WO2005061523A1

WO2005061523A1 - Glycosaminoglycan (gag) mimetics

Info

Publication number: WO2005061523A1
Application number: PCT/AU2004/001800
Authority: WO
Inventors: Robert Hugh Don; Vito Ferro; Ian Bytheway; Siska Cochran; Jon Krueger Fairweather; Edward Timothy Hammond; Tomislav Karoli; Cai Ping Li; Ligong Liu
Original assignee: Progen Industries Limited
Priority date: 2003-12-23
Filing date: 2004-12-21
Publication date: 2005-07-07
Also published as: CN1906203A; EP1699806A1; CA2551181A1; KR20060129296A; RU2006126718A; BRPI0417750A; MXPA06007194A; JP2007515434A; NO20063366L; IL176474A0

Abstract

The invention relates to compounds that are designed to mimic the structure of GAGs; methods for the preparation of the compounds; compositions comprising the compounds; and use of the compounds and compositions thereof for the anti-angiogenic, anti-metastatic, anti-inflammatory, anticoagulant, antithrombotic, and/or antimicrobial treatment of a mammalian subject.

Description

GLYCOSAMINOGLYCAN (GAG) MIMETICS

TECHNICAL FIELD 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 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 ofthe compounds and compositions thereof in the treatment of a mammalian subject having a condition amenable to treatment with such agents. 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 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 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 [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 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 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 ofthe compounds described herein are that they have fewer sulfo groups and are of lower molecular weight than previously described 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-defined 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, 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 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. 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 ofthe subject compounds. According to a first embodiment of the invention, there is provided a compound of the formula

wherein: n is an integer of from 0 to 2; Z is N, N(O), O. S, S(O), S(O)₂, P, P(O), P(O)₂, Si, Si(O), or Si(O)₂; each X is independently C, C(O), N, N(O), O, S, S(O), S(O)₂, P. P(O), P(O)₂, Si, Si(O),)₂ or is a bond; and each of R_\ to R₆ 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; phosphoryl groups such as phosphate, thiophosphate -O-P(S)(OH)₂; phosphate esters -O-P(O)(OR)₂; thiophosphate esters -O-P(S)(OR)₂; phosphonate -O-P(O)OHR; thiophosphonate -O-P(S)OHR; substituted phosphonate -O-P(O)OR₁R₂; substituted thiophosphonate -O-P(S)OR₁R₂; -O-P(S)(OH)(SH); and cyclic phosphate; other phosphorus containing compounds such.as phosphoramidite -O-P(OR)-NR₁R₂; and phosphoramidate -O-P(O)(OR)-NR_!R₂; sulfur groups such as -O-S(O)(OH), -SH, -SR, -S(→O)-R, S(O)₂R, RO-S(O)₂\ -O-SO₂NH₂, -O-SO₂RiR₂ or sulfamide -NHSO₂NH₂; amino groups such as -NHR, -N ιR₂, -NHAc, -NHCOR, -NH-O-COR, - NHSO₃, -NHSO₂R, -N(SO₂R)₂, and/or amidino groups such as -NH- C(=NH)NH₂ and/or ureido groups such as -NH-CO-NRiR₂ or thiouriedo groups such as -H-C(S)-NH₂; another unit ofthe structure I, attached through any position, where Z, X and R_t to R₆ are as defined above; or a substructure based upon a group ofthe following formula:

wherein: Y is a bond or is selected from the group consisting of: straight chain, 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 each of R₇ to Rπ is independently at least one structure according to formula I, or a structure according to formula II; with the provisos that: when Z is O, and X is O or a bond, then all of Ri to R₅ are not H or CH OH; or when Z is N and X is O or a bond, then all of Ri to R₆ are not H. According to a second embodiment ofthe 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 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. 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. In other embodiments of the invention, there are provided processes for synthesising the compounds according to the first embodimrent as defined above. 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 ofthe groups Ri to R₅ may be connected to each other to form a bicyclic strucure; or the cyclic structure of formula I may contain a double bond, i.e., two contiguous XRi to XR₅ groups may be bonds. Preferred compounds ofthe 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 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 FGF fibroblast growth factor aFGF acidic fibroblast growth factor (or FGF-1) bFGF basic fibroblast growth factor (or FGF-2) NEGF vascular endothelial growth factor SPR surface plasmon resonance HSN 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, 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. 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. 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 are typically administered as a component of a pharmaceutical composition as described in the following paragraphs. Pharmaceutical 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, 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: 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 which is pyrogen-firee 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 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. 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. 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. 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 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. 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 Mn²⁺ and Zn²⁺, 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 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. 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 ofthe compounds ofthe invention can be transformed in vivo or in vitro into the parent compounds. Typically, at least one of the biological activities of a parent 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 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. 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 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 NEGF. The compounds thus have utility as antiangiogenic, antimetastatic and/or anti-inflammatory agents in the treatment of mammalian subjects including humans. 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. 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 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 infection resulting from pathogens which utilise HS as an attachment/entry receptor [6], for example, HSN, HIN, Dengue virus, Yellow fever virus, Cytomegalovirus and Hepatitis C virus. Similarly, the compounds ofthe invention are also suited for the treatment or prevention of infection resulting from non-viral microbial pathogens which utilise HS as an attachment/entry, for example, Plasmodium (malaria). Most notable is the inhibition by the compounds ofthe invention ofthe cell-to-cell spread of HSN-1 and HSN-2. Having broadly described the invention, non-limiting examples ofthe compounds, their synthesis, and their biological activities, will now be given with reference to the accompanying Tables which will be briefly described in the following section of this specification. General Procedures General procedure for al ylation and deprotection ofdiols The diol (1 eq.) in DMF was added dropwise to a cooled (0°), stirred suspension of pre- washed (hexane) ΝaH (5 eq.) in DMF. Once the addition was complete, stirring was maintained (0°→r.t., 20 min). The mixture was cooled (0°, 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 (0°) 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 MeCΝ). The crude mixture andjXTsOH-HjO (50 mg) in MeOH/MeCΝ (1:1) was heated under reflux (1 h). The mixture was cooled (r.t.) and Et₃Ν (100 μL) was added prior to evaporation ofthe 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 SOytrimethylamine (2 eq per hydroxyl group) in DMF was heated (60°, o/n). The cooled (r.t.) reaction mixture was treated with MeOH and then made basic (to pH>10) by the addition of Na₂CO₃ (10% w/w). The mixture was filtered and the filtrate evaporated and co-evaporated (H₂O). Where deacylation of the sulfated product was required, the crude product was taken up in water and IM NaOH was added (2 eq per acyl group). When deprotection was complete the product was carried through to the next stage. The crude sulfated material in H₂O was subjected to size exclusion chromatography. The pure fractions were evaporated and co-evaporated (H₂O) and then lyophilised (H₂O) to yield the sulfated product. When required, after lyophilisation the product was passed through an ion- exchange resin column (AG^®-50W-X8, Na⁺ form, 1x4 cm, deionized H O, 15 mL) in order to transfer the product uniformly into the sodium salt form. The solution collected was 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 NH₄HCO₃, collecting 2.8 min (7.8 mL) 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 (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 NaCI. 0.1 M HC1 (95 ml) was 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 μL of fraction solution per well. 55 μL 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. General procedure for NIS glycosylations Glycosyl acceptor (1 eq), thioglycoside donor (1.1 eq), 500 mg of freshly activated powdered 3 A 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 (~1 h) before 400 μL of Et₃N was added. Evaporation (in vacuo) onto silica gel and flash chromatography yielded the glycosylated product. General procedure for Ugi four-component reaction Solutions ofthe acid (1 eq), amine (1 eq), carbonyl compound (1 eq) and isocyanide (1 eq) in MeOH, MeOH-THF (varied ratios) or CHC1₃ 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 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 ofthe 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. 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 HC1 and extracted with CHC1₃. The organic phase was separated and washed with cold 0.5 M HC1 (x2), brine, and dried (MgSO₄). 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 Zemplen deacetylation/debenzoylation: 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^1" 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. 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 (Bϋchi 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 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 1H NMR, freeze- dried and used directly for sulfonation. Methylation of hydroxyl groups 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. Iodomethane (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. 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-H₂O 50:2:1, 20:2:1 to 10:2:1) to give the corresponding triazole product. Example 1: PG2038

Step a: Methyl 3,4,6-tri- -acetyl-2-0-benzyl- -O-galactopyranosyl-(l-→4)-2,3,6- tri-O-benzyl-β-O-glucopyranoside. Methyl 2,3,6-tri-O-benzyl- -O-glucopyranoside [17] (150 mg, 322 μmol), methyl 3,4,6- tri-O-acetyl-2-O-benzyl-l-thio-fi-O-galactopyranoside [18] (151 mg, 354 μmol) and 200 mg of 3A molecular sieves were subjected to the general NIS glycosylation procedure using 95 mg (422 μmol) 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 μL of acetic anhydride, 200 of μL Et₃N and 2 mg of DMAP, and the solution was stirred for 1 h before evaporation and flash chromatography (gradient elution 25:75 to 30:70 EtOAc:hexanes) to give 180 mg (66%) of the title compound as a colourless glass. 1H n.m.r. (400 MHz, CDC1₃) δ: 7.05-7.35 (m, 20H, 4^χPh), 5.74 (d, 1H, J_1;2= 4.0, HI¹¹), 5.29 (dd, 1H, J₃,₄ ^**** 3.2, J_4,5 = 1.2, H4¹¹), 5.23 (dd, 1H, J₂,₃ = 10.8, H3^π), 4.92 (d, 1H, J_gem= 12.0, PhCH₂), 4.85 (d, 1H, J_gem -=- 10.8, PhCH₂), 4.55-4.69 (m, 4H, PhCH₂), 4.42 (AB, 1H, J_gem = 12.0, PhCH₂), 4.40 (AB, 1H, PhCH₂), 4.32 (d, 1H, J_1;2 = 7.6, HI¹), 4.10 (dt, 1H, J₅,₆ = 6.8, H5^π), 3.88-3.96 (m, H, HS^Hδ¹), 3.82 (dd, 1H, J_gem = 11.1, H6^π), 3.70-3.76 (m. 4H, H2^χH6^I+H2^II+H3^I), 3.56 (s, 3H, OMe), 3.5-3.6 (m, 1H, H4¹), 3.45 (dd, 1H, J_2,3 = 9.0, H2¹), 2.02 (s, 3H, Ac), 1.93 (s, 3H, Ac), 1.88 (s, 3H, Ac). ¹³C n.m.r. (100 MHz, CDC1₃) δ: 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, 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-0-acetyl-a-O-galactopyranosyl-(l→4)-fi-O-glucopyranoside. Pearlman's catalyst (20 mg) and 20 μL of acetic acid were added to a solution of 90 mg (106 μmol) of methyl 3,4,6-tri-0-acetyl-2-0-benzyl-a-O-galactopyranosyl-(l→4)-2,3,6- tri-O-benzyl-β-O-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%) ofthe title compound. 1H n.m.r. (400 MHz, CD₃OD) δ: 5.39 (br d, 1H, J₃,₄ = 3.0, H4^π), 5.32 (d, 1H, J_1;2= 3.8, HI¹¹), 5.10 (dd, 1H₅ J_2!3 = 10.6, H3^π), 4.38 (br t, 1H, J_5,6 = 6.8, H5^π), 4.20 (d, 1H, J₁₎₂ ^*= 7.8, HI¹), 4.09 (app d (ABX), 2H, J_5,6 = 6.5,Η6^Π), 4.00 (dd, 1H, H2^π), 3.92 (dd, 1H, J_5;6A= 1.7, J_gem= 12.2, H6A¹), 3.80 (dd, 1H, J_5j6B= 4.8, H6B¹), 3.62 (dis t, 1H, J₂,₃~_3;4= 9.1, H3¹), 3.56 (part obs t, 1H, J_3j4~_4j5 = 9.3, H4¹), 3.53 (s, 3H, OMe), 3.42 (ddd, IH, J_4j5 = 9.4, H5¹), 3.22 (dd, IH, J_2;3 = 9.1, H2¹), 2.10 (s, 3H, AcO), 2.05 (s, 3H, AcO), 2.00 (s, 3H, AcO).

Step c: Methyl 2-0-sulfo- -O-galactopyranosyl-(l→4)-2,3,6-tri-0-sulfo~ -O-glucopyranoside, tetrasodium salt (PG2038) 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). 1H NMR (D₂O, 400 MHz): 5.473 (d, IH, Jπi-aiX 3.6, HI¹¹), 4.833 (d, IH, J_π-2i = 2.8, HI¹), 4.60 (overlapped with water, IH, H3¹), 4.551 (m, IH, H2¹), 4.306 (dd, IH, π-3π = 10.2, H2^π), 4.17-4.06 (m, 4H, H4¹, H5¹ and H6¹), 3.902 (d, IH, J₃iι-₄iι =^* 3.6, H4^π), 3.867 (dd, IH, H3^π), 3.616 (dd, IH, J_6axii_-6eqii = 12.0, J₅ιι_-6axπ = 7.2, Hoax¹¹), 3.564 (dd, IH, J₅ii_-6eqii= 5.2, H6eq^π), 3.363 (dd, IH, H5^π), 3.343 (s, 3H, CH₃O). Example 2: PG2046 and PG2047 Step a: 2-Azido-3, 4, 6-tri-0-benzoyl-2-deoxy-a-D-glucopyranosyl-(l→4)-l, 6-anhydro-2-azido- 2-deoxy-3-0-benzyl- -D-glucopyranose A solution of 3,4,6-tri-0-acetyl-2-azido-2-deoxy-D-glucopyranosyl trichloro- acetimidate [19] (201 mg, 0.453 mmol) and l,6-anhydro-2-azido-3-0-benzyl-2-deoxy-fi-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 μL, 0.091 mmol) was introduced drop-wise and stirring maintained (-20°, 10 min). Et₃N (100 μL) 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 Zemplen deacetylation general procedure. The product was subjected to aqueous workup (EtOAc) to yield a colourless oil (98 mg). This residue was co-evaporated (2 x 10 mL MeCN). BzCl (210 μL, 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°→r.t., 2 min) before evaporation and co-evaporation (toluene) of the solvent. The residue was 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). 1H NMR (400 MHz, CDC1₃) 3.l l (s, 1 H; H-2¹), 3.41 (dd, 1 H, J_1;2 3.7, J_2,3 10.7 Hz; H-6¹), 3.61 (s, 1 H; H- 3¹), 3.39 (s, 1 H; H-4¹), 4.05 (d, 1 H, J_6>6 7.3 Hz; H-6¹), 4.41-4.49 (m, 2 H; H-6¹¹), 4.55, 4.68 (AB quartet, J_A,_B 11.9 Hz; CH₂Ph), 4.79 (ddd, 1 H, J_4;5 10.3, J_5;6 2.9, 5.9 Hz; H-5^π), 4.91 (br d, 1 H, J_5,6 5.5 Hz; H-5¹), 5.08 (d, 1 H, J_lj2 3.6 Hz; H-l^π), 5.51 (dd, 1 H, J_3>4 9.5, J_4;5 10.2 Hz, H- 4^π), 5.60 (s, 1 H,; H-l¹), 6.10 (dd, 1 H, J_2j3 10.7, J₃,₄ 9.3 Hz; H-3^π), 7.29-7.55, 7.89-8.03 (2 m, 20 H; ArH). ¹³C NMR (100 MHz, CDC1₃) δ 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^l-6^l, C2^π-6^π, CH₂Ph), 100.71, 101.16 (2 C; C-l¹, C-l^π), 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-0-benzoyl~2-deoxy-β-O-glucopyranosyl-(l→4)-l, 6-anhydro-2- azido-2-deoxy-3-0-benzyl-fi-O-glucopyranose as a colourless oil (27 mg, 12%, 3 steps). 1H NMR (400 MHz, CDC1₃) 3.19 (s, 1 H; H-2¹), 3.74 (dd, 1 H, J_5;6 6.2, J_6;6 7.1 Hz; H-6¹), 3.79-3.88 (m, 2 H; H-2^π, H-3¹), 3.88 (ddd, J_4;5 9.2, J_5;6 3.1, 4.7 Hz; H-5^π), 3.95 (br s, 1 H; H- 4¹), 4.10 (d, 1 H, J_6;6 7.3 Hz; H-6¹), 4.34 (dd, 1 H; J_5,6 4.9, J_6,6 12.2 Hz; H-6^π), 4.50 (dd, 1 H, J₅,₆ 3.1, J₆,₆ 12.3 Hz, H-6^π), 4.52, 4.59 (AB quartet, J_A,_B 12.0 Hz; CH₂Ph), 4.65 (d, 1 H, Jι_,2 7.9 Hz; H-l^π), 4.69 (br d, 1 H, J₅,₆ 5.5 Hz; H-5¹), 5.44 (t, 1 H, J₂,₃=₃,₄ 9.7 Hz; H-3^π), 5.49 (br s, 1 H; H-l¹), 5.51 (t, 1 H, J_3A^_ι5 9.6 Hz; H-4^π), 7.23-7.50, 7.84-7.96 (2 m, 20 H; ArH). Step b: 2-Deoxy-2-sulfamido-a-O-glucopyranosyl-(l→4)-l, 6-anhydro-2-deoxy-2-sulfamido-3- 0-benzyl- -O-glucopyranose, disodium salt (PG2046) A mixture of 2-azido-3,4,6-tri-0-benzoyl-2-deoxy-a-O-glucopyranosyl-(l→4)-l,6- anhydro-2-azido-2-deoxy-3-0-benzyl- -D-glucopyranoside (127 μmol), 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 μm) and evaporated. The crude amine was purified by SPE (300 mg C18 Waters cartridge, equilibrated with 5:95 MeOH:H₂O, gradient eluted 5:95 to 100:0 MeOH:H₂O) to yield 53 mg of the diamine (58%). Without further purification, to the diamine was added DMF (5 mL), SO₃ ^«Me₃N (41 mg, 295 μmol) and NaHCO₃ (40 mg, 475 μmol). The mixture was heated to 60° for 1 h then cooled to rt and quenched with ice and Na₂CO₃ (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 μL, IM) were added and the solution was stirred overnight then loaded directly onto the SEC column (general procedures) to yield 22 mg (28 % over three steps) of the title compound. 1H NMR (400 MHz, D₂O, solvent suppressed) δ: 7.35-7.21 (m, 5H, ArH), 5.43 (br s, IH, HI¹), 5.18 (d, IH, J_1-2 ^*= 3.6, HI¹¹), 4.72-4.69¹ (m, IH, H5¹), 4.54-4.52¹ (m, 2H, ArCH₂), 4.05 (d, IH, J_gem = 7.9, H6A¹), 3.85 (br s, IH, H3¹), 3.76-3.58 (m, 5H), 3.51 (dd, IH, J_2-3 = 10.4, J_3-4 = 9.1, H3^π), 3.34 (t, IH, J_3-4~4-5 = 9.2, H4^π), 3.23 (br s, IH, H2¹), 3.12 (dd, IH, H2^π). ¹³C NMR (100 MHz, CDC1₃) δ: 133.3, 124.8, 124.6, 124.4, 96.9, 95.1, 72.7, 71.5, 70.8, 68.3, 68.2, 67.2, 66.0, 61.0, 56.6, 54.0, 49.8.

Step c: 2-Deoxy-2-sulfamido-a-O-glucopyranosyl-(l→4)-l, 6-anhydro-2-deoxy-2-sulfamido- - O-glucopyranoside, disodium salt (PG2047) A mixture of 2-deoxy-2-sulfamido-a-O-glucopyranosyl-(l→4)-l, 6-anhydro-2-deoxy-2- sulfamido-3-O-benzyl-β-O-glucopyranoside, disodium salt (12.9 mg, 20.8 μmol) and Pearlman's catalyst (5 mg) in purified water (2 mL) was subjected to 50 psi H₂ overnight. The mixture was filtered and lyophilised to yield 10.7 mg (98 %) of the title compound. 1H NMR (400 MHz, D₂O) δ: 5.47 (br s, IH, HI¹), 5.20 (d, IH, J_1-2 = 3.5, HI¹¹), 4.68 (br d, IH, J_5-4 = 5.5, H5), 4.07 (d, IH, J_gem = 1.6, H6A¹), 3.98 (br s, IH, H3¹), 3.75-3.64 (m, 4H), 3.52 (t, IH, J₂.₃.-₃-₄ = 9.3, H3^π), 3.34 (t, IH, J_3-4^.₅ = 9.3, H4^π), 3.13 (obs. dd², IH, H2^π), 3.11 (br s, IH, H2¹). Example 3: PG2039 and PG2037 Step a: Methyl 3,4-di-0-acetyl-2,6-di-0-benzyl-a-O-galactopyranosyl-(l→4)-2,3,6- tri-0-benzyl- -O-glucopyranoside Methyl 2,3,6-tri-O-benzyl-β-O-glucopyranoside (287 mg; 618 μmol), 302 mg (618 μmol) of ethyl 3,4-di-0-acetyl-2,6-0-dibenzyl-l-thio-fi-D-galactopyranoside [21] and 700 mg of 3 A molecular sieves were subjected to the general NIS glycosylation procedure using 181 mg (803 μmol, 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%). 1H NMR (400 MHz, CDC1₃, 400 MHz): 7.40-7.12 (m, 25H, Ph), 5.818 (d, IH, J_m._ιι = 3.6, HI¹¹), 5.481 (d, IH, J_41I-3iι = 3.2, H4^π), 5.309 (dd, IH, J₃ii_-2n = 10.8, J_31I-4π = 3.2, H3^π), 4.980 (d, IH, J_gem = 11.6, a-PhCH₂), 4.904 (d, IH, J_gem = 11.2, b-PhCH₂), 4.748 (d, IH, J_gem = 11.6, a-PhCH₂), 4.67-4.57 (m, 3H, b-PhCH₂ and c-PhCH₂), 4.479 (d, IH, J_gem = 12.8, d-PhCH₂), 4.443 (d, IH, J_gem ^*= 12.8, d-PhCH₂), 4.415 (d, IH, J_gem = 11.6, e-PhCH₂), 4.360 (d, IH, J_ιua = 8.0, HI¹), 4.201 (d, IH, J_gem = 12.6, e-PhCH₂), 4.153 (t, IH, J_5II-6aχiι = 7.2, J₅ii_-6eqii -= 6.0, H5¹¹), 4.072 (t, IH, J_4I-3i = 9.0, J_41-5i = 9.0, H4¹), 3.858 (dd, IH, J₂π_-3π = 10.8, J_2π-1π = 3.6, H2^π), 3.82-3.76 (m, 3H, H3¹, Hoax¹ and H6 eq¹), 3.597 (s, 3H, OMe), 3.62-3.57 (m, IH, H5¹), 3.507 (t, IH, J_2I._3I =

Affected by the solvent suppression signal. Partially obscured by H2¹. 8.4, J2HI = 8.0, H2¹), 3.347 (dd, IH, J_6eqii_-6axii = 9.2, J_6eqπ-5iι = 6.0, H6eq^π), 3.291 (dd, IH, J_6axii-_6ec.ii *--- 9.2, J_6axII-5„ = 7.2, Hoax¹¹), 1.958 (s, 3H, OAc), 1.930 (s, 3H, OAc). ¹³C NMR (100 MHz, CDCI₃, 100 MHz): 169.94 (CO), 169.78 (CO), 138.88, 138.35, 138.24, 137.73 and 137.64 (5x ipso-V ), 128.25, 128.22, 128.21, 128.15, 128.12, 128.00, 127.80, 127.57, 127.52, 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-0-acetyl-a-O-galactopyranosyl-(l→4)- -D-glucopyranoside. Following the standard debenzylation procedure, methyl 3,4-di-0-acetyl-2,6-di- 0-benzyl-a-O-galactopyranosyl-(l→4)-2,3,6-tri-0-benzyl-fi-O-glucopyranoside (88 mg, 98.8 μmol) was deprotected to give the title compound as a colourless powder (42 mg, 97%). 1H NMR (D₂O, 400 MHz): 5.394 (d, IH, J_in-2n= 3.6, HI¹¹), 5.294 (d, IH, J_4π-3πX 3.2, H4^π), 4.953 (dd, IH, J_3II.2II ^*--- 10.4, J3II-4H- 3.2, H3ⁿ), 4.229 (d, IH, J_n-2I-= 8.4, HI¹), 4.080 (t, IH, J_5π-6axiι = 6.4, J_5n-6eqii *= 6.0, H5^π), 3.965 (dd, IH, J_2n-3ii= 10.4, J__._m = 3.6, H2^π), 3.803 (dd, IH, J_6eqι_-6eqι = 12.0, J_6eqι_-5ι= 1.6, Hόeq¹), 3.67-3.59 (m, 2H, Hδax¹ and H3¹), 3.54-3.40 (m, 4H, H4¹, H5¹ and H6^π), 3.407 (s, 3H, OMe), 3.134 (dd, IH, ι-31 = 9.2, J__IΛ_\ **^** 8.4, H2¹), 2.012 (s, 3H, OAc), 1.909 (s, 3H, OAc). ¹³C NMR (D₂O, 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-0-sulfo-a-O-galactopyranosyl-(l→4)-2,3,6-tri-0-sulfo- -O- glucopyranoside, pentasodium salt (PG2039) Following the standard sulfonation/deacetylation procedures, 42 mg (95.4 μmol) of methyl 3,4-di-0-acetyl-a-O-galactopyranosyl-(l→4)- -O-glucopyranoside was converted to the title compound as a white powder (14.8 mg, 18%, CE: 6.12 min). 1H NMR (D₂O, 400 MHz): 5.404 (d, IH, J_in-2n = 3.6, HI¹¹), 4.756 (d, IH, Jn_-2ι= 3.6, HI¹), 4.60 (overlappped with water, IH, H3¹), 4.448 (dd, IH, J₂ι_-3ι = 3.2, H2¹), 4.296 (dd, IH, n-₃₁₁ = 10.0, H2^π), 4.23-4.00 (m, 7H, H6¹, H5¹, H6^π, H4¹ and H5^π), 3.958 (dd, IH, J₃ii_-4n = 3.6, J_4n-5„ ^*= 0.8, H4^π), 3.930 (dd, lH, H3^π), 3.367 (s, 3H, CH₃O).

Step d: Methyl 2,6-di-0-benzyl-3,4-di-0-methyl~ -O-galactopyranosyl-(l→4)-2,3,6-tri-0- benzyl- -O-glucopyranoside Following the standard deacetylation and methylation procedures, methyl 3,4-di-O- acetyl-2, 6-di-0-benzyl-a-O-galactopyranosyl-(l→4)-2, 3, 6-tri-O-benzyl-β-O-glucopyranoside (72 mg, 80.8 μmol) was converted into the title compound as colourless gum (62.7 mg, 93%). 1H NMR (CDCI₃, 400 MHz): 7.35-7.08 (m, 25H, Ph), 5.717 (d, IH, Jιπ_-2π = 3.6, HI¹¹), 4.856 (d, IH, J_gem ^*= 11.2, a-PhCH₂), 4.843 (d, IH, J_gem ^*= 10.8, b-PhCH₂), 4.695 (d, 2H, J_gem = 12.0, a-PhCH₂ and c-PhCH₂), 4.631 (d, IH, J_gem = 12.4, d-PhCH₂), 4.571 (d, IH, J_gem = 10.8, b-PhCH₂), 4.500 (d, IH, J^_rrX 12.4, d-PhCH₂), 4.450 (d, IH, J_gem = 11.6, c-PhCH₂), 4.433 (d, IH, J_gem = 11.2, e-PhCH₂), 4.359 (d, IH, J_eaa = 11.2, e-PhCH₂), 4.303 (d, IH, J_1I-2ι= 7.6, HI¹), 3.949 (t, IH, J_4I-3I = 9.0, J41-51 = 9.0, H4¹), 3.871 (dd, IH, J_5π-6axII = 7.2, J_5Ii_-6eqii = 6.4, H5^π), 3.791 (dd, IH, J__-m = 10.4, J_2π-m = 3.6, H2¹¹), 3.77-3.68 (m, 4H, H4^π, H3¹, Hδax¹ and Hόeq¹)), 3.59-3.53 (m, 2H, H5¹ and H6^π), 3.551 (s, 3H, OMe), 3.51-3.40 (m, 3H, H3^π, H6^π and H2¹), 3.492 (s, 3H, OMe), 3.433 (s, 3H, OMe). Step e: Methyl 3,4-di-0-methyl-a-O-galactopyranosyl-(l→4)-fi-O-glucopyranoside Following the standard debenzylation procedure, methyl 2,6-di-0-benzyl-3,4-di-0- methyl-a-O-galactopyranosyl-(l→4)-2,3,6-tri-0-benzyl- -O-glucopyranoside (62.1 mg, 75.1 μmol) was deprotected to give the title compound as colourless gum (28 mg, 97%). 1H NMR (D₂0, 400 MHz): 5.232 (d, IH, J_m-w = 4.4, HI¹¹), 4.217 (d, IH, J_1I-2ι- 8.0, HI¹), 3.83-3.75 (m, 3H, H4^π, H5^π and H6¹), 3.682 (dd, IH, J₂n_-3πX 10.4, J_2Iι_-ιπ = 4.4, H2^π), 3.64-3.52 (m, 4H, H6¹, H3^π and H6^π), 3.47-3.38 (m, 3H, H4¹, H5¹ and H3^π), 3.400 (s, 3H, OMe), 3.340 (s, 6H, 2xOMe), 3.117 (dd, IH, J21-₃1 = 9.6, J_ι-u = 8.0, H2¹). ¹³C NMR (D₂O, 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-O-galactopyranosyl-(l→4)-2, 3, 6-tri-O- sulfo-fi-O-glucopyranoside, pentasodium salt (PG2037) Following the standard sulfonation procedure, methyl 3,4-di-O-methyl-a-O- galactopyranosyl-(l→4)- -O-glucopyranoside (28 mg, 72.8 μmol) gave the title compound (3.2 mg, 4.9%). 1H NMR (400 MHz, D₂O): 5.357 (d, IH, J_ln-2ii= 3.2, HI¹¹), 4.766 (d, IH, J_π-2ι = 3.6, HI¹), 4.60 (overlappped with water, IH, H3¹), 4.455 (dd, IH, J₂ι_-3ι= 2.8, H2¹), 4.304 (dd, IH, J₂iι_-3π = 10.0, H2^π), 4.22-3.99 (m, 5H, H5¹, H6¹, H4¹ and H5^π), 4.002 (d, 2H, J₅₁1-_6I1 = 6.8, H6^π), 3.886 (d, IH, J₃π-₄iι= 3.2, H4^π), 3.667 (dd, IH, H3^π), 3.398 (s, 3H, CH₃O), 3.367 (s, 3H, CH₃O), 3.356 (s, 3H, CH₃O). Example 4: PG2053 and PG2042 Methyl 4-0-Allyl-2,3-di-0-sulfo- -L-rhamnoside, disodium salt (PG2053). The title compound was obtained from methyl 2,3-O-isopropylidene- -L- rhamnopyranoside [22] via the general alkylation (with allyl bromide) and deprotection procedure followed by the general sulfonation procedure, as a colourless powder. CE t_m = 10.48 min. 1H NMR (400 MHz, D₂O) £ 1.19 (d, 3 H, J₅,₆ 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; OCH₂), 4.41-4.42 (m, 1 H; H-3), 4.63-4.64 (m, 2 H; H-2), 4.83 (s, 1 H; H-l), 5.07-5.21 (m, 2 H; ^*=CH₂), 5.76-5.88 (m, 1 H; =CH). When a reduced quantity (1 eq.) of SO₃»trimethylamine was employed, methyl 4-0- allyl-2-O-sulfo-a- -rhamnoside, sodium salt (PG2042) was exclusively obtained. CE t_m > 25.00 min. 1H NMR (400 MHz, D₂O) £1.19 (d, 3 H, J₅,₆ 6.4 Hz; H-6), 3.16 (t, 1 H, J_3,4 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; OCH₂), 4.34-4.35 (m, 1 H; H-2), 4.80 (s, 1 H; H-l), 5.08-5.22 (m, 2 H; =CH₂), 5.78-5.88 (m, 1 H; -CH). Example 5: PG2024 Methyl 4-0-Benzyl-2,3-di-0-sulfo- -L-rhamnoside, disodium salt (PG2024) The title compound was obtained from methyl 2,3-O-isopropylidene- -L- rhamnopyranoside via the general alkylation (with benzyl bromide) and deprotection procedure followed by the general sulfonation procedure, as a colourless powder. CE t_m = 10.82 min. 1H NMR (400 MHz, D₂O) £1.00 (d, 3 H, J_5,6 6.8 Hz; H-6), 3.23 (s, 3 H; OMe); 3.78-3.80 (m, 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, J_A,_B 12.0 Hz; CH₂Ph), 4.90 (dd, 1 H, J_1;2 1.2 Hz; H-l), 7.20-7.36 (m, 5 H; ArH). Example 6: PG2054 Step a: Methyl 4-O-benzoyl-a- -rhamnoside A solution of methyl 2,3- -isopropylidene- - -rhamnopyranoside (200 mg, 920 μmol), benzoyl chloride (193 mg, 1.38 mmol) and Et₃N (364 μL, 2.76 mmol) in DCM (10 mL) was stirred overnight. The resulting suspension (Et₃N^»HCl precipitates) was diluted with DCM (50 mL) and washed with NaHCO₃ (sat. aqueous), water then brine, dried (MgSO₄) and evaporated. The residue was taken up in 50 mL of 1:1 MeCN:H₂O and p-TsOH (10 mg) was 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, CDC1₃) δ: 8.03-8.00 (m, 2H, Hortho), 7.55 (tt, IH, JHp-Hm = 7.5, J_Hp-Ho = 1.3, Hpara), 7.43-7.39 (m, 2H, Hmeta), 5.09 (dis t, IH, J_{4-3~ -5} = 9.3, H4), 4.73 (br s, IH, HI), 4.01-3.97 (m, 2H, H2+H3), 3.91 (dq, IH, J_4-5 = 9.7, J_5-6 = 6.4, H5), 3.53-3.46 (br s, 2H, OH), 3.38 (s, 3H, OMe), 1.25 (d, 3H, H6). ¹³C NMR (100 MHz, CDC1₃) δ: 167.1, 133.3, 129.8, 129.5, 128.3, 100.6, 75.7, 70.8, 70.1, 65.7, 55.0, 17.4. Step b: Methyl 4-0-Benzoyl-2,3-di-0-sulfo-a-L-rhamnoside, Disodium salt (PG2054) The title compound was obtained from methyl 4-O-benzoyl- - -rhamnoside via the general sulfonation procedure as a colourless powder. CE t_m = 11.14 min. 1H NMR (400

MHz, D₂O) £ 1.14 (d, 3 H, J_5,6 6.3 Hz; H-6), 3.33 (s, 3 H; OMe), 3.99-4.07 (m, 1 H; H-5), 4.66-4.73 (m, 2 H; H-2, -3), 4.95 (d, 1 H, J_1;2 1.4 Hz; H-l), 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-l,2-dihydro-O-glucal. A mixture of tri-O-acetyl-O-glucal (1.7 g, 6.25 mmol), AcOH (50 μL) and Pd(OH)₂/C (100 mg) in MeOH (15 mL) was vigorously stirred under H₂ (1 atm.) overnight. The mixture was filtered, the solvent evaporated and the residue subjected to flash chromatography (10- 50% EtOAc/hexanes) to yield tri-0-acetyl-l,2-dihydro-O-glucal as a colourless oil. This residue was co-evaporated (2 x 10 mL MeCN) then subjected to the Zemplen deacetylation general procedure to yield 1,2-dihydro-D-glucal as a colourless oil (825 mg, 89%). This residue was co-evaporated (2 x 10 mL MeCN). -TsOH.H₂O (50 mg) was added to a solution of the 1,2-dihydro-O-glucal (495 mg, 3.34 mmol) and α,α-dimethoxytoluene (753 μL, 5.01 mmol) in DMF (5 mL) and the combined mixture stirred (60°, 1 h). Et₃N (100 μL) was introduced and the solvent was evaporated. The residue was subjected to flash chromatography (0-5% MeOH/CHCl₃) to yield the title compound as colourless needles (503 mg, 64%). 1H NMR (400 MHz, CDC1₃) £ 1.72-2.01 (m, 2 H; H-2), 3.27-3.33 (m, 1 H; 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-l), 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). ¹³C NMR (100 MHz, CDCI₃) £ 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 (CHPh), 126.43, 128.55, 129.34, 137.50 (4 C; Ph).

Step b: 3-0-Benzyl-4,6-di-0-sulfo-l,2-dihydro-O-glucal, Disodium salt (PG2041). 4,6-0-Benzylidene-l,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 t_m = 15.40 min. 1H NMR (400 MHz, CDC1₃) £ 1.48-1.53, 1.97-2.03 (2 m, 2 H; H-2), 3.30-3.71 (m, 1 H; H-l), 3.52-3.57 (m, 1 H; H-5), 3.60-3.66 (m, 1 H; H-3), 3.78- 3.83 (m, 1 H; H-l), 3.97 (dd, 1 H, J_5;6 8.0, J₆,₆ 11.4 Hz; H-6), 3.98 (t, 1 H, J₃,_4=4,s 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; CH₂Ph), 7.21-7.36 (m, 5 H; Ph). Example 8: PG2030

Step a: 1, 6-Anhydro-3-0-methyl- -O-glucopyranose. -Toluenesulfonyl chloride (790 mg, 4.14 mmol) was added to a cooled (0°) suspension of 3-O-methyl-D-glucopyranose (804 mg, 4.14 mmol) in pyridine (10 mL) and the reaction mixture stirred (0°→r.t, 1.5 h). Ac₂O (1.5 mL, 15 mmol) and N,N-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 ofthe 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 ΝaOH (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), Ac₂O (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 residual oil was subjected to flash chromatography (20-50% EtOAc/hexanes) to yield an inseparable mixture of 2,4-di-0-acetyl-l,6-anhydro-3-0-methyl- -D-glucopyranose (a) and l,2,4-tri-0-acetyl-3-0-methyl-6-0-tosyl- -O-glucopyranose (b) (in a ratio of 3:1) as a pale yellow oil (466 mg). The ratio was determined by integration of the H-l and 3-OMe signals observed in the 1HΝMR spectrum. Partial 1H NMR (400 MHz, CDC1₃) £ 3.32 (s, 3 H; OMe b), 3.45 (s, 3 H; OMe a); 5.22 (br s, 1 H; H-l b), 5.42 (br s, 1 H; H-l a). The mixture of the two compounds (456 mg) was subjected to the Zemplen 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). 1HNMR (400 MHz, CDC1₃): £ 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 (dd, 1 H, J_5,6 = 5.6, J₆,₆ = 7.2 Hz; H-6), 4.06 (d, 1 H, J_6>6 = 7.2 Hz; H-6), 4.48-4.51 (m, 1 H; H- 5), 4.39 (br s, 1 H; H-l). Step b: 1, 6-Anhydro-4-0-benzyl-3-0-methyl- -O-glucopyranose. A mixture of l,6-anhydro-3-0-methyl-β-O-glucopyranose (155 mg, 0.88 mmol) and Bu₂SnO (241 mg, 0.97 mmol) in toluene (18 mL) was heated under reflux (with azeotropic removal of water) until the solution was one-half the original volume. The mixture was cooled (80°), BnBr (104 μL, 0.88 mmol) and BvuNBr (567 mg, 1.76 mmol) were introduced and stirring continued (o/n). The mixture was treated with MeOH (2 mL) and H₂O (1 mL) with continued stirring (10 min) prior to evaporation of the solvent. The residue was subjected to 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%). 1H NMR (400 MHz, CDC1₃): £ 2.58 (d, 1 H, J_2;OH 6.4 Hz; OH), 3.32-3.43 (m, 5 H; H-3, H-4, OMe), 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; CH₂Ph), 5.39-5.40 (m, 1 Η; Η-l), 7.28-7.36 (m, 5 H; ArH). Secondly, l,6-anhydro-2-0-benzyl-3-0-methyl-$-D-glucopyranose was afforded as a colourless oil (91 mg, 39%). 1H NMR (400 MHz, CDC1₃): £ 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, J_5,6 6.0 Hz, J_6,6 7.2 Hz; H-6), 4.08 (dd, 1 H, J₅,₆ 0.8 Hz, J₆,₆ 7.2 Hz; H-6), 4.47-4.49 (m, 1 H; H-5), 4.56, 4.62 (AB quartet, J_AjB 12.0 Hz; CH₂Ph), 5.40-5.41 (m, 1 Η; Η-l), 7.26-7.36 (m, 5 Η; ArΗ). Step c: 1, 6-Anhydro-4-0-benzyl-3-0-methyl-2-0-sulfo-β-D-glucopyranose, sodium salt (PG2030) l,6-Anhydro-4-0-benzyl-3-0-methyl-^>-D-glucopyranose (84 mg, 0.32 mmol) was sulfonated according to the general procedure and subjected to flash chromatography (50/2/l→10/2/l EtOAc/MeOΗ/Η₂O) prior to SEC to yield the title compound as a pale yellow coloured powder (70 mg, 60%); CE t_m = 5.62 min; 1H NMR (400 MHz, D₂O) £3.19 (s, 3 H; OCH₃); 3.43-3.45 (m, 1 H; H-4), 3.52-3.53 (m, 1 H; H-3), 3.57 (dd, 1 H, J_5;6 = 5.9 Hz, J_6,6 = 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), 4.59-4.61 (m, 3 H; H-2, CH₂Ph), 5.41 (br s, 1 Η; Η-l), 7.22-7.34 (m, 5 Η; ArΗ). Example 9: PG2012 and PG2013 Step a: ^'N-benzyl-^~N-(cyclohexylacetamido)-l, 2, 3, 4-tetra-O-acetyl- -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 MeOΗ, 2.45 mL, 4.89 mmol), formaldehyde (2 M in MeOΗ, 2.45 mL, 4.89 mmol) and cyclohexylisocyanide (1 M in MeOΗ, 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)-O-glucuronamide as a yellow foam. 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). 1H NMR (CDCI₃, 400 MHz) was very complicated due to the presence of anomers and rotamers. The spectrum was not simplified after the temperature was raised to 55 °C. However, in pyridine-^ at 100 °C, each set of rotamers was coalesced in some degree into much more simplified structure, thus two anomers were clearly observed (α:β ratio = 69:31). 1H NMR (CDC1₃, 400 MHz, 25 °C): 7.41-7.14 (m, 5H, Ph), 6.337 (d, 0.39H, J= 3.6), 6.300 (d, 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 (m, 2.25H), 5.28-5.09 (m, 1.3H), 4.92-4.58 (m, 2.25H), 4.411 (d, J= 10) and 4.395 (d, J= 14, 0.55H), 4.271 (d, 0.1 IH, 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 (m, 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 singlet, 12H, Ac), 1.89-1.55 (m, 5H, cyclohexyl-CH₂), 1.41-0.83 (m, 5H, cyclohexyl-CH₂). 1H NMR (CDCI₃, 400 MHz, 55 °C): 7.38-7.16 (m, 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 (m, 1.3H), 5.52-5.41 (m, IH,), 5.28-5.10 (m, 1.4H), 4.85-4.58 (m, 2.4H), 4.48-4.40 (m, 0.6H), 4.318 (d, 0.1H, J = 9.2), 4.205 (d, 0.1H, J= 17.6), 4.02-3.93 (m, 0.9H), 3.84-3.62 (m, 2.2H), 2.179, 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 (m, 5H, cyclohexyl-CH₂), 1.42-0.88 (m, 5H, cyclohexyl-CH₂). 1H NMR (pyridine- d , 400 MHz, δ7.22, 100 °C): only typical sugar protons are given; the remaining signals (except acetate singlets) were complicated and appeared as broad lumps, α-anomer, 6.672 (d, J = 3.6, glu-Hl), 5.456 (dd, J= 9.6, 3.6, glu-H2); β-anomer, 6.206 (d, J= 8.0, glu-Hl), 5.741 (t, J= 9.2, glu-H4 or H5), 5.515 (dd, J^**** 8.8, 8.0, glu-H2).

Step b: Y\-benzyl-^~ -(cyclohexylacetamido)-l, 2, 3, 4-teti"a-0-sulfo-a~D-glucuronamide, tetrasodium salt (PG2012) and~ -benzyl-^~N-(cyclohexylacetamido)-l,2,3-tri-0-sulfo-a-D- glucuronamide, trisodium salt (PG2013) Following the general procedure for deacetylation, the above tetraacete (0.441 g, 0.747 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 EtOAc, MeCN, MeCN-Et₃N (10:1), MeCN-Et₃N-H₂O (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 (D₂O, 400 MHz): two rotamers in a ratio of 56:44. major rotamer, δ 7.36-7.11 (m, 5H, Ph), 5.946 (d, IH, J- 3.2, HI), 4.894 (d, IH, J^*= 9.6, H5), 4.748 (d, IH, J= 16, a-CH₂), 4.685 (d, IH, J^*= 16, a-CH₂), 4.502 (t, IH, J= 10.4, 9.6, H3), 4.306 (dd, IH, J= 9.6, 3.6, H2), 4.005 (t, IH, J= 9.6, 8.8, H4), 3.869 (s, 2H, b-CH₂), 3.42-3.32 (m, IH, cyclohexyl-CHN), 1.64-1.36 (m, 5H, cyclohexyl-CH₂), 1.20-0.92 (m, 5H, cyclohexyl-CH₂); minor rotamer, 7.36-7.11 (m, 5H, Ph), 5.905 (d, IH, J= 3.2, HI), 4.578 (d, IH, J= 10, H5), 4.523 (s, 2H, c-CH₂), 4.478 (t, IH, J= 10.4, 9.6, H3), 4.321 (d, IH, J= 17.6, d-CH₂), 4.281 (dd, IH, J^*= 9.6, 3.2, H2), 4.039 (t, IH, J= 9.6, 9.2, H4), 3.900 (d, IH, J = 17.6, d-CH₂), 3.42-3.32 (m, IH, cyclohexyl-CHN), 1.64-1.36 (m, 5H, cyclohexyl-CH₂), 1.20-0.92 (m, 5H, cyclohexyl-CH₂). ¹³C NMR (D₂O, 100 MHz, no reference): double-up of each signals due to two rotamers, 169.96 (amide-CON), 169.75 (amide-CON), 168.91 (amide-CON), 168.85 (amide-CON), 135.45 (ipso-Fh), 135.20 (ipso- Ph), 129.16, 129.07, 128.47, 128.32, 128.20 and 128.13 (meta-, ortho- and para-V ), 95.67 and 95.65 (glu-Cl), 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-CH₂), 51.12 (c-CH₂), 50.32 (d-CH₂), 50.02 (b-CH₂), 49.25 and 49.00 (cyclohexyl-CHN), 31.89 and 31.86, 25.08 and 25.05, 24.47 and 24.38 (cyclohexyl-CH₂). ES-LRMS (+ve, m/z): C₂₁H₂₇N₂Na₃O₁₆S₃ required 728.02, found 751 (M+Na⁺), 729 (M+H⁺); ES-HRMS (+ve, m/z): M+Na⁺, C₂₁H₂₇N₂Na₄O₁₆S₃ required 751.0113, found 750.1087; M+H⁺, C₂₁H₂₈N₂Na₃O₁₆S₃ required 729.0294, found 729.0242. The polar part was purified by LH20 column (x2) and ion exchange column to give tetrasulfate PG2012 as an off-white powder after lyophilisation (7.6 mg, 1.5%). 1H NMR (D₂O, 400 MHz): two rotamers in a molar ratio of 70:30. Major rotamer, δ 7.34-7.16 (m, 5H, Ph), 5.954 (d, IH, J= 3.6, HI), 5.235 (d, IH, J= 9.6, H5), 4.904 (d, IH, J= 15.6, a-CH₂), 4.67-4.57 (overlapped with water, IH, H3), 4.536 (t, IH, J= 9.6, 8.8, H4), 4.466 (d, IH, J= 15.6, a-CH₂), 4.394 (dd, IH, J= 9.8, 3.4, H2), 3.927 (d, IH, J= 16.8, b-CH₂), 3.749 (d, IH, J= 16.8, b-CH₂), 3.30-3.20 (m, IH, cyclohexyl-CHN), 1.65-1.35 (m, 5H, cyclohexyl-CH₂), 1.18-0.92 (m, 5H, cyclohexyl-CH₂); minor rotamer, 7.34-7.16 (m, 5H, Ph), 5.912 (d, IH, J= 3.4, HI), 4.77-4.72 (m, 2H, H5 and H3 or H4), 4.689 (d, IH, J = 15.2, c-CH₂), 4.67-4.56 (overlapped with water, IH, H4 or H3), 4.373 (dd, IH, J= 9.8, 3.4, H2), 4.256 (d, IH, J= 18.4, d-CH₂), 4.215 (d, IH, J ^*= 15.2, c-CH₂), 3.936 (d, IH, J^*= 18.4, d-CH₂), 3.36-3.26 (m, IH, cyclohexyl-CHN), 1.65-1.35 (m, 5H, cyclohexyl-CH₂), 1.18-0.92 (m, 5H, cyclohexyl-CH₂). ¹³C NMR (D₂0, 100 MHz, no reference): major rotamer, 172.35 (amide-CON), 171.69 (amide- CON), 137.22 (ipso-? ), 131.71 and 131.58 (meta- and ortho-?h), 131.11 (pαrα-Ph), 97.68 (glu-Cl), 78.08 (glu-C4), 77.60 (glu-C3), 76.43 (glu-C2), 70.10 (glu-C5), 55.81 (a-CH₂), 53.17 (b-CH₂), 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-Cl), 78.22 (glu-C4), 77.77 (glu-C3), 76.33 (glu-C2), 71.01 (glu-C5), 53.26 (d-CH₂), 53.79 (c-CH₂), 52.10 (cyclohexyl-CHN), 34.28 (cylcohexyl-CH₂), 27.52 (cylcohexyl-CH₂), 27.08 (cylcohexyl-CH₂). ES-MS (+ve, m/z): C₂₁H₂₆N₂Na₄O₁₉S₄ required 829.96, found 853 (M+Na⁺), 831 (M+l ). ES- HRMS (+ve, m/z): M+Na⁺, C₂₁H₂₆N₂Na₅O₁₉S₄ required 852.9501, found 852.9334; M+H^1", C₂₁H₂₇N₂Na₄O₁₉S₄ required 830.9682, found 830.9635. Example 10: PG2064 Step a: 2-(N-acetyl-^'N-cyclohexyl)amino-^'N-(methyl 2,3,4-tri-0-benzyl-6-deoxy-a-D- 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 μL, 119 μmol), cyclohexylamine (2 M in MeOH, 60 μL, 119 μmol), formaldehyde (2 M in MeOH, 60 μL, 119 μmol) and methyl 2,3,4-tri-0-benzyl-6-deoxy-6-isocyano- -D-mannopyranoside (0.721 M in CHC1₃, 150 μL, 108 μmol) 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 (CDC1₃, 400 MHz): two rotamers in a ratio of 72:28. δ 7.38-7.26 (m, 15H, 3 x C₆H₅), 6.933 (t, 72% x IH, J = 4.4, NH in major rotamer), 6.357 (t, . 28% x IH, J= 5.8, NH in minor rotamer), 4.91-4.41 (m, 7H, sugar-Hl and 3 x PhCH₂), 4.04- 3.42 (m, 9H, sugar-H2-6, NCH₂CO and cyclohexyl-CH), 3.305 (s, 72% x 3H, CH₃O in major rotamer), 3.266 (s, 28% x 3H, CH₃O in minor rotamer), 2.067 (s, 72% x 3H, CH₃CO in major rotamer), 2.012 (s, 28% x 3H, CH₃CO in major rotamer), 1.85-1.00 (m, 10H, cyclohexyl-CH₂). Step b: 2-(N-acetyl-^~N-cyclohexyl)amino-^'N-( methyl 6-deoxy -2,3,4-tri-O-sulfo-a-D- 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 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 exchange column to give the title compound as a white fluffy powder after lyophilisation (3.1 mg, 7.0%, two steps). 1H NMR (D₂O, int. ref. acetone at 2.05, 400 MHz): two rotamers in a ratio of 63:37. δ 4.844 (s, IH, sugar-Hl), 4.678 (s, IH, sugar-H2), 4.51-4.45 (m, IH, sugar-H3), 4.240 (t, 37% x IH, J= 9.6, sugar-H4 in minor rotamer), 4.214 (t, 63% x IH, J= 9.6, sugar-H4 in major rotamer), 3.980 (s, 37% x 2H, COCH₂N in minor rotamer), 3.825 (s, 63%) x 2H, COCH₂N in major rotamer), 3.78-3.59 (m, 3H, sugar-H5, one sugar-H6 and cyclohexyl-CH), 3.31-3.17 (m, 4H, one sugar-H6 and CH₃O [3.253, s, 3H]), 2.060 (s, 67% x 3H, CH₃CO in major rotamer), 1.900 (s, 33% x 3H, CH₃CO in minor rotamer), 1.70-0.88 (m, 10H, cyclohexyl-CH₂). 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 ofthe following three reagents: ethylamine (2 M in MeOH, 60 μL, 119 μmol), formaldehyde (2 M in MeOH, 60 μL, 119 μmol) and methyl 2,3,4-tri-O- benzyl-6-deoxy-6-isocyano-a-D-mannopyranoside (0.721 M in CHCI₃, 150 μL, 108 μmol) 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%). 1H NMR (CDCI₃, 400 MHz): two rotamers in a ratio of 73:27. δ 7.38-7.25 (m, 15H, Ph), 6.598 (t, 73% x IH, J= 6, NH), 6.529 (t, 27% x IH, J= 6, NH), 4.93-4.61 (m, 7H, sugar-Hl and 3 x PhCH₂), 4.14-3.24 (m, 16H, sugar 6 x H, NCH₂CO, 2 x CH₃O [singlets at 3.660 and 3.301, 73%; 3.648 and 3.276, 27%] and ethyl-CH₂), 2.70-2.42 (m, 4H, COCH₂CH₂CO), 1.138 (t, 73% x 3H, J= 7, ethyl-CH₃), 1.014 (t, 27% x 3H, J= 7, ethyl-CH₃). ¹³C (100 MHz, CDCI₃, δ 77.0): major rotamer, 173.32, 171.73, 168.94, 138.20, 138.17, 138.09, 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) 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 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 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). ^!H NMR (D₂O, int. ref. acetone at 2.05, 400 MHz): two rotamers in a ratio of 70:30. δ 4.86-4.84 (m, IH, sugar-Hl), 4.69-4.67 (m, IH, sugar-H2), 4.50-4.46 (m, IH, sugar-H3), 4.28-4.19 (m, IH, sugar-H4), 4.072 (s, 30% x 2H, 2H of COCH₂N in minor rotamer), 3.987 (d, 35% x 2H, J= 16.8, IH of COCH₂N in major rotamer), 3.815 (d, 35% x 2H, J= 16.8, IH of COCH₂N in major rotamer), 3.79-3.69 (m, 2H, sugar-H5 and one sugar- H6), 3.44-3.18 (m, 6H, one sugar-H6, ethyl-CH₂ and CH₃O [3.245, s, 3H]), 2.633 (t, J= 6.8) and 2.45-2.37 (m, total 4H, COCH₂CH₂CO₂), 1.054 (t, 70% x 3H, J^**** 7.2, CH₃O), 0.906 (t, 30% χ 3H, J= 7.2, CH₃O). 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 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 μL, 119 μmol) and 2-isocyanoethyl 2,3,4,6-tetra-O-benzyl-a-D-mannopyranoside (0.762 M in CHCI₃, 157 μL, 120 μmol) 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%). 1H NMR (CDCI₃, 400 MHz): δ 7.39-7.06 (m, 24H, 4 x C₆H₅ and 1 x H ), 6.731 (t, IH, J= 6.0, NH), 4.878 (d, IH, J= 10.8, a-CH₂), 4.844 (d, IH, J= 2.0, sugar-Hl), 4.770 (d, IH, J= 12.4, b-CH₂), 4.723 (d, IH, J= 12.4, b-CH₂), 4.640 (s, 2H, c-CH₂), 4.589 (d, IH, J= 11.6, d-CH₂), 4.535 (d, IH, J= 11.6, d-CH₂), 4.505 (d, IH, J= 10.8, a-CH₂), 4.446 (d, IH, J= 14.8, e-CH₂), 4.362 (d, IH, J= 14.8, e-CH₂), 3.90-3.51 (m, 12H), 3.38-3.29 (m, IH). ¹³C (100 MHz, CDC1₃, δ 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, 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 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 column to give PG2075 as a white fluffy powder after lyophilisation (10.6 mg, 28%, two steps). 1H NMR (D₂O, int. ref. acetone at 2.05, 400 MHz): δ 7.30-7.11 (m, 4H, Ar), 5.00-4.97 (m, IH, sugar-Hl), 4.72-4.28 (m, 3H, sugar-H2, H3 and H4), 4.21-3.30 (m, 11H, sugar-H5, H6 and 4 x CH₂). Example 13: PG2014 Step a Following the general procedure for the Ugi reaction, 2-(benzyl3,4,6-tri-0-benzyl- -D- mannopyranoside-2-yl) acetic acid (50 mg, 0.0835 mmol) and a solution of each following three reagents: benzylamine (2 M in MeOH, 41.8 μL, 0.0835 mmol), formaldehyde (2 M in MeOH, 41.8 μL, 0.0835 mmol) and 2-isocyanoethyl 2,3,4,6-tetra-O-benzyl- -D- mannopyranoside (0.415 M in MeOH, 201.4 μL, 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%). 1H NMR (400 MHz): two rotamers around amide CO-NH single bond in a ratio of 66:34. δ 7.40-7.05 (m, 45H, 9 x C₆H₅), 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, Hl^'-major rotamer) and 5.046 (s, 0.34H, Hl'-minor rotamer), 4.86-4.20 (m, 21H), 3.97-3.48 (m, 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 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 sodium salt by passing through an ion exchange column to give PG2014 as a white powder (16.6 mg, 44%, two steps). 1H NMR (D₂O, 400 MHz, complicated due to two rotamers): δ 7.32-7.14 (m, 5H, Ph), 5.80-5.66 (m, 0.5H), 5.44-5.39 (m, 0.5H), 5.04-4.96 (m, 1.5H), 4.80- 4.20 (m, 9H, overlapped with water), 4.18-3.78 (m, 7.5H), 3.76-3.46 (m, 1.5H), 3.42-2.98 (m, 3.5H). Example 14: PG2016 Step a Following the general procedure for the Ugi reaction, tr rø-l,4-diaminocyclohexane (6.3 mg, 0.055 mmol) and a solution of each following three reagents: 2 -(methyl 2,3,4-tri-O- benzyl -O-mannopyranoside-6-yl)acetic acid (0.91 M in MeOH, 121 μL, 0.11 mmol), formaldehyde (2 M in MeOH, 55 μL, 0.11 mmol) and cyclohexylisocyanide (1 M in MeOH, 110 μL, 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 colourless gum, 33.0 mg, 43% (Rf = 0.24, DCM-MeOH 95:5 or Rf ^*=^* 0.48, MeCN-EtOAc 1:1). 1H NMR (CDC1₃, 400 MHz, very complicated due to rotamers): δ 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 (m, 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 (m, 16H), 1.36-1.00 (m, 12H). 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 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%). 1H NMR (D₂O, 400 MHz): δ 4.97-4.92 (m, 2H, man-Hl), 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 OCH₂CO), 3.98-3.80 (m, 8H, man-H5, man-H6 and NCH₂CO), 3.80-3.32 (m, 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-CH₂). ES-MS (+ve, m/z): C₄₀H₆₂N₄Na₆O₃₄S₆ required 1472.10, found 1495 (M+Na⁺), 1473 (M+H⁺). ES-HRMS (+ve, m/z): M+Na⁺, C₄₀H₆₂N₄Na₇O₃₄S₆ required 1495.0853, found 1495.0957; M+H , C₄₀H₆₃N₄Na₆O₃₄S₆ required 1473.1034, found 1473.1082. Example 15: PG2015 Step a Following the general procedure for the Ugi reaction, 3,3-dimethylglutaric acid (7.1 mg, 0.0443 mmol) and a solution of each following three reagents: 3-aminopropyl 2,3,4,6- tetra-O-benzyl- -D-mannopyranoside (0.642 M in MeOH, 138 μL, 0.0886 mmol), formaldehyde (2 M in MeOH, 44.3 μL, 0.0886 mmol) and cyclohexylisocyanide (1 M in MeOH, 88.6 μL, 0..0886 mmol) were 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 colourless gum, 32.3 mg, 46% (Rf = 0.45, hexane-EtOAc 1 :3). 1H NMR (CDC1₃, 400 MHz, very complicated due to rotamers): δ 7.38-7.21 (m, 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 (m, 4H), 4.76-4.59 (m, 10H), 4.54-4.45 (m, 4H), 4.00-3.62 (m, 20H), 3.46-3.14 (m, 6H), 2.52-2.22 (m, 4H), 1.90-1.52 (m, 15H), 1.34-1.00 (m, 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) 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%). 1H NMR (D₂O, 400 MHz): δ 5.020 (d, 2H, J = 1.6, man-Hl), 4.759 (br s, 2H, man-H2), 4.66-4.56 (m, 2H, man-H3, overlapped with water), 4.46-4.41 ,(m, 2H, man-H6), 4.265 (t, 2H, J= 9.6, 9.2, man-H4), 4.10-3.96 (m, 4H, man-H5 and man-H6), 4.05-3.14 (m, 14H, NCH₂CO, cyclohexyl-CH and NCH₂CH₂CH₂O), 2.50-2.11 (m, 4Η, CCH₂CO), 1.84-1.42 (m, 14H, cyclohexyl-CH₂ and NCH₂CH₂CH₂O), 1.24-0.93 (m, 16H, cyclohexyl-CH₂ and Me). ES-MS (+ve, m/z): C₄₁H₉₃N_nO₃₇S₇ (7 x SO₃NH₄) required 1556, found 1578 (M+Na^"1"), 1556 (M+H⁺). ES-HRMS (+ve, m/z): M+H⁺ C₄₁H₉₃NπO₃₇S₇ required 1556.3857, found 1556.3783. Example 16: PG2155.

Ethyl 2,6-Di-0-benzyl-3,4-di-0-sulfo-β-D-galactopyranoside, disodium salt (PG2155) The title compound was obtained from ethyl 2,6-di-0-benzyl-3,4-di-0-sulfo-β-D- galactopyranoside [23] via the general sulfonation procedure as a colourless powder. 1H NMR (400 MHz, D₂O) £ 1.10 (dd, 3 H; CH₂CH₃); 2.49-2.66 (m, 2H, CH₂CH₃); 3.59 (dd, 1 H, J_w 9.7 Hz; H-2); 3.65 (dd, 1 H, J₅,_6a 3.3, J_6a,_6b 11.0 Hz; H-6a); 3.68 (dd, IH, J₅,_6b 4.0 Hz; H-6b); 3.83 (m, 1 H; H-5); 4.36 (dd, 1 H, J₃,₄ 3.0 Hz; H-3); 4.46 (s, 2 H; CH₂Ph); 4.48 (d, 1 H; H-l); 4.60, 4.75 (AB quartet, J 10.3 Hz; CH₂Ph); 4.85 (dd, 1 H; J₄,₅ 0.0 Hz; H-4); 7.22-7.29, 7.37-7.39 (2 m, 10 H; ArH). Example 17: PG2163.

Step a: Methyl 4-0-allyl-6-azido-6-deoxy-2,3-di-0-isopropylidene- -D-mannopyranoside A solution of methyl 6-azido-6-deoxy-a-D-mannopyranoside (311 mg, 1.419 mmol) in 2,2-dimethoxypropane (4.7 mL, 0.3 M) was treated with (±)-camphor-lO-sulfonic acid (16 mg, 0.0709 mmol, 5 mol%). The mixture was stirred at r.t. for 1 h. TLC indicated the complete conversion to the product (Rf = 0.40, EtOAc-hexane = 17:83). The mixture was basified by addition of sat. Na₂CO₃ (aq. sol.) and evaporated under vacuum. The residue was extracted with EtOAc (30 mL) and the EtOAc solution washed with brine, dried (MgSO₄). 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 in mineral oil, 163 mg, 4.257 mmol, 3 eq) for lh. Allyl bromide (360 μL, 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 (2.5x18 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). 1H NMR (CDC1₃, 400 MHz): 5.85 (m, IH, allyl-2'), 5.23 (ddd, IH, J₂.₃._tran_s = 17.2, J₃,_-gem= 3.6, J_v.? = 1.6, H3'_tøris), 5.17-5.13 (m, IH, H3'_cis), 4.89 (s, IH, HI), 4.35 (dddd, IH, J_rgem = 12.4, J_v._? = 5.2, J= 1.6, HI'), 4.16 (dd, IH, J_2-3 = 5.6, J_3-4 = 7.2, H3), 4.09 (d, IH, H2), 4.05 (dddd, IH, HI'), 3.67 (ddd, IH, J_4-5 = 10.4, J_5-6ax= 6.8, J_5-6eq ^*= 2.4, H5), 3.48 (dd, IH, J₆ax-6e_q *= 13.2, H6eq), 3.40 (dd, IH, J_6aχ-_6eq = 13.2, J_5-6ax = 6.8, H6ax), 3.33 (dd, IH, H5), 1.50 (s, 3H, Me), 1.30 (s, 3H, Me). ¹³C NMR (CDC1₃, 100 MHz): 134.4, 117.1, 109.2, 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- -D-mannopyranoside Methyl 4-0-allyl-6-azido-6-deoxy-2, 3-di-O-isopropylidene-a-D-mannopyranoside (56 mg, 0.187 mmol) was dissolved in MeCN-MeOH-H₂O (3 mL, 3 mL and 0.2 mL respectively) 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 1x18 cm, eluted with EtOAc-hexane 1:6 to 2:1) to give the product as a colourless waxy solid (34.8 mg, 72%). 1H NMR (CDC1₃, 400 MHz): 5.91 (m, IH, allyl-H2'), 5.28 (ddd, IH, J^ s = 16.8, J3.trans.₃Ois = 3.0, J_r-3. = 1.6, allyl-H3'trans), 5.20 (ddd, IH, J₂._-3._cIs = 10.0, J^ans-sOi_s = 3.0, J_v.y = 1.6, allyl-ffi'cV), 4.72 (ddd, IH, J_1-2 = 2.0, HI), 4.28 (dddd, IH, J_gem = 12.4, J _-2. = 5.6, J= 1.6, allyl-1*), 4.13 (dddd, IH, allyl-1'), 3.92 (dd, IH, J_2-3 = 3.6, H2), 3.88 (dd, IH, J_3-4 = 9.6, H3), 3.70 (ddd, IH, J _-5 ^*= 9.6, J_5-6ax= 5.6, J_5-6eq= 2.8, H5), 3.54-3.44 (m, 3H, H4, H6ax and H6eq), 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-0-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 (EtOAc-MeOH-H₂O=10:2:l). 1H NMR (D₂O, 400 MHz): 5.88-5.76 (m, IH, allyl-2'), 5.20 (d, IH, J₂'-₃tπ-n_s = 17.2, allyl-3 'trans), 5.12 (d, IH, J₂._-3'cis = 10.0, allyl-3'cis), 4.91 (s, IH, HI), 4.65 (br s, IH, J_2-3 = 3.2, H2), 4.48 (dd, IH, J₂ = 3.2, J_3-4= 9.2, H3), 4.21 (dd, IH, J_gern= 11.6, J_v._x = 5.6, allyl-1'), 4.00 (dd, IH, J_v._> = 6.4, allyl-1'), 3.71-3.67 (m, IH, H5), 3.58 (dd, IH, J_6eq-_6aχ = 13.6, J_5-6eq = 2.0, H6eq), 3.58 (dd, IH, J_4-5 ^*= 9.6, H4), 3.46 (dd, IH, J_6eq-6ax = 13.6, J₅._6sκ = 5.6, H6ax), 3.30 (s, 3H, MeO). ¹³C NMR (D₂O, 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-0-benzylidene-a-D-mannopyranoside Methyl 6-azido-6-deoxy-α-D-mannopyranoside (1.011 g, 4.61 mmol) was dissolved in anhydrous DMF (9 mL) and acetonitrile (9 mL). Benzaldehyde dimethyl acetal (1.38 mL, 9.22 mmol, 2 eq) and (±)-camphor-lO-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, 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 IM ammonium chloride solution (50 mL). The less 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 HC1 solution (50 mL) for another 20 min. TLC indicated no further change. The DCM phase was separated and washed with brine- IM NaOH, dried (MgSO₄). 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 (CDC1₃, 400 MHz): two benzylidene epimers in a ratio of 1:1. 7.49-7.36 (m, 5H, C₆H₅), 6.126 and 5.902 (2xs, IH, benzylidene-CH), 5.066 and 4.987 (2xs, IH, sugar-Hl), 4.396 (dd, 0.5H, J= 6.4, 5.6, sugar-H3), 4.248 (dd, 0.5H, J= 6.4, 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 (m, 4H), 3.466 and 3.424 (2xs, 3H, CH₃O), 2.984 (br s, IH, OH). ¹³C NMR (CDCI₃, 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-3-0-benzyl-6-deoxy-a-D-mannopyranoside and methyl 6-azido-2-0- benzyl-6-deoxy- a-D-mannopyranoside A solution of methyl 6-azido-6-deoxy-2,3-di-O-benzylidene-α-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 addition, the mixture was stirred at 70 °C for 6 h, cooled to 0 °C and basified by addition of solid Na₂CO₃. The cold mixture was filtered and the cake washed with EtOAc. The filtrate and washings was extracted once with sat. Na₂CO₃. Evaporation gave a gum, which was purified by column chromatography (silica 2.5x18 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%, Rf - 0.45, EtOAc-hexane=l:l); 1H NMR (CDCI₃, 400 MHz): 7.41-7.32 (m, 5H, Ph), 4.78 (d, IH, J_1-2 = 1.6, HI), 4.70 (d, IH, J_gem = 12.0, CH₂), 4.56 (d, IH, CH₂), 4.02 (dd, IH, J_2-3 = 3.2, H2), 3.78 (dd, IH, J_3-4 = 8.4, J_4-5 = 10.0, H4), 3.73 (ddd, IH, J_5-6ax= 6.0, J_5-6eq ^*= 3.2, H5), 3.64 (dd, IH, H3), 3.52 (dd, IH, J_6aχ_-6eq = 13.2, H6eq), 3.47 (dd, IH, J_6ax._6eq = 13.2, J_5-6ax = 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- mannopyranoside (colourless waxy solid, 62 mg, 26%, Rf = 0.27, EtOAc-hexane-=l:l). 1H NMR (CDCI₃, 400 MHz): 7.38-7.28 (m, 5H, Ph), 4.78 (s, IH, HI), 4.71 (d, IH, J= 11.6, CH₂), 4.53 (d, IH, = 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, IH, J= 13.2, H6ax), 3.38 (s, 3H, MeO), 2.83 (br s, 2H, 2xOH). Step c: Methyl 6-azido-2-0-benzyl-6-deoxy-2,3-di-0-sulfonato-a-D-mannopyranoside disodium salt (PG2160) Methyl 6-azido-2-0-benzyl-6-deoxy-a-D-mannopyranoside was sulfonated according to the standard procedure to yield the title compound as a white powder, 64 mg, 59%. 1H NMR (D₂O, 400 MHz): 7.38-7.26 (m, 5H, Ph), 4.72 (d, IH, J_gem = 12.0, CH₂Ph), 4.59 (d, IH, J_1-2 = 2.0, HI), 4.58 (d, IH, CH₂Ph), 4.49 (d, IH, J_2-3 = 2.8, J_3-4 = 9.6, H3), 4.44 (dd, IH, J_4-5 = 9.6, H4), 4.07 (dd, IH, H2), 3.78 (ddd, IH, J_5-6ax = 5.6, J_5-6eq = 2.4, H5), 3.62 (dd, IH, J_6ax-6eq = 13.2, H6eq), 3.51 (dd, IH, J_6ax-_6eq= 13.2, J_5-6ax= 5.6, H6ax), 3.22 (s, 3H, MeO). Step d: Methyl 6-azido-3-0-benzyl-6-deoxy-2,4-di-0-sulfonato-a-D-mannopyranoside 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%. 1H NMR (D₂O, 400 MHz): 7.42-7.21 (m, 5H, Ph), 4.92 (d, IH, J_1-2 = 2.4, HI), 4.67 (d, IH, J_gem- 12.4, CH₂Ph), 4.60 (d, IH, CH₂Ph), 4.56 (dd, IH, J_2-3 = 3.2, H2), 4.35 (dd, IH, J_3-4 = 9.6, J_4-5 = 9.6, H4), 3.80 (dd, IH, H3), 3.75 (ddd, IH, J_5-6ax - 6.0, J_5-6eq = 2.8, H5), 3.66 (dd, IH, J_6ax-6eq-= 13.4, H6eq), 3.54 (dd, IH, J_6ax-6eq= 13.4, J_5-6ax= 6.0, H6ax), 3.29 (s, 3H, MeO). Step e: Methyl 6-[l '-(4-phenyl)triazolyl]-2-0-benzyl-6-deoxy-2,3-di-0-sulfonato-a-D- mannopyranoside disodium salt (PG2173) Methyl 6-azido-2-0-benzyl-6-deoxy-2, 3 -di-O-sulfonato- -D-mannopyranoside disod- 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-H₂O = 10:2:1. 1H NMR (D₂O, 400 MHz): 8.26 (s, IH, triazole), 7.64-7.60 (m, 2H), 7.37-7.15 (m, 8H), 4.89 (dd, IH, J^*= 14.4, 2.8, H3), 4.67 (d, IH, J= 12.0, PhCH₂), 4.57-4.39 (m, 5H, PhCH₂, HI, H4 and H6eq and H6ax), 4.04 (dd, IH, J= 2.8, 2.0, H2), 3.99 (ddd, IH, J= 9.2, 8.8, 2.4, H5), 2.83 (s, 3H, MeO). Example 19: PG2170 Allyl 6-azido-2, 3-0-disulfonato-6-deoxy-4-0-(l-naphthylmethyl)- a-D-mannopyranoside disodium salt (containing 10% of 2-naphthylmethyl isomer) (PG2170) The title compound, prepared analogously to PG2163 beginning with allyl 6-azido-6- deoxy- a-D-mannopyranoside, was obtained as a white powder 87.5 mg, 87%, Rf = 0.28

(major), 0.22 (minor), EtOAc-MeOH-H₂O = 10:2:1. 1H NMR (D₂0, 400 MHz): 7.87 (d, IH, J = 8.4, naphthyl), 7.65-7.54 (m, 2H, naphthyl), 7.33-7.19 (m, 4H, naphthyl), 5.68 (ddt, IH, Jaiiyi2'-3'trans = 22.0, n_yi2'-3'cis = 10.8, J_aiiyii'-2' = 6.0, allyl-2'), 5.23 (AB quartet, 2H, J_gem = 12.0, naphthyl-CH₂), 5.17-5.02 (m, 3H, allyl-3' and HI), 4.74 (dd, IH, J_1-2-= 2.0, J_2-3 = 3.2, H2), 4.64 (d, IH, J_3-4= 9.6, H3), 3.90 (dd, IH, ιι_yιr_gem= 13.2, J- 6.0, allyl-1'), 3.81 (dd, IH, allyl-1'), 3.64 (t, IH, J_4-5 = 9.6, H4), 3.39 (ddd, IH, J_5-6eq= 2.0, J_5-6ax= 5.2, H5), 2.78 (dd, IH, J₆e_q-6ax = 13.6, H6eq), 2.68 (dd, IH,

13.6, H6ax). Typical signals for minor isomer 2-naphthylmethyl derivative: 4.84 (AB quartet, 2H, J_gem = 11.2, naphthyl-CH₂), 3.52 (ddd, IH, J₄.₅ = 10.0, J_5-6eq= 2.4, J_5-6ax= 6.0, H5), 3.07 (dd, IH, J_6eq-6ax= 13.6, H6eq), 2.96 (dd, IH, _eci-_δax*--- 13.6,

6.0, H6ax). The source ofthe 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 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 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 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, K_d. 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 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. For each K_d measurement, solutions were prepared containing a fixed concentration of protein and varying concentrations ofthe ligand in buffer. Ligands binding to FGF-1 and VEGF were measured in HBS-EP buffer (10 mM HEPES, pH 7.4, 150 mM NaCI, 3.0 mM EDTA and 0.005% (v/v) polysorbate 20), while binding to FGF-2 was measured in HBS-EP buffer 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 μL of solution was injected at 5-40 μL/min and the relative binding response measured. All surface binding experiments were performed at 25 °C. The surface was regenerated by injection of 40 μL of 4M NaCI at 40 μL/min, followed by injection of 40 μL of buffer at 40 μL/min. Sensorgram data were analysed using the BIAevaluation software (BIAcore).

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 equation ^p]=- ^p\ \total r_n. where r is the relative binding response and r_m 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 complex, the equilibrium equation is

and the binding equation [24] can be expressed as

The K_d values given are the values fit, using the binding equation, to a plot of [P] versus [L]_totai- Where K_d values were measured in duplicate, the values represent the average ofthe duplicate measurements. It has been shown that GAG mimetics that bind tightly to these 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., 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 AHl) [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]. In both assays the compounds were tested at 200 μM. (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 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 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 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 The results ofthe tests as described in the preceding section are presented in Tables 1 to

5. Table 1

PG# KdaFGF Kd bFGF Kd VEGF KdFGF-4

R_A,R_F,R_H=OMe; R_B,Rc,R_E,Rι=OS0₃Na; 2037 47.7 μM 507 μM 645 μM

R_D=CH₂OS0₃Na; R_G=H 2038 77.9 μM 2.10 mM 368 μM

R_A=OMe; R_F,R_H=OH; R_B,Rc,R_E,R OS0₃Na; 2039 21.8 μM 3.50 mM 1.27 mM

R_F,R_G,R_I=OH; R_D-R_A=-CH₂0-; R_B,R_E=NHS0₃Na; 2046 6.35 mM 3.70 mM 1.50 mM

Rc=OBn; R_H=H

R_F,R_G,RRc⁼OH; R_D-R_A=-CH₂0-; R_B,R_E=NHS0₃Na; 2047 388 μM 1.95 mM 2.55 mM R_H=H

R_F,R_H,R_I=OH; R_A=OMe; R_B.RcR_E^OSOsNa; 2063 1.39 mM 2.35 mM 2.59 mM _D>R_G ⁼H

Table 2

PG# KdaFGF Kd bFGF Kd VEGF

R_K=OMe; R_M,Ro=OS0₃Na; R_Q=OBn; R_R=CH₃; 2023 1.76 mM 4.90 mM 2.27 mM R_J>R_J )R_P)R_S ⁼H

R_K=OMe; R_M,Ro^*=0SO₃Na; R_P=OBn; R_R=CH₃; 2024 4.73 mM 3.65 mM 6.40 mM

R_K=OMe,R_M,Ro=OS0₃Na;R_Q=Oallyl;R_R=CH₃; ^ ^^ _{>1000mM 236 M}

K_jjl _ji ^K-P_jK-S-'-!

^J_J1^R^L>_R1 D^")^CΛΛPJ^K0R^"-^_;τ1?-I^{M=OSθ3Na:RN=OMe;RQ=}°^Bn; 2030 317 μM 4.61 mM

? ^;^ ^;5^=CH2θS°^{3Na; 2}°4 9.38 mM 5.10 mM 1.04 mM

^ ΛJ,K ,K_N,^; _R ^RQϊ, _S-11 ^{3Na;Rθ=OH;Rp=}°^{allyl;RR=CH3;} 2042 3.05 mM 10.7 mM 2.59 mM PG # Kd aFGF Kd bFGF Kd VEGF 2043 6.43 mM 17.4 mM 1.73 mM

RK =OMe; R_M,Ro=OS0₃Na; R_P=OOCCH₂CH₂Ph; R_R=CH₃; 2044 366 μM 1.55 mM 1.65 mM R_J,R_L,R_N,R_Q>R_S ⁼H

Rj/R_K=H/OMe (anomeric mixture); R_S-R_N ⁼ -CH₂0-; 2045 392 μM 3.40 mM 1.07 mM R_M=OS0₃Na; R_Q=OBn; R_L,R₀,R_P,R_R=H

R_K=OMe; R_N,R_M=OBn; Rg-=OS0₃Na; R_s=CH₂OS0₃Na; 2049 1.51 mM » 60.0 μM 2.72 mM R_J,R_L,R_O,R_P!R_R ⁼H

R_K=OMe; R_M =OS0₃Na; R_N,Ro=OBn; 2050 3.31 mM 8.25 mM 10.00 mM R_J,R_L,RO,RP,RR,R_S ⁼H

2051 2.46 mM > 20.4 mM 4.63 mM

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OOCCH₂OPh; R_R=CH₃; 2052 5.92 mM 4.50 mM 686 μM R_{JJ L},R_N)R_Q>R_S ⁼H

R_K=OMe; R_M,Ro⁼OS0₃Na; R_P=Oallyl; R_R=CH₃; 2053 1.30 mM 5.17 mM 343 μM R_J)R _>RN_{J Q})R_S ⁼H

R_K=OMe; R_M,R₀-=OS0₃Na; R_P=OBz; R_R=CH₃; 2054 454 μM 2.73 mM 403 μM R_J)RL)R_N;R_Q>RS⁼H

R_K=OMe; R_M,Ro=^*OS0₃Na; R_P=OOCPh(p-OMe); R_R=CH₃; 2056 797 μM 2.45 mM 485 μM R_J)R_L,R_N) _QJR_S ⁼H

2079 1.92 mM ~ 3.45 mM 1.73 mM

R_S-R_N= -CH₂0-; R_M=OS0₃Na; R_Q=OBn; 2080 1.62 mM ~ 11.7 mM 1.36 mM R_J;RK)R _> O)RP)RR⁼H 2085 9.60 mM ~ 17.4 mM 8.90 mM

R_K=OMe; R_M)Ro=OS0₃Na; R_P=0(CH₂)₃OPh; R_R=CH₃; 2086 3.05 mM 1.50 mM R_J>R ₎R_N)R_Q)R_S ^=:H

R_K=OMe; R_M;Ro-=OS0₃Na; R_P=OH; R_R=CH₃; 2087 566 μM 2.35 mM 899 μM R_J;R_L, _{NJ Q})R_S ⁼H

R_K=OMe; R_M,Ro=OS0₃Na; R_P=0(CH₂)₃Ph; R_R=CH₃; 2088 676 μM 3.00 mM 761 μM _J)R _;RN_»R_Q)R_S ⁼H

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OCH₂(2-Napthyl); 2089 1.20 mM 2.15 mM 2.33 mM R_R=CH₃; R_J,R_L,RN_;R_Q,R_S ⁼H

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OCH₂(£)CH=CHPh; 2090 3.85 mM 2.50 mM 3.02 mM R_R=CH₃; R_J,R_L,R_N,R_Q,RS=H

R_K=OMe; R_M,R₀=OS0₃Na; R_P=OCH₂(l-Napthyl); 2091 1.37 mM 1.50 mM 1.98 mM R_R=CH₃; R_J,R_L,R_N,R_Q,R_S-=H PG # Kd aFGF Kd bFGF Kd VEGF

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OCH₂Ph(p-Me); R_R=CH₃; 2092 2.70 mM 2.85 mM 2.86 mM RJ,R_L,R_N,RQ,R_S=H

R_κ=NHCOCH₂θPh(2,4-di-Cl); R_MjR_N,R_Q=OSθ₃Na; 2096 35.7 μM 141 μM 20.4 μM R_s ^*=CH₂OS0₃Na; R_J,R_L,R_O;R_P,RR=H

Rj=OMe; R_L,R_N=OBz; R₀=OSO₃Na; R_s=CH₂OS0₃Na; 2097 127 μM 2.05 mM 267 μM K_>R _{J OJ}RP;R_R ⁼H

R_K=OMe; R_M,Ro=0SO₃Na; R_P-=OCH₂Ph(p-CF₃); R_R=CH₃; 2098 X85 mM 2.65 mM 2.60 mM R.,RL_>R_N>RQ_!R_S ⁼H R_P=OCH₂Ph(».-CF₃); R_R=CH₃; 2099 1.30 mM 2.85 mM 5.70 mM

Rj=OMe; R_L,R_Q=OS0₃Na; R_N=Oallyl; R_s=CH₂Oallyl; 2100 1.25 mM 18.1 mM 146 μM R_KJR_{MJ OJ}RP_{J R}^H

Rj=OMe; R_L,R_N=OH; R_Q=OS0₃Na; R_s=CH₂OS0₃Na; 2101 77.3 μM 188 μM R_{K> 5}R_O; _P3R_R ⁼H

R_K=OMe; R_M,R₀=OS0₃Na; R_P=OMe; R_R=CH₃; 2102 116 μM 1.30 mM 206 μM

R_J;R_L>R_NJR_QJRS⁼H

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OCH₂Cyclopropyl; 2103 5.50 mM 4.20 mM 3.00 mM R_R=CH₃; R_J,R ,R_N,R_Q,R_S=H

R_K=N₃; R_M,Ro^*=OS0₃Na; R_P=OBn; R_R=CH₃; 2104 1.80 mM 2.45 mM 3.30 mM R_J,R ;R_{N> Q>}R_S ⁼H

R_J=N₃; R_M=OS0₃Na;R₀=OH; R_P=OBn; R_R=CH₃; 2105 1.85 mM 2.10 mM 8.30 mM R_K, L)R_N;R_Q, _S ⁼H

R_K=OBn; R_M,Ro=OS0₃Na; R_P=OMe; R_R=CH₃; 2106 1.31 mM 3.43 mM 1.45 mM RJ_;R _JR_NJR_Q;R_S ⁼H

R_K=OMe; R_M,R_N=OOCPh( -OMe); R_Q=OS0₃Na; 2107 645 μM R_s=CH₂OS0₃Na; R_J,R_L,RO,RP,RR=H

R_K=OMe; RM,R_N=OCH₂(£)CH=CHP1.; R_Q=OS0₃Na; 2108 563 μM R_s=CH₂OS0₃Na; R_J,RL,R_O,R_P,RR=H

R_K=OMe; R_M,R₀=OS0₃Na; R_P=OOCP (3,4-di-Cl); 2111 1.30 mM R_R=CH; RJ,R_L,RN,R_Q,R_S ⁼H 1.60 mM

R_K=OMe; R_M,R₀=OS0₃Na; R_P=OOCCH₂Ph(3,4-di-Cl); 2113 R_R=CH₃; R_J,R_L,R_N,R_Q,R_S ⁼H 1.45 mM 1.60 mM 1.60 mM PG# KdaFGF Kd bFGF Kd VEGF

2114 3.85 mM 2.30 mM 888 μM

2129 5.40 mM 9.10 mM 3.00 mM

R_s=CH₂Oallyl; 2130 1.05 mM 7.85 mM 361 μM

R_K=OMe; R_M,Ro=OS0₃Na; R_P=OEt; R_R=CH₃; 2131 8.30 mM 7.20 mM 21.8 mM J_JRL_JRN_JRQ_JRS¹³"!!

2139 884 μM ~2.70mM 383 μM

Rj=OMe; R_L,R_Q=OS0₃Na; R_N=Oallyl; 2142 3.00 mM 481 μM Rs^*=CH₂OCH₂(CH₃)C=CH₂; RK,RM;RO_>RP) R⁼H 1.10 mM 398 μM

R_N=Oallyl; R_s=CH₂OH; 2145 ~5.95mM ~23.0mM 1.60 mM R_N=Oallyl; R_s=CH₂OBn; 2147 1.50 mM 9.10 mM 2.10 mM

R_s=CH₂OCH₂(3- 2148 2.40 mM ~13.0mM 981 μM

2149 2.50 mM ~6.70mM 709 μM

2150 »6.00mM ~24.2mM 7.80 mM

R_s=CH₂Oallyl; 2151 ^• 3.50 mM ~9.90mM 935 μM

2153 ~11.5mM »42.1mM -ll.lmM

2154 ~3.70mM ~26.7mM 2.15 mM

PG # Kd aFGF Kd bFGF Kd VEGF

R_N=Oallyl; R_S=CH₂N₃; 2156 360 μM 1.65 mM 1.04 mM

Rj=OMe; R_L=OH;R_N=OS0₃Na; R_Q=OCH₂(2-napthyl); 2158 1.55 mM ~ 10.3 mM 985 μM

Rj=OMe; R_L,RQ=OH; R_N=OS0₃Na; R_S=CH₂NH₂; 2159 1.90 mM ^■ 62.3 mM 6.40 mM

Rj=OMe; R_L=OBn; R_N,R_Q=OS0₃Na; R_S=CH₂N₃; 2160 4.40 mM 2.50 mM 12.9 mM

Rj=OMe; R_L,R_N=OS0₃Na; R_Q=Oallyl; R_S=CH₂N₃; 2163 396 μM 4.80 mM 61.2 μM

Rj=OMe; R_L,R_N=OS0₃Na; Ro=OCH₂(2-napthyl); 2164 1.35 mM 1.70 mM 1.30 mM

Rj/R_K=H/OMe (anomeric mixture); RS-RN⁼ -CH₂0-; 2165 1.13 mM ~ 25.5 mM 1.70 mM R_M=OBn; R_Q=OS0₃Na; RJ,R_K,RL,RO,RP,RR=H 2166 3.60 mM 1.90 mM 2.70 mM

2171 845 μM ~ 18.9 mM 2.00 mM

Rj=OMe; R_L=OBn; R_N,R_Q=OS0₃Na; R_S=CH₂NH₂; 2172 3.80 mM ~ 5.90 mM 2.30 mM RKJ M. OJRPJRR^31"!!

Rj=OMe; R_L=OBn; H₂(4-phenyl- 2173 18.9 μM 918 μM 89.3 μM [l,2,3]triazol-l-yl);

Rj=Oallyl; R_L=OH; R_N=OS0₃Na; R_Q=OBz; R_S=CH₂N₃; 2174 278 μM ~ 19.3 mM 846 μM

PG # Kd aFGF Kd bFGF Kd VEGF R_S=CH₂(4- l-yl); 2178 130 μM 1.20 mM 60.9 μM

2179 52.9 μM 143 μM 10.3 μM 2180 91.9 μM 1.90 mM

Rι=OMe; R_L,R_N=OS0₃Na; R_Q=Oallyl; R_S=CH₂(4- (CH₂NHCOCH₂OPh)-[l,2,3]triazol-l-yl); 2181 365 μM 203 μM

RK_>RM;RO_JRP_;R_R ⁼H

Rj=OMe; R_L,R_N=OS0₃Na; R_Q=Oallyl; R_S=CH₂(4- 2182 107 μM (CH₂NHCOPh)-[l,2,3]triazol-l-yl); R_K,R_M,Ro,R_P,R_R=H 847 μM

Rj=OMe; R_L,R_N=OS0₃Na; Rς Oallyl; R_S=CH₂(4-(CH₂-.V- 2183 324 μM phthalimido)-[l,2,3]triazol-l-yl); R_K,R_M,Ro,R_P,R_R=H 82.7 μM

Rj=OMe; R_L,R_N=OS0₃Na; Ro=Oallyl; R_S=CH₂(4- (CH₂ HS0₂Ph(p-Me))-[l,2,3]triazol-l-yl); 2184 388 μM 1.6 mM

RK_J M) _0JR_P;R_R ⁼H

Rj=OMe; R_L,R_N=O [l,2,3]triazol-l-yl);

Rj=OMe; R_L=OS0₃Na; R_N=OH; Ro=OCH₂(2-napthyl); Rs⁼CH₂N₃; R_K,R ,RO_JRP_J R⁼H 2187 320 μM

Rj=OMe; R_L)R_N=OS0₃Na; Rς Oallyl; R_s=CH₂NHS0₂Me; 2189

RK_{> >}R₀;R_P;RR⁼H 191 μM 35.0 μM

Rj=OMe; R_L,R_N=OS0₃Na; R_Q=Oallyl; R_S=CH₂(4- (CH₂NHCO(o-C0₂Na)phenyl)-[ 1 ,2,3]triazol- 1-yl); 2193 1.20 mM 270 μM RK_JRM_JR_OJRP₎RR⁼H

; 2194 1.25 mM >2.8 mM

R _>RM_>RO_IRP_;RR⁼H

PG # Kd aFGF Kd bFGF Kd VEGF

R_K=OBn; R_M,R₀ ^*=OS0₃Na; R_P=OBn; R_R=CH₃; 2196 170 μM 2.50 mM R_J,R_L,R_N,R_Q,R_S=H

Table 3

PG # Kd aFGF Kd bFGF Kd VEGF

R_τ=l,2,3,4-tetra-0-sodiιun sulfonato-D-glucuronoyl;

R_τ= 1 -O-Me-2,3 ,4-tri-O-sodium sulfonato-α-D- mannopyranos-6-yl-acetyl; Ru=CH₂CH₂OS0₃Na; Rγ=H ; 2008 296 μM 551 μM 335 μM R_w=cyclohexyl

R_T=Ac; Ru=2-(2,3,4,6-tetra-0-sodium sulfonato-α-D- mannopyranos-l-C^*-yl-)-ethyl; Rv=H; R_w=2-(2,3,4,6-tetra- 2009 428 μM (9-sodium sulfonato-α-D-mam opyranos- 1 -0-yl-)-ethyl

R_τ=3-(2,3,4,6-tetra-C-sodium sulfonato-α-D- mannopyranos- 1 -0-yl-)-propyl; Ro="COCH₂CH₂Ph; 2010 556 μM R_w=cyclohexyl; R_v-H

R_τ=l,2,3,4-tetra-0-sodium sulfonato-D-glucuronoyl; 2011 62.4 μM Ru=Bn; R ^cyclohexyl; R_v=P

R_τ=l,2,3,4-tetra-0-sodium sulfonato-α-D-glucuronoyl; 2012 122 μM 505 μM Ru=Bn; R ⁼cyclohexyl; R_V=H

R_τ=l,3,4,6-tetra-0-sodium sulfonato-α-D-mannopyranos-2- yl-acetyl; Ru=Bn; Rγ=H; R_w=2-(2,3,4,6-tetra-0-sodium 2014 5.09 μM 85.1 μM 8.82 μM sulfonato-α-D-mannopyranos- 1 -0-yl-)-ethyl

R_τ=3-(2,3,4,6-tetra-( -sodium sulfonato-α-D- mannopyranos-l-0-yl-)-propyl; R_υ= CO(CH₂)₃Ph; Rv=H; 2018 R =cyclohexyl

R_τ=l,2,3,4-tetra-0-sodium sulfonato-α-D-glucuronoyl; 2020 Ru,Rw=Bn; R_V=H 104 μM 206 μM 437 μM

R_τ=l-0-Me-2,3,4-tri-C^*-sodium sulfonato-α-D- 2032 mannopyranos-6-yl-acetyl; Ru=Bn; R_w=cyclohexyl; Rγ=H 260 μM 201 μM 705 μM PG# Kd aFGF Kd bFGF Kd VEGF

Rτ=l-0-Me-2,3,4-tri-0-sodium sulfonato-α-D- mannopyranos-6-yl-acetyl; Ru=Bn; Rv^H; R_w=2-(2,3,4,6- 2034 37.6 μM 16.5 μM 115 μM tetra-O-sodium sulfonato-α-D-mannopyranos- 1 -0-yl-)-ethyl

R_T=Ac; Ru=Bn; R_V=H; R_w=2-(2,3,4,6-tetra-0-sodium 2035 sulfonato-α-D-mannopyranos- 1 -<9-yl-)-ethyl 24.8 μM 287 μM 76.6 μM

118 μM 2.50 mM 1.10 mM

R_T=Ac; Ru=CH₂CH₂Ph; R_V=H; R_w=6-deoxy-l~0-Me-2,3,4- 2058 224 μM 682 μM tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 109 μM

R_T=Ac; Ru=CH₂CH₂Ph; R_V=H; R^ό-deoxy-l-O-Me-2,3,4- 2058 224 μM 682 μM tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 109 μM

R_T=Ac; Ru=Bn; R_V=H; R_w=6-deoxy-l-0-Me-2,3,4-tri-C>- 2059 140 μM sodium sulfonato-α-D-mannopyranos-6-yl 192 μM 77.0 μM

R_T=Ac; Ru=Bn; R_V=H; Rw=6-deoxy-l-C>-Me-2,3,4-tri-0- 2059 140 μM sodium sulfonato-α-D-mannopyranos-6-yl 192 μM 77.0 μM

R_T=Ac; Ru=Ph; R_V=H; R_w=6-deoxy-l-0-Me-2,3,4-tri-0- 2060 196 μM 481 μM 76.3 μM sodium sulfonato-α-D-mannopyranos-6-yl

R_T=Ac; Ru=cyclohexyl; R_V=H; Rw=6-deoxy-l-0-Me-2,3,4- 2064 314 μM 413 μM 1.70 mM tri-O-sodium sulfonato-α-D-mannopyranos-6-yl

Rτ=Ac; Ru=CH₂CH₂OS0₃Na; R_V=H; R_w=6-deoxy-l-0- 2065 94.8 μM 241 μM 283 μM Me-2,3 ,4-tri-0-sodium sulfonato-α-D-mannopyranos-6-yl

R_T=m-ClPhCH₂CO; Ru=H;

2066 37.4 μM 433 μM 45.3 μM 2,3,4-tri-(9-sodium sulfonato-α-D-marmopyranos-6-yl

R_T=Et; Ru=CO(CH₂)₂COONa; Rγ=H; R_w=6-deoxy-l-0- 2068 338 μM 291 μM 207 μM Me-2,3 ,4-tri-O-sodium sulfonato-α-D-mamιopyranos-6-yl

R_T=Et; Ru=CO(CH₂)_wCOONa; Rv==H; Rw=6-deoxy-l-0- 2069 160 μM 477 μM 104 μM Me-2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl

R_T=Et; Ru=CO(CH₂)₉OS0₃Na; R_V=H; Rw=6-deoxy-l-0- 2070 l l l μM 243 μM 545 μM Me-2,3,4-tri-0-sodium sulfonato-α-D-mannopyranos-6-yl

R_T=Et; Ru=CO(CH₂)_wCOONa; R_V=H; Rw=6-deoxy-l-0- Me-2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl, 2071 119 μM 2.24 mM 161 μM mixture of mono- and di- sulfates

R_T=Ac; Ru=cyclohexyl; R_V=H; R =6-deoxy-l-0-Me-2,3,4- tri-O-sodium sulfonato-α-D-mannopyranos-6-yl, mixture of 2072 264 μM 2.98 mM 277 μM mono- and di-sulfates

sulfonato-α-D-mannopyranos- 1 -< -yl-)-ethyl 2073 97.4 μM 236 μM 402 μM

R_T=Ac; Ru=(CH₂)₂Ph; R_V=H; R_w=2-(2,3,4,6-tetra-( - sodium sulfonato-α-D-mannopyranos- 1 -0-yl-)-ethyl 2074 11.8 μM 113 μM 28.8 μM

R_τ= m-ClPhCH₂CO; R_U;R_V=H; Rw=2-(2,3,4,6-tetra-0- sodium sulfonato-α-D-mannopyranos-l-C>-yl-)-ethyl 2075 171 μM 837 μM 90.8 μM PG # Kd aFGF Kd bFGF Kd VEGF

R_T=Et; Ru=CO(CH₂)₂C0₂Na; Rγ=H; R_w=2-(2,3,4,6-tetra- 2076 43.4 μM 118 μM 40.3 μM O-sodium sulfonato-α-D-mannopyranos- 1 -0-yl-)-ethyl

R_T=Et; R_u=CO(CH₂)₄C0₂Na; Rγ=H; R_w=2-(2,3,4,6-tetra- 2077 43.6 μM 188 μM 81.1 μM O-sodium sulfonato-α-D-mannopyranos- 1 -<9-yl-)-ethyl

R_T=Et; Ru=CO(CH₂)₉OS0₃Na; R_V=H; R_w=2-(2,3,4,6-tetra- 2078 20.0 μM O-sodium sulfonato-α-D-mannopyranos- 1 -Oyl-)-ethyl 157 μM 49.6 μM

Rr=Bz; Ru=Et; R_V=H; Rw=6-deoxy-l-0-Me-2,3,4-tri-0- 2081 sodium sulfonato-α-D-mannopyranos-6-yl 366 μM 480 μM 1.10 mM

R_T=CO(CH₂)₂Ph; R₀=Et; Rγ=H; R_w=6-deoxy-l-0-Me- 2082 2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 596 μM

403 μM 80.7 μM

R_T=COCH₂OS0₃Na; Ru=Et; Rγ=H; Rw=6-deoxy-l-0-Me- 2084 161 μM 2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 192 μM 277 μM

R_w=cyclohexyl; Ru=Ac; R_V=H; R_τ=6-deoxy-l-0-Me-2,3,4- 2094 246 μM tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 565 μM l.lO mM

R_w=cyclohexyl; Ru=Ac; R_V=H; R_τ=6-deoxy-l-0-Me-2,3- 0-benzylidene,4-0-sodium sulfonato-α-D-mannopyranos-6- 2115 5.10 mM 3.90 mM yi

2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 369 μM 411 μM 3.00 mM

R_T=Ac; Ru=cycloheptyl; Rγ=H; R^ό-deoxy-l-O-Me^^- 2117 1.50 mM di-O-sodium sulfonato-α-D-mannopyranos-6-yl 2.90 mM

R_T=Ac; Ru=cyclooctyl; R_V=H; R^ό-deoxy-l-O-Me^^-di- 2120 1.60 mM O-sodium sulfonato-α-D-mamιopyranos-6-yl 11.0 mM

R_T=COCH₂Ph(p-CF₃); Ru=Et; R_V=H; R_w=6-deoxy-l-0- 2122 Me-2,4-di-0-sodium sulfonato-α-D-mannopyranos-6-yl 3.70 mM 1.20 mM

R_T=COCH₂Ph(p-CF₃); Ru=Et; Rγ=H; Rw=6-deoxy-l-0- 2124 242 μM Me-2,3-di-0-sodium sulfonato-α-D-mannopyranos-6-yl 570 μM

R =cyclohexyl; Ru=Ac; Rv=H; R_τ=6-deoxy-l-C-Me-4-0- 2125 26.6 mM sodium sulfonato-α-D-mannopyranos-6-yl ~ 166 mM

R_T=Ac; Ru=cyclododecyl; R_V=H; R^ό-deoxy-l-OMe- 2126 2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl 265 μM 483 μM 1.20 mM

R_T=Ac; Ru=4-t-butylcyclohexyl; Rv=H; R_w=6-deoxy-l-< - 2132 Me-2,3,4-tri-0-sodium sulfonato-α-D-mannopyranos-6-yl 243 μM 544 μM 1.00 mM

R_T=Ac; Ru=l-(l-adamantyl)-ethyl; Rγ=H; R^ό-deoxy-l- 2133 0-Me-2,4-di-0-sodium sulfonato-α-D-mannopyranos-6-yl 398 μM

di-O-sodium sulfonato-α-D-mannopyranos-6-yl PG# Kd aFGF Kd bFGF Kd VEGF

R_τ=6-deoxy- 1 -<9-Me-2,3 ,4-tri-0-sodium sulfonato-α-D- mannopyranos-6-yl; Ru=CH₂CO]SfHcyclo exyl; 2138 418 μM 449 μM 1.34 mM R_w=cyclohexyl; R_V=H

R_w=cyclohexyl; Ru=CHO; R_V=H; R_τ=6-deoxy-l-0-Me- 2162 1.20 mM 2,3 ,4-tri-O-sodium sulfonato-α-D-mannopyranos-6-yl

Table 4

PG # Kd aFGF Kd bFGF Kd VEGF

R_x=COCH₂C(CH₃)₂CH₂CO;

2015 2.94 μM 7.56 μM 267 nM sulfo-α-D-mannopyranos- 1 -0-yl)-propyl

R_x= 1 ,4-tτ-αrø-cyclohexyl; R_γ= 1 -O-Me-2,3 ,4-tri-O-sodium 2016 32.6 μM 81.8 μM 931 nM sulfo-α-D-mannopyranos-6-yl-acetyl

2057 18.8 μM 61.6 μM 55.6 μM sulfo-α-D-mannopyranos- 1 -0-yl)-ethyl, undersulfated

2062 10.3 μM 29.7 μM 17.3 μM sulfo-α-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 PG# HSV-1 Infectivity HSV-2 Infectivity HSV-1 Spread HSV-2 Spread

2000 100.8 NT (=nottested) 82.1 NT

2001 85.6 NT 88.3

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 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. The foregoing embodiments are illustrative only ofthe principles ofthe 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. The term "comprise" and variants ofthe 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 disclosures constitute common general knowledge in Australia.

REFERENCES

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[3] 20179369 Tumova, S.; Woods, A.; Couchman, J.R. Int. J. Biochem. Cell Biol. 2000, 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. [8] Petitou, M.; Herault, J.P.; Bernat, A.; Driguez, P.A.; Duchaussoy, P.; Lormeau, J.C.; Herbert, J.M. Nature 1999, 398, 417. [9] Yeh, B.K.; Eliseenkova, AN.; Plotnikov, A.Ν.; 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; De Clercq, E.; Presta, M. Mol. Pharmacol. 1999, 56, 204.

[I I] Sola, F.; Farao, M.; Pesenti, E.; Marsiglio, A.; Mongelli, N.; Grandi, M. Cancer Chemother. Pharmacol. 1995, 36, 211.

[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, 651. [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] Dόmling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168 and references cited therein. [16] Lockhoff, O.; 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, N.; Trinh, L.; Shiloach, J.; Robbins, J.B.; Donohue-Rolfe, A.; Calderwood, S.B. Bioconjugate Chem. 1996, 7, 45.

[19] Dasgupta, F.; Masada, R.I. Carbohydr. Res. 2002, 337, 1055.

[20] Hori. H.; Νishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54, 1346.

[21 ] Prepared analogously to ref. 18. [22] Liptak, A.; Imre, J.; Nanasi, P. Carbohydr. Res. 1981, 92, 154. [23] Agoston, K.; Kerekgyartό, J.; Hajkό, J.; Batta, G.; Lefeber, D J.; Kamerling, J.P.; Nliegenthart, J.F. Chem. Eur. J. 2002, 8, 151. [24] Cochran, S.; Li, C; Fairweather, J.K.; Kett, W.C; Coombe, D.R.; Ferro, N. J. Med. Chem. 2003, 46, 4601.

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[28] Duff, R.; Rapp, F. Nat. New Biol. 1971, 233, 48.

Claims

A compound of the formula

wherein: n is an integer of from 0 to 2;

Z is N, N(O), O, S, S(O), S(O)₂, P, P(O), P(O)₂, Si, Si(O), or Si(O)₂; each X is independently C, C(O), N, N(O), O, S, S(O), S(O)₂, P, P(O), P(O)₂, Si, Si(O),)₂ or is a bond; and each of Ri to R₆ 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; phosphoryl groups such as phosphate, thiophosphate -O-P(S)(OH) ; phosphate esters -O-P(O)(OR)₂; thiophosphate esters -O-P(S)(OR)₂; phosphonate -O-P(O)OHR; thiophosphonate -O-P(S)OHR; substituted phosphonate -O-P(O)OR₁R₂; substituted thiophosphonate -O-P(S)OR₁R₂; -O-P(S)(OH)(SH); and cyclic phosphate; other phosphorus containing compounds such as phosphoramidite -O-P(OR)-NR₁R₂; and phosphoramidate -O-P(O)(OR)- RιRa; sulfur groups such as -O-S(O)(OH), -SH, -SR, -S(→O)-R, S(O)₂R, RO-S(O)₂\ -O-SO₂NH₂, -O-SO₂R₁R₂ or sulfamide -NHSO₂NH₂; amino groups such as -NHR, -NRιR₂, -NHAc, -NHCOR, -NH-O-COR, - NHSO₃, -NHSO₂R, -N(SO₂R)₂, and/or amidino groups such as -NH- C(=NH)NH₂ and/or ureido groups such as -NH-CO-NRiR₂ or thiouriedo groups such as -H-C(S)-NH₂; another unit ofthe structure I, attached through any position, where Z, X and Ri to R₆ are as defined above; or a substructure based upon a group ofthe following formula:

wherein: Y is a bond or is selected from the group consisting of: straight chain, 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 each of R to Ri 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 O, and X is O or a bond, then all of Ri to R₅ are not H or CH₂OH; or when Z is N and X is O or a bond, then all of Ri to R₆ are not H.

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 ofthe compounds of Tables 1-4 ofthe description.

4. 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 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 1 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 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 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.

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, 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.