WO1994000477A1 - Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire - Google Patents

Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire Download PDF

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Publication number
WO1994000477A1
WO1994000477A1 PCT/US1993/006110 US9306110W WO9400477A1 WO 1994000477 A1 WO1994000477 A1 WO 1994000477A1 US 9306110 W US9306110 W US 9306110W WO 9400477 A1 WO9400477 A1 WO 9400477A1
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Prior art keywords
compound
selectin
benzoyl
benzyl
formula
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PCT/US1993/006110
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English (en)
Inventor
Saeed Abbas
Falguni Dasgupta
Darwin Asa
John H. Musser
Mina Nashed
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Glycomed Incorporated
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Publication date
Application filed by Glycomed Incorporated filed Critical Glycomed Incorporated
Priority to JP6502607A priority Critical patent/JPH08500820A/ja
Priority to AU46526/93A priority patent/AU678373B2/en
Priority to EP93916790A priority patent/EP0648223A4/fr
Publication of WO1994000477A1 publication Critical patent/WO1994000477A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • L-SELECTIN appears to bind a sialic acid bearing Ugand based on neuraminidase treatment of peripheral lymph node high endothelial venules which inhibits L-SELECTIN recognition.
  • soluble L-SELECTIN in direct binding/inhibition assays suggests that certain carbohydrate moieties may be important ligand components including mannose and fucose, particularly when sulfated or phosphorylated. Imai et al., 1990 J. Cell Biol. Il l, 1225-1232. More recent studies suggest that L-Selectin binds to sialyl Lewis X. Foxall, C, et al., (1992) Cell, in press.
  • R 2 is H, lower alkyl(l-4C), alkylaryl or one or more additional saccharide residues;
  • X is -CHR ⁇ CHOR ⁇ Cffi ⁇ OR 1 wherein R 4 and R 5 are each independently H, lower alkyl(l-4C), or taken together result in a five- or six-membered ring optionally containing a heteroatom selected from the group consisting of O, S, and NR 1 ; said five- or six-membered ring optionally substituted with one substituent selected from the group consisting of R ⁇ CH 2 OR ⁇ OR 1 , OOCR 1 , NR 1 NHCOR 1 , and SR 1 with the proviso that if X represents a hexose substituent R 4 and R 5 , taken together, cannot provide a hexose substituent.
  • the invention is directed to a method to synthesize lactose derivatives which method comprises contacting an intermediate of the formula
  • each R 6 is independently H, lower alkyl (1-4C), or a protecting group; and wherein Y 1 is H, OH 6 , OOCR 6 , or SR 6 ; wherein at least one R 6 , which is at the position to be substituted, and at most one adjacent R 6 is H and all other R 6 s are protecting groups; and R 7 is a protecting group, with an electrophile-donating moiety to obtain a product wherein the electrophile is substituted for the H of the OH at the position to be substituted.
  • the invention is directed to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating inflammation using these compositions.
  • the invention is directed to compounds of formula 2 and additional intermediates in the synthesis of selectin binding ligands or other useful lactosyl residue-containing moieties.
  • the invention provides compounds that are useful in the treatment of inflammation by virtue of their ability to bind to selectin receptors. For example,
  • Figure 1 shows a diagrammatic view of the role believed to be played by one of the selectin receptors, ELAM-1, in mediating inflammation. Blood vessels are lined with endothelial cells capable of producing the ELAM-1 surface receptor.
  • both the selectin and the putative ligand may be in solution for a time sufficient for a complex to form consisting of the selectin and ligand , followed by separating the complex from uncomplexed selectin and ligand, and measuring the amount of complex formed.
  • the amount of uncomplexed selectin or compound could be measured.
  • a variation of the above assay is to genetically engineer cells to express high levels of L-SELECTIN, E-SELECTIN, or P-SELECTIN on their surface, and to use the cells in lieu of purified selectin.
  • Radiolabeled COS cells have been used in this type of assay, and can be transfected with cDNA that encodes for L- SELECTIN, E-SELECTIN or P-SELECTIN. After the cells have had a sufficient time to adhere to the ligand coated microtiter well, non-adherent cells are removed and the number of adherent cells determined. The number of adherent cells reflects the capacity of the ligand to bind to the selectin.
  • E-SELECTIN ligands For example, a complete cDNA for the ELAM-1 receptor was obtained by PCR starting with total RNA isolated from IL-1 stimulated human umbilical vein endothelium. The resulting cDNA was inserted into the CDM8 plasmid (see Aruffo, A., and Seed, B., Proc. Natl. Acad. Sci. USA (1987) 84:8573) and the plasmid amplified in coli. Plasmid DNA from individual colonies was isolated and used to transfect COS cells. Positive plasmids were selected by their ability to generate COS cells that support HL-60 cell adhesion. DNA sequencing positively identified one of these clones as encoding for ELAM-1 (Bevilacqua,
  • Putative E-SELECTIN encoding plasmids were selected based on the ability of these transfected COS cells to support HL-60 cell adhesion 72 h posttransfection.
  • a positive cDNA whose sequence corresponded to the published sequence of E-SELECTIN with two nucleic acid substitutions was used in all experiments.
  • COS cells were transfected with 1 ⁇ g of this plasmid DNA per 3.5 - 5.0 x 10 5 cells, with 400 ⁇ g/ml DEAE-dextran and 100 ⁇ M chloroquine for 4 h, followed by a brief exposure to 10% DMSO in PBS. Cells were metabolically radiolabeled overnight with carrier free 32 PO 4 and harvested in PBS supplemented with 0.02% azide and 2 mM EDTA at 72 h posttransfection for use in cell adhesion studies.
  • E-SELECTIN transfected COS cells produced by the above method may be used to assay for glucuronyl glycolipid ligands.
  • COS cells may be transfected with cDNAs that encode L-SELECTIN and/or P-SELECTIN.
  • L-SELECTIN IgG chimera constructs have been previously described by Watson S. R. et al., (1990) J. Cell Biol. 110: 2221-2229. This chimera contains two complement binding domains, consistent with its natural expression. See Watson S. R. et al., (1991) J. Cell Biol. 115:235-243.
  • P-SELECTIN chimera was constructed in a similar manner as described by Walz, G., et al (1990) Science 250, 1132-1135, and Aruffo, A. et al.(1991) Cell, 67, 35-
  • any candidate compound of the formula 1 may be verified to bind ELAM-1 receptors by a positive result in the foregoing assays.
  • the compounds of formula 1 are also useful as detection reagents to determine the presence or absence of selectin or related carbohydrate-binding receptor ligands.
  • a biological sample suspected to contain selectin receptor protein or a receptor protein closely related thereto is treated with the compound of formula 1 under conditions wherein complexation occurs between the receptor protein and the formula 1 compound, and the formation of the complex is detected.
  • a wide variety of protocols may be utilized in such procedures, analogous to protocols applied in immunoassays. Thus, direct assay wherein the amount of complex formed is directly measured may be utilized; alternatively, competition assays may be used wherein labeled selectin receptor protein is supplied along with, and in competition with, the biological sample.
  • the compounds of formula 1 in labeled form so that the complex is detected directly; in alternate procedures, the complex may be detected by size separations, secondary labeling reagents, or other alternate means.
  • Suitable labels are known in the art, and include radioactive labels, fluorescent labels, enzyme labels, chromogenic labels, or composites of these approaches.
  • the compounds of formula 1 may also be used as competitive diagnostic reagents to detect the quantity of selectin receptor-binding components, such as surface ligands, in biological fluids.
  • the compounds of formula 1 are labeled as described above and mixed with the biological sample and contacted with the appropriate receptor protein; the diminution of binding of the labeled compound of formula 1 to selectin receptor in the presence of biological sample is then determined.
  • Antibodies may also be prepared to the compounds of formula 1 by coupling these compounds to suitable carriers and administering the coupled materials to mammalian or other vertebrate subjects in standard immunization protocols with proper inclusion of adjuvants.
  • suitable immunogenic carriers include, for example, Keyhole Limpet Hemocyanin (KLH), tetanus toxoid, various serum albumins such as bovine serum albumin (BSA) and certain viral proteins such as rotaviral VP6 protein.
  • KLH Keyhole Limpet Hemocyanin
  • BSA bovine serum albumin
  • viral proteins such as rotaviral VP6 protein
  • Suitable vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • Formulations may employ a variety of excipients including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin cellulose, magnesium carbonate, and the like.
  • Oral compositions may be taken in the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders. Particularly useful is the administration of the subject ligand molecules directly in transdermal formulations with permeation enhancers such as DMSO. Other topical formulations can be administered to treat dermal inflammation. In addition, transmucosal administration may be effected using penetrants such as bile salts or fusidic acid derivatives optionally in combination with additional detergent molecules. These formulations are useful in the preparation of suppositories, for example, or nasal sprays.
  • the vehicle composition will include traditional binders and carriers, such as polyalkylene glycols, or triglycerides. Such suppositories may be formed from mixtures containing the active ingredient in the range of about
  • Intranasal formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function.
  • Diluents such as water, aqueous saline or other known substances can be employed with the subject invention.
  • the nasal formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride.
  • a surfactant may be present to enhance absorption of the subject proteins by the nasal mucosa.
  • compositions of the instant invention will contain from less than 1% to about 95% of the active ingredient, preferably about 10% to about 50%.
  • the active ingredient preferably about 10% to about 50%.
  • between about 10 mg and 50 mg will be administered to a child and between about 50 mg and 1000 mg will be administered to an adult.
  • the frequency of administration will be determined by the care given based on patient responsiveness.
  • Other effective dosages can be readily determined by one of ordinary skill in the art through routine trials establishing dose response curves.
  • it will be noted that it may not be desirable to completely block all selectin receptors of a particular type.
  • at least some of the white blood cells or neutrophils must be brought into the tissue in the areas where any wound, infection or disease state is occurring.
  • the amount of the selectin ligands administered as blocking agents must be adjusted carefully based on the particular needs of the patient while taking into consideration a variety of factors such as the type of disease that is being treated.
  • Formulations of the present invention might also be administered to prevent the undesirable after effects of tissue damage resulting from heart attacks.
  • a heart attack occurs and the patient has been revived, such as by the application of anticoagulants or thrombolytic (e.g., tPA)
  • thrombolytic e.g., tPA
  • the endothelial lining where a clot was formed has often suffered damage.
  • the antithrombotic has removed the clot
  • the damaged tissue beneath the clot and other damaged tissue in the endothelial lining which has been deprived of oxygen become activated.
  • the activated endothelial cells then synthesize selectin receptors, for example ELAM-1 receptors, within hours of the cells being damaged.
  • the receptors are extended into the blood vessels where they adhere to glycolipid ligand molecules on the surface of white blood cells. Large numbers of white blood cells are quickly captured and brought into the tissue surrounding the area of activated endothelial cells, resulting in inflammation, swelling and necrosis which
  • formulations of the invention In addition to treating patients suffering from the trauma resulting from heart attack, patients suffering from actual physical trauma could be treated with formulations of the invention in order to relieve the amount of inflammation and swelling which normally result after an area of the body is subjected to severe trauma.
  • Other conditions treatable using formulations of the invention include various types of arthritis and adult respiratory distress syndrome.
  • the compounds of formula 2 are intermediates in the preparation of compounds which contain a lactosyl unit.
  • the compounds of formula 2 are useful in the preparation of compounds of formula 1 whose use is described hereinabove.
  • alternative compounds containing a lactose residue may also be prepared, such as:
  • X, Y, and R 1 , and R 3 are as above defined illustrate the multivalent compounds of the invention.
  • carriers including proteins such as BSA or HSA, a multiplicity of peptides including, for example, pentapeptides, decapeptides, pentadecapeptides, and the like.
  • the peptides or proteins contain the desired number of amino acid residues having free amino groups in their side chains; however, other functional groups, such as sulfhydryl groups or hydroxyl groups can also be used to obtain stable linkages.
  • the carbohydrate ligands of the invention may be oxidized to contain carboxyl groups at the reducing terminus which can then be derivatized with either free amino groups to form amides or with hydroxyl groups to form esters.
  • the compounds of the invention of Formula 1 may be synthesized using an intermediate of Formula 2.
  • the intermediate of Formula 2 in one embodiment, can be prepared directly from D-lactose using standard procedures. In this conversion, D-lactose is converted to the octaacetate in crystalline form, in over 95% yield in the method described by Hudson, C, and Kuns, A., J Am Chem Soc (1925) 47:2052.
  • the octaacetate is, in turn, converted in more than 90% yield by the method of Hudson, C. (supra) or of Fischer, E. and Fischer, H., Ber (1910) 43:2521 to the corresponding lactosyl bromide, also a crystalline compound.
  • the protected lactosyl bromide is converted by the method of Jansson, K., et al., J Org Chem (1988) 53:5629, in over 60% yield to the corresponding acylated trimethylsilyl ethyl lactose, which can be deprotected by deacylation in quantitative yield to obtain 2-(trimethylsilyl)ethyl lactoside, 2-(trimethylsilyl)ethyl ⁇ -D- galactopyranosyl- ⁇ -D glucopyranoside.
  • Alternative protecting groups at position 1 of the disaccharide may also be used.
  • R 7 is a protecting group, preferably SE or Bn, wherein SE represents -CH 2 CH 2 SiMe 3 and Bn is benzyl.
  • Reaction Scheme 1 outlines the formation of one embodiment of the compounds of Formula 2 from this intermediate, where Bz represents benzoyl: Reaction Scheme 1
  • the intermediate 1_ m &y then be further derivatized at the free hydroxyl at the 3-position of the glucoside residue or this position may be protected and the compound deprotected at positions 3 and 4 of the galactosyl residue and further derivatized at position 3. Position 4 of the galactosyl residue is relatively unreactive.
  • Reaction Scheme 2A A typical scheme for utilization of this key intermediate 1_ is shown in Reaction Scheme 2A. (In this scheme, Bz is benzoyl (PhCO-) and Bn is benzyl (PhCH 2 -).
  • intermediate 11. may be phosphorylated to yield intermediate .14 which upon deacylation and hydrogenation yields the final product J ⁇ .
  • This compound would be expected to act as a selectin ligand.
  • alkyl refers to a saturated straight or branched chain or cyclic hydrocarbyl residue containing 1-6C; lower alkyl is similarly defined but containing only 1-4C.
  • alkylaryl is of the formula (CH 2 ) m -Ar wherein m is 1-10 and Ar is a mono- or bicyclic aromatic residue optionally containing one or more heteroatoms.
  • Ar include phenyl, naphthyl, quinolyl, pyridyl, pyrimidinyl, benzthiazoyl, benzimidazoyl, and the like.
  • R7 is a protecting group suitable for saccharide residues.
  • Typical protecting groups include benzyl, benzoyl, various silylalkyl groups, such as trimethylsilylethyl (SE), and the like.
  • Exemplary compounds of formula 1 of the invention are those wherein R 3 is S0 4 -2, P0 4 -2, or other similar charged moiety.
  • Additional exemplary compounds of formula 1 include those wherein X is: 6-methyl-3,4,5-trihydroxypyran-2-yl,
  • R 1 are H or methyl
  • Y is H, OH, OCH 3 or OAc
  • X is -CH 2 (CHOH) 3 H, 3,4,5-trihydroxypyran-2-yl, 3,4,5-trihydroxy-6-methylpyran-2-yl, 3,4,5- trimethoxypyran-2-yl, 3,4,5-trimethoxy-6-methylpyran-2-yl, 3,4,5-trihydroxyfuran-2- yl, 3,4,5-trimethoxyfuran-2-yl, 2,3,4-trihydroxybenzoyl, or 2,3,4- trihydroxynaphthoyl; and R 3 is S0 4 -2, P0 4 -2, or other similar charged moiety.
  • T.l.c. (8.5:1.5 toluene-ethyl acetate) revealed the presence of a major product, faster-migrating than the starting acetal. A small proportion of a still faster-migrating product (pentabenzoate) was also revealed by t.l.c.
  • the mixture was poured into ice-water and extracted with dichloromethane. The dichloromethane solution was successively washed with water, aqueous NaHCO 3 , and water, dried (NajSO , and concentrated.
  • the mixture was filtered ( Celite bed) directly onto Amberlite IR 120 (Na + ) cation-exchange resin, and the solids thoroughly washed with aqueous methanol. After stirring with the resin for lh, the mixture was filtered and concentrated to a small volume, which was applied to a column of silica gel and eluted with 5:4:1 chloroform-methanol- water. Fractions corresponding to the product were pooled, concentrated to a small volume and treated with Amberlite IR 120 (Na + ) cation-exchange resin.
  • Example 13 Preparation of a Multivalent Ligand, N,6N,6N' Tris (20) Lys-Tyr-Lys Compound 13a or 13b, prepared in Example 12, may be derivatized to the peptide Lys-Tyr-Lys to obtain the trivalent conjugate derivatized at the two ⁇ - amino lysine groups and the ⁇ -amino N-terminal of the peptide.
  • the results would show the formation of the derivatized peptide as containing 1, 2 or 3 moieties of compound 13a or 13b.
  • the trivalent derivative would be especially effective in inhibiting the binding of lactose to hepatocytes in an assay conducted as described by Lee, R. et al., Biochem (1984) 23:4255.
  • 13a and 13b were added at final concentrations ranging from 1.5 to 5.0 mM to the soluble receptor and allowed to react at 37 °C for 45 minutes.
  • the solutions were then placed in the microtiter wells that had been washed after being blocked, and the plates incubated at 37 C for 45 minutes to allow the soluble receptor to bind to the known natural ligand, 2,3 sLex glycolipid.
  • the positive control was the signal produced by soluble "multivalent" receptor reacted with only the ligand evaporated to the microtiter well. This was considered "100 % binding.”
  • the signal produced by receptor previously reacted with inhibitor is divided by the signal produced by the positive control, multiplied by 100, to calculate % receptor bound in the presence of the inhibitor. The reciprocal of this is % inhibition.

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Abstract

L'invention se rapporte à des composés et à des procédés de préparation de ces composés, lesquels répondent à la formule (1) et se lient à des récepteurs de sélectine, modulant ainsi la progression des inflammations, du cancer et de maladies apparentées en modulant les phénomènes d'adhésion cellule-cellule, formule dans laquelle chaque R représente indépendamment H ou alkyle inférieur (1-4C); R2 représente H, OH, ou alkyle inférieur (1-4C), alkylaryle ou un ou plusieurs restes de saccharide supplémentaires; R3 représente une fraction charge négative comprenant SO4--, PO4--, ou un groupe apparenté; Y représente H ou alkyle inférieur (1-4C); et X représente -CHR?4(CHOR1)¿2CHR?5OR1, R4 et R5¿ représentent chacun indépendamment H, alkyle inférieur (1-4C) ou constituent ensemble un noyau à cinq ou six éléments contenant éventuellement un hétéroatome choisi dans le groupe composé de O, S et NR1; ledit noyau à cinq ou six éléments étant éventuellement substitué par un substituant choisi dans le groupe composé de R1, CH2OR?1, OR1, OOCR1, NR1¿2, NHCOR?1 et SR1¿, à condition que si X représente un substituant hexose, R3 et R4 ne peuvent pas ensemble constituer un substituant hexose.
PCT/US1993/006110 1992-06-29 1993-06-25 Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire WO1994000477A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6502607A JPH08500820A (ja) 1992-06-29 1993-06-25 細胞接着インヒビターとしての置換されたラクトース誘導体
AU46526/93A AU678373B2 (en) 1992-06-29 1993-06-25 Substituted lactose derivatives as cell adhesion inhibitors
EP93916790A EP0648223A4 (fr) 1992-06-29 1993-06-25 Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire.

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Application Number Priority Date Filing Date Title
US91070992A 1992-06-29 1992-06-29
US07/910,709 1992-06-29

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AU (1) AU678373B2 (fr)
CA (1) CA2138645A1 (fr)
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Cited By (11)

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WO1995021180A1 (fr) * 1994-02-01 1995-08-10 Glycomed Incorporated Derives de lactose substitues, utilises comme inhibiteurs de l'adhesion cellulaire
EP0714903A1 (fr) * 1994-10-10 1996-06-05 Hoechst Aktiengesellschaft Nouveaux carbohydrat conjugués utilisés comme inhibiteurs d'adhésion cellulaire
US5589465A (en) * 1994-09-30 1996-12-31 Akira Hasegawa Glycolipid derivatives acting as ligands for selectins
WO1997000881A1 (fr) * 1995-06-22 1997-01-09 Nippon Shinyaku Co., Ltd. Derives de la moranoline
EP0758243A1 (fr) * 1994-04-29 1997-02-19 Texas Biotechnology Corporation FIXATION DE LA E-SELECTINE ET/OU DE LA P-SELECTINE SUR LA SIALYL-LEWIS-?x OU LA SIALYL-LEWIS-?a
WO1997007809A1 (fr) * 1995-08-23 1997-03-06 The Regents Of The University Of California Inhibiteurs de selectines a base de disaccharides sulfates, procedes de synthese et utilisation therapeutique
US5620864A (en) * 1992-06-29 1997-04-15 Health Research, Inc. Acceptor for fucosyl transferase
EP0811634A1 (fr) * 1995-08-09 1997-12-10 Daikin Industries, Limited Derives de sialyl-lewis x fluores et produits intermediaires utilises dans leur synthese
US5962424A (en) * 1995-02-21 1999-10-05 Arch Development Corporation Methods and compositions for targeting selectins
US6008203A (en) * 1995-07-14 1999-12-28 Glycotech Corp. Methods for treatment of EGF receptor associated cancers
WO2001017566A2 (fr) * 1999-09-08 2001-03-15 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Agents de contraste de type l-selectine

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FR2929510B1 (fr) * 2008-04-02 2011-01-21 Lvmh Rech Utilisation d'au moins un glycoside d'alkyle en tant qu'agen qu'agent anti-vieillissement et/ou calmant des peaux sensibles dans des compositions cosmetiques, et methodes de soin cosmetique utilisant les dites compositions.

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US5326752A (en) * 1991-11-27 1994-07-05 Glycomed Incorporated Substituted lactose and lactosamine derivatives as cell adhesion inhibitors
CA2100412A1 (fr) * 1992-07-15 1994-01-16 Yutaka Yamada Derives de glycolipides

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Carbohydrate Research, Vol. 19(1), issued 1971, BEVERDIGE et al., "Isolation of Three Oligosaccharides from the Mucilage from the Bark of Ulmus fulva (slippery-elm mucilage)", pages 107-116. *
Journal of Carbohydrate Chemistry, Vol. 7(3), issued 1988, WESTERDUIN et al., "An Approach to the Synthesis of Four Rhodomicrobium Vanniellii Lipid A Analogs", pages 617-644. *
See also references of EP0648223A4 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5620864A (en) * 1992-06-29 1997-04-15 Health Research, Inc. Acceptor for fucosyl transferase
US5783693A (en) * 1993-11-19 1998-07-21 The Regents Of The University Of California Methods for synthesizing sulfated disaccharide inhibitors of selectins
WO1995021180A1 (fr) * 1994-02-01 1995-08-10 Glycomed Incorporated Derives de lactose substitues, utilises comme inhibiteurs de l'adhesion cellulaire
AU681010B2 (en) * 1994-02-01 1997-08-14 Glycomed Incorporated Substituted lactose derivatives as cell adhesion inhibitors
EP0758243A4 (fr) * 1994-04-29 1997-08-20 Texas Biotechnology Corp FIXATION DE LA E-SELECTINE ET/OU DE LA P-SELECTINE SUR LA SIALYL-LEWIS-?x OU LA SIALYL-LEWIS-?a
EP0758243A1 (fr) * 1994-04-29 1997-02-19 Texas Biotechnology Corporation FIXATION DE LA E-SELECTINE ET/OU DE LA P-SELECTINE SUR LA SIALYL-LEWIS-?x OU LA SIALYL-LEWIS-?a
US5589465A (en) * 1994-09-30 1996-12-31 Akira Hasegawa Glycolipid derivatives acting as ligands for selectins
EP0714903A1 (fr) * 1994-10-10 1996-06-05 Hoechst Aktiengesellschaft Nouveaux carbohydrat conjugués utilisés comme inhibiteurs d'adhésion cellulaire
US5858994A (en) * 1994-10-10 1999-01-12 Hoechst Aktiengesellschaft Carbohydrate conjugates as inhibitors of cell adhesion
US5962424A (en) * 1995-02-21 1999-10-05 Arch Development Corporation Methods and compositions for targeting selectins
WO1997000881A1 (fr) * 1995-06-22 1997-01-09 Nippon Shinyaku Co., Ltd. Derives de la moranoline
US6008203A (en) * 1995-07-14 1999-12-28 Glycotech Corp. Methods for treatment of EGF receptor associated cancers
US6281202B1 (en) 1995-07-14 2001-08-28 Glycotech Corp. Pharmaceutical compositions for treatment of EGF receptor associated cancers
EP0811634A1 (fr) * 1995-08-09 1997-12-10 Daikin Industries, Limited Derives de sialyl-lewis x fluores et produits intermediaires utilises dans leur synthese
EP0811634A4 (fr) * 1995-08-09 1998-07-08 Daikin Ind Ltd Derives de sialyl-lewis x fluores et produits intermediaires utilises dans leur synthese
WO1997007809A1 (fr) * 1995-08-23 1997-03-06 The Regents Of The University Of California Inhibiteurs de selectines a base de disaccharides sulfates, procedes de synthese et utilisation therapeutique
US5977080A (en) * 1995-08-23 1999-11-02 The Regents Of The University Of California Sulfated disaccharide inhibitors of selectins, methods for synthesis and therapeutic use
WO2001017566A2 (fr) * 1999-09-08 2001-03-15 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Agents de contraste de type l-selectine
WO2001017566A3 (fr) * 1999-09-08 2001-12-20 Diagnostikforschung Inst Agents de contraste de type l-selectine

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EP0648223A1 (fr) 1995-04-19
EP0648223A4 (fr) 1996-07-31
AU678373B2 (en) 1997-05-29
JPH08500820A (ja) 1996-01-30
AU4652693A (en) 1994-01-24
CA2138645A1 (fr) 1994-01-06

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