated 2-deoxygalactose as the starting material. This gave a colorless product (95% yield for the second step).

The product was obtained as a mixture of the α and β anomers.

These can be separated by the usual methods, for example, HPLC, column chromatography. P.f. 105-109 ° C Anal. Cale. For C10H13FN2O6 Requires C 43.48 H 4.74 N 10.14 Found C 43.13 H 4.90 N 9.60 1 H NMR (/? - anomer): d 1.98-2.12 (2H, m, CH), 3.83 (3H, m, CH, CH2), 3.94 (1H, m, CH), 4.11 (1H, m, CH), 5.81 (1H, dd, CH), 8.12 (1H, d, = CH). 1H-NMR (a-anomer): d 1.98-2.2 (2H, m, CH), 3.8-3.9 (2H, m, CH), 3. 95-4.0 (1H, m, CH), 4.15 (1H, m, CH), 4.6 (1H, m, CH), 6.30-6.35 (1H, dd, CH), 8.2 (1H, d, = CH). Example 6 1- (ß-L-2-Arabinopyranosyl) -5-fluorouracil and 1- (-L-2-Arabinopyranosyl) -5-fluorouracil The above compound was prepared using the method described in Example 1, using peracetylated L-arabinose as the starting material. This gave a colorless product (68% yield for the second step). The product was obtained as a mixture of the α and β anomers. These can be separated by the usual methods, for example, HPLC, column chromatography. P.f. 185-190 ° C Anal. Cale. For CgHnFNzOe (+ 0.5H2O) Requires C 39.85 H 4.43 N 10.33 Found C 39.67 H 4.48 N 9.86 1 H NMR (ß): d 3.85-4.0 (4H, m, CH, CH2), 4.05-4.15 (1H, m, CH ), 4. 4-4.45 (1H, m, CH), 5.55 (1H, d, CH), 8.05-8.1 (1H, d, = CH). 1H-NMR (a): d 3.8 (4H, m, CH, CH2), 4.05-4.15 (1H, m, CH), 4.2-4.25 (1H, m, CH), 5.9 (1H, d, CH), 8.0-8.02 (1H, d, = CH). Example 7 1- (β-D-2-0-acetylg to actopyranosyl) -5-flu gold uracil A mixture of 1-β-D-galactopyranosyl-5-fluorouracil (0.38 g, 1.30 mmol) and triphenylmethyl chloride (0.54 g, 1.95 mmol) was stirred in pyridine (5 mL) at room temperature for 2 h. The reaction mixture was co-evaporated under reduced pressure with toluene (x3) and the crude product purified by flash chromatography (20: 1-10: 1 DCM / MeOH) to give 1- (β-D-5-0-tritylgalactopyranosyl) -5-fluorouracil.

The above product (0.14 g, 0.26 mmol) and p-toluenesulfonic acid (0.065 g, cat.) Were stirred in a mixture of 2,2-dimethoxypropane (5 mL) and acetone (5 mL) at room temperature overnight. The reaction was neutralized with triethylamine (10 drops) and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH 50: 1) to give 1- (β-D-3,4-isopropylidene-6-0-triethylgalactopyranosyl) -5-fluorouracil. The above product of isopropylidene (0.92 g, 0.16 mmol) was stirred in a mixture of pyridine (4 mL) and acetic anhydride (4 mL) at room temperature for 2 hours. The reaction was co-evaporated under reduced pressure with toluene (x3) and the product 1- (β-D-2-0-acetyl-3,4-isopropylidyl-6-0-triethylgalactopyranosyl) -5-fluorouracil used in next step without additional purification. The previous product (0.13 g, 0.21 mmol) was heated in acetic acid (70%, 20 mL) 70-80 ° C, overnight. The reaction mixture was coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (15: 1 DCM / MeOH) to give the desired product. H-NMR (DMSO): d 1.90 (3H, s, CH3), 3.49 (3H, m, CH, CH2), 3.71 (2H, m, CH), 3.79 (1H, m, CH), 4.60-4.71 (2H , s, OH), 5.02 (1H, dd, CH), 5.10-5.18 (1H, s, OH), 5.52 (1H, dd, CH), 8.08 (1H, d, CH). Example 8 1- (ß-D-2,6-di-0-acetylgalactopyranosyl) -5-fluorouracil A mixture of 1-β-Digalactopyranosyl-5-fluorouracil (0.10 g, 0.34 mmol), imidazole (0.026 g, 0.38 mol) and tert-butylchlorodiphenylsilane (0.1 ml, 0.38 mmol) was stirred in DMF (2 ml) at room temperature for 18 hr. The reaction mixture was coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (15: 1-8: 1 DCM / MeOH) to give 1-β-D-6-0-tert-butyldiphenylsilyl-galactopyranosyl- 5-fluorouracil. The above silyl ether product (0.16 g, 0.3 mmol) and pyridinium p-toluene disulfonate (0.078 g), 0.30 mmole) was stirred at room temperature in a mixture of acetone (2 ml) and 2,2-dimethoxypropane (2 ml) for 30 minutes. The reaction mixture was then heated at 80 ° C for 36 hours. After cooling to room temperature, the reaction was evaporated under reduced pressure and purified by flash chromatography (DCM / MeOH 30: 1) to give 1-β-D-3,4-isopropyldi-yl-6-0-ter- butyldiphenylsilyl-galactopyranosyl-5-fluorouracil. The above isopropylidene product (0.13 g, 0.25 mmol) was stirred in a mixture of pyridine (2 mL) and acetic anhydride (2 mL) at room temperature for 2 hours. The reaction mixture was coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (100: 1-80: 1 DCM MeOH) to give 1-β-D-2-0-acetyl-3,4-isopropyldi -yl-6-0-tert-butyldiphenylsilyl-galactopyranosyl-5-fluorouradyl. The above product (0.12 g, 0.20 mmol) was treated with tetrabutylammonium fluoride (1.1M solution in THF); 0.2 mL, 0.20 mmol) in THF (2 mL) at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure and purified by flash chromatography (DCM / MeOH 25: 1) to give 1-β-D-2-0-acetyl-3,4-isopropyldi-yl-galactopyranosyl-5-fluorouracil . The isopropylidene product (0.0 g, 0.19 mmol) was stirred in a mixture of pyridine (2 mL) and acetic anhydride (2 mL) at room temperature for 1.5 hours. The reaction mixture was coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (100: 1 DCM / MeOH) to give 1-β-D-2,6-di-0-acetyl-3,4- isopropyldi-yl-galactopyranosyl-5-fluro uracil. Finally, the previous product (0.06 g, 0.14 mmol) was treated with acetic acid (70%, 10 ml) at 80 ° C for 18 h. After coevaporation under reduced pressure with toluene (x3), the desired product was purified by flash chromatography (DCM / MeOH 30: 1-20: 1) to give the desired product (0.031 g, 57%). 1 H NMR (DMSO): d 1.90 (3 H, s, CH 3), 3.49 (3 H, m, CH, CH 2), 3.71 (2 H, m, CH), 3.79 (1 H,, CH), 4.60-4.71 (2 H, s, OH), 5.02 (1H, dd, CH), 5.10-5.18 (1H, s, OH), 5.52 (1H, dd, CH), 8.08 (1H, d, CH). Example 9 1- (β-D-2-deoxy-2-N-acetyl-6-0-acetyl to actopyranosyl) -5-flu-uracil gold A mixture of 1- (β-D-2-deoxy-2-N -acetylgalactopyranosyl) -5-fluorouracil (0.085 g, 0.26 mmol), imidazole (0.019 g, 0.28 mmol) and tert-butylchlorodiphenylsilane (0.073 g, 01.28 mmol) was stirred in DMF (2 mL) at 80 ° C for 12 days. The reaction mixture was cooled, coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (DCM / MeOH 20: 1-10: 1) to give 1- (β-D-2-deoxy-2-) N-acetyl-6-0-tert-butyldiphenylsilyl-galactopyranosyl) -5-fluorouracil. The above silyl ether product (0.1 g, 0.18 mmol) and pyridinyl p-toluenesulfonate (0.044 g, 0.18 mmol) was stirred at room temperature in a mixture of acetone (3 mL) and 2,2-dimethoxypropane (3 mL). ) for 30 minutes. The reaction mixture was then heated at 70 ° C for 17 hours. After cooling to room temperature, the reaction was evaporated under reduced pressure and then purified by flash chromatography (DCM / MeOH 30: 1-25: 1) to give 1- (β-D-2-deoxy-2-N- acetyl-3,4-isopropyldi-yl-6-0-tert-buti Id ifenylsilyl-balactopyranosyl) -5-fl uoro uracil. The above product (0.057 g, 0.09 mmol) was treated with terbutylammonium fluoride (1.1 M solution in THF, 0.1 mL, 0.11 mmol) in THF (2 mL) at room temperature for 17 h. The reaction mixture was evaporated under reduced pressure and purified by flash chromatography (DCM / MeOH 10: 1-5: 1) to give 1- (β-D-2-deoxy-2-N-acetyl-3,4- isopropyldigalactopyranosyl) -5-fluorouracil. The isopropylidene product (0.028 g, 0.08 mmol) was stirred in a mixture of pyridine (1 ml) and acetic anhydride (1 ml) at room temperature for 1 h. The reaction mixture was coevaporated under reduced pressure with toluene (x3) and purified by flash chromatography (DCM / MeOH 60: 1) to give 1- (β-D-2-deoxy-2-N-acetyl-6-0 -acetyl-3,4-isopropyldi-yl-galactopyranosyl) -5-fluorouracil. Finally, the previous product (0.024 g, 0.06 mmol) was treated with acetic acid (70%, 10 ml) at 70 ° C for 2 days. After coevaporation under reduced pressure with toluene (x3) the desired product was purified by flash chromatography (DCM / MeOH 20: 1-10: 1) to give the desired product (0.01 g, 46%). 1 H NMR (DMSO) d 1.77 (3 H, s, CH 3), 2.04 (3 H, s, CH 3), 3.41 (2H, m.OH, CH), 3.74 (2H, m.OH, CH), 3.92 (1H, m, CH), 4.14 (2H, m, CH), 4.98 (1H, s, NH), 5.41 ( 1H, dd, CH), 7.89 (1H, dd, NH), 8.11 (1H, dd, CH). Example 10 1 - (ß-D-2-deoxy-2-N-acetylgalactopyranosyl) -5-fluorouracil The above compound was prepared using the method described in Example 1, using pre-acetylated D-2-deoxy-2-N-acetylgalactose as the starting material. 1H-NMR (D20): d 2.0 (3H, s, CH3), 3.82-3.9 (2H, m, CH), 3.92-4.02 (2H, m, CH), 4.1 (1H, d, CH), 4.2-4.25 (1H, dd, CH), 5.7 (1H, dd, CH), 8.05 (1H, d, = CH). Example 11 1-ß-D-Galactopyranosyl-5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated galactose and flucytosine as the starting materials. This gave a colorless product (yield of 55% for the second step). P.f. 170-175 ° C. Anal. Cale. For C? 0H14FN3O6 (+ H20) Requires C 38.83 H 5.17 N 13.59 Found C 39.21 H 4.14 N 12.25 1 H NMR: d 3.8 (2H, m, CH), 3..85-4.9 (3H, m, CH, CH2) , 4.08 (1H, s, CH), 8.0 (1H, d, = CH).

Example 12 1- (ß-D-2-Deoxyglucopyranosyl) -5-flurorocitosine and 1- (a-D-2-deoxyglucopyranosyl) -5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated 2-deoxyglucose and flucytosine as the starting materials. This gave a colorless product (85% yield for the second step). The product was obtained as a mixture of the α and β anomers.

These can be separated by the usual methods, for example, HPLC, column chromatography. P.f. 105-109 ° C Anal. Cale. For C? 0H1 FN3O5 (+ H20) Requires C 40.95 H 4.46 N 14.33 Found C 42.15 H 5.35 N 14.20 1H NMR (^ -anomer): d 2.15-2.19 (1H, m, CH), 2.39-2.43 (1H, m , CH), 3.32 (1H, m, CH), 3.78-3.89 (2H, m, CH2), 4.08 (1H, m, CH), 4. 18 (1H, m, CH), 6.12 (1H, dd, CH), 8.0 (1H, m, = CH) 1 H-NMR (a-anomer): d 1.95-2.05 (1H, m, CH), 2.2-2.35 (1H, m, CH), 3. 45-3.55 (1H, m, CH), 3.6-3.75 (2H, m, CH), 3.85-3.95 (1H, m, CH), 4.0-4.05 (1H, m, CH), 5.95-6.0 (1H, m, CH), 7.95 (1H, d, = CH).

Example 13 1 -a-D-ma no piranosyl-5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated mannose and flucytosine as the starting materials. This gave a colorless crystalline product (75% yield for the second step). P.f. 145-150 ° C Anal. Cale. For C? 0H14FN3O6 (+ H20) Requires C 38.83 H 5.17 N 13.59 Found C 39.17 H 5.10 N 13.55 1H NMR: d 3.75 -3.78 (1H, dd, CH), 3.98 (1H, s, CH), 4.1 (1H, m, CH), 4.2-4.3 (3H, m, CH, CH2), 6.04-6.1 (1H, d, CH), 8.0 (1H, d, = CH). Example 14 1- (β-2-deoxygalactopyranosyl) -5-f luocytosine and 1- (α-D-2-deoxygalactopyranosyl) -5-fluorocytosine The above compound was prepared using the method described in Example 1, using peracetylated D-2-deoxygalactose and 5-fluorocytosine as the starting materials. The product was obtained as a mixture of the α and β anomers. These can be separated by the usual methods, for example, HPLC, column chromatography. 1H-NMR (D20): d 2.21 (EH, s, CH3), 3.79 (2H, m, CH2), 3.91 (2H, m, CH, CH), 4.08 (1H, d, CH), 4.15 (1H, m , CH), 5.63 (1H, dd, CH), 8.00 (1H, d, CH). Example 15 1 - (ß-D-2-Deoxig a lact or pyranesyl) -5- fluorouracil and 1- (a-D-2-Deoxygalactopyranosyl) -5-fluorouracil The above compound was prepared using the method described in Example 1, using peracetylated D-2-deoxygalactose and 5-fluorocytosine as the starting materials. The product was obtained as a mixture of the α and β anomers. These can be separated by the usual methods, for example, HPLC, column chromatography. 1H-NMR (D20 ^ -product): d 1.81 (1H, m, CH), 1.95 (1H, m, CH), 3.68 (3H, m, CH2, CH), 3.80 (1H, d, CH), 3.95 ( 1H, m, CH), 5.62 (1H, dd, CH), 7.90 (1H, d, CH). 1H-NMR (D20 a-product): d 2.13 (2H, m, CH2), 3.62 (1H, dd, CH), 3.77 (1H, m, CH), 3.90 (2H, m, CH2), 4.18 (1H, m, CH), 6.00 (1H, d, CH), 7.81 (1H, d, CH). Example 16 1-ß-L-a rabbi no pyranosyl-5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated L-arabinosine and 5-fluorocytosine as the starting materials. 1H-NMR (D20): d 3.78 (3H, m, CH2, CH), 3.94 (2H, m, CH, CH), 5.42. (1H, dd, CH), 7.83 (1H, d, CH). Example 17 1-a-D-lix or pyra no if I -5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated D-lixose and 5-fluorocytosine as the starting materials. 1H-NMR (D20): d 3.95 (2H, m, CH2), 4.18 (2H, m, CH, CH), 4.25 (1H, t, CH), 5.91 (1H, dd, CH), 8.00 (1H, d , CH). Example 18 1-ß-D-arabinopyranosi-5-f luocytosine The above compound was prepared using the method described in Example 1, using peracetylated D-arabinosine as the starting material. 1 H NMR (D 20): d 3.77 (3 H, m, CH 2, CH), 3.92 (2 H, m, CH), 5.42 (1 H, dd, CH), 7.84 (1 H, d, CH). Example 19 Toxicity The toxicity of Compound 1 (as described in the Example 1), in relation to 5-FU was determined in nude mice. Clinical grade 5-FU was used to provide a point of comparison with other toxicity studies in the literature. The animals were injected six times ip, in groups of 5, every 48 hours, with several doses of 5-FU or Compound 1.

Table 1: simple bolus toxicity of 5FU and Compound 1 # NCI database * MAD: maximum achievable dose Example 20 In Vivo Efficacy Naked mice were inoculated with subcutaneous human HepG2 flank tumors to determine the antitumor activity of compound 1 in vivo. After allowing tumors to develop over the first seven days, we try to prevent tumor progression by seven treatments ip every 48 hours at a dose of 1300 mg / kg. Compounds 1, 6, 2 and 10 (as described in Examples 1, 6, 2 and 10) significantly decreased the regimen by which the disease progressed in treated animals, while maintaining a very healthy appearance. This led to an increased survival time of treated mice on untreated animals, without causing toxic side effects to the animals (Tables 2 and 3).

Tab-la 2: Number of mice that survive after tumor inoculation.

Table 3: Average tumor size (sacrificed)

Claims (48)

1. CLAIMS 1. A compound of the formula (I): wherein: R is halogen; And it is hydrogen, NH2, SH or OH; X is: where: any of R or R2 is a ligature, with the other being hydrogen: any of R3 or R4 is hydrogen, with the other being hydrogen,
2. OH, OAc or NHAc; R5 is OH or OAc; either R7 or R8 is hydrogen, with the other being OH or OAc;
3. R9 is hydrogen, CH2OH with the proviso that when R4 is OH, OAc or NHAc, then R9 is hydrogen; that when R3 is hydrogen or hydroxy, R4 is hydrogen and R5, R or R6 is hydroxy, then the compound is not the L-enantiomer; that when R, R5 and R7 are all OAc, then Rg is not CH2OH; and that when the compound is not 2-deoxy-β-D-ribopyranosyl-1-bromo-5-uracil, 2-deoxy-aD-ribopyranosyl-1-bromo-5-uracil, 1- (β-D-2- deoxyg! ucopyranosi!) - 5-fluorouration, 1 - (-D-2-deoxyg luco pira nos) -iiiiiii? u? uid u ?,? - (- -.-ucau? iy? u ^ vjμ ?? ari? "> ??) - u-iJiu ?? uuic? iiu, i - \ p - D-2-deoxypiucyranosyl) -5-bromouracil, 1- (aD-2-deoxyglucopyranosyl) -5-iodination or 1- (ß-D-2-deoxyglucopyranosyl) -5-iodouracil, and enantiomers of said compounds 2. A compound according to claim 1, wherein: R is fluorine, and is OH; and R1 and R2 are as defined in formula I, either R3 or R4 is hydrogen with the other being OH 'Rs is OH, either R7 or R8 is hydrogen with the other being OH, R9 is hydrogen or CH2OH. A compound according to claim 1, wherein: R is fluorine; Y is NH2;
4. R, and R2 are as defined in formula I; any of R3 or R is hydrogen with the other being OH; R5 is OH; any of R7 or R8 is hydrogen with the other being OH; Rg is hydrogen or CH2OH. 4. A compound according to claim 2, which is 1-? -D-Galactopyranosyl-5-fluorouracil.
5. 5. A compound according to claim 2, which is 1-a-D-Galactopyranosyl-5-fluorouracil.
6. 6. A compound according to claim 2, which is 1-a-D-m to nopyranosyl-5-fl uoro uracil.
7. 7. A compound according to claim 2, which is 1 - (? - D-2-Deoxy-2-N-acetylagactopyranosyl) -5-fluorouracil.
8. 8. A compound according to claim 2, which is 1- (/ -D-2-Deoxygalactopyranosyl) -5-fluorouracil.
9. 9. A compound according to claim 2, which is 1- (ar-D-2-D-esoxigalactopyranosyl) -5-fluorouracil.
10. 10. A compound according to claim 2, which is 1-β-L-A-rabinopyranosyl-5-f-urea uracil.
11. 11. A compound according to claim 2, which is 1-a-L-Arabinopyranosyl-5-fluorouracil.
12. 12. A compound according to claim 2, which is 1 -? - L-Galactopyranosyl-5-fluorouracil.
13. 13. A compound according to claim 2, which is 1-ar-L-Galactopyranosyl-5-fluorourazole.
14. 14. A compound according to claim 2, which is 1-β-D-2-0-Acetylgalactopyranosyl-5-fluorouracil.
15. 15. A compound according to claim 2, which is 1 - (/? - D-2, 6-Di-O-Acetylgalactopiranos i l) -5-f I uoro uracil.
16. 16. A compound according to claim 2, which is 1- (β-D-2-deoxy-2-N-acetyl-6-0-acetylgalactopyranosyl) -5-fluorouracil.
17. 17. A compound according to claim 2, which is: 1-? - D-Galactopyranosyl-5-fluorouracil.
18. 18. A compound according to claim 2, which is 1-a-D-mannopyranosyl-5-fl uoro uracil.
19. 19. A compound according to claim 2, which is 1 - (? - D-2-Deoxy-2-N-acetylagactopyranosyl) -5-fluorouracil.
20. 20. A compound according to claim 2, which is 1- (? -D-2-Deoxygalactopyranosyl) -5-fluorouracil.
21. 21. A compound according to claim 2, which is 1 - /? - L-Ara bino pyranosyl-5-fluoro uracil.
22. 22. A compound according to claim 2, which is 1-β-L-Ga the cyto pyran os i I-5-f I uoro uracil.
23. 23. A compound according to claim 2, which is 1- a-L-Gala ctopyranosyl-5-fl uoro uracil.
24. 24. A compound according to claim 3, which is 1-? -D-Galactopyranosyl-5-fluorocytosine; 1- (? -D-2-Deoxyglucopyira i I) - 5-f luocytosine; 1- (a-D-2-deoxyg I ucop i ranosil) -5-f luocytosine; 1-a-D-Manopyranosyl-5-f luocytosine; 1 - (? - D-2-Deoxy-2-N-acetylgalactopyranosyl) -5-f luorocytosine; 1 - (^ - D-2-Deoxygalactopyranosyl) -5-f luorocytosine; 1-. { a-D-2-Deoxygalactopyranosyl) -5-f luocytosine; 1 -? -L-Arabinopira nos i I- 5-f luocytosine; 1-a-D-Lixopyranosi I-5-f luocytosine; and 1-? -D-Arabinopyranosyl-5-f luocytosine.
25. 25. A compound according to claim 3, which is 1- [alpha] -D-galactopyranosyl-5-fluorocytosine.
26. 26. A compound according to claim 3, which is 1- (β-D-2-Deoxyglucan pyros i I) - 5-f Ioro cytosine.
27. 27. A compound according to claim 3, which is 1- (a-D-2-deoxyglucopyranosyl) -5-fluorocytosine.
28. 28. A compound according to claim 3, which is 1-a-D-Manopyranosyl-5-fluorocytosine.
29. 29. A compound according to claim 3, which is 1- (a-D-2-deoxygalactopyranosyl) -5-fl uoro cytosine.
30. 30. A compound according to any of claims 1 to 29, for use in medicine.
31. 31. A process for the preparation of a compound as defined in any of claims 1 to 29, comprising: (a) treating a compound of the general formula (III): (III) with a carbohydrate derivative of the general formula (IV): (IV) wherein R a, or R 2a independently represents hydrogen or any suitable donor group eg, halogen. OAc or SMe; either R3a or R4a is hydrogen with the other being hydrogen, OAc or NHAc; either R7a or R8a is hydrogen with the other being OAc; and R9a is hydrogen or CH2OAc, in the presence of a silylating reagent eg, hexamethyldisilazane and trimethylsilyl chloride and a catalyst, e.g., CF3S03H, NaBF4, SnCl4, ZnCl2, TiCl4, TmsOTf, BF3.Et20 optionally followed by the conversion of one or more OAc groups to the OH groups; (b) reacting a compound of the formula (V): (V) wherein R1b and R2b are NHCONH2 or hydrogen and R3a, R4a, R7a, R8a and R9a are as defined in formula (IV), with a compound of formula (VI) or (VII): (SAW) (VII) where Y represents O or S, Rio represents alkoxy, Rn represents halogen and R 2 represents hydrogen, alkyl, Na or K, in the presence of a base, e.g., sodium methoxide; (c) treating a compound of the general formula (X): (X) wherein R 1c or R 2c is NH 2 with the other being hydrogen and R 3a, R 4a, R 7a, R a and R a are as defined in general formula (V), with a compound of the general formula (XI): Y (XI) wherein R13 represents an alkyl group, and R and R12 are as defined above, optionally followed by the conversion of one or more groups of OAc to OH groups; and therefore optionally (d) converting a compound of the general formula (I) to another compound of the general formula (I).
32. 32. A pharmaceutical formulation comprising a compound as defined in any of claims 1 to 29 and optionally one or more pharmaceutically acceptable excipients, diluents or vehicles.
33. 33. A pharmaceutical formulation according to claim 32, comprising 1-β-D-galactopyranosyl-5-fluorouracil, 1-β-L-galactopyranosyl-5-fluorouracil, 1- (β-D-2-deoxy-N -acetylgalactosaminopyranosyl) -5-fluorouracil or 1-β-L-arabinopyranosyl-5-fluorouracil.
34. 34. A pharmaceutical formulation according to claim 32, comprising 1-β-D-galactopyranosyl-5-fluorocytosine, 1- (β-D-2-deoxyglucopyranosyl-5-fluorocytosine or 1- (β-D-2-deoxygalactopyranosyl) ) -5-f luocytosine
35. 35. The use of a compound of the formula wherein: R is halogen; And it is hydrogen, NH2, SH or OH; X is: wherein: either RT OR R2 is a ligation, 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 with the proviso that when R is OH, OAc or NHAc, then Rg is hydrogen; that when R3 is hydrogen or hydroxy, R4 is hydrogen and R5, R or R6 is hydroxy, then the compound is not the L-enantiomer; and enantiomers of said compounds in the manufacture of a medicament for the treatment of cancer.
36. 36. The use according to claim 35, wherein the compound is as defined in any of the claims 4 to 23.
37. 37. The use of a compound of the formula: wherein: R is halogen; And it is hydrogen, NH2, SH or OH; X is: wherein: either R1 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; Rg is hydrogen, CH2OH with the proviso that when R4 is OH, OAc or NHAc, then R9 is hydrogen; and enantiomers of said compounds in the manufacture of a medicament for the treatment of a fungal infection.
38. 38. The use according to claim 37, wherein the compound is as defined in any of claims 24 to 29.
39. 39. A method for the treatment of cancer which comprises the step of administering to a patient an effective amount. of a compound according to claim 35 or claim 36.
40. 40. A method according to claim 39, which is for the treatment of cancer in the liver.
41. 41. A method for the prophylaxis or treatment of metastatic liver cancer which comprises the step of administering to a patient an effective amount of a compound as defined in claim 35 or claim 36.
42. 42. A method of. according to any of claims 39 to 41, wherein the compound administered is 1-β-D-galactopyrosine i I-5-fluorouracil, 1-β-L-galactopyranosyl-5-fluorouracil, 1- (β- D-2-deoxy-N-acetylgalactosaminopyranosyl) -5-fluorouracil or 1-β-L-arabinopyranosyl-5-fluorouracil.
43. 43. A method for the treatment of a fungal infection comprising the step of administering to a patient an effective amount of a compound according to claim 37 or claim 38.
44. 44. A method according to claim 43, wherein the The compound administered is 1-β-D-galactopyranosyl-5-fluorocytosine, 1 (β-D-2-deoxyglucopyranosyl) -5-fluorocytosine or 1- (β-D-2-deoxygalactopyranosyl) -5-fluorocytosine.
45. 45. The use of a compound according to the claim 35 or claim 36, in the manufacture of a medicament for use in the prophylaxis or treatment of psoriasis.
46. 46. A method for the prophylaxis or treatment of psoriasis which comprises the step of administering to a patient an effective amount of a compound as defined in claim 35 or claim 36.
47. 47. The use of a compound according to claim 35 or claim 36, in the manufacture of a medicament to prevent cell division.
48. 48. A method for preventing cell division which comprises administering to a subject an effective amount of a compound as defined in claim 35 or claim 36.