AU2004303434A1 - Glycosaminoglycan (GAG) mimetics - Google Patents

Description

WO 2005/061523 PCT/AU2004/001800 GLYCOSAMINOGLYCAN (GAG) MIMETICS TECHNICAL FIELD 5 The invention that is the subject of this application lies in the area of compounds that mimic the structure of certain carbohydrates. More particularly, the invention lies in the area of glycosaminoglycan (GAG) mimetics. Specifically, the invention relates to compounds comprising at least one charged group that are designed to mimic the structure of GAGs. The invention also relates to methods for 10 the preparation of the compounds, compositions comprising the compounds, and use of the compounds and compositions thereof for the antiangiogenic, antimetastatic, anti-inflammatory, anticoagulant, antithiombotic, and/or antimicrobial treatment of a mammalian subject. The invention further relates to the use of the compounds and compositions thereof in the treatment of a mammalian subject having a condition amenable to treatment with such agents. 15 BACKGROUND ART Glycosaminoglycans (GAGs) are linear, polyanionic polysaccharides that are produced by most animal cells and are usually found attached to a protein core [1,2]. GAGs occur abundantly (as proteoglycans) and are extruded by cells to the cell surface and into the extracellular matrix (ECM) [3]. It has been recognised that GAGs, especially those belonging 20 to the heparan sulfate (HS) family (HS-GAGs), mediate numerous physiological processes. For example, HS-GAGs play key roles in cell growth and development, angiogenesis, coagulation, tumour metastasis, cell adhesion, activation of growth factors, binding of cytokines and chemokines, and infection by bacteria and viruses [4-6]. In recent years there has been a dramatic increase in the list of proteins that interact with GAGs and the list 25 continues to grow. The emerging view is that unique sequences of extracellular GAGS bind specifically to important proteins and by doing so influence fundamental biological processes. It has been shown that molecules that mimic the structure of certain GAGs-which molecules are referred to as "GAG mimetics"-can bind to GAG-binding proteins and modulate their biological activity: e.g., the activation of AT-III by various pentasaccharides 30 [7,8], or the activation of fibroblast growth factors (FGFs) by sucrose octasulfate [9]. Similarly, it has been shown that GAG mimetics can antagonise the binding of a GAG to its target protein and in so doing inhibit that protein's biological or disease function. For example, anticancer agents that have been developed to target HS-binding angiogenic growth factors WO 2005/061523 PCT/AU2004/001800 -2 include polysulfonated compounds [10], suramin and the related suradistas [11], and sulfated oligosaccharides [12,13]. The present invention relates to novel, small molecule GAG mimetics that bind to GAG-binding proteins and modulate their functions. The compounds incorporate at least one 5 negatively charged group (preferably a sulfo group) to interact with the positively charged residues in the GAG-binding site of the target proteins, and also contain one or more substituents to form interactions with other protein residues in and around the above-mentioned binding site. Important and distinguishing features of the compounds described herein are that they have fewer sulfo groups and are of lower molecular weight than previously described 10 polysulfated GAG mimetics such as the sulfated oligosaccharides [12,13]. Another important feature is that their structures are based on cyclic scaffolds (e.g., a monosaccharide) with sulfo groups and other substituents placed in specific, pre-defimed orientations about the ring, thus differing significantly from the simple, randomly charged GAG mimetics described by Kisilevsky [14]. The binding of the compounds described herein to a selection of HS-binding, 15 angiogenic growth factors is demonstrated via a surface plasmon resonance (SPR) solution affinity assay. Additionally, a selection of compounds are shown to inhibit the HS-mediated infection of cells and cell-to-cell spread by herpes simplex virus. One aspect of the present invention is the utilisation of the Ugi reaction [15,16] to provide a diverse array of GAG mimetics. The capacity for variation in the manner in which 20 the individual charged structures are connected to one another or to other functional groups as well as the scope of application to mimic the diverse structural variation of GAGs is demonstrated. As will be apparent to those skilled in the art, the functionalisation of the cyclic scaffolds is not limited to the Ugi reaction. For example, the use of many other reactions such as alkylation, acylation and cycloaddition is demonstrated. 25 SUMMARY OF THE INVENTION It is an object of the invention to provide novel charged compounds that have utility as GAG mimetics. It is a further object of the invention to provide effective synthetic routes for the preparation of the subject compounds. 30 According to a first embodiment of the invention, there is provided a compound of the formula WO 2005/061523 PCT/AU2004/001800 -3

XR

5

R

4 X R6

R

3 X n XR I

XR

2 wherein: n is an integer of from 0 to 2; 5 Z is N, N(O), 0, S, S(O), S(0)2, P, P(O), P(O) 2 , Si, Si(O), or Si(0) 2 ; each X is independently C, C(O), N, N(0), 0, S, S(0), S(0) 2 , P, P(O), P(0) 2 , Si, Si(O), or Si(O) 2 or is a bond; and each of R, to R 6 is independently a bond or is selected from the group consisting of: hydrogen; 10 halogen; straight chain, cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; phosphoryl groups such as phosphate, thiophosphate -0-P(S)(OH) 2 ; phosphate esters -0-P(O)(OR) 2 ; thiophosphate esters -0-P(S)(OR) 2 ; phosphonate 15 -0-P(O)OHR; thiophosphonate -0-P(S)OHR; substituted phosphonate -0-P(O)ORIR 2 ; substituted thiophosphonate -O-P(S)ORiR 2 ; -0-P(S)(OH)(SH); and cyclic phosphate; other phosphorus containing compounds such.as phosphoramidite -0-P(OR)-NRR 2 ; and phosphoramidate -0-P(O)(OR)-NRR 2 ; 20 sulfur groups such as -0-S(0)(OH), -SH, -SR, -S(--+O)-R, S(0) 2 R, RO-S(0)2, -0-SO 2

NH

2 , -0-S0 2 RiR 2 or sulfamide -NHSO 2

NH

2 ; amino groups such as -NHR, -NRiR 2 , -NHAc, -NHCOR, -NH-0-COR, NHS03, -NHSO 2 R, -N(SO 2

R)

2 , and/or amidino groups such as -NH

C(=NH)NH

2 and/or ureido groups such as -NH-CO-NRiR 2 or thiouriedo groups 25 such as -H-C(S)-NH 2 ; another unit of the structure I, attached through any position, where Z, X and R 1 to R 6 are as defined above; or a substructure based upon a group of the following formula: WO 2005/061523 PCT/AU2004/001800 -4 0 YR 10 R7Y' Nt N YR11 H/Y Y O

R

8

R

9 wherein: Y is a bond or is selected from the group consisting of: straight chain, 5 cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted alkyl; straight chain, cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted acyl; and aryl, substituted aryl, heteroaryl; and 10 each of R 7 to RI is independently at least one structure according to formula I, or a structure according to formula II; with the provisos that: when Z is 0, and X is 0 or a bond, then all of R 1 to R 5 are not H or CH 2 OH; or when Z is N and X is 0 or a bond, then all of R 1 to R 6 are not H. 15 According to a second embodiment of the invention, there is provided a pharmaceutical or veterinary composition for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which composition comprises at least one compound according to the first embodiment together with a pharmaceutically or veterinarially acceptable carrier or diluent for 20 said at least one compound. According to a third embodiment of the invention, there is provided the use of a compound according to the first embodiment in the manufacture of a medicament for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection. 25 According to a fourth embodiment of the invention there is provided a method for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which method comprises administering to the subject an effective amount of at least one compound according to the first embodiment, or a composition comprising said at least one compound. 30 In other embodiments of the invention, there are provided processes for synthesising the compounds according to the first embodimrent as defined above.

WO 2005/061523 PCT/AU2004/001800 -5 With further regard to the compounds of the first embodiment, if not otherwise specified, alkyl, aryl and other substituent groups are used in accordance with their usual meaning in the art. For example, alkyl and aryl groups would normally have from 1 to 10 carbon atoms. Additionally, two of the groups R 1 to Rs may be connected to each other to form 5 a bicyclic strucure; or the cyclic structure of formula I may contain a double bond, i.e., two contiguous XR 1 to XR 5 groups may be bonds. Preferred compounds of the invention have the general structures of formulae III-VI, as defined in Tables 1-4 below. In order that the invention may be more readily understood and put into practice, one or 10 more preferred embodiments thereof will now be described, by way of example only. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The following abbreviations are used herein: GAG glycosaminoglycan HS heparan sulfate 15 FGF fibroblast growth factor aFGF acidic fibroblast growth factor (or FGF-1) bFGF basic fibroblast growth factor (or FGF-2) VEGF vascular endothelial growth factor SPR surface plasmon resonance 20 HSV herpes simplex virus The present inventors have found that a broad range of compounds with GAG mimetic properties can be synthesised using a number of different strategies as illustrated below in the examples. These compounds have utility in the prevention or treatment in mammalian subjects of a disorder resulting from angiogenesis, metastasis, inflammation, microbial infections, 25 coagulation or thrombosis. This utility results from the ability of the compounds to modulate the activity of GAG-binding proteins responsible for disease processes. The GAG mimetics of the invention, as indicated above, can be synthesised using a number of different routes, including the Ugi reaction, and generally incorporating sulfonation in the process. 30 Preferred compounds according to the first embodiment of the invention as defined above include those embraced by generic structures I and II and those included in Tables 1-4 below.

WO 2005/061523 PCT/AU2004/001800 -6 As indicated above, the compounds according to the invention have utility in the prevention or treatment in mammalian subjects of a disorder resulting from angiogenesis, metastasis, inflammation, microbial infection, coagulation or thrombosis. The compounds have particular utility in the treatment of the foregoing disorders in humans. The compounds 5 are typically administered as a component of a pharmaceutical composition as described in the following paragraphs. Phannaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatine or an adjuvant or an inert diluent. Liquid pharmaceutical compositions generally include a liquid carrier such as water, 10 petroleum, animal or vegetable oils, a mineral oil or a synthetic oil. Physiological saline solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Such compositions and preparations will generally contain at least 0.1 wt% of the compound. Parenteral administration includes administration by the following routes: 15 intravenously, cutaneously or subcutaneously, nasally, intramuscularly, intraocularly, transepithelially, intraperitoneally and topically. Topical administration includes dermal, ocular, rectal, nasal, as well as administration by inhalation or by aerosol means. For intravenous, cutaneous or subcutaneous injection, or injection at a site where treatment is desired, the active ingredient will be in the form of a parenterally acceptable aqueous solution 20 which is pyrogen-free and has suitable pH, isotonicity and stability. Those of skill in the art will be well able to prepare suitable solutions using, for example, solutions of the subject compounds or derivatives thereof. In addition to the at least one compound and a carrier or diluent, compositions according to the invention can further include a pharmaceutically or veterinarially acceptable 25 excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant or any other material known to those of skill in the art. It will be appreciated by the person of skill that such materials should be non-toxic and should not interfere with the efficacy of the compound(s). The precise nature of any additive may depend on the route of administration of the composition: that is, whether the composition is to be administered orally or parenterally. 30 With regard to buffers, aqueous compositions typically include such substances so as to maintain the composition at a close to physiological pH or at least within a range of about pH 5.0 to about pH 8.0.

WO 2005/061523 PCT/AU2004/001800 -7 Compositions according to the invention can also include active ingredients in addition to the at least one compound. Such ingredients will be principally chosen for their efficacy as antiangiogenic, antimetastatic, anti-inflammatory, anticoagulant, antithrombotic, antimicrobial agents but can be chosen for their efficacy against any associated condition. 5 A pharmaceutical or veterinary composition according to the invention will be administered to a subject in either a prophylactically effective or a therapeutically effective amount as necessary for the particular situation under consideration. The actual amount of at least one compound administered by way of a composition, and rate and time-course of administration, will depend on the nature and severity of the condition being treated or the 10 prophylaxis required. Prescription of treatment such as decisions on dosage and the like will be within the skill of the medical practitioner or veterinarian responsible for the care of the subject. Typically however, compositions for administration to a human subject will include between about 0.01 and 100 mg of the compound per kg of body weight and more preferably between about 0.1 and 10 mg/kg of body weight. 15 The compounds can be included in compositions as pharmaceutically or veterinarially acceptable derivatives thereof. As used herein "derivatives" of the compounds includes salts, coordination complexes with metal irons such as Mn 2 + and Zn 2 +, esters such as in vivo hydrolysable esters, free acids or bases, hydrates, or prodrugs. Compounds having acidic groups such as phosphates or sulfates can form salts with alkaline or alkaline earth metals such 20 as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl) amine. Salts can also be formed between compounds with basic groups, such as amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds having both acidic and basic groups can form internal salts. 25 Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques that will be well known to those of skill in the art. Prodrug derivatives of the compounds of the invention can be transformed in vivo or in vitro into the parent compounds. Typically, at least one of the biological activities of a parent 30 compound may be suppressed in the prodrug form of the compound, and can be activated by conversion of the prodrug to the parent compound or a metabolite thereof. Examples of prodrugs are glycolipid derivatives in which one or more lipid moieties are provided as substituents on the moieties, leading to the release of the free form of the compound by WO 2005/061523 PCT/AU2004/001800 -8 cleavage with an enzyme having phospholipase activity. Prodrugs of compounds of the invention include the use of protecting groups which may be removed in vivo to release the active compound or serve to inhibit clearance of the drug. Suitable protecting groups will be known to those of skill in the art and include an acetate group. 5 As also indicated above, compounds according to the invention have utility in the manufacture of a medicament for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis and/or microbial infection. Processes for the manufacture of such medicaments will be known to those of skill in the art and include the processes used to manufacture the pharmaceutical 10 compositions described above. The compounds falling within the scope of the invention have been found to have bind growth factors. In particular, it has been established that the compounds have affinity for aFGF, bFGF and VEGF. The compounds thus have utility as antiangiogenic, antimetastatic and/or anti-inflammatory agents in the treatment of mammalian subjects including humans. 15 The uses of the compounds include the treatment of angiogenesis-dependent diseases such as angiogenesis associated with the growth of solid tumours, and proliferative retinopathies, as well as the treatment of inflammatory diseases and conditions such as rheumatoid arthritis. The compounds may also activate the growth factors and could thus be used in cardiovascular treatments. 20 As further indicated above, the compounds of the invention additionally have utility as anticoagulant or antithrombotic agents. The compounds can therefore be used for both the prophylaxis and treatment of many thrombotic and cardiovascular diseases, the most notable of these being deep venous thrombosis, pulmonary embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina and myocardial infarction. Since compositions of the 25 charged aminoacid compounds can be delivered orally, the compounds are an attractive alternative to warfarin, a widely used oral anticoagulant with severe side effects. The compounds of the invention additonally have been found to inhibit viral infection and thus have utility as antiviral agents in the treatment or prevention of many viral infections. The compounds of the invention are particularly suited for the treatment or prevention of 30 infection resulting from pathogens which utilise HS as an attachment/entry receptor [6], for example, HSV, HIV, Dengue virus, Yellow fever virus, Cytomegalovirus and Hepatitis C virus. Similarly, the compounds of the invention are also suited for the treatment or prevention of infection resulting from non-viral microbial pathogens which utilise HS as an WO 2005/061523 PCT/AU2004/001800 -9 attachment/entry, for example, Plasmodium (malaria). Most notable is the inhibition by the compounds of the invention of the cell-to-cell spread of HSV-1 and HSV-2. Having broadly described the invention, non-limiting examples of the compounds, their synthesis, and their biological activities, will now be given with reference to the accompanying 5 Tables which will be briefly described in the following section of this specification. General Procedures General procedure for alkylation and deprotection of diols The diol (1 eq.) in DMF was added dropwise to a cooled (00), stirred suspension of pre washed (hexane) NaH (5 eq.) in DMF. Once the addition was complete, stirring was 10 maintained (0 0 -- +r.t., 20 min). The mixture was cooled (00, 5 min) and the alkyl halide (2 eq.) was introduced dropwise with continued stirring (0*-+r.t., o/n). The mixture was cooled once again (00) and MeOH (5 mL) was introduced with continued stirring (5 min). The solvent was evaporated and the residue subjected to workup (EtOAc) and flash chromatography to homogeneity (TLC). This residue was co-evaporated (2 x 10 mL MeCN). The crude mixture 15 and p-TsOH-H 2 0 (50 mg) in MeOH/MeCN (1:1) was heated under reflux (1 h). The mixture was cooled (r.t.) and Et 3 N (100 pL) was added prior to evaporation of the solvent. The residue was subjected to flash chromatography (EtOAc/hexane) to yield the diol. General procedure for sulfonation of alcohols A mixture of the alcohol and SO 3 -trimethylamine (2 eq per hydroxyl group) in DMF 20 was heated (600, o/n). The cooled (r.t.) reaction mixture was treated with MeOH and then made basic (to pH>10) by the addition of Na 2

CO

3 (10% w/w). The mixture was filtered and the filtrate evaporated and co-evaporated (H20). Where deacylation of the sulfated product was required, the crude product was taken up in water and 1M NaOH was added (2 eq per acyl group). When deprotection was complete the product was carried through to the next stage. 25 The crude sulfated material in H20 was subjected to size exclusion chromatography. The pure fractions were evaporated and co-evaporated (H20) and then lyophilised (H 2 0) to yield the sulfated product. When required, after lyophilisation the product was passed through an ion exchange resin column (AG*-50W-X8, Na' form, 1 x4 cm, deionized H20, 15 mL) in order to transfer the product uniformly into the sodium salt form. The solution collected was 30 evaporated and lyophilised to give the final product as a colourless glass or white power. Size exclusion chromatography Size exclusion chromatography (SEC) was performed over Bio-Gel P-2 in a 5 x 100 cm column with a flow rate of 2.8 mL/min of 0.1 M NH 4

HCO

3 , collecting 2.8 min (7.8 mL) WO 2005/061523 PCT/AU2004/001800 - 10 fractions. Fractions were analysed for carbohydrate content by TLC (charring) and/or for poly charged species by the dimethyl methylene blue test, and then for purity by capillary electrophoresis (CE) and those deemed to be free of salt were pooled and lyophilised. In the cases of the presence of undersulfated by-products or other salt contaminants 5 (normally only small amounts, but often detected), an LH20 SEC step (2 x 95 cm, deionized water, 1.2 mL/min, 3.5 min per vial) was applied to remove them completely. Dimethyl methylene blue Test Dimethyl methylene blue (DMB) reagent was prepared by dissolving 16 mg of DMB in 1 L of deionized water containing 3.04 g of glycine, 2.37 g of NaCl. 0.1 M HCI (95 ml) was 10 added to adjust the pH to 3.0. The stock solution was stored in a brown coloured bottle at r.t. (the solution was stable for at least 3 months under such conditions). A 96-well microtitre plate was loaded with 10 pL of fraction solution per well. 55 tL of DMB stock solution was added into each used well. An instant colour change from blue to pink indicated the presence of polycharged species, i.e., sulfated product fractions. 15 General procedure for NIS glycosylations Glycosyl acceptor (1 eq), thioglycoside donor (1.1 eq), 500 mg of freshly activated powdered 3A molecular sieves and 10 mL of dry DCM were stirred at -20" for 20 min before 1.3 eq of NIS and 1 drop of TfOH were added. Stirring was continued at -20' until the reaction was complete by TLC (-4 h) before 400 pL of Et 3 N was added. Evaporation (in vacuo) onto 20 silica gel and flash chromatography yielded the glycosylated product. General procedure for Ugi four-component reaction Solutions of the acid (1 eq), amine (1 eq), carbonyl compound (1 eq) and isocyanide (1 eq) in MeOH, MeOH-THF (varied ratios) or CHCl 3 were transferred into a reaction vial (final concentration: 0.1-0.5 M). When D-glucuronic acid was the acid component, it was added as a 25. solid. In the case of bis-acid, bis-amine, bis-aldehyde or bis-isocyanide, the amount was 0.5 eq. The mixture was stirred or shaken at r.t. or 60 'C for 1 h to 5 days. The progress of the reaction was monitored by TLC. The mixture was evaporated and the residue was purified by flash chromatography or dried completely under high vacuum followed by direct peracetylation and purification by flash chromatography. 30 General procedure for acetylation of hydroxyl groups: The corresponding alcohol was dissolved in DCM-pyridine (15:1 v/v, 0.15 M) containing DMAP (0.42 mol%). Acetic anhydride (2 eq per hydroxyl) was added and the mixture was stirred at r.t. o/n. The mixture was poured into ice-chilled 0.5 M HCl and WO 2005/061523 PCT/AU2004/001800 - 11 extracted with CHCl 3 . The organic phase was separated and washed with cold 0.5 M HCl (x2), brine, and dried (MgSO 4 ). The solution was filtered and evaporated. The residue was purified by flash chromatography (gradient elution with hexane-EtOAc) to give pure product. General procedure for Zemnplin deacetylation/debenzoylation: 5 A solution of the acetate/benzoate in anhydrous MeOH (0.1 M) was treated with a solution of sodium methoxide in MeOH (1.35 M, 0.2-0.6 eq). The mixture was stirred at r.t. for 1-3 h (monitored by TLC). Acidic resin AG*-50W-X8 (H+ form) was added to adjust the pH to 6-7, the mixture was filtered and the resin was rinsed with MeOH. The combined filtrate and washings were evaporated in vacuo and thoroughly dried to give the poly-ol product. 10 General procedure for deprotection of benzyl ethers via hydrogenolysis To a solution of the benzyl ether-protected compound (0.03 mmol) in MeOH or EtOH (2 mL) was added 5% Pd/C or 20% Pd(OH) 2 on charcoal (30 mg or excess). The mixture was loaded in a miniclave (Bichi AG, Uster/Switzerland) and stirred under hydrogen atmosphere (50 psi) for 2-10 h. Alternatively, the mixture was bubbled with hydrogen gas for 1 h then 15 stirred at r.t. under 1 atmosphere of hydrogen for 1-5 days. The reaction was monitored by TLC (EtOAc or MeCN-water 10:1). The mixture was filtered and rinsed with MeOH, or EtOH. The filtrate was evaporated and dried under high vacuum, checked by IH NMR, freeze dried and used directly for sulfonation. Methylation of hydroxyl groups 20 The dried poly-ol was dissolved in anhydrous DMF (0.04 M) under argon and stirred with NaH (60% suspension in mineral oil, 1.2 eq per hydroxyl) at r.t. for 1 h. lodomethane (1.2 eq per hydroxyl) was added and stirring continued o/n. MeOH was added and the mixture was evaporated onto silica and purified by flash chromatography. General procedure for Huisgen cycloaddition reactions. 25 The sulfated sugar azide was dissolved in water (0.75 M) and a solution of acetylene in t-butanol (0.9 M, 1 eq) was added. To this mixture was added a solution of copper (II) sulfate (0.3 M in water, 5 mol%) and a solution of sodium ascorbate (1 M, in water, 20 mol%). The mixture was shaken on a minishaker at r.t. o/n, and purified by column chromatography (silica 1x18 cm, gradient elution with EtOAc-MeOH-H 2 0 50:2:1, 20:2:1 to 10:2:1) to give the 30 corresponding triazole product.

WO 2005/061523 PCT/AU2004/001800 - 12 Example 1: PG2038 Step a: Methyl 3,4,6-tri-O-acetyi-2-0-benzyl-a-D-galactopyranosyl-(1--->4)-2,3,6 tri-O-benzyl-P-D-glucopyranoside. Methyl 2,3,6-tri-0-benzyl-I-D-glucopyranoside [17] (150 mg, 322 Lmol), methyl 3,4,6 5 tri-O-acetyl-2-0-benzyl-1-thio-p-D-galactopyranoside [18] (151 mg, 3 54 [tmol) and 200 mg of 3A molecular sieves were subjected to the general NIS glycosylation procedure using 95 mg (422 4mol) of NIS. Flash chromatography (gradient elution 20:80 to 25:75 EtOAc:hexanes) yielded 274 mg of partially deacetylated material. To this mixture was added 10 mL of DCM, 200 ptL of acetic anhydride, 200 of tL Et 3 N and 2 mg of DMAP, and the solution was stirred 10 for 1 h before evaporation and flash chromatography (gradient elation 25:75 to 30:70 EtOAc:hexanes) to give 180 mg (66%) of the title compound as a colourless glass. 'H n.m.r. (400 MHz, CDCl 3 ) 6: 7.05-7.35 (m, 20H, 4xPh), 5.74 (d, 1H, Ji, 2 = 4.0, Hl"), 5.29 (dd, 1H, J 3

,

4 = 3.2, J 4

,

5 = 1.2, H4"), 5.23 (dd, 1H, J 2

,

3 = 10.8, H3"), 4.92 (d, 1H, Jgem= 12.0, PhCH 2 ), 4.85 (d, 1H, Jgem= 10.8, PhCH 2 ), 4.55-4.69 (m, 4H, PhCH 2 ), 4.42 (AB, 1H, Jgem = 12.0, PhCH 2 ), 4.40 15 (AB, 1H, PhCH 2 ), 4.32 (d, 1H, J1, 2 = 7.6, H1'), 4.10 (dt, 1H, J 5

,

6 = 6.8, H5), 3.88-3.96 (m, H, H5'1H6'), 3.82 (dd, 1H, Jgem= 11.1, H6"), 3.70-3.76 (m, 4H, H2xH6'+H2"+H3'), 3.56 (s, 3H, OMe), 3.5-3.6 (m, 1H, H4'), 3.45 (dd, 1H, J 2

,

3 = 9.0, H2'), 2.02 (s, 3H, Ac), 1.93 (s, 3H, Ac), 1.88 (s, 3H, Ac). 1 3 C n.m.r. (100 MHz, CDCl 3 ) 6: 170.17, 170.06, 169.87, 138.82, 138.20, 138.13, 137.68, 128.33, 128.25, 128.19, 128.04, 127.61, 127.57, 127.49, 127.46, 127.01, 20 126.39, 104.42, 97.12, 84.49, 82.26, 74.46, 74.27, 73.69, 73.31, 73.28, 73.02, 69.47, 69.17, 68.35, 66.60, 61.62, 56.96, 20.69, 20.63, 20.58. Step b: Methyl 3,4,6-tri-O-acetyl-a-D-galactopyranosyl-(1->4)-f-D-glucopyranoside. Pearlman's catalyst (20 mg) and 20 pL of acetic acid were added to a solution of 90 mg (106 pLmol) of methyl 3,4,6-tri-O-acetyl-2-0-benzyl-a-D-galactopyranosyl-(]-+4)-2,3,6 25 tri-O-benzyl-p-D-glucopyranoside in 10 mL of MeOH. An atmosphere of hydrogen was applied with 3 vacuum purges and the suspension was stirred for 3 days. After filtration, evaporation and co-evaporation with PhMe the residue was subjected to flash chromatography (gradient elution 100:0 to 100:3 EtOAc:MeH) to yield 47 mg (91%) of the title compound. 'H n.m.r. (400 MHz, CD 3 0D) 6: 5.39 (br d, IH, J 3 ,4= 3.0, H4"), 5.32 (d, IH, J1,2= 3.8, Hl"), 5.10 30 (dd, IH, J2,3= 10.6, H3"), 4.38 (br t, 1H, J5,6= 6.8, H5"), 4.20 (d, 1H, J1, 2 = 7.8, Hi'), 4.09 (app d (ABX), 2H, JS, 6 = 6.5,,H6"), 4.00 (dd, 1H, H2"), 3.92 (dd, 1H, J,6A= 1.7, Jgem= 12.2, H6A'), 3.80 (dd, IH, J5,6B= 4.8, H6B'), 3.62 (dis t, 1H, J2,3~3,4= 9.1, H3'), 3.56 (part obs t, 1H, J 3

,

4 ~4, 5

=

WO 2005/061523 PCT/AU2004/001800 - 13 9.3, H4'), 3.53 (s, 3H, OMe), 3.42 (ddd, 1H, J, 5 = 9.4, 115), 3.22 (dd, 1H, J 2

,

3 = 9.1, H2'), 2.10 (s, 3H, AcO), 2.05 (s, 3H, AcO), 2.00 (s, 3H, AcO). Step c: Methyl 2-0-sulfo-a-D-galactopyranosyl-(-*4)-2,3,6-tri-0-sulfo-I-D-glucopyranoside, tetrasodium salt (PG2038) 5 The above disaccharide (32.2 mg, 0.667 mmol), was subjected to the standard sulfonation and deacetylation procedures to give the title compound as a white foam (4.0 mg, 7.8%, 96% purity, CE: 7.18 min). 'HNMR (D 2 0, 400 MHz): 5.473 (d, 1H, JI 1 .- 2 1 = 3.6, H 11 ), 4.833 (d, 1H, Ju-21= 2.8, Hi'), 4.60 (overlapped with water, 1H, H31), 4.551 (m, 1H, H2'), 4.306 (dd, 1H, J21..3r = 10.2, H2"), 4.17-4.06 (m, 4H, H4', H5' and H6'), 3.902 (d, 1H, J 3 1 I-4 1 = 10 3.6, H4"), 3.867 (dd, 1H, H3r), 3.616 (dd, 1H, Jaxn-6eqn = 12.0, J- 6 ax 11 = 7.2, H6ax"), 3.564 (dd, 1H, JII-6eqII= 5.2, H6eq), 3.363 (dd, 1H, H5'), 3.343 (s, 3H, CH 3 0). Example 2: PG2046 and PG2047 Step a: 2-Azido-3,4,6-tri-O-benzoyl-2-deoxy-a-D-glucopyranosyl-(]--+4)-1,6-anhydro-2-azido 2-deoxy-3-0-benzyl-j-D-glucopyranose 15 A solution of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-glucopyranosyl trichloro acetinidate [19] (201 mg, 0.453 mmol) and 1,6-anhydro-2-azido-3-0-benzyl-2-deoxy-3-D glucopyranose [20] (84 mg, 0.302 mmol) in 1,2-DCE (5 mL) was stirred in the presence of activated mol. sieves (300 mg of 3A powder) under an atmosphere of argon (r.t., 30 min). The mixture was cooled (-20') with continued stirring (10 min) and TBDMSOTf (21 pL, 20 0.091 mmol) was introduced drop-wise and stirring maintained (-20', 10 min). EtsN (100 pL) was introduced and the mixture filtered and evaporated. The residue was subjected to aqueous workup (EtOAc) and flash chromatography (10-40% EtOAc/hexanes) to yield a pale yellow coloured oil (130 mg). This residue was co-evaporated (2 x 10 mL MeCN) then subjected to the Zempl6n deacetylation general procedure. The product was subjected to aqueous workup 25 (EtOAc) to yield a colourless oil (98 mg). This residue was co-evaporated (2 x 10 mL MeCN). BzCl (210 tL, 1.81 mmol) was added to a solution of the crude product (0.302 mmol, max.) and pyridine (2 mL) in 1,2-DCE (3 mL) and the combined mixture stirred (r.t., o/n). The mixture was cooled (0*) and MeOH (2 mL) was introduced with continued stirring (0 0 -+r.t., 2 min) before evaporation and co-evaporation (toluene) of the solvent. The residue was 30 subjected to aqueous workup (EtOAc) and flash chromatography (10-30% EtOAc/hexanes) to yield two compounds. Firstly, the title compound as a colourless foam (101 mg, 46%,*3 steps). 'H NMR (400 MHz, CDCl 3 ) 33.11 (s, 1 H; H-21), 3.41 (dd, 1 H, Ji,2 3.7, J2,3 10.7 Hz; H-6'), 3.61 (s, 1 H; H- WO 2005/061523 PCT/AU2004/001800 - 14 31), 3.39 (s, 1 H; H-4'), 4.05 (d, 1 H, J 6

,

6 7.3 Hz; H-61), 4.41-4.49 (in, 2 H; H-6"), 4.55, 4.68 (AB quartet, JA,B 11.9 Hz; CH 2 Ph), 4.79 (ddd, 1 H, J 4

,

5 10.3, J 5

,

6 2.9, 5.9 Hz; H-5"), 4.91 (br d, 1 H, J 5

,

6 5.5 Hz; H-5'), 5.08 (d, 1 H, J 1

,

2 3.6 Hz; H-1), 5.51 (dd, 1 H, J 3

,

4 9.5, J 4

,

5 10.2 Hz, H 41), 5.60 (s, 1 H,; H-1), 6.10 (dd, 1 H, J 2

,

3 10.7, J 3

,

4 9.3 Hz; H-3"), 7.29-7.55, 7.89-8.03 (2 m, 5 20 H; ArH). 3 C NMR (100 MHz, CDC1 3 ) 8 58.74, 61.47, 63.30, 64.84, 69.19, 69.49, 70.52, 73.17, 74.62, 78.12, 79.57 (11 C; C-2'-61, C2"-6, CH 2 Ph), 100.71, 101.16 (2 C; C-i', C-i"), 128.10, 128.42, 128.57, 128.61, 128.64, 128.81, 128.88, 129.15, 129.86, 129.90, 130.06, 130.17, 133.43, 133.53, 133.74, 137.48 (Ar), 165.61, 165.62, 166.26 (3 C; C=O). Next, 2-azido-3,4,6-tri-O-benzoyl-2-deoxy-f-D-glucopyranosyl-(1-4)-1,6-anhydro-2 10 azido-2-deoxy-3-0-benzyl-p-D-glucopyranoSe as a colourless oil (27 mg, 12%, 3 steps). 'H NMR (400 MHz, CDCl 3 ) 5 3.19 (s, I H; H-2'), 3.74 (dd, 1 H, Js, 6 6.2, J 6

,

6 7.1 Hz; H-6'), 3.79-3.88 (in, 2 H; H-2", H-3'), 3.88 (ddd, J4,5 9.2, J, 6 3.1, 4.7 Hz; H-5"), 3.95 (br s, 1 H; H 4'), 4.10 (d, 1 H, J 6

,

6 7.3 Hz; H-6'), 4.34 (dd, 1 H; J, 6 4.9, 16,6 12.2 Hz; H-60), 4.50 (dd, 1 H,

J

5

,

6 3.1, J 6

,

6 12.3 Hz, H-6"), 4.52, 4.59 (AB quartet, JA,B 12.0 Hz; CH 2 Ph), 4.65 (d, 1 H, J1, 2 15 7.9 Hz; H-i"), 4.69 (br d, 1 H, J 5

,

6 5.5 Hz; H-5'), 5.44 (t, 1 H, J2,3=3,4 9.7 Hz; H-3"), 5.49 (br s, 1 H; H-1'), 5.51 (t, 1 H, J 3

,

4

=

4

,

5 9.6 Hz; H-4"), 7.23 -7.50, 7.84-7.96 (2 m, 20 H; ArH). Step b: 2-Deoxy-2-sulfamido-a-D-glucopyranosyl-(1-+4)-1,6-anhydro-2-deoxy-2-sulfainido-3 O-benzyl-P-D-glucopyranose, disodium salt (PG2046) A mixture of 2-azido-3,4,6-tri-O-benzoyl-2-deoxy-a-D-glucopyranosyl-(]-+4)-1,6 20 anhydro-2-azido-2-deoxy-3-0-benzyl-%-D-glucopyranoside (127 pLmol), Pearlman's catalyst (11 mg), and ammonium formate (300 mg) in 2:1 MeOH:EtOAc (7 mL) was heated to 65' under argon until complete by TLC. The mixture was cooled to r.t., filtered (0.2 pm) and evaporated. The crude amine was purified by SPE (300 mg C18 Waters cartridge, equilibrated with 5:95 MeOH:H 2 0, gradient eluted 5:95 to 100:0 MeOH:H 2 0) to yield 53 mg of the 25 diamine (58%). Without further purification, to the diamine was added DMF (5 mL), S03-Me 3 N (41 mg, 295 Lmol) and NaHCO 3 (40 mg, 475 punol). The mixture was heated to 600 for 1 h then cooled to rt and quenched with ice and Na 2

CO

3 (sat. aqueous). This suspension was stored at -18' o/n and the sample was filtered. The filtrate was evaporated. Water (1 mL) and NaOH (250 ptL, IM) were added and the solution was stirred overnight then loaded 30 directly onto the SEC column (general procedures) to yield 22 mg (28 % over three steps) of the title compound. 'H NMR (400 MHz, D 2 0, solvent suppressed) 6: 7.35-7.21 (in, 5H, ArH), WO 2005/061523 PCT/AU2004/001800 - 15 5.43 (br s, 1H, Hi'), 5.18 (d, 1H, J 1

-

2 = 3.6, H 1 ), 4.72-4.69' (n, 1H, H5), 4.54-4.521 (in, 2H, ArCH 2 ), 4.05 (d, 1H, Jgem = 7.9, H6A'), 3.85 (br s, 1H, H3'), 3.76-3.58 (in, 5H), 3.51 (dd, 1H, J2-3= 10.4, J 3 .4 = 9.1, H3"), 3.34 (t, 1H, J34~4.5 = 9.2, H4"), 3.23 (br s, 1H, H2'), 3.12 (dd, 1H, H2"). "C NMR (100 MHz, CDC1 3 ) 8:133.3, 124.8, 124.6, 124.4, 96.9, 95.1, 72.7, 71.5, 70.8, 5 68.3, 68.2, 67.2, 66.0, 61.0, 56.6, 54.0, 49.8. Step c: 2-Deoxy-2-sulfamido-a-D-glucopyranosyl-(-->4)-1,6-anhydro-2-deoxy-2-sufamido-3 D-glucopyranoside, disodium salt (PG2047) A mixture of 2-deoxy-2-sulfamido-a-D-glucopyranosyl-(1--4)-1,6-anhydro-2-deoxy-2 sulfamido-3-0-benzyl-P-D-glucopyranoside, disodium salt (12.9 mg, 20.8 !Imol) and 10 Pearlman's catalyst (5 mg) in purified water (2 mL) was subjected to 50 psi H 2 overnight. The mixture was filtered and lyophilised to yield 10.7 mg (98 %) of the title compound. 'H NMR (400 MHz, D 2 0) 6: 5.47 (br s, 1H, HI'), 5.20 (d, 1H, J1.2= 3.5, Hi"), 4.68 (br d, 1H, J.

4 = 5.5, H5), 4.07 (d, 1H, Jgem= 7

.

6 , -16A'), 3.98 (br s, 1H, 113'), 3.75-3.64 (m, 4H), 3.52 (t, 1H, J2.3~3-4= 9.3, H3"), 3.34 (t, 1H, J 3 -4-4.. = 9.3, H4"), 3.13 (obs. dd 2 , 1H, H2"), 3.11 (br s, 1H, 15 H2'). Example 3: PG2039 and PG2037 Step a: Methyl 3,4-di-O-acetyl-2,6-di-O-benzyl-t-D-galactopyranosyl-(-->4)-2,3,6 tri-O-benzyl--D-glucopyranoside Methyl 2,3,6-tri-O-benzyl-f-D-glucopyranoside (287 mg; 618 prmol), 302 mg (618 20 [tmol) of ethyl 3,4-di-O-acetyl-2,6-0-dibenzyl-1-thio-j-D-galactopyranoside [21] and 700 mg of 3A molecular sieves were subjected to the general NIS glycosylation procedure using 181 mg (803 pumol, 1.3eq) of NIS. Flash chromatography (2.5 x 20 cm, gradient elution 1:5 to 1:3 EtOAc:Hexanes) yielded the title compound as a colourless gum (176 mg, 32%). 'H NMR (400 MHz, CDCl 3 , 400 MHz): 7.40-7.12 (n, 25H, Ph), 5.818 (d, 1H, JIr.

2 r = 3.6, Hi"), 5.481 25 (d, 1H, J 4 11-311 = 3.2, H4"), 5.309 (dd, 1H, J 3 11

.

211 = 10.8, J 311

.

4 11 = 3.2, 113"), 4.980 (d, 1H, Jgem= 11.6, a-PhCH 2 ), 4.904 (d, 111, Jgem = 11.2, b-PhCH 2 ), 4.748 (d, 1HI, Jgem = 11.6, a-PhCH 2 ), 4.67-4.57 (m, 311, b-PhCH 2 and c-PhCH 2 ), 4.479 (d, 1H, Jgen = 12.8, d-PhCH 2 ), 4.443 (d, 1H, Jge = 12.8, d-PhCH 2 ), 4.415 (d, 1H, Jgem = 11.6, e-PhCH 2 ), 4.360 (d, 1H, J11-21 = 8.0, Hi'), 4.201 (d, 1H, Jgem= 12.6, e-PhCH 2 ), 4.153 (t, 1H, J 51 16 r = 7.2, J511-6equ= 6.0, 115), 4.072 (t, 30 1H, J 41

.

31 = 9.0, J 41 .51= 9.0, H4'), 3.858 (dd, 1H, J 2 r.

3 I = 10.8, J 21 -m 1 = 3.6, 112), 3.82-3.76 (in, 3H, H31, H6ax' and H6 eq'), 3.597 (s, 311, OMe), 3.62-3.57 (in, 1H, H5'), 3.507 (t, 1H, J21.31= 1 Affected by the solvent suppression signal. 2 Partially obscured by H2'.

WO 2005/061523 PCT/AU2004/001800 - 16 8.4, J 2 1 -r = 8.0, H21), 3.347 (dd, 1H, JeqII-6axI 9.2, J6eqII-sII = 6.0, H6eq), 3.291 (dd, 1H, J6axr-6eqn= 9.2, Joaxr- 5 r = 7.2, H6ax"), 1.958 (s, 3H, OAc), 1.930 (s, 3H, OAc). 1 3 C NMR (100 MHz, CDC1 3 , 100 MHz): 169.94 (CO), 169.78 (CO), 138.88, 138.35, 138.24, 137.73 and 137.64 (5x ipso-Ph), 128.25, 128.22, 128.21, 128.15, 128.12, 128.00, 127.80, 127.57, 127.52, 5 127.46, 127.41, 127.37, 126.93, 126.37, 104.40, 97.16, 84.63, 82.31, 74.42, 74.30, 73.70, 73.25, 73.16, 73.14, 72.98, 69.73, 69.07, 68.89, 67.64, 67.50, 56.86, 20.71, 20.55. Step b: Methyl 3,4-di-O-acetyl-a-D-galactopyranosyl-(--+4)--D-glucopyranoside. Following the standard debenzylation procedure, methyl 3,4-di-O-acetyl-2,6-di O-benzyl-a-D-galactopyranosyl-(]-+4)-2,3,6-tri-O-benzyl-f-D-glucopyranoside (88 mg, 98.8 10 smol) was deprotected to give the title compound as a colourless powder (42 mg, 97%). 'H NMR (D 2 0, 400 MHz): 5.394 (d, 1H, J 1 -2 1 = 3.6, Hl"), 5.294 (d, 1H, J 4 1-31 = 3.2, H4"), 4.953 (dd, 1H, J 311 -2 11 = 10.4, J 3 r.

4 , = 3.2, H3r), 4.229 (d, 1H, JI-21= 8.4, Hi'), 4.080 (t, 1H, J 5

-

6 axI = 6

.

4 , J511-6eg = 6.0, H5"), 3.965 (dd, 1H, J 2 1i-3I = 10.4, J 2 nIii= 3.6, H2"), 3.803 (dd, 1H, J6eqI-6eq = 12.0, J6eqI-51= 1.6, H6eg'), 3.67-3.59 (m, 2H, H6ax' and H3'), 3.54-3.40 (m, 4H, H41, H5' and 15 H6"), 3.407 (s, 3H, OMe), 3.134 (dd, 1H, J 2 I-3I= 9.2, J 2 1 -, = 8.4, H2'), 2.012 (s, 3H, OAc), 1.909 (s, 3H, OAc). 13C NMR (D 2 0, 100 MHz): 173.57, 173.47, 103.20, 99.71, 77.12, 76.30, 74.57, 73.09, 70.89, 69.94, 69.04, 66.45, 60.82, 60.18, 57.31, 20.34, 20.09. Step c: Methyl 2,6-di-O-sulfo-a-D-galactopyranosyl-(1-+4)-2,3,6-tri-O-sufo--D glucopyranoside, pentasodium salt (PG2039) 20 Following the standard sulfonation/deacetylation procedures, 42 mg (95.4 tmol) of methyl 3,4-di-O-acetyl-a-D-galactopyranosyl-(--+4)--D-glucopyranoside was converted to the title compound as a white powder (14.8 mg, 18%, CE: 6.12 min). 1H NMR (D 2 0, 400 MHz): 5.404 (d, 1H, Jil-2 1 = 3.6, Hl"), 4.756 (d, 1H, J,..

2 1= 3.6, Hi'), 4.60 (overlappped with water, 1H, H3'), 4.448 (dd, 1H, J 2 1.31= 3.2, H2'), 4.296 (dd, 1H, J21..311 10.0, H2"), 4.23-4.00 25 (m, 7H, H6', H5', H6", H4' and H5"), 3.958 (dd, 1H, J 3 r..

4 r = 3.6, J 4 r- 5 = 0.8, H4"), 3.930 (dd, 1H, H3"), 3.367 (s, 3H, CH 3 0). Step d: Methyl 2,6-di-O-benzyl-3,4-di-0-methyl-a-D-galactopyranosyl-(I->4)-2,3,6-tri-0 benzyl-D-D-glucopyranoside Following the standard deacetylation and methylation procedures, methyl 3,4-di-0 30 acetyl-2,6-di-O-benzyl-a-D-galactopyranosyl-( ->4)-2,3,6-tri-0-benzyl-p-D-gluCopyranoside (72 mg, 80.8 ptmol) was converted into the title compound as colourless gum (62.7 mg, 93%). 'H NMR (CDC1 3 , 400 MHz): 7.35-7.08 (m, 25H, Ph), 5.717 (d, 1H, Jin .

2 r = 3.6, Hl"), 4.856 (d, 1H, Jgem= 11.2, a-PhCH 2 ), 4.843 (d, 1H, Jgem= 10.8, b-PhCH 2 ), 4.695 (d, 2H, Jgem= 12.0, WO 2005/061523 PCT/AU2004/001800 - 17 a-PhCH 2 and c-PhCH 2 ), 4.631 (d, 1H, Jgem = 12.4, d-PhCH 2 ), 4.571 (d, 1H, Jgem = 10.8, b-PhCH 2 ), 4.500 (d, 1H, Jgem= 12.4, d-PhCH 2 ), 4.450 (d, 1H, Jgem= 11.6, c-PhCH 2 ), 4.433 (d, 1H, Jgem= 11.2, e-PhCH 2 ), 4.359 (d, 1H, Jgem= 11.2, e-PhCH 2 ), 4.303 (d, 1H, Ju-21= 7.6, H11), 3.949 (t, 1H, J 4

I..

3 1 = 9.0, J 4

..

5 1= 9.0, H41), 3.871 (dd, 1H, J 5

II-

6 aII = 7.2, JII-6eq = 6.4, H5")r 5 3.791 (dd, 1H, J 21 1

-

3 1 r = 10.4, J 2 11-in= 3.6, H2"), 3.77-3.68 (m, 4H, H4, H3', H6ax' and H6eq)), 3.59-3.53 (m, 2H, H5' and H6"), 3.551 (s, 3H, OMe), 3.51-3.40 (m, 3H, H3", H6 and H2), 3.492 (s, 3H, OMe), 3.433 (s, 3H, OMe). Step e: Methyl 3,4-di-0-methyl-a-D-galactopyranosyl-(--4)-p-D-glucopyranoside Following the standard debenzylation procedure, methyl 2,6-di-O-benzyl-3,4-di-0 10 methyl-a-D-galactopyranosyl-(1-+ 4

)-

2 ,3,6-tri-0-benzyl-p-D-glucopyranoside (62.7 mg, 75.1 pmol) was deprotected to give the title compound as colourless gum (28 mg, 97%). 'H NMR

(D

2 0, 400 MHz): 5.232 (d, 1H, Ji1-2r = 4.4, Hl1), 4.217 (d, 1H, J11-21= 8.0, H11), 3.83-3.75 (m, 3H, H4", H5" and H6'), 3.682 (dd, 1H, J 2

..

3 I = 10.4, J211 i = 4.4,142"), 3.64-3.52 (m, 4H, H61, H3" and H6"), 3.47-3.38 (m, 3H, H41, H5' and H3"), 3.400 (s, 3H, OMe), 3.340 (s, 6H, 15 2xOMe), 3.117 (dd, 1H, J 2 1.31 = 9.6, J 2 1-1 = 8.0, H2'). "C NMR (D20, 100 MHz): 103.20, 99.64, 79.35, 76.92, 76.34, 75.35, 74.65, 73.06, 72.03, 68.00, 61.02, 60.89, 60.86, 57.30, 56.94. Stepf Methyl 3,4-di-0-methyl-2,6-di-0-sulfo-a--galactopyranosyl-(1-+4)-2,3,6-tri-0 sulfo-P-D-glucopyranoside, pentasodium salt (PG2037) Following the standard sulfonation procedure, methyl 3,4-di-0-methyl-a-D 20 galactopyranosyl-(1--+4)-f-D-glucopyranoside (28 mg, 72.8 pnol) gave the title compound (3.2 mg, 4.9%). 'H NMR (400 MHz, D20): 5.357 (d, 1H, J 1 r-2r = 3.2, H1"), 4.766 (d, 1H, Jr- 2 1 = 3.6, H11'), 4.60 (overlappped with water, 1H, H31), 4.455 (dd, 1H, J 2 1.

3 1 = 2.8, H2'), 4.304 (dd, 1H, J2n-3r = 10.0, H2"), 4.22-3.99 (m, 5H, H5', H6', H4' and H5"), 4.002 (d, 2H, J- 6 I = 6.8, H6"), 3.886 (d, 1H, J31-41= 3.2, H4"), 3.667 (dd, 1H, H3"), 3.398 (s, 3H, CH 3 0), 3.367 (s, 3H, 25 CH 3 0), 3.356 (s, 3H, CH 3 0). Example 4: PG2053 and PG2042 Methyl 4-0-Allyl-2,3-di-0-sulfo-a-L-rhamnoside, disodium salt (PG2053). The title compound was obtained from methyl 2,3-0-isopropylidene-a-L rhamnopyranoside [22] via the general alkylation (with allyl bromide) and deprotection 30 procedure followed by the general sulfonation procedure, as a colourless powder. CE tm = 10.48 min. 'H NMR (400 MHz, D20) 51.19 (d, 3 H, J, 6 6.4 Hz; H-6), 3.26 (s, 3 H; OMe); 3.29-3.40 (m, 1 H; H-4), 3.59-3.67 (m, 1 H; H-5), 4.00-4.05, 4.18-4.22 (2 m, 2 H; OCH 2

),

WO 2005/061523 PCT/AU2004/001800 - 18 4.41-4.42 (m, 1 H; H-3), 4.63-4.64 (m, 2 H; H-2), 4.83 (s, 1 H; H-1), 5.07-5.21 (m, 2 H;

=CH

2 ), 5.76-5.88 (m, 1 H; =CH). When a reduced quantity (1 eq.) of S03-trimethylamine was employed, methyl 4-0 allyl-2-0-sulfo-a-L-rhamnoside, sodium salt (PG2042) was exclusively obtained. CE tm > 5 25.00 min. 'H NMR (400 MHz, D 2 0) 81.19 (d, 3 H, J 5

,

6 6.4 Hz; H-6), 3.16 (t, 1 H, J3,4 3.1,

J

4

,

5 9.7 Hz; H-4), 3.25 (s, 3 H; OMe), 3.54-3.58 (m, 1 H; H-5), 3.76 (dd, 1 H, J 2

,

3 9.7 Hz; H-3), 4.03-4.18 (m, 2 H; OCH 2 ), 4.34-4.35 (m, 1 H; H-2), 4.80 (s, 1 H; H-1), 5.08-5.22 (m, 2 H;

=CH

2 ), 5.78-5.88 (m, 1 H; =CH). Example 5: PG2024 10 Methyl 4-0-Benzyl-2,3-di-O-sulfo-a-L-rhamnoside, disodium salt (PG2024) The title compound was obtained from methyl 2,3-0-isopropylidene-a-L rhamnopyranoside via the general alkylation (with benzyl bromide) and deprotection procedure followed by the general sulfonation procedure, as a colourless powder. CE tm= 10.82 min. 'H NMR (400 MHz, D 2 0) 81.00 (d, 3 H, J 5

,

6 6.8 Hz; H-6), 3.23 (s, 3 H; 15 OMe); 3.78-3.80 (in, 1 H; H-4), 3.88-3.94 (m, 1 H; H-5), 4.41-4.43 (m, 1 H; H-2), 4.52-4.56 (m, 2 H; H-3), 4.54, 4.78 (AB quartet, JAB 12.0 Hz; CH 2 Ph), 4.90 (dd, 1 H, J 1

,

2 1.2 Hz; H-1), 7.20-7.36 (in, 5 H; ArH). Example 6: PG2054 Step a: Methyl 4-0-benzoyl-a-L-rhamnoside 20 A solution of methyl 2,3-0-isopropylidene-a-L-rhamnopyranoside (200 mg, 920 ptmol), benzoyl chloride (193 mg, 1.38 mmol) and Et 3 N (364 ptL, 2.76 mmol) in DCM (10 mL) was stirred overnight. The resulting suspension (Et 3 N-HCl precipitates) was diluted with DCM (50 mL) and washed with NaHCO 3 (sat. aqueous), water then brine, dried (MgSO 4 ) and evaporated. The residue was taken up in 50 mL of 1:1 MeCN:H 2 0 and p-TsOH (10 mg) was 25 added. The resulting solution was stirred until the reaction was complete (TLC, ~4 h), evaporated and subjected to flash chromatography (1:1 EtOAc:hexanes) to give 165 mg (64 % over two steps) of the title compound as a colourless solid. 1H NMR (400 MHz, CDC1 3 ) 8: 8.03-8.00 (m, 2H, Hortho), 7.55 (tt, 1H, JHp-Hm = 7.5, JHp-Ho = 1.3, Hpara), 7.43-7.39 (m, 2H, Hmeta), 5.09 (dis t, 1H, J 4 -3~4- 5 = 9.3, H4), 4.73 (br s, 1H, Hi), 4.01-3.97 (m, 2H, H2+H3), 30 3.91 (dq, 1H, J 4 5 = 9.7, J5.6 = 6.4, H5), 3.53-3.46 (br s, 2H, OH), 3.38 (s, 3H, OMe), 1.25 (d, 3H, H6). 13 C NMR (100 MHz, CDCl 3 ) 6: 167.1, 133.3, 129.8, 129.5, 128.3, 100.6, 75.7, 70.8, 70.1, 65.7, 55.0, 17.4.

WO 2005/061523 PCT/AU2004/001800 -19 Step b: Methyl 4-0-Benzoyl-2,3-di-O-sulfo-a-L-rhamnloside, Disodium salt (PG2054) The title compound was obtained from methyl 4-0-benzoyl-a-L-rhamnoside via the general sulfonation procedure as a colourless powder. CE tm = 11.14 min. 'H NMR (400 MHz, D 2 0) 51.14 (d, 3 H, J 5

,

6 6.3 Hz; H-6), 3.33 (s, 3 H; OMe), 3.99-4.07 (in, 1 H; H-5), 5 4.66-4.73 (m, 2 H; H-2, -3), 4.95 (d, 1 H, J 1

,

2 1.4 Hz; H-1), 5.04 (t, 1 H, J 3

,

4

=

4

,

5 9.6 Hz; H-4), 7.35-7.41, 7.53-7.55, 7.92-7.93 (3 m, 5 H; Ph). Example 7: PG2041 Step a: 4,6-0-Benzylidene-1,2-dihydro-D-glucal. A mixture of tri-O-acetyl-D-glucal (1.7 g, 6.25 mmol), AcOH (50 piL) and Pd(OH) 2 /C 10 (100 mg) in MeOH (15 mL) was vigorously stirred under H 2 (1 atm.) overnight. The mixture was filtered, the solvent evaporated and the residue subjected to flash chromatography (10 50% EtOAc/hexanes) to yield tri-O-acetyl-1,2-dihydro-D-glucal as a colourless oil. This residue was co-evaporated (2 x 10 mL MeCN) then subjected to the Zempl6n deacetylation general procedure to yield 1,2-dihydro-D-glucal as a colourless oil (825 mg, 89%). This 15 residue was co-evaporated (2 x 10 mL MeCN). p-TsOH.H 2 0 (50 mg) was added to a solution of the 1,2-dihydro-D-glucal (495 mg, 3.34 rmmol) and a,a-dimethoxytoluene (753 pL, 5.01 mmol) in DMF (5 mL) and the combined mixture stirred (600, 1 h). Et 3 N (100 ptL) was introduced and the solvent was evaporated. The residue was subjected to flash chromatography (0-5% MeOH/CHCl 3 ) to yield the title 20 compound as colourless needles (503 mg, 64%). 1 H NMR (400 MHz, CDCl 3 ) 81.72-2.01 (m, 2 H; H-2), 3.27-3.33 (m, 1 -; H-5), 3.41 (dd, 1 H, J 3

,

4 8.8, J 5

,

6 9.1 Hz; H-4), 3.49-3.56 (m, 1 H; H-3), 3.67 (t, 1 H, J 5

,

6

=

6

,

6 10.3 Hz; H-6), 3.81-3.87, 3.93-3.98 (2 m, 2 H; H-1), 4.25 (dd, 1 H;

J

5

,

6 4.9 Hz; H-6), 5.53 (s, 1 H; CHPh), 7.23-7.52 (m, 5 H, CHPh). 13 C NMR (100 MHz, CDCl 3 ) 5 33.47 (C-2); 66.46, 69.07, 69.64, 71.32 (4 C; C-1,-4,-5,-6), 84.14, (C-3), 102.16 25 (CHPh), 126.43, 128.55, 129.34, 137.50 (4 C; Ph). Step b: 3-0-Benzyl-4,6-di-O-sulfo-1,2-dihydro-D-glucal, Disodiun salt (PG2041). 4,6-0-Benzylidene-1,2-dihydro-D-glucal was subjected to the alkylation (benzyl bromide), de-protection and sulfonation general procedures to yield the title compound as a colourless powder. CE tm = 15.40 min. 'H NMR (400 MHz, CDCl 3 ) 31.48-1.53, 1.97-2.03 (2 30 m, 2 H; H-2), 3.30-3.71 (m, 1 H; H-1), 3.52-3.57 (in, 1 H; H-5), 3.60-3.66 (m, 1 H; H-3), 3.78 3.83 (m, 1 H; H-1), 3.97 (dd, 1 H, J 5

,

6 8.0, J 6

,

6 11.4 Hz; H-6), 3.98 (t, 1 H, J3,4=4,5 8.9 Hz; H-4), 4.34 (dd, 1 H, J 5

,

6 2.3 Hz; H-6), 4.52-4.67 (m, 2 H; CH 2 Ph), 7.21-7.36 (m, 5 H; Ph).

WO 2005/061523 PCT/AU2004/001800 - 20 Example 8: PG2030 Step a: 1,6-,Anhydro-3-0-methyl-I-D-glucopyranose. p-Toluenesulfonyl chloride (790 mg, 4.14 mmol) was added to a cooled (00) suspension of 3-0-niethyl-D-glucopyranose (804.mg, 4.14 mmol) in pyridine (10 mL) and the reaction 5 mixture stirred (0 0 -- r.t, 1.5 h). Ac 2 0 (1.5 mL, 15 mmol) and NN-dimethylaminopyrdine (50 mg) were then introduced and stirring continued (r.t., 4 h). The mixture was then cooled (0*) and MeOH (3 mL) was added and stirring maintained (10 min) prior to evaporation of the solvent. The residual oil was dissolved (EtOAc) and subjected to workup yielding the tosylate as a pale yellow coloured oil (1.93 g). A mixture of the crude tosylate (1.93 g) and NaOH 10 (20 mL of 1.0 M, 20 mmol) in EtOH (20 mL) was heated (80', 1 h). The mixture was neutralised with acetic acid and the solvent evaporated and co-evaporated (toluene). The crude residue was treated with pyridine (10 mL), Ac 2 0 (5 mL) and NN-dimethylaminopyridine (50 mg) and the combined mixture stirred (r.t., o/n). The mixture was treated with ice-water (10 mL) and stirring continued (r.t., 3 h) before being subjected to workup (EtOAc). The 15 residual oil was subjected to flash chromatography (20-50% EtOAc/hexanes) to yield an inseparable mixture of 2,4-di-O-acetyl-1,6-anhydro-3-0-niethyl--D-glucopyranose (a) and 1,2,4-tri-O-acetyl-3-0-methyl-6-0-tosyl-a-D-glucopyranose (b) (in a ratio of 3:1) as a pale yellow oil (466 mg). The ratio was determined by integration of the H-1 and 3-OMe signals observed in the 1H NMR spectrum. Partial 'H NMR (400 MHz, CDCl 3 ) 8 3.32 (s, 3 H; 20 OMe b), 3.45 (s, 3 H; OMe a); 5.22 (br s, 1 H; H-1 b), 5.42 (br s, 1 H; H-1 a). The mixture of the two compounds (456 mg) was subjected to the Zempldn deacetylation general method and the residue subjected to flash chromatography (0-5% MeOH/EtOAc) to yield the title compound as a colourless oil (162 mg, 33%, 3 steps). 'H NMR (400 MHz, CDCl 3 ): 5 3.27 3.30 (m, 1 H; H-3), 3.38 (s, 3 H; OMe), 3.57-3.59 (m, 1 H; H-2), 3.63-3.65 (m, 1 H; H-4), 3.70 25 (dd, 1 H, J 5

,

6 = 5.6, J 6

,

6 = 7.2 Hz; H-6), 4.06 (d, 1 H, J6,6 = 7.2 Hz; H-6), 4.48-4.51 (m, 1 H; H 5), 4.39 (br s, 1 H; H-1). Step b: 1, 6-Anhydro-4-0-benzyl-3-0-methyl--D-glucopyranose. A mixture of 1, 6-anhydro-3-0-methyl-%-D-glucopyranose (155 mg, 0.88 mmol) and Bu 2 SnO (241 mg, 0.97 mmol) in toluene (18 mL) was heated under reflux (with azeotropic 30 removal of water) until the solution was one-half the original volume. The mixture was cooled (800), BnBr (104 tL, 0.88 mmol) and Bu 4 NBr (567 mg, 1.76 mmol) were introduced and stirring continued (o/n). The mixture was treated with MeOH (2 mL) and H20 (1 mL) with continued stirring (10 min) prior to evaporation of the solvent. The residue was subjected to WO 2005/061523 PCT/AU2004/001800 -21 workup (EtOAc) and flash chromatography (20-60% EtOAc/ hexanes) to yield two compounds. Firstly, the title compound was produced as a colourless oil (94 mg, 40%). 1 H NMR (400 MHz, CDC1 3 ): 5 2.58 (d, 1 H, J 2 ,OH 6.4 Hz; OH), 3.32-3.43 (m, 5 H; H-3, H-4, OMe), 5 3.52-3.57 (m, 1 H; H-2), 3.68-3.72, 4.01-4.04 (2 m, 2 H; H-6), 4.55-4.58 (m, 1 H; H-5), 4.64 (s, 2 H; CH 2 Ph), 5.39-5.40 (m, 1 H; H-1), 7.28-7.36 (m, 5 H; ArH). Secondly, 1,6-anhydro-2-0-benzyl-3-0-methyl-0-D-glucopyranose was afforded as a colourless oil (91 mg, 39%). 'H NMR (400 MHz, CDCl 3 ): 3 2.90 (br s, 1 H; OH), 3.31-3.34 (m, 4 H; H-2, OMe), 3.36-3.38 (m, 1 H; H-3), 3.58 (br s, 1 H; H-4), 3.68 (dd, 1 H, J5,6 6.0 Hz, 10 J6,6 7.2 Hz; H-6), 4.08 (dd, 1 H, J 5

,

6 0.8 Hz, J 6

,

6 7.2 Hz; H-6), 4.47-4.49 (m, 1 H; H-5), 4.56, 4.62 (AB quartet, JA,B 12.0 Hz; CH 2 Ph), 5.40-5.41 (m, 1 H; H-1), 7.26-7.36 (m, 5 H; ArH). Step c: 1, 6-Anhydro-4-0-benzyl-3-0-methyl-2-0-sufo--D-glucopyranose, sodium salt (PG2030) 1,6-Anhydro-4-0-benzyl-3-0-methyl--D-glucopyranose (84 mg, 0.32 mmol) was 15 sulfonated according to the general procedure and subjected to flash chromatography (50/2/1->10/2/1 EtOAc/MeOH/H 2 0) prior to SEC to yield the title compound as a pale yellow coloured powder (70 mg, 60%); CE tm = 5.62 min; 'H NMR (400 MHz, D 2 0) ,3.19 (s, 3 H;

OCH

3 ); 3.43-3.45 (m, 1 H; H-4), 3.52-3.53 (m, 1 H; H-3), 3.57 (dd, 1 H, Js,6 = 5.9 Hz, J6,6= 7.8 Hz; H-6), 3.82 (dd, 1 H, J5,6 = 1.1 Hz, J6,6 = 7.8 Hz; H-6), 3.97-3.99 (m, 1 H; H-5), 20 4.59-4.61 (m, 3 H; H-2, CH 2 Ph), 5.41 (br s, 1 H; H-1), 7.22-7.34 (m, 5 H; ArH). Example 9: PG2012 and PG2013 Step a: N-benzyl-N-(cyclohexylacetanido)-1,2,3,4-tetra-O-acetyl-D-glucuronamide Following the general procedure for the Ugi reaction, D-glucuronic acid (0.950 g, 4.89 mmol), and solutions of each of the following three reagents: benzylamine (2 M in MeOH, 25 2.45 mL, 4.89 mmol), formaldehyde (2 M in MeOH, 2.45 mL, 4.89 mmol) and cyclohexylisocyanide (1 M in MeOH, 4.89 mL, 4.89 mmol) were loaded into a reaction vessel and the mixture stirred at r.t. for 19 h. The volatiles were removed under reduced pressure and dried under high vacuum to afford N-benzyl-N-(cyclohexylacetamido)-D-glucuronamide as a yellow foam. 30 Following the general procedure for acetylation, the above crude Ugi product was peracetylated to give the title compound as pale-yellow foam 1.929 g, 66% (two steps, Rf = 0.37, hexane-EtOAc 1:1) after flash chromatography (gradient elution with hexanes-EtOAc 2:1 to 1:1). 1 H NMR (CDCl 3 , 400 MHz) was very complicated due to the presence of anomers and WO 2005/061523 PCT/AU2004/001800 -22 rotamers. The spectrum was not simplified after the temperature was raised to 55 'C. However, in pyridine-d 6 at 100 *C, each set of rotamers was coalesced in some degree into much more simplified structure, thus two anomers were clearly observed (a: P ratio = 69:31). 'H NMR (CDCl 3 , 400 MHz, 25 *C): 7.41-7.14 (in, 5H, Ph), 6.337 (d, 0.39H, J= 3.6), 6.300 (d, 5 0.29H, J= 3.6), 5.969 (br d, 0.52H, J= 8), 5.823 (br d, 0.09H, J= 8.4), 5.66-5.41 (in, 2.25H), 5.28-5.09 (in, 1.3H), 4.92-4.58 (in, 2.25H), 4.411 (d, J= 10) and 4.395 (d, J= 14, 0.55H), 4.271 (d, 0.11H, J= 9.6), 4.219 (d, 0.09H, J= 17.2), 4.125 (d, 0.17H, J= 14), 4.098 (d, 0.17H, J= 14.4), 3.994 (d, J= 15.2) and 3.963 (d, J= 14.8, 0.89H), 3.82-3.59 (in, 2.04H), 2.190, 2.111, 2.038, 2.033, 2.025, 2.023, 2.016, 2.014, 2.008, 1.998, 1.983, 1.944 and 1.927 (all 10 singlet, 12H, Ac), 1.89-1.55 (m, 5H, cyclohexyl-CH2), 1.41-0.83 (in, 5H, cyclohexyl-CH 2 ). 1H NMR (CDCl 3 , 400 MHz, 55 C): 7.38-7.16 (in, 5H, Ph), 6.336 (d, J= 3.2, ) and 6.153 (d, J= 3.2, 0.7H ), 5.939 (br d, 0.6H, J= 6.8), 5.721 (br d, 0.2H, J= 7.2), 5.65-5.55 (in, 1.3H), 5.52-5.41 (in, 1H,), 5.28-5.10 (in, 1.4H), 4.85-4.58 (in, 2.4H), 4.48-4.40 (in, 0.6H), 4.318 (d, 0.1H, J= 9.2), 4.205 (d, 0.1H, J= 17.6), 4.02-3.93 (in, 0.9H), 3.84-3.62 (in, 2.2H), 2.179, 15 2.090, 2.021, 2.012, 2.001, 1.989, 1.983, 1.975, 1.968, 1.959 and 1.935 (all singlet, 12H, Ac), 1.88-1.56 (in, 5H, cyclohexyl-CH 2 ), 1.42-0.88 (in, 5H, cyclohexyl-CH 2 ). 1H NMR (pyridine d 6 , 400 MHz, 87.22, 100 'C): only typical sugar protons are given; the remaining signals (except acetate singlets) were complicated and appeared as broad lumps. a-anomer, 6.672 (d, J = 3.6, glu-H1), 5.456 (dd, J = 9.6, 3.6, glu-H2); P-anomer, 6.206 (d, J= 8.0, glu-H1), 5.741 (t, 20 J= 9.2, glu-H4 or H5), 5.515 (dd, J= 8.8, 8.0, glu-H2). Step b: N-benzyl-N-(cyclohexylacetanido)-1,2,3,4-tetra-O-sulfo-a-D-glucuronanide, tetrasodium salt (PG2012) and N-benzyl-N-(cyclohexylacetamido)-1, 2,3-tri-O-sulfo-a-D glucuronamide, trisodium salt (PG2013) Following the general procedure for deacetylation, the above tetraacete (0.441 g, 0.747 25 mmol) was deacetylated to give N-benzyl-N-(cyclohexylacetamido)-D-glucuronamide as pale yellow glass (0.316 g, 100%). Following the general procedure for sulfonation, the above tetrol (0.257 g, 0.608 mmol) was sulfonated (using sulfur trioxide pyridine complex, 60 'C, 19 h). The residue was co evaporated with toluene and purified by flash chromatography [2.5 x 20cm, eluted with 30 EtOAc, MeCN, MeCN-Et 3 N (10:1), MeCN-Et 3

N-H

2 0 (110:2:11)]. The fractions were divided into two parts according to TLC and CE. The less polar part was purified again by flash chromatography, LH20 (x2) and ion exchange chromatography to give trisulfate PG2013 as white fluffy powder after lyophilisation (19.3 mg, 4.4%). 1H NMR (D 2 0, 400 MHz): two WO 2005/061523 PCT/AU2004/001800 - 23 rotamers in a ratio of 56:44. major rotamer, 6 7.36-7.11 (m, 5H, Ph), 5.946 (d, iH, J= 3.2, Hi), 4.894 (d, 1H, J= 9.6, H5), 4.748 (d, 1H, J= 16, a-CH 2 ), 4.685 (d, 1H, J= 16, a-CH 2 ), 4.502 (t, 1H, J= 10.4, 9.6, H3), 4.306 (dd, 1 H, J= 9.6, 3.6, H2), 4.005 (t, 1H, J= 9.6, 8.8, H4), 3.869 (s, 2H, b-CH 2 ), 3.42-3.32 (m, 1H, cyclohexyl-CHN), 1.64-1.36 (m, 5H, cyclohexyl-CH 2 ), 5 1.20-0.92 (in, 5H, cyclohexyl-CH 2 ); minor rotamer, 7.36-7.11 (in, 5H, Ph), 5.905 (d, 1H, J= 3.2, Hi), 4.578 (d, 1H, J= 10, H5), 4.523 (s, 2H, c-CH 2 ), 4.478 (t, 1H, J= 10.4, 9.6, H3), 4.321 (d, 1H, J= 17.6, d-CH 2 ), 4.281 (dd, 1H, J= 9.6, 3.2, H2), 4.039 (t, 1H, J= 9.6, 9.2, H4), 3.900 (d, 1H, J = 17.6, d-CH 2 ), 3.42-3.32 (m, 1H, cyclohexyl-CHN), 1.64-1.36 (m, 5H, cyclohexyl-CH2), 1.20-0.92 (in, 5H, cyclohexyl-CH2). 13 C NMR (D 2 0, 100 MHz, no 10 reference): double-up of each signals due to two rotamers, 169.96 (ainide-CON), 169.75 (amide-CON), 168.91 (amide-CON), 168.85 (amide-CON), 135.45 (ipso-Ph), 135.20 (ipso Ph), 129.16, 129.07, 128.47, 128.32, 128.20 and 128.13 (meta-, ortho- and para-Ph), 95.67 and 95.65 (glu-C1), 77.84 and 77.75 (glu-C3), 73.76 and 73.71 (glu-C2), 70.66 and 70.18 (glu C4), 69.23 and 68.70 (glu-C5), 52.87 (a-CH 2 ), 51.12 (c-CH 2 ), 50.32 (d-CH 2 ), 50.02 (b-CH 2 ), 15 49.25 and 49.00 (cyclohexyl-CHN), 31.89 and 31.86, 25.08 and 25.05, 24.47 and 24.38 (cyclohexyl-CH 2 ). ES-LRMS (+ve, m/z): C 21

H

27

N

2 Na 3

O

1 6

S

3 required 728.02, found 751 (M+Na*), 729 (M+H); ES-HRMS (+ve, m/z): M+Na+, C 2 1

H

27

N

2 Na 4

O

16

S

3 required 751.0113, found 750.1087; M+H t , C 2 1

H

28

N

2 Na 3 0 1

S

3 required 729.0294, found 729.0242. The polar part was purified by LH20 column (x2) and ion exchange colunin to give 20 tetrasulfate PG2012 as an off-white powder after lyophilisation (7.6 mg, 1.5%). 1 H NMR

(D

2 0, 400 MHz): two rotamers in a molar ratio of 70:30. Major rotamer, 6 7.34-7.16 (m, 5H, Ph), 5.954 (d, 1H, J= 3.6, H1), 5.235 (d, 1H, J= 9.6, H5), 4.904 (d, 1H, J= 15.6, a-CH 2 ), 4.67-4.57 (overlapped with water, 1H, H3), 4.536 (t, 1H, J= 9.6, 8.8, H4), 4.466 (d, 1H, J= 15.6, a-CH 2 ), 4.394 (dd, 1H, J= 9.8, 3.4, H2), 3.927 (d, 1H, J= 16.8, b-CH 2 ), 3.749 (d, 1H, J= 25 16.8, b-CH 2 ), 3.30-3.20 (m, 1H, cyclohexyl-CHN), 1.65-1.35 (in, 5H, cyclohexyl-CH 2 ), 1.18-0.92 (m, 5H, cyclohexyl-CH 2 ); minor rotamer, 7.34-7.16 (m, 5H, Ph), 5.912 (d, 1H, J= 3.4, Hi), 4.77-4.72 (m, 2H, H5 and H3 or H4), 4.689 (d, 1H, J= 15.2, c-CH 2 ), 4.67-4.56 (overlapped with water, 1H, H4 or H3), 4.373 (dd, 1H, J= 9.8, 3.4, H2), 4.256 (d, 1H, J= 18.4, d-CH 2 ), 4.215 (d, 1H, J= 15.2, c-CH 2 ), 3.936 (d, 1H, J= 18.4, d-CH 2 ), 3.36-3.26 (in, 1 H, 30 cyclohexyl-CHN), 1.65-1.35 (m, 5H, cyclohexyl-CH 2 ), 1.18-0.92 (m, 5H, cyclohexyl-CH 2 ). 13C NMR (D 2 0, 100 MHz, no reference): major rotamer, 172.35 (amide-CON), 171.69 (amide CON), 137.22 (ipso-Ph), 131.71 and 131.58 (meta- and ortho-Ph), 131.11 (para-Ph), 97.68 (glu-C1), 78.08 (glu-C4), 77.60 (glu-C3), 76.43 (glu-C2), 70.10 (glu-C5), 55.81 (a-CH 2 ), 53.17 WO 2005/061523 PCT/AU2004/001800 -24 (b-CH 2 ), 51.77 (cyclohexyl-CHN), 34.17 (cylcohexyl-CH2), 27.56 (cylcohexyl-CH2), 27.13 (cylcohexyl-CH2); minor rotamer (only typical peaks shown), 97.65 (glu-C 1), 78.22 (glu-C4), 77.77 (glu-C3), 76.33 (glu-C2), 71.01 (glu-C5), 53.26 (d-CH 2 ), 53.79 (c-CH 2 ), 52.10 (cyclohexyl-CHN), 34.28 (cylcohexyl-CH 2 ), 27.52 (cylcohexyl-CH 2 ), 27.08 (cylcohexyl-CH2). 5 ES-MS (+ve, n/z): C 2 1

H

26

N

2 Na 4

O

19

S

4 required 829.96, found 853 (M+Na*), 831 (M+H). ES HRMS (+ve, m/z): M+Na*, C 2 1

H

26

N

2 Na 5

O

19

S

4 required 852.9501, found 852.9334; M+H*,

C

2 1

H

27

N

2 Na 4

O

19

S

4 required 830.9682, found 830.9635. Example 10: PG2064 Step a: 2-(N-acetyl-N-cyclohexyl)amino-N-(methyl 2,3,4-tri-O-benzyl-6-deoxy-a-D 10 mannopyranos-6-yl)acetamide Following the general procedure for the Ugi reaction, a solution of each of the following four reagents: acetic acid (2 M in MeOH, 60 tL, 119 pLmol), cyclohexylamine (2 M in MeOH, 60 tL, 119 pimol), formaldehyde (2 M in MeOH, 60 [tL, 119 ptmol) and methyl 2,3,4-tri-O-benzyl-6-deoxy-6-isocyano-a-D-mannopyranoside (0.721 M in CHC1 3 , 150 pL, 108 15 ptmol) was loaded into a 4 mL sample vial and the mixture stirred at 60 C for 19 h. The volatiles were removed under reduced pressure and purified by flash chromatography (gradient elution with hexane-EtOAc 4:1 to 1:4) to afford the title compound as a colourless gum, 42 mg, 60% (Rf = 0.49, EtOAc). 1H NMR (CDCl 3 , 400 MHz): two rotamers in a ratio of 72:28. 6 7.38-7.26 (in, 15H, 3 x C 6

H

5 ), 6.933 (t, 72% x 1H, J= 4.4, NH in major rotamer), 6.357 (t,, 20 28% x 1H, J= 5.8, NH in minor rotamer), 4.91-4.41 (in, 7H, sugar-H1 and 3 x PhCH 2 ), 4.04 3.42 (in, 9H, sugar-H2-6, NCH 2 CO and cyclohexyl-CH), 3.305 (s, 72% x 3H, CH 3 0 in major rotamer), 3.266 (s, 28% x 3H, CH 3 0 in minor rotamer), 2.067 (s, -72% x 3H, CH 3 CO in major rotamer), 2.012 (s, 28% x 3H, CH 3 CO in major rotamer), 1.85-1.00 (in, 10H, cyclohexyl-CH 2 ). Step b: 2-(N-acetyl-N-cyclohexyl)amino-N-( methyl 6-deoxy -2,3,4-tri-O-sulfo-a-D 25 mannopyranos-6-yl)acetamide, trisodium salt (PG2064) Following the general procedure for deprotection of benzyl ethers, a mixture of the above tribenzyl ether (42 mg, 0.065 mmol), 20% palladium on activated charcoal (22 mg) in MeOH (2 mL) was stirred under hydrogen atmosphere at 50 psi for 10 h. General work-up gave the triol intermediate as a colourless gum. Following the general procedure for 30 sulfonation, the triol was sulfonated (sulfur trioxide trimethylamine complex, 60 *C, 19 h) and the crude was evaporated. The residue was purified via sequential SEC (Bio Gel P-2 followed by LH20). The pure product was converted to the sodium salt by passing through an ion WO 2005/061523 PCT/AU2004/001800 -25 exchange column to give the title compound as a white fluffy powder after lyophilisation (3.1 mg, 7.0%, two steps). 1H NMR (D 2 0, int. ref. acetone at 2.05, 400 MHz): two rotamers in a ratio of 63:37. 8 4.844 (s, 1H, sugar-Hi), 4.678 (s, 1H, sugar-H2), 4.51-4.45 (in, 1H, sugar-H3), 4.240 (t, 37% x 1H, J= 9.6, sugar-H4 in minor rotamer), 4.214 (t, 63% x 1H, J= 5 9.6, sugar-H4 in major rotamer), 3.980 (s, 37% x 2H, COCH 2 N in minor rotamer), 3.825 (s, 63% x 2H, COCH 2 N in major rotame'r), 3.78-3.59 (in, 3H, sugar-H5, one sugar-H6 and cyclohexyl-CH), 3.31-3.17 (in, 4H, one sugar-H6 and CH 3 0 [3.253, s, 3H]), 2.060 (s, 67% x 3H, CH 3 CO in major rotamer), 1.900 (s, 33% x 3H, CH 3 CO in minor rotamer), 1.70-0.88 (in, 1 OH, cyclohexyl-CH2). 10 Example 11: PG2068 Step a Following the general procedure for the Ugi reaction, monomethyl succinate (15.7 mg, 0.119 mmol) and a solution of each of the following three reagents: ethylamine (2 M in MeOH, 60 tL, 119 ptmol), formaldehyde (2 M in MeOH, 60 pL, 119 pmol) and methyl 2,3,4-tri-0 15 benzyl-6-deoxy-6-isocyano-a-D-mannopyranoside (0.721 M in CHCl 3 , 150 gL, 108 pmol) was loaded into a 2 mL sample vial and the mixture stirred at r.t. for 19 h. The volatiles were removed under reduced pressure and purified by flash chromatography (gradient elution with hexane-EtOAc 1:1 to 1:4 then EtOAc) to afford pure product as a colourless gum (46.8 mg, 65%). 'H NMR (CDCl 3 , 400 MHz): two rotamers in a ratio of 73:27. 8 7.38-7.25 (in, 15H, 20 Ph), 6.598 (t, 73% x 1H, J= 6, NH), 6.529 (t, 27% x 1H, J= 6, NH), 4.93-4.61 (in, 7H, sugar-Hi and 3 x PhCH 2 ), 4.14-3.24 (in, 16H, sugar 6 x H, NCH 2 CO, 2 x CH 3 0 [singlets at 3.660 and 3.301, 73%; 3.648 and 3.276, 27%] and ethyl-CH 2 ), 2.70-2.42 (in, 4H,

COCH

2

CH

2 CO), 1.138 (t, 73% x 3H, J= 7, ethyl-CH 3 ), 1.014 (t, 27% x 3H, J= 7, ethyl-CH 3 ). 13 C (100 MHz, CDC1 3 , 8 77.0): major rotamer, 173.32, 171.73, 168.94, 138.20, 138.17, 138.09, 25 128.22, 128.18, 128.10, 127.76, 127.63, 127.49, 127.46, 98.94, 79.97, 75.38, 75.01, 74.84, 73.01, 72.01, 70.10, 54.63, 51.63, 49.84, 43.59, 39.63, 28.99, 27.24, 13.45. minor rotamer (only non-overlapped peaks), 173.26, 171.54, 168.01, 128.27, 127.69, 127.55, 98.98, 79.85, 75.14, 74.40, 72.86, 71.92, 69.97, 54.74, 50.91, 49.72, 42.10, 28.90, 27.83, 12.29. Step b (PG2068) 30 Following the general procedure for deprotection of benzyl ethers, a mixture of the above tribenzyl ether (46.8 mg, 0.0706 mmol), 20% palladium on activated charcoal (30 mg) in MeOH (3 mL) was stirred under hydrogen atmosphere at 50 psi for 2 h. General work-up gave WO 2005/061523 PCT/AU2004/001800 -26 the triol intermediate as a colourless gum. Following the general procedure for sulfonation, the triol was sulfonated (sulfur trioxide trimethylamine complex, 60 'C, 19 h). The residue was dissolved in IM NaOH (3 mL, 0.16 M). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified via sequential 5 SEC (Bio-Gel P-2 followed by LH20). The pure product was converted into the sodium salt by passing through an ion exchange column to give the PG2068 as a white powder (4.9 mg, 9.8%, two steps). 1H NMR (D 2 0, int. ref. acetone at 2.05, 400 MHz): two rotamers in a ratio of 70:30. 8 4.86-4.84 (m, iH, sugar-Hi), 4.69-4.67 (in, 1H, sugar-H2), 4.50-4.46 (in, 1H, sugar-H3), 4.28-4.19 (in, IH, sugar-H4), 4.072 (s, 30% x 2H, 2H of COCH 2 N in minor 10 rotamer), 3.987 (d, 35% x 2H, J= 16.8, 1H of COCH 2 N in major rotamer), 3.815 (d, 35% x 2H, J= 16.8, 1H of COCH 2 N in major rotamer), 3.79-3.69 (in, 2H, sugar-H5 and one sugar H6), 3.44-3.18 (in, 6H, one sugar-H6, ethyl-CH 2 and CH 3 0 [3.245, s, 3H]), 2.633 (t, J= 6.8) and 2.45-2.37 (in, total 4H, COCH 2

CH

2

CO

2 ), 1.054 (t, 70% x 3H, J= 7.2, CH 3 0), 0.906 (t, 30% x 3H, J= 7.2, CH 3 0). 15 Example 12: PG2075 Step a 3-Chlorophenylacetic acid (223 mg, 1.307 mmol) was dissolved in MeCN (3 mL). Ammonia solution (28%, 0.26 mL, 3.8 mmol) was added. The mixture was swirled for a while and evaporated in vacuo. The residue was suspended in MeCN (3 mL), filtered and the white 20 solid was washed with MeCN and freeze-dried to afford ammonium 3-chlorophenylacetate (0.195 g, 80%). Following the general procedure for the Ugi reaction, the above ammonium salt (22.5 mg, 0.120 mmol) and a solution of each following two reagents: formaldehyde (2 M in MeOH, 60 pLL, 119 ptmol) and 2-isocyanoethyl 2,3,4,6-tetra-O-benzyl-a-D-mannopyranoside (0.762 M 25 in CHC1 3 , 157 ptL, 120 pimol) was loaded into a 2 mL sample vial and the mixture stirred at r.t. for 19 h. The volatiles were removed under reduced pressure and the residue purified by flash chromatography to give the product as a colourless gum (34.8 mg, 37%). 'H NMR (CDCl 3 , 400 MHz): 8 7.39-7.06 (m, 24H, 4 x C 6

H

5 and 1 x C 6

H

4 ), 6.731 (t, 1H, J= 6.0, NH), 4.878 (d, 1H, J= 10.8, a-CH 2 ), 4.844 (d, iH, J= 2.0, sugar-Hi), 4.770 (d, 1H, J= 12.4, b-CH 2 ), 4.723 (d, 30 1H, J= 12.4, b-CH 2 ), 4.640 (s, 2H, c-CH 2 ), 4.589 (d, 1H, J= 11.6, d-CH 2 ), 4.535 (d, iH, J= 11.6, d-CH 2 ), 4.505 (d, 1H, J= 10.8, a-CH 2 ), 4.446 (d, 1H, J= 14.8, e-CH 2 ), 4.362 (d, 1H, J= 14.8, e-CH2), 3.90-3.51 (in, 12H), 3.38-3.29 (in, 1H). 1 3 C (100 MHz, CDCl 3 , 8 77.0): 169.67, 166.81, 138.27, 138.11, 137.70, 135.16, 134.31, 129.82, 129.40, 128.34, 128.31, 128.01, WO 2005/061523 PCT/AU2004/001800 - 27 127.85, 127.78, 127.70, 127.68, 127.60, 127.53, 127.46, 98.90, 79.96, 75.08, 75.04, 74.71, 73.58, 72.73, 72.19, 72.13, 69.78, 68.49, 63.17, 40.25, 39.27. Step b (PG2075) Following the general procedure for deprotection of benzyl ethers, a mixture of the 5 above tetrabenzyl ether (34.8 mg, 0.0439 mmol), 20% palladium on activated charcoal (26 mg) in MeOH (2 mL) was stirred under hydrogen atmosphere at 50 psi for 2 h. General work-up gave the tetrol intermediate as a colourless gum. Following the general procedure for sulfonation, the above tetrol was sulfonated . The residue was purified via SEC (Bio-Gel P-2). The pure product was converted into the sodium salt by passing through an ion exchange 10 column to give PG2075 as a white fluffy powder after lyophilisation (10.6 mg, 28%, two steps). 1H NMR (D 2 0, int. ref. acetone at 2.05, 400 MHz): 8 7.30-7.11 (m, 4H, Ar), 5.00-4.97 (in, 1H, sugar-Hi), 4.72-4.28 (in, 3H, sugar-H2, H3 and H4), 4.21-3.30 (in, 11H, sugar-H5, H6 and 4 x CH 2 ). Example 13: PG2014 15 Step a Following the general procedure for the Ugi reaction, 2-(benzyl3,4,6-tri-0-benzyl-a-D mannopyranoside-2-yl)acetic acid (50 mg, 0.0835 mmol) and a solution of each following three reagents: benzylamine (2 M in MeDH, 41.8 tL, 0.0835 mmol), formaldehyde (2 M in MeOH, 41.8 pL, 0.0835 mmol) and 2-isocyanoethyl 2,3,4,6-tetra-O-benzyl-a-D 20 mannopyranoside (0.415 M in MeOH, 201.4 pL, 0.0835 mmol) was loaded into a 2 mL sample vial and the mixture stirred at r.t. for 19 h. General work-up gave the product as a colourless gum (38.9 mg, 36%). 'H NMR (400 MHz): two rotamers around amide CO-NH single bond in a ratio of 66:34. 5 7.40-7.05 (in, 45H, 9 x C 6

H

5 ), 6.66 (t, 0.66H, J= 5.6, CONH-major rotamer) and 6.40 (t, 0.34H, J = 5.4, CONH-minor rotamer), 5.104 (d, 0.66H, J = 1.2, H1'-major 25 rotamer) and 5.046 (s, 0.34H, H11-minor rotamer), 4.86-4.20 (in, 21H), 3.97-3.48 (in, 16H), 3.36 (q, 0.66H, J= 5.6, major rotamer) and 3.26 (q, 0.34H, J= 5.6, minor rotamer). Step b (PG2014). Following the general procedure for the deprotection of benzyl ethers, a mixture of the above octabenzyl ether (35 mg, 0.0267 mmol) and 20% palladium on activated charcoal (10 30 mg) in EtOH (4 mL) was stirred under hydrogen atmosphere at 50 psi for 2 h. General work up gave the octol intermediate as a colourless gum. Following the general procedure for sulfonation, the above octol was sulfonated (sulfur trioxide trimethylamine complex, 60 *C, 19 h). The residue was purified via SEC (Bio-Gel P-2). The pure product was converted into the WO 2005/061523 PCT/AU2004/001800 -28 sodium salt by passing through an ion exchange column to give PG2014 as a white powder (16.6 mg, 44%, two steps). 'H NMR (D 2 0, 400 MHz, complicated due to two rotamers): 8 7.32-7.14 (m, 5H, Ph), 5.80-5.66 (m, 0.5H), 5.44-5.39 (in, 0.5H), 5.04-4.96 (in, 1.5H), 4.80 4.20 (m, 9H, overlapped with water), 4.18-3.78 (m, 7.5H), 3.76-3.46 (in, 1.5H), 3.42-2.98 (in, 5 3.5H). Example 14: PG2016 Step a Following the general procedure for the Ugi reaction, trans-1,4-diaminocyclohexane (6.3 mg, 0.055 mmol) and a solution of each following three reagents: 2-(methyl 2,3,4-tri-0 10 benzyla-D-mannopyranoside-6-yl)acetic acid (0.91 M in MeOH, 121 pL, 0.11 mmol), formaldehyde (2 M in MeOH, 55 ptL, 0.11 mmol) and cyclohexylisocyanide (1 M in MeOH, 110 pL, 0.11 mmol) was loaded into a 2 mL sample vial and the mixture stirred at r.t. for 5 days. The volatiles were removed under reduced pressure and purified by flash chromatography (gradient elution with hexanes-EtOAc 2:1 to 1:4) to give the product as a 15 colourless gum, 33.0 mg, 43% (Rf= 0.24, DCM-MeOH 95:5 or Rf= 0.48, MeCN-EtOAc 1:1). 'H NMR (CDCl 3 , 400 MHz, very complicated due to rotamers): 6 7.50-7.20 (m, 30H, Ph), 6.62 (br s, 1.1H), 6.48 (br s, 0.38H), 5.96 (br d, 0.26H, J= 8), 5.79 (br d, 0.26H, J= 10), 4.92-4.85 (in, 2H), 4.78-4.56 (m, 12H), 4.28-4.22 (m, 2.8H), 4.35-4.06 (m, 1.6H), 3.94-3.56 (m, 19.6H), 3.28 (s, 6H, OMe), 1.88-1.42 (in, 16H), 1.36-1.00 (m, 12H). 20 Step b. (PG2016). Following the general procedure for the deprotection of benzyl ethers, a mixture of the above hexabenzyl ether (33 mg, 0.0235 mmol) and 20% palladium on activated charcoal (65 mg) in MeOH (2.8 mL) was stirred under hydrogen atmosphere at 1 atm for 5 days. General work-up gave the hexol intermediate as a colourless gum. Following the general procedure for 25 sulfonation, the above hexol was sulfonated. The residue was purified via sequential column chromatography (SEC on Bio-Gel P-2 followed by ion exchange column) to give PG2016 as a white powder (12.2 mg, 35%). 'H NMR (D 2 0, 400 MHz): 8 4.97-4.92 (in, 2H, man-Hi), 4.77 4.75 (m, 2H, man-H2), 4.58-4.52 (m, 2H, man-H3), 4.46-4.08 (m, 6H, containing man-H4 at 4.46-4.36, and OCH 2 CO), 3.98-3.80 (m, 8H, man-H5, man-H6 and NCH 2 CO), 3.80-3.32 (m, 30 6H, containing man-H6 at 3.80-3.64, and cyclohexyl-CH), 3.318 (s, 6H, OMe), 1.82-1.34 (m, 18H, cyclohexyl-CH2), 1.26-1.00 (m, 10H, cyclohexyl-CH 2 ). ES-MS (+ve, n/z):

C

40

H

62

N

4 Na 6

O

34

S

6 required 1472.10, found 1495 (M+Na*), 1473 (M+H*). ES-HRMS (+ve, WO 2005/061523 PCT/AU2004/001800 -29 m/z): M+Na+, C 4 oH 62

N

4 Na 7

O

3 4S 6 required 1495.0853, found 1495.0957; M+H,

C

40

H

63

N

4 Na 6

O

34

S

6 required 1473.1034, found 1473.1082. Example 15: PG2015 Step a 5 Following the general procedure for the Ugi reaction, 3,3-dinethylglutaric acid (7.1 ig, 0.0443 mmol) and a solution of each following three reagents: 3-aminopropyl 2,3,4,6 tetra-O-benzyl-a-D-mannopyranoside (0.642 M in MeOH, 138 ptL, 0.0886 mmol), formaldehyde (2 M in MeOH, 44.3 [tL, 0.0886 mmol) and cyclohexylisocyanide (1 M in MeOH, 88.6 pL, 0..0886 mmol) were loaded into a 2 mL sample vial and the mixture stirred at 10 r.t. for 5 days. The volatiles were removed under reduced pressure and purified by flash chromatography (gradient elution with hexanes-EtOAc 2:1 to 1:4) to give the product as a colourless gum, 32.3 mg, 46% (Rf = 0.45, hexane-EtOAc 1:3). 'H NMR (CDCl 3 , 400 MHz, very complicated due to rotamers): 6 7.38-7.21 (in, 40H, Ph), 7.003 (d, 0.41H, J= 7.7), 6.930 (br s, 0,21H), 6.726 (d, 0.4H, J= 8.4), 6.597 (d, 0.73H, J= 8.8), 6.487 (br s, 0.25H), 4.85-4.78 15 (in, 4H), 4.76-4.59 (in, 10H), 4.54-4.45 (in, 4H), 4.00-3.62 (in, 20H), 3.46-3.14 (in, 6H), 2.52-2.22 (m, 4H), 1.90-1.52 (in, 15H), 1.34-1.00 (in, 15H). Step b (PG2015). Following the general procedure for the deprotection of benzyl ethers, a mixture of the above hexabenzyl ether (32.3 mg, 0.0202 mmol), 20% palladium on activated charcoal (41 mg) 20 in MeOH (2.8 mL) was stirred under hydrogen atmosphere at 1 atm for 5 days. General work up gave the octol intermediate as a colourless gum. Following the general procedure for sulfonation, the above octol was sulfonated. The residue was purified via SEC (Bio-Gel P-2) to give PG2015 as a white powder (12.6 mg, 37%). 'H NMR (D 2 0, 400 MHz): 6 5.020 (d, 2H, J = 1.6, man-Hi), 4.759 (br s, 2H, man-H2), 4.66-4.56 (in, 2H, man-H3, overlapped with 25 water), 4.46-4.41, (m, 2H, man-H6), 4.265 (t, 2H, J= 9.6, 9.2, man-H4), 4.10-3.96 (in, 4H, ian-H5 and man-H6), 4.05-3.14 (m, 14H, NCH 2 CO, cyclohexyl-CH and NCH 2

CH

2

CH

2 0), 2.50-2.11 (in, 4H, CCH 2 CO), 1.84-1.42 (m, 14H, cyclohexyl-CH2 and NCH 2

CH

2

CH

2 0), 1.24-0.93 (in, 16H, cyclohexyl-CH2 and Me). ES-MS (+ve, m/z): C 4 1

H

93

N

1 0 37 S7 (7 x S0 3

NH

4 ) required 1556, found 1578 (M+Na*), 1556 (M+H+). ES-HRMS (+ve, m/z): M+H* 30 C 41

H

93

N

1 0 37

S

7 required 1556.3857, found 1556.3783.

WO 2005/061523 PCT/AU2004/001800 -30 Example 16: PG2155. Ethyl 2,6-Di-O-benzyl-3,4-di-O-sulfo-/3-D-galactopyranoside, disodiui salt (PG2155) The title compound was obtained from ethyl 2,6-di-O-benzyl-3,4-di-O-sulfo-#3-D galactopyranoside [23] via the general sulfonation procedure as a colourless powder. 'H NMR 5 (400 MHz, D 2 0) .8 1.10 (dd, 3 H; CH 2

CH

3 ); 2.49-2.66 (in, 2H, CH 2

CH

3 ); 3.59 (dd, 1 H, J,22,3 9.7 Hz; H-2); 3.65 (dd, 1 H, J,6a 3.3, J, 6 b 11.0 Hz; H-6a); 3.68 (dd, 1H, J, 6 b 4.0 Hz; H-6b); 3.83 (in, 1 H; H-5); 4.36 (dd, 1 H, J 3

,

4 3.0 Hz; H-3); 4.46 (s, 2 H; CH 2 Ph); 4.48 (d, 1 H; H-1); 4.60, 4.75 (AB quartet, J 10.3 Hz; CH 2 Ph); 4.85 (dd, 1 H; J 4

,

5 0.0 Hz; H-4); 7.22-7.29, 7.37-7.39 (2 m, 10 H; ArH). 10 Example 17: PG2163. Step a: Methyl 4-0-allyl-6-azido-6-deoxy-2,3-di-0-isopropylidene-a-D-mannopyranoside A solution of methyl 6-azido-6-deoxy-a-D-nannopyranoside (311 mg, 1.419 mmol) in 2,2-dimethoxypropane (4.7 mL, 0.3 M) was treated with (1)-camphor-10-sulfonic acid (16 mg, 0.0709 mmol, 5 mol%). The mixture was stirred at r.t. for 1 h. TLC indicated the complete 15 conversion to the product (Rf = 0.40, EtOAc-hexane = 17:83). The mixture was basified by addition of sat. Na 2

CO

3 (aq. sol.) and evaporated under vacuum. The residue was extracted with EtOAc (30 mL) and the EtOAc solution washed with brine, dried (MgS04). Filtration and evaporation gave a gum, which was co-evaporated with toluene once. The final colourless gum was dissolved in anhydrous DMF (3.5 mL, 0.4 M) and stirred with NaH (60% dispersion 20 in mineral oil, 163 mg, 4.257 mmol, 3 eq) for ih. Allyl bromide (360 pL, 4.257 mmol, 3 eq) was added and the mixture stirred at r.t. for another 6 h, treated with methanol (1 mL) and evaporated to dryness. The residue was purified by silica column chromatography (2.5xl 8 cm, eluted with EtOAc-hexane 1:10 to 1:6) to give the title compound as a colourless gum (0.281 mg, 66% over 2 steps). 'H NMR (CDC1 3 , 400 MHz): 5.85 (in, 1H, allyl-2'), 5.23 (ddd, 1H, 25 J 2

-

3 'trns= 17.2, J-gem= 3.6, Jr..

3 = 1.6, H3'trans), 5.17-5.13 (in, 1H, H3'ci,), 4.89 (s, 1H, Hi), 4.35 (dddd, 1H, Jsem= 12.4, Jr-.

2 ,= 5.2, J= 1.6, Hi'), 4.16 (dd, 1H, J 2

.

3 = 5.6, J 3 4= 7.2, H3), 4.09 (d, 1H, H2), 4.05 (dddd, 1H, Hi'), 3.67 (ddd, 1H, J 4

.

5 = 10.4, J-a = 6.8, J5-6eq = 2.4, H5), 3.48 (dd, IH, Jax-6eq= 13.2, H6eq), 3.40 (dd, 1H, Jx-6eq = 13.2, J 5

-

6 ax = 6.8, H6ax), 3.33 (dd, 1H, H5), 1.50 (s, 3H, Me), 1.30 (s, 3H, Me). 13C NMR (CDCl 3 , 100 MHz): 134.4, 117.1, 109.2, 30 98.0, 78.2, 76.2, 75.6, 71.5, 68.0, 54.9, 51.6, 27.8, 26.1. Step b: Methyl 4-0-allyl-6-azido-6-deoxy-a-D-mannopyranoside Methyl 4-O-allyl-6-azido-6-deoxy-2,3-di-0-isopropylidene-a-D-mannopyranoside (56 mg, 0.187 mmol) was dissolved in MeCN-MeOH-H 2 0 (3 mL, 3 mL and 0.2 mL respectively) WO 2005/061523 PCT/AU2004/001800 -31 and treated with p-toluenesulfonic acid monohydrate (7 mg, 0.0374 mmol, 20 mol%). The mixture was stirred at r.t. for 5 h and triethylamine (0.4 mL) added. The mixture was evaporated and the residue purified by column chromatography (silica lx18 cm, eluted with EtOAc-hexane 1:6 to 2:1) to give the product as a colourless waxy solid (34.8 mg, 72%). IH 5 NMR (CDC1 3 , 400 MHz): 5.91 (m, 1H, allyl-H2'), 5.28 (ddd, 1H, J 2 '-3'trans = 16.8, Jtrans- 3 'cis = 3.0, Jr..y3 = 1.6, allyl-H3'trans), 5.20 (ddd, 1H, J2'-3',1s = 10.0, J 3 'trans- 3 'oIs 3.0, Jip 3 ' = 1.6, allyl-H3'c's), 4.72 (ddd, 1H, J1.

2 = 2.0, Hi), 4.28 (dddd, 1H, Jgem = 12.4, Jx- 2 '= 5.6, J= 1.6, allyl-l'), 4.13 (dddd, IH, allyl-l'), 3.92 (dd, 1H, J 2

.

3 = 3.6, H2), 3.88 (dd, 1H, J 3 4 = 9.6, H3), 3.70 (ddd, 1H, J 4

.

5 = 9.6, J- 6 ax= 5.6, J5-6eq = 2.8, H5), 3.54-3.44 (in, 3H, H4, H6ax and H6eq), 10 3.39 (s, 3H, MeO), 2.62 (br s, 2H, OH). Step c: Methyl 4-0-allyl-6-azido-2-0-benzyl-6-deoxy-2,3-di-O-sulfonato-a-D mannopyranoside disodium salt (PG2163) Methyl 4-0-allyl-6-azido-6-deoxy-a-D-mannopyranoside was sulfonated according to the standard procedure to yield the title compound as a white powder, 55 mg (89%). Rf = 0.20 15 (EtOAc-MeOH-H 2 O=10:2:1). 1 H NMR (D 2 0, 400 MHz): 5.88-5.76 (m, IH, allyl-2'), 5.20 (d, 1H, J 2 -3'trans = 17.2, allyl-3'trans), 5.12 (d, 1H, J 2

'

3 ois = 10.0, allyl-3'cis), 4.91 (s, 1H, HI), 4.65 (br s, 1H, J 2 3= 3.2, H2), 4.48 (dd, 1H, J 2 .= 3.2, J 3

.

4 = 9.2, H3), 4.21 (dd, 1H, Jgem 11.6, J' 2 '= 5.6, allyl-l'), 4.00 (dd, 1H, Jp- 2 '= 6.4, allyl-l'), 3.71-3.67 (in, 1H, H5), 3.58 (dd, 1H, J6eq-6ax= 13.6, J.6eq = 2.0, H6eq), 3.58 (dd, 1H, J 4

.

5 = 9.6, H4), 3.46 (dd, 1H, J6eq-ax= 13.6, J 5

-

6 ax= 5.6, 20 H6ax), 3.30 (s, 3H, MeO). 13 C NMR (D 2 0, 100 MHz, internal MeOH at 49.05 ppm): 133.9, 119.2, 98.4, 76.1, 75.3, 74.2, 73.1, 70.7, 55.4, 50.8. Example 18: PG2160, PG2161 and PG2173. Step a: Methyl 6-azido-6-deoxy-2,3-di-O-benzylidene-a-D-mannopyranoside Methyl 6-azido-6-deoxy-oc-D-mannopyranoside (1.011 g, 4.61 imol) was dissolved in 25 anhydrous DMF (9 mL) and acetonitrile (9 mL). Benzaldehyde dimethyl acetal (1.38 mL, 9.22 mmol, 2 eq) and (1)-camphor-10-sulfonic acid (214 mg, 0.922 mmol, 20 mol%) were added in that order. The mixture was stirred under house vacuum at 60 'C (external) overnight, and the volatile materials were removed on rotavap. The residue was loaded on silica gel and purified by column (silica 2.5x20 cm, gradient elution with hexane-ethyl aceate 10:1, 9:1, 7:1, 5:1, 4:1, 30 3:1 to 2:1). The fractions were pooled into two parts. The less polar part (Rf = 0.55 and 0.51, hexane-EtOAc 3:1) was a mixture of 4-acetals and the polar part was mainly the 4-OH product. The mixtures were combined and evaporated. The residue was re-dissolved in dichloromethane (50 mL) and stirred with 1M ammonium chloride solution (50 mL). The less WO 2005/061523 PCT/AU2004/001800 -32 polar spots were slowly disappeared and converted into the polar product. However, the conversion was not further improved after 40 min. Thus the dichloromethane phase was separated and stirred with 0.5 M HCl solution (50 mL) for another 20 min. TLC indicated no further change. The DCM phase was separated and washed with brine-1M NaOH, dried 5 (MgSO 4 ). The dried DCM solution was filtered, evaporated and the residue was purified by silica column as above to give the title compound as a colourless gummy solid (0.543 g, 38%, Rf = 0.29, EtOAc-hexane = 1:3). 1H NMR (CDCl 3 , 400 MHz): two benzylidene epimers in a ratio of 1:1. 7.49-7.36 (In, 5H, C 6

H

5 ), 6.126 and 5.902 (2xs, 1H, benzylidene-CH), 5.066 and 4.987 (2xs, 1H, sugar-Hi), 4.396 (dd, 0.5H, J= 6.4, 5.6, sugar-H3), 4.248 (dd, 0.5H, J= 6.4, 10 6.0, sugar-H3), 4.214 (dd, 0.5H, J= 6.0, sugar-H2), 4.102 (dd, 0.5H, J = 4.8, sugar-H2), 3.86-3.38 (in, 4H), 3.466 and 3.424 (2xs, 3H, CH 3 0), 2.984 (br s, 1H, OH). "C NMR (CDCl 3 , 100 MHz): 138.01, 136.41, 129.38, 128.99, 128.24, 128.12, 126.41, 125.86, 103.85, 102.60, 97.74, 97.53, 79.36, 77.75, 77.47, 74.81, 70.00, 68.91, 68.42, 66.97, 54.78, 51.18 and 51.10. Step b: Methyl 6-azido-3-O-benzyl-6-deoxy-a-D-mannopyranoside and methyl 6-azido-2-0 15 benzyl-6-deoxy-a-D-mannopyranoside A solution of methyl 6-azido-6-deoxy-2,3-di-O-benzylidene-c-D-mannopyranoside (240 mg, 0.781 mmol) in DMF (7.8 mL, 0.1 M) was treated with sodium cyanoborohydride (589 mg, 9.37 mmol, 12 eq) and molecular sieve 3A (1 g). The mixture was stirred at r.t. for 20 min, then at 70 *C while TFA (0.361 mL, 4.686 mmol, 6 eq) was added slowly. After 20 addition, the mixture was stirred at 70 *C for 6 h, cooled to 0 'C and basified by addition of solid Na 2

CO

3 . The cold mixture was filtered and the cake washed with EtOAc. The filtrate and washings was extracted once with sat. Na 2

CO

3 . Evaporation gave a gum, which was purified by column chromatography (silica 2.5x1 8 cm, eluted with EtOAc-hexane 1:4 to 1:1) to give methyl 6-azido-3-0-benzyl-6-deoxy-a-D-mannopyranoside (colourless gum, 64 mg, 26%, 25 Rf = 0.45, EtOAc-hexane=l:1); 1H NMR (CDCl 3 , 400 MHz): 7.41-7.32 (in, 5H, Ph), 4.78 (d, 1H, J1.

2 = 1.6, HI), 4.70 (d, 1H, Jgem= 12.0, CH 2 ), 4.56 (d, 1H, CH 2 ), 4.02 (dd, 1H, J 2

..

3 = 3.2, H2), 3.78 (dd, 1H, J 3

-

4 = 8.4, J 4

.

5 = 10.0, H4), 3.73 (ddd, 1H, J 5 .6ax = 6.0, J5-6eq= 3.2, H5), 3.64 (dd, 1H, H3), 3.52 (dd, 1H, Jax-eq = 13.2, H6eq), 3.47 (dd, 1H, Jx..eq = 13.2, J 5

-

6 ax = 6.0, H6ax), 3.40 (s, 3H, MeO), 2.21 (br s, 2H, 2xOH) and methyl 6-azido-2-0-benzyl-6-deoxy-a-D 30 mannopyranoside (colourless waxy solid, 62 mg, 26%, Rf = 0.27, EtOAc-hexane=1:1). 'H NMR (CDCl 3 , 400 MHz): 7.38-7.28 (m, 5H, Ph), 4.78 (s, 1H, Hi), 4.71 (d, 1H, J= 11.6, CH 2 ), 4.53 (d, 1H, J= 11.6, CH2), 3.75-3.61 (m, 4H, H2, H3, H4 and H5), 3.53 (dd, 1H, J= 13.2, 1.5, H6eq), 3.46-3.40 (dm, 1H, J= 13.2, H6ax), 3.38 (s, 3H, MeO), 2.83 (br s, 2H, 2x0H).

WO 2005/061523 PCT/AU2004/001800 -33 Step c: Methyl 6-azido-2-0-benzyl-6-deoxy-2,3-di-O-sulfonato-a-D-mannopyranoside disodium salt (PG2160) Methyl 6-azido-2-0-benzyl-6-deoxy-a-D-nannopyranoside was sulfonated according to the standard procedure to yield the title compound as a white powder, 64 mg, 59%. 'H NMR 5 (D 2 0, 400 MHz): 7.38-7.26 (m, 5H, Ph), 4.72 (d, 1H, Jgem = 12.0, CH 2 Ph), 4.59 (d, 1H, J-2 = 2.0, HI), 4.58 (d, 1H, CH 2 Ph), 4.49 (d, 1H, J 2 -3 = 2.8, J 34 = 9.6, H3), 4.44 (dd, 1H, J 4 5 = 9.6, H4), 4.07 (dd, 1H, H2), 3.78 (ddd, 1H, J 5

-

6 ax 5.6, J5-6eq = 2.4, H5), 3.62 (dd, 1H, J6ax-6eq 13.2, H6eq), 3.51 (dd, 1H, Jax-6eq= 13.2, Js-6= 5.6, H6ax), 3.22 (s, 3H, MeO). Step d. Methyl 6-azido-3-0-benzyl-6-deoxy-2,4-di-O-sulfonato-a-D-nannopyranoside 10 disodium salt (PG2161) Methyl 6-azido-3-0-benzyl-6-deoxy-a-D-mannopyranoside (64 mg) was sulfonated according to the standard procedure to yield the title compound as a white powder, 58 mg, 66%. 'H NMR (D 2 0, 400 MHz): 7.42-7.21 (m, 5H, Ph), 4.92 (d, 1H, Ji-2 = 2.4, Hi), 4.67 (d, 1H, Jgem= 12.4, CH 2 Ph), 4.60 (d, 1H, CH 2 Ph), 4.56 (dd, 1H, J 2 -3 = 3.2, H2), 4.35 (dd, 1H, J 3

.

4 = 15 9.6, J 4 5 = 9.6, H4), 3.80 (dd, 1H, H3), 3.75 (ddd, 1H, J- 6 ax = 6.0, J5-6.eq = 2.8, H5), 3.66 (dd, 1H, Jax-6eq= 13.4, H6eq), 3.54 (dd, iH, Jax-6eq= 13.4, J 5

-

6 ax= 6.0, H6ax), 3.29 (s, 3H, MeO). Step e: Methyl 6-['-(4-phenyl)triazolyl]-2-0-benzyl-6-deoxy-2,3-di-O-sulfonato-a-D mannopyranoside disodium salt (PG2173) Methyl 6-azido-2-0-benzyl-6-deoxy-2,3-di-O-sulfonato-c-D-nannopyranoside disod 20 ium salt was subjected to the Huisgen reaction general procedure using phenyl acetylene to yield the title compound as a white powder 6.8 mg, 67%, Rf = 0.34, EtOAc-MeOH-H 2 0 = 10:2:1. 'H NMR (D 2 0, 400 MHz): 8.26 (s, 1H, triazole), 7.64-7.60 (m, 2H), 7.37-7.15 (m, 8H), 4.89 (dd, 1H, J= 14.4, 2.8, H3), 4.67 (d, 1H, J= 12.0, PhCH 2 ), 4.57-4.39 (m, 5H, PhCH 2 , Hi, H4 and H6eq and H6ax), 4.04 (dd, 1H, J= 2.8, 2.0, H2), 3.99 (ddd, 1H, J= 9.2, 8.8, 2.4, 25 H5), 2.83 (s, 3H, MeO). Example 19: PG2170 Allyl 6-azido-2,3-0-disulfonato-6-deoxy-4-0-(1-naphthylnethyl)-a-D-mannopyranoside disodium salt (containing 10% of 2-naphthylmethyl isomer) (PG21 70) The title compound, prepared analogously to PG2163 beginning with allyl 6-azido-6 30 deoxy-a-D-mannopyranoside, was obtained as a white powder 87.5 mg, 87%, Rf= 0.28 (major), 0.22 (minor), EtOAc-MeOH-H 2 0 = 10:2:1. 1 H NMR (D 2 0, 400 MHz): 7.87 (d, 1H, J = 8.4, naphthyl), 7.65-7.54 (m, 2H, naphthyl), 7.33-7.19 (m, 4H, naphthyl), 5.68 (ddt, 1H, JanyI2'-3'trans= 22.0, Jan1yI-cks= 10.8, Jallyll-2'= 6.0, allyl-2'), 5.23 (AB quartet, 2H, Jgem= 12.0, WO 2005/061523 PCT/AU2004/001800 -34 naphthyl-CH 2 ), 5.17-5.02 (m, 3H, allyl-3' and Hi), 4.74 (dd, 1H, J 1

..

2 = 2.0, J 2 -3= 3.2, H2), 4.64 (d, lH, J 3

-

4 = 9.6, H3), 3.90 (dd, 1H, JaiiyIIgem= 13.2, J= 6.0, allyl-1'), 3.81 (dd, 1H, allyl-l'), 3.64 (t, 1H, J 4

-

5 = 9.6, H4), 3.39 (ddd, 1H, J.

6 eq= 2.0, J6.= 5.2, H5), 2.78 (dd, 1H, J6eq-6ax= 13.6, H6eq), 2.68 (dd, 1H, J 5

-.

6 a= 5.2, J6eq-6x= 13.6, H6ax). Typical signals for minor isomer 5 2-naphthylmethyl derivative: 4.84 (AB quartet, 2H, Jgem= 11.2, naphthyl-CH 2 ), 3.52 (ddd, 1H, J4.s= 10.0, J-6eq = 2.4, J-6,sax= 6.0, H5), 3.07 (dd, 1H, J6eq-6x= 13.6, H6eq), 2.96 (dd, 1H, J6eq-6ax= 13.6, Js- 6 = 6.0, H6ax). The source of the minor isomer is the commercial 9:1 mixture of 1- and 2-bromomethylnapthalene used in step a. Additional compounds were synthesized using appropriate modifications of the 10 syntheses detailed above in Examples 1 to 19. These additional compounds are included in the tables giving the results of biological testing of compounds according to the invention. Example 20 Biological Testing of Compounds Methods 15 1. Growth Factor Binding Binding affinities of ligands for the growth factors were measured using a surface plasmon resonance (SPR) based solution affinity assay. The principle of the assay is that heparin immobilised on a sensorchip surface distinguishes between free and bound growth factor in an equilibrated solution of the growth factor and a ligand. Upon injection of the 20 solution, the free growth factor binds to the immobilised heparin, is detected as an increase in the SPR response and its concentration thus determined. A decrease in the free growth factor concentration as a function of the ligand concentration allows for the calculation of the dissociation constant, Kd. It is important to note that ligand binding to the growth factors can only be detected when the interaction involves the heparin binding site, thus eliminating the 25 chance of evaluating non-specific binding to other sites on the protein. A 1:1 stoichiometry has been assumed for all protein:ligand interactions. The preparation of heparin-coated sensorchips, via immobilisation of biotinylated BSA heparin on a streptavidin-coated sensorchip, has been described [24]. Heparin has also been immobilised via aldehyde coupling using either adipic acid dihydrazide or 1,4-diaminobutane. 30 For each Kd measurement, solutions were prepared containing a fixed concentration of protein and varying concentrations of the ligand in buffer. Ligands binding to FGF-1 and VEGF were measured in HBS-EP buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3.0 mM EDTA and 0.005% (v/v) polysorbate 20), while binding to FGF-2 was measured in HBS-EP buffer WO 2005/061523 PCT/AU2004/001800 -35 containing 0.3 M NaCi [24]. Prior to injection, samples were maintained at 4 'C to maximise protein stability. For each assay mixture, 50-200 ptL of solution was injected at 5-40 pL/min and the relative binding response measured. All surface binding experiments were performed at 25 'C. The surface was regenerated by injection of 40 PL of 4M NaCl at 40 pL/min, 5 followed by injection of 40 iL of buffer at 40 pL/min. Sensorgram data were analysed using the BIAevaluation software (BlAcore). Background sensorgrams were subtracted from experimental sensorgrams to produce curves of specific binding, and baselines were subsequently adjusted to zero for all curves. The relative binding response for each injection was converted to free protein concentration using the 10 equation [P]= r [P].oi r, where r is the relative binding response and r.. is the maximal binding response. Binding equilibria established in solution prior to injection were assumed to be of 1:1 stoichiometry. Therefore, for the equilibrium, P+L ' P-L where P corresponds to the growth factor protein, L is the ligand, and P-L is the protein:ligand 15 complex, the equilibrium equation is K _[P][L] dp] and the binding equation [24] can be expressed as [p3 = [p3 (Kd + [L]lotal + [r total) + (Kd_+_[ ltotai + [lil 0 ,)2 The Kd values given are the values fit, using the binding equation, to a plot of [P] versus [L] 1 ora. Where Kd values were measured in duplicate, the values represent the average of the duplicate measurements. It has been shown that GAG mimetics that bind tightly to these 20 growth factors elicit a biological response in vivo [24]. 2. Antiviral Assays. Selected compounds were tested against two types of herpes simplex virus (HSV), i.e., WO 2005/061523 PCT/AU2004/001800 -36 HSV-1 and HSV-2, in two assays for inhibition of viral infectivity and cell-to-cell spread, as described by Nyberg et al. [25]. Monolayer cultures of African green monkey kidney cells (GMK AH1) [26] cultivated in 6-well cluster plates, were used. The viral strains used were herpes simplex virus type 1 (HSV-1) KOS321 strain [27] and HSV-2 strain 333 [28]. 5 In both assays the compounds were tested at 200 pM. (i) In the assay of HSV infectivity, the compounds were mixed with the virus, incubated for 10 min at room temperature and then the mixture was added to cells, and kept on cells for lh only to allow (or not) the virus attachment to/entry into the cells. Thus this assay reflects whether or not the compound in question has the 10 ability to bind to the virus particles and block its attachment to/entry into the cells. An inhibition is manifested as a decreased number of viral plaques. (ii) The next assay, termed HSV spread, relies on the addition of compound to the cells after the virus attachment/entry steps have already occurred. This assay reflects whether the examined compound has the ability to inhibit virus transmission from 15 an infected to an uninfected cell (cell-to-cell spread) and in addition whether the compound has the ability to enter the cells and inhibit viral replication. Lack of compound activity in the assay of virus infectivity but some activity in the virus spread assay suggests that the compound acts by entering the cells and inhibition of viral replication step(s). An inhibition is manifested as a reduction in the size of 20 viral plaques. The results (see Table 5) are expressed as % of control, ie., as the number (infectivity assay) or the size (spread assay) of viral plaques developed in the presence of compound relative to the mock-treated controls (no compound). Results 25 The results of the tests as described in the preceding section are presented in Tables 1 to 5. Table 1 RH Ri RG O RR R 0 RA 30 WO 2005/061523 PCT/AU20041001800 -37 PG # Kd aFGF Kd bFGF Kd VEGF Kd iFGF-4 RA,RF,RH,RIOMe; RB,Rc,RE=OSO 3 Na; 2019 218 uiM 657 iiM 912 jaM

RD=CH

2

OSO

3 Na; RG=H RA,RF,RH=OMe; RB,Rc,RE,Ri=OSO 3 Na; 2037 47.7 jaM 507 jaM 645 jaM

RD=CH

2

OSO

3 Na; R 0 ,=H RF,RH,Ri=OH; RA=OMe; RB,RC-,REOSO 3 Na; 2038 77.9 jaM 2.10 mM 368 jaM

RD=CH-

2

OSO

3 Na; RG-H RA=OMe; RF,RHIOH; RB,&,RE,Ri=OSO 3 Na; 2039 21.8 jaM 3.50 mM 1.27 mM

RD=CH

2

OSO

3 Na; Rj-H RF,RG,RI=OH; RD-RA=-CH2O-; RB,RE =NHSO 3 Na; 2046 6.35 mM 3.70 mM 1.50 mMv R~c7OBn; RH=H RF,RGo,RI,Rc=OH; RD-RA=-CH 2 O-; RB,RE=NHSO 3 Na; 2047 388 jaM 1.95 mlv 2.55 mM RH=H

RF,RH,R

1 =OH; RAgOMe; RB,Rc,REOSO 3 Na; 2063 1.39 mM 2.35 mlv 2.59 mM RD,RO=-H Table 2 RR Rs RQ",-- 0 IV RN R RL RM 5 PGA# Kd aFGF Kd bFGF Kd VEGF RKOMe; RM,RoOSO 3 Na; RQ OBII; RR =CH 3 ; 2023 1.76 mM 4.90 mM 2.27 mM RI,RL,RN,R,Rs=H RK=OMe; RM,R&--OSO 3 Na; Rp=OBn; RR=CHS; 2024 4.73 mM 3.65 mM 6.40 mMv RJ,RL,RN,RQ,Rs=H RK ;OMe; RM,RN=OBz; RQ=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2028 1.10 mM 9.25 mM > 1.65 mM RJ,RL,RO,Rp,RR=H RK=OMe; Rm,RO=OSO 3 Na; RQ=Oallyl; RR=CH 3 ; 2029 1.34 mMv > 10.00 mM 236 jaM Rj,RL,RN,Rp,Rs=H RS-RK= -CH 2 O-; RM=OSO 3 Na; RN=OMe; R<=OBn; 2030 317 p.M 4.61 mM Rj,RL,RO,Rp,RR=H

RN=O(CH

2

)

3 OPh;RQ='OSO 3 Na; Rs=CH 2 OSO3Na; 2040 12.9 mM 7.50 mM 2.44 mMv Rj,RK,RL,RM,Ro,Rp,RR'7H RN=OBn;RQ=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2041 9.3 8 mM 5.10 mM 1.04 mMv Rj,RK,RL,RM,R0,RP,RR=H RKOMe; RM=OSO 3 Na; R 0 =OH; Rp=Oallyl; RR=CH 3 ; 2042 3.05 mM 10.7 niM 2,59 mM Rj,RL,RN,RQ,Rs=H WO 2005/061523 PCT/AU2004/001800 -38 PG # KdaFGF Kd bFGF Kd VEGF RN=OMe;Ro=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2043 6.43 mM 17.4 mM 1.73 mM RJ,RK,RL,R,Ro,R,RR=H RK =OMe; R,Ro=OSO 3 Na; Rp=OOCCH 2

CH

2 Ph; Ra=CH 3 ; 2044 366 pM 1.55 mM 1.65 mM Rj,RL,RN,R,Rs=H Rj/RK=H/OMe (anomeric mixture); Rs-RN= -CH 2 0-; 2045 392 pM 3.40 mM 1.07 mM RM=OSO3Na; Rq=OBn; RL,RO,RP,RR=H RK=OMe; RN,R=OH; Ro=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2048 233 pM 5.30 mM 796 gM Rj,RL,RO,Rp,RR7H RK=OMe; RN,RM=OBn; Ro=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2049 1.51 mM >> 60.0 pM 2.72 mM Rj,RL,R,R,RR=H RK=OMe; Rm =OSO 3 Na; RN,Ro=OBn; 2050 3.31 mM 8.25 mM ~ 10.00 mM Rj,RL,R,R,RR,Rs=H RK=OMe; R,RN=OBn; Ro=OSO 3 Na; 2051 2.46 mM > 20.4 mM 4.63 mM Rj,RL,RO,RP,RR,Rs=H RK=OMe; R,Ro=OSO 3 Na; Re=OOCCH 2 OPh; RR=CH 3 ; 2052 5.92 mM 4.50 mM 686 M Rj,RL,RN,RQ,Rs=H Rx=OMe; R,Ro=OSO 3 Na; Rp=Oa11y1; RR=CH 3 ; 2053 1.30 mM 5.17 mM 343 gM Rj,RL,RN,R,Rs=H RK=OMe; R,RO=OSO 3 Na; R,=OBz; RR=CH 3 ; 2054 454 pM 2.73 mM 403 pM Rj,RL,RN,RQ,Rs=H RKOMe; R,Ro=OSO 3 Na; Rp=OOCPh(p-OMe); RR=CH3; 2056 797 pM 2.45 mM 485 M Rj,RL,RN,R,Rs=H Rs-RN= -CH 2 0-; RL=OSO 3 Na; R 0 =OBn; 2079 1.92 mM ~ 3.45 mM 1.73 mM Rj,RK,R,Ro,R,RR=H Rs-RN= -CH 2 0-; RM=OSO 3 Na; R 0 =OBn; 2080 1.62 mM - 11.7 mM 1.36 mM RJ,RK,RL,R,R,RR=H RK=OMe; R,Ro=OSO 3 Na; Rp=OCH 2 Cyclohexyl; RR=CH 3 ; 2085 9.60 mM ~ 17.4 mM 8.90 mM RJ,RL,RN,RQ,RS=H RK=OMe; R,Ro=OSO 3 Na; R,=O(CH 2

)

3 OPh; RR=CH3; 2086 3.05 mM 1.50 mM RJ,RL,RN,RQ,Rs=H RK=OMe; R,RO=OSO3Na; Rp=OH; RR=CH 3 ; 2087 566 pM 2.35 mM 899 pM Rj,RL,RN,RQ,Rs=H RK=OMe; R,Ro=OSO 3 Na; Rp=O(CH2) 3 Ph; RR=CH 3 ; 2088 676 pM 3.00 mM 761 pM RJ,RL,RN,R,Rs=H RK=OMe; RM,RO=OSO 3 Na; Rp=OCH 2 (2-Napthy1); 2089 1.20 mM 2.15 mM 2.33 mM

RR=CH

3 ; RJ,RL,RN,R,RS=H RK=OMe; R,Ro=OSO 3 Na; Rp=OCH 2 (E)CH=CHPh; 2090 3.85 mM 2.50 mM 3.02 mM

RR=CH

3 ; RI,RL,RN,R,Rs=H RK=OMe; R,RO=OSO 3 Na; Rp=OCH 2 (1-Napthyl); 2091 1.37 mM 1.50 mM 1.98 mM

RR=CH

3 ; RJ,RL,RN,R,Rs=H WO 2005/061523 PCT/AU20041001800 -39 PG#4 KdaFGF Kd bFGF Kd VEGF RK=OMe; RmRO=OSO 3 Na; Rp=OCH 2 Ph(p-Me); ReCH 3 ; 2092 2.70 mM 2.85 mM 2.86 mM Rj,RL,RN,R 4 Q,Rs=H RK7OMe; Rm,R.O=-OSO 3 Na; Rp=OOCPh(p-NO 2 ); RR =CH 3 ; 2093 10 m 16 M 86g Rj,RL,RN,RQ,Rs=H

RK=NHCOCH

2 OPh(2,4-di-C1); Rm,RN,RQ=OS0 3 Na; 2096 35.7 IiM 141 i'M 20.4 4'M Rs=CH 2

OSO

3 Na; RJ,RL,Ro,Rp,RRH Rj=OMe; RLR=OBz; RQ=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2097 127 i'M 2.05 mM 267 i'M RK,Rm,R,Rp,RRH RK=OMe; Rm,RO=OSO 3 Na; Rp=OCH 2 Ph(p-CF 3 ); RR=CH 3 ; 2098 -7.85 mM 2.65 mM 2.60 mMv RI,RL,RN,RQ,Rs=H RK7OMe; RM,RO=OSO 3 Na; Rp=OCH2Ph(m-CF 3 ); RR7CH 3 ; 2099 1.30 mM 2.85 mM 5.70 mlv Rj,RL,RN,RQ,Rs=H Rj=OMe; RL,RQ=OSO 3 Na; RN=Oallyl; Rs=GH 2 Oa1y1; 2100 1.25 mnM -18.1 mM 146 i'M RK,Rm,Ro,Rp,RRH Rj -OMe; RL,RN=OH; RQ=OSO 3 Na; Rs=CH 2

OSO

3 Na; 2101 77.3 i'M 188 i'M RK,Rm,R,Rp,RRH RK-OMe; Rm,RO=OSO 3 Na; Rp=OMe; RRCH 3 ; 2102 116 [tM 1.30 mM 206 i'M Rj,RL,RN,RQ,Rs=H RK=OMe; Rm,RO=-OSOJNa; Rp=OCH 2 Cyclopropyl; 2103 5.50 mM 4.20 muM 3.00 mMv RR7CH 3 ; RJ,RL,RN,RQ,RSH

RK=N

3 ; RM,RO=OSO 3 Na; Rp=OBn; RR=CH 3 ; 2104 1.80 mM 2.45 mMv 3.30 mMv RJ,RL,RN,RQ,Rs=H Rj=N 3 ; RM=OSO 3 Na;RO=OH; Rp=OBn; RRr=CH 3 ; 2105 1.85 mMv 2.10 mM 8.30 mM RK,RL,RN,RQ,Rs=H RK=-OBn; Rpj 1

,R

0

=OSO

3 Na; Rp=OMe; RRCH 3 ; 2106 1.31 mM 3.43 mMv 1.45 mM RI,RL,RN,RQ,Rs=H RK=OMe; RM,RNOOCPh(p-OMe); R 0

=OSO

3 Na; 20 4 L Rs=CH 2

OSO

3 Na; RJ,RLR,Rp,RRH 20 4 ' RK7OMe; Rm,RNOCH 2 (E)CH=CR~h; RQ=OSO 3 Na; 2108 563 pM Rs=CH,OSO 3 Na; RJ,RL,Ro,Rp,RRH RK=OMe; Rm,RN=OOCPh(p-NO2D; R=OS0 3 Na; 2109 441 gM 1.00 mM Rs=CH 2

OSO

3 Na; RJ,RL,RO,Rp,RR =H RK-Rs=-OCH 2 -; Rm=3-phenyl-[1,2,3]triazol-l-yl; 2110 2.80 mM

RN,RQ=OSO

3 Na; Rj,RL,R,Rp,RRH RK=OMe; Rm,RO=OSO 3 Na; Rp=OOCPh(3,4-di-C1); 2111 1.30 mM 1.60 mM

RR=CH

3 ; Rj,RL,RNRQ,Rs=H RK=OMe; Rm,RO=OSO 3 Na; Rp=OOCCH 2 Ph(nz-C1); 2112 2.30 mMv 2.55 mM 4.10mM RR7CH 3 ; RJ,RL,RN,RQ,Rs=H RK=OMe; Rm,RO=OSO 3 Na; Rp=OOCCH 2 Ph(3,4-di-C1); 2113 1.45 mM 1.60 mM 1.60 mM RR=CH3; Rj,RL,RN,RQ,Rs=H WO 2005/061523 PCT/AU2004/001800 - 40 PG # Kd aFGF Kd bFGF Kd VEGF RK=OMe; RM,RO=OSO 3 Na; Rp=OOCCH2Ph(p-CF3); 2114 3.85 mM 2.30 mM 888 pM RR=CH3; RJ,RL,RN,RQ,Rs=H Rj=OMe; RL=OMe; RN=Oallyl; R 0

=OSO

3 Na; 2129 5.40 mM 9.10mM 3.00 mM Rs=CH 2

OSO

3 Na; RK,R,R,Rp,RR"H Rr=OMe; RL,RN=OSO 3 Na; Ry=OMe; Rs=CH 2 Oallyl; 2130 1.05 mM 7.85 mM 361 gM RK,Rm,Ro,Rp,RR=H RK=OMe; R,Ro=OSO 3 Na; Rp=OEt; RR=CH 3 ; 2131 8.30 mM 7.20 mM - 21.8 mM RJ,RL,RN,RQ,Rs=H R=OMe; RL,RN,RQ=OAc; Rs=CH 2

OSO

3 Na; 2137 > 20.0 mM - 8.80 mM RK,RM,Ro,Rp,RR=H Rj=OMe; RL,RQ=OSO3Na; RN=Oallyl; Rs=CH20C(Ph3); 2139 884 pM 2.70 mM 383 pM RK,RM,Ro,Rp,RR=H RrOMe; RL=OSO 3 Na; RN=Oallyl; RQ-OCH 2

(CH

3

)C=CH

2 ; 2140 1.90 mM 862 pM Rs=CH 2 0CH 2

(CH

3

)C=CH

2 ; RK,R,R,Rp,RR=H Rj=OMe; RL,RQ=OSO3Na; RN=Oallyl; Rs-CH 2 OMe; 2141 4.90 mM 613 pM RK,RM,Ro,Rp,RR=H Rj=OMe; RL,Ro=OSO 3 Na; RN=Oallyl; 2142 3.00 mM 481 pM Rs=CH 2 0CH 2

(CH

3 )C=CH2; RK,Rm,R 0 ,Rp,RR=H RK=Oallyl; RM=OMe;RN=4-phenyl-[1,2,3]triazol-1- 2143 1.10 mM 398 sM yl,Rr=OSO 3 Na; Rs=CH 2

OSO

3 Na; RJ,RL,Ro,Rp,RRA=H

RK=NHCOCH

2 OPh(2,4-di-Cl); R,RN,R=OH; 2144 6.00 mM 3.00 mM Rs-CH 2

OSO

3 Na; RJ,RL,R,Rp,RRH R=OMe; RL,RQ=OSO 3 Na; RN=Oallyl; Rs=CH 2 OH; 2145 - 5.95 mM ~ 23.0 mM 1.60 mM RK,Rm,Ro,Rp,R,=H R=OMe; RL,RQ=OSO 3 Na; RN=Oallyl; Rs=CH 2 OBn; 2147 1.50 mM 9.10 mM 2.10 mM RK,RM,Ro,Rp,RR=H

R

1 =OMe; RL,RQ=OSO 3 Na; RN=Oallyl; Rs=CH20CH2(3- 2148 2.40 mM ~ 13.0 mM 981 pM pyridyl); RK,RM,Ro,Rp,RR=H

R

1 =OMe; RL,Rc=OSO 3 Na; RN=OCI-1 2 (2-napthyl); 2149 2.50 mM ~ 6.70 mM 709 pM Rs=CH 2 OH; RK,R,R,Rp,R=H

R

1 =OMe; RL,RQ=OSO 3 Na; RN=OBn; Rs=CH 2 OH; 2150 >> 6.00 mM ~ 24.2 mM 7.80 mM RK,R,Ro,Rp,RR=H

R

1 =OMe; RL,RQ=OSO 3 Na; RN=OBn; Rs=CH 2 Oallyl; 2151 3.50 mM ~ 9.90 mM 935 pM RK,R,Ro,Rp,RC=H RK=OMe; R,Ro=OSO 3 Na; Rp=OPr; RR=CH 3 ; 2152 ~ 6.30 mM 3.40 mM RJ,RL,RN,R,Rs=H Rj=OMe; RL,RQ=OH; RN=OSO 3 Na; Rs=CH 2

N

3 ; 2153 - 11.5 mM >> 42.1 mM ~11.1 mM RK,R,Ro,Rp,RR=H Rj=OMe; RL,RN=-OCHPhO-; Rg=OSO 3 Na; Rs=CH 2

N

3 ; 2154 - 3.70 mM ~ 26.7 mM 2.15 mM RK,R,Ro,R,RRH WO 2005/061523 PCT/AU2004/001800 -41 PG# KdaFGF Kd bFGF Kd VEGF RK=SEt; Rm-OBn; RN,Rp=OSO 3 Na; Rs=CH 2 OBn; 2155 188 pM 1.06 mM 448 gM RJ,RL,Ro,RQ,RR-H Rr=OMe; RL,RQ=OSO3Na; RN=Oallyl; Rs=CH 2

N

3 ; 2156 360 pM 1.65 mM 1.04 mM RK,RM,Ro,R,RR=H Rj=OMe; RL,RNq=OSO 3 Na; R=OBn; Rs=CH 2

N

3 ; 2157 444 pM 3.30 mM 144 gM RK,RM,Ro,Rp,RR=H RtOMe; RL=OH;RN=OSO 3 Na; RQ=OCH 2 (2-napthyl); 2158 1.55 mM ~ 10.3 mM 985 gM Rs=CH 2

N

3 ; RK,R,Ro,R,RR=H Rj=OMe; RL,RQ-OH; RN=OSO 3 Na; Rs=CH 2

NH

2 ; 2159 1.90 mM - 62.3 mM 6.40 mM RK,RM,RO,RP,RR=H Rt=OMe; RL=OBn; RN,RQ=OSO 3 Na; Rs=CH 2

N

3 ; 2160 4.40 mM 2.50 miM - 12.9 mM RK,Rm,Ro,R,RR=H RgOMe; RL,RO=OSO 3 Na; RN=OBn; Rs=CH 2

N

3 ; 2161 - 18.2 mM ~ 10.6 mM RK,R,Ro,R,RR=H

R

1 =OMe; RL,RN=OSO 3 Na; RQ=Oallyl; Rs=CH 2

N

3 ; 2163 396 pM 4.80 mlM 61.2 pM RK,RN,R,R,RR=H R=OMe; RL,RN=OSO 3 Na; RQ=OCH 2 (2-napthyl); 2164 1.35 mM 1.70 mM 1.30 mlM Rs=CH 2

N

3 ; RK,R,R,R,RRH RJ/RK=H/OMe (anomeric mixture); Rs-RN= -CH 2 0-; 2165 1.13 mM ~ 25.5 mM 1.70 mM RM=OBn; RQ=OSO 3 Na; Rj,RK,RL,Ro,R,RR=H RK=SMe; R,Ro=OSO 3 Na; R=OBn; Re=CH 3 ; 2166 3.60 mM 1.90 mM 2.70 mM Rj,RL,RN,R,Rs=H RK=OBn; RM,Ro=OSO 3 Na; Rr=OBn; RR=CH 3 ; 2168 1.90 mM 1.20 mM RJ,RL,RN,R,Rs=H

R

3 =Oallyl; RLRN=OSO 3 Na; R=OCH 2 (1-napthyl); 2170 277 paM 1.35 mM 106 pM Rs=CH 2

N

3 ; RK,RM,RO,RP,RRH Rj=OMe; RL,RQ-OSO 3 Na; RN=OBn; Rs=CH2NH 2 ; 2171 845 pM ~ 18.9 mM 2.00 mM RK,R,R,R,R=H Rj=OMe; RL=OBn; RN,R(=OSO 3 Na; Rs=CH 2

NH

2 ; 2172 3.80mM ~ 5.90 mM 2.30 mM RK,R,Ro,R,R=H Rj=OMe; RL=OBn; RN,R 0

-OSO

3 Na; Rs=CH 2 (4-phenyl- 2173 18.9 pM 918 pM 89.3 pM [1,2,3]triazol-1-yl); RK,R,R,R,RRH Rj=Oallyl; RL=OH; RN=OSO 3 Na; RQ=OBz; Rs=CH 2

N

3 ; 2174 278 pM 19.3 mM 846 pM RK,R,Ro,R,RR=H

R

1 =OMe; RLRN=OSO 3 Na; RgOallyl; Rs=CH 2 NH2; 2175 465 M 136 pM RK,RM,,R,RR=H Rj=OMe; RL,RN=OSO3Na; R 0 0Oallyl; Rs=CH 2 (4- 2176 693 pM 256 [M (CH2NH2)-[1,2,3]triazol-1-yl); RK,RM,Ro,R,RR=H RK=OMe; R,Ro=OSO 3 Na; Ry=OCO-Cyclohexyl;

RR=CH

3 ; 2177 - 9.40 mM Rj,RL,RN,R,Rs=H WO 2005/061523 PCT/AU20041001800 - 42 PG 4 Kd aFGF Kd bFGF Kd VEGF

R

3 =OMe; RL,RN=OSO3Na; RQ=Oally1; Rs=CH 2 (4

(CI{

2 NHCO(2-napthyl))-[1,2,3]triazol-1-y1); 2178 130 [tM 1.20mn-M 60.9 [iM RK,Rm,Ro,Rp,RR =H RI=OMe; RL,RN=OSO3Na; RQ=Oa1y1; RS=CH 2 (4

(CH

2 NHCO-Cyclohexyl)-Ijl,2,3]triazol-1-yl); 2179 52.9 jiM 143 jiM 10.3 jiM RK,,RM4,RO,Rp,RR=H

R

3 =OMe; RL,RN=OS0sNa; RQ=Oa11yl; Rs=CH 2 (4

(CH

2 NI-CO-Ph(p-OMe))-[1,2,3]triazol-1-yl); 2180 91.9 jiM 1.90 mmv RK,Rm,R,Rp,RR4IH

R

1 =OMe; RL,RN=OSO3Na; RQ=Oallyl; Rs=CH 2 (4

(CH

2 N7FCOCF 2 OPh)4[1,2,3]triazol-1-yl); 2181 365 jiM 203 jiM RK,Rm,Ro,Rp,RR=II Rj=OMe; RL,R.I-OSOSNa; RQ-=Oa1y1; Rs=CH 2 (4- 2182 107 pM 847 [M

(CH

2 NI-COPh)-II1,2,3]triazol- 1-yl); RK,RM,R,Rp,RRH Rj=OMe; RL,RN=OSO 3 Na; RQ=Oallyl; Rs=CH 2 (4-(CH 2 -N- 2183 324 IiM 82.7 pM phthalimido)-[1 ,2,3]triazol- l-yl); RK,Rm,R,Rp,RRH Rj=OMe; RL,RN=OSO 3 Na; RQ=Oa1yl; RsGCH 2 (4

(CH

2

NHSO

2 Ph(p-Me))-II1,2,3]triazol-1-yl); 2184 388 jiM 1.6miM RK,RNI,Ro,Rp,RR=H Rj=OMe; RL,RN=OSO3Na; RQ=Oallyl; Rs=CH 2 (4-Ph- 2185 421 [LM 440 pM L1,2,3]triazol-1-yl); RK,RMq,RO,Rp,RR'7H Rj=OMe; RL,RN=OSO3Na; RQ=Oallyl; Rs"CH 2 (4-t-butyl- 2186 88.6 jiM >4.6 mM j[1,2,3]triazol-1-y1); RK,RM,RO,Rp,RpR=H Rj=OMe; RL=OSO 3 Na; RN=OH; RQ-OCH 2 (2-napthy1); 2187 320 jiM Rs=CH 2

N

3 ; RK,RM,Ro,Rp,RRH Rj=OMe; RL,RN=OSO 3 Na; RQ=OCH 2 (2-naPthY1); 2188 1.22 i-n 821 pM Rs=CH 2

N

3 ; RK,Rm,Ro,Rp,RRH Rj=OMe; RL,RN=OSO 3 Na; RQ=-Oa11yl; Rs=CH 2

NHSO

2 Me; 2189 191 jiM 35.0 IM RK,Rm,R,Rp,RR=H Rj=OMe; RL,RN4OSO 3 Na; RQ=Oally1; Rs=CH 2

NHCOCH

3 ; 210 48g9.0M RK,Rm,R,Rp,RRH210 48iM9. M Rj=OMe; RL,RN=OSO 3 Na; RQ=Oallyl; Rs=CH 2 NIIBz; 2191 1.39 mMv 317 pLM RK,Rm,Ro,Rp,RRH

R

3 =OMe; RLRN=OSO 3 Na; RQ=Oallyl; RS=CH 2 NHCOPh(p- 2192 1.85 mM 222 pM OMe); RK,Rm,RoRp,RR==H Rj=OMe; RL,RN=OSO 3 Na; RQ=Oallyl; Rs=CH 2 (4

(CH

2 NI{CO(o-CO 2 Na)phenyl)-[1,2,3]triazol-1-ylD; 2193 1.20mMd\ 270 pM RK,Rm,R,Rp,RRH Rj=OMe; RL,RN=OSO 3 Na; RQ=Oallyl; Rs=CH 2 (4

(CH

2 NHCOPh(3,4,5-tri-OMe))-[ 1,2,3]triazol-1-yl); 2194 1.25 mM >2.8 miM RK,Rm,R,Rp,RRH Rj=OPh(p-OMe); RL,RN=OSO 3 Na; R 0 =OBn; Rs=CH 2

N

3 ; 2195 1.05 mM 751 pM RK,Rm,R,Rp,RRH WO 2005/061523 PCT/AU2004/001800 - 43 PG# KdaFGF Kd bFGF Kd VEGF RK=OBn; R,Ro=OSO 3 Na; Ry=OBn; RR=CH 3 ; 2196 170 pM 2.50 mM Rj,RL,RN,R,Rs=H Rr=OMe; RL,RN=OSO3Na; Ro=Oallyl; Rs=CH 2 (4

(CH

2 0CH 2 Ph(p-OMe))-[1,2,3]triazol-1-yl); 2197 131 pM 381 gM RK,RM,RO,Rp,RR H Table 3 R NRw V 5 Ru O PG # Kd aFGF Kd bFGF Kd VEGF RT=1,2,3,4-tetra-0-sodiun sulfonato-D-glucuronoyl; 2007 2.34 mM Ru=CH 2

CH

2

OSO

3 Na; Rw=cyclohexyl; Rv-H RT=1-0-Me-2,3,4-tri-O-sodium sulfonato-a-D mannopyranos-6-yl-acetyl; Ru-CH 2

CH

2

OSO

3 Na; Rv=H; 2008 296 pM 551 gM 335 pM Rw=cyclohexyl Rt=Ac; Ru=2-(2,3,4,6-tetra-0-sodium sulfonato-a-D mannopyranos-1-0-yl-)-ethyl; Ry=H; Rw=2-(2,3,4,6-tetra- 2009 428 4M 0-sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl

R

1 =3-(2,3,4,6-tetra-0-sodium sulfonato-a-D mannopyranos- 1-0-yl-)-propyl; Ru=COCH 2

CH

2 Ph; 2010 556 pM Rw=cyclohexyl; Rv=H RT=1,2,3,4-tetra-0-sodium sulfonato-D-glucuronoyl; 2011 62.4 pM Ru=Bn; Rw=cyclohexyl; Rv=Ph RT=1,2,3,4-tetra-O-sodium sulfonato-a-D-glucuronoyl; 2012 122 pM 505 gM Ru=Bn; Rw=cyclohexyl; Rv=H RT=1,2,3-tri-0-sodium sulfonato-a-D-glucuronoyl; Ru=Bn; 2013 587 pM 1.16 mM Rw=cyclohexyl; Ry=H RT=1,3,4,6-tetra-O-sodium sulfonato-a-D-mannopyranos-2 yl-acetyl; Ru=Bn; Ry=H; Rw=2-(2,3,4,6-tetra-0-sodium 2014 5.09 paM 85.1 PM 8.82 [tM sulfonato-u-D-mannopyranos-1-0-yl-)-ethyl RT=3-(2,3,4,6-tetra-0-sodium sulfonato-a-D mannopyranos-1-0-yl-)-propyl; Ru= CO(CH 2

)

3 Ph; Rv=H; 2018 Rw=cyclohexyl RT=1,2,3,4-tetra-O-sodium sulfonato-a-D-glucuronoyl; 2020 104 jM 206 pM 437 [aM Ru,Rw=Bn; Rv=H RT=1-0-Me-2,3,4-tri-O-sodium sulfonato-a-D- 2032 260 pM 201 pM 705 M mannopyranos-6-yl-acetyl; Ru=Bn; Rw=cyclohexyl; Rv=H WO 2005/061523 PCT/AU2004/001800 - 44 PG # KdaFGF Kd bFGF Kd VEGF Rk=1-O-Me-2,3,4-tri-O-sodiun sulfonato-a-D mannopyranos-6-yl-acetyl; Ru=Bn; Rv=H; Rw=2-(2,3,4,6- 2034 37.6 ptM 16.5 pM 115 PM tetra-O-sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl RT=Ac; Ru=Bn; Ry=H; Rw=2-(2,3,4,6-tetra-O-sodium 2035 24.8 pM 287 M 76.6 FM sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl RT=Ac; Ru=Bn; Ry=H; Rw=2-(2,3,4,6-tetra-O-sodium 2036 118 pM 2.50mM 1.10mM sulfonato-p-D-mannopyranos-1-O-yl-)-ethyl RT=Ac; Ru=CH 2

CH

2 Ph; Ry=H; Rw=6-deoxy-1-0-Me-2,3,4- 2058 224 gM 682 jiM 109 ptM tri-O-sodium sulfonato-a-D-mannopyranos-6-yl R-=Ac; Ru=CH 2

CH

2 Ph; R=H; Rw=6-deoxy-1-0-Me-2,3,4 tri-O-sodium sulfonato-a-D-mannopyranos-6-yl 2058 224 [tM 682 gM 109 [IM RT=Ac; Ru=Bn; Ry=H; Rw=6-deoxy-1-0-Me-2,3,4-tri-0- 2059 140 pM 192 piM 77.0 ptM sodium sulfonato-a-D-mannopyranos-6-yl RT=Ac; Ru=Bn; Rv=H; Rw-6-deoxy-1-0-Me-2,3,4-tri-0- 2059 140 gM 192 pM 77.0 [LM sodium sulfonato-a-D-mannopyranos-6-yl R-=Ac; Ru=Ph; Rv=H; Rw=6-deoxy-1-0-Me-2,3,4-tri-0- 2060 196 pM 481 jM 76.3 FM sodium sulfonato-a-D-mannopyranos-6-yl R-r=Ac; Ru=cyclohexyl; Rv=H; Rw=6-deoxy-1-0-Me-2,3,4- 2064 314 piM 413 pM 1.70 mM tri-O-sodium sulfonato-ca-D-mannopyranos-6-yl R-=Ac; Ru=CH 2

CH

2

OSO

3 Na; Ry=H; Rw=6-deoxy-1-0- 2065 94.8 pM 241 [M 283 pLM Me-2,3,4-tri-O-sodium sulfonato-a-D-mannopyranos-6-yl RT=m-ClPhCH 2 CO; Ru=H; Ry=H; Rw=6-deoxy-1-0-Me- 2066 37.4 pM 433 pM 45.3 M 2,3,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl RT=Et; Ru=CO(CH 2

)

2 COONa; Rv=H; Rw=6-deoxy-1-0- 2068 338 pM 291 gM 207 gM Me-2,3,4-tri-O-sodium sulfonato-a-D-mannopyranos-6-yl RT=Et; Ru=CO(CH2)wCOONa; Rv=H; Rw=6-deoxy-1-0- 2069 160 pM 477 pM 104 pM Me-2,3,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl RT=Et; Ru=CO(CH 2

)

9

OSO

3 Na; Rv=H; Rw=6-deoxy-1-0- 2070 111 pM 243 M 545 pM Me-2,3,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl RT=Et; Ru=CO(CH2)wCOONa; Rv=H; Rw=6-deoxy-1-0 Me-2,3,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl, 2071 119 pM 2.24 mM 161 pM mixture of mono- and di- sulfates Rr=Ac; Ru=cyclohexyl; Rv=H; Rw=6-deoxy-1-0-Me-2,3,4 tri-0-sodium sulfonato-a-D-mannopyranos-6-yl, mixture of 2072 264 pM 2.98 mM 277 pM mono- and di-sulfates Rt=Ac; Ru=Ph; Rv=H; Rw=2-(2,3,4,6-tetra-O-sodium 2073 97.4 pM 236 pM 402 pM sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl Rr=Ac; Ru=(CH 2

)

2 Ph; Rv=H; Rw=2-(2,3,4,6-tetra-O- 2074 11.8 pM 113 pM 28.8 pM sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl RT= m-ClPhCH 2 CO; Ru,Rv=H; Rw=2-(2,3,4,6-tetra-0- 2075 171 pM 837 pM 90.8 pM sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl WO 2005/061523 PCT/AU20041001800 - 45 PG 4 Kd aFGF Kd bFGF Kd VEGF Ri=Et; Ru=CO(CH 2

)

2

CO

2 Na; Rv,=H; RW=2-(2,3,4,6-tetra- 2076 43.4 jiM 118 PiM 40.3 jiM 0-sodium sulfonato-a-D-mannopyranos-l -0-yl-)-ethyl RT=Et; Ru=CO(CH 2

)

4

CO

2 Na; Rv=H; Ruw=2-(2,3,4,6-tetra- 27 36g 8 m 8. L 0-sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl 07 4. i 18jM 8. i RT=Et; Ru=CO(CH 2

)

9

OSO

3 Na; Rv=H; Rw=2-(2,3,4,6-tetra- 2078 20.0 [tM 157 jiM 49.6 jiM 0-sodium sulfonato-a-D-mannopyranos-1-0-yl-)-ethyl RTBz; Ru=Et; Rv=H; Rw=6-deoxy-1-0-Me-2,3,4-tri-0- 2081 366 jiM 480 jiM 1.10 mM sodium sulfonato-ax-D-mannopyranos-6-yl

RT=CO(CH

2

)

2 Ph; Ru=Et; Rv,=H; Rw=6-deoxy-1-0-Me- 2082 596 jiM 2,3 ,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl Rt=GO(CH 2

)

3 Ph; Ru=Et; Rv=H; Rwt6-deoxy-1-0-Me- 2083 453 jiM 403 jiM 80.7 jiM 2,3 ,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl

RT=COCH

2 OSO3Na; Ru=Et; Rv=H; Rw=6-deoxy-1-0-Me- 2084 161 jiM 192 jiM 277 jiM 2,3 ,4-tri-0-sodium sulfonato-a-IJ-mannopyranos-6-yl Rwcyclohexyl; Ru=Ac; Rv=H; R-[=6-deoxy-1-0-Me-2,3,4- 2094 246 jiM 565 jiM 1.10 mM tri- 0-sodium sulfonato-a-D-inannopyranos-6-y1 R~vcyclohexyl; Ru Ac; Rv=H; R-,r6-deoxy-1 -0-Me-2,3 0-benzylidene,4-O-sodium sulfonato-a-D-mannopyranos-6- 2115 5,10 mM 3.90 mMv y 1 RTrAc; Rucycloheptyl; Rv=H; Rw=6-deoxy-1-0-Me- 2116 369 gM 411 gM 3.00 mM 2,3,4-tri-0-sodium sulfonato-oa-D-mannopyranos-6-yl iI RT=Ac; Rucycloheptyl; Rv=H; Rw=6-deoxy-1-0-Me-2,4- 2117 1.50 mM 2.90 mM di-0-sodium sulfonato-a-D-mannopyranos-6-yl RT=Ac; Rucyclooctyl; Rv=H; Rw=6-deoxy-1-O-Me-2,4-di- 2120 1.60 mM -11.0 mM 0-sodium. sulfonato-a-D-maniiopyranos-6-yl

RT=COCH

2 Ph(p-CF 3 ); Ru=Et; Rv=H; Rw=6deoxy10 2122 3.70 mM 1.20 mM Me-2,4-di-0-sodiurn sulfonato-ca-D-mannopyranos-6-y1

RT=COCH

2 Ph(p-CF 3 ); RU=Et; Rv=H; Rw=6-deoxy-1-O- 2124 242 jiM 570 jiM Me-2,3-di-0-sodium sulfonato-ca-D-mannopyranos-6-y1 Rw=cyclohexy1; Ru=Ac; Rv=H; RT=6-deoxy-1--0-Me-4-0- 2125 26.6 mMv- 166 mM sodium sulfonato-a-D-mannopyranos-6-yl RTrAC; Rujcyclododecyl; Rv=H; Rw=6-deoxy-1-O-Me- 2126 265 jiM 483 jiM 1.20 mM 2,3,4-tri-0-sodium sulfonato-a-D-mannopyranos-6-yl RT=AC; Ru=4tbutycyclohexyl; Rv=H; RW=6-deoxy-1-0- 2132 243 jiM 544 jiM 1.00 mM Me-2,3,4-tri-O-sodium sulfonato-a-D-mannopyranos-6-yl RT =Ac; Rur1-(1-adamanty)-ethyl; RV=H; RW=6-deoxy-1- 2133 398 jiM 0-Me-2,4-di-0-sodium sulfonato-a-D-mannopyranos-6-yl

RT=CO(CH

2

)

3 Ph; Ru'=Et; Rv=H; Rw=6-deoxy-1-O-Me-2,4- 2135 di-0-sodium sulfonato-a-D-mannopyranos-6-yl WO 2005/061523 PCT/AU2004/001800 - 46 PG # Kd aFGF Kd bFGF Kd VEGF RT=6-deoxy-1 -0-Me-2,3,4-tri-O-sodium sulfonato-a-D mannopyranos-6-yl; Ru=CH 2 CONHcyclohexy1; 2138 418 pLM 449 pLM 1.34 mM Rw=cyclohexyl; Rv=H Rw=cyclohexyl; Ru=CHO; Rv=H; RT=6-deoxy-1-0-Me- 2162 1.20 mM 2,3,4-tri-O-sodium sulfonato-a-D-mannopyranos-6-yl Table 4 H H aN' N Rx"Y Nav 0 Ry Ry 0 5 PG # Kd aFGF Kd bFGF Kd VEGF Rx=COCH 2

C(CH

3

)

2 CH2CO; Ry=3-(2,3,4,6-tetra-O-sodium 2015 2.94 pM 7.56 pM 267 nM sulfo-a-D-mannopyranos-1 -0-yl)-propyl Rx=1,4-trans-cyclohexy1; Ry=1-O-Me-2,3,4-tri-O-sodium 2016 32.6 pM 81.8 pM 931 nM sulfo-a-D-mannopyranos-6-yl-acetyl Rx=COCH 2

C(CH

3 )2CH 2 CO; Ry=2-(2,3,4,6-tetra-O-sodium 2057 18.8 pM 61.6 pM 55.6 pM sulfo-a-D-mannopyranos-1 -0-yl)-ethyl, undersulfated Rx=COCH 2

C(CH

3 )2CH 2 CO; Ry=2-(2,3,4,6-tetra-O-sodium 2062 10.3 pM 29.7 pM 17.3 pM sulfo-a-D-mannopyranos-1-0-yl)-ethyl Table 5: Antiviral Testing Results PG# HSV-1 Infectivity HSV-2 Infectivity HSV-1 Spread HSV-2 Spread 2000 100.8 NT (= not tested) 82.1 NT 2001 85.6 NT 88.3 NT 2002 89.2 NT 113.8 NT 2003 97 NT 95.2 NT 2005 102.8 NT 131.7 NT 2040 106.6 NT 86.2 NT 2041 108.3 NT 60 NT 2042 92 NT 107.6 NT WO 2005/061523 PCT/AU2004/001800 - 47 PG# HSV-1 Infectivity HSV-2 Infectivity HSV-1 Spread HSV-2 Spread 2000 100.8 NT (= not tested) 82.1 NT 2001 85.6 NT 88.3 NT 2002 89.2 NT 113.8 NT 2003 97 NT 95.2 NT 2005 102.8 NT 131.7 NT 2040 106.6 NT 86.2 NT 2041 108.3 NT 60 NT 2044 73.5 NT 77.9 NT 2085 99.2 NT 64.1 52.8 2091 81.8 135.6 74.9 58.9 2092 90.3 101.4 75.4 50 2093 90.3 121.6 74.9 55.5 2097 101.8 111.5 45 42.2 2098 81.8 116.3 68.4 54.4 2099 89.5 115.9 76 43.3 2103 80.8 112 94.2 70 2111 100.3 105.3 57.9 55.5 2112 95.6 90.9 74.9 76.7 2113 95.1 91.3 46.2 31.1 2114 86.4 99 71.3 68.9 2139 86.8 81.8 47.8 20 2146 108.5 92 56.2 52.8 2145 92.1 76 73.7 77.8 2151 100 75.5 84.5 86.1 WO 2005/061523 PCT/AU2004/001800 - 48 The results presented in Tables 1 to 4 demonstrate that the broad range of compounds embraced by the invention have strong affinity for GAG-binding growth factors and may thus serve as modulators of their activity. The results in presented in Table 5 demonstrate that the compounds do indeed possess in vivo activity. 5 The foregoing embodiments are illustrative only of the principles of the invention, and various modifications and changes will readily occur to those skilled in the art. The invention is capable of being practiced and carried out in various ways and in other embodiments. It is also to be understood that the terminology employed herein is for the purpose of description and should not be regarded as limiting. 10 The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required. Any reference to publications cited in this specification is not an admission that the 15 disclosures constitute common general knowledge in Australia.

WO 2005/061523 PCT/AU2004/001800 - 49 REFERENCES [1] Kjellen, L.; Lindahl, U. Annu. Rev. Biochem. 1991, 60, 443. [2] Sugahara, K.; Kitagawa, H. Curr. Opin. Struct. Biol. 2000, 10, 518. [3] 20179369 Tumova, S.; Woods, A.; Couchman, J.R. Int. J Biochem. Cell Biol. 2000, 5 32, 269. [4] Capila, I.; Linhardt, R.J. Angew. Chem. Int. Ed. 2002, 41, 391. [5] Casu, B.; Lindahl, U. Adv. Carbohydr. Chem. Biochem. 2001, 57, 159. [6] Liu, J.; Thorp, S.C. Med. Res. Rev. 2002, 22, 1. [7] van Boeckel, C.A.A.; Petitou, M. Angew. Chem. Int. Ed. Engl. 1993, 32, 1671. 10 [8] Petitou, M.; H6rault, J.P.; Bernat, A.; Driguez, P.A.; Duchaussoy, P.; Lorneau, J.C.; Herbert, J.M. Nature 1999, 398, 417. [9] Yeh, B.K.; Eliseenkova, A.V.; Plotnikov, A.N.; Green, D.; Pinnell, J.; Polat, T.; Gritli-Linde, A.; Linhardt, R.J.; Mohammadi, M. Mol. Cell. Biol. 2002, 22, 7184. [10] Liekens, S.; Leali, D.; Neyts, J.; Esnouf, R.; Rusnati, M.; Dell Era, P.; Maudgal, P.C.; 15 De Clercq, E.; Presta, M. Mol. Pharmacol. 1999, 56, 204. [11] Sola, F.; Farao, M.; Pesenti, E.; Marsiglio, A.; Mongelli, N.; Grandi, M. Cancer Chemother. Pharmacol. 1995, 36, 217. [12] Foxall, C.; Wei, Z.; Schaefer, M.E.; Casabonne, M.; Fugedi, P.; Peto, C.; Castellot, J.J., Jr; Brandley, B.K. J Cell. Physiol. 1996, 168, 657. 20 [13] Parish, C.R.; Freeman, C.; Brown, K.J.; Francis, D.J.; Cowden, W.B. Cancer Res. 1999, 59, 3433. [14] Kisilevsky, R.; Green, A.M.; Gervais, F. 2001, US Patent No. 6,310,073. [15] D6mling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168 and references cited therein. 25 [16] Lockhoff, 0.; Frappa, I. Combinatorial Chemistry & High Throughput Screening 2002, 5, 361 and references cited therein. [17] Hanessian, S. Preparative Carbohydrate Chemistry; Chapter 3; Marcel Dekker Inc.: New York, 1996. [18] Pozsgay, V.; Trinh, L.; Shiloach, J.; Robbins, J.B.; Donohue-Rolfe, A.; Calderwood, 30 S.B. Bioconjugate Chem. 1996, 7, 45. [19] Dasgupta, F.; Masada, R.I. Carbohydr. Res. 2002, 337, 1055. [20] Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J Org. Chem. 1989, 54, 1346. [21] Prepared analogously to ref. 18.

WO 2005/061523 PCT/AU2004/001800 - 50 [22] Liptik, A.; Imre, J.; Ndnisi, P. Carbohydr. Res. 1981, 92, 154. [23] Agoston, K.; Kerdkgyart6, J.; Hajk6, J.; Batta, G.; Lefeber, D.J.; Kamerling, J.P.; Vliegenthart, J.F. Chem. Eur. J 2002, 8, 151. [24] Cochran, S.; Li, C.; Fairweather, J.K.; Kett, W.C.; Coombe, D.R.; Ferro, V. J Med. 5 Chem. 2003, 46, 4601. [25] Nyberg, K.; Ekblad, M.; Bergstr6m, T.; Freeman, C.; Parish, C.R.; Ferro, V.; Trybala, E. Antiviral Res. 2004, 63, 15. [26] Gunalp, A. Proc. Soc. Exp. Biol. Med. 1965, 118, 185. [27] Holland, T.C.; Homa, F.L.; Marlin, S.D.; Levine, M.; Glorioso, J. J Virol. 1984, 52, 10 566. [28] Duff, R.; Rapp, F. Nat. New Biol. 1971, 233, 48.

Claims (14)

1. A compound of the fonnula XR 5 R 4 X R6 R 3 X n XR 1 XR 2 5 wherein: n is an integer of from 0 to

2; Z is N, N(O), 0, S, S(O), S(0) 2 , P, P(O), P(0) 2 , Si, Si(O), or Si(0) 2 ; each X is independently C, C(O), N, N(O), 0, S, S(0), S(0) 2 , P, P(O), P(O) 2 , Si, Si(O), or Si(0) 2 or is a bond; and 10 each of R 1 to R 6 is independently a bond or is selected from the group consisting of: hydrogen; halogen; straight chain, cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; 15 phosphoryl groups such as phosphate, thiophosphate -0-P(S)(OH)2; phosphate esters -0-P(O)(OR) 2 ; thiophosphate esters -0-P(S)(OR) 2 ; phosphonate -0-P(O)OHR; thiophosphonate -0-P(S)OHR; substituted phosphonate -0-P(O)OR1R 2 ; substituted thiophosphonate -0-P(S)OR1R 2 ; -0-P(S)(OH)(SH); and cyclic phosphate; 20 other phosphorus containing compounds such as phosphoramidite -0-P(OR)-NRIR 2 ; and phosphoramidate -0-P(O)(OR)-NR 1 R 2 ; sulfur groups such as -0-S(0)(OH), -SH, -SR, -S(--+O)-R, S(0) 2 R, RO-S(0) 2 ~, -0-SO 2 NH 2 , -0-S0 2 RR 2 or sulfamide -NHSO 2 NH 2 ; amino groups such as -NHR, -NR 1 R 2 , -NHAc, -NHCOR, -NH-0-COR, 25 NHSO 3 , -NHSO 2 R, -N(S0 2 R) 2 , and/or amidino groups such as -NH C(=NH)NH 2 and/or ureido groups such as -NH-CO-NR 1 R 2 or thiouriedo groups such as -H-C(S)-NH 2 ; another unit of the structure I, attached through any position, where Z, X and R 1 to R 6 are as defined above; or 30 a substructure based upon a group of the following formula: WO 2005/061523 PCT/AU2004/001800 -52 0 YR 10 R 7 Y-T N.J N YR11 HY Y o R 8 R 9 wherein: Y is a bond or is selected from the group consisting of: straight chain, 5 cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted alkyl; straight chain, cyclic, branched, substituted, heterocyclic, heteroatom substituted or unsubstituted acyl; and aryl, substituted aryl, heteroaryl; and 10 each of R 7 to R, I is independently at least one structure according to formula I, or a structure according to formula II; with the provisos that: when Z is 0, and X is 0 or a bond, then all of R 1 to R 5 are not H or CH 2 OH; or when Z is N and X is 0 or a bond, then all of R 1 to R 6 are not H. 15 2. A compound according to claim 1, wherein said compound is PG2024, PG2037, PG2046, PG2155, as hereinbefore described.

3. A compound according to claim 1, wherein said compound is any one of the compounds of Tables 1-4 of the description.

4. A pharmaceutical or veterinary composition for the prevention or treatment in a 20 mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which composition comprises at least one compound according to claim 1 together with a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound.

5. The composition according to claim 4 which further includes a pharmaceutically or 25 veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant.

6. The composition according to claim 4, wherein said compound is present therein as an ester, a free acid or base, a hydrate, or a prodrug.

7. Use of a compound according to claim 1 in the manufacture of a medicament for the 30 prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection. WO 2005/061523 PCT/AU2004/001800 - 53

8. The use according to claim 7, wherein said mammalian subject is a human subject.

9. A method for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which method comprises administering to the subject an effective amount 5 of at least one compound according to claim 1, or a composition comprising said at least one compound.

10. The method according to claim 9 wherein said mammalian subject is a human subject.

11. The method according to claim 9, wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumour. 10

12. The method according to claim 9, wherein said disorder resulting from inflammation is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, allograft rejection or chronic asthma.

13. The method according to claim 9, wherein said disorder resulting from coagulation and/or thrombosis is deep venous thrombosis, pulmonary embolism, thrombotic stroke, 15 peripheral arterial thrombosis, unstable angina or myocardial infarction.

14. The method according to claim 9, wherein said disorder resulting from viral infection is Herpes Simplex. WO 2005/061523 PCT/AU2004/001800 54 AMENDED CLAIMS [(received by the International Bureau on 11 May 2005 (11.05.05); original claims 1-2 amended; remaining claims unchanged (3 pages)] 1. A compound of the formula XR 5 R 4 X 0 R 3 X XR 1 I XR 2 wherein: each X is independently CH2, C(O), N, 0, S, S(0), S(0) 2 , or is a bond; and each of Ri to R5 is independently a bond or is selected from the group consisting of: hydrogen; halogen; azide; an R group defined as Cl to C8 alkyl or alkenyl, aryl or heteroaryl optionally further substituted by: an alkoxy, aryl, heteroaryl or aryloxy group; -COOH, -S(O) 2 OI, phosphate, carboxylate or tetrazolyl; -S(0) 2 0H, -S(0)OH, -S(O)R, S(0) 2 R, -S(0) 2 NH 2 , -S(O) 2 0R, -S(O)OR; -C(O)R; phosphate, carboxylate or tetrazolyl; an unsubstituted or substituted heterocylic group, wherein the substitution is by: an alkyl or aryl group, -CH 2 NHC(O)R -CH 2 N(C(O)R) 2 , -CH 2 OR, wherein R is as defined above; connected to a different R 1 to R 5 to form a new cyclic group; a substructure based upon a group of the following formula: 0 YR 10 R 7 Y Nk/ N YR11 Ra ' R 8 R 9 wherein: Y is H, R or -C(O)R, wherein R is as defined above; AMENDED SHEET (ARTICLE 191 WO 2005/061523 PCT/AU2004/001800 55 at least one, but not more than two of R 7 to R 1 is independently a structure according to formula I; or a structure comprising a second unit according to formula 11 linked via a "Y" group wherein each unit is independently substituted by R 7 to Rla; with the provisos that: when R2 is -C4 3 , -S(0) 2 014 or -i at least one of R 2 to R 5 is not -H or S(O)2OH; when a substructure of type II is not present and none of R, -R 5 form an anhydro bridge, no more than two of R-Rs are -S(0) 2 0H and the stereochemistry of I is not gluco or galacto; 2 A compound according to claim 1, wherein said compound is PG2024, PG2037, PG2173, PG2198, as hereinbefore described. 3. A compound according to claim 1, wherein said compound is any one of the compounds of Tables 1-4 of the description. 4. A pharmaceutical or veterinary composition for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, intammation, coagulation, thrombosis, and/or microbial infection, which composition comprises at least one compound according to claim 1 together with a pharmaceutically or veterinarially acceptable carrier or diluent for said at least one compound. 5. The composition according to claim 4 which further includes a pharmaceutically or veterinarially acceptable excipient, buffer, stabiliser, isotonicising agent, preservative or antioxidant. 6. The composition according to claim 4, wherein said compound is present therein as an ester, a free acid or base, a hydrate, or a prodrug. 7. Use of a compound according to claim I in the manufacture of a medicament for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection. 8. The use according to claim 7, wherein said xnammalian subject is a human subject. 9. A method for the prevention or treatment in a mammalian subject of a disorder resulting from angiogenesis, metastasis, inflammation, coagulation, thrombosis, and/or microbial infection, which method comprises administering to the subject an effective amount of at least one compound according to claim 1, or a composition comprising said at least one compound. AMENDED SHEET (ARTICLE 19) WO 2005/061523 PCT/AU2004/001800 56 10. The method according to claim 9 wherein said mammalian subject is a human subject. 11. The method according to claim 9, wherein said disorder resulting from angiogenesis is a proliferative retinopathy or angiogenesis resulting from the growth of a solid tumour. 12. The method according to claim 9, wherein said disorder resulting from inflammation is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, allograft rejection or chronic asthma. 13. The method according to claim 9, wherein said disorder resulting from coagulation and/or thrombosis is deep venous thrombosis, pulmonamy embolism, thrombotic stroke, peripheral arterial thrombosis, unstable angina or myocardial infarction. 14. The method according to claim 9, wherein said disorder resulting from viral infection is Herpes Simplex. AMENDED SHEET (ARTICLE 19)