WO1995000527A1 - Glycosides fucosyles inhibiteurs de l'adhesion bacterienne - Google Patents

Glycosides fucosyles inhibiteurs de l'adhesion bacterienne Download PDF

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Publication number
WO1995000527A1
WO1995000527A1 PCT/SE1994/000604 SE9400604W WO9500527A1 WO 1995000527 A1 WO1995000527 A1 WO 1995000527A1 SE 9400604 W SE9400604 W SE 9400604W WO 9500527 A1 WO9500527 A1 WO 9500527A1
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WIPO (PCT)
Prior art keywords
fucα1
alkyl
spacer
group
2galβ1
Prior art date
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PCT/SE1994/000604
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English (en)
Inventor
Karin Ingeborg Eklind
Hans Roland LÖNN
Anna-Karin Ulla Edit Tiden
Original Assignee
Astra Aktiebolag
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Filing date
Publication date
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to AU70891/94A priority Critical patent/AU7089194A/en
Priority to EP94919945A priority patent/EP0706528A1/fr
Priority to JP7502720A priority patent/JPH08512026A/ja
Publication of WO1995000527A1 publication Critical patent/WO1995000527A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to the use of L-fucose-containing glycoside derivatives for the preparation of pharmaceutical compositions for the treatment or prophylaxis of conditions involving gastrointestinal infections by Helicobacter pylori , a method of treating such conditions using the derivatives, as well as novel glycoside derivatives.
  • Helicobacter pylori is a microaerophilic spiral shaped organism (originally assigned to the genus Campylobacter) which is found in the stomach and generally appears to have an exclusive habitat in the human gastric mucosa. It has been estimated that this bacterium infects the gastric mucosa of more than 60% of adult humans by the time they are 60 years old. Moreover, H. pylori has been implicated as a contributing factor in a number of pathological conditions, including acute (type B) gastritis, gastric and duodenal ulcers, atrophic gastritis, and gastric adenocarcinoma. Tissue tropism of bacteria is partly governed by the ability of a bacterial strain to adjust to the local chem
  • bacteria adhere to proteins or glycoconjugates (glycosphingolipids, glycoproteins) on or in the vicinity of epithelial cell surfaces (mucus), and a number of specific bacterial adhesin-protein and
  • colonization factor antigens to mediate the binding of H.
  • the invention concerns the use of mono-, di-, tri- or
  • oligosaccharide glycoside derivatives having at least one terminal group Y, as defined below, derived from L-fucose, said derivatives being compounds of the general formula Ia, Ib, Ic, Id, Ie or If
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z g , Z 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 and Z 16 independently are O, S, CH 2 , or NR 25 , where R 25 is hydrogen, C 1-24 -alkyl, C 2-24 -alkenyl, C 1-24 -alkylcarbonyl, or benzoyl optionally substituted with hydroxy, amino, C 1-4 -alkyl, C 1-4 -alkoxy, nitro, halogen, phenoxy, or mono- or di-halogen-C 1-4 -alkyl; ;
  • R 1 , R 2 , and R 3 each independently are H, halogen, azido, guanidinyl, branched or unbranched C 1-24 -alkyl,
  • a group CR 4 R 5 wherein R 4 and R 5 independently are H, or C 1-4 -alkyl;
  • R 20 is H, C 1-24 -alkyl, C 2-24 -alkenyl,
  • R 1A , R 2A , R 3A , R 4A , R 1B , R 2B , R 3B , R 4B , R 1C , R 2C , R 3C , R 4 C , R 1D , R 2D , R 3D , R 4D , R 1E , R 2E , R 3E , an d R 4E each
  • R 1B , R 2B , R 3B , or R 4B is Z 3 , Z 5 , Z 8 or Z 12 , that one of R 1C , R 2C , R 3C , or R 4C is Z 6 , Z 9 or Z 13 , that one of R 1D , R 2D , R 3D , or R 4D is Z 10 , or Z 14 , that one of
  • R 1E , R 2E , R 3E , or R 4E is Z 15 , that at least one and at the most five of R 1A , R 2A , R 3A , R 4A , R 1B , R 2B , R 3B , R 4B ,
  • R 1C , R 2C , R 3C , R 4C , R 1D , R 2D , R 3D , R 4D , R 1E , R 2E , R 3E , and R 4E is a group of the formula VII, and
  • R 1D , R 2D , R 3D , and R 4D CH 2 in D and the configurations of the substituents R 1E , R 2E , R 3E , and R 4E CH 2 in E independently are D-gluco, L-gluco, D-galacto, L-galacto, D-manno , L-manno, D-talo , L-talo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-ido, or L-ido;
  • R is a branched or unbranched C 1-24 -alkyl, C 2-24 -alkenyl,
  • aryl-C 1-4 -alkylcarbonyl group optionally substituted in the aryl moiety with hydroxy, amino, C 1-4 -alkyl,
  • heterocyclyl-C 1-4 -alkylcarbonyl a group of the formula II or IIa
  • R 30 is H, carboxy, C 1-4 -alkoxycarbonyl, hydroxy, amino, or a matrix MA, q is an integer from 1 to 24, and m is 0 or 2; or a group of the formula III or Ilia
  • R 40 CH 2 CH(CH 2 R 50 )CH 2 - IV wherein R 40 and R 50 independently are halogen; or a group Q-(Spacer) r -, where r is an integer 0 or 1, and Q is a matrix MA or a group -COO-MA; in therapy, especially for the treatment or prophylaxis in humans of conditions involving infection by Helicobacter pylori of human gastric mucosa.
  • Another aspect of the invention relates to the use of said compounds for the preparation of pharmaceutical compositions for use against the above mentioned conditions.
  • C 1-4 -alkyl C 1-8 -alkyl
  • C 1-24 -alkyl as a separate group or as part of a group
  • alkyl groups with 1-4, 1-8 or 1-24 carbon atoms which may be straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, dimethy1butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl, etc.
  • C 1-4 -alkyl is used herein when substituents are defined.
  • C 3-8 -cycloalkyl as a group or as part of a group designates a cyclic alkyl group with 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • 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,
  • C 2-24 -alkynyl designates an alkyl group with 2-24 carbon atoms and incorporating a triple bond, e.g. ethynyl,
  • halogen designates Cl, Br, I and F, preferably F and Cl.
  • C 1-4 -alkoxy and C 1-24 -alkoxy designate groups comprising an oxa function substituted with an alkyl group as defined above.
  • aryl and “aryloxy” , either as a separate group or as part of a group, designates phenyl or naphthyl, preferably phenyl .
  • aryl-amide defines either aryl-NH-C (O) - e. g.
  • terpenyl moiety designates groups derived from some of the various unsaturated hydrocarbon compounds generically known as the terpenes, namely the monoterpenes and the
  • sesquiterpenes as well as hydroxy or oxo derivatives thereof .
  • examples of such groups are myrcenyl , (-) -limonenyl ,
  • oligosaccharide designates an oligosaccharide containing 4-10 monosaccharide units, preferably 4-7 monosaccharide units, the monosaccharide units being selected from aldohexoses (i.e. D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-talose,
  • aldohexoses i.e. D-glucose, L-glucose, D-galactose, L-galactose, D-mannose, L-mannose, D-talose
  • a mono- or di-halogen-C 1-4 -alkyl group may be substituted in any position and if substituted with 2 halogen atoms, the halogen atoms may be the same or different.
  • heterocyclyl designates a monocyclic 5- or
  • Typical but non-limiting examples of such groups may comprise pyrrolyl, pyrazolyl, pyridinyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, furyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2H-1,3-thiazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 6H-1,3-thiazinyl, 6H-1,3-thiazinyl
  • acyl residue of a naturally occurring amino acid designates the acyl residue of the L-amino acids occurring in proteins in nature, e.g. alanyl, valyl, leucyl, isoleucyl, prolinyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparagyl, glutamyl, lysyl, arginyl, histidyl and the acyl residues of aspartic acid and glutamic acid, the acyl residue referring both to the carboxy group next to the amino function as well as the carboxy group at the end of the respective side chains, preferably, however, the carboxy groups next to the amino functions.
  • sphingoid refers to D-erythro-2-amino-1,3-octadecanediol, its homologs and stereoisomers and to hydroxy and unsaturated derivatives thereof, including ceramide (see further definitions in Journ. of Lipid Research, vol. 19, (1978), 617-631).
  • steroids refers to well-known steroids as
  • betamethasone prednosolone, prednisone etc.
  • matrix as used herein and designated as "MA"
  • proteins glycoproteins, polypeptides, polysaccharides,
  • proteins are preferably bonded through nucleophilic groups in the proteins, e.g. groups such as amino, hydroxyl and mercapto groups.
  • Proteins or polypeptides themselves may be any of a wide variety of substances, in particular biologically compatible proteins such as globulins, albumins such as human serum albumin (HSA), bovine serum albumin (BSA) or sheep serum albumin (SSA), ovalbumin, fibrins, or "key-hole” limpet
  • HSA human serum albumin
  • BSA bovine serum albumin
  • SSA sheep serum albumin
  • ovalbumin ovalbumin
  • fibrins or "key-hole” limpet
  • haemocyanin KLH
  • glycoproteins such as bovine or human whole casein or lectins, and the like.
  • matrices are synthetic polymers where one or several amino acids are coupled to a polymer of defined size(s), e.g.
  • polypeptides the linkage to the remainder of the group R may be through amino groups or through carboxyl groups.
  • the polysaccharides, to which the O-, S-, C-, or N-glycosidic compounds are attached, may be any of a wide variety of polysaccharides.
  • the aglycon part of the compound of formula Ia, Ib, Ic, Id, Ie or If may be bonded through hydroxy1 groups on ordinary polysaccharides such as cellulose, sepharose, starch or glycogen, through amino groups on amino saccharides such as chitosane or aminated sepharose, and through mercapto groups of thio-modified polysaccharides.
  • Liposomes may be any biocompatible, biodegradable microesicular system compose of one or several bilayers surrounding aqueous compartments, within which a variety of agents can be
  • hydrophobic agents in the lipid bilayers and hydrophilic agents in the inner aqueous space hydrophobic agents in the lipid bilayers and hydrophilic agents in the inner aqueous space.
  • Liposomes are composed of phospholipids, such as egg yolk phospholipids, soya phospholipids, synthetic
  • Emulsions are heterogenous mixtures of two or more imiscible liquids. To stabilize these systems an emulsifier is added. The emulsifier is oriented at the interface of the imisible liquids and usually only one phase persist in dropted form. Emulsions fall into two general categories.
  • heterogenous system described by droplets of an organic liquid dispersed in a continuous water phase is called oil-in-water emulsion (o/w).
  • oil-in-water emulsion o/w
  • water-in-oil emulsion w/o
  • Any vegetable oil such as soybean oil, safflower oil, sesame oil, peanut oil, cottonseed oil, borago oil, sunflower oil. corn oil, olive oil,- medium chain triglycerides (such as
  • Miglyol R may be used as internal or continuous phase.
  • plastics to which the aglycon part of the compounds of the formula Ia, Ib, Ic, Id, Ie or If may be attached are animated latex, thiolated, aminated, or hydroxylated
  • polystyrene polyacrylamide and polyvinyl alcohol.
  • Other possible carriers are beads and gels of carbohydrate origin or polymers where carbohydrates are used in combination with other polymeric materials such as sephacryl. These gels are further substituted with groups such as amino, thiols, cyano, active esters and disulfides.
  • the plastics in question may be in the form of e.g. beads or film.
  • inorganic material to which the aglycon part of the compounds of the formula Ia, Ib, Ic, Id, Ie or If may be attached are silicon oxide materials such as silica gel, zeolite, diatomaceous earth, or the surface of various glass or silica gel types such as thiolated or aminated glass, where the silica gel or the glass may be in the form of e.g. beads.
  • silicon oxide materials such as silica gel, zeolite, diatomaceous earth, or the surface of various glass or silica gel types such as thiolated or aminated glass, where the silica gel or the glass may be in the form of e.g. beads.
  • Another example of an inorganic material is aluminium oxide.
  • Particularly preferred matrix MA is human serum albumin (HSA), bovine serum albumin (BSA) and polyacrylamide (PAA).
  • HSA human serum albumin
  • BSA bovine serum albumin
  • PAA polyacrylamide
  • an interesting embodiment of the invention is when the compound of formula Ia, Ib, Ic, Id, Ie or If comprises a matrix MA, said matrix incorporating a multiplicity (i.e. 2 or more, such as 2-100 when the matrix is a protein such as BSA or HSA, or
  • R-group-containing groups on the cyclic groups A, B, C, D and E correspond to the stereochemical patterns formed by the 2-, 3-, and 4-hydroxy groups and the 5-hydroxymethyl group in
  • L-galacto-pyranosyl unit and that the group Y therefore is a L-fucose unit or a derivative thereof.
  • Z 13 , Z 14 , Z 15 and Z 16 are O. It is also preferred that at the most four, more preferably at the most three, in particular one or two of R 1A , R 2A , R 3A , R 4A ,
  • R 2E , R 3E , or R 4E is a group of formula VII. It is also preferred that R 1A is a group VII in the
  • R 1A , R 2A , R 3A and R 4A CH 2 in A are D-galacto, A being in the ⁇ -configuration.
  • Particularly preferred compounds are those wherein R 1A is a group VII in the ⁇ -configuration and the configuration of R 1A , R 2A , R 3A and R 4A CH 2 in A are D-galacto, A being in the
  • R 2B is Z 3 , Z 5 , Z 8 , or Z 12 , and the configuration of R 1B , R 2B , R 3B , and R 4B CH 2 in B are D-gluco, B being in the ⁇ -configuration.
  • R 1B is an acetamido group.
  • Particularly preferred compounds are those wherein R 1A is a group VII in the ⁇ -configuration; the configuration of R 1A ,
  • R 2A , R 3A and R 4 ACH 2 in A are D-galacto, A being in the
  • R 2B is Z 3 , Z 5 , Z 8 , or Z 12 ;
  • R 1B , R 2B , R 3B , and R 4B CH 2 in B are D-gluco, B being in the ⁇ -configuration and R 1B is an acetamido group.
  • A-Z 8 -B-Z 9 -C-Z 10 -D is
  • GalNAc ⁇ 1-3 (Fuc ⁇ 1-2) Gal ⁇ 1-3 (Fuc ⁇ 1-4) GlcNAc ⁇ 1-3Gal ⁇ or
  • GalNAc ⁇ 1-3 (Fuc ⁇ 1-2) Gal ⁇ 1-3 (Fuc ⁇ 1-4 ) GlcNAc ⁇ 1-3Gal ⁇ 1-4Glc ⁇ .
  • R 3B is a group of the formula VII in the ⁇ -configuration.
  • Particularly preferred compounds are those wherein the
  • R 1A , R 2A , R 3A , and R 4A CH 2 in A and of R 1B , R 2B , R 3B , and R 4B CH 2 in B are D-galacto
  • the configurations of R 1C , R 2C , R 3C , and R 4C CH 2 in C are D-gluco, A being in the ⁇ -configuration, and B and C being in the ⁇ -configuration, and in which R 1B and R 3C are groups of the formula VII in the ⁇ -configuration, and in which R 1A and R 1C are acetamido groups
  • R 2B is Z 5 , Z 8 or Z 12
  • R 2C is Z 6 , Z 9 or Z 13 .
  • carbohydrate moiety contains the structure Y-Z 1 -A- where Z 1 is O and the L-fucose unit Y is linked to the 2-position of A.
  • Examples of interesting basic carbohydrate structures in this class are those having the following formulae where the substituents R 2 , R 2 , R 3 , R 1A , R 2A , R 3A , and R 4A each are
  • R 1 , R 2 , R 3 , R 1A , R 2A , R 3A , and R 4A should be considered as being able to assume all the meanings defined above in connection with the formulae la, lb, Ic, Id, Ie and If.
  • the structure Y-Z 1 -A- may be
  • R 4B , R 1C , R 2C , R 3 C , R 4C , R 1D , R 2D , R 3D , R 4D , R 1E , R 2E , R 3E , or R 4E in Y, A, B, C, D, and E are not hydroxyl, they may preferably be selected among the following:
  • H, Cl, F azido, guanidyl, methyl, ethyl, propyl, vinyl, allyl, prop-1-enyl, ethynyl, prop-2-ynyl, prop-1-ynyl, acetyl, cyclopropyl, cyclopropylmethyl, methoxymethyl, hydroxymethyl, phenyl, oxo, methylene, thiol, amino, 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,
  • octadecanoyloxy acetamido, N-methylacetamido, acetylthio, glycyloxy, or alanyloxy.
  • cyclobutylmethyl cyclopentylmethyl, cyclopentylprop-3-yl, cyclohexyl, cyclohexylmethyl, cyclohexylprop-3-yl, cycloheptyl, phenyl, 4-nitrophenyl, benzyl, 4-phenylprop-1-yl,
  • the linkage between the matrix MA and the remainder of R may typically be through any of the spacers well known in the field of protein conjugates, cf. for example J.H. Pazur, Adv. Carbohydr. Chem. Biochem . , Vol 39, (1980), 405-447; Y.C. Lee & R.T. Lee, "Glycoconjugates", Vol. 4 Part B, 57-83, Ed. Horowitz, Academic Press, N.Y.
  • Spacer is intended to mean a molecule moiety which links the active substance to a carrier.
  • a spacer molecule is designed to have two different
  • the Spacer can be defined as (W) v -S'-P', wherein S' is an C 1-24 alkyl, an C 2-24 alkenyl, an C 1-24 alkylaryl, an arylc 1-24 alkyl an arylC 1-24 alkylaryl, an C 1-24 alkylarylC 1-24 alkyl group which groups may be interrupted by carbonyl, thiocarbonyl,
  • 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 ,
  • the atom of the sugar moiety which linkages to the spacer is selected among from the following: -O-, -S-, -NH-, -CH 2 - preferably -O-.
  • the various groups R carrying the matrix MA may themselves comprise the spacer and the linkage.
  • Specific and typical examples of linkages are those formed through amino group- or keto group- containing matrices.
  • Such linkages between the spacer and the matrix may have the following general structures:
  • each matrix unit may be mono- or multivalent and may vary between 1 to 10,000, depending on the nature of the matrix.
  • PAA polyacrylamide
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula Ia, Ib, Ic, Id, Ie or If as defined above or a mixture thereof in
  • anti-ulcer medicament is intended to denote any substance or composition which is able to reduce or participate in reducsing gastrointestinal ulcerations, in particular
  • compositions according to the invention containing such
  • substances or compositions have the potential advantage of being able to provide a dual effect by on the one hand reducing the ulceration and on the other hand simultaneously lowering the degree of infection in the stomach by H. pylori by
  • the pharmaceutical composition prepared is adapted to be administered in combination with a preparation for standard therapy of gastritis or ulcus, such as preparations containing anti-ulcer or anti-gastritis medicaments, e.g.
  • gastric secretion inhibiting compounds such as omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine, or nizatidine, or antacids such as magnesium hydroxide, aluminium hydroxide, calcium carbonate, sodium carbonate, sodium hydrogen carbonate, simethicone or aluminium magnesium hydroxide or a hydrate thereof (such as the
  • magaldrate monohydrate known as magaldrate
  • the pharmaceutical composition prepared is adapted to be administered in combination with a preparation for a course of therapy with an antibacterial agent, such as an antibacterial agent selected from those listed above, in particular preparations containing ⁇ -lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; or macrolides such as erythromycin, or clarithromycin; or
  • an antibacterial agent such as an antibacterial agent selected from those listed above, in particular preparations containing ⁇ -lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime; or macrolides such as erythromycin, or clarithromycin; or
  • tetracyclines such as tetracycline or doxycycline
  • aminoglycosides such as gentamycin, kanamycin or amikacin; or quinolones such as norfloxacin, ciprofloxacin or enoxacin; or others such as metronidazole, nitrofurantoin or
  • the invention concerns all novel compounds among those having the formula Ia, Ib, Ic, Id, Ie or If defined above.
  • the compounds of formula Ia, Ib, Ic, Id, Ie or If can be prepared according to several general methods using
  • protective groups can be removed or can form part of the compound in question.
  • the compounds of the invention can e.g. be prepared as shown in the scheme below. In the scheme, although specific
  • step 1 a monosaccharide, e.g. L-fucose, D-galactose, D-glucose, 2-deoxy-2-phthalimido-D-glucose,
  • Ra-glycosides 2-deoxy-2-phthalimido-D-galactose, D-mannose, is converted to a glycoside, with aglycons (Ra), e.g. SEt, SPh, OTMSEt, O-allyl or OBn (known aglycons in the art), to form the R a -glycoside derivative in such a way that the R a -glycoside is possible to transform to a glycosyl donator by activation of the anomeric centre.
  • Ra aglycons
  • the Ra-glycosides can be prepared as follows: A
  • monosaccharide as above is per-O-acylated with acetic anhydride in pyridine or with acetic anhydride-sodium acetate or with benzoyl chloride in pyridine.
  • the monosaccharide per-O-acylate is reacted with, e.g. hydrogen bromide or hydrogen chloride in a suitable solvent such as, e.g. acetic acid or
  • the aglycon (Ra) is transferred to the monosaccharide by reacting a suitable thiol or alcohol, e.g. HSEt, HSPh, HOTMSEt, HO-allyl, or HOBn with the monosaccharide per-O-acylate using a Lewis acid such as boron trifluoride etherate (see e.g. R. J. Ferrier and R. H. Furneaux, Carbohydr. Res . 52 (1976), 63-68, J. Dahmen, T. Frejd, G. Grönberg, T. Lave, G. Magnusson, and G. Noori, Carbohydr. Res . 116 (1983), 303-307), or trimethylsilyl trifluoromethanesulfonate (see T. Ogawa, K. Beppu, S.
  • monosaccharide derivative in question is a per-O-acylated glycosyl bromide or chloride, promoters such as silver
  • step 2 the monosaccharide Ra-glycoside is further derivatized.
  • New functional groups (Rb) which will form part of the final product or act as protective groups during the subsequent glycosylation steps are introduced.
  • functional group transformations are: OH-groups to ethers or esters (see e.g. Protective Groups in Organic Synthesis edited by T. W. Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York, 1991), OH-groups to carbonates (see e.g. J. March,
  • step 3 condensation of the Ra-glycosides substituted with functional groups (Rb) (protective groups known inn the art) from above are performed.
  • Rb functional groups known inn the art
  • O-glycosidic linkages One Ra-glycoside derivative is transformed to a glycosyl donor by activation at the anomeric centre, and reacted with another Ra-glycoside which has been transformed to a glycosyl acceptor by removing one or several protective groups (see e.g. H. Paulsen, Angew. Chem . Int . Ed. Engl . 21 (1982), 155-173, R. R. Schmidt, Angew. Chem. Int . Ed. Engl . 25 (1986), 212-235, P. Fügedi, P. J. Garegg, H. L ⁇ nn, and T.
  • step 4 the substituent (R c ) at the
  • R c is defined as (Z 1 -Z 16 )-R , wherein R and Z 1 -Z 16 have the definition given for compounds Ia, Ib, Ic, Id, Ie and If.
  • the term "( Z 1 -Z 16 ) -R" shall be read as Z 1 -R, Z 2 -R, Z 3 -R whil Z 16 -R.
  • nucleophile leads to O-, C-, S-, or N-glycosidic derivatives, respectively.
  • a final product is obtained after removal of protective groups, if necessary.
  • the Rc-glycoside derivative is further transformed via different routes to the final product (see e.g. Y. G. Lee, and R. T. Lee, Glycoconjugates , 121-164, edited by H. J. Allen, and E. C. Kisailus, Dekker, New York, 1992, R. Roy, F. D. Tropper, and A. Romanowska, J. Soc , Chem . Commun . (1992), 1611-1613, or C. P. Sotwell and Y. C. Lee, Adv.
  • glycosides with or without a spacer are performed by known methods, for example as described in E. Kallin, H. Lönn, T.
  • the general strategy for preparation of these conjugates has been to attach an olefinic group to a carbohydrate, and then copolymerize this derivative with acrylamide.
  • the olefinic group has been introduced into the carbohydrate molecule either as an allyl glycoside at an early stage by acryloylation of an amino function of a mono-, di-, tri- or oligosaccharide derivative or by other known methods.
  • the compounds of the invention can be administered systemically or locally and are preferably administered orally or by
  • a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or an ingestible capsule, and such preparations
  • compositions comprise a further aspect of the invention.
  • Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to human or mammals being treated.
  • the compounds may also be used without carrier material.
  • compositions may be mentioned tablets, capsules, dragees, solutions, drops, such as nasal drops, aerosols for inhalation, nasal spray, liposomes, etc.
  • active substance will comprise between 0.01 and 99 % by weight of the preparation, e.g. between 0.5 and 20% by weight for preparations intended for injection and between 0.1 and 50% by weight for preparations intended for oral
  • the preparations are preferably in unit dosage form, whether as single dosage units or as multiple dosage units.
  • the active ingredient may be mixed with
  • pulverulent carriers e.g. lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose derivative or gelatine and also may include lubricants such as magnesium or calcium stearate or a Carbowax ® or other polyethylene glycol waxes and compressed to form tablets or cores for dragees. If dragees are required, the cores may be coated with e.g. concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or , alternatively, with a film forming agent dissolved in easily volatile organic solvents or mixtures of organic solvents.
  • pulverulent carriers e.g. lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose
  • Dyestuffs can be added to these coatings, e.g. to distinguish between different contents of active substance.
  • the active substance may be admixed with a Carbowax ® or a suitable oil such as e.g. sesame oil, olive oil, or arachis oil.
  • Hard gelatine capsules may contain granulates of the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches, e.g.
  • compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. By using several layers of the active drug, separated by slowly dissolving coatings, sustained release tablets are obtained. Another way of preparing sustained release tablets is to divide the dose of the active drug into granules with coatings of different thickness and compress the granules into tablets together with the carrier substance.
  • the active substance can also be incorporated in slowly
  • dissolving tablets made of e.g. fat and wax substances or evenly distributed in a tablet of an insoluble substance such as a physiologically inert plastic substance.
  • Liquid preparations for oral application may be in the form of elixirs, syrups or suspensions, e.g. solutions containing from about 0.1% to 20% by weight of the active substance, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally aroma, saccharin and/or carboxymethylcellulose as dispersing agents.
  • the formulations can additionally include wetting agent, emulsifying and suspending agents, preserving agents and sweetening agents.
  • preparations may comprise an aqueous solution of the active drug or a
  • physiologically acceptable salt thereof desirably in a concentration of 0.5-20% and optionally also a stabilizing agent and/or buffer substances in aqueous solution.
  • Dosage units of the solution may advantageously be enclosed in ampoules.
  • the dosage at which the active ingredients may be administered may vary within a wide range and will depend on various factors such as e.g. the severity of the infection, the age of the patient etc. and may have to be individually adjusted.
  • compositions of the subject invention preferably contain from about 1 mg to about 50 g, more
  • the active ingredient preferably from about 10 mg to about 5 g per day of the active ingredient and may be divided into multiple doses.
  • Fab-MS was run on a Nermag 1010L, with an lontech FAB gun and a matrix of thioglycerol. Optical rotations were measured using a Perkin Elmer 241 polarimeter.
  • Thin layer chromatography (TLC) was performed on Merck DC-Fertigplatten (Kiselgel 60 F254 0.25 mm) and spots were visualized by UV or by spraying with 10% sulphuric acid followed by charring at elevated temperature, or by spraying with phospohomolybdic acid or ninhydrin in n-butanol (0.5%).
  • Silica gel 60 (40-63 ⁇ m) and Amicon Matrex ® Silica Si 0.35-0.70 m was used for column chromatography.
  • Trifluoromethanesulfonic acid (2 ⁇ l, 0.023 mmol) was added to a stirred mixture of ethyl 3-O-(tri-O-benzyl- ⁇ -L-fucopyranosyl)-4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio- ⁇ -D-glucopyranoside (1) (100 mg, 0.117 mmol), (prepared according to H. Lönn, Carbohydr. Res .
  • Trifluoromethanesulfonic acid (30 ⁇ l, 0.35 mmol) was added to a stirred mixture of (1), 3,3-dimethyl-butan-1-ol (317 ⁇ l, 2.62 mmol), N-iodosuccinimide (602 mg, 2.62 mmol), and ground molecular sieves (1.5 g, 3A) in dichloromethane-diethyl ether (2:1, 45 ml) at -30°C. After 45 min the reaction mixture was filtered through a layer of Celite into an aqueous solution of sodium hydrogen carbonate and sodium bisulphite. The organic layer was separated, washed with aqueous sodium chloride, and concentrated.
  • Ethyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio- ⁇ -D-galactopyranoside (25) was deacetylated with sodium methoxide in methanol (50 ml, pH 12) and subsequently benzoylated with benzoylchloride (1.96 gr., 14 mmol) in pyridine (20 ml)
  • Crystalline 26 was obtained in almost quantitative yield (3.44 gr., 97%).
  • reaction was quenched by addition of triethylamine at 0°C.
  • the solution was filtered through a layer of celite, diluted with dichloromethane and washed twice with aqueous Na 2 S 2 O 3 (10%) and finally with water.
  • the azidoderivative (33) was synthesized from the thioglycoside (26) (1004 mg, 1.68 mmol) and 1-azido-8-hydroxy-3,6-dioxaoctane (686 mg, 3.35 mmol; prepared according to C.R. Bertozzi, M.D. Bednarski, J. Org. Chem., 1991, 56, 4326-4329) according to a procedure similar to the one used for synthesis of derivative (28) (TLC; toluene:EtOAc 6:1) showed complete conversion within 40 minutes.
  • 13 C ⁇ 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: ⁇ 50.6 (CH 2 N 3 ), 68.7, 68.8, 70.0, 70.2,
  • Disaccaride (34) was synthesized from compound (33) (500 mg, 0.82 mmol) and thioethylglycoside (14) (512 mg, 1.07 mmol) according to the procedure described for the corresponding derivative (29). Preparative TLC gave 683 mg (81%) of the title compound (34) as an oil.
  • HSA Human Serum Albumine
  • the degree of substitution was determined by Time of Flight masspectroscopy to 5 mol disaccharide/mol protein.
  • the mixture was diluted with water (5 mL) and concentrated to half the original volume.
  • the residue was diluted to 20 mL with water and concentrated to 5 mL. This process was repeated once, then the residue was diluted to 10 mL and lyophilized.
  • the crude product was put on a Bio-gel P2-column, and the fraction containing Lewis B glycosylamine (40) was collected, (20 mg 80%).
  • Trisaccharide (47) (73mg, 56.2 ⁇ mol) was dissolved in absolute ethanol (7 ml) with water (0.25 ml) and glacial acetic acid (2 ⁇ l). The solution was hydrogenated over 10% Pd/C (152 mg) at 50 PSI at room temperature for 1 hour.
  • TLC ethyl
  • the crude compound (48) (46 mg) was dissolved in aqueous ammonia (25%, 4 ml) and stirred at room temperatur.
  • aqueous ammonia (25%, 4 ml)
  • Freeze-drying of the polymeric fraction eluted in the void volume gave 13.1 mg of the polymer (50) were the 1 H NMR analysis of the product showed an average incorporation of 1 trisaccharide per 7.6 acrylamide units, and 11.9 mg of polymer (50) were the 1 H NMR analysis of the product showed an average incorporation of 1 trisaccharide per 10.3 acrylamide units.
  • the compound (51) (157 mg, 0.19 mmol) and the compound (14) (362 mg, 0.76 mmol) were dissolved in dichloromethane (100 ml), and 3g 4 ⁇ molecular sieve (MS) were added and stirred for 20 min.
  • Dimethyl (methylthio) sulfonium triflate (DMTST) (207 mg, 0.80 mmol) was added and stirring was continued for 1.5 hour.
  • 2 ml of triethylamine was added and stirring was continued for another 20 min. Filtration through celite, concentration and column chromatography (toluen: ethylacetate, 1:1) gave the title compound (52) (142 mg, 0.086 mmol, 45%).
  • the compound (52) (140 mg, 0.084 mmol) was dissolved in 11 ml ethanol and 10% Pd/C (150 mg) was added. The reaction mixture was hydrogenated at atmospheric pressure for 15 minutes.
  • the tetrasaccharide (53) (78 mg, 0.05 mmol) was dissolved in absolute ethanol (8 ml) with water (0.25 ml) and glacial acetic acid (2 ⁇ L). The solution was rapidly stirred with 10% Pd/C (150 mg) under hydrogen (50 PSI) at room temperature for 1 hour. When TLC (ethyl acetate:acetic acid:methanol:water 12:3 3:1; showed complete conversion, the reaction mixture was filtered thorugh a layer of celite and concentrated. The crude compound (54) (35 mg) was used in the next reaction without further purification.
  • Non-infected samples from normal adult human gastric tissue obtained from Huddinge Sjukhus, Sweden were used to study Helicobacter pylori adherence. All samples were fixed in 4% formalin and subsequently embedded in paraffin.
  • Huddinge Sjukhus of Helicobacter pylori were used.
  • Helicobacter pylori was cultured at 37°C on Brucella Agar supplemented with 10% bovine blood and 1% IsoVitalex (Becton Dickinson Microbiology System, Cockeyville, MD) under
  • microaerophilic conditions 5% O 2 , 10% CO 2 , 85% N 2
  • 98% humidity 5 days after inoculation, bacteria from one full-grown plate were resuspended by gentle pipetting in 25 ml of 0.1M NaCl/ 0.1M sodium carbonate, pH 9.0. 250 ⁇ l of a freshly prepared 10 mg/ml solution of fluorescein
  • L-fucose-containing compounds e.g. LNF1-HSA.
  • the given values in the table are the average number of adhered bacteria on three different areas per section comparing treated (with compound) with untreated tissue sections.
  • n 1 per 12.3 acrylamide moieties
  • n 1 per 5 acrylamide moieties

Abstract

Dérivés glycosidiques de mono, di, tri ou oligosaccharides présentant au moins un groupe terminal dérivé du L-fucose. Ces composés sont efficaces dans la thérapie ou la prophylaxie chez l'homme d'états relatifs à l'infection de la muqueuse gastrique par l'Heliobacter pylori; ainsi que leur méthode de préparation et celle de compositions pharmaceutiques les contenant.
PCT/SE1994/000604 1993-06-25 1994-06-17 Glycosides fucosyles inhibiteurs de l'adhesion bacterienne WO1995000527A1 (fr)

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EP1020474A1 (fr) * 1997-08-22 2000-07-19 Kabushiki Kaisha Yakult Honsha Derives d'oligosaccharides et leur procede d'obtention
WO2000056343A1 (fr) * 1999-03-19 2000-09-28 Boren Thomas Structures glucidiques de n-acetyl lactosamine fucosyle sialyle permettant d'inhiber l'adhesion bacterienne
US6204431B1 (en) 1994-03-09 2001-03-20 Abbott Laboratories Transgenic non-human mammals expressing heterologous glycosyltransferase DNA sequences produce oligosaccharides and glycoproteins in their milk
US7517980B2 (en) * 2005-08-09 2009-04-14 Glycomimetics, Inc. Glycomimetric inhibitors of the PA-IL lectin, PA-IIL lectin or both the lectins from Pseudomonas
US8921328B2 (en) 2010-09-14 2014-12-30 Glycomimetics, Inc. E-selectin antagonists
WO2014210397A1 (fr) * 2013-06-26 2014-12-31 Academia Sinica Antigènes rm2 et leur utilisation
US9109002B2 (en) 2011-12-22 2015-08-18 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US9867841B2 (en) 2012-12-07 2018-01-16 Glycomimetics, Inc. Compounds, compositions and methods using E-selectin antagonists for mobilization of hematopoietic cells
US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US11045485B2 (en) 2016-01-22 2021-06-29 Glycomimetics, Inc. Glycomimetic inhibitors of PA-IL and PA-IIL lectins
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11197877B2 (en) 2017-03-15 2021-12-14 Glycomimetics. Inc. Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists
US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
US11433086B2 (en) 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11707474B2 (en) 2018-03-05 2023-07-25 Glycomimetics, Inc. Methods for treating acute myeloid leukemia and related conditions
US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
US11845771B2 (en) 2018-12-27 2023-12-19 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11873317B2 (en) 2018-12-27 2024-01-16 Glycomimetics, Inc. Galectin-3 inhibiting c-glycosides

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EP2692740A1 (fr) * 2012-07-30 2014-02-05 Le Centre National De La Recherche Scientifique Compositions de glycane, leurs procédés de préparation et leurs utilisations en tant que médicament
US20150366195A1 (en) * 2013-01-31 2015-12-24 Pioneer Hi-Bred International, Inc. Synthetic lipochitooligosaccharides for improvement of plant growth and yield

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Cited By (28)

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Publication number Priority date Publication date Assignee Title
US6204431B1 (en) 1994-03-09 2001-03-20 Abbott Laboratories Transgenic non-human mammals expressing heterologous glycosyltransferase DNA sequences produce oligosaccharides and glycoproteins in their milk
EP1020474A1 (fr) * 1997-08-22 2000-07-19 Kabushiki Kaisha Yakult Honsha Derives d'oligosaccharides et leur procede d'obtention
EP1020474A4 (fr) * 1997-08-22 2001-10-17 Yakult Honsha Kk Derives d'oligosaccharides et leur procede d'obtention
WO2000056343A1 (fr) * 1999-03-19 2000-09-28 Boren Thomas Structures glucidiques de n-acetyl lactosamine fucosyle sialyle permettant d'inhiber l'adhesion bacterienne
US7517980B2 (en) * 2005-08-09 2009-04-14 Glycomimetics, Inc. Glycomimetric inhibitors of the PA-IL lectin, PA-IIL lectin or both the lectins from Pseudomonas
US8258290B2 (en) * 2005-08-09 2012-09-04 Glycomimetics, Inc. Glycomimetic inhibitors of the PA-IL lectin, PA-IIL lectin or both the lectins from pseudomonas
US8921328B2 (en) 2010-09-14 2014-12-30 Glycomimetics, Inc. E-selectin antagonists
US9109002B2 (en) 2011-12-22 2015-08-18 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US9796745B2 (en) 2011-12-22 2017-10-24 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US10526361B2 (en) 2011-12-22 2020-01-07 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US10766916B2 (en) 2011-12-22 2020-09-08 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US11332491B2 (en) 2011-12-22 2022-05-17 Glycomimetics, Inc. E-selectin antagonist compounds, compositions, and methods of use
US9867841B2 (en) 2012-12-07 2018-01-16 Glycomimetics, Inc. Compounds, compositions and methods using E-selectin antagonists for mobilization of hematopoietic cells
WO2014210397A1 (fr) * 2013-06-26 2014-12-31 Academia Sinica Antigènes rm2 et leur utilisation
US10519181B2 (en) 2014-12-03 2019-12-31 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectins and CXCR4 chemokine receptors
US11045485B2 (en) 2016-01-22 2021-06-29 Glycomimetics, Inc. Glycomimetic inhibitors of PA-IL and PA-IIL lectins
US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
US11433086B2 (en) 2016-08-08 2022-09-06 Glycomimetics, Inc. Combination of T-cell checkpoint inhibitors with inhibitors of e-selectin or CXCR4, or with heterobifunctional inhibitors of both E-selectin and CXCR4
US11072625B2 (en) 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11780873B2 (en) 2016-10-07 2023-10-10 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
US11197877B2 (en) 2017-03-15 2021-12-14 Glycomimetics. Inc. Galactopyranosyl-cyclohexyl derivauves as E-selectin antagonists
US11878026B2 (en) 2017-03-15 2024-01-23 Glycomimetics, Inc. Galactopyranosyl-cyclohexyl derivatives as e-selectin antagonists
US11712446B2 (en) 2017-11-30 2023-08-01 Glycomimetics, Inc. Methods of mobilizing marrow infiltrating lymphocytes and uses thereof
US11548908B2 (en) 2017-12-29 2023-01-10 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11707474B2 (en) 2018-03-05 2023-07-25 Glycomimetics, Inc. Methods for treating acute myeloid leukemia and related conditions
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
US11845771B2 (en) 2018-12-27 2023-12-19 Glycomimetics, Inc. Heterobifunctional inhibitors of E-selectin and galectin-3
US11873317B2 (en) 2018-12-27 2024-01-16 Glycomimetics, Inc. Galectin-3 inhibiting c-glycosides

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IL110074A0 (en) 1994-10-07
DK76193D0 (da) 1993-06-25
AU7089194A (en) 1995-01-17
LT3446B (en) 1995-10-25
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IS4181A (is) 1994-12-26
EP0706528A1 (fr) 1996-04-17

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