GB2450088A

GB2450088A - Optionally modified monosaccharides with imine/iminium or glycosidic amine/ammonium group for use in modifying the level of cytokines & in therapy

Info

Publication number: GB2450088A
Application number: GB0711140A
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: WO2008152421A2; GB0711140D0; WO2008152421A3

Abstract

There is disclosed <SL> <LI>(i) a method of modifying the level of a cytokine and <LI>(ii) a method of testing for a modification in the level of a cytokine, </SL> which comprises contacting a compound, or a pharmaceutically acceptable salt thereof, with a cell (in vivo, ex vivo or in vitro), wherein the compound comprises: ```at least one monosaccharide subunit comprising a directly bonded =NR or =NR2+ ```group, or a glycosidic -NR2, -NR3+, ```wherein R is H, a monosaccharide subunit or hydrocarbyl group ```or 2 or 3 R groups, together with the nitrogen to which they are attached, form a ```monosaccharide subunit or cyclic hydrocarbyl group; ```each hydrocarbyl group, which includes acyl, is optionally substituted and optionally ```includes one or more hetero atoms in its hydrocarbon skeleton; ```each monosaccharide subunit is optionally modified (as defined in the application) ```and optionally substituted, and polysaccharide, oligosaccharide, peptide and protein derivatives comprising such compounds, and mixtures thereof, subject to various provisos defined in claims 1, 7, 13, 19, 44 and 89. Such compounds also find application in the treatment and/or prevention of inflammation and autoimmune disorders. There is disclosed a method of modifying the level of VEGF (in vivo, ex vivo or in vitro) contacting a cell with the compound PHA (phyrohaemagglutinin), or a structurally similar protein.

Description

New Methods

Technical Field

The present invention is directed to methods of modifying, or testing for a modification in, the level of a cytokine in vivo, ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell, said compound comprising at least one glycosidic amine group. The present invention is also directed to a method of modifying the level of VEGF in vivo, ex z'ii'o or in vitro, said method comprising contacting a compound with a cell, wherein the compound is PHA (phytohaemagglutinin), or a structurally similar protein.

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-ILlS, anti-1L5, anti-1L17). In spite of these advances, however, there is still a need for further drugs that are able to modify cytokine levels.

A number of glcosylamines are known to be biologically active, for example, di-f3-D-glucosylamine I has been shown to inhibit ILgiucosidases (Kolarova et al, carho/ydrate Research, 273, (1995), pp. 109-114), although this activity was greatly reduced when N-acetylated.

This compound has also been implicated as an anti-inflammatory agent (see US 5,631,245). \Vhen administered to mice by parenteral routes, it inhibits articular inflammation (Bolton et al, Inf/amm. Res., Suppl. 2, (2005), p. 5121), however it is inactive when given by the oral route, the glycosylamine group being readily hydrolysed under the acid conditions of the stomach. Although the mechanism by which it operates is not clear, it inhibits antigen induced immune cell proliferation and interleukin-2, interleukin-lO and IFN synthesis by antigen stimulated mice spleen cells in z'itro. These actions are consistent with an anti-inflammatory and anti-immune profile of activity. In addition, di-13-D-glucosylamine 1 prevents the development of ocular inflammation resulting from the reactivation of feline herpes infection (Roberts et al, XII Annual Meeting of the ACVO, October 11-14, 1990, Scottsdale, AZ). However, further research into such compounds and their effects is needed.

Summary of the Invention

The present invention relates to a method of modifying the level of a cytokine in vii'o, ex i'ivo or in i'i/ro, 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 comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded =NR2 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

The present invention also relates to a method of testing for a modification in the level of a cytokine in vivo, ex z'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 comprises at least one monosaccharide subunit comprising a glycosidic NR2 group, a glycosidic -NR31 group, a directly bonded NR group, or a directly bonded NR24 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

In a preferred embodiment of the present invention, the compound or salt thereof comprises at least one monosaccharide subunit comprising a glycosidic -NR2 group or a glycosidic -NRc group, or a tautomer thereof.

In a preferred embodiment of the present invention, the cytokine is selected from GM-CSF, IL-i; IL-1B, IL-2, IL-4, IL-5, IL-6, 1L-7, IL-8, IL-b, IL-12, IL-13, IL-17, GCSF, VEGF, TNFac, RANTES, MCP-1 or IFNy. 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 present invention, the modification is no change or an increase in the level of cytokine IL-b.

A first aspect of the present invention relates to a method of modifying the level of a cytokine in i.'ii'o, 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 comprising a glycosidic -NR, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR7 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

A second aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in t'ivo, ex vivo or in z'ilro, 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 comprising a glycosidic -NR, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR, group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

In one embodiment of either the first or the second 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, TNFo, RANTES, MCP-1 or IFNy.

The modification may be an increase or decrease in the level of the cytokine.

Preferably the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-Icc, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TNFoc or IFNy. Alternatively, the modification is an increase in the level of a cvtokine selected from IL-7 or VEGF.

In another embodiment of either the first or the second aspect of the present invention: (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (d) one R group is a monosaccharide subunit and OflC R group is hydrogen; and/or (e) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (f two R groups are independently monosaccharide subunits; and/or (g two R groups are independently hydrocarbyl groups; and/or (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (i) one or two R groups are independently hydrogen, or a C1-C6 alkyl, C2-C6 acyl, C2-C6 halo-acyl, or C1,() alkoxycarbonyl group; and/or (j) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

A third aspect of the present invention relates to a method of modifying the level of a cytokine in viva, cx 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 comprising a glycosidic -NR, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR2 group; wherein each R is independently a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

-

A fourth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in viva, cx 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 comprising a glycosidic -NR2 group, a glvcosidic -NR3 group, a directly bonded =NR group, or a directly bonded =NR-, group; wherein each R is independently a further monosaccharide subunit, or a hvdrocarbyl group, or two or three R groups and the nitrogcn atom to which they arc attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstjtuted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arvialkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylarvl group which optionally includes one or more heteroatoms in its carbon skeleton.

In one embodiment of either the third or the fourth aspect of the present invention, the cytokine is selected from GM-CSF, IL-lcz, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-b, IL-12, IL-13, IL-17, GCSF, VEGF, TNFcc, RANTES, MCP-1 or IFNy.

The modification may be an increase or decrease in the level of the cytokine.

Preferably the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-lcz, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TNFo or IFN'y. Alternatively the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.

In another embodiment of either the third or the fourth aspect of the present invention: (a) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (b) two R groups are independently monosaccharide subunits; and/or (c) two R groups are independently hydrocarbyl groups; and/or (d) one or two R groups are independently an alkyl, acyl or alkoxycarbonyl group; and/or (e) one or two R groups are independently a C1-C6 alkyl, C,-C6 acyl, C,-C halo-acyl, or C120 alkoxycarbonyl group; and/or (f one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

A fifth aspect of the present invention relates to a method of modifying the level of a cytokinc selected from GM-CSF, IL-1, IL-113, 1L-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNFoc, RANTES or MCP-1 ii, vii'o, 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 comprises at least one monosaccharide subunit comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR, group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

A sixth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from GM-CSF, IL-1x, IL-113, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES or MCP-1 in z'iz'o, ex rivo or in ri/re, 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 comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR7 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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. The modification may be an increase or decrease in the level of the cytokine.

In one embodiment of either the fifth or the sixth aspect of the present invention, the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-1a, IL-113, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, GCSF or TNFoc.

In another embodiment of either the fifth or the sixth aspect of the present invention, the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.

In yet another embodiment of either the fifth or the sixth aspect of the present invention: (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (d) one R group is a monosaccharide subunit and one R group is hydrogen; and/or (e) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (f) two R groups are independently monosaccharide subunits; and/or (g) two R groups are independently hydrocarbyl groups; and/or -10 - (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (i) one or two R groups are independently hydrogen, or a C1-alkyl, C,-C6 acyl, C2-C6 halo-acyl, or C12(, alkoxycarbonyl group; and/or (j) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

In one embodiment of any of the preceding aspects of the present invention, the compound or salt thereof further comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-SO,-OR', -O-S02-N(R')., or -NR'-SO2-N(R'), group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group.

A seventh aspect of the present invention relates to a method of modifying the level of a cvtokine in i'iz'o, ex i'iz'o or in z'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound or salt thereof comprises (i) at least one monosaccharide subunit comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR, group, wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; and (ii) at least one sulphate group, wherein a sulphate group is a -O-SO.,-OR, -NR'-SO,-OR', -0-SO,-N(R')2 or -NR'-S02-N(R')., group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

-11 -An eighth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in vivo, ex vipo 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 (i) at least one monosaccharide subunit comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded NR group, or a directly bonded group, wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; and (ii) at least one sulphate group, wherein a sulphate group is a -O--S02-OR', -NR'-SO,-OR', -O-S02-N(R'), or -NR'-S02-N(R)., group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

In one embodiment of either the seventh or the eighth aspect of the present invention, the cytokine is selected from GM-CSF, IL-Icc, IL-113, IL-2, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-b, IL-12, IL-13, IL-17, GCSF, VEGF, TNFcc, RANTES, MCP-1 or IFN'y. The modification may be an increase or decrease in the level of the cytokine. Preferably the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-icc, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TN Fcc or IFN'y. Alternatively, the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.

-12 -In another embodiment of either the seventh or the eighth aspect of the present invention: (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hvdrocarbyl group; and/or (d) one R group is a monosaccharide subunit and one R group is hydrogen; and/or (e) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (f) two R groups are independently monosaccharide subunits; and/or (g) two R groups are independently hydrocarbyl groups; and/or (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (i) one or two R groups are independently hydrogen, or a Cl-c alkyl, C2-C6 acyl, C-C6 halo-acyl, or C120 alkoxycarbonyl group; and/or (j) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

The following paragraphs apply equally to all of the preceding aspects of the present invention.

In one embodiment of the present invention, the compound or salt thereof comprises a sequence of at least two monosaccharide subunits directly linked by a glycosidic -NR-group, a glycosidic -NR,t group, a directly bonded =N-group, or a directly bonded NR-group; preferably directly linked by a glycosidic -NR-group or a glycosidic -NR2t group; alternatively preferably directly linked by a glvcosidic -NR-group or a directly bonded =N-group.

For the purposes of the present invention, when two monosaccharide subunits are directly linked' by a glycosidic -NR-group, a glycosidic -NR7-group, a directly bonded =N-group, or a directly bonded NRt group, the group 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 poly-or oligosaccharide. The glycosidic -NR-group or the glvcosidic -NR,-group may be linked to one or both of the monosaccharide subunits by a glycosidic bond.

The directly bonded =N-group or the directly bonded NR-group may be linked to one or neither of the monosaccharide subunits by a glycosidic bond.

The compound or salt thereof may comprise at least two monosaccharide subunits, each of which is substituted with at least one sulphate group.

In one embodiment of the present invention, the at least one monosaccharide subunit is not substituted with an -OR"' group, wherein R" is any group comprising a further monosaccharide subunit.

In one embodiment, the compound or salt thereof 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. Preferably, the first and second pyranosyl subunits form a disaccharide.

In a preferred embodiment, 1-50, or 2-30, or 3-15, or 6-12, 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 su!phate 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all 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, aid 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 (i.e. two monosaccharide subunits directly linked to each other), in one embodiment, one, two or three hvdroxyl 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 one embodiment, the compound or salt thereof contains 1-100, 1-20, 1-12, 2-10, 2-8, 2-6 or 2-4 monosaccharide subunits.

Alternatively, the compound or salt thereof may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits. The compound or salt thereof may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 monosaccharide subunits. The compound or salt thereof may comprise a sequence of 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits.

It is preferred that, in total, including any further monosaccharide subunits, the compounds used in the present invention contain 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 compounds 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.

-15 -All monosaccharide subunits are independently aldosyl or ketosyl monosaccharides.

Preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently triosyl, tetrosyl, pentosyl, hexosl, heptosyl, octosyl or nonosyl monosaccharides. More preferably, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently glycerosyl, ervthrosyl, threosyl, ribosyl, arabinosyl, xvlosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl or fucosyl monosaccharides.

In a preferred embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently tetrosyl monosaccharides or higher, and the ring of those monosaccharides is furanosyl. In an alternative preferred embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently pentosyl monosaccharides or higher, and the ring of those monosaccharides is pvranosyl.

Preferred compounds for use in the present invention include: (a) ,$-di-glucosylamjne; (b) a mono-, di-, tn-, tetra-, penta-, hexa-,hepta-or octasulphated j3-di-glucosylamine, or a mixture thereof (c) a mono-, di-, tn-, tetra-, penta-, hexa-, hepta-or octasulphated N-acetyl-f3,f3digIucosylamjn or a mixture thereof (d) a mono-, di-, tn-, tetra-, penta-, hexa-, hepta-or octasuiphated N-ethyl-j3digJucosylamjne or a mixture thereof or (e) a suiphated di-(4,4'glucosylgJucosy1)amjne A ninth aspect of the present invention relates to a method of modifying the level of a cytokinc in i'ivo, ex i.'ii'o or in ri/re, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound or salt thereof contains one monosaccharide subunit comprising a glycosidic -NR, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR2 group; -16 -wherein each R is independently hydrogen, or a hvdrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein the monosaccharide subunit and/or the further monosaccharide subunit independently are optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

A tenth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in i.'iz'o, ex,. ii'o or iii vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound or salt thereof contains one monosaccharide subunit comprising a glycosidic -NW, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR, group; wherein each R is independently hydrogen, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein the monosaccharide subunit and/or the further monosaccharide subunit independently are optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

In one embodiment of either the ninth or the tenth aspect of the present invention, the cytokine is selected from GM-CSF, IL-1x, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-b, IL-12, IL-13, IL-17, GCSF, VEGF, TNFoc, RANTES, MCP-1 or IFNy.

The modification may be an increase or decrease in the level of the cytokine.

Preferably, the modification is a decrease in the level of a cytokine selected from -17 -GM-CSF, IL-2, IL-4, IL-5, IL-6, IL-b, IL-13, IL-17, TNFoc or 1FN'y. Alternatively, the modification is an increase in the level of cytokine VEGF.

in another embodiment of either the ninth or the tenth aspect of the present invention: (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (d) two R groups are independently hydrocarbyl groups; and/or (e) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (f one or two R groups are independently hydrogen, or a C1-C6 alkyl, C,-C acyl, C,-C6 halo-acyl, or C120 alkoxycarbonyl group; and/or (g) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

In a preferred embodiment of either the ninth or the tenth aspect of the present invention, 1-9, or 2-8, or 3-4 hydroxyl groups on the monosaccharide subunit and/or the further monosaccharide subunit independently have been replaced with a sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-S02-OR', -O-S02-N(R)7 or -NR'-S02-N(R')., group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group.

in the ninth and the tenth aspect of the present invention, the monosaccharide subunit and/or the further monosaccharide subunit are independently aldosyl or ketosyl monosaccharides. Preferably the monosaccharide subunit and/or the further monosaccharide subunit are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosyl or nonosyl monosaccharides. More preferably the monosaccharide subunit and/or the further monosaccharide subunit are independently glycerosyl, ervthrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl or fucosvl monosaccharides.

-18 -In a preferred embodiment of the ninth or the tenth aspect of the present invention, the monosaccharide subunit and/or the further monosaccharide subunit are independently tetrosyl monosaccharides or higher, and the ring of those monosaccharides is furanosyl. In an alternative preferred embodiment of the ninth or the tenth aspect of the present invention, the monosaccharide subunit and/or the further monosaccharide subunit are independently pcntosyl monosaccharides or higher, and the ring of those monosaccharides is pyranosyl.

In a preferred embodiment of the ninth or the tenth aspect of the present invention, the compound used contains, in total, including any further monosaccharide subunits, one or two monosaccharide subunits, preferably only one monosaccharide subunit.

For the purposes of the present invention, a saccharide' is any compound comprising at least one monosaccharide subunit, optionally substituted and/or optionally modified. Thus, by this definition, a compound of the present invention is a saccharide. A saccharide may be a mono-, oligo-or polysaccharide. An oligosaccharide' may comprise between 2 and 10 monosaccharide subunits and may therefore be a disaccharide, trisaccharide, tetrasaccharjde, pentasaccharide, hexasaccharjde heptasaccharide, octasaccharide, nonasaccharjde, or decasaccharjde.

A polysaccharide' may comprise 11 or more monosaccharide subunits.

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.

-19 -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 glycosidic bond. One distinguishes between a-and f3-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 a-glvcosidic 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.

For the purposes of the present invention, a glycosylamine' is any compound comprising at least one monosaccharide subunit with a glycosidic amine group.

Thus, by this definition, a compound of the present invention is a glycosylamine. A glucosylamine' is any compound comprising at least one glucose subunit with a glycosidic amine group. A j-di-glucosylamine' is any compound comprising at least two glucose subunits linked by a fj-glycosidic amine group. A f,-glycosidic amine group is linked to the anomeric carbons of two monosaccharide subunits, with both glycosidic bonds being f-glycosidic bonds.

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: - 20 -

ONR NHR

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 pK2 (relative to water) of less than 40, preferably less than 30, preferably less than 25, preferably less than 20. It is also undersjood 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 predominaniiy 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

NHR

C D E

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: -21 -As used herein, where it is specified that a first group is located 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 f3 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, 8 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 c&-positions relative to the group Y:

G

For the purposes of the present invention, the term directly bonded' used in relation to a monosaccharide subunit Comprising a group, means that the group is bonded to the carbon backbone of the monosaccharide subunit without any intervening atoms being present.

Each monosaccharide subunit independently may be substituted and/or modified.

-22 -In a substituted monosaccharide subunit: (a) independently one or more of the hydroxyl groups of the monosaccharide subunit is replaced with -I-I, -F, -Cl, -Br, -I, -CF3, -CCI3, -CBr3, -CT3, -SH, -NH7, -N4, -NH=NH,, -CN, -NO,, -COOH, R2ORb, R2SRb, -R-SO-R', RaSO,Rb, RaSO ORb, -WO-SO,R", WSO,N(Rb) RaNRbSO Rb RaOS0,0Rb, RaOSO,N(R),, R2NRbSO,ORb, _Ra_NR_SO,_N(Rb),, _R2N(Rh),, _Ra_N(Rb) +, -R'-B(R"),, _R2_P(Rb),, _Ra_pO(Rb),, R2Si(Rb), RCORh, RaCOORb, -R20-CO R', RCo N(Rb),, RaOCO.ORb, N(R'),, .Ra.NRb COORb, R9CSRb, RaCSORb, Ra0CS Rb, Ra.CS N(R"),, Ra NR" CS-R', RaOCSORb, RaOCSN(Rb),, RaNRCSORb, R2NRF)CSN(Rb),, or -R'; preferably 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, R2ORl), -W-S-R", SORb, SO Rb, SO,_ORb, O_S0,_Rb, 0SO _ORh, R2N(Rb),, _R2N(R), _R2Si(Rb)3, RaCORb, WCOORb, Ra0C0RI, RaCON(Rh),,, (b) independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -I, -CF3, -CCJ3, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH,, -CN, -NO,, -COOH, RaO:Rb, RaS.Rb RaSORb, WS0,Rb, RaS0 0Rb, RaOSO,-Rb, RSo -N(R"),, -W0-SO 0Rh, WOSO,-N(Rb),, _Ra_NR)_So,_N (R'),, _Ra_N (Rb),, _Ra_N (Rb) + _Ra_B (R"), _Ra_P(Rb),, -R2-P0(R'),, Ra5j(R, WCORb, RaCOORb -R20-CO-R", WCON(Rb),,, WNRbC0Rb, -R2O-CO-OR", WOcO...N(Rb), .Ra.NRbCO ORb RaNRbC0N(Rb),,, -W-CS-R', WCSORb, Ra0CSRb RaCSN(Rb),, RaOCSORb, preferably independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -I, -CF3, -CC!3, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH,, -CN, -NO,, -COOH, Ra0Rb, WSRb, SORb, SO,Rb, S(),0Rb, OS0Rb RaO...SOORb RaN(Rb),, RN(Rb) + WC0Rb, WCOORb, WOC0Rb, RaCON(Rb),, WNRbCORb, RaOCO0Rb, RaCS.Rb or Rb; and/or -23 - (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(R'D,; and/or (d) independently two hydroxyl groups of the monosaccharide subunit are together replaced with S0Rc, S02_Rc, or NRb_R; 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; Rb is independently hydrogen, an 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; 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 1-10 carbon atoms; and M is a metal; provided that the monosaccharide subunit comprises at least one 0S0Rb, 0S07Rb, 0S03Rb, 0Si(Rb)3, 0C0Rb, 0C0,Rb, or -OM.

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 wherein Rb is independently hydrogen, an 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. -24-

Each hydrocarbyl group independently may be a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylarvl or alkynviaryl 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.

A substituted hydrocarbyl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CCl., -CBr3, -Cl3, -OH, -SH, -NH2, -N3, -NH=NH,, -CN, -NO,, -cooi, RaORb, RaSRb, RaSORb, RaSO,Rb, RaSO,ORb, RaOSO,Rb, RaSO,N (Rb,, RaNRIJSO,Rb, WOsO,ORb, -WO-SO,-N (Rb),, RaNRI)SOORb, RaNRI)SoN (R, RaN (Ri') ,, RaN (R'), -R2-B (Rb), -R2-P(R"),, RaP()(Rb) , RaSj(Rb)3, RaCORb, RCO_ORb, _WOCO_Rb, RaCON(Rb),, RaNRLCORb, WOCOORb, RaOCON(Rb).,, RaNRICON(Rb) RCSRb, RaCSORb, RaOCSRb, RaCSN(RI,, RaNRI)CSRb, RaOCsORb, WOCSN(Rb),, WNRI)CS...ORb, WNRCSN(Rb),, Rb, or a monosaccharide subunit; preferably a substituted hydrocarbyl group may be substituted with one or more of -F, -Cl, -Br, -I, -CF3, -CCI3, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH,, -CN, -NO,, -COOH, -W-O-R", R2SRL), SORb, SO,Rb, SO,ORb, OSO,Rb, OSO,ORb, -W-N(R"),, R2N(Rb)3+, RaSj(Rb)3, WCORb, RaCOORb WOCORb, -W-Co-N(R"),, R2NRbCORb, RaO.COORb Ra.CsRb Rb, or a monosaccharide subunit; wherein: -R2-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 Rb is independently hydrogen, an 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.

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 \V. Greene and Peter G. M. Wuts (Wiley-Interscience, 3k" edition, 1999).

In one embodiment, the compound or salt thereof comprises at least one monosaccharide subunit comprising a glycosidic -NL group or a directly bonded =NR group. In an alternative embodiment, the compound or salt thereof comprises at least one monosaccharide subunit comprising a glycosidic -NR2 group or a glycosidic -NR3 group, or a tautomer or thereof.

In another embodiment, the glycosidic -NW, group is not -NHacyl, and/or the glycosidic -NR3 group is not -NH2acyl, and/or the directly bonded =NR group is not =Nacyl, and/or the directly bonded NR, group is not NHacyl.

In one embodiment of the present invention, none of the R groups are acyl. In another embodiment, none of the R groups contain an aromatic group.

In one embodiment of the present invention, each R group that is not hydrogen contains 1-12 carbon atoms. Each R group that is not hydrogen may contain 1-7, 1-6 or 1-4 carbon atoms.

In one embodiment, the compounds used in the present invention comprise: (a) at least two or at least three sulphate groups; and/or (b) at least one -0-50,-OR', -NR'-SO,-QR' or -O-SO,-N(R)., group; and/or (c) at least one -OSO1R' group; and/or (d) 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 (e) 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 -26 -the pyranosyl subunit; preferably the pyranosyl subunit is part of a disaccharide; and/or (f) 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; preferably the pyranosyl subunit is part of an oligosaccharide or a polysaccharide; and/or (g) at least one, two or three sulphate groups, located on primary hydroxyl positions; and/or (h) a sulphate group which is provided on a monosaccharide subunit comprising a glycosidic amine group.

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: In another embodiment of the present invention, the compound or salt thereof is a partially or fully suiphated saccharide.

In another embodiment, the compound or salt thereof comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-S01-OR', -O-S02-N(R)2 or -NR'-S02-N(R')2 group, and wherein 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 optionally includes one or more heteroatoms in its carbon skeleton. Preferably 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 -0S03 Lit, -0S03 Nat, -0S03 K, -0S03 Cu, or -0S03 Ag, or two -OSO3R' together are (-OSO3)2 Mg2, (-OSO3D. Ca2, (-0S03D2 Cu2, or (-0S03)2 Zn2, or three -OSO3R' together are (-0S03D3 A13; typical -NR'-S07-OR' groups comprise the same metal cations.

All monosaccharide subunits are independently in the D-or L-configuration.

The stereochemistry of each glcosidic bond is independently a or Preferred compounds for use in the present invention include: (a) a glucoslamine; (b) 1 -benzamido-I -deoxy-2,3,4,6-tetra potassium sulphonatoglucose; or (c) I -N -octyl-1-N -decanoyl-i-amino-i -deoxy-6-potassium suiphonate-muraml-D-isoglutamyl-alanine.

In one embodiment of the present invention, two R groups and the nitrogen atom to which they are attached, together do not form a heterocyclic aromatic group. In another embodiment, the atom connectivity S-O-P is not present in any monosaccharide subunit and/or in the entire compound. In yet another embodiment, the compound does not contain the group -O-P(0)(OH)-O-SO2OH.

In another embodiment, the compound is not a nucleoside and/or not a nucleotide.

In yet another embodiment, the compound does not comprise a ribose subunit comprising a glycosidic tertiary amine.

In one embodiment of the present invention, none of the monosaccharide subunits is pyranosyl with N-substitution at the 2- position relative to the anomeric carbon of the pyranosyl subunit. Preferably none of the monosaccharide subunits is N-In one embodiment of the present invention, none of the monosaCcharide subunits is pyranosyl with a -CO2Q group attached to the 5-position relative to the anomeric carbon of the pyranosyl subunit, wherein Q is hydrogen or a hydrocarbyl group.

Preferably, none of the monosaccharide subunits has a -CO2Q group attached to the -28 - 5-position and/or the u-position relative to the anomeric carbon of the monosaccharide subunit. Preferably, none of the monosaccharide subunits is In one embodiment of the present invention, the compounds contain no sulphate groups.

In another embodiment of the present invention, where the compound contains, in total, only one monosaccharide subunit, the compound contains no sulphate groups. Jo

Preferred compounds for use in the present invention include: (a) a non-sulphated fj-di-glucosy1amine; (b) a non-sulphated (c) a non-sulphated N-ethyl-j-di-glucosylamifle; or (d) a non-suiphated di-(4,4'g1ucosylgIucosyl)amine.

An eleventh aspect of the present invention relates to a method of modifying the level of a cytokine in vii'o, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (I): wherein: R is Ac, Me, Et, COCP, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stercoisomer or a salt thereof.

In one embodiment of the eleventh aspect of the present invention, R is Ac and all R" are H, or a tautomer or a stereoisomer thereof.

A twelfth aspect oi the present invention relates to a method of modifying the level of a cytokine selected from GM-CSF, IL-lcx, IL-IB, IL-4, IL-5, IL-6, IL-7, IL-8, IL- 12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES or MCP-1 in vii'o, ex vii.'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (I): (I) wherein: RisH; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.

In one embodiment of the twelfth aspect of the present invention, R is H and all R" are H, or a tautomer or a stereoisomer thereof.

In either the eleventh or the twelfth aspect of the present invention, the 8 R" groups may be 8 x SOIR', or 7 x SO3R' and I x H, or 6 x SO3R' and 2 x H, or 5 x SO3R' and 3 x H, or 4 x SO3R' and 4 x H, or 3 x SO3R' and 5 x H, or 2 x SO3R' and 6 x H, or I x SO3R' and 7 x H, or 8 x H. A thirteenth aspect of the present invention relates to a method of modifying the level of a cytokine in z;ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (II): -30 -(II) wherein: R is H, Ac, Me, Et, COCF1, or COPh; each R" is SO1R' or H; and eachR'isH,Li,NaorK; or a tautomer, a stereoisomer or a salt thereof.

The 14 R" groups may be 14 x SO1R', or 13 x SOJR' and I x H, or 12 x SO3R' and 2 x H, or Ii x SO3R' and 3 x H, or 10 x SO3R' and 4 x H, or 9 x SO3R' and 5 x H, or 8 x SO3R' and 6 x H, or 7 x SO3R' and 7 x H, or 6 x SO3R' and 8 x H, or 5 x SO3R' and 9 x H, or 4 x SO1R' and 10 x H, or 3 x SO1R' and 11 x H, or 2 x SO3R' and 12 x H, or I x SO3R' and 13 x H, or 14 x H. A fourteenth aspect of the present invention relates to a method of modifying the level of a cytokine in t'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (III): OSO3K () HO2C..%.jj95,>_91419 CO2H $ / HN-'ç (HI) )___NHR Me -31 -wherein R is H, CHO or COMe; or a tautomer, a stereoisomer or a salt thereof.

A fifteenth aspect of the present invention relates to a method of modifying the level of a cytokine in vii'o, ex z.'ivo or in pitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (IV): R"O R"O 0 R"O NHR

OR (IV)

wherein: R is H, Ac, Me, Et, COCE, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.

In one embodiment of the fifteenth aspect of the present invention, R is H or Ac and all R" are H, or a tautomer or a stereoisomer thereof.

The 4 R" groups may be 4 x SO3R', or 3 x SOR' and I x H, or 2 x SO3R' and 2 x H, or 1 x SO3R' and 3 x H, or 4 x H. A sixteenth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in z'ii'o, ex i'ivo or in i'itro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (I): -32 -wherein: R is Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or 1-1; and each R'is H,Li, Na or K; or a tautomer, a stereoisomer or a salt thereof In one embodiment of the sixteenth aspect of the present invention, R is Ac and all are H, or a tautomer or a stereoisomer thereof.

A seventeenth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine selected from GM-CSF, IL-lot, IL-lB, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNFot, RANTES or MCP-1 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 has the formula (I): wherein: RisH; each R" is SO3R or H; and eachR'isH,Li,NaorK; or a tautomer, a stereoisomer or a salt thereof.

In one embodiment of the seventeenth aspect of the present invention, R is H and all R" are H, or a tautomer or a stereoisomer thereof.

-33 -In either the sixteenth or the seventeenth aspect of the present invention, the 8 R" groups may be 8 x SO3R', or 7 x SO3R' and I x H, or 6 x SO3R' and 2 x H, or 5 x SOR' and 3 x H, or 4 x SO.R' and 4 x H, or 3 x SOR' and 5 x H, or 2 x SO3R' and 6xH,orlxSO3R'and7xH,or8xH.

An eighteenth aspect of the present invention relates to a method oftesting for a modification in the level of a cytokine in i.'ivo, ex i'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (II): (II) wherein: R is H, Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.

The 14 R" groups may be 14 x SO3R', or 13 x SO3R' and I x H, or 12 x SO3R' and 2 x H, or II x SO3R' and 3 x H, or 10 x SO3R' and 4 x H, or 9 x SO3R' and 5 x H, or 8 X SOR' and 6 x H, or 7 x SO3R' and 7 x H, or 6 x SO3R' and 8 x H, or 5 x SO3R' and 9 x H, or 4 x SO3R' and 10 x H, or 3 x SO3R' and 11 x H, or 2 x SO1R' and 12 x H, or I x SO3R' and 13 x H, or 14 x H. A nineteenth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in i'ivo, ex z'ii'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; -34-wherein the compound has the formula (III): o o K HO2C OCO2H (III) )__NITIR Me wherein R is H, CHO or COMe; or a tautomer, a stereoisomer or a salt thereof.

A twentieth aspect of the present invention relates to a method of testing for a modification in the level of a cytokine in i'iz'o, ex t'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (IV): R"O Rb 0 R"o NHR

OR (IV)

wherein: R is H, Ac, Me, Et, COCF, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.

In one embodiment of the twentieth aspect of the present invention, R is H or Ac and all R" are H, or a tautomer or a stereoisomer thereof.

-35 -The 4 R" groups may be 4 x SO3R', or 3 x SO3R' and I x H, or 2 x SO1R' and 2 x H, or Ix SO3R' and 3x I-I, or 4x H. In a preferred embodiment of any of the eleventh to twentieth aspects of the present invention, at least one R" is SO3R'.

A preferred embodiment of any of the eleventh to twentieth aspects of the present invention provides for the use of stereoisomers of the compounds having formula (I), (II), (III) or (IV) as defined above.

In one embodiment of any of the eleventh, thirteenth, fourteenth, fifteenth, sixteenth, eighteenth, nineteenth or twentieth aspects of the present invention, the cvtokine is selected from GM-CSF, IL-bc, IL-113, IL-2, 1L-4, IL-5, IL-6, IL-7, IL-8, IL-lU, IL-12, IL-13, IL-I7, GCSF, VEGF, TNFcc, RANTES, MCP-I or IFNy. The modification may be an increase or decrease in the level of the cytokine. Preferably the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-lcx, IL-I13, IL-2, IL-4, IL-5, IL-6, IL-lU, IL-12, IL-I3, IL-17, GCSF, TNFx or IFNy. Alternatively, the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.

In one embodiment of the twelfth or seventeenth aspects of the present invention, the modification is an increase or decrease in the level of the cytokine. Preferably the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-bc, IL-IB, IL-4, IL-5, IL-6, IL-12, IL-13, IL-17, GCSF or TNF. Alternatively, the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.

The following paragraphs apply equally to all aspects of the present invention.

In one embodiment, the compound used in the present invention is a salt, preferably a pharmaceutically acceptable salt.

-36 -The compounds 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, perchioric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, 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, trifluoromethanesuiphonic, ethanesuiphoni c, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic, naphthalene-2-suiphonic or camphorsuiphonic 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 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.

In addition to pharmaceutically acceptable salts, the use of other salts is included in the present invention.

-37 -The present invention encompasses the use of salts, derivatives, solvates, clathrates and/or hydrates (including anhydrous forms) of the compounds in the methods of the present invention. Preferably these are pharmaceutically acceptable salts, derivatives, solvates, clathrates and/or hydrates (including anhydrous forms) of the compounds.

The present invention encompasses the use of quaternary ammonium salts of the compounds, wherein the nitrogen of the glycosidic amine group is further substituted by a substituent other than hydrogen, resulting in a positive charge on the nitrogen, balanced by a suitable counter-anion. Preferably the substituent is alkyl, preferably methyl or ethyl. Suitable counter-anions include any of those formed in the process of generating acid addition salts as discussed above.

Preferably, the methods of the present invention do not use quaternarv ammonium salts.

The compounds used in 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 the use of racemic mixtures of the compounds as well as enantiomerically enriched and substantially enantiomerically pure isomers of the compounds. For the purposes of this invention, a substantially enantiomerically pure' isomer of a 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. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups. Preferably an alkyl group is straightchained or branched and 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-C6 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 -38 -an alkyl group containing from 1 to 4 carbon atoms. An alkvlene' 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. Examples of alkenyl groups are vinyl, allyl, but-1-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C2-C1., 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. Examples of alkynyl groups are ethynyl, propargyl, but-l-ynyl and but-2-ynvl groups. Preferably an alkynyl group is straight-chained or branched and 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 C2-C() 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 -COR' group, wherein R' is hydrogen, or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arvlalkynyl, alkylaryl, alkenylaryl or alkynylaryl group. Examples of acyl groups are formyl, acetyl, trifluoroacetyl, propanoyl and benzoyl groups. Preferably an acyl group is straight- chained or branched and 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 -39 group containing from I to 12 carbon atoms. More preferably an acyl group is a C1-C acyl group, which is defined as an acyl group containing from 1 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 ary!' group is defined as a monovalent aromatic hydrocarbon. Examples of aryl groups are phcnyl, 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 C-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.

For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, 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, -CCI3, -CBr3, -Cl3, -OH, -SH, -NH2, -N3, -NH=NH,, -CN, -NO,, -COOH, -R-O-R', RPSOR?, -R-SO,-R, -R-SO,-OR", -RO-SO,-R, -R-SO2-N(R'),, -RO-SO,-OR, -RO-SO,-N(R),, -R-NR'-SO,-N(R),, -Rn-N (R),, _R_N(RV)3+, -R-B(R),, -R-P(R')2, _R_PO(R?),, -R-Si(R)3, -R-CO-R, -R-CO-OR, -RO-CO-R, -R-CO-N(R)7, -R-NR-CO-R, -RO-CO-OR, -RO-CO-N(R),, -R-NR-CO-N(R),, -R-CS-R, -R-CS-OR, -RO-CS-R, -R-CS-N(W')2, -R-NR-CS-R, -RO:CS-OR, ROCS-N(R),, -R-NR-CS-OR", -RNRLCSN(RY),, or -R; preferably monovalently with one or more of -F, -Cl, -Br, -I, -CF3, -CC13, -CBr3, -CT3, -OH, -SH, -NH,, -N3, -NHNH,, -CN, -NO,, -COON, RPORV, -R-S-R, -SO-Ri', SO,R'e, -SO,-OR, -O-SO,-R", -O-SO,-OR, -R-N(R),, -R-N(R)3, RSi(R1)3, -R-CO-R, RCOOR?, -40--RO-C0-R, -R-CO-N(R),, RPOCOOR?, -R-CS-R', or or divalently with one or more of -R-, 0, S, or =NR; or trivalently with one or more of =N-R-. 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. -Ri' is independently hydrogen, or a substituted or unsubstituted alkyl or aryl group, optionally including one or more hcteroatoms 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 -Rn-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, 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, 3'" 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. in one embodiment of the present invention, the compound or salt thereof further comprises a polysaccharide, oligosaccharide, peptide or protein covalently linked to the remainder of the compound.

As used herein, the term peptide' refers to a group comprising I to 50 amide bonds. As used herein, the term protein' refers to a group comprising 51 or more amide bonds. A peptidyl or proteinyl group may comprise any type of amino acid subunit. The amino acid subunits may be naturally occurring or synthetic.

Preferably, all amino acid subunits are naturally occurring. The amino acid subunits may be -, -, y-or 8-amino acid subunits, or a mixture thereof. Preferably, all amino acid subunits are a-amino acid subunits.

-41 -Any polysaccharide, oligosaccharide, peptide or protein derivative of the present invention may be further protected and/or suiphated. Suitable protecting groups for protecting polysaccharide, oligosaccharide, peptide and protein derivatives 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).

Preferably, in any of the above aspects of the present invention, the total number of amino acid residues within the compound is in the range of from I to 1,000, preferably 1 to 100, preferably 1 to 10, preferably 2 to 8.

Preferably, in any of the above aspects of the present invention, the molecular weight of the compound is in the range of from 100 to 100,000 Da, preferably 11)0 to 50,000 Da, preferably 200 to 10,000 Da, preferably 300 to 5,000 Da, preferably /5 300 to 3,500 Da.

Preferably, in any of the above aspects of the present invention, the total number of carbon atoms in the compound is in the range of from 4 to 10,000, preferably 4 to 1,000, preferably 6 to 500, preferably 6 to 100, preferably 6 to 50.

Preferably, in any of the above aspects of the present invention, the total number of monosaccharide subunits in the compound is in the range of from I to 1000, preferably I to 100, preferably I to 10, preferably I to 8.

Preferably, in any of the above aspects of the present invention, the total number of glycosidic bonds in the compound is in the range of from I to 1,000, preferably I to 100, preferably I to 10, preferably I to 8.

In another embodiment, a mixture of compounds differing only in their stereochemistry at the anomeric centre and/or in their degree of sulphation and/or their position of sulphation is used. Preferably 50%, 75%, 80%, 85%, 90%, 95% or 99% of the compounds or derivatives lie within three consecutive degrees of -42 - suiphation. Preferably the three consecutive degrees of sulphation are three-to five-fold suiphation, four-to six-fold sulphation, or five-to seven-fold sulphation.

For the purposes of the present invention, a sulphate group' is a -O-SO-OR', -NR'-SO,-OR', -()-S07-N(R')2 or -NR'-S02-N(R'), group, wherein each R' is independently hydrogen, a metal, a monosaccharide subunit, or a hydrocarbyl group.

Preferably a sulphate group is a -OSOR' group. Preferably R' is hydrogen or a metal. 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 suiphated compound' is a mixture of compounds, 80%, 85%, 90% or more of which have from three to five sulphate groups. A compound used in the present invention, which is of a specific degree of sulphation, 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.

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 sulphation. 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 (Wilev-lnterscience, 3 edition, 1999). Methods of protecting and sulphating 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).

A twenty-first aspect of the present invention relates to a method of modifying the level of VEGF in i'ivo, ex vit'o or in i'itro, said method comprising contacting a compound with a cell, wherein the compound is PHA (phytohaemagglutinin) or a -43 -protein that shares at least 75% of its amino acid sequence with PHA. Preferably, the protein shares at least 80%, 85%, 90%, 95% or 99% of its amino acid sequence with PHA. Preferably the method is a method of decreasing the level of VEGF.

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 a preferred embodiment of any of the second, fourth, sixth, eighth, tenth, or sixteenth to twentieth aspects of the present invention, the method of testing relates to a method of observing an increase or a decrease in the level of the cytokine to be tested.

In one embodiment of any of the second, fourth, sixth, eighth, tenth, or sixteenth to twentieth aspects of the present invention, the cvtokine level is tested using a radioimmunoassay, fluorescence activated cell sorting (FACS), 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.

In any embodiment 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.

In any embodiment of the present invention, it is preferred that the compound 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 is in fluid communication with the cell at a concentration of between 0.001 and 1000 M, preferably between 0.005 and 200 1iM, preferably between 0.0075 and 50 riM, preferably about 0.01 M. In any embodiment of the present invention, it is preferred that the method is pcrformed in i'iro, preferably in such a manner that the contacting occurs after gastrointestinal absorption of the compound, and/or preferably such that the modification, increase or decrease of the cytokine level is non-gastrointestinal.

Alternatively, in any embodiment of the present invention, the method may be performed in i'ilro, preferably for a non-therapeutic purpose.

In one embodiment of any of the second, fourth, sixth, eighth, tenth, or sixteenth to twentieth aspects of the present invention, it is preferred 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 one embodiment of any 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.

-45 -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 or 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 10%, greater than 25%, greater than 50%, or greater than 75%.

In one embodiment of the present invention, the method is 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.

In any of the second, fourth, sixth, eighth, tenth, or sixteenth to twentieth aspects 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.

Where the method relates to a disease or condition, the disease or condition may be inflammation. Preferably the inflammation is chronic inflammation. Preferably 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.

The inflammation may occur as a result of psoriasis, sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behçet'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, l-IIV infection, AIDS, multiple sclerosis, systemic lupus erythematosus, septic shock, an allergy, a hyposensitivity, a hypersensitivity, hypersensitivity following the reactivation of -46 -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 or a wound.

Where the method relates to a disease or condition, the disease or condition may be an autoimmune disease.

In one embodiment, the autoimmune disease is selected from acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune adrenalitis, autoimrnune 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. Optionally, the autoimmune disease is not Coeliac disease, Crohn's disease or ulcerative colitis.

More 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 melli tus, 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, -47 -pemphigus, pernicious anaemia, polyarth ntis, 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.

Where the method relates to a disease or condition, the disease or condition may also be an inflammatory disorder, a proliferative disorder, an immune disorder, an angiogenesisdependent disorder, a sensitivity disorder, an adverse endocrine reaction or a degenerative disorder.

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

Alternatively the inflammatory disorder, proliferative disorder, immune disorder, angiogenesis-d ependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder is an autoimmune disorder, an immunodeficiency 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 rnyeloid 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.depenen 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, angiogenesisdependent disorder, sensitivity disorder, adverse endocrine reaction or degenerative disorder may also be keratitis (including herpetic keratitis), herpes simplex or shingles.

In one embodiment, the inflammation, inflammator disorder, proliferative disorder, immune disorder, angiogenesisdepenent 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, lymphocytic colitis, ischaemic colitis, diversion colitis, infective colitis or indeterminate colitis.

-49 -In any embodiment of the present invention, the method 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.

Where the method relates to a disease or condition, the disease or condition may be 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 11 disorder, or post-natal depression.

In any embodiment of the present invention, the method 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.

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 spondvlitis, antiphospholipid syndrome, autoimmune Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet's disease, biliary cirrhosis, bullou s pemphigoid, canavan disease, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, diffuse cerebral sclerosis of schilder, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia fibromyo sitis, Fuchs heterochromic iridocyclitis, Graves' disease, -50 -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, polychond ri tis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, 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, polymyo sitis, Goodpasture's syndrome, interstitial granulomatous dermatitis with arthritis, lupus erythematosus (SLE, IDLE, 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 (HAV), hepatitis B virus (HBV), hepatitis D virus (HDV), hepatitis E virus (HEV), hepatitis F virus (HFV), hepatitis G virus (HGV)), human immunodeficiency virus; neoplastic diseases, leukemia, lmphoma, 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, gliosarcoma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma), oligodendroglial tumours, ependymal cell -51 -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 lymph omas, plasmacytoma, granulocytic sarcoma, germ cell tumours, tumours of the meninges, allergies, rhinitis, bronchitis, asthma, 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 hypersensitivities, optic contact hypersensitivities, leprosy and other mycobacterium infections, eczema acne, chicken pox, hypertension, adrenal autoimmunity, myasthenia gravis, and myositis.

Where the method relates to a disease, condition or a wound, the disease, condition or a wound may be gastrointestinal or non-gastrointestinal.

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.

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, inflammation of the entire alimentary canal is excluded, in which case the inflammation is referred to as non-alimentary canal inflammation'.

-52 -Similarly, the term non-gastrointestinal disorder, disease or wound' refers to disorders, diseases or wounds to the extent that they occur in any part of a body other than the gastrointestines, including disorders, diseases or wounds occurring in any other part of the alimentary canal. Non-gastrointestinal disorders, diseases or wounds may display some symptoms in the gastrointestines.

Optionally, disorders, diseases or wounds 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 disorder, disease or wound to be treated or prevented is a non-gastrointestinal disorder, disease or wound without symptoms in the gastrointestines'.

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

Optionally, disorders, diseases or wounds 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 disorder, disease or wound to be treated is a non-alimentary canal disorder, disease or wound without symptoms in the alimentary canal'.

In any aspect of the present invention relating to treatment, prevention, or testing, the treatment of, prevention of, test for, or test against, inflammation, a disorder, a disease or a wound may be performed via gastrointestinal absorption of the compound.

The term gastrointestinal absorption' of the compound refers to absorption that occurs systemically via the gastrointestines. To achieve gastrointestinal absorption, -53 -the compound may be administered, for example, orally, rectally or by tube feeding.

Preferably the administration is oral.

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.

In any embodiment of the present invention, the compound may be provided in the form of a medicament. Any of the medicaments employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration.

Preferably, the mode of administration selected is that most appropriate to the disorder or disease to be treated or prevented. For example, oral administration may be preferred for the treatment or prevention of rheumatoid arthritis, oral or topical administration may be preferred for the treatment or prevention of psoriasis, and airway administration may be preferred for the treatment or prevention of asthma.

For oral administration, the compounds will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lo2enges, 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, 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 arid 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 -54-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 granulcs 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.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For parenteral use, the compounds will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose.

Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. The compounds of the invention may also be presented as liposome formulations.

For topical and transdermal administration, the compounds will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.

-55 -Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.

The dose of the compounds used in 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, preferabJy 100 mg to 11) g, preferably I g to 5 g of active ingredient per unit dosage form.

A final aspect of the present invention relates to a unit dosage form comprising at least I mg of a compound suitable for use in any one of the preceding aspects of the present invention. Preferably, the unit dosage form is suitable for oral administration. Preferably, the unit dosage form comprises at least 10 mg, at least 100 mg, at least 500 mg, at least I g, at least 2.5 g, at least 5 g, at least 7.5 g, at least g, at least 20 g or at least 50 g of the compound.

The 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 effect of glucosylamine (MGA), 13,13-diglucosylamine (DiBBGA) and N-acetyl-B,13-diglucosylamine (NAcetyl DiBBGA) on PHA stimulated IL-1o synthesis in human whole blood.

-56 -Figure 2 shows the effect of glucosylamine (MGA), 13,I3-diglucosylamrne (DiBBGA) and N-acetyl-13,13.diglucosylamine (NAcetyl DiBBGA) on PHA stimulated IL-I3 synthesis in human whole blood.

Figure 3 shows the effect of glucosylamine (MGA), B,I3-diglucosylamjne (DiBBGA) and N-acetyl-fl,Bdiglucosyjamjne (NAcetyl DIBBGA) on PHA stimulated IL-2 synthesis in human whole blood.

Figure 4 shows the effect of glucosylarnine (MGA), B,13-diglucosylamine (DiBBGA) and N-acetylB,Bdiglucosy1amin (NAcetyl DiBBGA) on PHA stimulated IL-4 synthesis in human whole blood.

Figure 5 shows the effect of glucosylamine (MGA), 13,13-diglucosylamine (DiBBGA) and N-acetvl-13,13-diglucosyjamine (NAcetyl DiBBGA) on PHA stimulated IL-5 synthesis in human whole blood.

Figure 6 shows the effect of glucosylamine (MGA), 13,13-diglucosylamjne (DiBBGA) and N-acetvl-13,I3diglucosyjamine (NAcetyl DiBBGA) on P1-IA stimulated IL-6 synthesis in human whole blood.

Figure 7 shows the effect of glucosylamine (MGA), 13,13-diglucosylamine (DiBBGA) and N-acetylB,l3diglucosyJamjne (NAcetyl DiBBGA) on PHA stimulated IL-7 synthesis in human whole blood.

Figure 8 shows the effect of glucosylamine (MGA), B,B-diglucosylamjne (DiBBGA) and N-acetyl13,l3diglucosyJamine (NAcetyl DiBBGA) on PHA stimulated IL-b synthesis in human whole blood.

Figure 9 shows the effect of glucosylamine (MGA), 13,B-diglucosylamine (DiBBGA) and N-acetyl-B,B-diglucosylamine (NAcetyl DiBBGA) on PHA stimulated IL-12 synthesis in human whole blood.

-57 -Figure 10 shows the effect of glucosylamine (MGA), 13,B-diglucosylamine (DiBBGA) and N-acetyll3,BdiglucosyJamjne (NAcetyl DiBBGA) on PHA stimulated IL-13 synthesis in human whole blood.

Figure 11 shows the effect of glucosylamine (MGA), I3,13-diglucosylamine (DiBBGA) and N-acetylB,13diglucosyJamjn (NAcetyl DiBBGA) on PHA stimulated IL-17 synthesis in human whole blood.

Figure 12 shows the effect of glucosylamine (MGA), 13,13-diglucosylamjne (DiBBGA) and N-acetyl-13,13-diglucosylamine (NAcetyl DiBBGA) on PHA stimulated IFN? synthesis in human whole blood.

Figure 13 shows the effect of glucosylamine (MGA), 13,B-diglucosylamine (DiBBGA) and N-acetvl-B,B-diglucosylamine (NAcetyl DiBBGA) on PHA stimulated GCSF synthesis in human whole blood.

Figure 14 shows the effect of glucosylamine (MGA), !3,B-diglucosylamjne (DiBBGA) and N-acetylB,l3diglucosy1amine (NAcetyl DiBBGA) on PHA stimulated GM-CSF synthesis in human whole blood.

Figure 15 shows the effect of glucosylamine (MGA), B,13-diglucosylamjne (DiBBGA) and N-acetyI-B,l3-diglucosylamjn (NAcetyl DiBBGA) on VEGF synthesis in human whole blood in which the VEGF synthesis has been inhibited by PHA.

Figure 16 shows the effect of glucosylamine (MGA), 13,B-diglucosylamine (DiBBGA) and N-acetyl-13,B-diglucosylamjne (NAcetyl DiBBGA) on PHA stimulated TNFx synthesis in human whole blood.

Figure 17 shows the effect of various concentrations of PHA on TNFoc synthesis in human whole blood.

Figure 18 shows the inhibition of PHA stimulated TNFo synthesis in human whole blood by glucosylamine over a range of concentrations.

-58 -Figure 19 shows the inhibition of PHA stimulated TNF synthesis in human whole blood by B,I3-diglucosylamine over a range of concentrations.

Figure 20 shows the inhibition of PHA stimulated TNFcx synthesis in human whole blood by N-acctvl-13,i3diglucosylamine over a range of concentrations.

Figure 21 shows the effect on differentiated U937 human macrophage TNF synthesis by glucosylamine (MGA) over a range of concentrations.

Figure 22 shows the inhibition of differentiated U937 human macrophage TNFo synthesis by 13,13-diglucosylamine (DiBBGA) over a range of concentrations.

Figure 23 shows the inhibition of differentiated U937 human macrophage TNFcL synthesis by N-acetyl-13,I3diglucosylamine (NAcetyl DiBBGA) over a range of concentrations.

Biological Examples

PFL4 stimulated human whole blood tokine synthesis lVho/e blood cu/tare: 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 test drug and PHA solution were added to non-control samples. The drugs tested were glucosylamine (MGA), I3,13-diglucosylamine (DiBBGA) and N-acetyl-B,13-diglucosylamine (NAcetyl DiBBGA). Final drug concentrations tested were 100tM, 1.tM, 0.lp.M and 0.01tM.

All samples were tested in triplicate.

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 -59 -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 et a!, was followed (CytokJne, 2006, 33, pp. 156- 165). The culture supernatants were analysed once for concentrations of IL-Icc, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-b, IL-12, IL-13, IL-17, IFNy, GCSF, GM-CSF, MCP-1, RANTES, VEGF and TNFcc. 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 (BioRad 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-Plex suspension array system (Bio-Rad Laboratories) and the Bio-Plex 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-b, IL-12 and IL-17, 2.8 pg/mI for IL-2, IL-4, IL-6, IL-13 and TNFcc, 2.32 pg/mI for IFNy, and 8.32 pg/mI for GM-CSF.

Results: PHA stimulated all cytokines except VEGF which was inhibited. IL-8, MCP-1 and RANTES were outside the range of the assay. The action of 0.Ol1iM glucosylamine (MGA), 13,B-diglucosylarnine (DiB BGA) and N-acetyl-B,13-diglucosylamine (NAcetyl DiBBGA) on PHA stimulated synthesis of IL-Icc, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-b, IL-12, IL-13, IL-17, IFNy, GCSF, GM-CSF, VEGF and TNFoc is shown in Figures 1 to 16 respectively.

-60 - It can be seen that glucosylamine inhibits the P1-lA stimulated synthesis of IL-2, IL- 5, IL-6, IL-b, GM-CSF and TNFoc, whilst levels of VEGF (inhibited by PHA) are stimulated.

!3,13-diglucosvjamjne and N-acetyi-B,Bdigiucosylamine inhibit the PHA stimulated synthesis of IL-1, IL-1, IL-2, IL-4, IL-5, IL-6, 1L-lO, IL-12, IL-13, IL-17, IFNy, GCSF, GM-CSF and TNFo.

P1-IA stimulated human whole blood TNFa synthesis W7ho/e blood culture: As used above.

TNFa ELISA: The following TNFoc 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-weil plates.

Results: PHA stimulation on a subject's whole blood in culture is shown in Figure 17. At zero PHA concentration TNFx levels were below the limit of detection, and at a PHA concentration of 2.5.Lg/ml TNFcL levels were low for all four days. At a PHA concentration of 5g1g/ml (control) TNFc concentration increased from 600 pg/mi at day 1 to a peak of -2000 pg/mi at day 3, and then dropped to -190() pg/mi at day 4. This level of stimulation was comparable to that reported by Lagreiius et a!.

The effect of glucosylamine on PHA-induced TNFx synthesis is shown in Figure 18. The synthesis of TNFa is entirely suppressed by the drug at all concentrations other than I 00M, indicating a bell-shaped concentration effect curve.

The effect of B,13-diglucosylarnine on PHA-induced TNF synthesis is shown in Figure 19. Again, the synthesis of TNF is entirely suppressed by the drug at all concentrations other than 100pM.

-61 -The effect of NacetylI3,B.digJucosyIamjn on PHA-induced TNFoc synthesis is shown in Figure 20. The inhibition of the synthesis of TNFoe by the drug was observed at all concentrations.

LPS stirnu/aled 11937 rnicrophage TNFa synthesis U937 human monocytes were incubated with 5 tg/ml PMA (phorbol myristate acetate) for 5 days in order to induce differentiation. In separate assays, glucosylamine (MGA), B,I3-diglucosylamine (DiBBGA) and N-acetyl-13,13-diglucosylamine (NAcetyl DiBBGA) were added to the macrophages produced at concentrations of 0 (control), 0.10, 1.00, 10.00 and 100.00 gM. TNFc synthesis was then optionally induced by 80 nM ips (lipopolysaccharide) treatment for 72 hours.

The results are shown in Figures 21 to 23 respectively. It can be seen that 13,13-diglucosylamine (DiBBGA) and N-acetyI13,f3dig1ucosy1amjn (NAcetyl DiBBGA) inhibit TNFx synthesis at all concentrations down to 0.1gM.

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

-62 -Claims 1. A method of modifying the level of a cytokine in

i'ii.'o, 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 comprising a glycosidic -NW, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded =NR2 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkvlaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
2. A method of testing for a modification in the level of a cytokine in vivo, ex viz'o or i/i 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 comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR2 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, -63 -arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
3. A method as claimed in claim I or claim 2, wherein the cvtokine is selected from GM-CSF IL-1o, IL-113, 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 IFNy.
4. A method as claimed in claim I or claim 2, wherein the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-I, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TNFx or IFNy.
5. A method as claimed in claim I or claim 2, wherein the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.
6. A method as claimed in any one of the preceding claims, wherein (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (d) one R group is a monosaccharide subunit and one R group is hydrogen; and/or (e) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (f two R groups are independently monosaccharide subunits; and/or (g) two R groups are independently hydrocarbyl groups; and/or (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (i) one or two R groups are independently hydrogen, or a C1-C6 alkyl, C7-C6 acyl, C2-C6 halo-acyl, or C17() alkoxycarbonyl group; and/or (j) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group. -64-
7. A method of modifying the level of a cytokine in vivo, ex i'iro 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 comprising a glycosidic -NR., group, a glycosidic -NRc group, a directly bonded =NR group, or a directly bonded =NR, group; wherein each R is independently a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hvdrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkvl, arylalkenyl, arylalkynyl, alkylarvi, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
8. A method of testing for a modification in the level of a cytokine in z'ivo, ex 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 comprising a glycosidic -NR, group, a glycosidic -NRc group, a directly bonded =NR group, or a directly bonded NR2 group; wherein each R is independently a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.

-65 -
9. A method as claimed in claim 7 or claim 8, wherein the cytokine is selected from GM-CSF, IL-1o, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-b, IL-12, IL-13, IL-17, GCSF, VEGF, TNFc, RANTES, MCP-1 or IFNy.
10. A method as claimed in claim 7 or claim 8, wherein the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-1o, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TNF or IFNy.
11. A method as claimed in claim 7 or claim 8, wherein the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.
12. A method as claimed in any one of claims 7 to 11, wherein (a) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (b) two R groups are independently monosaccharide subunits; and/or (c) two R groups are independently hydrocarbyl groups; and/or (d) one or two R groups are independently an alkyl, acyl or alkoxycarbonyl group; and/or (e) one or two R groups are independently a C1-C6 alkyl, C2-C6 acyl, C,-C halo-acyl, or C120 alkoxycarbonyl group; and/or (f) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.
13. A method of modifying the level of a cytokine selected from GM-CSF, IL-1, IL-1B, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES or MCP-1 in:ivo, ex i'iz'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 comprising a glycosidic -NW, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR2 group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to -66 -which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkvl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenvl, arylalkvnyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
14. A method of testing for a modification in the level of a cytokine selected from GM-CSF, IL-1, IL-113, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES or MCP-1 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 comprising a glycosidic -NR, group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR, group; wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is 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.
15. A method as claimed in claim 13 or claim 14, wherein the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-1o, IL-113, IL-4, IL-5, IL-6, IL-12, JL-13, IL-17, GCSF or TNFoc.
16. A method as claimed in claim 13 or claim 14, wherein the modification is an increase in the level of a cvtokine selected from IL-7 or VEGF.
17. A method as claimed in any one of claims 13 to 16, wherein (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (d) one R group is a monosaccharide subunit and one R group is hydrogen; and/or (e) one R group is a hvdrocarbyl group and one R group is hydrogen; and/or (f) two R groups are independently monosaccharide subunits; and/or (g) two R groups are independently hydrocarbyl groups; and/or (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (i) one or two R groups are independently hydrogen, or a C1-C6 alkyl, C,-C6 acyl, C,-C() halo-acyl, or C120 alkoxycarbonyl group; and/or () one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.
18. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof further comprises at least one sulphate group, wherein a sulphate group is a -O-SO-OR', -NR'-S02-OR', -O-S02-N(R)2 or -NR'-SO,-N(R), group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group.
19. A method of modifying the level of a cytokine in i'ivo, 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 (i) at least one monosaccharide subunit comprising a glycosidic -NR7 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded -68 - =NR2 group, wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; and (ii) at least one sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-SO,-OR', -O-SO.,-N(R)., or -NR'-S07-N(R)2 group, wherein each R' is independentJr hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstjtuted, 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.
20. A method of testing for a modification in the level of a cytokine in z.'iz.'o, ex z.'ivo or in i'itro, said method comprising contactitig a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound or salt thereof comprises (i) at least one monosaccharide subunit comprising a glycosidic -NR2 group, a glvcosidic -NR3 group, a directly bonded NR group, or a directly bonded group, wherein each R is independently hydrogen, a further monosaccharide subunit, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; and (ii) at least one sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-S02-OR', -O-S02-N(R')2 or -NR'-SO,-N(R')1 group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group; wherein each monosaccharide subunit independently is optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, -69 -arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
21. A method as claimed in claim 19 or claim 20, wherein the cytokine is selected from GM-CSF, IL-1o, IL-113, IL-2, IL-4, IL-5, JL-6, IL-7, IL-8, IL-lO, IL- 12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES, MCP-1 or IFNy.
22. A method as claimed in claim 19 or claim 20, wherein the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-1, IL-113, IL-2, IL-4, IL-5, IL-6, IL-b, IL-12, IL-13, IL-17, GCSF, TNF or IFNy.
23. A method as claimed in claim 19 or claim 20, wherein the modification is an increase in the level of a cytokine selected from IL-7 or VEGF.
24. A method as claimed in any one of the claims 19 to 23, wherein (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a monosaccharide subunit and one R group is a hydrocarbyl group; and/or (d) one R group is a monosaccharide subunit and one R group is hydrogen; and/or (e) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (f) two R groups are independently monosaccharide subunits; and/or (g) two R groups are independently hydrocarbyl groups; and/or (h) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbony! group; and/or (i) one or two R groups are independently hydrogen, or a C1-C6 alkyl, C,-C6 acyl, C7-C halo-acyl, or C1,() alkoxycarbonyl group; and/or (j) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.

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25. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises a sequence of at least two monosaccharide subunits directly linked by a glycosidic -NR-group, a glycosidic -NR2t group, a directly bonded =N-group, or a directly bonded =NR-group.
26. A method as claimed in claim 25, wherein the glycosidic -NR-group or the glvcosidic -NR2t group is linked to one or both of the monosaccharide subunits by a glycosidic bond.

1(1
27. A method as claimed in claim 25, wherein the directly bonded =N-group or the directly bonded NR-group is linked to one or neither of the monosaccharide subunits by a glycosidic bond.
28. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises a sequence of at least two monosaccharide subunits directly linked by a glycosidic -NR-group or a directly bonded =N-group.
29. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least two monosaccharide subunits, each of which is substituted with at least one sulphate group.
30. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof 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 ó-position relative to the anomeric carbon of the pyranosyl subunit.
31. A method as claimed in claim 30, wherein the first and second pyranosyl subunits form a disaccharide.

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32. A method as claimed in any one of the preceding claims, wherein 1-50, or 2-30, or 3-15, or 6-12, or all the hydroxyl groups on the monosaccharide subunits independently have been replaced with a sulphate group.
33. 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits independently have been replaced with a sulphate group.
34. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof contains 1-100, 1-20, 1-12, 2-10, 2-8, 2-6 or 2-4 monosaccharide subunits.
35. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits.
36. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 monosaccharide subunits.
37. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises a sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more monosaccharide subunits.
38. A method as claimed in any one of the preceding claims, wherein all monosaccharide subunits are independently aldosyl or ketosyl monosaccharides.
39. A method as claimed in claim 38, wherein 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosyl or nonosyl monosaccharides.
40. A method as claimed in claim 39, wherein 1,2, 3,4, 5,6,7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently glycero syl, erythrosyl, threosyl, -72 -ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl, talosyl, rhamnosyl or fucosyl monosaccharides.
41. A method as claimed in any one of the preceding claims, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently tetrosyl monosaccharides or higher, and the ring of those monosaccharides is furanosyl.
42. A method as claimed in any one of the preceding claims, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all monosaccharide subunits are independently pentosyl monosaccharides or higher, and the ring of those monosaccharides is pyranosyl.
43. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof is: (a) 3j-di-glucosylamine; (b) a mono-, di-, tn-, tetra-, penta-, hexa-, hepta-or octasulphated f,f-di-glucosylamine, or a mixture thereof (c) a mono-, di-, tn-, tetra-, penta-, hexa-, hepta-or octasulphated N-acetyl-j-di-glucosylamine, or a mixture thereof (d) a mono-, di-, tn-, tetra-, penta-, hexa-, hepta-or octasulphated N-ethyl-f4-di-glucosylamine, or a mixture thereof; or (e) a sulphated di-(4,4'-glucosylglucosyl)amine.
44. A method of modifying the level of a cytokine in i'ivo, ex vivo 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 monosaccharide subunit comprising a glycosidic -NR2 group, a glycosidic -NR3 group, a directly bonded =NR group, or a directly bonded NR7 group; wherein each R is independently hydrogen, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hvdrocarbyl group; -73 -wherein the monosaccharide subunit and/or the further monosaccharide subunit independently are optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstjtuted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arvlalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
45. A method of testing for a modification in the level of a cytokine i/i viz'o, cx rho 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 monosaccharide subunit comprising a glycosidic -NR, group, a glycosidic NR. group, a directly bonded =NR group, or a directly bonded NR, group; wherein each R is independently hydrogen, or a hydrocarbyl group, or two or three R groups and the nitrogen atom to which they are attached, together form a further monosaccharide subunit or a cyclic hydrocarbyl group; wherein the monosaccharide subunit and/or the further monosaccharide subunit independently are optionally substituted and/or optionally modified; and wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, arvl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
46. A method as claimed in claim 44 or claim 45, wherein the cytokine is selected from GM-CSF, IL-bc, IL-113, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-b, IL- 12, IL-13, IL-17, GCSF, VEGF, TNFac, RANTES, MCP-1 or IFNy.
47. A method as claimed in claim 44 or claim 45, wherein the modification is a decrease in the level of a cytokine selected from GM-CSF, IL-2, IL-4, IL-5, IL-6, IL-b, IL-13, IL-17, TNFoc or IFNy.
48. A method as claimed in claim 44 or claim 45, wherein the modification is an increase in the level of cytokine VEGF. -74-
49. A method as claimed any one of claims 44 to 48, wherein (a) one R group is not hydrogen; and/or (b) two R groups are not hydrogen; and/or (c) one R group is a hydrocarbyl group and one R group is hydrogen; and/or (d) two R groups are independently hydrocarbyl groups; and/or (e) one or two R groups are independently hydrogen, or an alkyl, acyl or alkoxycarbonyl group; and/or (f one or two R groups are independently hydrogen, or a C1-C6 alkyl, C,-C6 acyl, C,-C6 halo-acyl, or C120 alkoxycarbonyl group; and/or (g) one or two R groups are independently a methyl, ethyl, acetyl, trifluoroacetyl, Boc, Fmoc, or Zervas group.
50. A method as claimed in any one of claims 44 to 49, wherein 1-9, or 2-8, or 3-4 hydroxyl groups on the monosaccharide subunit and/or the further monosaccharide subunit independently have been replaced with a sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-S07-OR', -O-S02-N(R')2 or -NR'-SO,-N(R'). group, wherein each R' is independently hydrogen, a metal, a further monosaccharide subunit, or a hydrocarbyl group.
51. A method as claimed in any one of claims 44 to 50, wherein the monosaccharide subunit and/or the further monosaccharide subunit are independently aldosyl or ketosyl monosaccharides.
52. A method as claimed in claim 51, wherein the monosaccharide subunit and/or the further monosaccharide subunit are independently triosyl, tetrosyl, pentosyl, hexosyl, heptosyl, octosvl or nonosyl monosaccharides.
53. A method as claimed in claim 52, wherein the monosaccharide subunit and/or the further monosaccharide subunit are independently glycerosyl, erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosvl, talosyl, rhamnosyl or fucosyl monosaccharides.

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54. A method as claimed in any one of claims 44 to 53, wherein the monosaccharide subunit and/or the further monosaccharide subunit are independently tetrosyl monosaccharides or higher, and the ring of those monosaccharides is furanosyl.
55. A method as claimed in any one of claims 44 to 53, wherein the monosaccharide subunit and/or the further monosaccharide subunit are independently pentosyl monosaccharides or higher, and the ring of those monosaccharides is pyranosyl.
56. A method as claimed in any one of the preceding claims, wherein all monosaccharide subunits are independently ring-closed or open-chain or a mixture of ring-closed and open-chain.
57. A method as claimed in any one of the preceding claims, wherein one or more monosaccharide subunit is substituted and/or modified.
58. 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, -CCI3, -CBr3, -Cl3, -SI-I, -NH,, -N3, -NI-I=NH2, -CN, -NO,, -COOH, RaORb, .Ra..SRb -W-SO-R", RSO -R", WSO,ORb, WOSO,Rb, RaSO,N(Rb),, -R2NRbSO,Rb, RaOSO,ORb, -WO-SO,-N (R"),, _Ra_NR_SO,_N (Rb),, -R2-N (Rb),, _Ra_N (Rb) +, _Ra_B (Rb),, _R2_P(Rb),, _Ra_PO (Rb),, -W-Si(R, .RaCORb RaCOOR, -WO-Cc) Rb, WCON(Rb),, RaOCOORb, RaCON(Rb) WNRI)CO.ORb, -W-CS-OR", RaOCSRb RaCSN(Rb),, RaNRbCSRb, RaOCSORb, RaOCSN (Rb),, RaNRbCSORb, or -R"; and/or (b) independently one, two or three of the hydrogens of the monosaccharide subunit is replaced with -F, -Cl, -Br, -I, -CF3, -CCI3, -CBr3, -Cl3, -OH, -SH, -NH,, -N3, -NH=NH,, -CN, -NO,, -COOH, -W-O-R', R2SRb, -76 -RaSORb, Ra.SO,Rt), RaSO,ORb, RaSO,N(R),, RaNRbSO,Rb, WOSO,0Rb, WOSO,N(Rb),, -Rn-N Rb_SO,_N (R"), _Ra_N (R"),, _Ra_N (Rb) +, -R2-B (Rb),, _Ra_P(Rb),, -R2-PO (R"), R2Si(Rb) , R2CORb, RaCOORb, -WO-Co-R", -R2-CO-N(R") , RaOCOORh, -R20-CO N(R"),, RaNRh CO-OR", , RaCS-R, RaCSORb, WOCSRb, RaCSN(RI)),, R2NRhCSRb, RaOCsORh, -WO-CS-N (R"),, R2NRbCSORh (R,, 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 hydroxvl group, is replaced with 0, S, NRb, or N(R)),+; and/or (d) independently two hydroxyl groups of the monosaccharide subunit are together replaced with SORc, -SO,-W-, or wherein: -R2-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; Rb is independently hydrogen, an 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; 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 M is a metal; provided that the monosaccharide subunit comprises at least one OS0Rb, -OSO7R", -OSO3R', -OSi(R")3, -OCOR", -OCO,R", or -OM.
59. 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 -77 - (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 NRb, wherein -R" is independently hydrogen, an optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylarvl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton.
60. A method as claimed in any one of the preceding claims, whereineach hydrocarbyl group is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which comprises 1-15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.
61. A method as claimed in claim 60, wherein a substituted hydrocarbyl group is substituted with one or more of -F, -Cl, -Br, -I, CF;, -CCJ3, -CBr3, -Cl3, -OH, -SI-I, -NH1, -N3, -NH=NH,, -CN, -NO1, -COOH, RaORb, R2SRb, RaSORI, RaSO,,Rb RaSOIORb, RaOSO,Rb, W-501-N(R"),, ROSO,ORb -R2O-SO,-N(R, RaNRbSO,.ORb RNRb.SO...N(Rb) _Ra_N(R) , _Ra_N(Rb) + _Ra_B(Rb), _Ra_P(Rb),, _Ra_PO(Rb),, _Ra_Sj(Rb)3, _Ra_CO_Rb, WCOORb, RaOCORb, -W-CO-N(R, -WO-CO-OR", RaOCON(Rh),,, WNRtCON(Rb),, -W-CS-R", RaOCSR, RCSN(Rb),, RaNRbCSRb, RaOCSORb, WOCSN (Rb),, WNRbCS.N(Rb)1, -R", or a 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 Rb is independently hydrogen, an optionally substituted monosaccharide subunit, or a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, ai-vlalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylarvi group which optionally includes one or more heteroatoms in its carbon skeleton.

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62. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least one monosaccharide subunit comprising a glycosidic -NW, group or a directly bonded =NR group.
63. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least two or at least three sulphate groups.
64. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least one -O-S07-OR', -NR'-S02-OR' or -O-S02-N (R')2 group.
65. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least one -OSO3R' group.
66. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises 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.
67. A method as claimed in claim 66, 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.
68. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof 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.
69. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least one, two or three sulphate groups, located on primary hydroxyl positions.

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70. A method as claimed in any one of the preceding claims, wherein a sulphate group is provided on a monosaccharide subunit comprising a glycosidic amine group.
71. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof is a partially or fully suiphated saccharide.
72. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof comprises at least one sulphate group, wherein a sulphate group is a -O-SO,-OR', -NR'-S02-OR', -O-SO,-N(R')2 or -NR'-S02-N(R),, group, and wherein R' is independently hydrogen, a metal, or 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.
73. A method as claimed in claim 72, wherein R' is independently hydrogen, an alkali metal, an earth alkali metal, copper, silver, zinc, or a C1-C6 alkyl group.
74. A method as claimed in any one of the preceding claims, wherein all monosaccharide subunits are independently in the D-or L-configuration.
75. A method as claimed in any one of the preceding claims, wherein the stereochemistry of each glycosidic bond is independently a or
76. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof is: (a) a glucosylamine; (b) I -benzamido-1 -deoxy-2,3,4,6-tetra potassium sulphonatoglucose; or (c) 1 -N-octyl-I -N-decanoyl-I-amino-I -deoxy-6-potassium sulphonate-muramyl-D-isoglutamylalanine.

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77. A method as claimed in any one of the preceding claims, wherein two R groups and the nitrogen atom to which they are attached, together do not form a heterocyclic aromatic group.
78. A method as claimed in any one of the preceding claims, wherein the atom connectivity S-O-P is not present in any monosaccharide subunit and/or in the entire compound.
79. A method as claimed in any one of the preceding claims, wherein the compound does not contain the group -O-P(=O)(OH)OSQ,Oj-j.
80. A method as claimed in any one of the preceding claims, wherein the compound is not a nucleoside and/or not a nucleotide.

/5
81. A method as claimed in any one of the preceding claims, wherein the compound does not comprise a ribose subunit comprising a glycosidic tertiary amine.
82. A method as claimed in any one of the preceding claims, wherein none of the monosaccharide subunits is pyranosyl with N-substitution at the 2-position relative to the anomeric carbon of the pyranosyl subunit.
83. A method as claimed in any one of the preceding claims, wherein none of the monosaccharide subunits is N-substituted cx to the anomeric carbon.
84. A method as claimed in any one of claims I to 17, wherein the compound or salt thereof is: (a) a non-sulphated j-di-glucosylamine; (b) a non-sulphated N-acetyl-3j-di-glucosylamine; (c) a non-suiphated N-ethyl-fj3diglucosylamjne; or (d) a non-suiphated di-(4,4'-glucosylglucosyl) amine.

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85. A method of modifying the level of a cytokine in vii'o, ex viz'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (I): wherein: R is Ac, Me, Et, COCF, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
86. A method as claimed in claim 85, wherein R is Ac and all R" are H, or a tautomer, a stereoisomer or a salt thereof.
87. A method of modifying the level of a cytokine selected from GM-CSF, IL-lcx, IL-113, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNFo, RANTES or MCP-1 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 has the formula (I): wherein: RisH; each R" is SO3R or H; and each R is H, Li, Na or K; -82-or a tautomer, a stereoisomer or a salt thereof.
88. A method as claimed in claim 87, wherein R is H and all R" are H, or a tautomer, a stereoisomer or a salt thereof.
89. A method of modifying the level of a cytokine in vh'o, 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 has the formula (II): (11) wherein: R is H, Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
90. A method of modifying the level of a cytokine in i'h'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 has the formula (III): -83 -OSO3K o Me wherein R is H, CHO or COMe; or a tautomer, a stereoisomer or a salt thereof.
91. A method of modifying the level of a cytokine in nyc, ex nine or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (IV): R"O Rb 0 R"O NHR

OR (IV)

wherein: R is H, Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
92. A method as claimed in claim 91, wherein R is H or Ac and all R" are H, or a tautomer, a stereoisomer or a salt thereof. -84-
93. A method of testing for a modification in the level of a cytokine 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 has the formula (I): wherein: R is Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
94. A method as claimed in claim 93, wherein R is Ac and all R" are H, or a tautomer, a stereoisomer or a salt thereof.
95. A method of testing for a modification in the level of a cytokine selected from GM-CSF, IL-l, IL-113, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-13, IL-17, GCSF, VEGF, TNF, RANTES or MCP-1 in vivo, ex z'ivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (I): wherein: RisH; each R" is SO3R' or H; and each R' is H, Li, Na or K; -85 -or a tautomer, a stereoisomer or a salt thereof.
96. A method as claimed in claim 95, wherein R is H and all R" are H, or a tautomer, a stereoisomer or a salt thereof.
97. A method of testing for a modification in the level of a cytokine in i'iz'o, ex i'iro or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (II): Rb (II) wherein: R is H, Ac, Me, Et, COCF1, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
98. A method of testing for a modification in the level of a cytokine in t'ivo, ex vivo or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (III): -86 -OSO3K o Me

HN

(111) NHR Me wherein R is H, CHO or COMe; or a tautomer, a stereoisomer or a salt thereof.
99. A method of testing for a modification in the level of a cytokine in vit'o, ex i'iz'o or in vitro, said method comprising contacting a compound or a pharmaceutically acceptable salt thereof with a cell; wherein the compound has the formula (IV): R"O\ R"O-_---.-NHR

OR (IV)

wherein: R is H, Ac, Me, Et, COCF3, or COPh; each R" is SO3R' or H; and each R' is H, Li, Na or K; or a tautomer, a stereoisomer or a salt thereof.
100. A method as claimed in claim 99, wherein R is H or Ac and all R" are H, or a tautomer, a stereoisomer or a salt thereof.

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101. A method as claimed in any one of claims 85, 87, 89, 90, 91, 93, 95, 97, 98 or 99, wherein at least one R" is SO3R'.
102. A method as claimed in any one of the preceding claims, wherein the compound or salt thereof further comprises a polysaccharide, oligosaccharide, peptide or protein covalently linked to the remainder of the compound.
103. A method as claimed in any one of the preceding claims, wherein a mixture of compounds differing only in their stereochemistry at the anomeric centre and/or in their degree of sulphation and/or their position of sulphation is used.
104. A method as claimed in claim 103, wherein 50%, 75%, 80%, 85%, 90%, 95% or 99% of the compounds or derivatives lie within three consecutive degrees of sulphation.
105. A method as claimed in claim 104, wherein the three consecutive degrees of sulphation are three-to five-fold suiphation, four-to six-fold suiphation, or five-to seven-fold sulphation.
106. A method as claimed in any one of the preceding claims, wherein the cell is a human cell.
107. A method as claimed in any one of the preceding claims, wherein the cell is a blood cell.
108. A method as claimed in any one of the preceding claims, wherein the method is a method of treating or preventing a disease or condition.
109. A method as claimed in claim 108, wherein the disease or condition is inflammation.
110. A method as claimed in claim 109, wherein the inflammation is chronic inflammation.
111. A method as claimed in claim 109 or claim 110, 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.
112. A method as claimed in any one of claims 109 to 111, wherein the inflammation occurs as a result of psoriasis, sarcoidosis, arthritis, rheumatoid arthritis, osteoarthritis, Behçet'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 neurodegenerative disease, an inflammatory degenerative disease, osteochondral defects, keratitis (including herpetic keratitis), herpes simplex, shingles or a wound.
113. A method as claimed in claim 108, wherein the disease or condition is an autoimmune disease.
114. A method as claimed in claim 113, wherein the autoimmune disease is selected from acute disseminated encephalitis, Addison's disease, ankvlosing spondylitis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polygland ular failure, autoimmune thyroiditis, Coeliac disease, Crohn s disease, diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GB 5), 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 -89 -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.
115. A method as claimed in any one of claims 108 to 114, wherein the disease or condition is non-gastrointestinal.
116. A method of modifying the level of VEGF in i'ii'o, ex z.'ivo or in i'itro, said method comprising contacting a compound with a cell, wherein the compound is P1-IA (phytohaemagglutinin) or a protein that shares at least 75% of its amino acid sequence with PHA.