LT3446B - Fucolsylated glycosides as inhibitor of bacterial adherence - Google Patents

Abstract

Mono-, di-, tri- or oligosaccharide glycoside derivatives having at least one terminal group which is derived from L-fucose. The compounds are useful for therapy or prophylaxis in conditions involving infection by Heliobacter pylori of human gastric mucosa. Another object of the present invention is to provide a process for their preparation and pharmaceutical compositions.

Description

The present invention relates to the use of L-fucose-containing glycosidic derivatives in the preparation of pharmaceutical compositions; for the treatment and prophylaxis of diseases caused by Helicobacter pylori infections of the stomach and intestines using these derivatives, as well as with novel glycosidic derivatives.

Helicobater pylori is a microaerophilic, spiral-shaped organism (descended from the genus Campylobacter) that is found in the stomach and appears to reside exclusively in the human gastric mucosa. It is estimated that this bacterium infects the gastric mucosa in more than 60% of adults by the age of 60. In addition, H. pylori is thought to be involved in a number of pathological ailments, including acute (type B) gastritis, gastric and duodenal ulcer, atrophic, gastritis, and gastric adenocarcinoma.

The tropism of bacterial tissues may be partially controlled by the ability of the bacterial strain to adapt to the local chemical environment in which they live. In addition, adhesion is a prerequisite for settling them out of their new habitat, for example due to peristaltic gastrointestinal motions. In mammals, bacteria adhere to proteins or glycoproteins (glycosphingolipids, glycoproteins) on and around epithelial cell surfaces (mucus), and several specific interactions between bacterial protein and carbohydrate adhesion have been described in the literature.

With respect to H. pylori, studies in model systems such as mouse adrenal Yl cells (see DG Evans, DJ, Jr. Evans, & DY Graham, (1989) Infect. Immun. 57, 2272-2278) suggested that surface-bound flexible The fibrous structures surrounding this bacterium serve as binding or colonization factor antigens to mediate the binding of H. pylori to the cellular glycoprotein receptor containing sialic acid.

The invention relates to glycosidic derivatives of mono-, di-, tri- or oligosaccharides having at least one terminal group Y as defined below derived from L-fucose, said derivatives being compounds of the general formulas Ia, Ib, Ic, Id, Ie and If:

YZ ^ R AZ ₂ -R ₃ -bz ₄ -r

Ia Ib Ic

AZ ₅ -BZ ₆ -CZ ₇ -R AZ ₈ -BZ ₉ -CZ ₁₀ -DZ _n -R

Id Ie

A - zi ₂ ~ B ~ zi j ^- C ^- Z14 - D ^- Z, E - ZI8-R

If which

Ζ _η Z ₂ , Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , Z ₈ , Z g, Z ₁₀ , Z _n , Z ₁₂ , Z ₁₃ , Z ₁₄ , Z, ₅ and Z _{16 are} independently O, S, CH ₂ or NR ₂₅ wherein R ₂₅ is hydrogen, C, ₂₄ alkyl, C ₂ . _24- alkenyl, C ₂₄ -C ₂₄ alkylcarbonyl or benzoyl, which may optionally have hydroxyl, amino, C 1 -C 4; _{A 4-} alkyl, C 1 -C ₄ alkoxyl, nitro, halo, phenoxy or mono- or dihalo-C ₁ -C ₄ alkyl;

in which

In formulas Y, A, B, C, D and E, a curved line is a bond in either the a- or β- configuration;

R _x , R _2, and R j are each independently H, halogen, azide, guanidinyl, branched or unbranched C ₁ . ₂₄ alkyl, C ₂ . ₂₄ alkenyl, C ₂ _ ₂₄ alkynyl, C ₃ _g cycloalkyl, C ₃ _ _s cycloalkyl-C ₁ _ ₂₄ alkyl or C ₁ _ ₁₂ alkoxy-C ₁ _ ₁₂ alkyl group which may optionally contain a hydroxyl, amino, halogen or oxo group; aryl or arylC 1-6 alkyl which may optionally have hydroxyl, amino, C _{1 in the} aryl group. _4- alkyl, C _1-4 -alkoxylognitro, halogen, phenoxy or mono- or dihalo-C ₁ . _{A 4-} alkyl substituent; tri (C _1-4 alkyl) silylethyl; oxo group; = SR ₄ R ₅ group, where

R ₄ and R _{5 are} independently H or C _x , ₄ alkyl; or XR _,; , a group where

X is O, S, NR ₂₀ or = N- and

R ₁₀ is H, branched or unbranched C ₁ -C ₂₄ alkyl, C ₂ . _{A group of 24-} alkenyl, C ₂ -C ₂₄ -alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₂₄ -alkyl or C ₁ -C ₁₂ -alkoxy-C ₁ -C ₁₂ -alkyl which may optionally substituted with hydroxyl, amino, halogen or oxo; aryl, aryl-C 1-4 alkyl or heterocyclyl-C ₁ . _4-alkyl optionally substituted in the aryl or heterocyclyl moiety with hydroxy, amino, C ₁ _ ₄ alkyl, C _{first A 4-} alkoxyl, nitro, halogen, phenoxy or mono- or dihalo-C 1-6 alkyl substituent; tri (C 1-6 alkyl) silylethyl; tri _{(first 4} -alkyl) yarn; tri (C ^ ₄ alkyl) silylethoxymethyl; acyl residues of naturally occurring amino acids; C ₁ -C ₂₄ alkylcarbonyl; C ₂ _ ₂₄ -alkenilkarbonilas; C ₃ _ ₈ cycloalkyl-C ₁ _ ₂₄ -alkylcarbonyl; arylcarbonyl; or terpenyl; and

R ₂₀ is H, C ₁ . _24- alkyl, C ₂ -C ₂₄ -alkenyl, C ₁ -C ₂₄ -alkylcarbonyl or optionally containing a benzene ring hydroxyl, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl, nitro, halo, phenoxy or mono- or dihalogen -C ₁ -C ₄ -al is substituted by benzoyl or phthaloyl;

RlA ' ^R 2Ar ^R 3A <R4az R-1B' ^R 2B ' ^R 3B' RflBr RlC ' ^R 2C' ^R 3C ' ^R 4C' ^ IND ' ^R 2D, R _3D , R'.e, ^R 2e / ^R 3e, ^R 4e each independently is as defined above for R _1z R ₂ and R _3, or is a group of Formula VII

YZi VII wherein Y and Z · are as defined above;

with condition, that one of R _1B , ^R 2B, ^R 3B or ^R 4B is Z ₃ 1 Z ₈ or z ₁₂ , that one of ^R 1C ' ^{R 2} Cl ^R 3C or ^R 4C is z ₆ < Z, or Zl3f that one of Rid, ^R 2D ' ^R 3D or ^R 4D is Zio or Z ₁₄ , that one of R _1E , ^R 2Ef ^R 3E or ^R 4E is ^ 15 '

that at least one and not more than five of R _1A , R _2A , ^R 3A » ^R 4Ar ^R 1b, ^R 2B» ^R 3B 'R 4b, R 1c, ^R 2dc ^R 3c < ^R 4Cr ^R 1D' ^R 2D ' ^R 3D' ^R 4D , Rie / ^R 2e, ^R 3e + ^{r R} 4e is a group of formula VII,

and that R _1A of Group A, ^R 2A '1 ^ 3A and R _4a CH ₂ alternate confi- gures, Group B R 1B / ^R 2h / ^R 3B and R _4B CH ₂ alternate confi- gures, Group C R 1C ' ^R 2C! ^R 3C and R _4c CH ₂ alternate confi- gures, Group D R _1D z ^R 2D ' R _3d and CH ₂ R _4D alternate

the CH ₂ substituent configurations of group E, R _1E , R _2E , R _3E and R _4E are independently D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-toluose, L configurations of -tolose, D-alose, L-alose, D-altrose, L-altrose, D-gulose, L-gulose, D-idose and L-idose;

R is hydrogen, branched or unbranched C 1. ₂₄ alkyl, C ₂ _ ₂₄ alkenyl, C _{2nd 24-} alkynyl, C ₃ . ₈ cycloalkyl, C ₃ _ ₈ cycloalkyl-C _{first 24} alkyl, Cj. ^ - alkoksiCj. ^ - alkyl, C _{1 24 -alkylcarbonyl,} C2. ₂₄ -alkenylcarbonyl or C ₃ . _{An 8-} cycloalkyl-C ₁ -C ₂₄ alkylcarbonyl group which may optionally be substituted by hydroxyl, amino, halogen or oxo; aryl or aryl-Cj. _{A 4-} alkyl, arylcarbonyl or aryl-C 1-4 alkylcarbonyl group which may optionally contain hydroxyl, amino, C _{1 in the} aryl group. _4- alkyl, C 1-4 -alkoxyl, nitro, halogen, phenoxy or mono- or dihaloC 1-6 -alkyl; terpenyl; tri (C _1-4 alkyl) silylethyl; heterocyclyl; heterocyclyl-C 1-6 alkyl; or heterocyclyl-C _1-4 alkylcarbonyl;

a group of formula II or Ha

R ₃₀ - (CH _{2) q} -S (O) _m -CH ₂ CH ₂ - II [R _3o - (CH _{2) q} -S (O) _m -CH _2] 2 CH-CH ₂ - Ha, wherein R ₃₀ is H, carboxyl, C _1-6 alkoxycarbonyl, hydroxyl, amino or MA matrix, q is an integer from 1 to 24 and m is 0 or 2; or a group of formula III or IIla

Phe-S (O) _m -CH ₂ CH ₂ [Phe-S (O) _m -CH ₂ ] ₂ CH-CH ₂ III

IIIa wherein m is as defined above, and each Phe is phenyl optionally substituted with hydroxy, amino, C ^ alkyl, C ₁ _ ₄ -alkoxyl, nitro, halogen, phenoxy, or mono- or di-C _{first 4-} alkyl substituent; or fenilCi ^ alkyl, which is optionally a phenyl group is substituted with one hydroxy, amino, C _1-4 alkyl, C _{first 4} -alkoxyl, nitro, halogen, phenoxy or mono- or dihalogenC ₁ _ ₄ alkyl substituent;

a group of formula IV

R ₄₀ CH ₂ CH (CH ₂ R ₅₀ ) CH ₂ IV wherein R ₄₀ and R _{50 are} independently halogen; or

Q- (spacer) _r is a group wherein r is an integer 0 or 1 and Q is an MA matrix or a -COO-MA group;

for use in therapy, in particular for the treatment and prophylaxis of humans in cases of gastric mucosa infected with Helicobacter pylori. On the other hand, the invention relates to the use of said compounds for the preparation of pharmaceutically acceptable compositions for the treatment of the aforementioned diseases.

Invention context, the terms C ₁ _ ₄ -alkyl, C ₁ _ _g alkyl, C ₁ _ ₂₄ -alkyl as a separate group or as part represents an alkyl group having 1-4, 1-8 or 1-24 carbon atoms which may constitute a a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, dimethylbutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl,

The term carbon chain, as used herein, is defined as C ₁ -C ₂₄ alkyl, but may also have a lower number of carbon atoms than C ₁ . _4- alkyl, C 1-8 alkyl. The term C ₁ _ ₄ alkyl is used herein when substituents are defined.

The term C ₃ _g cycloalkyl as a group or part of a group designates a cyclic alkyl group with 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term C ₂ _ ₂₄ alkenyl designates unsaturated alkyl groups with 2-24 carbon atoms which may be straight or branched, preferably straight, in which the double bond may be present anywhere in the chain, for example vinyl, 1-propenyl, 2- propenyl, hexenyl, decenyl. hexadecenyl, octadecenyl. The term C ₂ _ ₂₄ alkynyl represents an alkyl group with 2-24 carbon atoms containing a triple bond such as ethynyl,

I-propynyl, 2-propynyl, 2-butynyl and 1.1. The term halogen means Cl, Br, I and F, more preferably F and Cl. Term C ₁ . _4- alkoxyl and C ₁ . ₂ ^_ 4 alkoxy mean a group consisting of an oxo functional group substituted with an alkyl group as defined above.

The terms aryl and aryloxy, as a single group or as part of a group, denote phenyl or naphthyl, more preferably phenyl.

The term arylamide defines either aryl-NH-C (O) -, e.g. anilides, or aryl-C (O) -NH-, e.g. benzamide.

The term terpenyl group refers to groups derived from several different unsaturated hydrocarbon compounds, commonly referred to as terpenes, namely monoterpenes and sesquiterpenes, as well as their hydroxy or oxo derivatives. Mircenyl, (-) - limonenyl, terpineolyl, (+) - α-pinenyl, geraniolyl, (-) - mentholyl, (-) - camparyl, farnesolyl, β-eudesmolyl and manoolyl are examples of these groups.

In this context, the term oligosaccharide refers to an oligosaccharide containing 4-10 monosaccharides, more preferably 4-7 monosaccharides, monosaccharides selected from aldohexoses (i.e., D-glucose, L-glucose, D-galactose, L-galactose, L-mannose, , D-thalose, L-thalose, D-alose, L-alose, D-altrose, L-altrose, D-gulose, L-gulose, D-idose or L-idose) or derivatives thereof, wherein the oligosaccharides may be linear or branched, provided that the longest oligosaccharide chain contains no more than seven monosaccharides.

As indicated above, the curved lines at the gurations of the ring oxygen atom, which are glycosidic. It is clear that in the particular Y, A, B, C, a- or β-configuration of the connections in other groups.

Y, A, B, C, D and carbon atoms mean that these

The bonds in the E groups are either a- or β-confi each of these bonds in D and E can be independently of the corresponding

The mono- or di-halo-C ₁₄ -alkyl group may be substituted at any position and if two halogen substituents are present, the halogen atoms may be the same or different.

The term heterocyclic refers to a monocyclic 5- or 6-membered or fused bicyclic (5-membered or 6-membered ring) aromatic partially or fully saturated heterocyclic group containing from 1 to 4 heteroatoms in each ring wherein the heteroatoms may be optionally selected from O, S. and N, and bonded either through a carbon atom or through a nitrogen atom. Pyrrolyl, pyrazolyl, pyridinyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, furyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3oxazinyl, 2H- 1,3-thiazinyl, 4H-1,3-thiazinyl, 6H1,3-thiazinyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, indolyl, purinyl, piperidyl or piperidine, morpholinyl or morpholine, piperazinyl, tetrahydrofuryl, thiazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrrolidinyl, 1 H-tetrazolyl is or 2H the only examples in this group.

The term acyl residue of naturally occurring amino acids denotes acyl residues of L-amino acids present in natural proteins, e.g., alanyl, valyl, leucyl, isoleucyl, proline, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparagl, lysyl, arginyl, histidyl, and the acyl residue of asparagine and glutamine indicate both the immediate amino group and the carboxyl group at the end of their respective side chains, but the carboxyl group adjacent to the amino functional group is more preferred.

an acylic acid residue, a carboxyl group present at

The term sphingoid refers to D-erythro-2-amino-1,3-octadecanediol, its homologs and stereoisomers, and its hydroxyl and unsaturated derivatives, including ceramide (see further definitions in Journ. Of Lipid Research, Vol. 19, (1978), 617). -631).

io

The term steroid refers to well known steroids such as cholesterol, cortisone, hydrocortisone, corticosterone, betamethasone, prednisolone, prednisone and others.

The term matrix as used herein and referred to as MA refers to any organic or inorganic, polymeric or macromolecular structure to which a 0-, S-, C- or N- glycosidic compound is attached covalently or, for example, hydrophobically by attachment. Ia, Ib, Ic, Id, Ie or lf, aglycone portion. Examples of such matrices include proteins, glycoproteins, polypeptides, polysaccharides, liposomes, emulsions, plastic polymer residues, and inorganic materials. Preferably, protein residues bind via nucleophilic groups of proteins, such as amino, hydroxyl and mercaptan. The proteins and polypeptides themselves can be any of a variety of substances, especially biocompatible proteins such as globulins, albumins such as human serum albumin (HSA), bovine serum albumin (BSA) or sheep serum albumin (SSA), ovalbumin, fibrins or keyhole shells hemocyanin (KLH), glycoproteins such as bovine or human unsubstituted casein or lecithins, and the like. Synthetic polymers in which one or more amino acids are attached to a defined size (s), a polymer such as polysin or oligolysin, are other examples of such matrices. Different proteins or polypeptides can be attached to the R group residue via an amino or carboxyl group. The polysaccharides to which the 0-, S-, C- or N-glycosidic compounds are attached may also be present in a variety of polysaccharides. The aglycone moiety of the compound represented by the formulas Ia, Ib, Ic Id, Ie or lf may be attached to the hydroxyl groups of simple polysaccharides such as cellulose, sepharose, starch or glycogen to amino LT 3446 B n.

the amino groups of saccharides such as chitosan or aminated sepharose; and mercaptan groups attached to polysaccharides modified with sulfur.

Liposomes can be any biologically, biologically degradable microvesicle system consisting of one or more biosheets surrounding water-filled chambers, which may contain a variety of reagents: hydrophobic reagents inside lipid bisheets and hydrophilic reagents in the inner aqueous cavity. The physicochemical properties of liposomes are mainly dependent on the composition of the lipids.

Liposomes are composed of phospholipids such as egg yolk phospholipids, soy phospholipids, synthetic phosphotidylcholine (DMPC) and / or dipalmtoyl phosphatidylchlorine (DMPC), or purified from lipids, or from gums, other than genes,

Emulsions are heterogeneous mixtures of two or more immiscible liquids. Emulsifiers are added to stabilize these systems. The emulsifier is disposed between immiscible liquids and generally has only one phase in drip form.

Emulsions come in two main types. Heterogeneous systems characterized by the distribution of droplets of organic liquid in the continuous water phase are called oil-in-water emulsions (o / w). On the other hand, heterogeneous systems characterized by the distribution of water droplets in a continuous oil phase are called water-in-oil emulsions (w / o).

Any vegetable oil such as soybean oil, safflower oil, sesame oil, peanut oil, cotton oil, borage oil, sunflower oil, corn oil, olive oil, medium chain triglycerides (like Miglyol ¹ ®) or acetylated monoglycerides can be used as a dispersing phase or a dispersion medium.

Aminated latex, substituted sulfur, aminated or hydroxylated polystyrene, polyacrylamide and polyvinyl alcohol are examples of plastics to which aglycone moieties of the compounds of formulas la, lb, lc, ld, Ie and If can be attached. Other possible carriers include carbohydrate beads and gels or polymers that combine carbohydrates with other polymeric materials such as sephacryl. These gels are further substituted with groups such as amino, thiols, cyano, activated esters and disulfides. The plastics in question may be in the form of spheres or films.

Among the inorganic materials to which the compounds of the formulas Ia, lb, lc, ld, Ie and If may be attached, the aglycone is silica, such as: silica gel, zeolite, diatomite or various types of glass or silica gel, such as substituted surfaces of sulfur or aminated glasses, where the silica gel or glass may be, for example, in the form of beads. Another example of an inorganic material may be alumina.

Particularly acceptable MA matrices are human serum albumin (HSA), bovine serum albumin (BSA), and polyacrylamide (PAA).

An interesting embodiment of the present invention is when a compound of formula la, lb, lc, ld, Ie or If has a MA matrix which is highly activated (i.e. 2 or more, for example 10-100 when the matrix is a protein such as BSA or HSA, or 10-10000 when the matrix is a polymer such as polyacrylamide) of groups corresponding to formulas Ia, Ib, Ic, Id, Ie and If. Several such groups have been found to significantly improve the inhibitory effect of the compound as a whole due to its multivalent action on bacteria. It is also possible that the bacteria may even agglutinate in the presence of several groups corresponding to formulas Ia, Ib, Ic, Id, Ie or If.

When, in connection with the definition of formulas Ia, Ib, Ic, Id, Ie or If, it is stated that the CH ₂ substituent configurations of R _1A , R _2A , R _3A and R _{4A in} Group A, R _1B , i \ _{2B in} Group B,

R-2B> ^ 3b R4BCH2

R20 ^ 30 and R _4c CH ₂ configurations of the substituents C groups R _lc configurations of the substituents D groups R _1D, R _2D, R _3D and R _4D CH ₂ configurations of the substituents, and E groups R _1E, R _2E R _3E and R _4E The CH ₂ substituent configurations are independently D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-tolose, L-tolose, D-alose, L-alose, D-altrose, In the configuration of L-altrose, D-gulose, L-gulose, D-idose and L-idose, this is to say that the stereochemical substitution pattern which can be obtained by the various R groups or groups containing R groups in cyclic A, B , C, D, and E, meet

The stereochemistry of the 2-, 3- and 4-hydroxy groups and the 5-hydroxymethyl group on D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-tolose, L-tolose, D in -alose, L -allose, D-altrose, L-altrose, D-gulose, L-gulose, D-idose and L-idose, respectively.

It will be _appreciated that in the groups R _1z R ₂ , R ₃ and CH ₃ , Y is of such a configuration that the L-galactopyranose compound is obtained and therefore Y is L-fucose or a derivative thereof.

Preferably, the compounds represented by the formulas Ia, Ib,

Ic, Z ₁₀ z Id, Zii t Ie or If, Z _lf Z ₂ , Ζχ ₂ , Z ₁₃ , Z ₁₄ , Z ₁₅ and Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , z ₈ , Z ₁₆ are 0. Z ₈ , Yes pat more acceptable, when not more than four, yet better at most three, especially one or two from R-1Z R-2 A i ^ 3Az P-4AZ ^ 1Β »^ 2Bz P-3B z ^ 4Bz H-1Cz ^ 2Cz & 3CZ ^ 4Cz R-1DZ ^ 2Dz RaD / ^ 4DZ RlE '^ 2Ez f ^ 3E ^ar R _4E is a group as described VII formula.

It is also better when R _1A is in group VII in configuration a.

It is also preferable for the CH _{1 of} R _1A , R _2A , R _3A and R _{4A of Part A to} have the D-galactose configuration in the A β configuration.

Particularly preferred compounds are those wherein R _1A is in group VII in configuration a, and in part A R _1A , R _2A , R _3A and R _4A CH ₂ have the D-galactose configuration in the A β configuration, especially when A is Fucal-2Ga ^.

It is also more preferred when R _2B is Z ₃ , Z ₅ , Z ₈ or

Z ₁₂ and B of R _1B , R _2B , R _3B and R _4B CH ₂ have D-glucose configuration in B β configuration.

It is also more preferred when R _1B is an acetamide group.

Particularly preferred compounds are those wherein R _1A is a group VII in configuration a; Part A of R _1A , R _2A , R _3A and R _4A CH ₂ has the configuration of Dgalactose in the A β configuration; R _2B is Z ₃ , Z ₅ , Z ₈ or Z ₁₂ ; and in Part B, R _1B , R _2B , R _3B and R _4B CH ₂ have the D-glucose configuration in the B β configuration, and R _1B is an acetamide group.

Of particular interest are compounds wherein AZ ₃ -B is Fucotl-2ΰ3ΐβ1-30ΐοΝΑοβ or Fucal-2Ga ^ l-3 (Fucal-4) ΰΙοΝΑοβ, compounds wherein AZ ₅ -BZ ₆ -C is Εηοα1-2α3ΐβ1-3Θ1οΝΑοβ1EN 3446 B

3Gaip or Fucal-2Gaipi-3 (Fucal-4) GlcNAcpl-3Gaip, compounds wherein A-Zg-BZ ₉ -CZ ₁₀ -D is GalNAcal-3 (Fucal2) Gaipi-3 (Fucal-4) GlcNAc3l-3Gaip or Fucal -2Galpl3 (Fucal-4) GlcNAcss-3Gaipi-4GlcP, compounds in which Z ₁₂ -BZ -CZ _{13 14 15} -E is -DZ GalNAcal-3 (Fucal-2) Galpl3 (Fucal-4) GlcNAcl-3Gaipi-4Glc3 .

It is also more preferred when R _3B is a group of formula VII in the α configuration.

Particularly preferred compounds are those wherein Part A R _1A , R _2A , R _3A and R _4a CH ₂ and Part B R _1B , R _2B , R _3B and R _4B CH ₂ have the Dgalactose configuration and Part C R _1c , R _2C , R _3C and R _4c CH ₂ has the D-glucose configuration in the A α configuration and the B and C β configuration, wherein R _1B and R _3C are groups corresponding to formula VII in the α configuration wherein R _1A and R _1C are acetamide groups, and R _2B is Z ₅ , Z ₈ or Z ₁₂ and R _{2 C} is Z ₆ , Z ₉ or Z ₃₃ .

Of particular interest is the class of compounds wherein the carbohydrate moiety has a YZ _t -A- structure wherein Z _: is O and the L-fucose compound Y is attached at the A 2 position. In this class, interesting basic carbohydrate structures having formulas wherein R _1f R ₂ , R ₃ , R _1A , R _2A , R _3A and R _{4A are} each designated OH, although this should not be considered as a limitation of the definition of R-substituents in this case; rather, R _{lz is} said to be R ₂ , R ₃ , R _1A , R _2A , R _3A , and

R _4A can have all the meanings defined above for Formulas Ia, Ib, Ic, Id, Ie or lf. Thus the structure YZ ^ A- can be:

Fucal-2Alipi ->

Fucal-2Altpl

Fucal-2Glcpi

Fucctl-2Man3l - »

Fucotl-2Guipi ->

Fucal-2IdoPl ->

Fucal-2Galpl

Fucal-2Yes

When Y, A, B, C, D and E parts Ri, r ₂ , r ₃ , R _1a , R _2a , R3A, R4A, R-1B, ^ 2B, ^ 3Β 'R-4B < R10 R2C, R3C, R4C, Rid, R2D, R3D, R4D, R] .E <^ 2E '^ 3E and R _4E groups is not hydroxyls, this it is better to choose them from these:

H, Cl, F, azide guanidyl, methyl, ethyl, propyl, vinyl, aul, prop-1-enyl, ethynyl, prop-2-vinyl, prop-1-ynyl, acetyl, cyclopropyl, cyclopropylmethyl, methoxymethyl, hydroxymethyl, phenyl oxo, methylene, thiol, amine, methoxy, ethoxy, propoxy, butoxy, hexyloxy, decyloxy, tetradecyloxy, octadecyloxy, vinyloxy, allyloxy, 1-propen-1-yloxy, crotyloxy, 3- buten-1-yloxy, 2-hexen-1-yloxy, 5-hexen-1-yloxy, 5-decen-1-yloxy, 9-decen-1-yloxy, 11-tetradecen-1-yloxy, oleolyl, ethynyloxy, 2-propynyl-1-yloxy, 1-propynyl-1-yloxy, methylthio, methylamine, dimethylamine, cyclopropoxy, cyclopropylmethoxy, methoxymethoxy, phenoxy, benzyloxy, 2-furylmethoxy, 2 -thienylmethoxy, 2-pyridylmethoxy, trimethylsilyloxy, trimethylsilylethyloxy, acetoxy, propionyloxy, butyryloxy, hexanoyloxy, decanoyloxy, tatradecanoyloxy, octadecanoyloxy, acetamide, N-methylacetamide, acetylthio, toad.

Among R group Anglicans the following are interesting:

methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, heptyl, isoheptyl, 4-methylhexyl, 3-methylhexyl, 2-methylhexyl, 1-methylhexyl, 3-ethylpentyl, 2-ethylpentyl, 1-ethylpentyl, 1-propylbutyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, tetracosyl, cyclopropyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylprop-3-yl, cyclohexyl, cyclohexylmethyl, cyclohexylprop-3-yl, cycloheptyl, phenyl, 4-nitrophenyl, benzyl, 4-phenylprop-1-yl, 3-hexylthio-2- (h) ) methylprop-1-yl, 3-hexylsulfonyl-2- (hexylsulfonyl) methylprop-1-yl,

3-decylthio-2- (decylthio) methylprop-1-yl, 3-decylsulfonyl-2 (decylsulfonyl) methylprop-1-yl, 8-amino-3 group,

6-dioxaoct-1-yl, 1,3-dihydroxyprop-2-yl, 1,3-diaminprop-2-yl, 3-hydroxy-2- (hydroxymethyl) prop-1-yl,

2-phenylthioethyl, or trimethylsilylethyl.

In a group R having an MA matrix, the relationship between this MA matrix and the remainder of R can generally be made using spacers well known in the field of composite proteins, for example,

J.H. Pazur, Adv. Carbohydr. Chem. Biochem., Vol. 39, 405-447 (1980); Y.C. Lee & R. T. Lee, Glycoconjugates, Vol. 4 Part B, 57-83, Ed. Horowitz, Academic Press, N. Y. (1982); and G. Magnusson, FEMS Symposium, 215-228 (1986). In this context, the term spacer refers to a group of molecules that binds an active substance to a carrier. The spacer molecule is constructed to have two different functional groups, each of which specifically reacts with another functional group, and there is a linear group between the two functional groups. By attaching the active ingredient to the carrier via a spacer, the active substance 3446 B becomes more accessible, e.g., to H. pylori adhesives or colonization factor antigens.

The spacer can be defined as (W) _v -S'-P *, where S 'is C! ₂₄ alkyl, C _{2 24} alkenyl, C ₁₂₄ aryl, arylC _l _ ₂₄ alkylaryl, C ^ alkilarilCj ₂₄ alkyl group which may be interrupted by carbonyl, thiocarbonyl, oxycarbonyl, carbonyloxy, carbonylamino, aminocarbonyl, azo-, oxo or tiogrupėmis ; aryl group, aryloxy, C,. _24- alkoxyl, polyethylene glycol group, steroid group, sphingoid group; all groups may be substituted with carboxyl, C _1-4 alkylcarbonyl, amide, hydroxyl, alkoxy, aryloxy, phenoxy;

P 'is NH-C (S), NH-C (O), C (O), NH, C (S), C (O) 0, (O) CO, SO, SO ₂ , SO · ,, SO ₄ , PO j, PO ą;

W is NH-C (S), NH-C (O), C (O), C (S), C (O) O, (O) CO, SO,

SO ₂ , SO ₃ , SO ₄ , PO ₂ , PO ₃ , PO ₄ , with the proviso that Z _lz Z ₂ , Z ₄ , Z ₇ , Z ,, or Z ₁₆ is CH ₂ or W cannot be PO ₂ , provided that when Z ,, Z ₂ , Z ₄ , Z ₇ , Z _n or Z ₁₆ is O or S, then W cannot be (O) CO, SO ₄ , or PO ₄ , and provided that when Z ., Z ₂ , Z ₄ , Z ,, Z ,, or Z- ₍ ... Is NH, then W cannot be NH-C (S), NH-C (O), (O) CO, (O) CO, SO ₄ or PO ₄ , and v is an integer 0 or 1.

The atom of the sugar group which connects with the spacer is selected from -O-, -S-, -NH-, CH ₂ -, preferably -O-.

In the compounds represented by the formulas la, lb, lc, ld, Ie or If, the various R groups containing the MA matrix may themselves have a spacer and a bond. Typical and conventional methods of coupling are coupled via matrices containing amino or keto groups. Such joints between spacer and matrix may have the following common structures:

-NH-C (S) -NH- or -C (O) -NH, or -NH-CfOj-, where the atoms marked in bold and italic type belong to the given matrix.

The number of structures represented by the formulas Ia, Ib, lc, Id, le or If on each unit of the matrix can be mono- or multivalent and can vary from 1 to 10,000 depending on the nature of the matrix.

The following is a list of non-limiting examples of spacers that fit between Q and the remainder of R:

In the lists shown, thicker and corresponding to the matrix.

above and below, the atoms in italics are represented by the Vertical Curved Line on the left and right ends of the spacer above, indicating that the ends have bonds. Among the compounds represented by the formulas Ia, lb, lc, Id, Ie or If and having a matrix moiety, the following may be mentioned:

S

O

CNH-8SA

o

When used in the above examples, the forged means a mono-, di-, tri- or oligosaccharide as mentioned in the text and m 'is an integer from 0 to 5 and p is an integer from 0 to 13.

When the above matrices are illustrated with BSA, HSA, and polyacrylamide (PAA), they may be replaced by any protein or peptide or other matrix noted in the text.

Representative examples of useful compounds represented by formulas Ia, lb, lc, Id, Ie or If are:

Fucal-2Gal3l-O-Propyl

Fucctl-2GaiP 1-0-Isopropyl

Fucal-2Gaipi-O-butyl

Fucal-2Gaipi-O-tert-butyl

Fucal-2Galpl-O-Hexyl

Fucal-2Gaipi-O-octyl

Fucal-2Gaipi-O-decil

Fucal-2Gaipi-O-tetradecyl

Fucal-2Gal3l-O-Octadecyl

Fucal-2Gaipi-O- (C ₆ bisulfide)

Fucal-2Gaipi-O- (C ₁₀ bissulfase)

Fucal-2Gaipi-O- (C _fe bissulfone)

Fucal-2Gaipi-O- (C ₁₀ bissulfone)

Fucal-2Gaipi-O- (8-amino-3,6-dioxaoct-1-yl)

Fucal-2Ga1β1-3GlcNAcPl-0-Propyl

Fucal-2Galβl-3Gl · cNAcβl-O-Isopropyl

Fucal-2Gal ^ l-3GlcNAcpl-O-Butyl

Fucal-2Gaipi-301οΝΑοβ1-0-1θΓΐ.butyl

Fucal-2Galpl-3GIοΝΑοβ1-0-hexyl

Fucal - 2Ga ^ l -3β1οΝΑοβ1 -O-octyl

Fucal - 2Ga ^ l - 3GlcNAcPl-O-decyl

Fucαl-2Galβl-3GlcNAcβl-O-tetradecyl

Fucotl -2Gaipi-3GlcNAcPl-0-octadecyl

Fucal-2Gaipi-3GlcNAcP-10- (C ₆ bisulfide)

Fucotl - 2Gaipi -3GlcNAcP ~ 1-0- (C ₆ bissulfone)

Fucal-2Gaipi-3G1cNAcP-1-O- (8-Amino-3,6-dioxaoct-1-yl)

Fucal-2Gaipi-3Glc3l-O-propyl

Fucotl - 2Galpl -3GlcP 1-0-i zopropyl

Fucotl - 2Gaipi -3GlcPl-O-Butyl

Fucotl-2Gaip 1 -3Glcpi-O-tert.butyl

Fucal-2Gaipi-3Glc3l-O-Hexyl

Fucotl - 2Gaipi -3GlcPl-O-oct i las

Fucal-2Gal3l-3GlcPl-O-tetradecyl

Fucal-2Gaipi-3GlcPl-O-Octadecyl

Fuc-2Gal3l 3GlcPl-O- (C ₆ bissulfidas)

Fucotl-2Gaipi-3GlcP-1-0- (C ₆ bisulfone)

Fucctl-2Gal3l-3Glc0-1-O- (8-amino-3,6-dioxaoctyl) where

C ₆ bissulfide = 3-hexylthio-2- (hexylthio) methylprop-1-yl · C ₁₀ bissulfide = 3-decylthio-2- (decylthio) methylprop-1-ylCgbissulfone = 3-hexylsulfonyl-2- (hexylsulfonyl) methylprop- l-ylC ₁₀ bissulfone = 3-decisulfonyl-2- (decylsulfonyl) methylprop-1-ylThe following compounds are of interest:

Fucotl-2Galpl -O-Me

Fucotl -3G Ιοβΐ -O-Me

Fucotl-3GlcNAcPl-O-Me

The Fucotl-3GlcNAcPl-spacer is 1-BSA

Fucotl-3GlcNAcPl -O tetradecyl

Fucotl -4GlcNAc3l -O-Me

Fucotl-4GlcNAc3l- spacer 2-polyacrylamide

Fucotl-4GicNAcPl-O tetradecyl

Fucotl - 4Gaipi -O-Me

Fucotl -6Gaipi-O-Me

Fucal-6Gaipi-gasket 2-polyacrylamide

Fucal-2Gaipi-gasket 2-polyacrylamide

Fucal-2Gaipi-gasket 1-BSA

Fucal-2Gaipi-gasket 1-HSA

Fucal-2Gaipi-gasket 4-BSA

Fucal-2Galpl-gasket 4-HSA

Fucal-2Gaipi-gasket 5-polyacrylamide

Fucal-2Gaipi-0 tetradecyl

Fucal-2Galpl-3GlcNAcPl-spacer 5-polyacrylamide

Fucal-2Gaipi-3GlcNAcPl-spacer 4-BSA

Fucal-2Gaipi-3GlcNAcPl-gasket 4-HSA

Fucal-2Gaipi-3GlcNAcPl-spacer 2-polyacrylamide

Fucal-2Gaipi-3GlcNAcPl-gasket 1-HSA

Fucal-2Galpl-3GlcNAc3l-spacer 1-BSA

Fucal-2Galpl-3GlcNAcpl-O-tetradecyl

Fucal-2Gal3l-3GlcPl-gasket 1-HSA

Fucal-2Gaipi-3GlcPl-gasket 1-BSA

Fucal-2Gal3l-3Glc3l-spacer 4-HSA

Fucal-2Gaipi-3GlcPl-gasket 4-BSA

Fucal-2Gaipi-3Glc3l-gasket 2-polyacrylamide

Fucal-2Gaipi-3Glc3l-spacer-5-polyacrylamide

Fucal-2Gaipi-3 (Fucal-4) GlcPl-spacer 1-HSA

Fucal-2Gaipi-3 (Fucal-4) GlcPl-spacer 1-BSA

Fucal-2Gaipi-3 (Fucal-4) GlcPl-spacer 4-HSA

Fucal-2Gaipi-3 (Fucal-4) GlcPl-spacer 4-BSA

Fucal-2Gaipi-3 (Fucal-4) GlcPl-gasket 2-olacrylamide

Fucal-2Gaipi-3 (Fucal-4) GlcPl Seal 5-Polyacrylamide

Fucal-2GaiPl-3 (Fucal-4) GlcNAcPl-3Gi-gasket 3-BSA

Fucal-2Galpl-3 (Fucal-4) GlcNAcPl-3Gi-Seal 2-Polyacrylamide

Fuoal-2Gaipi-3 (Fucal-4) GlcNAcPl-3Gaipi-Gasket 5-Polyacrylamide

Fucal-2Gaipi-3 (Fucal-4) GlcNAcPl-3Gaip1-0-tetradecyl

Fucal-2Gaipi-4Glcpl-spacer is 1-BSA

Fucal-2Gaipi-3GlcPl-gasket 2-polyacrylamide

Fucal-2Gaipi-4GlcPl-O-tetradecyl

Galpl-4 (Fucal-3) GlcNAcpl-spacer 1-BSA

Gaipi-4 (Fucal-3) GlcNAcPl-Seal 2-Polyacrylamide

Gaipi-4 (Fucal-3) GlcNAcPl-O-tetradecyl

Fucal-2Gaipi-3GlcNAcPl-3Gaipi-gasket 3-BSA

Fucal-2Galpl-3GlcNAcpl-3Galpl-gasket 3-HSA

Fucal-2Galpl-3GlcNAcpl-3Galpl Seal 5-Polyacrylamide

Fucal-2Gaipi-3GlcNAcPl-3Gaipi-gasket 1-HSA

Fucal-2Gaipi-3GlcNAcpl-3Gaipi-gasket 5-BSA

Fucal-2Galpl-3GlcNAc3l-3Galpl-gasket 4-HSA

Fucal-2Gaipi-3GlcNAc3l-3Gaipi-gasket 4-BSA

Fucal-2Gaipi-3GlcNAcPl-3Gaipi-gasket 2-polyacrylamide

Fucal-2Galpl-3GlcNAcpl-3Galpl-O-tetradecyl

GalNAcal-3 (Fucal-2) 3Gaipi-3 (EUaal-4) GlcNAcpl-3Gaipi Gasket 3-BSA

GalNAcal-3 (Fucal-2) 3Gaipi-3 (Fucal-4) GlcNAcPl-3Gaipi-Seal 2-Polyacrylamide

GalNAcal-3 (Fucal-2) 3Galpl-3 (Fualal-4) GlcNAcpi-3Galpl-O-tetradecyl

Fucal-2Gaipi-4 (Fucal-3) GlcPl-spacer 1-BSA

Fucal-2Galpl-4 (Fucal-3) GlcPl-Gasket 2-Polyacrylamide

Fucal-2Gaipi-4 (Fucal-3) GlcPl-O-tetradecyl

Fucal-2 (3-O-methyl) Gaipi-O-tetradecyl

Fucal-2 (3-O-methyl) Gaipi-gasket 1-BSA

Fucal-2 (3-O-methyl) Galpl-spacer 2-polyacrylamide

Fucal-2 (3-O-allyl) Gaipi-gasket 1-BSA

Fucal-2 (3-O-allyl) Gaipi-gasket 2-polyacrylamide

Fucal-2 (3-O-allyl) Gaipi-O-tetradecyl

Fucal-2 (3-O-Propyl) Gaipi-Gasket 1-HSA

Fucal-2 (3-O-Propyl) Gaipi-Gasket 1-BSA

Fucal-2 (3-O-propyl) Gaipi-gasket 2-polyacrylamide

Fucal-2 (3-O-Propyl) Gaipi-Gasket 4-HSA

Fucal-2 (3-O-Propyl) Gaipi-Gasket 4-BSA

Fucal-2 (3-O-propyl) Gaipi-gasket 5-polyacrylamide

Fucal-2 (3-O-butyl) Gaipi-gasket 1-BSA

Fucal-2 (3-O-butyl) Gaipi-gasket 2-polyacrylamide

Fucal-2 (3-O-butyl) Gaipi-O-tetradecyl

Fucal-2 (3-O-methyl) Gaipi-3GlcNAcPl-spacer 1-BSA

Fucal-2 (3-O-methyl) Galpl-3GlcNAcpl-spacer 2-polyacrylamide

Fucal-2 (3-O-methyl) Gaipi-3GlcNAcPl-O-Tetradecyl

Fucal-2 (3-O-Allyl) Gaipi-3GlcNAcPl Gasket 1-BSA

Fucal-2 (3-O-Allyl) Gaipi-3GlcNAcPl-Seal 2-Polyacrylamide

Fucal-2 (3-O-allyl) Gaipi-3GlcNAcPl-O-tetradecyl

Fucal-2 (3-O-propyl) Galpl-3GlcNAcPl-spacer 1-HSA Fucal-2 (3-O-propyl) Gaipi-3GlcNAcPl-spacer 1-BSA Fucal-2 (3-O-propyl) Gaipi-3GlcNAcPl- gasket 2-polyacrylamide Fucal-2 (3-O-propyl) Gaipi-3GlcNAcPl-gasket 4-HSA Fucal-2 (3-O-propyl) gaipi-3GlcNAcPl-gasket 4-BSA Fuoal-2 (3-O-propyl) Gaipi-3G1cNAcpl-spacer 5-polyacrylamide Fucal-2 (3-O-butyl) Gaipi-3G1cNAcPl-spacer 1-BSA Fuoal-2 (3-O-butyl) Gaipi-3G1cNAcpl-spacer 2-polyacrylamide Fucal-2 (3- 0-be) Gaipi-3GleNAcPl-O-tetradecyl Fucal-2 (3-O-propyl) Gaipi-3 (Fucal-4) GlcNAcPl-spacer 1-HSA Fucal-2 (3-O-propyl) Gaipi-3 (Fucal) -4) GlcNAcPl-spacer 1-BSA Fucal-2 (3-O-propyl) Galpl-3 (Fucal-4) GlcNAcPl-spacer 2-polyacrylamide Fucal-2 (3-O-propyl) Gaipi-3 (Fucal-4) ) GlcNAcPl-spacer 4-HSA Fucal-2 (3-O-propyl) Gaipi-3 (Fucal-4) GlcNAcPl-spacer 4-BSA Fucal-2 (3-O-propyl) Galpl-3 (Fucal-4) GlcNAcPl gasket 5-polyacrylamide Fucal-2 (3-O-methyl) Gaipi-4GlcNAcPl-gasket 1-BSA Fucal-2 (3-O-methyl) Galpl-4GlcNAcpl-gasket 2-polyacrylamide as Fucal-2 (3-O-methyl) Gaipi-4GlcNAcpl-O-tetradecyl Fucal-2 (3-O-allyl) Gaipi-4GlcNAcpl-spacer 1-BSA Fucal-2 (3-O-allyl) Gaipi-4GlcNAcpl- spacer 2-polyacrylamide Fucal-2 (3-O-allyl) Gaipi-4GlcNAcPl-O-tetradecyl Fucal-2 (3-O-butyl) Gaipi-4GlcNAcPl-spacer 1-BSA Fucal-2 (3-O-butyl) Galpl -4GlcNAcpi-spacer 2-polyacrylamide Fucal-2 (3-O-butyl) Gaipi-4GlcNAcPl-O-tetradecyl Fucal-2 (3-O-methyl) Gaipi-3G1cPl-spacer 1-BSA Fucal-2 (3-O- methyl) Gaipi-3GlcPl-spacer 2-polyacrylamide Fucal-2 (3-O-methyl) Gaipi-3GlcPl-O-tetradecyl Fucal-2 (3-O-allyl) Gaipi-3GlcPl-spacer 1-BSA Fucal-2 (3 -O-allyl) Gaipi-3GlcPl-spacer 2-polyacrylamide Fucal-2 (3-O-allyl) Gaipi-3GlcPl-O-tetradecyl Fucal-2 (3-O-butyl) Gaipi-3GlcPl-spacer 1-BSA Fucal- 2 (3-O-butyl) Galpl-3GlcPl-spacer 2-polyacrylamide Fucal-2 (3-O-butyl) Gaipi-3Glcpi-O-tetradecyl Fucal-2Gaipi-4GlcNAcPl-spacer 1-BSA

Fucal-2Gaipi-4GlcNAcPl-spacer 2-polyacrylamide

Fucal-2Gaipi-4GlcNAcPl-O-tetradecyl

Galal-3 (Fucal-2) Galpl-gasket 1-BSA

Galal-3 (Fucal-2) Gaipi-gasket 2-polyacrylamide

Galal-3 (Fucal-2) Galpl-O-tetradecyl

GalNAcal-3 (Fucal-2) Galpl-4Glcpl-spacer 1-BSA

GalNAcal-3 (Fucal-2) Gaipi-4GlcPl-spacer 2-polyacrylamide GalNAcal-3 (Fucal-2) Gaipi-4Glcpi-O-tetradecyl Galpl-3 (Fucal-4) GlcNAcpi-3Galpl-4Glc3l-spacer 1-BSA Gaipa -3 (Fucal-4) GlcNAcpl-3Gα1-4GlcPl-spacer 2-polyacrylamide Gaipi-3 (Fucal-4) GlcNAcβl-3Galβl-4Glcβl-O-tetradecyl ΰβ1β1-3 (Fucal-4) GlcNAcP1-spacer Ga ^ 1-3 (Fucal-4) ΰΙσΝΑοβΙ-ΐΒΓρΐ ^ ΪΒ 2-polyacrylamide Gaipi-3 (Fucal-4) GlcNAcβl-O-tetradecyl

For the purposes of this application, particular compounds or portions thereof may be named or presented in a concise form in accordance with the guidelines for glycoproteins, glycopeptides and peptidoglycans proposed by the International Commission on Pure & Applied Chemistry and the International Union of Pure & Applied Chemistry. ., Vol 60, No. 9, pp. 1389-1988).

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of Formulas Ia, Ib, Ic, Id, Ie and If as defined above, or a mixture thereof with at least one anti-ophthalmic drug or at least one antibacterial compound or mixture thereof, and pharmaceutically an acceptable carrier.

The term anti-ophthalmic drug refers to a substance or composition that can reduce or participate in the reduction of ulcer formation in the gastrointestinal tract, particularly gastric and duodenal ulcers. A pharmaceutical composition according to the present invention containing such substances or compositions is potentially superior in that it has the dual effect of reducing ulceration on the one hand and reducing H. pylori infection in the stomach on the other, preventing bacteria from sticking to or reducing their adhesion to gastric and duodenal mucosa, which further improves the treatment of ulcer. Suitable anti-ophthalmic drugs include gastric secretion inhibiting compounds (particularly acid secretion inhibiting compounds) and antacids.

In a more preferred aspect of the present invention, the pharmaceutical composition is formulated for administration with a preparation commonly used in the treatment of gastritis or ulcer, such as preparations containing anti-opiate or anti-gastric agents such as omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine or nizatidine, or antacids such as magnesium hydroxide, aluminum hydroxide, calcium carbonate, sodium carbonate, sodium bicarbonate, simethicone or aluminum magnesium hydroxide or its hydrate (known as monohydrate), .

In another more preferred aspect of the present invention, the pharmaceutical composition is formulated for administration with a formulation for use in a course of treatment with an anti-bacterial agent such as the antibacterial agents described above, specifically formulations containing β-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefixime; or macrolides such as erythromycin or clarithromycin; or tetracyclines such as tetracycline or doxycycline; or aminoglycosides such as gentamicin, kanamycin or amikacin; or quinolones such as norfloxacin, ciprofloxacin or enoxacin; or other substances such as metronidazole, nitrofurantoin or chioramphenicol; or preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate.

In yet another aspect, the compounds Ib, Ic, Id, le and the invention are described

If formulas.

related above to all new defined Ia,

The compounds represented by the formulas Ia, Ib, Ic, Id, le and If may be prepared according to several general methods using monosaccharides or oligosaccharides as starting materials. Functional group transformations may be performed before or after glycosidic linkages are formed. Optionally, reactions that are specific to certain sites or the use of blocking with blocking groups may be required to transform functional groups at particular sites. The protecting groups may be removed or may form part of the compound of interest.

The compounds of the present invention may be obtained, for example, from the scheme below. While this scheme may show specific substituents or configurations, it must be understood with an appropriate degree of generality, various groups may acquire values from the full range as defined in the general formulas Ia, Ib, Ic, Id, le and If.

MONOSACHARIDES stage

OH OH Stage

Ra stage

In the first step, a monosaccharide such as L-fucose, D-galactose, D-glucose, 2-deoxy-2-phthalimid-D-glucose,

2-Deoxy-2-phthalimid-D-galactose, D-mannose, is converted into a glycoside with aglycones (Ra) e.g. SEt, SPh, OTMSEt, O-allyl or OBn (known aglycones in the art) to give R _a - a glycosidic derivative such that this R _a -glycoside can be transformed into a glycoside donor by activation of the anomeric center. This R _a -glycoside can be prepared as follows: The above monosaccharide is over-O-acylated with acetic anhydride pyridine or with acetic anhydride-sodium acetate or with benzoyl chloride pyridine. The per-O-acylated monosaccharide is treated with, for example, hydrobromic acid or hydrochloric acid in a suitable solvent, such as acetic acid or dichloromethane, to form the per-O-acylated glycoside bromide or chloride (e.g., about O-acylation and glycoside halide synthesis). see ML Wolfrom and A. Thompson, Methods in Carbohydrate Chemistry, Vol. 2, 211-215, ed. RIWhistler and ML Wolfrom, Academic Press, New York, 1963, G. Hewit and G. Fletcher Jr., ibid. 226-228, and RULemieux, ibid., 223-224). The aglycone (Ra) is coupled to the monosaccharide by reaction with an appropriate thioalcohol or alcohol, such as HSEt, HSPh, HSPh, HOTMSEt, HO-allyl or HOBn, with a per-Oacylated monosaccharide using a Lewis acid such as boron trifluoride ether (see e.g. RJ Ferrier and RH Furneaux, Carbohydr Res 52 (1976) 63-68,

J. Dahmen, T. Frejd, G. Gronberg, T. Lave, G. Magnusson, and G. Noori, Carbohydr. Res. 116 (1983), 303-307), or trimethylsilyl trifluoromethanesulfonate (see T. Ogawa, K. Beppu, S. Nakabayshi, Carbohydr. Res. 93 (1981), C6-C9) as a promoter. The reaction is carried out in suitable solvents such as chloroform, dichloromethane and / or toluene. When the monosaccharide derivative in question is per-O-acylated glycoside bromide or chloride, promoters such as silver trifluoromethanesulfonate or mercury (II) salts may be used (see, e.g., H. Paulsen, Angew, Chem. Int. Ed. Engi. 21 (1982), 155-173) and the reaction is carried out in suitable solvents such as dichloromethane and / or toluene.

The monosaccharide R _α -glycosides are obtained after des-O-acylation using sodium methoxide (see, e.g., Thompson, ML Wolfrom, and E. Pascu, Methods in Carbohydrate Chemistry, Vol. 2, 215-220, ed. R. L. Vihistler, and ML Wolfrom, Academic Press, New York, 1963) in methanol or methanol containing additional solvents such as dichloromethane or tetrahydrofuran.

In the second step, the monosaccharide R _α -glycoside is further modified. New functional groups (Rb) are introduced which will form part of the final product or act as blockers in subsequent glycosylation steps. Examples of functional group transformations include: OH groups, ethers or esters (see, e.g., Protective Groups in Organic Synthesis, ed. TW Greene and PGM Wuts, John Wiley & Sons INC., New York, 1991), OH groups i. , carbonates (see, e.g., J.March, Advanced Organic Chemistry Reaction Mechanisms, and Structure, 347, 3rd ed., John Wiley & Sons, New York, 1985, and references therein), reductive removal of OH groups via halides, sulfonates, or other pathways (see, e.g., J.March, Advanced Organic Chemistry, Reaction Mechanisms and Structure, 389-392, 394, 3rd Edition, John Wiley & Sons, New York, 1985, and references therein). and HH Baer, Pure Appl. Chem. 61 (7) (1989), 1217-1234, and references therein), OH groups to halogens (see, e.g., J. March, Advanced Organic Chemistry - Reaction Mechanisms, and Structure, 381-286, 3rd ed., John Wiley & Sons, New York, 1985, and references therein), OH groups to azido groups (see, e.g., J. March, Advanced Organ. c Chemistry - Reaction Mechanisms, and Structure, 380, 3rd edition, John Wiley & Sons, New

York, 1985, and references therein, and H.H. Baer, Pure Appl. Chem. 61 (7) (1989), 1217-1234, and references therein), OH groups to amino groups via azides or other routes (see, e.g., J. March, Advanced Organic Chemistry - Reaction Mechanisms, 798800, 1106, 3rd ed., John Wiley & Sons, New York, 1985 and references therein, and HH Baer, Pure Appl. Chem. 61 (7) (1989), 1217-1234, and references therein) OH- groups (see, e.g., J. March, Advanced Organic Chemistry - Reaction Mechanisms, and Structure, 1048-1120, 3rd Edition, John Wiley & Sons, New York, 1985, and references therein). . OH groups to exomethylene derivatives via ketogroups or other routes (see, e.g., J. March, John Wiley & Sons, Advanced Organic Chemistry, Reaction Mechanisms, and Structure, 400-404, 407, 845-854, 3rd ed. New York, 1985, and references therein), OH groups to alkyl groups via exomethylene derivatives and subsequent hydrogenation or other routes (see, e.g., HO House, Modern Synthetic Reactions,

1-130, 2nd edition, W. A. Benjamin, Ine., Menlo Park.

C.A., 1972, and references therein, or J. Yoshimura, Adv. Carbohydr. Chem. Biochem. 42 (1984), 69-134), and the substitution of OH groups with heterocyclic groups via different pathways (see, e.g., A. R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, 1985).

The third step involves condensation of the R _a -glycosides having the substituents described above for the functional groups (Rb) (a protecting group known in the art). In the case of an O-glycosidic linkage: one R _a -glycoside derivative is transformed into a glycosyl donor by activation at its anomeric center and exposed to another R _a -glycoside that has been transformed into a glycosyl acceptor by removing one or more blocking agents (see, e.g., H. Paulsen, Angew. Chem. Int. Ed. Engi., 21, 155-173 (1982), RR Schmidt,

Angew, Chem. Int. Ed. Engi. 25 (1986), 212-235, P. Fugedi, P. J. Garegg, H. Lonn, and T. Norberg, Glycoconj. J. 4 (1987), 97-108, Protective Groups in Organic Synthesis, eds., T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Ine., New York, 1991). On C-glycosidic bonds see, R. R. Smidth, and G. Effenberger, Liebigs Ann. Chem. (1987), 825-831, S. Czernecki, and G. Ville, Composite Materials (1989), 610-612, R. Preuss, and R. R. Schmidt.

Carbohydr. Chem. 10 (5) (1992), 887-900, O. Martin, ir

W. Lai, J. Org. Chem. 58 (1993), 176-185, or C.R. Bertozzi, P.D. Hoeprich, Jr., and M.D. Bednarski, <7. Org. Chem. 57 (1992), 6092-6094. For S-glycosidic bonds see, e.g., L-X Wang, N. Sakairi, and H. Kuzuhars, J. Chem. Soc. Perkin Trans. 1 (1990), 1677-1982, or

M. Blanc-Meusser, L. Vigne, H. Driguez, J. Lehman, J. Streck, and K. Urbahns, Carbohydr. Res. 224 (1982),

59-71. Further glycosidic linkages can be introduced by repeating step three.

In the fourth step, substituents (R _c ) are introduced at the reducing end. Rc is defined as (Ζχ-Ζ ₁₆ ) -R, where R and Ζχ-Ζ _{16 are} defined in Ia, Ib, Ic, Id, Ie and If. The term (Ζχ-Ζ ₁₆ ) -R must be interpreted as Ζχ-R, Z ₂ -R, Z ₃ -R,. . . Z ₁₆ -R. Activation of the oligosaccharide R _α -glycoside derivative obtained in Step 3 at the anomeric center of the reducing end and treatment with a suitable nucleophile yields 0-, C-, S- or N- glycosidic derivatives, respectively. If necessary, the final product is obtained by removing the protecting groups. When the compound of the invention is present in a compound with a particular matrix, the R _c glycoside derivative is further transformed by various routes into the final product (see, e.g., YG Lee, and RT Lee, Glycoconjugate, 121-164, edited by HJ Allen, and EC Kisailus, Dekker , New York, 1992, R. Roy, FD Tropper, and A. Romanowska, J. Soc. Chem. Commun. (1992), 1611-1613, or CP Sotwell and YC Lee,

Adv. Carbohydr. Chem. Biochem., Vol. 37 (1980), 225-281).

Copolymerization reactions to prepare copolymers of acrylamide and mono-, di-, tri- or oligosaccharide glycosides with or without a spacer according to known methods, for example, described by E. Kallin, H. Lonn, T. Norberg and M. Elofsson, J. Carbohydr. Chemistry S (4), 597-611 (1989) or M. Andersso and S. Oscarsson, Bioconjugate Chemistry, vol. 4 (3): 246-247 (1993). According to the general strategy for preparing these compounds, an olefinic group was attached to the hydrocarbon and then the derivative was copolymerized with acrylamide. The olefinic group was introduced into the carbohydrate or as an allyl glycoside at an early stage by acryloylation of the amino functional groups of the mono-, di-, tri- or oligosaccharide derivatives or by other known means.

As noted above, pharmaceutical preparations containing compounds of the general formulas Ia, Ib, lc, Id, Ie and If form another aspect of the invention.

The compounds of the present invention may be administered for general or topical administration and more preferred routes of administration are oral, injectable, rectal, transdermal, infusion or inhalation, as pharmaceutical compositions containing the active ingredients in the form of the parent compounds or pharmaceutically acceptable salts thereof. an acceptable carrier, which may be a solid, semi-solid or liquid form, or a swallowable capsule, and such formulations form another aspect of the invention. Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and of low toxicity to be suitable for administration to humans and animals to be treated. The compounds may also be administered without carriers. Examples of pharmaceutical preparations include tablets, capsules, dragees, solutions, droplets, nasal drops, inhalation aerosols, nasal spray, liposomes, and the like. Typically, the active ingredient will contain between 0.01 and 99% by weight of the formulation, e.g., between 0.05 and 20% by weight, in formulations for injection and between 0.1 and 50% by weight in formulations for oral use.

Preferably, the formulations are dosed, be it single dose preparations or multiple dose preparations.

In the preparation of dosage forms for oral administration containing the compounds of the invention, the active ingredient may be admixed with commonly used solid dust carriers such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, cereal starch, cereal starch, , laminar powder or citrus powder, cellulose derivative or gelatin, and may also contain lubricants such as magnesium or calcium stearate or Carbowax® or other polyethylene glycol waxes and compressed to form tablets or dragee cores. If the contents of the required dragee can be coated, for example, with concentrated sugar solutions which may contain gum arabic, talc, and / or titanium dioxide, or otherwise with a film-forming reagent dissolved in volatile organic solvents or mixtures of organic solvents. Dyes may be added to these coatings, for example, to distinguish the contents of the different active ingredients. When preparing soft gelatine capsules composed of gelatin and, for example, glycerol and plasticizer or similarly coated capsules, the active ingredient may be blended with Carbowax® or suitable oils such as sesame, olive or arachis oil. The hard gelatine capsules may contain granules of the active substance with solid dustable carriers such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch or cereal starch or amylopectin, cellulose derivatives and also gelatin, as magnesium stearate or stearic acid.

The formulations of the present invention may be formulated so as to release the active ingredient rapidly, sustainedly or over a period of time following administration to the patient, according to well-known procedures.

Multiple layers of the active drug, separated by slow dissolving shells, yield sustained release tablets. Another method of making sustained release tablets is to divide the dose of the active ingredient into pellets of different thickness and compress the pellets into tablets together with a carrier.

The active ingredient may also be incorporated into slow-release tablets made, for example, of fat and waxy substances or of a uniformly distributed tablet of an insoluble material such as physiologically inert plastic material.

Liquid preparations for oral use may be in the form of an elixir, syrup or suspension, for example, in the form of solutions containing from about 0.1% to about 20% by weight of active substance, sugar as well as ethanol, water, glycerol, propyl glycol optionally, a perfume, saccharin and / or carboxymethylcellulose as a dispersing agent. The formulations may additionally contain wetting agents, emulsifying and suspending agents, preservatives and sweetening agents.

Formulations for parenteral administration by injection may contain an aqueous solution of the active ingredient or a physiologically acceptable salt thereof, preferably in a concentration of 0.5 to 20%, and may also provide an optional stabilizing agent and / or buffering agent in aqueous solution. Ideally, the dosage units are sealed in ampoules.

There is limited knowledge of compounds that inhibit the adhesion of Helicobacter pylori to the mucosal surface and which are useful in the prevention or treatment of gastrointestinal disorders and diseases caused or promoted by Helicobacter pylori. Due to this limited knowledge, the doses of active ingredient administered may vary widely and may depend on various factors such as the severity of the infection, the age of the patient, etc. and may need to be individually adjusted.

More preferably, the pharmaceutical compositions of the invention contain from about 1 mg to about 50 g, preferably from about 10 mg to about 5 g, of the active ingredient per day and may be divided into multiple doses.

The invention is further illustrated by the following non-limiting examples.

below

R = OMe

NH ₂ χ CH ₃ COOh

15-18

OBn I OBn

H ₃ C

OBn ^ SEl

OBn = OCHjPh

OBn

R = ° ^ ^z ^ Si (CH ₃ ) 3

O

Οθζ e O Ph

R ^β θ ′ ^νΖ ^ Si (CH ₃ ) ₃

NHAc =

O

CH _{3 0} Bn = OCHjPh

R =

R = SEt • SEt

O

OAc =

O

OBn

H ₃ C

19 R = SEt 21 R = OMe 20 R = OMe OBn = OCH ₂ Ph 23 ^R = 0 Him NHAc = HN i OBn = OCH ₂ Ph 0 OAc = o ^A CH ₃ OH Hoe H ₃ CO

NHAc

R = OMe

R «

^Bn ? ^ OBn 8nO -K »» · SEt OR, ^Bn ? < ^OBn OR, 25 R, = Ac 27 R, = Bz. R ₂ = -CH ₂ CH ₂ N ₃ 26 R, = Bz 28 R, = H. R ₂ = -CH ₂ CH ₂ N ₃ 32 R, = Bz. R ₂ = - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ N ₃ 33 R, = K, R ₂ = - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ N ₃

r ₂ = -ch ₂ ch ₂ nh ₂ r ₂ = -CH ₂ CH ₂ NHCOCH ₂ R ₂ = - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ N ₃ R ₂ = - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ NH ₂ R ₂ = - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ NHCOCHCH ₂

o

NPhth = n'jT j

R, = Ac R ₂ = NPhth

R 1 = OH R ₂ = NHAc

46th R 1 = Bn r ₂ = n ₃ R ₃ = CHPh 47 R 1 = Bn R ₂ = NHCOCF 3 Rj = CHPh 48 R 1 = H R ₂ = NHCOCF 3 Rj = H 49 R 1 = H r ₂ = nhcochch ₂ R ₃ = H

R 1 = H 51 R 1 = H

R ₂ = NHAc R ₃ . R ₄ = CHPh R ₂ = NHAc R ₄ = HR ₃ = OBn

52 R 1 = Bn r ₂ = n ₃ r ₄ = Bn 53 R 1 = Bn R ₂ = NHCOCFa R ₄ = Bn 54 R 1 = H r ₂ = nhcocf ₃ r ₄ = h 55 fi, = H r ₂ = nhcoch ₂ r ₄ = h

OH

Fucal -2Gaipi -3 (Fuca1 -4) GlcNAcpi -3Gaipi -4Glcp-R,

R 1 = OH

R 1 = NH ₂

R 1 = NHCOCHCH ₂

42 r _{2 =} Fucal -2Galp1-3 (Fuca1-4) GlcNAcpi-3Gaipi-4Glcpi -NH H ₂ Ni J 38 R ₂ = Fucal-2Gaipi-O (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ NH 58 R ₂ = Fucal-2Gaipi-CH ₂ CH ₂ NH 1 h ₂ n- < ^c 1 50 R ₂ «Fucal-2Gaipi-3GlcNAcpi-CH ₂ CH ₂ NH <h ₂ n— ( 56 R ₂ = Fucal -2Gaipi -3 (Fuca1 -4) GlcNAcpi -CH ₂ CH ₂ NH (

0 = 0 0 = 0 0 = 0 0 = 0

General Methods ¹ H and ¹³ C NMR spectra of Examples 1-6 were recorded with a Varian Gemini 300 spectrometer and with a Varian Unity 400 MHz spectrometer. The following reference signals were used in Examples 1-6: CHCl 3, δ 7.25 ( ^X H from CDCl 3); CHCl ₃ , δ 77.9 ( ¹³ C from CDCl ₃ ); (CH ₃ ) ₂ CO, δ

2.24 or CHD ₂ OH δ 3.31 ( ^X H of D ₂ O); (CH ₃ ) ₂ CO, δ 33.19 ar

CHD ₂ OH δ 51.89 ( ¹³ C from D2O); CHD2OH δ 3.31 ( ^T H from CD3OD).

The H and C NMR spectra of all other samples were recorded at 25 ° C in CDC1 ₃ medium (using tetramethylsilane as the ³ H internal standard, and CDC1 ₃ δ 77.9 for ¹³ C). The NMR spectra recorded for all compounds were consistent with the postulated structures, and only selected data were reported. Mass spectra to determine the degree of substitution of carbohydrate components against proteins were obtained with a VG TOFSPEC linear flight mass spectrometer. FAB-MS was performed on a Nergman 1010L, with an Iontech FAB cannon and a thioglycerol matrix. The rotation of the polarization plane was measured using a Perkin Elmer 241 polarimeter. Thin layer chromatography (TLC) was performed on Merk DC-Fertigplatten (Kiselgel 60 F254 0.25 mm) and the spots were visualized by UV or spraying with 10% sulfuric acid followed by heating or spraying with phosphomolybdic acid or ninhydrin in 0.5% n-butanol. ). Silica gel 60 (40-63 λτη) and Amicon Matrex® Silicia Si 0.35-0.70 m were used for column chromatography.

Separation was also performed on Chromatotron® rotary TLC using a 1-2 mm layer of silica gel 60 PF254 with gypsum. All Biogel® P-2 columns were washed with 1% n.butanol in deionized water unless otherwise stated.

EXAMPLE

Methyl 2-acetamide-2-deoxy-3-0-αL-fucopyranosyl-β-D-glucopyranoside (4) (i) Methyl 4,6-O-benzylidene-3-O- (tri-O-benzyl-αL-fucopyranosyl) -2-deoxy-2-phthalimide-PD-glucopyranoside (2)

Trifluoromethanesulfonic acid (2 μΐ 0.023 mmol) was added to the stirred ethyl 3-0- (tri-O-benzyl-αL-fucopyranosyl) -4,6-O-benzylidene-2-deoxy-2-phthalimid-1-thioβ-D- glucopyranoside (1) (100 mg, 0.117 mmol) (prepared by H. Lonn, Carbohydr. Res. 139 (1985), 105-113), methanol (7 μΐ, 0.175 mmol), N-iodosuccinimide (40 mg, 0.175) mmol) and a mixture of triturated molecular sieves (100 mg, 3 A) in dichloromethane-diethyl ether (3 mL, 2: 1) at -30 ° C. After 45 min, the reaction mixture was filtered through a pad of Celite into an aqueous solution of sodium bicarbonate and sodium bisulfite. The organic layer was separated, washed with aqueous sodium chloride and concentrated. Column chromatography (toluene acetyl acetate, 20: 1) gave the amorphous (2) (93 mg,

97%), [α] D -16.2 ° (c 1.0, CHCl 3).

1 H NMR (CDCl 3 ·, δ): 7.80 to 7.0 (24H, benzyl and phthaloyl), 5.29 (d, 1H, J 8.6 Hz, H 1), 4.84 to 4.25 (5H, CH ₂ Ph), 4.84 pis, 1H, H1), 4.66 (dd, 1H, J 8.5 and 10.3 Hz, H-3), 4.48 to 4.43 (m , 1H, H-3 '), 4.35 (dd, 1H, J 8.6 and 10.3 Hz, H-2), 4.08 (pldd, 1H, J 6.4 and 13.0 Hz, H-5 '), 3.91 to 3.81 (2H), 3.78 to 3.66 (4H), 3.51 to 3.47 (1H), 3.48 (s, 3H, OCH ₃ ) , 0.90 (d, 3H, CH ₃ ).

C NMR (CDCl3, δ): 168.0 (CO), 138.8 to 123.0 (benzyl), 101.1 (CHPh), 99.7 (C-1 '), 99.4 (C-1),

82.1, 79, 5, 78.0, 75.7, 75.5, 74.6, 73.0, 72.5, 68.6,

67.2 (C-5 '), 66.1, 56.9 (OCH ₃ ), 55.5 (C-2), 16.3 (CH ₃ ).

(ii) Methyl 2-acetamide-3-0- (2,3,4-tri-O-benzyl-α-fucopyranosyl) -4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside (3)

A solution of (2) (1.13 g, 1.36 mmol) and hydrazine hydrate (3.3 mL, 68 mmol) in aqueous 59% ethanol was heated at reflux for 20 h, cooled and concentrated. The residue was acetylated with acetic anhydride-pyridine (50 mL, 1: 1) overnight. The solution was concentrated and the column chromatography (heptane-ethyl acetate, 1: 1 residue gave crude (3) which was used directly in the next step.

³ H NMR (CGCl ₃ , δ): 7.50 to 7.23 (20H, benzyl), 5.71 (d, 1H, J 7.4, NH), 5.52 (s, 1H, CH ₂ Ph), 5.09 (d, 1H, Hl ') 4.85 to 4.58 (6H, CH ₂ Ph), 4.82 (d, 1H, Hl), 4.37 (dd, 1H , J 4.6 and 10.4 Hz, H-6), 4.28 (bt, 1H, H-3), 4.12 to 4.05 (2H, H-2 'and H-5'), 3.95 (dd, 1H,

J 2.6 and 10.2 Hz, H-3 '), 3.78 (bt, 1H, H-6), 3.63 (bs, 1H, H-4 '), 3.60 (bt, 1H, H-4) , 3.53 (m, 1H, H-5), 3, 48 (s, 3H, OCH ₃ ), 3.42 (ddd, 1H, J 7.2, 8.2 and 9.5 Hz, H-2), 1.67 (s, 3H, NHAc), 0.84 (d, 3H, CH ₃ ). ¹³ C NMR data (CDC1 ₃ ), δ): 170.6 (CO), 138.6 to 126.2 (benzyl), 101.8 (C-1), 101, 6 (CHPh), 98.4 (C-1 '), 80, 8

(C-4), 79.8 (C-3 '), 77.6 (C-4'), 77.0 (C-2 'or C-5'),

75.1 (C-3), 74.9 (CH ₂ Ph), 72.5 (CH ₂ Ph), 68.8 (C-6), 66.9 (C-2 'or C-5'), 66 , 2 (C-5), 58.1 (C-2), 57.0 (OCH ₃ ),

23.2 (NHAc), 16.3 (CH ₃ ).

(iii) Methyl 2-acetamide-2-deoxy-3-O-α-L-fucopyranoic acid-β-D-glucopyranoside (4)

A solution of crude (3) (1.05 g) in acetic acid-ethyl acetate-water (9: 5: 1, 120 mL) was hydrogenated at 200 kPa 10% Pd / C (1 g) overnight. The mixture was filtered through a pad of Cel and concentrated 3434 B. Column chromatography (chloroformasmetanol IS-water, 65: 35: 6) of the residue gave amorphous (4) (469 mg, 90% over the range (2), [a] _n - 116 O ^{1 1} (c 1.0, water ).

H NMR data (D _? O, acetone atramin. δ,): 4.99 (d, 1H, J 4.0 Hz, H-1 '), 4.46 (d, 1H, J 8.7) Hz, H-1), 4, 33 (bdd, 1H, H-5 '), 3.98 to 3.45 (9H), 3.51 (s, 3H, OCH 3), 2.03 (s, 3H, NHAc), 1.17 (d, 3H, CH-).

'' c NMR (D ₂ 0, acetone atramine, δ) 177.6 (CO), 104.7 (Cl), 102.9 (C-1 '), 83.5, 78.8, 74, 7, 72.5,

71.6, 70.9, 69.9, 63.7, 60.0, 59.1 (C-2), 25.2 (NHAc),

18, 1 (CH-,).

EXAMPLE

3,3-Dimethylbutyl 2-acetamide-2-deoxy-3-0-αL-fucopyranosyl-pD-glucopyranoside (7) (i) 3,3-Dimethylbutyl 3-0- (2,3,4-tri-O- benzyl-α-fucopyranosyl) -4,6-O-benzylidene-2-deoxy-2-phthalimid-3-D-glucopyranoside (5)

Tri fluoromethanesulfonic acid (30 μΐ 0.35 mmol) was added to mixed (1), 3,3-dimethyl-butan-1-ol (317 μΐ, 2.62 mmol), N-iodosuccinimide (602 mg, 2.62 mmol) ) and triturated molecular sieve (1.5 mg, 3 A) in dichloromethane-diethyl ether (2: 1, 45 mL) at -30 ° C. After 45 min, the reaction mixture was filtered through a pad of Celite into an aqueous solution of sodium bicarbonate and sodium bisulfide. The organic layer was separated, washed with aqueous sodium chloride, and concentrated. Column chromatography (heptanoacetyl acetate, 6: 1) gave the residue amorphous (5) (1.42 g,

90%), [α] -22.2 (c, 1.0, CHCl 3).

^{Τ Η} NMR data (CDC1 _3, δ): 7.80 to 7.0 (24H, benzyl

and phthaloyl), 5.57 (s, 1H, CHPh), 5.35 (d, 1H, J 8.5 Hz, H-1), 4.84 (bs, 1H, H-1 '), 4.83 to 4.24 (5H, CH ₂ Ph), 4.65 (dd, 1H, J 8.3) and 10.3 Hz, H-3), 4.34 (dd, 1H, J 8.5 and 10.4 Hz, H-2), 4.07 (dd, 1H , J 5.5 and 10.4

Hz, H-5 '), 3.96 to 3.66 (7H, overlapping OCH ₂ ),

3.53 to 3.45 (2H, overlapping OCH ₂ ), 1.46 to 1.29 (m, 2H, CH ₂ C (CH ₃ ) ₃ ), 0.88 (d, 3H, J 6.4 Hz) ., CH ₃ ), 0.73 (s, 9H, CH ₂ C (CH ₃ ) ₃ ).

¹³ C NMR (CDCl ₃ , δ): 168.0 (CO), 138.8 to 123.0 (benzyl and phthaloyl), 101.1 (CHPh), 99.4 (C-1 '),

98.9 (Cl), 82.1, 79, 5 76, 0 75.7 (C-3), 75.6, 74, 6, 73.0, 72.6, 68.7, 67.3 ( OCH ₂ ), 6.72 (C-5), 66.2, 55.8 (C-2), 42.4 (CH ₂ C (CH ₃ ) ₃ ), 30.8 (CH ₂ C (CH _{3) 3} ), 29.4 (CH ₂ C (CH ₃ ) ₃ , 16.3 (CH ₃ ).

(ii) 3,3-Dimethylbutyl 3-0- (2,3,4-tri-O-benzyl-α-L-fucopyranosyl) -2-acetamide-4,6-O-benzylidene-2-deoxy-pD-glucopyranoside ( 6)

A solution of (5) (1.42 g, 1.58 mmol) and hydrazine hydrate (3.9 mL, 79 mmol) in aqueous 90% ethanol (100 mL) was heated under reflux for 20 h, cooled and concentrated. The residue is acetylated with acetic anhydride-pyridine (50 mL, 1: 1) overnight.

Concentrate the solution. Column chromatography (heptane-ethyl acetate 3: 1 containing 1% methanol) gave the amorphous (6) (1.16 g, 90%), [d] _D -74.7 ° (c,

1.0, CH ₃ Cl ₃ ).

1 H NMR (CDCl ₃ , δ): 7.50 to 7.20 (20H,

benzyl), 5.63 (d, 1H, J 7.3 Hz, NH), 5.51 (s, 1H, CH ₂ Ph), 5.07 (d, 1H, J 3.1 Hz, H-1 '), 4.93 to 4.57 (6H, CH ₂ Ph), 4.92 (d, 1H) , H-l), 4.39 to 4.29 (2H, H-6 and H-3), 4.11 to 4.04 (2H, H-2 'and H-5'), 3, 98 to 3, 85 (2H, H-3 'and OCH ₂ ), 3.77 (bt, 1H, H-6), 3 , 61 (pis,

1H, H-4 '), 3.55 (bt, 1H, H-4), 3.59 to 3.44 (2H, H-5 and OCH ₂ ), 3.33 (pldd, 1H, H-2). ) 1.63 (s, 3H, OAc), 1.56 to 1.40 (m, 2H, _CH? C (CH _{3) 3),} 0.89 (s, 9H, CH ₂ C (CH ₃₎ J,

0.82 (d, 3H, CH ₃ ).

¹³ C NMR (CDCl ₃ , δ): 170.4 (CO), 138.6 to 126.0 (benzyl), 101.6 (CHPh), 100.7 (Cl), 98.1 (C-1). '),

80.9 (C-4), 79.8 (C-3 '), 77.6 (C-4'), 77.0 (C-2 'or C5'), 74.9 (C-3) , 74.8 (CH ₂ Ph), 74.0 (CH ₂ Ph), 72.5 (CH ₂ Ph), 68.9 (OCH ₂ or H-6), 67.5 (OCH ₂ or H-6) ),

66.8 (C-5 'or C-2'), 66.2 (C-5 '), 58.6 (C-2), 42.7 (CH ₂ C (CH ₃ ) ₃ ), 29, 7 (CH ₂ C (CH ₃ ) ₃ ), 29.6 (C (CH ₃ ) ₃ ), 23.2 (NHAc), 16.2 (CH ₃ ).

(iii) 3,3-Dimethylbutyl 2-acetamide-2-deoxy-3-O-α-L-glucopyranosyl-β-D-glucopyranoside (7)

A solution of compound (6) (1.08 g, 1.33 mmol) in acetic acid: ethyl acetate: water 9: 5: 1 (120 mL) was hydrogenated at 200 kPa 10% Palladium on charcoal (Pd / C) (1 g) overnight. The mixture is filtered through a pad of Celite and concentrated. The residue from column chromatography (chloroform: methanol-water, 100: 30: 3) gave amorphous (7) (566 mg, 94% 0, [α] _D -109.7 ° (c, 1.0, water).

^Χ Η NMR (D ₂ O, acetone atramine, δ): 4.99 (d, 1H, H-1 ') 4.84 (s, 1H, CHPh), 4.34 (bdd, 1H, H- 5 '), 4.02 to

3.43 (11H), 2.01 (s, 3H, NHAc), 1.57 to 1.41 (m, 2H,

CH ₂ C (CH ₃ ) ₃ ), 1.17 (d, 3H, CH ₃ ), 0.90 (s, 9H, C (CH ₃ ) ₃ ).

¹³ C NMR data (D ₂ O, acetone support, δ): 177.3 (CO),

103.6 (C-1), 102.8 (C-1 '), 83.6, 78.8, 74.8, 72.5,

71.6, 70, 9, 69, 8, 63, 7, 58, 1 (C-2), 44.9 (CHC (CH ₃ ) ₃ ),

31.9 (C (CH ₃ ) ₃ ), 31.9 (C (CH ₃ ) ₃ ), 25.2 (NHAc), 18.1 (CH ₃ ).

EXAMPLE

Fucal-3GlcNAcpi-O-Intermediate 1-BSA Compound (11) (i) S-Azide-3,6-dioxaoctyl 3-O-tri-O-benzyl-α-fucopyranosyl) -4,6-O-benzylidene- 2-Deoxy-2-phthalimide-3-D-glucopyranoside (8) Rinsed with bisulfite

Trifluoromethanesulfonic acid (24 μΐ, 0.27 mmol) was added to stirred (1) (1.15 g, 1.34 mmol), 8-azide-3,6-dioxaoctan-1-ol (352 μΐ, 2.01 mmol) ( prepared by PH Amvam-Zollo and P. Sinai, Carbohydr. Res. 150 (1986), 199-212), N-iodosuccinimide (461 mg, 2.01 mmol) and truncated molecular sieves (1.15 g, 3 A). of dichloromethane-diethyl ether (30 mL, 2: 1) at -30 ° C. After 1 h, the reaction mixture was filtered through a pad of Celite into an aqueous solution of sodium bicarbonate and sodium. The organic layer was separated and centered with aqueous sodium chloride. Column chromatography ethyl acetate 2: 1) The residue gave amorphous (8)

79%), [α] _D -21.7 ° (c, 1.0, CHCl ₃ ).

and configure for (heptane (1.03 g ^H NMR data (CDC1 _3, δ): 7.80 to 7, 05 (24H, Bzl,

Phth), 5.59 (S, 1H, CHPh), 5.44 (d, 1H, J 8.6 Hz, H-1),

4.83 (bs, 1H, H-1 '), 4.83 to 4.24 (5H CH ₂ Ph), 4.65

(dd, 1H, J 8.5 and 10.3 Hz, H-3), 4.45 to 4.41 (1H, H-3 '), 4.39 (dd, 1H, J 8.6 and 10.3 Hz, H-2), 4.09 (dd, 1H, J 6.4 and 12.6 Hz, H-5 '), 3, 99 to 3.83 (3H, over- sliding OCH ₂ ), 3.81 to 3, 68 (5H, overlapping OCH ₂ ), 3.61 to 3.30 (11H, overlapping OCH ₂ and CH ₂ N ₃ ), 0.90 (d, 3H, J 6.4 Hz, CH ₃ ).

¹³ C NMR (CDCl ₃ , δ): 169.0 (CO), 138.9 to 123.1 (Bzl, Phth), 101.1 (CH ₂ Ph), 99.4 (C-1 '), 98.9 (Cl),

82, 1, 79, 6, 78.0, 75, 6, 75, 5, 74.7, 73, 1, 72.6, 70.5

70.4, 70.1, 69, 9 69, 168.7 67.2, 66, 2, 55, 7 (C-2),

50, 6 (CH ₂ N 3), 16.4 (CH ₃ ).

(ii) 8-Azide-3,6-dioxaoctyl 2-acetamide-3-O- (2,3,4-triO-benzyl-α-L-fucopyranosyl) -4,6-O-benzylidene-2-deoxy-β- D-glucopyranoside (9)

A solution of (8) (633 mg, 0.65 mmol) and hydrazine hydrate (1.6 mL, 33 mmol) in aqueous 90% ethanol (45 mL) was refluxed for 24 h, cooled and concentrated. The residue was acetylated with acetic anhydride-pyridine (50ml, 1: 1) overnight.

Concentrate the solution. Column chromatography (chloroform-acetone, 9: 1) and repeated chromatography (ethyl acetate-heptane, 3: 1) gave amorphous (9), (440 mg, 77%), [α] _D -72.6 ° (s, 1). , 0, CHCl ₃ ).

³ H NMR (CDCl ₃ , δ): 7.50 to 7.25 (20H, benzyl), 7.92 (d, 1H, J 5.9 Hz, NH), 5.51 (s, 1H, CHPh) ),

5.16 (d, 1H, J 3.5 Hz, H-1 '), 4.93 (d, 1H, J 7.7, H-1),

4.95 to 4.56 (6H, CH ₂ Ph), 4.34 (dd, 1H, J 4.9 and 10.4 Hz, H-6), 4.26 (bt, 1H, H-3) , 4.12 (pdd, 1H, H-5 '), 4.06 (dd, 1H, J 3.6 and 10.1 Hz, H-2'), 3.95 (dd, 1H, J 2, 7 and 10.1 Hz, H-3 '), 3.90 (bt, 1H, H-6), 3.81 to 3.45 (14H, overlapping OCH ₂ ), 3.40 (m, 2H, CH ₂ N 3), 1.74 (s, 3H, NHAc), 0.84 (d, 3H, J 6, 4 Hz, CH ₃ ).

¹³ C NMR (CDCl ₃ , δ): 170.4 (CO), 138.7 to 126.1 (benzyl), 101.5 (CHPh), 101.2 (Cl), 97.8 (C-1). '),

80.6 (C-4 '), 79.6 (C-3'), 77.7 (C-4 '), 76.7 (C-2' ar

C-5 '), 74.9 (C-3), 74.6 (CH ₂ Ph), 73.7 (CH ₂ Ph), 72.2 (CH ₂ Ph), 70.6 (CH ₂ O) , 70.6 (CH ₂ O), 70.4 (CH ₂ O), 69.9 (CH ₂ O), 68.8 (CH ₂ O), 68, 8 (H-6), 66.7 ( C-2 'or C-5'),

66.2 (C-5), 57.8 (C-2), 50.6 (CH ₂ N ₃ ), 23.2 (NHAc),

16.2 (CH ₃ ).

(iii) Acetic acid salt of 8-Amine-3,6-dioxaoctyl 2-acetamide-2-deoxy-3-Oa-L-fucopyranosyl-3-D-glucopyranoside (10)

A solution of (9) (57 mg, 0.065 mmol) dissolved in acid-water (9: 1, 30 mL) was hydrogenated at 200 kPa with 10% Pd / C (100 mg) overnight. The mixture was filtered through a pad of Celite and concentrated. Column chromatography on silica gel (chloroform-methanol-water, 4: 4: 1) followed by Al ₂ O ₃ (Merck, basic, 0, 063-0, 200 mm, chloroform-methanol-water, 4: 4). : 1) gave amorphous (10) (18 mg, 51%), [α] _D -70, 6 ° (c, 0.2 water).

NMR (D ₂ O, acetone atramine, δ): 4.98 (d, 1H, J 4.0 Hz, HI), 4.53 (d, 1H, J 8.6 Hz, HI), δ 32 (bdd, 1H, H-5 '), 4.05 to 3.42 (19H), 3.19 (m, 2H, CH ₂ NH _2), 2.01 (s, 3H, NHAc) 1 , 88 (CH ₃ COOH), 1.14 (d, 3H,

J 6, 6 Hz, CH ₃ ).

C NMR (D ₂ O, acetone atramine, δ): 184.2 (CH ₃ COOH), 103.8 (Cl), 102.8 (C-1 '), 83, 3, 78.8, 74 , 8,

72, 6, 72.5, 72.4, 72, 0, 71.5, 70, 9, 69, 8, 69, 4, 63, 7, 58.1 (C-2), 42, (CH ₂ NH ₂ ), 2 6, 3 (CH ₃ COOH), 25, 2 (NHAc), 25.2 (NHAc), 18.1 (CH ₃ ).

(iv) Fucal-3GlcNAcPl-O-Sealer 1-BSA-Compound (11)

Thiophosgene (67 μΐ, 0.0856 mmol) in acetone (6 mL) was added dropwise to an ice-cold solution of (10) (120 mg,

0.214 mmol) dissolved in water-ethanol-0.1 M phosphate buffer pH 7 (1: 1: 1, 30 mL). During the reaction, the pH was maintained near 6-7 with aqueous sodium hydroxide (1 M). After 20 min, the mixture was extracted with diethyl ether (30 mL), concentrated to a volume of 10 mL, and added to a solution of bovine serum albumin (695 mg,

10.7 mmol) in aqueous sodium bicarbonate (15 mL,

0.1 M, pH 9.3). The pH of the formulation is maintained at about 9 with aqueous sodium hydroxide (1M). After 24 h, the reaction mixture was desalted by filtration on (Filtron, omegacell 150, 10 K) and freeze-dried to give (11) (672 mg). The degree of substitution was determined by analyzing sugars (see M.A. Jermyn, Anai, Chem. 68 (1975), 332-335) to 15-18 mol disaccharides / mol protein.

EXAMPLE

2-Trimethylsilylethyl 2-acetamide-2-deoxy-4-O-α-fucopyranosyl-β-glucopyranoside (16) (i) Trimethylsilylethyl 3,6-di-O-benzoyl-2-deoxy-2-phthalimid-pdD-glucopyranoside (13) )

2-Trimethylsilylethyl-2-deoxy-2-phthalimide-β-D-glucopyranoside (12) (1.64 g, 4.0 mmol) was synthesized according to

K. Jansson, S. Ahlfors, T. Frejd, J. Kilhberg, G. Magnusson, J. Dahmen, G. Noori, and K. Stenvall, J. Org. Chem. 53 (1988) 5629-5647) was dissolved in pyridine-dichloromethane (3: 1, 24 mL) and cooled to -45 ° C. A mixture of benzoyl chloride (1060 mL, 9.1 mmol) and pyridine (900 mL ·) was added over a minute. The reaction was completed after 3 hours and methanol (40 mL) was added. The solvents were evaporated and the residue co-evaporated with toluene 3 times. Chromatography of the residue (SiO ₂ , heptane / ethyl acetate 2: 1 → 1: 1) gave pure (13) (2.38 g, 96%). [α] _D ²⁰ + 69.4 ° (c, 1.2, CHCl ₃ ).

¹ H NMR (CDCl ₃ , δ): d 7.3-8.2 (m, 14H, 2-O-benzyl, N-phthalamoyl), 5.88 (dd, 1H, J 7.1, 8.3 Hz, H-3),

5.46 (d, 1H, J 8.5 Hz, H-1), 4.79 (dABq, 1H, J 4.2,

12.4 Hz, H-6), 4.67 (dABq, 1H, J 1.9 11.7, Hz, H-6),

4.45 (dd, 1H, J 8.4, 10.8 Hz, H-2), 3.8-4.1 (m, 3H, H-4, H5, OCH ₂ CH _2), 3.57 (dt, 1H, J 7.2, 9.7 Hz, OCH ₂ CH ₂ ), 0.71.0 (m, 2H, CH ₂ Si), -0.15 (s, 6H, SiMe ₃ ).

(ii) 2-Trimethylsilylethyl 3,6-di-O-benzoyl-4-O- (2,3,4-tri-O-benzyl-α-L-fucopyranosyl) -2-deoxy-2-phthalimide-β-D-glucopyranoside (15)

Compound (13) was dissolved in dichloromethane-N, N-dimethylformamide (8 mL, 5: 3) and tetrabutylammonium bromide (664 mg, 2.06 mmol) and molecular sieves (3 A, 4 g, activated) were added. To the thioethyl 2,3,4-tri-O-benzyl-1-thio-4-L-fucopyranoside (14) (986 mg, 2.06 mmol) was synthesized according to H. Lonn, Carbohydr. Res. 139 (1985), 105-113) Bromine (122 mL, 2.37 mmol) in dichloromethane (2 mL) was added to a solution of dichloromethane (8 mL). After stirring for 15 min, cyclohexane (distilled) was added dropwise until the bromine color disappeared. This solution is then added to the above mixture containing compound (13) and stirred for 48 h. The mixture was filtered through Celite, the solvents evaporated and the residue co-evaporated with toluene 3 times. Column chromatography of the residue (heptane / ethyl acetate, 5: 1 → 1: 1) gave (15) (896 g, 85%), [α] D + 14.6 ° (c 1.2, CH 3 Cl 3).

NMR data (CDC1 _3, 6): 5.44 (d, 1H, J 8.5 Hz, Hl), 4.80 (d, 1H, J 3.6 Hz, Hl ").

(iii) 2-Trimethylsilylethyl 2-acetamide-2-deoxy-4-O- (aL-fucopyranosyl) -β-D-glucocopyranoside (16)

Compound (15) (760 mg, 0.74 mmol) was dissolved in methanol (7 mL) and sodium methoxide (220 mL, 2M in methanol) was added. The solution was stirred overnight at room temperature and neutralized with Amberlite IR-120 (H). After filtration and evaporation of the solvents, a syrup was obtained. This syrup was dissolved in acetic acid (15 mL) and 10% Pd / C (860 mg) was added. After 1.5 h of hydrogenation (100 kPa), the mixture was filtered and the solvents evaporated. The resulting syrup was dissolved in ethanol (18 mL) and hydrazine hydrate was added. The solution was heated under reflux for 3 h. Evaporation of the solvents and co-evaporation with ethanol 5 times gave a syrup which was dissolved in methanol-water (5: 1, 60 ml). Acetic anhydride (5 ml) was added and the solution stirred for 1.5 h. The solvents are evaporated. Column chromatography (SiO ₂ , dichloromethane / methanol, 5: 1) gave (16) (100 mg, 29%), [α] 20 D -113.5 ° (c 0.7, H ₂ O).

NMR (D ₂ O, δ): d 4.93 (d, 1H, J 3.66 Hz,

H-1 '), 4.52 (d, 1H, J 8.06 Hz, H-1).

EXAMPLE

Methyl 2-acetamide-2-deoxy-6-O-α-L-fucopyranosyl-3-D-glucopyranoside (22) (i) Ethyl 2-deoxy-2-phthalimide-1-thio-β-D-glucopyranoside (18)

Ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-1-thio-pD-glucopyranoside (17) (5.79 g, 12 mmol) (obtained from H. Lonn, Carbohydr. Res. (1985) 139, 105-112) was dissolved in methanol (250 mL) and methanolic sodium methoxide (0.2 M, 2.5 mL) was added. The solution was stirred for 15 h. After neutralization with acidic cationic resin (Bio-Rad AG® 50W-X8), filtration, evaporation and crystallization from water, (18) (3.83 g, 89%), m.p. t. 96 ° C; melt t. after recrystallization at 159-161 ° C; [α] D + 9.8 ° (c 0.9, methanol).

¹ H NMR (CD ₃ OD, CHD ₂ OD standard, δ) d: 7.91-7.79 (5H), 5.32 (d, 1H, J 10.5, Hz, H1), 4, 28 (dd, 1H, J 10 and 8 Hz, H-3), 4.05 (t, 1H, J 10.5 Hz, H-2), 3.93 (dd, 1H, J 12 and 2 Hz, H-6), 3.73 (dd, 1H, J 12 and 5.5 Hz, H-6),

3.46 (ddd, 1H, J 10, 5.5 and 2 Hz, H-5), 3.40 (dd, 1H, J 10 and 8 Hz, H-4), 2.74 (dkv, 1H, J 12.5 and 7.5 Hz,

SCH), 2.63 (dkv, 1H, J 12.5 and 7.5 Hz, SCH), and 1.17 (t, 3H, J 7.5 Hz, CH ₃ CH ₂ ).

(ii) Ethyl 3,4-di-O-acetyl-6-O- (2,3,4-tri-O-benzyl-α-L-fucopyranosyl) -2-deoxy) -2-phthalimide-1-thio-pD -glucopyranoside (19)

Bromine (0.485 mL) was added to a solution of ethyl 2,3,4-tri-O-benzyl-1-thio-α-α-fucopyranoside (14) (4.5 g, 9.4 mmol) in dichloromethane (70 mL) at 0 ° C. , 9.4 mmol). The mixture was stirred for 35 min and then evaporated twice with benzene. Cyclohexane (0.5 mL) was added and the mixture was evaporated again with benzene. The residue was dissolved in dichloromethane (25 mL) and then added over 1 h to a stirred mixture of compound (18) (3.32 g, 9.4 mmol), crushed molecular sieves (20 g, 4 A) and tetraethylammonium bromide ( 3.5 g) dimethylformamide (75 mL). The reaction mixture was stirred for 2 h at 0 ° C, then for 2 h at room temperature and then filtered through Celite. The filtrate is partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and concentrated. The residue was chromatographed (ethyl acetate / heptane; 1: 1 → 3: 1) to give the crude product, which was O-acetylated by stirring with acetic anhydride (50 mL) and pyridine (75 mL) at room temperature for 17 h.

Evaporation with toluene and chromatography (ethyl acetate: heptane; 1: 2 → 1: 3) gave (19) (3.3 g, 40%), [a]

4.6 ° (c 1.4, chloroform).

¹ H NMR (CHCl ₃ , δ): 7.90-7.83 (2H), 7.79-7.71 (2H), 7.45-7.24 (15H), 5.83 (dd, 1H, J 10 and 9.5 Hz, H-3),

5.43 (d, 1H, J 10.5 Hz, H-1), 5.09 (dd, 1H, J 10 and 9.5

Hz, H-4), 4.99 and 4.67 (2H, AB-System, J 11th , 5 Hz, ben- zill H), 4.97 (d, 1H, J 3.5 Hz, H-1 '), 4, 89 and 4.77 (2H, AB system, J, 12 Hz, benzyl H), 4, 79 and 4.73

(2H, AB-system, J, 12 Hz, benzyl H), 4.39 (t, 1H,

J 10.5 Hz), 4.06 (dd, 1H, J 10 and 3.5 Hz), 3.97-3.87 (3H), 3.76 (dd, 1H, J 12 and 6 Hz), 3.70-3, 62 (2H), 2.67 (dkv, 1H, J 12 and 7.5 Hz, SCH), 2.56 (dkv, 1H, J 12 and

7.5 Hz, SCH), 1.98 (s, 3H), CH ₃ CO), 1.87 (s, 3H, CH ₃ CO),

1.15 (1.3H, J 7.5Hz, CH ₃ CH ₂ ), 1.13 (d, 3H, J 7.5Hz,

Fuc-CH ₃ ).

Calculated,%: C ₄₇ H ₅₁ NO ₁₂ S Compounds: C 66.1; H, 6.02; N, 1.64; S, 3.75. Found; %: C, 66.4; H, 6.1; N, 1.55. S, 3.25.

(iii) Methyl 3,4-di-O-acetyl-6-O- (2,3,4-tri-O-benzyl-α-fucopyranosyl) -2-deoxy-2-phthalimide-β-D-glucopyranoside (20)

Trifluoromethanesulfonic acid (0.030 mL, 0.3 mmol) was added to a mixture of (19) (853 mg, mmol) methanol (0.102 mL, 2.5 mmol), N-iodosuccinimide (344 mg, 1.52 mmol) and triturated molecular sieves (0.9 g, 4 A) in dichloromethane-diethyl ether (2: 1, 25 mL) at -30 ° C. After 2.5 h, the reaction mixture was filtered through Celite into an aqueous solution of sodium bicarbonate and sodium bisulfite. The organic phase was separated, washed with saturated aqueous sodium chloride and concentrated. Chromatography of the residue (ethyl acetate-heptane, 2: 3) gave (20) (778 mg, 94%), [α] 25 D -2.8 ° (c, 1.1, chloroform).

¹ H NMR (CHCl ₃ , δ): 7, 90-7, 82 (2H), 7.78-7.70 (2H), 7.45-7.24 (15H), 5.79 (dd, 1H, J 11 and 9 Hz, H-3),

5.26 (d, 1H, J 8.5 Hz, H-1), 5.08 (dd, 1H, J 10 and 9 Hz, H-4), 4.99 and 4.67 (AB-system , 2H, J 11.5 Hz, benzyl H), 4.96 (d, 1H, J 3.5 Hz, H- 1 '), 4.88 and 4.77 (AB-System, 2H, J 12 Hz, benzyl H), 4, 81 and 4.69 (AB-

system, 2H, J 12 Hz, benzyl H), 4.28 (dd 1H, J 11 and

8.5 Hz, H-2), 4.07 (dd, 1H, J 10 and 3.5 Hz), 3.99-3.85 (3H), 3.77 (dd, 1H, J 12 and 6 Hz), 3.71-3.64 (2H), 3.34 (s, 3H, CH ₃ CO), 2.00 (s, 3H, CH ₃ CO), 1.86 (s, 3H, CH _3). CO), 1.14 (d, 3H, J 6.5 Hz, Fuc-CH ₃ ).

Calculated,%: C ₄₆ H ₄₉ NO ₁₃ : C 67.06; H, 5.99; N, 1.70. Found,%: C, 67.0; H, 6.1; N, 1.65.

(iv) Methyl 2-acetamide-6-O- (2,3,4-tri-O-benzyl-α-L-fucopyranosyl) -2-deoxy-β-D-glucopyranoside (21)

Compound (20) is deacetylated for 1.5 h with sodium methoxide (9.5 mM,

31.5 mL) in methanol solution. After neutralization with acidic cationic resin (Bio-Rad AG® 50W-X8), filtration and concentration, a residue was obtained which was dissolved in methanol (20 ml). Hydrazine monohydrate (0.8 mL) was added and the mixture was refluxed for 4 h and then cooled to 10 ° C. After the addition of water (15 mL) and acetic anhydride (5 mL), the reaction mixture was stirred at room temperature. After 20 min, a white precipitate was obtained. Addition of methanol (10 mL) improved the stirring. After an additional 2.5 h, pyridine (2 mL) was added to clarify the solution. The solution was then stirred for an additional 30 min. The methanol was evaporated and the aqueous residue was extracted with dichloromethane. The organic phase was washed with 1 M HCl and saturated aqueous sodium bicarbonate and concentrated. Chromatography of the residue (ethyl 10: 1) gave (21) (435 mg, 77%).

were crystallized from ethanol, acetate-methanol. t. 224-226Ύ (d) [et] ₀ ^Ώ -75.4 (c 0.9, CHC1 _3).

1 H NMR (CDCl ₃ -CD ₃ OD, 3: 1, CHD ₂ OD standard δ) d: 7.41-7.20 (15H), 4.91 and 4.61 (AB system, 2H, J 11.5 Hz,

benzyl H), 4, 80 and 4.70 (AB system, 2H, J 11.5 Hz, benzyl H), 4.78 (d, 1H, J 3 Hz, H-1 ' ), 4.75 (s, 2H, benzyl H), 4.24 (d, 1H, J 8.5 Hz, H-1), 4.09- 3, 97

(2H), 3.92 (dd, 1H, J 10 and 2.5 Hz), 3.86 (dd, 1H, J 11 and 2 Hz), 3.77-3.56 (3H), 3.42 (dd, 1H, J 9.5 and 8.5 Hz),

3.36 (s, 3H, CH ₃ CO), 1.97 (s, 3H, CH ₃ CO), 1.07 (d, 3H,

J 6.5 Hz, Fuc-CH ₃ ).

(v) Methyl 2-acetamide-2-deoxy-6-O-α-L-fucopyranosyl-β-D-glucopyranoside (22)

A solution of compound (21) (362 mg, 0.56 mmol) in acetic acid (50 mL) was hydrogenated at 230 kPa with 10% Pd / C (160 mg) overnight. The mixture is filtered through a pad of Celite and concentrated. The residue by column chromatography (chloroform-methanol-water, 65:40:10) gave amorphous (22) (192 mg, 90%), [0 ^ -106 ° (c 1.1, H ₂ O).

³ H NMR (D ₂ O, CH ₃ OH standard δ): 4.95 (d, 1H, J 4 Hz,

H-1 '), 4.46 (d, 1H, J 8.5 Hz, H1), 4.15 (kv, 1H, J 6.5 Hz), 4.02 (dd, 1H, J 12 and 1 , 5 Hz), 3, 92 (dd, 1H, J 10.5 and

3.5 Hz), 3.84-3.67 (4H), 3.62-3.49 (6H), 3.51 (s, CH ₃ 0), 1.24 (d, 3H, J 6, 5 Hz, Fuc-CH ₃ ).

¹³ C NMR (D ₂ O, CH ₃ OH standard, δ): 177.7, 105.0,

102, 4, 78.0, 76.9, 74, 8, 72.9, 72.5, 71.2, 70.3, 69, 7,

60.0, 58.5, 25.2, 18.3.

EXAMPLE

3,3-Dimethylbutyl 2-acetamide-2-deoxy-6-O-α-fucopyranosyl-4-D-glucopyranoside (24) (i) 3,3-Dimethylbutyl 3,4-di-O-acetyl-6-O- (2,3,4-Tri-Obenzyl-α-fucopyranosyl) -2-deoxy-2-phthalimide-4-D-glucopyranoside (23)

Trifluoromethanesulfonic acid (0.017 mL, 0.19 mmol) was added to a mixture of (19) (853 mg, mmol), 3,3-dimethylbutan-1-ol (0.182 mL, 1.5 mmol), N-iodosuccinimide. (344 mg, 1.52 mmol) and triturated molecular sieves (0.9 g, 4 A) in dichloromethane-diethyl ether (2: 1, 25 mL) at -30 ° C. After 1 h, additional 3,3-dimethylbutan-1-ol (0.100 mL, 0.82 mmol) and trifluoromethanesulfonic acid (0.015 mL, 0.17 mmol) were added and stirring was continued for 2.5 h. The reaction mixture was filtered through Celite into an aqueous solution of sodium bicarbonate and sodium bisulfite. The organic phase was washed with aqueous sodium chloride and concentrated. Chromatography of the residue (ethyl acetate-heptane, 2: 1) gave (23) (740 mg, 83%), [α] _D ²² -8.5 ° (c, 1.3, CHCl ₃ ).

NMR (CHCl ₃ , δ): 7.89-7.82 (2H), 7.78-7.70 (2H), 7.44-7.24 (15H), 5.79 (dd, 1H J 11 and 9 Hz, H-3),

5.32 (d, 1H, J 8.5 Hz, H1), 5.08 (dd, 1H, J 10 and 9 Hz, H-4), 4.99 and 4.66 (AB system, 2H, J 11.5 Hz, benzyl

H), 4.91 (d, 1H, J 3.5 Hz, H-1 '), system, 2H, J 12 Hz, benzyl H), system, 2H, J 12 Hz, benzyl H), 4.29 (dd 1H, J 11 and

8.5 Hz, H-2), 4.05 (dd, 1H, J 10 and 3.5 Hz), 3.99-3.73 (6H), 3.70-3.63 (2H), 3 , 38 (m, 1H), 1.98 (s, 3H,

CH ₃ CO), 1.87 (s, 3H, CH ₃ CO), 1.30 (m, 2H, OCH ₂ CH ₂ ), 1.13

4.88 and 4.77 {AB4.80 and 4.69 {AB (d, 3H, J 6.5 Hz, Fuc-CH

0, 69

9H).

Calculated,%: C ₅₁ H ₄₉ NO ₁₃ Compounds: C 69.3; H, 5.59; N, 1.59. Found; %; C, 68.4; H, 6.65; N, 1.75.

(ii) 3,3-Dimethylbutyl 2-acetamide-2-deoxy-6-O-α-L-fucopyranosyl-β-D-glucopyranoside (24)

Compound (23) (680 mg, 76 mmol) was dissolved in methanol (25 mL). Methanolic sodium methoxide (0.2 M in 1 mL) was added and the solution stirred for 3.5 h. After neutralization with acidic cationic resin (Bio-Rad AG 50W-X8), filtration and evaporation, a residue was obtained which was dissolved in methanol (20 ml). Hydrazine monohydrate (0.5 mL, 10.3 mmol) was added and the mixture was refluxed for 3.5 h and then cooled to 10 ° C. Water (10 ml), methanol (2 ml) and acetic anhydride (2.5 ml) were added and the mixture was stirred at room temperature for 2.5 h, during which additional portions of acetic anhydride (2.0 and 0.5 ml) were added. ). The methanol is evaporated and the aqueous residue is partitioned between dichloromethane and water. The aqueous phase is extracted with dichloromethane and the organic phase is concentrated. Chromatography of the residue (ethyl acetate / methanol; 20: 1) gave the product, which was dissolved in acetic acid (50 mL). 10% Pd / C (160 mg) was added and the mixture was hydrogenated for 4 h at 230 kPa at room temperature. The mixture is filtered through a pad of Celite and concentrated. Column chromatography of the residue (chloroform-methanol-water, 150: 40: 3 → 65:40:10) gave amorphous (24) (275 mg, 80%), [α] θ22-87.2 ° (c 0.95). , H ₂ O).

¹ H NMR (D ₂ O Hz, H -1 '), 4.54 (d, 6.5 Hz), 4.03-3.88 1.40 (2H, OCH ₂ CH ₂ ), (s, 9H).

, CH ₃ OH standard, δ): 4.94 (d, 1H, J 4)

1H, J 8.5 Hz, Hl), 4.15 (q, 1H, J (8H), 2.03 (s, 3H, CH ₃ CON), 1,581,24 (d, 3H, J Hz, Fuc- CH ₃ ), 0.90 ¹³ C NMR (D ₂ O, CH ₃ OH Stand, 102.4, 77, 9, 76, 9, 74.9, 73, 0, 72, 6, 45.0, 31.9, 25.2, 18.4.

δ): 177.5, 104.0,

71.0, 69, 7, 58.6,

Calculated,%: C ₂₀ H ₃₇ NO ₁₀ Compounds: C 53.2; H, 8.26;

N, 3.10. Found; %: C, 51.2; H, 8.25; N, 3.2.

EXAMPLE

Fucal-2Gaipi-O-spacer 4-HSA (31) (i) Ethyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio-β-galactopyranoside (25) (25) of acetobromogalactose (70.73 g, 0.172 mmol) according to the procedure described by S. Nilsson, H.

Lonn and T. Norberg, Glycoconjugate J., 1989, 6, 21-34.

(25) yield was 26.13 g (28%).

TLC: R _f 0.33 (heptane: ethyl acetate, 9: 2).

¹³ C NMR (CDCl ₃ , δ): 170.2 (CO), 139, 2, 138, 6 138, 4, (aromatic C), 84.2, 82.1, 78.1, 75.0, 74 , 1, 73.6,

72, 6, 70.3, 69.2, (Cl, 2.3, 4.5, 6, 3xCH ₂ Ph), 24.1 (SCH ₂ CH ₃ ), 21.6 (OCOCH ₃ ), 15, 4 (SCH ₂ CH ₃ ).

^{Τ Η} NMR (CDC1 ₃₎ δ: 5.43 (plt, 1H, J _{2, 3} 9.7 Hz, H-2), (d, 1H,

J _{1> 2} 11.9 Hz, Hl), 4.01 (bd, 1H, J _{3, 4} 2.9 Hz, H-4)

3.55 (dd 1H, H-3).

(ii) Ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (26)

Ethyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio-β-galactopyranoside (25) was deacetylated with sodium methoxide in methanol (50 mL, pH 12) and then benzoylated with benzoyl chloride (1.96). g, 14 mmol) in pyridine (20 mL) according to standard procedures.

Crystalline (26) is obtained in almost quantitative yield (3.44 g, 97%).

NMR (CDCl ₃ ) ³ H: δ 5.70 (1H, t, 9.8 Hz, H-2) r 2.60-2.80 (2H, m, CH ₂ CH ₃ ). ¹³ C: δ 14.8 23, 6 (SEt), 68, 6, 70.2, 71.7, 72 , 8, 73.6, 74.4 , 76.6, 127.5-138.6 (aromatic C), 165, 4 (C = O).

(iii) 2-Azididyl-3,4,6-tri-O-benzyl-3-D-galactopyranoside (28)

Trifluoromethanesulfonic acid (TfOH); 35 mg, 0.23 mmol ·; according to the method described by G. H. Veeneman, S.H. Van

Leeuwen, J.H. Boom, Tetraherdron Lett. 1990, 31, 1331) is added to a suspension consisting of thioglycoside (26) (700 mg, 1.17 mmol), 2-azaethanol (204 mg, 2.34 mmol);

prepared according to A. Ya. Chernyak and

Rao, Carbohydr. Res. 223 (1992) mmol). and AV Rama 303-309), quenched with N-iodine and triturated The solution was filtered with dichloromethane and Na ₂ S ₂ O ₃ (10%) and dried over magnesium succinimide (395 mg, 1.75 molecular sieves (3 A, 400 mg) in dichloromethane 25 mL) at 0 C. When TLC (toluene: ethyl acetate, 6: 1) showed complete conversion (<15 min) by adding triethylamine at 0 ° C.

the Celite layer is diluted, washed twice with water and finally with water. The organic phase was sulfated, filtered and concentrated and the residue was immediately subjected to TLC (toluene: acetyl acetate, 15: 1). Removal of the solvent afforded 672 mg of 2-azetidyl 2O-benzoyl-3,4,6-tri-O-benzyl-β-galactopyranoside (27) as a colorless oil (92%) treated with sodium methoxide in methanol (pH 11) at room temperature. at a temperature of 6 hours. The solution was neutralized with Dowex 50 H ⁺ resin, filtered and concentrated. The crystalline product (28) (540 mg, 89% of 2) is used without further purification to produce the disaccharide (29).

Compound (27): (CDCl ₃ ) 1H: δ 5.66 (1H, dd, 10.0, 7.9 Hz,

H-2), 4:57 (1H, d, 7.8 Hz H-1).

¹³ C: δ 50.7 (CH ₂ N ₃ ), 67, 3, 68.7, 71, 9, 72.5, 73, 6, 73, 9, 74.5, 101.4 (Cl), 127 , 6-137.8 (aromatic C), 165.3 (C = O).

Compound (28): ¹³ C: δ 50.7 (CH ₂ N ₃ ), 68.4, 68.7, 71.4,

72, 6, 73, 0, 73, 6, 73, 9, 74.5, 81.7, 103, 4 (C-1), 125.3138.4 (aromatic C).

(iv) 2-Azididyl 3,4,6-tri-O-benzyl-2-O- (2,3,4-tri-O-benzyl-α-L-fucopyranosyl) -β-D-galactopyranoside (29)

To a solution of thioethyl glycoside (14) in 400 mg, 0.836 mmol) of dichloromethane (10 mL) was added bromine (134 mg, 0.836 mmol) at 0 ° C. After about 5 min at 0 ° C, the solution was allowed to reach room temperature and the solvent was evaporated. After evaporation with toluene, the residue was dissolved in dichloromethane (2 mL) and added at room temperature to a suspension of tetraethylammonium bromide (176 mg, 0.836 mmol; prepared by RU Lemieux, KB Hendriks, RV Stiek, K. James, J. Am. Chem. Soc. 1975, 97:14, 4056), Compound (28) (290 mg, 0.558 mmol) and crushed molecular sieves (3 A, 300 mg) in CH ₂ Cl ₂ : DMF (4: 1.7 mL). ). TLC (toluene: ethyl acetate, 6: 1) showed complete conversion after stirring for 20 h. The mixture was filtered, diluted with dichloromethane and washed with water. The organic phase

dried of magnesium sulphate, filter is con- centered on ama in a vacuum. Preparative TLC gave the compound (29), thick of oil form (407 mg, 78%) • NMR (CDCl ₃ ) ^L3 C: δ 16, 5, 33.6, 50, 9, 66, 4, 66.9, 68.8, 71.4, 72.0, 72.8, 72, 9, 73.5, 73, 6, 74.4, 74.8, 75, 7,

78.1, 79, 6, 84.3, 97.3, 102.0, 125, 3, -129, 0 (aromatic C), 138, 0, 138, 3, 139, 0.

(v) 2-Aminethyl-2-β-α-L-fucopyranosyl-β-D-galactopyranoside (30)

The blocked disaccharide derivative (29) (80 mg, 85 µmol) was dissolved in ethanol (abs., 10 mL) and water (1 mL) and Pd / C (10%, 100 mg) were added. The mixture was hydrogenated and stirred rapidly at room temperature at 50 PSI. After 60 h, the reaction was filtered and the product was isolated (TLC, ethyl acetate: methanol: acetic acid: water, 5: 3: 3: 1,

R _f = 0.15). After concentration in vacuo, the residue was dissolved in aqueous pyridine / acetic acid (2.5% / l%, pH 5.4) and washed through a Bio Gel P-2 column. After evaporation and freeze-drying, 14 mg (44%) of (30) is obtained in the form of a white powder.

NMR (CDCl ₃ ) ¹³ C: δ 16.8, 39, 8, 61.1, 66.4, 67.1, 68.7,

69.6, 71, 9, 73.0, 75, 0, 78.4, 100, 0, 101.7.

(vi) Fucal-2Gaipi-O-Seal 4-HSA (31)

To the stirred ice-cold solution of thiophosgene (10 eq.) In tetrahydrofuran (2 mL) was added the amine derivative (30) of compound (30) in sodium borate buffer (0.85 M, pH 8.5). The solution was stirred at room temperature for 10 min and then extracted with diethyl ether (3 x 2 mL). The aqueous phase containing the isothiocyanate derivative was added to a solution of human serum albumin (HSA) (1/30 equiv.) In the same buffer system (0.5 ml). The pH was adjusted to 8.5 with aqueous sodium hydroxide (0.25 M) and the mixture was stirred at room temperature for 48 hours. After the reaction mixture is freeze-dried, purification is performed by centrifugation in Centriprep tubes (10KO). Freeze-drying of the purified solution gave HSA compound (31) in excellent yield (18 mg). The degree of substitution was determined using fly time mass spectroscopy up to 8 mol disaccharide / mol protein.

EXAMPLE

Fucal-2Gal / 10-spacer 1-IISA (36) (i) The azido derivative of 8-Azide-3,6-dioxaoctyl 3,4,6-tri-O-benzyl-β-galactopyranoside (33) is prepared from thioglycoside (26) (1004 mg, 1.68 mmol) and l-azide-8-hydroxy-3,6-dioxaoctane (686 mg, 3.35 mmol; obtained according to CR Bertozzi, MD Bednarski, J. Org. Chem., 1991 , 56, 4326LT 3446 B

4329), according to a procedure similar to that used in the synthesis of the compound (28). TLC (toluene: EtOAc 6: 1) showed complete concession within 40 min. Similar treatment and deacylation of 8-azido-3,6-dioxaoctyl 2-O-benzoyl-3,4,6-tri-O-benzyl-β-Dgalactopyranoside (32) afforded 933 mg (78% of 26) (33) of solid in the form of an oil.

Compound (32): NMR (CDCl ₃ ): 1H: δ 5.64 (1H, dd, 10.0, 7.9, Hz, H-2).

¹³ C: δ 50.6 (CH ₂ N ₃ ), 68, 7, 68, 9, 69, 8, 70.3, 70.5, 70.7,

71.8, 71, 9, 72, 6, 73, 6, 73, 8, 74, 6, 80, 0, 101, 6 (C-1).

Compound (33): ¹³ C: δ 50.6 (CH ₂ N ₃ ), 68.7, 68, 8, 70.0,

70.2, 70.5, 71.4, 72, 6, 73.3, 73, 5, 73, 8, 74.5, 81.9,

103.8 (C-1).

(ii) 8-Azide-3,6-dioxaoctyl 3,4,6-tri-O-benzyl-2-O (2,3,4-tri-O-benzyl-α-fucopyranosyl) -β-D-galactopyranoside (34)

The disaccharide (34) was synthesized from compound (33) (500 mg, 82 mmol) and thioethyl glycoside (14) (512 mg,

1.07 mmol) according to the procedure described for the corresponding derivative (29). Preparative TLC gave 683 mg (81%) of (34) as an oil.

NMR (CDCl ₃ ) ¹³ C: δ 18.3, 50.2, 66.2, 68, 2, 68.8, 70.0,

70.2, 70.3, 70.6, 71.2, 72, 0, 72.3, 72.5, 73, 0, 73, 3, 73, 6, 74.4, 74, 6, 75, 8, 78.0, 79, 7, 84.2, 98.6 102, 0.

(iii) 8-Amine-3,6-dioxaoctyl 2-O-α-L-fucopyranosyl-D-galactopyranoside (35)

8-Azide-3,6-dioxaoctyl 3,4,6-tri-O-benzyl-2-O- (2,3,4-tri-O-benzyl-alpha-fucopyranosyl) -β-D-galactopyranoside (34) ( 35 mg, 34 μιηοΐ) dissolved in ethyl acetate: ethanol: water 1: 2: 2 (volume, 12 mL) and acidified with 20 μΐ HOAc) according to the method described by S. Nilsson, PhD thesis, Lund University, April 1992) . The solution was hydrogenated at 50 PSI on 10% Pd / C (140 mg) at room temperature overnight and when TLC (ethyl acetate: methanol: acetic acid: water, 5: 3: 3: 1) showed complete deprotection, the mixture was filtered and evaporated. . Purification on a Bio-Gel P-2 column (water: pyridine: acetic acid, 25: 1 by volume, pH 5.4), concentration and freeze-drying gave compound (35) as a white powder (14 mg, 90%).

NMR (CDCl ₃ ) 68.1, 68.5,

74.8, 76, 6, ¹³ C: δ 15.2,

68.7, 69.2,

99.2 (C-1 '), (CH ₃ ), 38.9,

69.3, 69, 4,

101.4 (C-1).

60.7, 66.1,

69.6, 71.7,

66, 5, 73.4, (iv) Fucal-2Gaipi-O-gasket 1-HSA (36)

To an stirred solution of ice-thiophosgene (10 eq) in tetrahydrofuran (2 mL) was added the amino derivative (35) of compound (35) in sodium borate buffer (0.85 M, 2 mL, pH 8.5). The solution was stirred at room temperature for 10 min and then extracted with diethyl ether (3 x 2 mL). The aqueous phase containing the isothiocyanate derivative was added to a solution of human serum albumin (HSA) (1/30 equiv.) In the same buffer system (0.5 mL) adjusted to pH 8.5 with aqueous sodium hydroxide (0.25 M). the mixture was stirred at room temperature for 48 hours. After the reaction mixture is freeze-dried, purification is performed by centrifugation on Centriprep tubes (10KO). Drying of the purified solution gave the HSA compound (36) in excellent yield (33 mg).

The degree of substitution was determined using fly time mass spectroscopy to 5 mol disaccharides / mol protein.

EXAMPLE

Fucal-2Galp-O-spacer 2-PAA (38) (i) 8-N-Acrylamide-3,6-dioxaoctyl 2-O-α-L-fucopyracyclic β-D-galactopyranoside (37)

0.8 ml of deaerated 0.5 M sodium borate in aqueous buffer (pH 8.5) and 2.4 ml of deaerated methanol were added in 15 mg (35). The reaction mixture was purged with nitrogen and cooled to 0 ° C. 3.3 μΐ of acryloyl chloride was added and stirred for 10 min. The reaction mixture is concentrated at room temperature to about one third of its initial volume. Purification on a Bio-Gel® P-2 column and lyophilization gave (37), (14 mg, 83%).

NMR data ¹³ C (D ₂ O): δ

60.51, 66.31, 67.87, 69.12, 69.43, 71.50,

C-2,3,4,5; 5CH ₂ O),

68.19, 73.25, 98.88,

15.0, 68.30, 74.55 (C-1 '), (CH ₃ ), 38.54 (CH ₂ N),

68.50, 68, 98, 69.10, 76, 08 (C-2, 3,4,5,6;

101.16 (Cl), 126.92 and 129.43 (CH ₂ = CH ₂ ).

(ii) Fucal-2Gaipi-O-gasket 2-PAA (38)

To a solution of compound (37) (14 mg, 0.027 mmol) and acrylamide (9.7 mg, 0.14 mmol) in deaerated water (1 mL) was added first N, N, N'N'-tetramethylenediamine (6 μΐ). ) followed by ammonium persulfate (3.5 mg). The mixture was stirred at room temperature overnight. (38) The polymer is obtained by gel chromatography on a Bio-Gel P2 column. Freeze drying of the purified solution gave the PPA compound in excellent yield (17.9 mg). ^ -BMR showed an average binding of 1 oligosaccharide to 7 acrylamide units.

EXAMPLE

Fucal-2Galpl-3 (Fucal-4) GlcNAcp-3Gaipi-4GlcPl-NII-PAA (42) (i) Fucal-2Galpl-3 (Fucal-4) GlcNAcpl-3Galpl-4Glcpl-NH ₂ (40)

To a solution of Fucal-2Galpl-3 (Fucal-4) GlcNAcPl-3Galpl-4GlcP-1-OH (Lewis B Hexaccharide (39) purchased from Sep AB) was added solid ammonium bicarbonate in 25 mg water (1.25 mL) The mixture was stirred in an open vessel for 6 days, Ammonium bicarbonate was added at intervals, saturation was monitored by keeping a constant portion of the solid salt in the mixture, When TLC showed no further conversion, the mixture was diluted with water (5 mL) and concentrated to half volume. water to 20 mL and concentrate to 5 mL This process was repeated 1 more time and then the residue was diluted to 10 mL and lyophilized The untreated product was applied to a Bio-gel P2 column and the fraction containing Lewis B glycosylamine (40) was collected (20). mg, 80%).

NMR: ¹³ C (D ₂ O): δ 84, 66 (C-NH ₂ ), 97.54, 99, 33,

100.39, 100.72, 102.98, (Cl) carbon atoms of the non-reducing sugars units), 15.08, 15.13 (2xCH ₃ -fucose), 21.95 (CH ₃ -CON-GlcNAc).

(ii) Fuc 2Gaipi-3 (Fucal-4) GlcNAcl-3GalPl-4Glcpl-NHC0-CH = CH ₂ (41)

Sodium carbonate (50 mg) and deaerated methanol (0.5 mL) were added to a solution of glycosylamine (40) (20 mg, 0.02 mmol) in aqueous (0.5 mL). The mixture was stirred at 0 ° C until acryloyl chloride (60 μΐ, 0.74 mmol) in tetrahydrofuran (0.5 mL) was added over 5 min. After 10 min, the solution was diluted with water (3 mL) and concentrated to 2 mL. The solution was diluted again with water (2 mL), 200 μΐ tetrahydrofuran (solution inhibitor) was added and the resulting solution was concentrated to 1-2 mL. This solution was purified by gel filtration on a Bio-Gel® P2 column. The appropriate fractions were combined and lyophilized to give (41) (14 mg, 67%).

NMR: ¹³ C (D ₂ O): δ 81.28 (C-NHCOCHCH ₂ ), 97.42,

99.18, 100.25, 102.59, 102.85, (Cl carbon atoms of non-reducing sugars units), 14.99, 15.06, (2xCH ₃ fucose), 21.92 (CH ₃ -CON-GlcNAc) ), 125, 93, 130, 32, (CH ₂ = CH ₂ ).

Fab ms: pseudomolecular ion m / z; 1053 (M + H) and 1075 (M + Na) ⁺ .

(iii) Fucal-2Gal01-3 (Fucal-4) GlcNAcp-3Gaipi-4Glcpl-NHPAA (42)

Copolymerization of N-acryloyl glycosylamine with acrylamide. A solution of N-acryloylglycosylamine (41) (13 µmol) and acrylamide (53 µmol, 3.7 mg) in distilled water (200 μΐ) was deaerated with nitrogen purge for 20 min. The solution was then stirred at 0 ° C and N, N, N ', N ¹ -tetramethylenediamine (2 μΐ) and ammonium persulfate (1 mg) were added. The mixture was stirred slowly at 0 ° C for 2 hours and then at room temperature overnight. The clear solution was diluted with water (1 mL) and purified by gel filtration on a Bio-Gel® P2 column, washing with aqueous n-butanol (1%). Fractions containing the polymer were combined and lyophilized. Yield: 3 mg.

¹ H-NMR showed that approximately 1 Lewis-B unit corresponds to 5 CHCH ₂ units.

EXAMPLE

Fucal-2Galpl-3GlcNAcpi-O-5-PAA (50) (i) 2-Azididyl 4,6-O-benzylidene-2-deoxy-2-phthalimidβ-D-glucopyranoside (43)

Ethyl 4,6-O-benzylidene-2-deoxy-2-phthalimid-1-thio -? - D-glucopyranoside was synthesized according to H. Lonn, Carbohydr. Res. 139 (1985), 105-113) (0.5 g, 1.1 mmol) was dissolved in 20 mL of dichloromethane and 2-azidethanol (obtained according to A. Ya. Chernyak et al., Carbohydr. Res. 1992, 223, 303) was added. -309) (0. 148 g, 1.7 mmol) truncated 4 A molecular sieves and the mixture was stirred for 30 min. Dimethyl (methylthio) sulfonium triflate (DMTST) (0.439 g, 1.7 mmol) was added; obtained by P. Fugedi and P.J. Gregg, Carbohydr. Res., 149 (1989), 9-12) at room temperature and stirring was continued for 4 hours. TLC analysis (toluene-ethyl acetate) indicated that the starting material was gone and 1 mL of triethylamine was added to the reaction mixture and stirred for an additional 30 min. The reaction mixture was loaded onto a silica gel column and washed with toluene: ethyl acetate 6: 1 to give (372 mg, 72%). (43) of the compound.

NMR data: ¹³ C (CDCl ₃ ): δ 50.38, (CH ₂ -N); 56, 42 (CH-N);

66.2 (CH-O); 68.44, (CH ₂ O); 68.50 (CH-O); 68.53 (CH ₂ -O); 82.05 (CH-O); 98.89 (Cl); 101.83 (PhCH).

(ii) 2-Azetidyl 3- O- (2-O-acetyl-3,4,6-tri-O-benzyl-D-galactopyranosyl) -4,6-O-benzylidene-2-deoxy-2-phthalimide. -D-Glucopyranoside (44)

Ethyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (25) (818 mg, 1.5 mmol) and compound (43) (395 mg, 0 (85 mmol) in 30 mL of dichloromethane and crushed 4 A molecular sieves were added and the resulting mixture was stirred for 20 min. The reaction mixture was purged with nitrogen and DMTST (787 mg, 3.05 mmol, dissolved in 5 mL of dichloromethane) was added dropwise to the reaction mixture and 6 mL of dichloromethane was rinsed through a funnel. After 2 hours, 1 mL of triethylamine was added and stirred for 30 min, filtered, concentrated and column chromatography (toluene: ethyl acetate, 10: 1) gave three fractions. Fraction 1-product (97.32, 98.89; (C-1 and C-1 '). Fraction 2 nearly pure (44) (306 mg, 39%)).

NMR data: ¹³ C (CDCl ₃ ) support. tetramethylsilane (ppm): δ 20.32 (CH ₃ CO), 50.47 (CH ₂ N); 55.13, (CH-N);

66.57, 68.15, 68.20, 68.65, 71.58, 71.71, 72.17, 72.94, 73, 46, 74.38, 75, 15, 80, 47, 81, 08 (C-3,4,5,6; C2,3,4,5,6; 3xCH ₂ Ph CH ₂ O), 98.86 (Cl), 100.75, 101.23 (Cl and CHPh ), 168.84 (C = O).

(iii) 2-Azididyl 2-acetamide-3-O- (3,4,6-tri-O-benzyl-β-galactopyranosyl) -4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside (45)

To compound (44) (525 mg, 0.56 mmol) was added 50 mL of ethanol and refluxed with 1.1 mL of hydrazine hydrate overnight and TLC (toluene: ethyl acetate 1: 2) showed formation of a new product. After concentration and evaporation with toluene, dissolved in 45 ml of dichloromethane and rinsed with an equal volume of water, again evaporation of the crude monohydroxyamine with toluene. This crude product was dissolved in dichloromethane: methanol (1: 1, 15 mL) and added

1.5 ml of acetic anhydride. No starting material (TLC) was detected after 3 hours. Concentration and chromatography (toluene: ethyl acetate, 1: 2) gave (204 mg, 45%) of (45) Compound NMR ppm: ¹³ C (CDCl ₃ ): δ 23.59 (NHCOCH ₃ ), 50.59 (CN), 56.89 (CN); 66.40, 68.28, 68.56, 70.55, 72.44, 73.21,

73.40, 73.53, 74.60, 76.08, 79.75, 81.71, (C-3, 4, 5,

6; C-2 ', 3', 4 ', 5', 6 '; 3xCH ₂ Ph; CH ₂ O), 100, 97, 101.25, 103.48 (Cl, Cl ¹ and CHPh), 171.67 (C = O).

(iv) 2-Azididyl 2-acetamide-3-O- (3,4,6-tri-O-benzyl-20- (2,3,4-tri-O-benzyl-α-fucopyranosyl) -β- D-galactopyranosyl) -4,6-O-benzylidene-2-deoxy-D-glucopyranoside Compound (46) (45) (137 mg, 0.17 mmol), Compound (14) (162 mg, 0.34 mmol) ) was dissolved in dichloromethane (75 mL) and molecular sieves (4 A) were added and the mixture was stirred for 20 min. DMTST (96 mg, 0.37 mmol) was added and stirred for 1.5 h. 1 mL of triethylamine was added and stirred for a further 20 min. Filtration through Celite, concentration and column chromatography (toluene: ethyl acetate 1: 1) gave compound (46) (101 mg, 49%).

13th

NMR: C (NHCOCH ₃ ), 50.66

fucose), 23, 30 66.55, 67.17, 73.10, 73.51, 79, 43, 79.53, ', 3,4' ', 5; 102.13, (C-1,

(CDCl ₃ ): δ 16.83, (CH ₃ (CH ₂ -N), 57.40 (C-2);

67.96, 68.60, 72.31, 72, 91, 72, 99, 73, 04, 74.48, 74, 65, 76, 05, 76, 29, 76, 62, 77, 60, 83, 21 (C-3,4,5,6; C-2 ', 3', 4 ', 5', 6 '; C-2'

6xCH ₂ Ph), 97.67 (C-1 '), 100.94, 101.07,

C-1 ', CHPh), 170, 92 (C = O).

(v) 2-Trifluoroacetamidethyl 2-acetamide-3-O- (3,4,6-triO-benzyl-2-O- (2,3,4-tri-O-benzyl-α-fucopyranosyl) -βD-galactopyranosyl ) -4,6-O-Benzylidene-2-deoxy-D-glucopyranoside (47) (46) (135 mg, 0.11 mmol) was dissolved in 11 mol of ethanol and 10% Pd / C (140 mg) was added. The reaction mixture was hydrogenated at atmospheric pressure for 15 min. TLC analysis (ethyl acetate: methanol: acetic acid: water, 12: 3: 3: 1) showed that no starting material was present except for one ninhydrogen positive product. The mixture was filtered through Celite, concentrated and dissolved in dichloromethane (7 mL) and pyridine (3.5 mL), purged with nitrogen and cooled to 0 ° C. Trifluoroacetic anhydride (31 mL, 0.22 mmol) was added. After one hour, the mixture was concentrated and evaporated to two volumes.

with 2 ml of toluene. Column chromatography (toluene: ethyl acetate, 1: 3) 52%). gave (47) compound (73 mg, NMR data: ¹³ C (CDCl ₃ ): δ 17.06 (CH ₃ fucose) , 22.66 (NHCOCH ₃ ), 39, 59 (CH ₂ -N), 54 , 83 (C-2); 65.56, 66, 77,

67.78, 68.44, 68.69, 72.80, 73.05, 73.24, 2x73.46,

74.46, 74, 66, 76, 38, 77, 08, 77.80, 78, 91, 79, 96, 80.01, 82, 07 (C-3,4,5,6; C-2 ') , 3 ', 4', 5 ', 6'; C-2 '', 3 '', 4 '5' ';

6xCH ₂ Ph), 98.61 (Cl '), 101.22, 101, 99 102.35, (Cl,

C-1 ', CHPh), 171, 64 (NHCOCH 3).

(vi) 2-Trifluoroacetamidethyl 2-acetamide-2-deoxy-3-0 (2-O- (αL-fucopyranosyl) -β-D-galactopyranosyl) -β-D-Glucopyranoside (48) (47) Trisaccharide (73 mg, 56 mg). , 2 μπιοί) dissolved in absolute ethanol (7 mL) with water (0.25 mL) and glacial acetic acid (2 μΐ). The solution was hydrogenated with 10% Pd / C (152 mg) at 50 PSI at room temperature for one hour. When TLC (ethyl acetate: acetic acid: methanol: water, 12: 3: 3: 1; R _f = 0.14 for compound (48)) showed completion of conversion, the reaction mixture was filtered through a pad of Celite and concentrated. The crude solid residue (46 mg) was used in the subsequent reaction without further purification.

NMR: ¹³ C (NHCOCH ₃ ), 39.44 (C3.4,5,6; C 2 ', 4' 99, 92, 101,28 (Cl, (D ₂ O)): δ 16.59 (CH ₃ fucose), 21.85 (CH ₂ -N), 54.56 (C-2); 60.45-76, 95, 5, '6'; 2 '', 3 '', 4 '', 5 ''), 99.29, C-1', C-1 ''), 173.48 (NHCOCH ₃ ).

(vii) 2-Acrylamidoethyl 2-acetamide-2-deoxy-3-0-2-0-αL-fucopyranosyl-β-D-galactopyranosyl-β-D-glucopyranoside (49)

The crude compound (48) (46 mg) was dissolved in aqueous ammonia (25%, 4 mL) and stirred at room temperature. The reaction was completed after one hour and gave only the free amino derivative. (TLC ethyl acetate: acetic acid: methanol: water, 5: 3: 3: 1). After concentration and evaporation with toluene, a 0.5 g cartridge of Bond-Elut® (SCX, H ⁺ form) is purified by cationic resin. The samples were dissolved in 3 ml of water and the pH adjusted to pH 6 with aqueous acetic acid. Samples were loaded on a column and washed with 2M ammonia in methanol: water 1: 1 (5 mL). Fractions containing the free amine (positive for ninhydrogenation) were pooled, concentrated, lyophilized to give (30 mg, 0.05 mmol) of the crude amine.

1 ml of deaerated 0.5 M sodium borate, aq. buffer (pH 8.5) and deaerated methanol (3 mL). The reaction mixture was purged with nitrogen and cooled to 0 ° C, 6.4 μΐ (0.078 mmol) of acryloyl chloride was added and stirring continued for 10 minutes. The reaction mixture was concentrated at room temperature to one third of its initial volume by purification on a Bio-Gel® P-2 column and lyophilization to afford compound (49) (30 mg, 86% of compound (47)).

NMR data; ¹³ C (D ₂ O): δ 14.99 (-CH ₃ , fucose), 21.99 (NHCOCH ₃ ), 39.10 (CH ₂ N), 54.58 (C-2); 99.25, 99.93,

101.39 (Cl, C-1 ', Cl), 127.27, 129, 65 (CH ₂ = CH ₂ ).

(vii) Ευσα1-203ΐβ1-30ΐοΝΑοβ1-0-ΐ3Γρχ ^ Ϊ3 5-PAA (50)

2-Acrylamidoethyl 2-acetamide-2-deoxy-3-0-2-0-α-L-fucopyranosyl-β-D-galactopyranosyl-3-D-glucopyranoside

with acrylamide. 14 4 ohms 1) at room temperature (49) (18 mg, 29th ummol) solution (1 mL). At this slowly stirring

overnight, acid: methanol: water, add N, N, NN'-tetramethylenediamine (6 μΐ) and ammonium persulfate (3.5 mg) to the solution (stored in the dark and under nitrogen) at 0 ° C. The mixture was stirred at room temperature (ethyl acetate; acetic acid 5: 3: 3: 2) to indicate that almost all compound (49) was consumed and that a sintered parent product was formed. The polymer was purified by gel chromatography on a Bio-Gel® P-2 column eluting with aqueous n-butanol (1%) on a column. The washed fraction was freeze-dried to give 13.1 mg (50) of a polymer with ¹ H NMR analysis. 1 corresponds to trisaccharide

7.6 acrylamide units, and 11.9 mg (50) of a polymer whose NMR analysis showed that on average 1 trisaccharide corresponds to 10.3 acrylamide units.

EXAMPLE

Fucal-2Gaipi-3 (Fucal-4) GlcNAc31-O-Seal 5-PAA (55) (i) 2-Azididyl 2-acetamide-6-O-benzyl-3-O- (3,4,6-tri- Obenz i-β-D-galactopyranoside (1) -2-deoxy ß-β-D-glucopyranoside (51)

Diethyl ether saturated with hydrogen chloride is added at room temperature to stirred 2-azididyl-2-acetamide-3-β- (3,4,6-tri-O-benzyl-3-D-galactopyranosyl) 4,6-O-benzylidene. 2-deoxy-β-D-glucopyranoside (45) (420 mg, 0.52 mmol), sodium cyanoborohydride (200 mg,

3.2 mmol) and 3 A molecular sieve mixture in tetraLT 3446 B hydrofuran (20 mL) until the mixture was acidic (as shown by paper indicator; method according to M. Nilsson and T. Norberg Carbohydr. Res. 76, 183 (1988) 71-). 82).

The mixture was stirred for 20 min at room temperature and then triethylamine (0.30 mL) was added. The mixture was filtered through Celite, washed with water, dried and evaporated. The crude product was purified by column chromatography (toluene: ethyl acetate, 6: 1) to give pure compound (51) (266 mg, 0.32 mmol, 65%).

NMR: ¹³ C (CDCl ₃ ): δ 23.41, (NHCOCH ₃ ), 50.30 (CH ₂ N), 56.81 (CN); 66.3-81.9 (C-3,4,5,6; C-2 ', 3', 4 ', 5', 6 ';

4xCH ₂ Ph; CH ₂ O), 100, 90, 103, 21 (Cl, C-1 '), 173.4 (CO).

(ii) 2-Azididyl 2-acetamide-2-deoxy-4-O- (2,3,4-tri-O-benzyl-α-fucopyranosyl) -3-O- [3,4,6, -tri-O- benzyl 2-O (2,3,4-tri-O-benzyl-αL-fucopyranosyl) -β-D-galactopyranosyl] -β-D-glucopyranoside Compound (52) (51) (157 mg, 0.19 mmol) ) and compound (14) (362 mg, 0.76 mmol) were dissolved in dichloromethane (100 mL) and added to 3 g of molecular sieves (MS) 4A and stirred for 20 min followed by addition of dimethyl (methylthio) sulfonium triflate. (DMTST) (207 mg, 0.80 mmol) and stirred for 1.5 hours. Then add 2 ml of triethylamine and stir for a further 20 min. Filtration through Celite, concentration and column chromatography (toluene: ethyl acetate, 1: 1) afforded compound (52) (142 mg, 0.086 mmol, 45%).

NMR data: ¹³ C (CDCl ₃ ): δ 17.01, 16.81 (2xCH ₃ fucose),

23.20 (NHCOCH ₃ ), 50.35 (CH ₂ -N), 57.21 (C-2); 98.31,

99.70, 101.14, 102.30 (Cl, Cl ', 2xCl-fucose), 170.30 (C = O).

(iii) 2-Trifluoroacetamido 2-acetylamide-2-deoxy-4-O (2,3,4, -tri-O-benzyl-α-L-fucopyranosyl) -3-O- [3,4,6, tri -O-Benzyl-2-O- (2,3,4-tri-O-benzyl-α-fucopyranoyl) -β-β-galactopyranosyl] -β-D-glucopyranoside (53) (52) Compound (140 mg, 0.084 mmol) was dissolved in 11 mL of ethanol and 10% Pd / C (150 mg) was added. The reaction mixture was hydrogenated at atmospheric pressure for 15 minutes. TLC (ethyl acetate: methanol: acetic acid water, 12: 3: 3: 1) showed no starting material except for one ninhydrin positive product. The mixture was filtered through Celite, concentrated and dissolved in dichloromethane (10 mL) and pyridine (3.5 mL), purged with nitrogen and cooled to 0 ° C.

Trifluoroacetic anhydride (31 μΐ, 0.22 mmol) was added. After 1 hour, the mixture was concentrated and co-evaporated with 2 ml of toluene twice. Column chromatography (toluene: ethyl acetate, 1: 2) gave compound (53) (82.8 mg, 0.053 mmol, 63%).

NMR data: ¹³ C (CDCl ₃ ): δ 17.33, 16, 93 (2xCH ₃ fucose), 22.30 (NHCOCH 3), 39.25 (CH ₂ -N), 54.48 (C-2); 99, 03, 99.98, 101.63, 102.75 (Cl, C-1 ', 2xCl-fucose), 171.73 (NHCOCH ₃ ).

(iv) 2-Trifluoroacetamidethyl 2-acetamide-2-deoxy-3-0 (2-O-αL-fucopyranosyl-β-galactopyranosyl) -4-Oa-L-fucopyranosyl-β-D-glucopyranoside (54) (53) Tetrasaccharide (78 mg) , 0.05 mmol) was dissolved in absolute ethanol (8 mL) with water (0.25 mL) and glacial acetic acid (2 μΐ). The solution was rapidly stirred with 10% Pd / C (150 mg) in hydrogen (50 PSI) at room temperature for one hour. When TLC (ethyl acetate: acetic acid: methanol: water, 12: 3: 3: 1) showed the conversion to be complete, the reaction mixture was filtered through a pad of Celite and concentrated. The crude compound (54) (35 mg) was used in the subsequent reaction without further purification.

81 NMR data: ¹³ C (CDCl ₃ ): δ 16, 91, 16.53 ( 2xCH ₃ fucose), 22.15 (NHCOCH ₃ ), 39.14 ( CH ₂ N), 54.20 (C-2) ; 99, 33, 100.03, 101.73, 102.95 (C-1, C-1 ', 2xC-1 fucose), 173.30 (NHCOCH3) was absent no one was detected ¹³ c s ignalas in the aromatic field.

(v) Dissolving 2-acrylamidethyl 2-acetamide-2-deoxy-3-0- (2-O- (α-L-fucopyranosyl-3-D-galactopyranosyl) -4-OaL-fucopyracyclic β-D-glucopyranoside (55) 3 ml of water with aqueous acetic acid.

mg of crude compound (54) was dissolved in aqueous ammonia (25%, 4 mL) and stirred at room temperature.

The reaction was completed after one hour and yielded only the free amino derivative. After TLC (ethyl acetate: acetic acid: methanol: water, 5: 3: 3; 2), concentration and evaporation with toluene followed by purification with Bond-Elut® cartridge (SCX, H ⁺ form) with cationic resin. Samples and pH adjusted to pH 6 Samples were columned and washed with 2M ammonia in methanol: water, 1: 1 (5 mL).

Fractions containing the free amine (positive for ninhydrin) were pooled, concentrated, lyophilized to give the crude amine (20 mg).

To the crude amine was added 1 mL of deaerated 0.5 M sodium borate in water. buffer (pH 8.5) and deaerated methanol (3 mL). The reaction mixture was purged with nitrogen and cooled to 0 ° C. 6.0 μΐ acryloyl chloride was added and stirring continued for 10 minutes. The reaction mixture is concentrated at room temperature to about one third of its initial volume. Purification on a Bio-Gel 'P2 column and lyophilization gave pure compound (55) (15 mg).

NMR data: '' C (D ₂ O): δ 16, 90, 16, 45 (2xCH ₃ , fucose),

21.95 (NHCOCH 3), 39.51 (CH ₂ N), 54.31 (C-2); 99.21, 99.95,

101.56, 102.87, (C-1, C-1 ', 2xC-1 fucose), 127.21,

129.57 (CH = CH ₂ ), 173, 27 (NHCOCH ₃ ).

(vi) Fucal-2Galpl-3 (Fucal-4) GlcNAcPl-O-Seal 5-PAA (56)

Copolymerization of 2-acrylamidethyl 2-acetamide-2-deoxy-3-0-2-0-α-L-fucopyranosyl-β-D-galactopyranosyl-4-α-L-fucopyranosyl-3D-glucopyranoside (55) with acrylamide.

A solution of tetrasacchide (54) (15 mg, 20 µmol) in deaerated water (1 ml) was added at room temperature to acrylamide (8.3 mg, 120 µmol). To this slowly stirred solution (stored in the dark and under nitrogen) was added N, N, N ', N'-tetramethylenediamine (6 μΐ) at 0 ° C followed by ammonium persulfate (3.5 mg). The mixture was stirred at room temperature overnight. TLC (ethyl acetate: acetic acid: methanol: water, 5: 3: 3: 2) showed that all compound (49) was consumed and that a sintered parent product was formed. The polymer was purified by gel chromatography on a Bio-Gel® P2 column eluting with aqueous n-butanol (1%). The washed fraction in an empty volume was freeze-dried to give 20 mg (56) of polymer.

NMR analysis showed that on average 1 trisaccharide corresponds to 6 acrylamide units.

EXAMPLE

Fucal-2Galpl-O-spacer 5-PAA (58) (i) 2-Acrylamidoethyl 2-C-α-L-fucopyranosyl-β-D-galactopyranoside (57)

To 6.4 mg of compound (30) was added 0.3 ml of deaerated 0.5 M sodium borate in water. buffer (pH 8.5) and methanol (0.9 mL). The reaction mixture was purged with nitrogen and cooled to ° C. 2 μΐ of acryloyl chloride was added and stirring continued for 10 minutes. The reaction mixture is concentrated at room temperature to about one third of its initial volume. Purification on a Bio-Gel® P2 column and lyophilization gave compound (57) (4 mg, 57%).

NMR data: ⁷ Η (D ₂ O): δ 1.2 (d, CH ₃ fucose), 4.52 (dd, H 1), 5.22 (m, H-1 ′), 5.80 (dd, CH = CH ₂ ), 6.25 (m, CH = CH ₂ ).

(ii) Fucal-2Gaipi-O-gasket 5-PAA (58)

To a solution of compound (57) (4 mg, 9 µmol) and acrylamide (3.3 mg, 47 μιηοΐ) in deaerated water (0.75 mL) was added first N, N, N ', N'-tetramethylenediamine (2). μΐ) followed by ammonium persulfate (1.5 mg). The mixture was stirred at room temperature overnight. (58) The polymer was purified on a Bio-Gel® P-2 column (9.1 mg).

NMR data: ³ H (D ₂ O) showed that 1 attached oligosaccharide corresponds on average to 12.3 acrylamide units.

BIOLOGICAL EXPERIMENTS

Materials and Ways

In situ adhesion test for Helicobacter pylori

Uninfected specimens from normal adult gastric tissue (obtained from Huddinge Sjukhus, Sweden) were used to test for the adhesion of Helicobacter pylori. All samples were fixed in 4% formalin and subsequently dipped in paraffin.

Sections, 4 µm thick, placed on glass slides and stained with Steiner silver (to detect gastric cell types and to check for pathological abnormalities in tissue samples) and / or subsequently tested for adhesion.

Four clinical isolates of Helicobacter pylori, A4, A5, A7 and A8 (obtained from Huddinge Sjukhus) were used. Helicobacter pylori was grown at 37 ° C on Brucella agar supplemented with 10% bovine blood and 1% bovine Vitalex (Becton Dickinson Microbiology System, Cockeyville, MD) under microarrophilic conditions (5% O ₂ , 10% CO ₂ , 85% N ₂ ). and 98% moisture. Five days after inoculation, the bacteria were carefully suspended in 25 ml of 0.1 M NaCl / 0.1 M sodium carbonate, pH 9.0, from one fully infected plate. To the bacterial suspension was added 250 μΐ of a freshly prepared solution of 10 mg / ml fluorescein isothiocyanate (FITC, Sigma Chemical Co.) in dimethyl sulfoxide and kept for 1 hour at room temperature in the dark. Bacteria were harvested by centrifugation at 3000 xg for 10 minutes and resuspended by gentle pipetting in PBS + 0.05% polyoxyethylene sorbitol monolaurate (Tween 20) and recovered as a precipitate after centrifugation as described above. The washing procedure was repeated 3 times and the suspension was finally resuspended to an optical density of 0.2. The intensity of FITC labeling was uniform in all strains, as can be seen with a similar number of organisms under a fluorescence microscope. Samples of a uniform size of 1 ml were taken from the final suspensions and immediately used or stored at -20 ° C until use. No difference was found in the type of binding between strains labeled and immediately used and strains that were frozen and thawed once before use.

Tissue sections placed on slides were deparaffinized with Bio-Clear (Bio-Optica SpA) and absolute alcohol, 95% alcohol followed by 70% alcohol, rinsed with water then PBS and then stored for 45 min in blocking buffer (1). % gelatin / 0.05% Tween 20 in PBS). A suspension of FITC-labeled bacteria (optical density about 0.200-0.250) was mixed with an equal volume of concentrated solution of the compound. The mixture was stored for 2 hours at room temperature in the dark, 200 μΐ of this mixture was placed on tissue slides on slides and stored for 1 hour at room temperature in a humidified chamber. The slides were then washed 6 times with PBS before viewing with a fluorescent microscope.

Analysis

In situ adhesion bombardments were performed to determine the adhesiveness of Helicobacter pylori to human gastric tissue and to demonstrate inhibition of Helicobacter pylori with compounds containing terminal L-fucose, such as LNF1-HSA.

To determine the ability of L-fucose-containing compounds to terminate binding, a suspension of FITC-labeled bacteria (optical density about 0.200-0.250) is mixed with a concentrated solution of the compound. The mixture was initially stored for 2 hours at room temperature in the dark. 200 μΐ of this mixture was placed on a tissue section on a slide and held for 1 hour at room temperature. After incubation, the affected tissue sections were washed 6 times with PBS before analysis.

Tissue sections exposed to the test compound and untreated tissue sections were compared using fluorescence microscopy and image analysis (Neotech Image Grabber 24 / 1.1 was used to transmit the visible microscope image to the computer screen and Optilab 24 / 2.1.1 Grafted to count the bacteria adhering.

The resulting values in the table are averages of the adhered 5 bacteria in three different areas per section, comparing the affected (with compound) and unaffected tissue sections.

TABLE

COMPOUND CONC. SLOP. (middle small) t Fucal-2Gaipi-ta.rpicker 1] ₅ -HSA 2 mM 34% [Fucal-2Gaipi-gasket 4] ₈ -HSA 2 mM 35% [Fucal-2Gaipi-gasket 2] _n -PAA n = 112.3 for acrylamide units 2 mM 45% [Fucal-2Gaipi-gasket 5] _n -PAA n = 15 for acrylamide units 1 mM 53% [Fucal-2Gaipi-3GlcNAcPl-spacer 2] _n -PAA n = 17.6 for acrylamide units 2 mM 40% [Fucal-2Gaipi-3GlcNAcpl-Galpl-Gasket 3] ₃₅ -HSA (LNFI-SA) (Purchased from Sep AB, Sweden) 0.2 mM 72% [Fucal-2Galpl-3 (Fucal-4) GlcNAcpl-Galplug 3] ₃₂ -HSA (LND1-HSA) (Purchased from Sep AB, Sweden) 0.2 mM 71% [Fucal-2Gaipi-3 (Fucal-4) GlcNAcpi-Gaipi Sealant 3] _n -PAA n = 118 acrylamide units 0.2 mM 67% n = 15 for acrylamide units 0.2 mM 84% n = 16 for acrylamide units 0.2 mM 93% [GlcNAcal-3 (Fucal-2) Gaipi-3 (Fucal-4) GlcNAcPlGaipi Gasket 3] ₂₂ -HSA (Hepta-HSA) 0.2 mM 80%

(Purchased from Sep AB, Sweden)

Claims (40)

DEFINITION OF INVENTION 1. A compound represented by the general formulas Ia, lb, lc, Id, Ie or If: YZ _x -R AZ ₂ -R A-Z3-B-Z4-R Ia lb lc AZ ₅ -BZ ₆ -CZ ₇ -R AZ ₈ -BZ ₉ -CZ ₁₀ -DZ _n -R 10 Id Ie AZ ₁₂ BZ ₁₃ CZ ₁₄ -DZ ₁₅ EZ ₁₆ R, If 15 which Z _x , Z ₂ , Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , Z _a , Z ₉ , Z ₁₀ , Z _1X , Z ₁₂ , Z ₁₃ , Z ₁₄ , Z ₁₅ and Z _{16 are} independently O, S, CH ₂ or NR ₂₅ where R ₂₅ is hydrogen, C ₁ . _24- alkyl, C ₂ -C ₂₄ -alkenyl, C ₁ . _24- alkylcarbonyl or benzoyl optionally capable 20 be substituted by hydroxyl, amino, C ₁ _ ₄ alkyl, C ₁ _ ₄ -alkoxyl, nitro, halogen, phenoxy or mono- or dihalogenC ₁ _ ₄ alkyl substituent; in which In formulas Y, A, B, C, D, and E, the curved line is a bond in either the a - or β - configuration; R _x, R ₂ and R ₃ are each independently H, halogen, azido, guanidinyl, branched or unbranched C ₁ _ ₂₄ alkyl, C _{2nd 24} -alkenyl, C _2-2 4 ^- alkynyl, C ₃ _ ₈ cycloalkyl, C _{3rd 8-} cycloalkyl-C ₁ -C ₂₄ -alkyl or C ₁ . _{A 12-} alkoxy-C ₁ -C ₁₂ -alkyl group which may optionally be substituted by hydroxy, amino, halogen or oxo; aryl or aryl-C ₁ . _4-alkyl optionally substituted in the aryl moiety with hydroxy, amino, C _y _ ₄ alkyl, C _y _ ₄ -alkoxyl, nitro, halogen, phenoxy, or mono- or di-C _{first 4-} alkyl substituent; tri _(y _ ₄ -alkyl) silylethyl; oxo group; = SR ₄ R ₅ Group, where R ₄ and R _{5 are} independently H or C _x . _4- alkyl; or a group XR ₁₀ wherein X is O, S, NR ₂₀ or = N- and R ₁₀ is H, branched or unbranched C ₁ -C ₂₄ alkyl, C ₂ . _24- alkenyl, C ₂ -C ₂₄ -alkynyl, C ₃ . ₈ cycloalkyl, C ₃ _ ₈ -cikloalkilC ₁ _ ₂₄ alkyl, or C ° ₁ _ ₁₂ alkoxy-C _{first A 12-} alkyl group which may optionally be substituted by hydroxyl, amino, halogen or oxo; aryl, aryl-C ^ alkyl, or heterocyclyl-C ₁ _ ₄ alkyl, which is optionally substituted in the aryl or heterocyclyl moiety with hydroxy, amino, C _{first 4} alkyl, C ₁ _ ₄ -alkoxyl, nitro, halogen, phenoxy, or mono- or di-C ^ alkyl substituent; tri _{(ie. 4} alkyl) silylethyl; tri _{(first 4} -alkyl) yarn; tri _(y _ ₄ alkyl) silylethoxymethyl; acyl residues of naturally occurring amino acids; Cy. ^ - alkylcarbonyl; C _2-24 alkenyl; C ₃ _ ₈ thereof in kloalkil -g-C ^ -alkylcarbonyl; arylcarbonyl; or terpenyl; and R ₂₀ is H, C ₁ . _24- alkyl, C ₂ -C ₂₄ -alkenyl, C ₁ . ₂₄ -alkylcarbonyl or optionally a benzene ring with hydroxy, amino, C ₁ _ ₄ alkyl, C _first Benzoyl or phthaloyl of _4- alkoxyl, nitro, halo, phenoxy or mono- or dihalo-C 1-4 alkyl; RlAz R-2A 'R-3Af ^ 4A' RlB 'R' R9 R. R3 R4 R, 2Az ^Λ 3Αζ ^IX 4Az ^Λ 1Βζ ^lx 2Bz ^ Bz ^ 4 B> ^ INCZ ^ 2C '^ 3 {7 ^IX 4Cz ^lx lDz R _2D , R _3d , R _4d , R _1e , R _2e , R _3e and R _{4E are} each independently as defined above for R _x , R ₂ and R _3, or are a group of Formula VII YZ _X VII, wherein Y and Z _x are as defined above; provided that one of R or Z 14 that one of Rs 1EZ 1Bz R: Bz R3B or R4B is Z ₃ z 1Cz R2C or R4C is Z ₆ z ouch R3D or R4D is Z10 ^ 3E or R4E is Zl5z that 2At least one and not more than five of R _1A , R 2 4AZ ^ lEz that ibz R2EZ 'ZBz 3Bz R4BZ R 1CZ 2C r 3C z 4CZ R _X q, R 2DZ ^ 3Dz R3AZ R4DZ 3E and R _4e are a group of formula VII, and Groups R _1a , R _2a , Figures, Group B R ₁₀ , Figures, Group C R _1C , R _3A and R _4A CH ₂ substituent confR _2B , R 3B and R 4b ^CH 2 substituent configurations R _2C , R 3C R _4C CH ₂ substituent configurations, R _1D , R _2D , R _3d and R _4D CH ₂ substituent configurations, R _1E , R _2E , R _3E and R _4E CH ₂ substituent configurations independently of D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-tolose, L-tolose, D-alose , Configurations of L-allose, D-altrosis, L-altrosis, D-gulose, L-gulose, D-idose and L-idose; R is hydrogen, branched or unbranched C ₁ -C ₂₄ alkyl, C ₂ . ₂₄ alkenyl, C ₂ _ ₂₄ alkynyl, C ₃ _ ₈ cycloalkyl, C _{3rd B-} cycloalkyl-C ₁ . ₂₄ alkyl, C ₁ . _12- alkoxy-C ₁ -C ₁₂ -alkyl, C _x . ₂₄ -alkylcarbonyl, C ₂ . _{A 24} -alkenylcarbonyl or C3.8-cycloalkyl-Cx.24LT 3446 B alkylcarbonyl group which may optionally be substituted by hydroxyl, amino, halogen or oxo; aryl or aryl-C ^ alkyl, arylcarbonyl or aryl-C _l _ ₄ alkylcarbonyl group which is optionally an aryl group substituted with hydroxy, amino, C ^ alkyl, C ₁ _ ₄ -alkoxyl, nitro, halogen, phenoxy or mono- or dihalogenC ₁ . _4- alkyl substituent; terpenyl; tri (C ₁ _ ₄ alkyl) silylethyl; heterocyclyl; heterocyclyl-C ₁ . _4- alkyl; or heterocyclyl-C 1 _ _{L 4} -alkylcarbonyl; a group of formula II or Ha R ₃₀ - (CH ₂ ) _q -S (O) _m -CH ₂ CH ₂ - II [R ₃₀ - (CH ₂ ) _q -S (O) _m -CH ₂ ] ₂ CH-CH ₂ - Ha where R ₃₀ is H, carboxyl, C 1-4 alkoxycarbonyl, hydroxyl, amino or MA matrix, q is an integer from 1 to 24 and m is 0 or 2; or a group of formula III or IIla Phe-S (O) _m -CH ₂ CH ₂ - III [Phe-S (O) _m -CH ₂ ] ₂ CH-CH ₂ - IIIa wherein m is as defined above and each Phe is phenyl which may optionally have hydroxyl. , amino, C,. ₄ alkyl, C ₁ _ ₄ -alkoxyl, nitro, halogen, phenoxy, or mono- or di-Ci ^ alkyl substituent; or phenylC ₁ . _4- alkyl which may optionally have one hydroxyl, amino, C 1-4 alkyl, C _{x in the} phenyl group. _{A 4-} alkoxyl, nitro, halogen, phenoxy or mono- or dihaloC 1-6 alkyl substituent; a group of formula IV R ₄₀ CH ₂ CH (CH ₂ R ₅₀ ) CH ₂ IV wherein R ₄₀ and R _{50 are} independently halogen; or Q- (bridge) _r is a group where r is an integer 0 or 1. while Q is an MA matrix or a -COO-MA group; for use in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of human diseases caused by infection of the human gastric mucosa with Helicobacter pylori. Use according to claim 1, characterized in that Z _x , Z ₂ , Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , Z ₈ , Z ₉ , Z ₁₀ , Ζχχ, Z ₁₂ , Z ₁₃ , Z ₁₄ , Z _15, and Z ₁₆ are O. Use according to claim 1 or 2, characterized in that it contains at most four, preferably at most three, in particular one or two of R _1A , R _2A , R _3A , R-4AZ R 1BZ E _2b , R _3b , R _4b , R _1c , R _2c , R-3CZ ^ 4CZ ^ INZZ 2Dz ^ 3Dz ^ 4DZ R _1E , ^r 2ez R-3E or R _4E is a group of formula VII. Use according to any one of claims 1 to 3, characterized in that R _7A is a group VII in configuration a. Use according to any one of claims 1 to 3, characterized in that the CH _{2 of} R _1A , R _2A , R _3A and R _{4a of Part A} have the D-galactose configuration in the A 2 configuration. 6. Use according to any one of claims 1-3, characterized in that R ₁ is a group VII in the a-configuration, and A part of R _1A, R _2A, R _4A and R ₃ CH ₂ are D-galacto configuration, being in the β - configuration . 7. Use according to any one of claims 1-3, characterized in that R _2B is Z _3, Z _5, Z _8, or Z ₁₂ and Part B, R _1B, R _2B, R _3B and R _4B, CH ₂ are D-gluco configuration at B β - configuration. Use according to any one of claims 1 to 3, wherein R _1B is an acetamide group. Use according to any one of claims 1 to 3, characterized in that R _1A is a group VII in the α-configuration; Part A of R _1A , R _2A , R _3A and R _4A CH ₂ has Dgalactose configuration in A β configuration; R _2B is Z-, Z ₅ , Z ₈ or Z ₁₂ ; and in Part B, R _1B , R _2B , R _3B and R _4h CH ₂ have a D-glucose configuration in the B β configuration and R _1B is an acetamide group. Use according to any one of claims 1 to 9, wherein R _3b is a group of formula VII in the α-configuration. Use according to any one of claims 1 to 10, wherein divergent that that R _1A of Part A, ^ 3A and R _{4a in} CH ₂ and R in Part B ^ 3B R4bCH ₂ has D- galactose configuration and Part C R _1C , R _2C , R _3C and R _{4 (} -CH ₂ has the configuration of D-glucose in the α-configuration of A and in the β-configuration of B and C and wherein R _1B and R _3C are groups corresponding to formula VII in the α-configuration wherein R _1A and R _1C are acetamide and wherein R _2B is Z ₅ , Z _s or Z ₁₂ , o R, is Z., Z, or Z ₁₃ . 12th Use according to 6 t i s by the fact that A is Fuc 13th Use according to 9 t 1 s by the fact that A-Zj-B Aa other than α1-2Θ3ΐβ. Claims 1 to 4, wherein Fucal-2Ga ^ l-3? Fucal-2ΰβ1β1-3 (Fucal-4) ΰΙοΝΑοβ. Use according to claim 9, characterized in that AZ ₅ -BZ ₆ -C is Fucal-2 Like 1-3GlcNAca 13 Like or Fucal-2Gaipi-3 (Fucal-4) GlcNAcPl-3G Like. Use according to claim 9 or 11, characterized in that AZ ₈ -BZ ₉ -CZ ₁₀ -D is GalNAcal 3 (Fucal-2) Gaipi-3 (Fucal-4) GlcNAcPl-3GaiP or Fucal2Galpl-3 (Fucal-4). GlcNAcpl-3Galpl-4Glcp. 16. Use according to claim 11, characterized in that Z ₁₂ -BZ -CZ _{13 14 15} -E is -DZ GalNAcal-3 (Fucal-2) Galpl-3 (Fucal-4) GlcNAcl-3Gaipi-4Glcp. Use according to any one of claims 1 to 16, wherein R is a group Q (bridge) _r -, wherein r is an integer 0 or 1 and Q is a matrix (MA). Use according to any one of claims 1 to 17, characterized in that the bridge is defined as (W) _v -S'-P ', where S' is C ₁ . _24- alkyl, C ₂ -C ₂₄ -alkenyl, C ₁ . ₂₄ alkylaryl, arylC ₁ _ ₂₄ alkyl, arylC _{first 24} alkylaryl, C ₁ . ₂₄ alkilarilC ₁ _ ₂₄ alkyl group, these groups may be interrupted by carbonyl, thiocarbonyl, oxycarbonyl, carbonyloxy, carbonylamino, aminocarbonyl, azo, oxo or thio groups; aryl group, aryloxy, C ₁ . _24- alkoxyl, polyethylene glycol group, steroid group, sphingoid group; all groups may contain carboxyl, C ₁ . ₄ alkylcarbonyl, amide, hydroxyl, alkoxy, aryloxy, phenoxy; P 'is NH-C (S), NH-C (O), C (O), NH, C (S), C (O) O, (O) C0, SO, SO ₂ , SO ₃ , SO ₄ , PO ₃ , PO ₄ ; W is NH-C (S), NH-C (O), C (O), C (S), C (O) 0, (O) C0, SO, S0 ₂ , S0 ₃ , SO ₄ , PO ₂ , PO ₃ , PO ₄ , with the proviso that when Z _lz Z ₂ , Z ₄ , Z ₇ , Z _n or Z ₁₆ is CH ₂ , W cannot be PO ₂ , provided that when Z _T , Z ₂ , Z ₄ , Z ₇ , Z _u or Z ₁₆ is O or S, or W can not be (O) CO, so ₄ with PO ₄ , and with condition, that when Z ,, Z ₂ , Z ₄ , Z ,, Z _u or Zie is NH, or W cannot to be NH-C (S ), NH-C (O), (0) CO, so ₄ with PO ₄ , and v is healthy number 0 or 1. Use according to any one of claims 18, wherein the bridge is selected from Use according to any one of claims 1 to 17, wherein the matrix (MA) is human serum albumin (HSA), bovine serum albumin (BSA) or polyacrylamine (PAA). 21. The use of claim 1, wherein the compound is selected from [Fucal-2Gaipi -1 i 1 telis] _n -MA; [Fucal-2Gaipi-3GlcNAcP Bridge] _n -MA; [Fucal-2Galpl-3 (Fucal-4) GlcNAcp-bridge] _n -MA; [Fucal-2Galpl-3GlcNAcpl-3Galpl bridge] _n -MA; [Fucal-2Galpl-3 (Fucal-4) GlcNAcP-3Galpl-bridge] _n -MA; [GalNAcal-3 (Fucal-2) Galpl-3 (Fucotl-4) GlcNAcpl-3Galpha bridge] _n -MA; [Fucal-2Galpl-3 (Fucal-4) GlcNAcpl-3Galpl-4Glcpl-NH] _n -MA; [GalNAcal-3 (Fucal-2) Galpl-3 (Fucal-4) GlcNAcpl-3Gaipi4GlcPl- [bridge] _n -MA; wherein the bridge is selected from the group defined in claim 19, n is an integer from 1 to 40 when MA is HSA or BSA, and n is an integer from 10 to 10,000 when MA is PAA. 22. The use of claim 1, wherein the compound is selected from [Fucal-2Gaipi-bridge 1] _n -HSA; [Fucal-2Gal01-bridged 2] _n -PAA; [Fucal-2Gaipi-bridge 4] _n -HSA; [Fucal-2Gal3l-bridge 5] _n -PAA; [Fucal-2Galpl-3GlcNAcp-bridge 5] _n -PAA; [Fucctl-2Gaipi-3 (Fucal-4) GlcNAcP-bridge 5] _n -PAA; [Fucal-2Gaipi-3GlcNAcpi-3Gaipi-bridge 3] _n -HSA; [Fucal-2Gaipi-3 (Fucal-4) GlcNAcP-3Gaipi-bridge 3] _n -HSA; [Fucal-2Galpl-3 (Fucal-4) GlcNAcpl-3Galpl-4Glc 1-NH] _n -PAA; [GalNAcal-3 (Fucal-2) Galpl-3 (Fucal-4) GlcNAcPl-3Galpha-bridging 3] _n -HSA; wherein bridge 1, bridge 2, bridge 3, bridge 4, and bridge 5 are as defined in claim 19, n is an integer from 1 to 40 when MA is HSA, and n is an integer from 10 to 10,000 when MA is PAA. The use according to any one of claims 1 to 22, wherein the compound of the formulas Ia, Ib, Ic, Id, Ie or lf is adapted for administration in combination with a preparation commonly used in the therapeutic treatment of gastritis or ulcers, in particular preparations. containing omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine, nizethidine, magnesium hydroxide, aluminum hydroxide, calcium carbonate, simethicone or magaldrate. The use of _{T as} claimed in any one of claims 1 to 23, wherein the compound of formula Ia, Ib, 1c, Id, le or If is adapted for administration in combination with a preparation for use in antimicrobial treatment courses, in particular with preparations with: β-lactam antibiotics such as: amoxicillin, ampicillin, cephalothin, cefachlor or cefixime; or macrolides such as erythromycin or clarithromycin; or tetracyclines such as tetracycline or doxycycline; or aminoglycosides such as gentamicin, kanamycin or amikacin; or quinolones such as norfloxacin, ciprofloxacin or enoxacin; or other substances such as metronidazole, nitrofurantoin or chloramphenicol; or preparations containing bismuth salts, such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate. A compound of the formula Ia, Ib, lc, Id, le and If as defined in claims 1-22 for the treatment or prophylaxis against human diseases caused by infection of the human gastric mucosa by Helicobacter pylori. A compound of the formula Ia, Ib, lc, Id, le and If, as defined in claims 1-22, in combination with at least one anti-opiate or antigenic agent, or at least one antimicrobial agent or mixture thereof, for use in the prophylaxis or treatment of human disease, caused by infection of human gastric mucosa with Helicobacter pylori. A pharmaceutical composition comprising a compound of the formulas Ia, Ib, Ic, Id, Ie or If, as defined in claims 1-22, or a mixture of such compounds, together with at least one anti-opiate or antigenastrophic drug or at least one an antimicrobial agent or a mixture thereof and a pharmaceutically acceptable carrier. 28. The pharmaceutical composition of claim 27, wherein the anti-opiate or antigastritic medicament is selected from gastric secretion inhibiting compounds and antacids. 29. The pharmaceutical composition of claim 28, wherein the gastric secretagogue is selected from cimetidine, ranitidine, famotidine, nizatidine, omeprazole, lansoprazole, pantoprazole and sucralfate. 30. A pharmaceutical composition according to claim 28, wherein the antacid is selected from A1 (OH) ₃ , Mg (OH) ₂ , CaCO ₃ , Na ₂ CO ₃ , NaHCO ₃ , aluminum magnesium hydroxide or hydrate thereof, simethicone. 31. The pharmaceutical composition of claim 27, wherein the antimicrobial agent is selected from lactam antibiotics such as: amoxicillin, ampicillin, cephalothin, cefachlor or cefixime; macrolides such as erythromycin or clarithromycin; tetracyclines such as: tetracycline or doxycycline; aminoglycosides such as gentamicin, kanamycin or amikacin; quinolones such as norfloxacin, ciprofloxacin or enoxacin; bismuth salts such as bismut trate, bismuth subsalicylate, bismuth subke bismuth subnitrate or bismuth subgalate; heterc antibiotics such as metronidozole, rantoin, and benzene derivatives such as chloramphenic 32. A novel compound [Fucal-2Gal3l-bridge wherein bridge 1 is 1] _n -HSA, on is an integer from 1 to 40. 33. A new compound [Fucal-2Galpl-bridge where bridge 2 is 2] _n -PAA, on is an integer of 10-10000. 34. A novel compound [Fucal-2Galpl-thiile wherein bridge 4 is 4] _n -HSA, on is an integer from 1 to 40. 35. A new compound [Fucal-2Gaipi-bridge where bridge 5 is 5] _n -PAA, on is an integer of 10-10000. 36. New compound [Fucal-2Gaipi-3GlcNAcpi-bridge 5] _n -PAA, wherein bridge 5 and n are as defined in claim 35. A novel compound [Fucal-2Gaipi-3 (Fucal-4) GlcNAcPlate 5] _n -PAA, wherein bridge 5 and n are as defined in claim 35. 38. The novel compound of any one of claims 32-37, wherein the compound is for use in the treatment of gastritis or ulcer with a conventional formulation containing omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine, nizethidine, magnesium hydroxate, aluminum. hydroxate, calcium carbonate, simethicone or magaldrate. The novel compounds according to any one of claims 32 to 37, wherein the compound is adapted for use in combination with a preparation for use in a course of treatment with an antimicrobial agent, in particular with preparations comprising: β-lactam antibiotics such as: amoxicillin, ampicillin, cephalothin, cefachlor or cefixime; or macrolides such as erythromycin or clarithromycin; or tetracyclines such as tetracycline or doxycycline; or aminoglycosides such as gentamicin, kanamycin or amikacin; or quinolines such as norfloxacin, ciprofloxacin or enoxacin; or other substances such as metronidazole, nitrofurantoin or chloramphenicol; or preparations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate. 100 Novel compounds according to any one of claims 32 to 37 for use in therapy. 41. A process for the preparation of novel compounds according to any one of claims 32 to 37, which utilizes methods known in the art. 42. A process for the preparation of novel compounds of the formulas Ia, Ib, Ic, Id, Ie and lf, wherein i) converts the monosaccharide into a glycoside with an aglycone R _a to form an R _a -glycoside derivative so that that R _a -glycoside can be transformed into a glycosyl donor by activation of the anomeric center, ii) then introduces new functional groups R _b , iii) condensing R _b- substituted R _a -glycosides, if multiple glycosidic linkages are required, this step iii) is repeated, iv) then introducing a substituent R _c defined as (Z ₁ -Z ₁₆ ) -R at the reducing end, and, if necessary, remove the blocking groups.