GB2450087A

GB2450087A - Use of sulphated saccharides in the treatment of inflammatory and/or auto-immune diseases

Info

Publication number: GB2450087A
Application number: GB0711139A
Authority: GB
Inventors: Michael Peter Seed; Joe Albert Mancini; Laura Dugo; Margaret Lees; Michael Burnet; Hans Juergen Gutke
Original assignee: DIOSAMINE DEV CORP
Current assignee: DIOSAMINE DEV CORP
Priority date: 2007-06-11
Filing date: 2007-06-11
Publication date: 2008-12-17
Also published as: WO2008152423A3; WO2008152423A2; GB0711139D0

Abstract

Sulphated compounds containing one to twelve monosaccharide subunits have been found to be active in the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption, wherein none of the monosaccharide subunits is pyranosyl with N-sub stitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Also disclosed are methods of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease. Additionally, a method of modifying, or testing for a modification in, the level of a cytokine in vivo, ex vivo or in vitro is disclosed, said method comprising contacting a sulphated compound with a cell, wherein the compound comprises at least one monosaccharide subunit. The present invention also relates to unit dosage forms comprising at least 2.5 g of any of the above compounds. Preferred compounds include sucrose octasulphate and sucralfate.

Description

New Medical Use

Technical Field

The present invention relates to sulphated compounds containing one to twelve monosaccharide subunits, for the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption, wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2position relative to the anomeric carbon of the pyranosyl subunit. The present invention also relates to corresponding methods of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease. Additionally, the present invention relates to a method of modifying, or testing for a modification in, the level of a cytokine in vivo, cx viz.'o or in vitro, said method comprising contacting a suiphated compound with a cell, wherein the compound comprises at least one monosaccharide subunit. The present invention also relates to unit dosage forms comprising at least 2.5 g of any of the above compounds. Preferred compounds of the present invention are sucrose octasuiphate and sucralfate.

Background Art

Inflammation is the culmination of defensive cellular responses to invading pathogens. Inflammatory cells are recruited through chemokines released by damaged cells and activation of resident macrophages and dendritic cells. Processed antigens from invading organisms are presented in lymph nodes to antigen specific T-cells that proliferate and carry the memory of the first exposure. Subsequent exposure to the same pathogen results in an enhanced secondary response.

Mechanisms that control this response ensure that this phenomenon is selective against invading pathogens as opposed to the host.

However, defects in these mechanisms can give rise to chronic, debilitating, inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, and inflammatory bowel disease. Existing therapies for these diseases include cyclo-oxygenase inhibitors that prevent the release of prostaglandins, anti-inflammatory steroids that inhibit a wide variety of genes both related and unrelated to inflammation, anti-cytokine biologics (such as anti-TNF, and anti-ILl), anti-B cell therapy, as well as disease modifying drugs such as aurothiomalate, sulphasalazine or leflunomide that alter the immune response. Drug targets currently being pursued encompass a wide variety of mechanisms including MAP kinase inhibitors to prevent the synthesis of inflammatory cytokines, inhibitors of NFxB to prevent inflammatory gene expression, transrepressor steroids that do not alter non-inflammatory genes and novel anti-cytokine biologics (e.g. anti-1L6, anti- 1L15, anti-1L5, anti-1L17). In spite of these advances, however, there is still a need for further orally active anti-inflammatory drugs.

Large suiphated polysaccharides such as calcium pentosan polysulphate have been found to be mildly anti-inflammatory when administered orally, but are not anti-rheumatic (Smith et a!., Arthritis and Rheumatism, 1994, 37(1), pp. 125-136).

Glycosaminoglycan polvsaccharides with repeat disaccharide subunits possessing 2-amino and 6'-carboxylate groups have been found to possess anti-inflammatory and anti-rheumatic activity. For instance, chondroitin sulphate has been shown to have anti-arthritic activity when administered orally in rats and humans (Ronca et al., Osteoartbritis and Cartilage, 1998, 6(Suppl. A), pp. 14-21). Similarly, heparin has been shown to possess weak anti-asthma activity when given locally by inhalation (Lever et a!., Pulmonary Pharmacology and Therapeutics, 2001, 14, pp. 249-254), whilst di-and tri-sulphated disaccharides derived from heparan sulphate are effective at inhibiting adjuvant-induced arthritis in mice when administered orally (Cahalon et iii., International Immunology, 1997, 9(1O), pp. 1517-1522).

To date, however, only glycosaminoglycan-based sulphated mono-and oligo-saccharides have been shown to be active against non-gastrointestinal inflammation when administered orally.

A widely available non-glycosaminoglycan based suiphated disaccharide is sucralfate.

Sucralfate is an aluminium complex of sucrose octasuiphate (SOS) that is classified as a topical anti-ulcer drug. Its use for the oral treatment of gastric ulcers was known as long ago as 1965 (see US 3,432,489). Sucralfate has also been found to be effective in treating emesis and diarrhoea in small animals (US 4,945,085), and it has some activity against proximal inflammatory bowel disease and radiation- induced proctosigmoiditis on local rectal administration as an enema (Wright et a!., Digesth'e Diseases and Sciences, 1999, 44(9,), pp. 1899-1901; Kochhar et a!., Digesiive Diseases and Sciences, 1991, 36(1), pp. 103-107). These actions occur through the muco-adhesive properties of sucralfate binding to ulcers protecting the wound from gastric acid and promoting healing. In addition, SOS released from the sucralfate complex by gastric acid induces the synthesis of cytoprotective factors such as prostaglandin synthesis, basic-fibroblast growth factor accumulation and activation, nitric oxide synthesis and barrier mucin synthesis. Sucralfate also induces intestinal epithelial cell wound repair (Shindo el a!., J. Gastroentero/ogy, 2006, 41, pp. 450-461). These properties are related to the induction of nuclear factor kappa B (NFxB), as well as cyclo-oxygenase-2 (COX-2). It appears not to affect the Erk/MAP kinase pathways (Shindo et a!.). The anti-ulcer and anti-IBD properties of sucralfate and SOS are thus considered to be due to effects on improving mucosal integrity and healing.

These intracellular events are known to be pro-inflammatory. Prostaglandins are pro-inflammatory, and NFxB is one of the central nuclear factors that stimulates inflammatory gene expression (Natoli, FEBS Letters, 2006, 580, pp. 2843-2849).

The activation of bFGF is also pro-inflammatory (Van et al., JVor/dJ. Gastroenterology, 2006, 12, pp. 3060-3064).

In addition to gastro-intestinal use, sucralfate has also found application as a topical wound healing agent (EP 0 230 023) and as an anti-inflammatory agent when applied topically or intravenously (WO 89/05646).

To date, however, the only applications of sucralfate have been those where it has been able to act directly on the environment to which it has been administered.

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Summary of the Invention

A first aspect of the present invention relates to a compound or a pharmaceutically acceptable salt thereof, for the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption of the compound or salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-SO,-NR2 or -NR-S01-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

A second aspect of the present invention relates to a method of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, comprising administering a therapeutically or prophylactically effective amount of a compound or a pharmaceutically acceptable salt thereof to a patient in need thereof for gastrointestinal absorption, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-S07-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

For the purposes of the present invention, the term monosaccharide subunit' refers to a monosaccharide optionally substituted and/or optionally modified, which may or may not be part of a compound comprising more than one monosaccharide subunit. Thus, for the avoidance of doubt, it is noted that the present invention covers compounds comprising just one monosaccharide subunit, such as monosaccharides.

For the purposes of the present invention, where a compound contains x monosaccharide subunits', this means that the compound has x monosaccharide subunits and no more, unless it is explicitly mentioned that the compound contains or comprises further monosaccharide subunits. In contrast, where a compound comprises x monosaccharide subunits', this means that the compound has x or more monosaccharide subunits.

The single bond between an anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond. A glycosidic group is linked to the anomeric carbon of a monosaccharide subunit by a glvcosidic bond. One distinguishes between -and -glycosidic bonds depending on whether the participating anomeric carbon is in the o or f configuration. In the standard Haworth way of drawing monosaccharide subunits, an cx-glycosidic bond of a D-monosaccharide subunit emanates below the plane of the monosaccharide subunit and a -glycosidic bond emanates above that plane, and vice versa for an L-monosaccharide subunit.

All monosaccharide subunits are independently ring-closed or open-chain or a mixture of ring-closed and open-chain. Ring-closed and open-chain monosaccharide subunits are tautomers of each other, which exist in their cyclic and acyclic forms respectively (with respect to the portion of the molecule referred to).

For example, in the equilibrium below, A is the open-chain tautomer and B is the ring-closed tautomer:

O OH

Thus, in the context of the present invention, it is understood that any substituent that contains a hydrogen atom of moderate acidity (e.g. a hydroxyl, amino or thiol group proton) may interact with the it-bond illustrated so as to establish the above equilibrium. A hydrogen atom of moderate acidity' is defined as one with an approximate PKa (relative to water) of less than 40, preferably less than 30, preferably less than 25, preferably less than 20. It is also understood that in some cases it is not possible to establish the above equilibrium due to a lack of a suitable hydrogen atom and the relevant portion of the molecule is effectively locked' in its open-chain form. In other cases, the relevant portion of the molecule will exist predominantly in its ring-closed form with little or none of the open-chain form being detectable. It is also to be understood that more than one equilibrium may be established within a given portion of the molecule, for example, the scenario below may be established, wherein the molecule exists in two ring-closed forms C and E, and one open-chain form D.

HO HO -HO

A pyranosyl monosaccharide subunit is a cyclic saccharide with a six-membered ring. Pyranosyl monosaccharide F shown below has been marked with substituent X in the 2-position relative to the anomeric carbon of the pyranosyl subunit: As used herein, where it is specified that a first group is located cx to a second group, this means that the first group is attached to a carbon atom one bond removed from the carbon atom to which the second group is attached. Similarly, where it is specified that a first group is located j3 to a second group, this means that the first group is attached to a carbon atom two bonds removed from the carbon atom to which the second group is attached, and so on for groups located y, 6 etc. Where it is specified that a first group is located c to a second group, this means that the first group is attached to the furthest carbon atom removed, along a continuous chain of carbon atoms, from the carbon atom to which the second group is attached. Formula G below has been marked with substituents X in the -, f3-, y-, 6-and co-positions relative to the group Y: The following paragraphs, relating to the preferred structural features of the compounds of the present invention, apply equally to the compounds and salts of the first aspect, the methods of the second, fifth and sixth aspects, and the unit dosage forms of the seventh aspect of the present invention.

It is preferred that none of the monosaccharide subunits is N-substituted to the anomeric carbon.

It is preferred that none of the monosaccharide subunits is pyranosyl with a -CO2R" group attached to the 5-position relative to the anomeric carbon of the pyranosyl subunit, wherein R" is hydrogen or a hydrocarbyl group. Preferably, none of the monosaccharide subunits has a -CO2R" group attached to the 5-position and/or the co-position relative to the anomeric carbon of the monosaccharide subunit.

Preferably, none of the monosaccharide subunits is substituted with a -CO2R" group.

It is preferred that none of the monosaccharide subunits is N-substituted at the anomeric carbon.

The compound may contain one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits. The compound may contain two or three monosaccharide subunits. The compound may contain one monosaccharide subunit, or two monosaccharide subunits, or three monosaccharide subunits, or four monosaccharide subunits. The compound may contain two to six monosaccharide subunits, or two to eight monosaccharide subunits. The compound may comprise two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits directly linked by glycosidic -0-, -S-, and/or -NR'-linkages, wherein each R' is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group.

For the purposes of the present invention, when two monosaccharide subunits are directly linked' by a glycosidic linkage (such as -0-, -S-, or -NR'-), the linkage is directly bonded to both monosaccharide subunits without any intervening atoms being present, such that the compound comprising the two monosaccharide subunits is or comprises a poiy-or oligosaccharide.

It is preferred that, in total, including any further monosaccharide subunits, the compound contains one to twelve monosaccharide subunits, preferably one to eight monosaccharide subunits, preferably one to six monosaccharide subunits, preferably two to four monosaccharide subunits, preferably two to three monosaccharide subunits. Alternatively, the compound may contain, in total, including any further monosaccharide subunits, one monosaccharide subunit, or two monosaccharide subunits, or three monosaccharide subunits, or four monosaccharide subunits, or five monosaccharide subunits, or six monosaccharide subunits, or seven monosaccharide subunits, or eight monosaccharide subunits, or nine monosaccharide subunits, or ten monosaccharide subunits, or eleven monosaccharide subunits, or twelve monosaccharide subunits.

All monosaccharide subunits are independently aldosyl or ketosyl monosaccharide subunits. Preferably, one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosyl or nonosyl monosaccharide subunits. More preferably, one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently glycerosyl, ervthrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl, fucosyl, tetrulosyl, erythro-pentulosyl, threo-pentulosyl, psicosyl, fructosyl, sorbosyl or tagatosyl monosaccharide subunits. All monosaccharide subunits are independently in the D-or L-configuration.

In a preferred embodiment, one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently tetrosyl monosaccharide subunits or higher, and the ring of those monosaccharide subunits is furanosyl. in an alternative preferred embodiment, one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently pentosyl monosaccharide subunits or higher, and the ring of those monosaccharide subunits is pyranosyl.

The stereochemistry of each glycosidic bond is independently a or Preferably, the compound comprises a disaccharide or a disaccharide subunit. As used herein, a disaccharide' or a disaccharide subunit' refers to any two monosaccharide subunits directly linked by a glycosidic -0-linkage, wherein each monosaccharide subunit may. be substituted and/or modified. Preferably the disaccharide or the disaccharide subunit is a substituted sucrose, trehalose, isotrehalose, neotrehalose, maltose, lactose, cellobiose, gentiobiose, isomaltose, kolibiose, lactulo se, laminaribiose, leucrose, maltulose, melibiose, nigerose, planteobiose, rutinose, sophrose or turanose.

Each monosaccharide subunit may be substituted. Alternatively, each monosaccharide subunit may be non-substituted. Each monosaccharide subunit may be modified. Alternatively, each monosaccharide subunit may be non-modified.

In a substituted monosaccharide subunit: (a) independently one or more of the hydroxyl groups of the monosaccharide subunit is replaced with -H, -F, -Cl, -Br, -I, -CF3, -CCI3, -CBr3, -Cl3, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, RaORb, R2SRb, -W-sO-R", RaSO,Rb, R2S0,ORb, WOSO2Rb, WSO2N(Rb),, -10 -WNRbSO., R", RaOSO.,ORb, RaO SO-N(R').,, -R2-N Rb_SO,_N (Rb).,, _Ra_N (Rb).,, -R2-N (Rb) ,+, -R2-B (R1'), _R2_P(Rb) , _R2_PO(Rb).,, RaSi(R, R2CORb, WOCORF, RaOCOORI, -R'O-CO-N(R"),, -R2 NRbCOORI, WNRhCON(RI)).,, Ra.CS.Rb R2CSORb, WOCSRb, RaCSN(RL).,, RaNRbCSRh, -WO-CS-OR', -R20-CS-N (Rh),, RaN RbCSORb, RaN RhCSN (Rb)2, or Rb; preferably independently one or more of the hydroxyl groups of the monosaccharide subunit is replaced with -H, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -CT3, -SH, -NH,, -N4, -NH=NH,, -CN, -NO,, -COOH, RaORb, R2SRb SORb, SO.,Rb, SO -ORb, ...O.S).,.Rb OSO.,ORb, RaN(RD).,, RN(Rb) +, RaSi(R), RaOCOORL, RaCSRb, or Rb; and/or (b) independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -1, -CF3, -Cd3, -CBr3, -Cl3, -OH, -SF!, -NH2, -N3, -NH=NH,, -CN, -NO,, -COOH, WORb, RaSRb R2SO.,Rl), WOSO.,Rb, -W-SO.,-N (Rb).,, R2NRbSO Rb, RaOSO.,N(Rb).,, ORb, _Ra_NRb_SO.,_N(Rb).,, _Ra_N(RE) , _Ra_N(Rb), _Ra_B(Rb).,, _Ra_p(Rb) ...Ra_pO(Rb).,, -W-CO-R", .Ra...COORb RaCON(RI),, RaNRbCORb, RaOCOORF, ...RaOCO...N(Rb)., R2.CS.Rb WCSORb, RaOCSRI WCSN(Rb).,, RaOCSORb, -R20-CS-N (Rh,, RaNRbCSORb, Ra.NRbCS.N (Rb),, or preferably independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -1, -CF3, -Cdl,, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH.,, -CN, -NO,, -COOH, RaORb, RaSRb.SO.Rb SO.,Rb, SO.,ORb, OSO.,Rb, RaOSO.,OR), -R-N(R'), Ra.N(Rb).+ -W-CO-R', RaCOORI, .R2O...CO...Rb R2CON(Rb),, R2NRbCORb, R2OCOoRI),

.Ra.CS...Rh or Rb; and/or (c) independently one or more of the hydroxyl groups of the monosaccharide subunit, together with the hydrogen attached to the same carbon atom as the hydroxyl group, is replaced with 0, S, NRb, or N(Rb),+; and/or (d) independently two hydroxyl groups of the monosaccharide subunit are together replaced with SORc, -SO,-W-, or NRbR; wherein: -R'-is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-10 carbon atoms; -R is independently hydrogen, a further optionally substituted monosaccharide subunit with the proviso that a branched oligosaccharide is produced, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms; and Rc is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms...DTD: In a modified monosaccharide subunit: (a) the ring of the modified monosaccharide subunit, or what would be the ring in the ring-closed form of the modified monosaccharide subunit, is partially unsaturated; and/or (b) the ring oxygen of the modified monosaccharide subunit, or what would be the ring oxygen in the ring-closed form of the modified monosaccharide subunit, is replaced with -S-or -NR'-, wherein Rb is independently hydrogen, a further optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms.

Each hydrocarbyl group is independently a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arvlalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton. Preferably a hydrocarbyl group comprises 1-30, 1-20, 1-15, 1-12, 1-6 or 1-4 carbon atoms.

-12 -A substituted hydrocarbyl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH1, -CN, -NO2, -COOH, -W-O-R", WSRh, RaSO.RI), RaSO,RL, RaSO,ORb, RaOSO,RI), -R2-SO,-N (R"),, RaNRbSO,Rb, R()SO,ORb, RaOSON (Rb),, RaNRbSO,ORI), RaN RbSO,N (Rb),, -R2-N (Rb),, RaN (Rb) +, RaB (Rb),, Rap(RI3),, RaPO(Rb),, W Si(R, R2 CO Rb, Ra CO OR", RaOCORb, RaCON (R'),, RaOCOORb, -WO-CO-N (Rb),, R2NR})COORb, -w-NR"-CO-N(R'),, RaCSRb, RaCS.OR), -WO-CS-R", R2CSN(R)),, RaNRbCSRb, RaOCSORb RaNRbCSORb, -R-NR"-CS-N(R"),, -R", or a further monosaccharide subunit; preferably a substituted hydrocarbyl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CCl, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH,, -CN, -NO,, -COOH, -W-O-R", RaSRL), -SO-R", SOIRb, -SO,-OR", -O-SO,-R", -0-50,-OR", RaN (Rb),, RaN (R"), -R'-Si(R"), R2CORb, R2CO..ORb R2OCORE, -W-NR"-CO-R", RaOCOORl, RaCSRb -R", or a further monosaccharide subunit; wherein: is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-10 carbon atoms; and -R" is independently hydrogen, a further optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenvlaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms.

Any substituent, for example on a monosaccharide subunit or on a hydrocarbyl group, may be protected. Suitable protecting groups for protecting substituents are known in the art, for example from Protective Groups in Organic Synthesis' by Theodora W. Greene and Peter G. M. Wuts (Wiley-Interscience, 3 edition, 1999).

-13 -Preferably the compounds of the present invention comprise: (a) at least two or at least three sulphate groups; and/or (b) at least one -O-SO,-OR, -NR-S07-OR, or -O-S02-NR, group; and/or (c) at least one -OSO3R group; and/or (d) at least two monosaccharide subunits, each of which is substituted with at least one sulphate group; and/or (e) at least one pyranosyl subunit, which is substituted with one, two or three sulphate groups in the 2-, 3-and/or 6-position relative to the anomeric carbon of the pyranosyl subunit; preferably the pyranosyl subunit is part of a disaccharide; and/or (f) at least one pyranosyl subunit, which is substituted with two or three sulphate groups in the 2-, 3-and/or 6-position relative to the anomeric carbon of the pyranosyl subunit; preferably the pyranosyl subunit is part of a disaccharide; and/or (g) a first pyranosyl subunit, which is substituted with one sulphate group in the 2-or 6-position relative to the anomeric carbon of the pyranosyl subunit, and a second pyranosyl subunit, which is substituted with one sulphate group in the 2-or 3-position relative to the anomeric carbon of the pyranosyl subunit and one sulphate group in the 6-position relative to the anomeric carbon of the pyranosyl subunit; preferably the first and second pyranosyl subunits form a disaccharide; and/or (h) at least one pyranosyl subunit, which is substituted with one or two sulphate groups in the 4-and/or 6-position relative to the anomeric carbon of the pyranosl subunit; and/or (i) at least one, two or three sulphate groups, located on primary hydroxyl positions.

Formula H below has been marked with substituents X in the 2-, 3-, 4-and 6-positions relative to the anomeric carbon of the pyranosyl subunit (shown as X2, X3, X4 and X respectively): -14 -In a preferred embodiment, 1-35, .or 1-20, or 2-15, or 3-10, or 4-8, or all the hydroxyl groups on the monosaccharide subunits independently have been replaced with a sulphate group. The specified range relates to the total number of hydroxyl groups that have been replaced with a sulphate group across all the monosaccharide subunits within the compound.

In another preferred embodiment, 1-9, or 2-8, or 3-4 hydroxyl groups on each of one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits independently have been replaced with a sulphate group.

Here, the specified range relates to the number of hydroxyl groups that have been replaced with a sulphate group per individual monosaccharide subunit within the compound, and the specified number relates to the number of monosaccharide subunits on which the specified replacement has occurred.

Where the compound of the present invention comprises a disaccharide or a disaccharide subunit, in one embodiment one, two or three hydroxyl groups of the disaccharide or disaccharide subunit have been replaced with a sulphate group. in such an embodiment, the replacement ratio A:B, in relation to the number of hydroxyl groups replaced by sulphate groups on the first monosaccharide subunit (A) and on the second monosaccharide subunit (B) of the disaccharide or disaccharide subunit is preferably 2:1, 1:2, 2:0, 0:2, 1:1, 0:1 or 1:0.

In preferred embodiments of the present invention: (a) R is independently hydrogen, a metal, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which -15-optionally includes one or more heteroatoms in its carbon skeleton and preferably comprises 1-15 carbon atoms; and/or (b) R is independently hydrogen, an alkali metal, an earth alkali metal, copper, silver, zinc, or a C1-C6 alkyl group.

When R is a metal, then typically -OSO3R is -OSOLi, -OSONa, -OSO3K, -OSO3Cu, or -OSO3Ag, or two -OSO3R together are (-OSO3)1Mg2, (-OSO)2Ca2, (-OSO3)2Cu2, or (-)SO3),Zn2, or three -OSO3R together are (-OSO3 Al3; typical -NR-S02-OR groups comprise the same metal cations.

In another preferred embodiment, the compound is a partially or fully sulphated saccharide. Preferably, the compound is sucrose octasulphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptable salt thereof.

A third aspect of the present invention relates to a compound or a pharmaceutically acceptable salt thereof, for the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption of the compound or salt thereof, wherein the compound or salt thereof is sucrose octasulphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptablesalt thereof.

A fourth aspect of the present invention relates to a method of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, comprising administering a therapeutically or prophylactically effective amount of sucrose octasulphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptable salt thereof to a patient in need thereof for gastrointestinal absorption.

Optionally, any of the first to fourth aspects of the present invention may, instead of relating to the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, relate to a method of treating or preventing any non-gastrointestinal disease or condition.

-16 -The disease or condition may be, for instance, an inflammatory disorder, a proliferative disorder, an immune disorder, an angiogenesis-dependent disorder, a sensitivity disorder, an adverse endocrine reaction, a degenerative disorder or depression.

Alternatively, any of the first to fourth aspects of the present invention may, instead of relating to the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, relate to a method of treating a non-gastrointestinal wound or aiding non-gastrointestinal wound healing. Preferably, the wound is chronic, and/or has arisen from trauma, decubitis, cosmetic surgery, surgical therapy, organ and tissue transplantation, insect bites or burns.

Alternatively still, any of the first to fourth aspects of the present invention may, instead of relating to the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, relate to a method of aiding cartilage repair or cartilage regeneration.

A fifth aspect of the present invention relates to a method of modifying the level of a cytokine in vivo, ex vii'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-SO,-NL or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in i.'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

Preferably, in either the fifth or sixth aspect of the present invention, the cytokine is selected from GM-CSF, IL-1o, IL-IB, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-b, IL- 12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES, MCP-1 or IFN?. Preferably the modification is an increase or decrease in the level of the cytokine. Preferably the modification is to the level of the cytokine synthesised by the cell.

In one embodiment of the fifth or sixth aspect of the present invention, the modification is no change or an increase in the level of cytokine IL-lO.

As used herein, the term level of a cytokine' refers to the amount or concentration of the cytokine.

As used herein, a method of testing for a modification in the level of a cytokine' includes testing for an increase, a decrease, or no change in the level of that cytokine. Preferably, the test is for an increase or a decrease in the level of that cytokine.

In preferred embodiments of the sixth aspect of the present invention, the method of testing relates to a method of obser'ving an increase or a decrease in the level of the cytokine to be tested.

Preferably, in any embodiment of the sixth aspect of the present invention, the cytokine level is tested using a radioimmunoassay, fluorescence activated cell sorting (FAGS), a Northern blot analysis for mRNA, a gene chip assay, a gene activation assay, or an Enzyme-Linked ImmunoSorbent Assay (ELISA or EIA) such as an indirect ELISA, a sandwich ELISA, a competitive ELISA or an Enzyme-Linked Immunosorbent Spot assay (ELISpot). Preferably an ELISA is used. Preferably a bead-based sandwich ELISA is used, allowing for the levels of multiple cytokines to be measured simultaneously. -18-

A first embodiment of the fifth aspect of the present invention relates to a method of modifying the level of a cytokine selected from GMCSF, IL-icc, IL-7, IL-13, IL-17, GCSF or VEGF in viro, ex viva or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a.-O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NL group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A first embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from GMCSF, IL-Icc, IL-7, IL-13, IL-17, GCSF or VEGF in viva, ex viva or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S01-OR, -NR-SO,-OR, -O-S02-NR7 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

In the first embodiment of either the fifth or sixth aspect of the present invention, the modification may be a decrease in the level of a cytokine selected from GMCSF, IL-icc, IL-13, IL-17 or GCSF. Alternatively, the modification may be an increase in the level of a cytokine selected from IL-7 or VEGF.

A second embodiment of the fifth aspect of the present invention relates to a method of decreasing the level of cytokine IL-4 in vivo, ex viva or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO-,-OR, -O-SO,-NR2 or -NR-S02-NR2 group, wherein each -19 -R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A second embodiment of the sixth aspect of the present invention relates to a method of testing for a decrease in the level of cytokine IL-4 in z.'iz.'o, ex rii.'o or in i'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO-,-OR, -O-SO,-NR2 or -NR-SO,-NR7 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that the compound or salt thereof contains one to twelve monosaccharide subunits.

A third embodiment of the fifth aspect of the present invention relates to a method of modifying the level of a cytokine selected from IL-5 or IL-6 in vivo, ex ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-SO,-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

Preferably, the modification is a decrease in the level of a cytokine selected from IL-or IL-6.

A third embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from IL-5 or IL-6 in viz'o, ex rii'o or in vitro, said method comprising contacting a compound or a -20 -pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO.-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbvl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified. Preferably, the modification is a decrease in the level of a cytokine selected from IL-5 or IL-6.

A fourth embodiment of the fifth aspect of the present invention relates to a method of decreasing the level of cytokine IL-lO in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A fourth embodiment of the sixth aspect of the present invention relates to a method of testing for a decrease in the level of cytokine IL-b in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-SO-NR., or -NR-S07-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with I\Tsubstitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

-21 -A fifth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IL-12 in 1'iPO, ex t'ii'o or in i'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably the compound or salt thereof contains one to twelve monosaccharide subunits.

A fifth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine IL-12 in vii'o, ex i'ii'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S07-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably the compound or salt thereof contains one to twelve monosaccharide subunits.

A sixth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of a cytokine selected from IL-1B, RANTES or IL-8 in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt -22 -thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-SO-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hvdrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably, the modification is a decrease in the level of cytokine IL-lB.

A sixth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from IL-IB, RANTES or IL-8 in z'ipo, ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably, the modification is a decrease in the level of cytokine IL-lB.

In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that the method comprises contacting the compound or salt thereof with a blood cell and/or a human cell. Where the cell is a blood cell, it is preferred that the blood cell is an erythrocyte or a leukocyte such as a neutrophil, basophil, eosinophil, lymphocyte, monocyte, or macrophage.

A seventh embodiment of the fifth aspect of the present invention relates to a method of modifying the level of a cytokine selected from IL-4, IL-5, IL-lO, IL-12, MCP-l, RANTES, VEGF or TNFx in vivo, ex vivo or in vitro, said method comprising -23 -contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-S07-NR2 or -NR-SO,-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A seventh embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from IL-4, IL-5, IL-lO, IL-12, MCP-1, RANTES, VEGF or TNFac in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-S02-NR., or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

An eighth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IL-2 in nyc, ex vine or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S07-OR, -O-S09-NR, or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

An eighth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine IL-2 in vine, ex nyc or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof -24 -comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO-OR, -NR-S07-OR, -O-S09-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A ninth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IL-6 in z'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-S02-OR, -O-SO,-NR1 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A ninth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine IL-6 in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-SO,-OR, -O-S07-NR, or -NR-S07-NW, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A tenth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IL-lB in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound-or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-SO.-NR2 or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further -25 -monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

A tenth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine iL-lB in vii'o, ex viz'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S07-OR, -O-S07-NR., or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

An eleventh embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IFNy in vit'o, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-SO,-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

-26 -An eleventh embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine IFNy in i'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S09-OR, -O-SO,-NR2 or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

A twelfth embodiment of the fifth aspect of the present invention relates to a method of modifying the level of cytokine IL-6 in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

A twelfth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the level of cytokine IL-6 in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S07-OR, -O-SO,-NR, or -NR-SO-,-NR-, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

-27 -In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that the compound or salt thereof is in fluid communication with the cell for at least 12 hours, preferably for at least 1, 2, 3, 4, 5 or 10 days. Preferably, the compound or salt thereof is in fluid communication with the cell at a concentration of between 0.001 and 1000 1iM, preferably between 0.005 and 200 M, preferably between 0.0075 and 50 1iM, preferably about 0.01 M. In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that the method is performed in rii'o, preferably in such a manner that the contacting occurs after gastrointestinal absorption of the compound or salt thereof, and/or preferably such that the modification, increase or decrease of the cytokine level is non-gastrointestinal.

Alternatively, in any embodiment of the fifth or sixth aspect of the present invention, the method may be performed in z'itro, preferably for a non-therapeutic purpose.

A thirteenth embodiment of the fifth aspect of the present invention relates to a method of modifying the non-gastrointestinal level of a cytokine selected from IL-2, IL-4, IL-b, IFNy, TNFac or MCP-1 in vii'o, said method comprising the gastrointestinal absorption of a compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-SO,-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably the modification is a decrease in the level of a cytokine selected from IL-2, IL-4, IL-b, IFNy or TNFoc.

-28 -A thirteenth embodiment of the sixth aspect of the present invention relates to a method of testing for a modification in the non-gastrointestinal level of a cytokine selected from IL-2, IL-4, 1L-lO, IFNy, TNF or MCP-1 in vh'o, said method comprising the gastrointestinal absorption of a compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit. Preferably the modification is a decrease in the level of a cytokine selected from IL-2, IL-4, IL-lO, IFN'y or TNFx.

In any embodiment of the sixth aspect of the present invention, it ispreferred that the cytokine level is tested at intervals of between 30 minutes and 10 days, preferably at intervals of between 2 hours and 5 days, preferably at intervals of between 12 hours and 2 days, preferably the cytokine level is tested about once a day.

In any embodiment of the fifth or sixth aspect of the present invention, it is preferred that the modification in the cytokine level occurs and/or is observed over a period of at least 12 hours, preferably over at least 1, 2, 3, 4, 5 or 10 days.

It is generally preferred that the same type of modification of the cytokine level occurs over the entire period of modification and/or observation, i.e. that the cytokine level is increased or decreased over the entire period. Alternatively, however, the type of modification may change over the period of modification and/or observation. For instance, a period of increased cytokine level may be observed followed by a period of decreased cytokine level, and vice versa.

Alternatively still, periods of increased and/or decreased cytokine level may be accompanied by periods with no change in the cytokine level.

-29 -It is preferred that any increase and/or decrease in a cytokine level is statistically significant. Preferably any increase and/or decrease has a p-value of less than 0.2, less than 0.1, less than 0.05, less than 0.01, less than 0.001, or less than 0.0001.

In a further preferred embodiment, any increase and/or decrease in a cytokine level is greater than lO%, greater than 25%, greater than 50%, or greater than 75%.

In any embodiment of the fifth aspect of the present invention, the method may be a method of treating or preventing a disease or condition. Preferably the disease or condition is a disease or condition dependent upon the level of a cytokine.

The fifth aspect of the present invention also includes the use of the compounds or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of a disease or condition according to the methods of the fifth aspect of the present invention.

In any embodiment of the sixth aspect of the present invention, the method may be a method of testing for a disease or condition. Preferably the disease or condition is a disease or condition dependent upon the cytokine level to be tested.

In any embodiment of the sixth aspect of the present invention, the method may also be a method of testing the compound in order to determine its efficacy at treating or preventing a disease or condition and/or its propensity for inducing unwanted side-effects. Preferably the disease, condition or side-effect is a disease, condition or side-effect dependent upon the level of the cytokine to be tested.

In any embodiment of the fifth or sixth aspect of the present invention, the disease or condition may be inflammation or an autoimmune disease. The disease or condition may also be an inflammatory disorder, a proliferative disorder, an immune * disorder, an angiogenesis-dependent disorder, a sensitivity disorder, an adverse endocrine reaction, a degenerative disorder or depression. The disease or condition may be non-gastrointestinal.

-30 -The method of the fifth or sixth aspect of the present invention may be a method of treating a wound or aiding wound healing. The method may also be a method of testing the compound in order to determine its efficacy at treating a wound or aiding wound healing. Preferably, the wound is chronic, and/or has arisen from trauma, decubitis, cosmetic surgery, surgical therapy, organ and tissue transplantation, insect bites or burns.

The method of the fifth or sixth aspect of the present invention may be a method of aiding cartilage repair or cartilage regeneration. The method may also be a method of testing the compound in order to determine its efficacy at aiding cartilage repair or cartilage regeneration.

A seventh aspect of the present invention relates to a unit dosage form comprising at least 2.5 g of a compound of any one of the preceding aspects of the present invention, or a pharmaceutically acceptable salt thereof. Thus, the compound or pharmaceutically acceptable salt thereof may be one of the first or third aspects of the present invention, or one suitable for use in any of the methods of the second, fourth, fifth or sixth aspects of the present invention.

Preferably, the unit dosage form is suitable for oral administration. Preferably, the unit dosage form comprises at least 5 g, at least 7.5 g, at least 10 g, at least 20 g or at least 50 g of a compound of any one of the preceding aspects of the present invention.

The compounds of all aspects of the present invention can be used both, in their free base form and their acid addition salt form. For the purposes of this invention, a salt' of a compound of the present invention can be an acid addition salt. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, -31 -propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesuiphonic, trifluoromethanesulphonic, ethanesuiphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-suiphonic, naphthalene-2-suiphonic or camphorsulphonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). A preferred salt is a hydrohalogenic, sulphuric, phosphoric or organic acid addition salt. The acid addition salt may be a mono-, di-, tn-, tetra-or multi-acid addition salt, or a mixture thereof. A preferred salt is a multi-acid addition salt.

The compounds of all aspects of the present invention can also be used both, in their free acid form and their salt form. For the purposes of this invention, a salt' of a compound of the present invention can also be formed between a carboxylic acid, sulphate, or other suitable functionality of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, ammonium and choline. The salt may be a mono-, di-, tn-, tetra-or multi-salt, or a mixture thereof. Preferably the salt is a multi-sodium, potassium, magnesium, calcium, ammonium or choline salt. More preferably the salt is a multi-potassium salt. Preferably the salt is a pharmaceutically acceptable salt. In one embodiment of the present invention, each sulphate group of a compound of the present invention exists in its salt form.

The compounds of all aspects of the present invention may also encompass pharmaceutically acceptable salts, derivatives, solvates, clathrates and/or hydrates (including anhydrous forms) thereof.

The compounds of all aspects of the present invention may contain one or more chiral centres. The compounds may therefore exist in two or more stereoisomeric forms. The present invention encompasses racemic mixtures of the compounds of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers of the compounds of the present invention. For the purposes of this invention, a substantially enantiomerically pure' isomer of a -32 -compound comprises less than 5% of other isomers of the same compound, preferably less then 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%.

For the purposes of all aspects of the present invention, an alkyl' group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups, and which optionally includes one or more heteroatoms in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, i-butyl and n-pentyl groups. Preferably an alkyl group is straight-chained or branched. Preferably an alkyl group does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C1-C12 alkyl group, which is defined as an alkyl group containing from I to 12 carbon atoms.

More preferably an alkyl group is a C1-C alkyl group, which is defined as an alkyl group containing from I to 6 carbon atoms. An alkyl group may also be a C1-C4 alkyl group, which is defined as an alkyl group containing from I to 4 carbon atoms.

An alkylene' group is similarly defined as a divalent alkyl group.

An alkenyl' group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups, and which optionally includes one or more heteroatoms in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-I-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched. Preferably an alkenyl group does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C2-C12 alkenyl group, which is defined as an alkenyl group containing from 2 to 12 carbon atoms. More preferably an alkenyl group is a C2-C6 alkenyl group, which is defined as an alkenyl group containing from 2 to 6 carbon atoms. An alkenyl group may also be a C2-C4 alkenyl group, which is defined as an alkenyl group containing from 2 to 4 carbon atoms.

An alkenylene' group is similarly defined as a divalent alkenyl group.

An alkynyl' group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups, and which optionally includes one or more heteroatoms -33 -in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched. Preferably an alkynyl group does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a C,-C12 alkynyl group, which is defined as an alkynyl group containing from 2 to 12 carbon atoms. More preferably an alkynyl group is a C,-C6 alkynyl group, which is defined as an alkynyl group containing from 2 to 6 carbon atoms. An alkynyl group may also be a C2-C4 alkynyl group, which is defined as an alkynyl group containing from 2 to 4 carbon atoms.

An alkynylene' group is similarly defined as a divalent alkynyl group.

An acyl' group is defined as a -COW group, wherein R is hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton. Examples of acyl groups are formyl, acetyl, trifluoroacetyl, propanoyl and benzoyl groups. Preferably an acyl group is straight- chained or branched. Preferably an acyl group does not include any heteroatoms in its carbon skeleton. Preferably an acyl group is a C1-C1, acyl group, which is defined as an acyl group containing from I to 12 carbon atoms. More preferably an acyl group is a C1-C6 acyl group, which is defined as an acyl group containing from I to 6 carbon atoms. An acyl group may also be a C1-C4 acyl group, which is defined as an acyl group containing from I to 4 carbon atoms. An acyl group may also contain 1, 2, 3, 4, 5 or 6 carbon atoms.

An aryl' group is defined as a monovalent aromatic hydrocarbon, which optionally includes one or more heteroatoms in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C4-C14 aryl group, which is defined as an aryl group containing from 4 to 14 carbon atoms. More preferably an aryl group is a C6-C10 aryl group, which is defined as an aryl group containing from 6 to 10 carbon atoms. An arylene' group is similarly defined as a divalent aryl group.

-34 -For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arlalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. A typical example of an arylalkyl group is benzyl.

For the purposes of this invention, a substituted group may be substituted monovalently with one or more of -F, -Cl, -Br, -I, -CF3. -Cd3, -CBr3, -CL, -OH, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, -R-O-R, -R-S-R, RSOR?, RSO7R?, -R-SO7-OR, -RO-SO2-R, -R-SO7-N(R)7, -RO-SO,-OR, ROSO2N(RV)2, -R-NR-SO2-OR, -R-NR'-SO2-N(R)7, -R-N(R)2, -Rn-N (R)3, _R_B(R?)2, -R-P(R)7, _R_PO(R),, _R_Si(R?)3, -R-CO-R, RCOOR?, -RO-CO-R, RPCON(R'?)2, -R-NR-CO-R, -RO-CO-OR, -R'O-CO-N(R),, -R-NR-CO-OR, -R-NR-CO-N(R)7, -R1-CS-R, RCSORV, -R3O-CS-R, RCSN(R?)7, -R-NR-CS-R, -RO-CS-OR, -RO-CS-N(R)7, -R-NR'-CS-OR", or -R'; preferably monovalently with one or more of -F, -Cl, -Br, -I, -CF1, -CC13, -CBr3, -Cl3, -OH, -SH, -NH2, -N3, -NHNH,, -CN, -NO2, -COOH, -R-O-R', -R-S-R, -SO-R, -SO,-RT, -SO,-OR, -O-SO7-R, -O-SO2-OR, -Rn-N (R'?)2, -R-N (R)3, -R-Si(R')3, -R-CO-R, RPCOORV, -RO-CO-R, -R-CO-N(R'),, -RO-CO-OR, -R-CS-R, or -R; or divalently with one or more of -Rn-, 0, S, or NR'; or trivalently with one or more of N-Rn-. In this context, -Rn-is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group, optionally including one or more heteroatoms in its carbon skeleton. Rv is independently hydrogen, or a substituted or unsubstituted alkyl or aryl group, optionally including one or more heteroatoms in its carbon skeleton. Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s). Preferably the total number of carbon atoms in any given R'? or -R-group, including any further substitution on that group, is 1-50, preferably 1-20, preferably 1-10, preferably 1-6. Preferably a substituted group comprises 1, 2 or 3 substituents, preferably I or 2 substituents, -35 -Any optional substituent may be protected. Suitable protecting groups for protecting optional substituents are known in the art, for example from Protective Groups in Organic Synthesis' by Theodora W. Greene and Peter G. M. Wuts (Wiley-Interscience, edition, 1999).

For the purposes of this invention, a heteroatom is preferably a B, Si, N, P, 0 or S; more preferably a heteroatom is a N, 0 or S. Preferably, in all aspects of the present invention, the molecular weight of the compound in its free acid or base form is in the range of from 100 to 5100 Da, preferably 100 to 3500 Da, preferably 500 to 2000 Da, preferably 600 to 1000 Da.

A compound used in the present invention, which is of a specific degree of suiphation, i.e. a compound comprising x sulphate groups, may be a mixture of regioisomers, in which the positions of the sulphate groups on the compound vary.

The compounds used in the present invention can also be prepared and used as mixtures of x-to y-fold sulphated compounds. Preferably 50%, 75%, 80%, 85%, 90%, 95% or 99% of such compounds lie within three consecutive degrees of suiphation. Preferably the three consecutive degrees of suiphation are three-to five-fold sulphation, four-to six-fold suiphation, or five-to seven-fold suiphation.

For the purposes of the present invention, a sulphate group' is a -O-S01-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a monosaccharide subunit, or a hydrocarbyl group.

Preferably a sulphate group is a -OSO3R group. Preferably R is hydrogen. The terms suiphated' and sulphation' are defined accordingly.

For the purposes of the present invention, the term x-to y-fold sulphation' means a mixture of sulphated compounds, 80%, 85%, 90% or more of which have from x to y sulphate groups. Thus, for example, a three-to five-fold sulphated compound' is a mixture of compounds, 80%, 85%, 90% or more of which have from three to five sulphate groups.

-36 -Alternatively, if sulphation at specific positions of the compounds is desired, then substituents, in particular hydroxyl groups, on the monosaccharide subunit(s) may need protecting prior to directed suiphation. Suitable protecting groups are known in the art, for example, from Protective Groups in Organic Synthesis' by Theodora W. Greene and Peter G. M. Wuts (\Viley-Interscience, 3rd edition, 1999). Methods of protecting and suiphating saccharides are also known, for example, from Monosaccharides, Their Chemistry and Their Roles in Natural Products' by Peter Collins and R. Ferrier (John Wiley & Sons, 1998), Carbohydrate Chemistry' by Benjamin G. Davis and Antony J. Fairbanks (Oxford Chemistry Primers, Oxford University Press, 2002), and Preparative Carbohydrate Chemistry' by Stephen Hanessian (ed.) (Marcel Dekker Ltd, 1997).

In any aspect of the present invention, the compounds may be used in the form of a pharmaceutical composition, comprising the compound and a pharmaceutically acceptable carrier or diluent.

In one embodiment of any aspect of the present invention, the inflammation or autoimmune disease is inflammation. The inflammation may be chronic inflammation. The inflammation may occur as a result of an inflammatory disorder, occurs as a symptom of a non-inflammatory disorder, or is secondary to trauma, injury or autoimmunity.

The inflammation may occur as a result of psoriasis, sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, cancer, restenosis, papilloma, polyposis, fibrosis, proliferative bronchiolitis, tumour growth, proliferative periostitis, proliferative pulpitis, proliferative verrucous leukoplakia, macular degeneration, an autoimmune disorder, an immunodeficiency disorder, a transplant rejection disorder, a disorder related to a transplant, a disorder related to a renal, hepatic, corneal, cartilage, stem cell, chondrocyte, pulmonary, cardiac, vascular or myeloid transplant, HIV infection, AIDS, multiple sclerosis, systemic lupus erythematosus, septic shock, an allergy, a hyposensitivity, a hypersensitivity, hypersensitivity following the -37 -reactivation of herpes, diabetes, a degenerative disease or disorder, a degenerative joint disease, a neurodegenerative disease, an inflammatory degenerative disease, osteochond ral defects, keratitis (including herpetic keratitis), herpes simplex, shingles, a wound, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.

Preferably, the inflammation does not occur as a result of a gastrointestinal cancer or tumour, gastrointestinal polyposis, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.

In another embodiment of any aspect of the present invention, the inflammation or autoimmune disease is an autoimmune disease.

The autoimmune disease may be selected from acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, diabetes mellitus, Goodpasture's syndrome, Graves' disease, GuillainBarré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ()rd's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, Lyme disease, neuromyotonia, psoriasis, sarcoidosis, schizophrenia, scieroderma, ulcerative colitis, vitiligo or vulvodynia.

-38 -Preferably, the autoimmune disease is not Coeliac disease, Crohn's disease or ulcerative colitis.

Preferably, the autoimmune disease is selected from acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, a systemic connective tissue, disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia or Wegener's granulomatosis.

In any embodiment relating to an inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder, the disorder may be an inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.

In yet another embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is psoriasis, plaque psoriasis, pustular psoriasis, guttate psoriasis, psoriatic arthritis, inverse psoriasis or erythrodermic psoriasis. In another embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behçet's syndrome, asthma, chronic obstructive pulmonary disease, or atherosclerosis.

In another embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine -39 -reaction or degenerative disorder is cancer, restenosis, papilloma, polyposis, fibrosis, proliferative bronchiolitis, tumour growth, proliferative periostitis, proliferative pulpitis, proliferative verrucous leukoplakia, or macular degeneration.

Alternatively the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is an autoimmune disorder, an immunodeficiencv disorder, or a transplant rejection disorder including a disorder related to a transplant such as a disorder related to a renal, hepatic, corneal, cartilage, stem cell, chondrocyte, pulmonary, cardiac, vascular or myeloid transplant. Preferably, the autoimmune disorder, immunodeficiency disorder, or transplant rejection disorder is HIV infection, AIDS, multiple sclerosis, systemic lupus erythematosus or septic shock.

The inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder may also be an allergy, a hyposensitivity or a hypersensitivity, preferably hypersensitivity following the reactivation of herpes.

In yet another embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is diabetes. Preferably, the diabetes is diabetes mellitus, preferably type 1, type 2, gestational, malnutrition related, or impaired glucose tolerance related. Alternatively, the diabetes is diabetes insipidus, preferably central, nephrogenic, dipsogenic, or gestational.

In yet another embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is a degenerative disease or disorder, a degenerative joint disease, a neurodegenerative disease, an inflammatory degenerative disease, or an osteochondral defect. The inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder may also be keratitis (including herpetic keratitis), herpes simplex or shingles.

-40 -In one embodiment, the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-dependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is not, or does not occur as a result of a gastrointestinal cancer or tumour, gastrointestinal polyposis, Crohn's disease, ulcerative colitis, collagenous colitis, lvmphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.

In any embodiment relating to depression, preferably the depression is a major depressive disorder, more preferably catatonic features specification, melancholic features specification, atypical features specification, or psychotic features specification. In other embodiments, the depression is dysthymia, bipolar I disorder, bipolar TI disorder, or post-natal depression.

In addition to the disorders discussed above, the following is a non-exhaustive list of other disorders and diseases that may be treated, prevented, tested for, or may have compounds tested against by the methods of the present invention: osteochondral defects, post traumatic regeneration injury, ischemia, reperfusion injury, scarring, CNS trauma, spinal section, edema, repetitive strain injuries, tendonitis, carpal tunnel syndrome, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, biliary cirrhosis, bullous pemphigoid, canavan disease, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Straus s syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, diffuse cerebral sclerosis of schilder, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia fibromyositis, Fuchs heterochromic iridocyclitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, intermediate uveitis, juvenile arthritis, lichen planus, lupus, Méniêre's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polmyositis, -41 -dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjögren s syndrome, stiff-man syndrome, Takayasu's arteritis, temporal arteritis, giant cell arteritis, ulcerative colitis, vasculitis, vitiligo, VKH (Vogt-Koyanagi-Harada) disease, Wegener's granulomatosis, anti-phospholipid antibody syndrome (lupus anticoagulant, churg-strauss (allergic granulomatosis), dermatomyositis, polymyositis, Goodpasture's syndrome, interstitial granulomatous dermatitis with arthritis, lupus erythematosus (SLE, DLE, SCLE), mixed connective tissue disease, relapsing polychondritis, HLA-B27 associated conditions, ankylosing spondylitis,psoriasis, ulcerative colitis, IBD, Reiter's syndrome, uveal diseases, uveitis, paediatric uveitis, HLA-B27 associated uveitis, intermediate uveitis, posterior uveitis, iritis, degenerative diseases and disorders, degenerative joint disease, neurodegenerative diseases, inflammatory degenerative diseases, Alzheimer's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, viral diseases related to paramyxovirus, picornavirus, rhinovirus, coxsackie virus, influenza virus, herpes virus (including herpes I, herpes II, herpes zoster (shingles), herpetic conjunctivitis, keratitis, and genital herpes), adenovirus, parainfluenza virus, respiratory syncytial virus, echovirus, coronavirus, Epstein-Barr virus, cytomegalovirus, varicella zoster virus, hepatitis variants (including hepatitis C virus (HCV), hepatitis A virus (HAY), hepatitis B virus (HBV), hepatitis D virus (HDV), hepatitis E virus (HEY), hepatitis F virus (HFV), hepatitis G virus (HGV)), human immunodeficiency virus; neoplastic diseases, leukemia, lymphoma, myeloma, hepatomas, other major organ carcinomas and sarcomas, glioma, neuroblastoma, astrocytic and glial tumours, invasive and non-invasive tumours (anaplastic (malignant) astrocytoma, glioblastoma multiforme variants, giant cell glioblastoma, glio sarcoma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), oligodendroglial tumours, ependymal cell tumours, mixed gliomas, neuroepithelial tumours of uncertain origin, tumours of the choroid plexus, neuronal and mixed neuronal-glial tumours, pineal parenchyma tumours, tumours with neuroblastic or glioblastic elements (embryonal tumours), neuroblastoma, ganglioneuroblastoma, tumours of the sellar region, hematopoietic tumours, primary malignant lymphomas, plasmacytoma, granulocytic sarcoma, germ cell tumours, tumours of the meninges, allergies, rhinitis, bronchitis, asthma, -42 -conditions relating to excessively active or stimulated eosinophils, disorders related to transplants (such as renal, hepatic, corneal, cartilage, stem cell, chondrocyte, pulmonary, cardiac, vascular, and myeloid transplants), hypoglycemia, myocarditis (Chagas' disease and coxsackie myocarditis), autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura autoimmune neutropenia, sperm and testicular autoimmunity, intradermal infection (optionally with allergic reactions), acute and chronic bacterial infections (optionally with allergic reactions), skin contact hypersen sitivities, optic contact hypersensitivities, leprosy and other mycobacterium infections, eczema acne, chicken pox, hypertension, adrenal autoimmunity, myasthenia gravis, and myositis.

Preferably, in any embodiment of the present invention, the subject to be treated or tested is a mammal, preferably a human. The subject may also be a non-human, in which case, where the subject is tested, the subject may optionally be mutilated or sacrificed as a result of the test.

As used herein, the terms gastrointestinal' and gastrointestines' refer to any part of the stomach and any part of the alimentary canal thereafter, including the small intestine, large intestine and any other intestines if any, but not to any part of the alimentary canal prior to the stomach such as the mouth, pharynx or oesophagus.

The term alimentary canal' refers to the passage along which food passes through the body from the mouth to the anus.

The term gastrointestinal absorption' of the compounds of the present invention refers to absorption that occurs systemically via the gastrointestines. To achieve gastrointestinal absorption, the compounds of the present invention may be administered, for example, orally, rectally or by tube feeding. Preferably the administration is oral.

Thus, non-gastrointestinal inflammation' refers to inflammation occurring in any part of a body other than the gastrointestines, including inflammation of any other part of the alimentary canal. In some embodiments of the present invention, -43 -inflammation of the entire alimentary canal is excluded, in which case the inflammation is referred to as non-alimentary canal inflammation'.

Similarly, the term non-gastrointestinal autoimmune disease' refers to autoimmune diseases to the extent that they occur in any part of a body other than the gastrointestines, including autoimmune diseases occurring in any other part of the alimentary canal. Non-gastrointestinal autoimmune diseases may display some symptoms in the gastrointe stines.

Optionally, autoimmune diseases which display symptoms in the gastrointestines may be excluded from the scope of the present invention. Thus, in a preferred embodiment of the present invention, the autoimmune disease to be treated is a non-gastrointestinal autoimmune disease without symptoms in the gastrointestines'.

In some embodiments of the present invention, autoimmune diseases to the extent that they occur in the entire alimentary canal are excluded from the scope of the present invention, in which case the autoimmune disease to be treated is referred to as a non-alimentary canal autoimmune disease'. Non-alimentary canal autoimmune diseases may display some symptoms in the alimentary canal.

Optionally, autoimmune diseases which display symptoms in the alimentary canal may be excluded from the scope of the present invention. Thus, in a preferred embodiment of the present invention, the autoimmune disease to be treated is a non-alimentary canal autoimmune disease without symptoms in the alimentary canal'.

For oral administration, the compounds or pharmaceutical compositions of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.

Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, -44 -lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets.

Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Powders or granules for oral use may be provided in sachets or tubs. Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.

Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

The dose of the compounds or pharmaceutical compositions of the present invention will, of course, vary with the disorder or disease to be treated or prevented. In general, a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day, preferably in the range of 1.0 to 200 mg per kilogram body weight per day, preferably 50 to 100 mg per kilogram body weight per day. The desired dose is preferably presented once a day, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing I mg to 20 g, preferably 100 mg to 10 g, preferably I g to 5 g of active ingredient per unit dosage form. In another embodiment, the -45 -unit dosage form comprises at least 2.5 g of active ingredient per unit dosage form.

Preferably, the unit dosage form comprises at least 3 g, at least 4 g, at least 5 g, at least 6 g, at least 7.5 g, at least 10 g, at least 20 g or at least 50 g of active ingredient per unit dosage form.

The present invention will now be described with reference to the following examples. It will be appreciated that what follows is by way of example only and that modifications to detail may be made whilst still falling within the scope of the invention.

Brief Description of the Figures

Figure 1 shows the inhibition of mouse mBSA antigen induced arthritis after the oral administration of sucralfate at a dose of 200 mg/kg, and the abolition of this activity as a result of gastric acid suppression by lansoprazole. ANOVA followed by post hoc Dunnett's test, comparison with vehicle control, **zp<o.o1.

Figure 2 shows the inhibition of mouse mBSA antigen induced arthritis after the oral administration of sucrose octasulphate at a concentration of 100, 30 and 10 mg/kg. ANOVA followed by post hoc Dunnett's test, comparison with vehicle control, p<O.OS.

Figure 3 shows the inhibition of rat collagen induced arthritis, measured by clinical assessment, by sucrose octasulphate given orally once daily at 30 mg/kg (n = 7) on days 0-12 only. The rats were not dosed from day 13 onwards (control n = 13, mean s.e.m.).

Figure 4 shows the inhibition of rat collagen induced arthritis, measured by the change in volume of the hind paws, by sucrose octasulphate given orally once daily at 30 mg/kg (n = 7) on days 0-12 only. The rats were not dosed from day 13 onwards (control n = 13, mean s.e.m.).

-46 -Figure 5 shows the inhibition of mouse collagen arthritis, measured by clinical assessment, by sucrose octasulphate given orally at 100 mg/kg on days 0-35 (mean s.e.m.).

Figure 6 shows the inhibition of mouse collagen arthritis, measured by the change in volume of the hind paws, by sucrose octasuiphate given orally at 100 mg/kg on days 0-35 (mean s.c.m.).

Figure 7 shows the inhibition of mouse collagen arthritis by sucrose octasuiphate given orally at 100 mg/kg on days 0-35 (mean s.e.m.), as shown by assessment of the degree of bone erosion.

Figure 8 shows a reduction in collagen-induced lymphocyte proliferation ex ivo by sucrose octasulphate given orally to mice with collagen arthritis on days 0-31 (n = 4, mean s.c.m.).

Figure 9 shows the inhibition of PHA stimulated IL-1 synthesis in human whole blood by 0.01 pM sucrose octasulphate.

Figure 10 shows the inhibition of PHA stimulated IL-1f3 synthesis in human whole blood by 0.01 M sucrose octasuiphate.

Figure 11 shows the inhibition of PHA stimulated IL-2 synthesis in human whole blood by 0.01 M sucrose octasulphate.

Figure 12 shows the inhibition of PHA stimulated IL-4 synthesis in human whole blood by 0.01 M sucrose octasulphate.

Figure 13 shows the inhibition of PHA stimulated IL-S synthesis in human whole blood by 0.01 1iM sucrose octasuiphate.

Figure 14 shows the inhibition of PHA stimulated IL-6 synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

-47 -Figure 15 shows the further stimulation of PHA stimulated IL-7 synthesis in human whole blood by 0.01 p.M sucrose octasuiphate.

Figure 16 shows the effect on PHA stimulated IL-lU synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

Figure 17 shows the effect on P1-IA stimulated IL-12 synthesis in human whole blood by 0.01 p.M sucrose octasuiphate.

Figure 18 shows the inhibition of PHA stimulated IL-13 synthesis in human whole blood by 0.01 p.M sucrose octasuiphate.

Figure 19 shows the inhibition of PHA stimulated IL-17 synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

Figure 20 shows the inhibition of PHA stimulated IFNy synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

Figure 21 shows the inhibition of PHA stimulated GCSF synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

Figure 22 shows the inhibition of PHA stimulated GM-CSF synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

Figure 23 shows the 0.01 p.M sucrose octasulphate induced stimulation of VEGF synthesis in human whole blood in which the VEGF synthesis has been inhibited by PHA.

Figure 24 shows the inhibition of PHA stimulated TNFoc synthesis in human whole blood by 0.01 p.M sucrose octasulphate.

-48 -Figure 25 shows the effect of various concentrations of PHA on TNF synthesis in human whole blood.

Figure 26 shows the inhibition of PHA stimulated TNF synthesis in human whole blood b sucrose octasuiphate over a range of concentrations.

Figure 27 shows the inhibition of differentiated U937 human macrophage TNFoc synthesis by sucrose octasuiphate over a range of concentrations.

Biological Examples

Safety! Toxicity Studies Sucrose octasuiphate was administered to rats (n = 10) orally for 12 days at a dosage of 100 mg/kg/day. The rats were assessed for weight loss, piloerection, cleanliness, diarrhoea, polyuria, gait and behaviour. No adverse events were observed.

The above experiment was repeated on mice (n = 11) over 35 days. The straub tail behaviour was also observed. Again, no adverse events were observed.

Mouse _4ntigen-Induced Arthritis C57b1/6 mice were sensitised to methylated bovine serum albumin (mBSA) in Freund's complete adjuvant. 14 days later they were challenged with the intra- articular injection of mBSA in one stifle joint and saline in the other. The non-control mice, with or without gastric acid suppression by lansoprazole, were dosed orally, one hour prior to the challenge, with sucralfate (an aluminium complex of sucrose octasuiphate) at a dose of 200 mg/kg. Joint inflammation was assessed as an increase in diameter, measured with callipers. The results are shown in Figure 1.

It can be seen from this that an oral prophylactic dose of 200 mg/kg sucralfate significantly reduces joint inflammation, whereas no effect is observed if the gastric acid catalysed hydrolysis of the complex is inhibited.

-49 -In a second experiment, C57bl/6 mice were sensitised to methylated bovine serum albumin (mBSA) in Freund's complete adjuvant. 14 days later they were challenged with the intra-articular injection of mBSA in one stifle joint and saline in the other.

The non-control mice were dosed orally, one hour prior to the challenge, with sucrose octasuiphate at doses of 100 mg/kg, 30 mg/kg and 10 mg/kg respectively (n = 6 per treatment group). Joint inflammation was assessed as an increase in diameter, measured with callipers. The results are shown in Figure 2. It can be seen from this that an oral prophylactic dose of 100 mg/kg sucrose octasuiphate significantly reduces joint inflammation.

Rat Collagen-Induced Arthritis Preparation of collagen: Bovine nasal collagen II was dissolved to 2.0 mg/mI in 0.OIM acetic acid by gentle stirring overnight at 4 C at a concentration of 4 mg/ml. This was emulsified with ice-cold Freund's incomplete adjuvant (FIA) by addition of small volumes of the collagen II solution to the F1A and mixing to a ratio of 1:1.

Induction of arthritis: On day 0, rats were lightly anesthetised with halothane. The base of the tail was shaved and 100 pi collagen II / FIA emulsion (200 p.g collagen II) was injected intradermally at this site.

Dosing: The non-control rats (n = 7) were dosed orally with 30 mg/kg sucrose octasulphate in 0.2 ml water, once a day on days 0-12. The control rats (n = 13) were dosed orally with water.

Assessment: Arthritis development was assessed clinically and found to be confined to the ankle joints. This was measured by a clinical score given to each animal on an arbitrary scale. The paws were examined and any inflammation was noted. Each individual hind ankle was given a score between zero (no inflammation) and three (severe inflammation) giving a total clinical score of 6. Clinical assessments were taken on days 11, 14, 16, and 18.

-50 -The animals were also assessed quantitatively for hind paw inflammation through volumetric measurement by plethysmometry (Ugo Basille) and results expressed as 102 ml. The animals had a hind paw lowered into the measuring chamber to a uniform position and the paw volume was recorded. This was then repeated for the other hind paw. The results were averaged.

Results: The results of the clinical assessment are shown in Figure 3, and the results of the volumetric assessment are shown in Figure 4. It can be seen that sucrose octasulphate is effective at reducing rat collagen arthritis, when administered orally to at 30 mg/kg during the sensitisation phase of the disease development. No adverse events were observed. This dosing regime shows that the development of the immune response to auto-antigens is inhibited by the treatment, the anti-inflammatory effect being evident 7 days after the cessation of treatment.

Mouse Collagen-Induced Arthritis Preparation of collagen: Chick sternal collagen II was dissolved in 0.OIM acetic acid by gentle stirring overnight at 4 C at a concentration of 2 mg/mI. This was emulsified with ice-cold Freund's complete adjuvant (FCA: 2 mg/mi mycobacterium tuberculosis in Freund's incomplete adjuvant) by addition of small volumes of the collagen Ii solution to the FCA and mixing to a ratio of 1:1.

Induction of arthritis: Mice (n = 9) were lightly anaesthetised with halothane. The base of the tail was shaved and 100 iil collagen II / FCA emulsion (100 ig collagen II) was injected intradermally to the left hand side of this site. 21 days after initial sensitisation, collagen II was dissolved in acetic acid as above, emulsified 1:1 in Freund's incomplete adjuvant and 100 pi was injected into the base of the tail on the right hand side of the tail base. This day was taken as day 0.

Dosing: The non-control mice (n = 9) were dosed with sucrose octasulphate orally at a concentration of 100 mg/kg/day once a day on days 0-35.

-51 - 4sses.cmenf: Mice were individually marked and examined every other day from the time of the day of boost (day 0). The degree of arthritis was scored using an arbitrary scale on predetermined days. The animals' paws were examined and any inflammation was noted. Every inflamed main digit scored one, inflammation of the front paw scored one, inflammation of the hind paw scored one, and jn\Tolvement of the ankle scored one. Thus a maximal score for each animal was 22.

The animals were also assessed quantitatively for hind paw inflammation through volumetric measurement by plethysmometry (Ugo Basille) and results expressed as 102 ml. The animals had a hind paw lowered into the measuring chamber to a uniform position and the paw volume was recorded. This was then repeated for the other hind paw. The results were averaged.

A bone-erosion study was also performed as follows. After 35 days, the paws of the mice were fixed in formal saline. CT images were acquired from the fixed paws using a Siemens (formerly ImTek inc., Knoxville, Tennessee) Microcat II instrument. Key instrument parameters were: exposure 700 ms, X-ray voltage 80 kVp, anode current 280 pA. The source to detector distance was 437.7 mm and the source to centre distance was 207.6 mm (the paw was placed at the approximate centre of rotation. Scan duration was approximately 30 minutes. Images were reconstructed with 768 z slices each having 512 x 512 pixel resolution (32 mm x 32 mm). For isosurface plots, density thresholds were set by reference to intact mouse metatarsal bone. Using Siemens' AMIRA software, the density threshold was set at 800 units. The setting was used as a constant for the analysis of all exposures in a series ensuring that the images reported herein reflect surfaces with the same X-ray opacity. Printed full A4 size colour images of each paw were printed and assessed blind according to the following erosion score, termed the Seed-Mancini score: Score 0 anatomically normal joint Score I point erosion metatarsal near meta-tarso-phalangeal joint Score 2 as 1, with elongated erosion Score 3 as 2, with complete penetration -52 -Score 4 as 3, elongated erosion meta-tarsal, erosion in proximal phalangeal bone Score 5 as 4, complete penetrative erosion of proximal phalangeal bone Score 6 as 5, meta-tarso-phalangeal joint destroyed Results: The results of the clinical assessment are shown in Figure 5, and the results of the volumetric assessment are shown in Figure 6. The results of the bone-erosion study are shown in Figure 7. It can be seen that sucrose octasuiphate is effective at reducing mouse collagen-induced arthritis, when administered orally at 100 mg/kg/day during the immune development and effector phases of the disease development.

Antigen-Induced Lymphocyte Function Mice were exposed (sensitised) to a foreign antigen (in this case, collagen) for 35 days, then lymph node cells made up primarily of macrophages, dendritic cells and primed T-lymphocytes, were taken, cultured and exposed to the antigen. The T-cells respond by proliferating. The non-control mice (n = 3) were dosed orally with 100 mg/kg sucrose octasulphate once a day. The control mice (n = 4) were dosed orally with water. The results are shown in Figure 8. It can be seen that Sucrose octasuiphate administered orally to these mice induced a reduction in the collagen challenge response, indicating a drug-induced inhibition of arthritis immu no-pathology.

P1-IA stimulated human whole blood cvtokine siinthesis lVbole blood culture: Blood was taken from a healthy young male volunteer, into heparin Vacutainers'. Whole-blood was diluted to give a final concentration of 1/10 in culture medium (CM). CM consisted of RPMI 1640 with L-glutamine, penicillin and streptomycin. PHA (phytohaemagglutinin) solution and sucrose octasuiphate and PHA solution were added to non-control samples. Final drug concentrations tested were IOOIXM, 1pM, 0.lp.M and 0.01pM. All samples were tested in triplicate.

-53 -Reagents were placed in four sets of 24-well (6x4) flat-bottomed plates (Corning US) and incubated for 1, 2, 3 and 4 days respectively (incubator conditions: 37 C, humid and 5% C02). After each day, starting at day 1, a set of plates was centrifuged (at 400rpm for 6 minutes) and supernatant placed in individual 1.5m1 eppendorf tubes and stored at -80 C.

ELISA: The protocol of Lagrelius el al. was followed (ytokine, 2006, 33, pp. 156- 165). The culture supernatants were analysed once for concentrations of IL-1o, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-lO, IL-12, IL-13, IL-17, IFNy, GCSF, GM-CSF, MCP-1, RANTES, VEGF and TNF. The cytokines were measured simultaneously using a Bio-Plex assay. This assay employs a bead-based sandwich immunoassay technique. A monoclonal antibody specific for each cytokine of interest is coupled onto a particular set of beads with a known internal fluorescence, and several combinations of cytokine antibody coated beads can be included and thus multiple cytokines are measured simultaneously. The assay was performed according to the manufacturer's instructions using a Bio-Plex kit (Bio-Rad Laboratories). Briefly, 50 ml of standard or test sample along with 50 ml of mixed beads were added into the wells of a pre-wet 96-well microtitre plate. After 1 hour incubation and washing, 25 ml of detection antibody mixture was added and the samples were incubated for 30 minutes and then washed. Finally, 50 ml of streptavidin-PE was added and after 10 minutes incubation and washing, the beads were resuspended in 125 ml of assay buffer. The beads were analysed employing a Bio-Piex suspension array system (Bio-Rad Laboratories) and the Bio-PIex manager software (version 3.0). A minimum of 100 beads per region were analysed. A curve fit was applied to each standard curve according to the manufacturer's manual and sample concentrations were interpolated from the standard curves. The limit of quantification of cytokine detection using this method was 2 pg/mI for IL-5, IL-lO, IL-12 and IL-17, 2.8 pg/mi for IL-2, IL-4, IL-6, IL-13 and TNFo, 2.32 pg/mI for IFN?, and 8.32 pg/mi for GM-CSF.

Results: PHA increased the levels of all cytokines except VEGF, the level of which was reduced. IL-8, MCP-1 and RANTES were outside the range of the assay. The -54 -action of O.Olp.M sucrose octasuiphate on PHA stimulated synthesis of IL-1, IL-1f3, IL-2, IL-4, IL-5, IL-6, IL-7, IL-lO, JL-12, IL-13, IL-17, IFN', GCSF, GM-CSF, VEGF and TNFx is shown in Figures 9 to 24 respectively.

It can be seen that sucrose octasuiphate inhibits the PHA stimulated synthesis of IL-1x, IL-1f3, IL-2, IL-4, IL-5, IL-6, IL-lU, IL-13, IL-17, IFNy, GCSF, GM-CSF and TNF, whilst levels of IL-7 and VEGF are increased.

P1-IA stimulated human whole blood TNFa siintbesis lVho/e blood culture: As used above.

TNFa ELISA: The following TNFa assay test kits used were: BD OptElA -Human TNF Elisa set (BD Biosciences, UK) (cat: 555212, lot 42516). The corresponding kit protocol was followed for the assay using 96-well plates.

Results: PHA stimulation on a subject's whole blood in culture is shown in Figure 25. At zero PHA concentration TNFoc levels were below the limit of detection, and at a PHA concentration of 2.5.tg/mi TNFac levels were low for all four days. At a PHA concentration of 5p.g/ml (control) TNFcx concentration increased from -600 pg/ml at day 1 to a peak of -2000 pg/mi at day 3, and then dropped to -1900 pg/mi at day 4. This level of stimulation was comparable to that reported by Lagreiius et al. The effects of sucrose octasulphate on PHA-induced TNFac synthesis are shown in Figure 26. The synthesis of TNFx is entirely suppressed by the drug at all concentrations down to 0.Olp.M.

LPS stimulated U937 macropbge TNFa synthesis U937 human monocytes were incubated with 5 p.g/ml PMA (phorbol myristate acetate) for 5 days in order to induce differentiation. Sucrose octasulphate was added to the macrophages produced at concentrations of 0 (control), 0.10, 1.00, -55 -10.00 and 100.00 M. TNFcc synthesis was then optionally induced by 80 nM LPS (lipopolysaccharide) treatment for 72 hours. The results are shown in Figure 27. It can be seen that sucrose octasuiphate inhibited TNFo synthesis at all concentrations down to 0.1 M. It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the present invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

-56 -Claims 1. A compound or a pharmaceutically acceptable salt

thereof, for the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption of the compound or salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-S02-OR, -O-S07-NR2 or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2position relative to the anomeric carbon of the pyranosyl subunit.
2. A method of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, comprising administering a therapeutically or prophylactically effective amount of a compound or a pharmaceutically acceptable salt thereof to a patient in need thereof for gastrointestinal absorption, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2- position relative to the anomeric carbon of the pyranosyl subunit.
3. A compound as claimed in claim I or a method as claimed in claim 2, wherein none of the monosaccharide subunits is N-substituted x to the anomeric carbon.

-57 -
4. A compound or a method as claimed in any one of the preceding claims, wherein the compound contains one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits.
5. A compound or a method as claimed in any one of the preceding claims, wherein the compound contains two or three monosaccharide subunits.
6. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits directly linked by glycosidic -0-, -S-, and/or -NR'-linkages, wherein each R' is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group.
7. A compound or a method as claimed in any one of the preceding claims, wherein each monosaccharide subunit is independently an aldosyl or ketosyl monosaccharide subunit.
8. A compound or a method as claimed in claim 7, wherein one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosyl or nonosyl monosaccharide subunits.
9. A compound or a method as claimed in claim 8, wherein one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently glycerosvl, erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl, fuco syl, tetrulosyl, erythro-pentulosyl, threo-pentulosyl, psicosyl, fructosyl, sorbo syl or tagatosyl monosaccharide subunits.
10. A compound or a method as claimed in any one of the preceding claims, wherein all monosaccharide subunits are independently in the D-or L-configuration.

-58 -
11. A compound or a method as claimed in any one of the preceding claims, wherein one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently tetrosyl monosaccharide subunits or higher, and the ring of those monosaccharide subunits is furanosyl.
12. A compound or a method as claimed in any one of the preceding claims, wherein one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits are independently pentosyl monosaccharide subunits or higher, and the ring of those monosaccharide subunits is pyranosyl.
13. A compound or a method as claimed in any one of the preceding claims, wherein the stereochemistry of each glycosidic bond is independently a or
14. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises a disaccharide or a disaccharide subunit.
15. A compound or a method as claimed in claim 14, wherein the disaccharide or the disaccharide subunit is a substituted sucrose, trehalose, isotrehalose, neotrehalose, maltose, lactose, cellobiose, gentiobiose, isomaltose, kojibiose, lactulose, laminaribiose, leucrose, maltulose, melibiose, nigerose, planteobiose, rutinose, sophrose or turanose.
16. A compound or a method as claimed in any one of the preceding claims, wherein one or more monosaccharide subunit is substituted and/or modified.
17. A compound or a method as claimed in any one of the preceding claims, wherein in a substituted monosaccharide subunit: (a) independently one or more of the hydroxyl groups of the monosaccharide subunit is replaced with -H, -F, -Cl, -Br, -I, -CF3, -Cd3, -CBr3, -Cl3, -SH, -NH,, -N3, -NH=NH,, -CN, -NO, -COOH, RaORb, R2SRb, WSORb, WSO Rb, RaSO.,ORb, R2OSORI) .RaSO -N(R, R2NRbSO,Rb, -wo-so,-ORI,, RaOSO,N (R, wNRbso,oRb, _R2_NRb_S02_N(Rb)2, _R2_N(RE)2, _Ra_N(Rb)3+, _w_B(R")2, _Ra_P(Rb)2, _R2_PO(Rb),, -59 -RaSi(R, WC0RL, RaCOORl, R2OCORb, RaCON(R, RaOCOORl), RaOCON(RI) , RaNRI)COORb, RaCSR), RaCSORb, RaOCSRI), -W-CS-N(R"),, RaNRbCSRb, RaOCSORb, -WO-CS-N (Rb),, RaNRbCS()Rb RaN RbCSN (Rb),, or Rb; and/or (b) independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -I, -CF3. -Cd3, -CBr, -Cl3, -OH, -SH, -NH7, -N3, -NH=NH,, -CN, -NO,, -COOH, R2ORb, WSRb, WSORh, -R", RaSO ORb, RaOSO,Rb, R2sO,N(Rb),, RaOSO ORb, -wO-SO,-N(Rb),, RaNRhSO,ORb, to _Ra_NRb_SO,_N(Rb),, _Ra_N(Rl)),, _Ra_N(Rb) +, _Ra_B(Rb),, _Ra_p(Rb),, _Ra_pO(RI)),, -W-s(Rb), WCORb, RaCOORb R2OCORb, R2CON(Rb),, R0NRbCORI), RaOCOORI, RaOCON(Rb),, RaNRbCO.ORb WNRbCON(Rb),,, WCSRb, RaCSORl), RaOCSRb, RaCSN(Rb).,, -W-NR"-CS-R", RaOCSORI, RaOCSN (Rb),, .R2.NRh.CS...ORh RaNRt)CSN (Rb),, or Rh; and/or (c) independently one or more of the hydroxyl groups of the monosaccharide subunit, together with the hydrogen attached to the same carbon atom as the hydroxyl group, is replaced with 0, S, =NRb, or N(Rb)2; and/or (d) independently two hydroxyl groups of the monosaccharide subunit are together replaced with SORc, -SO,-R'-, or wherein: l(2 is independently a chemical bond, or a substituted or unsubstituted alkvlene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton; Rb is independently hydrogen, a further optionally substituted monosaccharide subunit with the proviso that a branched oligosaccharide is produced, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynvlaryl group which optionally includes one or more heteroatoms in its carbon skeleton; and Rc is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton.

-60 -
18. A compound or a method as claimed in any one of the preceding claims, wherein in a modified monosaccharide subunit: (a) the ring of the modified monosaccharide subunit, or what would be the ring in the ring-closed form of the modified monosaccharide subunit, is partially unsaturated; and/or (b) the ring oxygen of the modified monosaccharide subunit, or what would be the ring oxygen in the ring-closed form of the modified monosaccharide subunit, is replaced with -S-or -NR'-, wherein Rb is independently hydrogen, a further optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arvlalkyl, arylalkenyl, arylalkynyl, alkylarvi, alkenvlaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
19. A compound or a method as claimed in any one of the preceding claims, wherein each hydrocarbyl group is independently a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arlaIkynyl, alkylaryl, alkenylarvi or alkynylaryl group which comprises 1-15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.
20. A compound or a method as claimed in claim 19, wherein a substituted hydrocarbyl group is substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CC!3, -CBr3, -Cl3, -OH, -SH, -NH2, -N3, -NH=NH.,, -CN, -NO.,, -COOH, -W-O-R', _WSRb, _Ra.S0_Rb, _RaSO,_Rb, _Ra_SO.,ORl, -WO-SO.,R', RaSO,N(Rb),, WNRbSO.,Rb, RaOSO,ORb, WOSO,N(Rb),, -R-N Rb_SO.,_N (Rb),, _Ra_N (R"), -R2-N (Rb) +, _Ra_B (R")1, _Ra_p(Rb),,, _w_Po(Rt'), -R-Si(R, RaCORI, .R2COORb R2OCORb RaCON(Rb),, RaNRbCORb WOCOORL, RaOC()N(Rb), WNRbCOORb, .R NRLCON(Rb), RaCSRb, RaCSORb, WOCSRb, -W-Cs-N(R, RaOCSORb, WOCSN(Rb)2, RaNRbCSORb RaNRbCS.N(Rb)2 Rb, or a further monosaccharide subunit; wherein: -61 - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group which optionally includes one or more heteroatoms in its carbon skeleton; and Rb is independently hydrogen, a further optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arvialkenvi, ar'lalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
21. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least two or at least three sulphate groups.
22. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least one -O-SO,-OR, -NR-SO,-OR, or -O-S02-NR-, group.
23. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least one -OSO1R group.
24. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least two monosaccharide subunits, each of which is substituted with at least one sulphate group.
25. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least one pvranosyl subunit, which is substituted with one, two or three sulphate groups in the 2-, 3-and/or 6-position relative to the anomeric carbon of the pyranosyl subunit.
26. A compound or a method as claimed in claim 25, wherein the pyranosyl subunit is substituted with two or three sulphate groups in the 2-, 3-and/or 6-position relative to the anomeric carbon of the pyranosyl subunit.

-62 -
27. A compound or a method as claimed in claim 25 or 26, wherein the pyranosyl subunit is part of a disaccharide.
28. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises a first pyranosyl subunit, which is substituted with one sulphate group in the 2-or 6-position relative to the anomeric carbon of the pyranosyl subunit, and a second pyranosyl subunit, which is substituted with one sulphate group in the 2-or 3-position relative to the anomeric carbon of the pyranosyl subunit and one sulphate group in the 6-position relative to the anomeric carbon of the pyranosyl subunit.
29. A compound or a method as claimed in claim 28, wherein the first and second pyranosyl subunits form a disaccharide.
30. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least one pyranosyl subunit, which is substituted with one or two sulphate groups in the 4-and/or 6-position relative to the anomeric carbon of the pyranosyl subunit.
31. A compound or a method as claimed in any one of the preceding claims, wherein the compound comprises at least one, two or three sulphate groups, located on primary hydroxyl positions.
32. A compound or a method as claimed in any one of the preceding claims, wherein 1-35, or 1-20, or 2-15, or 3-10, or 4-8, or all the hydroxyl groups on the monosaccharide subunits independently have been replaced with a sulphate group.
33. A compound or a method as claimed in any one of the preceding claims, wherein 1-9, or 2-8, or
3-4 hydroxyl groups on each of one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve monosaccharide subunits independently have been replaced with a sulphate group.

-63 - 34. A compound or a method as claimed in any one of the preceding claims, wherein R is independently hydrogen, a metal, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynvi, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
35. A compound or a method as claimed in any one of the preceding claims, wherein R is independently hydrogen, an alkali metal, an earth alkali metal, copper, silver, zinc, or a C1-C(, alkyl group.
36. A compound or a method as claimed in any one of the preceding claims, wherein the compound is a partially or fully suiphated saccharide.
37. A compound or a method as claimed in any one of the preceding claims, wherein the compound is sucrose octasuiphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptable salt thereof.
38. A compound or a pharmaceutically acceptable salt thereof, for the treatment or prevention of non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, by gastrointestinal absorption of the compound or salt thereof, wherein the compound or salt thereof is sucrose octasulphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptable salt thereof.
39. A method of treating or preventing non-gastrointestinal inflammation or a non-gastrointestinal autoimmune disease, comprising administering a therapeutically or prophylactically effective amount of sucrose octasuiphate or sucralfate, or a tautomer, stereoisomer and/or pharmaceutically acceptable salt thereof to a patient in need thereof for gastrointestinal absorption.
40. A compound or a method as claimed in any one of the preceding claims, wherein the inflammation is chronic inflammation.

-64 -
41. A compound or a method as claimed in any one of the preceding claims, wherein the inflammation occurs as a result of an inflammatory disorder, occurs as a symptom of a non-inflammatory disorder, or is secondary to trauma, injury or autoimmunity.
42. A compound or a method as claimed in any one of the preceding claims, wherein the inflammation occurs as a result of psoriasis, sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, cancer, restenosis, papilloma, polyposis, fibrosis, proliferative bronchiolitis, tumour growth, proliferative periostitis, proliferative verrucous leukoplakia, macular degeneration, an autoimmune disorder, an immunodeficiency disorder, a transplant rejection disorder, a disorder related to a transplant, a disorder related to a renal, hepatic, corneal, cartilage, stem cell, chondrocyte, pulmonary, cardiac, vascular or myeloid transplant, HIV infection, AIDS, multiple sclerosis, systemic lupus erythematosus, septic shock, an allergy, a hyposensitivity, a hypersensitivity, hypersensitivity following the reactivation of herpes, diabetes, a degenerative disease or disorder, a degenerative joint disease, a neurodegenerauve disease, an inflammatory degenerative disease, osteochondral defects, keratitis (including herpetic keratitis), herpes simplex, shingles or a wound.
43. A compound or a method as claimed in any one of claims I to 39, wherein the non-gastrointestinal autoimmune disease is selected from acute disseminated encephalitis, Addison's disease, ankylo sing spondylitis, antiphospholipid antibody syndrome CAPS), aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, -65 -Behçet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, Lyme disease, neuromyotonia, psoriasis, sarcoidosis, schizophrenia, scleroderma, ulcerative colitis, vitiligo or vulvodynia.
44. A compound as claimed in any one of claims I to 43, wherein the compound or salt thereof is administrable orally, rectally or by tube feeding.
45. A compound as claimed in claim 44, wherein the compound or salt thereof is administrable orally.
46. A method as claimed in any one of claims I to 43, wherein the compound or salt thereof is administered by oral, rectal or tube feeding administration.
47. A method as claimed in claim 46, wherein the compound or salt thereof is administered by oral administration.
48. A method of modifying the level of a cytokine selected from GM-CSF, IL-Icc, IL-7, IL-13, IL-17, GCSF or VEGF in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-SO,-NR, or -NR-SO,-NR., group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and! or optionally modified.
49. A method of testing for a modification in the level of a cytokine selected from GM-CSF, IL-Icc, IL-7, IL-13, IL-17, GCSF or VEGF in vivo, ex viva or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-SO,-OR, -O-S02-NR7 or -NR-S02-NR., group, wherein each -66 -R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and / or optionally modified.
50. A method as claimed in claim 48 or 49, wherein the modification is a decrease of the level of a cytokine selected from GM-CSF, IL-1, IL-13, IL-17 or GCSF.
51. A method as claimed in claim 48 or 49, wherein the modification is an increase of the level of a cytokine selected from IL-7 or VEGR
52. A method of decreasing the level of cvtokine IL-4 in i'ivo, ex i'it'o or in itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-SO,-NR, or -NR-S07-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
53. A method of testing for a decrease in the level of cytokine IL-4 in vivo, ex or in i'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S01-OR, -O-S02-NR, or -NR-S07-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and / or optionally modified.
54. A method as claimed in any one of claims 48 to 53, wherein the compound or salt thereof contains one to twelve monosaccharide subunits.

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55. A method of modifying the level of a cytokine selected from IL-5 or IL-6 in ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
56. A method of testing for a modification in the level of a cytokine selected from IL-5 or IL-6 in vit'o, ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO-,-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and! or optionally modified.
57. A method as claimed in claim 55 or 56, wherein the modification is a decrease of the level of a cytokine selected from IL-5 or IL-6.
58. A method of decreasing the level of cytokine IL-lO in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

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59. A method of testing for a decrease in the level of cytokine IL-lO in vivo, ex i.'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S01-OR, -NR-S02-OR, -O-S02-NR7 or -NR-S07-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
60. A method as claimed in any one of claims 48 to 59, wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
61. A method of modifying the level of cytokine IL-12 in i'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S09-OR, -NR-S02-OR, -O-S02-NRI or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
62. A method of testing for a modification in the level of cytokine IL-12 in vii'o, ex viva or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO.-OR, -NR-S02-OR, -O-SO.,-NR, or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further -69 -monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
63. A method as claimed in claim 61 or 62, wherein the compound or salt thereof contains one to twelve monosaccharide subunits.
64. A method of modifying the level of a cytokine selected from IL-lB.

RANTES or IL-8 in vii'o, ex i.'ipo or in vi/ro said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-SO-,-NR2 or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
65. A method of testing for a modification in the level of a cytokine selected from IL-IB, RANTES or IL-8 in vipo, ex i'ii'o or in i'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-S02-NR7 or -NR-S07-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.

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66. A method as claimed in claim 64 or 65, wherein the modification is a decrease of the level of cytokine IL-lB.
67. A method as claimed in any one of claims 48 to 66, wherein the method comprises contacting the compound or salt thereof with a blood cell and/or a human cell.
68. A method of modifying the level of a cytokine selected from IL-4, IL-5, IL-lO, IL-12, MCP-1, RANTES, VEGF or TNFoc in vito, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-SO,-NR2 or -NR-S(),-NR. group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or ahydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
69. A method of testing for a modification in the level of a cytokine selected from IL-4, IL-5, IL-lU, IL-12, MCP-I, RANTES, VEGF or TNFoc in i'ivo, ex vii'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-S02-NR, or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
70. A method of modifying the level of cytokine IL-2 in z'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S07-NR2 or -NR-S02-NR-, group, -71 -wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
71. A method of testing for a modification in the level of cytokine IL-2 in i'iz'o, ex Pit'O or iii vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-S02-NR2 or w -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
72. A method of modifying the level of cytokine IL-6 in vivo, ex t'ivo or in vitro, /5 said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S01-OR, -NR-SO-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
73. A method of testing for a modification in the level of cytokine IL-6 in vivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-SO,-OR, -O-S02-NR7 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

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74. A method of modifying the level of cytokine IL-lB in i'ivo, ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least OflC sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
75. A method of testing for a modification in the level of cytokine IL-lB in i'ii'o, *ex riz.'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell and/or a human cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pvranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
76. A method of modifying the level of cytokine IFNy in vivo, ex viz'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further -monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with -73 -N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
77. A method of testing for a modification in the level of cvtokine IFNy in ii'o, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof comprises at least one monosaccharide subunit and at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-S02-OR, -O-S02-NR2 or -NR-SO,-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
78. A method of modifying the level of cytokine IL-6 in vivo, ex vii'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-S07-OR, -O-SO,-NR7 or -NR-S02-NR, group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.
79. A method of testing for a modification in the level of cytokine IL-6 in vii'o, ex z'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a blood cell, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S07-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, and wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified.

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80. A method as claimed in any one of claims 48 to 79, wherein the method is performed in vitro.
81. A method as claimed in any one of claims 48 to 79, wherein the method is performed in i'ii'o.
82. A method as claimed in claim 81, wherein the contacting occurs after gastrointestinal absorption of the compound or salt thereof.
83. A method as claimed in claim 81 or 82, wherein the modification, increase or decrease of the cytokine level is non-gastrointestinal.
84. A method of modifying the non-gastrointestinal level of a cytokine selected from IL-2, IL-4, IL-lO, IFN, TNFac or MCP-1 in vivo, said method comprising the gastrointestinal absorption of a compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-S02-OR, -NR-SO,-OR, -O-S02-NR2 or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
85. A method of testing for a modification in the non-gastrointestinal level of a cytokine selected from IL-2, IL-4, IL-b, IFN?, TNFoc or MCP-1 in vivo, said method comprising the gastrointestinal absorption of a compound or a pharmaceutically acceptable salt thereof, wherein the compound or salt thereof contains one to twelve monosaccharide subunits and comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR, -NR-S02-OR, -O-S07-NR, or -NR-S02-NR2 group, wherein each R is independently hydrogen, a metal, a further -75 -monosaccharide subunit or a hydrocarbyl group, wherein each monosaccharide subunit is independently optionally substituted and/or optionally modified, and wherein none of the monosaccharide subunits of the compound or salt thereof is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosl subunit.
86. A method as claimed in claim 84 or 85, wherein the modification is a decrease of the level of a cytokine selected from IL-2, IL-4, IL-b, IPNy or TNF.
87. A method as claimed in any one of claims 48 to 86, wherein the method is a method of treating or preventing a disease or condition.
88. A method as claimed in claim 87, wherein the disease or condition is inflammation.
89. A method as claimed in claim 88, wherein the inflammation is chronic inflammation.
90. A method as claimed in claim 88 or 89, wherein the inflammation occurs as a result of an inflammatory disorder, occurs as a symptom of a non-inflammatory disorder, or is secondary to trauma, injury or autoimmunity.
91. A method as claimed in any one of claims 88 to 90, wherein the inflammation occurs as a result of psoriasis, sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behcet's syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, cancer, restenosis, papilloma, polyposis, fibrosis, proliferative bronchiolitis, tumour growth, proliferative periostitis, proliferative verrucous leukoplakia, macular degeneration, an autoimmune disorder, an immunodeficiency disorder, a transplant rejection disorder, a disorder related to a transplant, a disorder related to a renal, hepatic, corneal, cartilage, stem cell, chondrocyte, pulmonary, cardiac, vascular or myeloid transplant, HIV infection, AIDS, multiple sclerosis, systemic lupus erythematosus, septic shock, an allergy, a hyposensitivity, a hypersensitivity, hypersensitivity following the reactivation of -76 -herpes, diabetes, a degenerative disease or disorder, a degenerative joint disease, a neurodegenerative disease, an inflammatory degenerative disease, osteochondral defects, keratitis (including herpetic keratitis), herpes simplex, shingles, a wound, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.
92. A method as claimed in claim 87, wherein the disease or condition is an autoimmune disease.
93. A method as claimed in claim 92, wherein the autoimmune disease is selected from acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis, Reiter's syndrome, Sjögren's syndrome, a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Behçet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, Lyme disease, neuromyotonia, psoriasis, sarcoidosis, schizophrenia, scleroderma, ulcerative colitis, vitiligo or vulvodynia.
94. A method as claimed in any one of claims 87 to 93, wherein the disease or condition is non-gastrointestinal.
95. A unit dosage form comprising at least 2.5 g of a compound of any one of claims I to 45.