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WO1986005789A1 - Derives d'hydrates de carbone et leurs compositions pour usage diagnostique ou therapeutique, et leurs procede d'utilisation - Google Patents

Derives d'hydrates de carbone et leurs compositions pour usage diagnostique ou therapeutique, et leurs procede d'utilisation Download PDF

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Publication number
WO1986005789A1
WO1986005789A1 PCT/SE1986/000131 SE8600131W WO8605789A1 WO 1986005789 A1 WO1986005789 A1 WO 1986005789A1 SE 8600131 W SE8600131 W SE 8600131W WO 8605789 A1 WO8605789 A1 WO 8605789A1
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WIPO (PCT)
Prior art keywords
hydrogen
compound according
bacteria
compound
independently
Prior art date
Application number
PCT/SE1986/000131
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English (en)
Inventor
Sigfrid Svensson
Per Anders MA^oRDH
Frank Lindh
Hans LÖNN
Elisabeth Kallin
Bo Nilsson
Olle MA^oNSSON
Original Assignee
Biocarb Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication of WO1986005789A1 publication Critical patent/WO1986005789A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof

Definitions

  • Carbohydrate derivatives and compositions thereof for therapeutic or diagnostic use and methods for their use.
  • the present invention relates to compounds which are useful for therapeutic treatment of infections as well as profylaxis and diagnosis in connection herewith.
  • the invention moreover covers a process for targeting of molecules to different organs of mammals including man.
  • the technique according to the invention is applicable to microorganisms of different kinds causing diseases, particularly pathogenic bacteria, such as cocci, preferably Grampositive, e.g. streptococci, pneumococci and staphylococci.
  • the invention relates to applications directed to staphylococci, such as Staphylococcus saprophvticus, and bacteria of the species Bordetella pertussis causing hooping cough.
  • the compositions according to the invention have the ability of inhibiting the activity of so called natural killer cells (NK-cells).
  • NK-cells natural killer cells
  • the technique according to the invention relating to targeting is applicable to cells and organs of mammals including man.
  • microorganism used in the present disclosure is intended to cover bacteria, viruses, animal and plant cells.
  • Staphylococcus saprophvticus is a bacterium which is frequent cause to urinary tract infections (UTI) mainly in younger women and older men. The bacterium is present on the skin of different animals and is a frequent contaminant on meat products. Staphylococcus saprophvticus has also been connected with mastitis.
  • glycoconjugates are absorbed by cells or organs due to the fact that cell membranes contain receptors of a proteinatious character. These receptors can be specific for carbohydrate structures of the glycoconjugates and these glycoconjugates can specifically be directed to certain cells or organs.
  • the present invention has for its purpose to provide a composition or substance having the ability of replacing the normal receptor function in vivo and in vitro in relation to pathogenic bacteria inclined to cause infections in human beings and animals.
  • Another object of the invention is to provide such composition or compound that can be used for the removal of bacteria from butcher products, contaminated surfaces, for example skin and buildings.
  • Yet another object of the invention is to provide a composition or compound that can be used in diagnosis of bacteria.
  • Still a further object of the invention is to provide a composition or substance that can be used for visualization of cells or organs.
  • the invention moreover provides a process for targeting of molecules to different cells or organs.
  • the invention is particularly applicable to receptor structures for Staphylococcus saprophvticus. NK-cells and li-vercells, but it should be observed that the invention is not limited to these particular cells. Through studies and experiments it has been found that the receptor for Staphylococcus saprophvticus. NK-cells and livercells can be replaced with compositions containing a compound having the formula:
  • R 1 and R 2 independently are hydrogen, lower alkyl, acyl or together form a cyclic amide or amine; wherein R 3 and R 4 independently are hydrogen, alkyl, an organic residue; and wherein n is ⁇ 2, the individual monomer residues of the compound (I) being independent of each other as to structure.
  • R 1 is hydrogen and R 2 has the formula:
  • R 5 , R 6 and R 7 are suitably all fluoro or chloro, particularly fluoro.
  • R 1 is hydrogen and R 2 is acyl, particularly acetyl or trifluoroacetyl.
  • R 3 and R 4 may suitably independently be hydrogen or lower alkyl.
  • n is 2 or more and n is preferably 2-100, particularly 2-20 and especially 2-10. Lower homologues are preferred in that n is preferably 2-6 and particularly 2.
  • the same conditions apply as given above in connection with compounds of formula I.
  • R 1 is hydrogen and R 2 is acetyl or trifluoroacetyl at least one of substituents R 2 is trifluoroacetyl.
  • the expression "lower” used in the present disclosure relates to a group containing 1-6 carbon atoms, particularly 1-4 carbon atoms and especially 1 or 2 carbon atoms.
  • substituent R 4 this may be of any type as long as it does not negatively affect the conditions in relation to the application of the invention.
  • Preferred values of R 4 are hydrogen, lower alkyl or a macromolecular carrier covalently bound to the carbohydrate residue, optionally via a coupling arm.
  • a macromolecular carrier there may be used a synthetically or naturally occurring polypeptide, polysaccharide, other polymer or particle. This is conventional in the art, see for example references 8-12, the contents of which are incorporated herein by reference.
  • the coup ling arm between the carbohydrate residue and the macromolecular carrier can be any of the following:
  • n' can vary between 1 and 15.
  • the haemagglutination reaction of sheep erythrocytes caused by S . saprophyticus is probably due to interaction between a membrane structure at the surface of the bacterium and receptors on the surface of the sheep erythrocytes containing compound I above.
  • the adhesion of S . saprophvticus to periurithral cells is probably due to interaction between a membrane structure at the surface of a bacterium and receptors of the surface of the epithelial cells containing the above-mentioned compound I.
  • the invention is not bound by any of these theories.
  • the active substance constituted by the compound of formula I can be used as such or in combination with a pharmaceutically acceptable carrier.
  • a composition for therapeutic treatment of mammals including man said composition containing a compound I according to the definition above in combination with such pharmaceutically acceptable carrier.
  • the active substances according to the present invention can be formulated for use in human or veterinary medicine for therapeutic, profylactic or diagnostic uses.
  • the active constituents are normally administered orally or rectally or by injection in the form of a pharmaceutical preparation containing the active constituents in combination with a pharmaceutically acceptable carrier, which may be solid, semisolid or liquid, or as a capsule, and such compositions constitute a further aspect of the invention.
  • a pharmaceutically acceptable carrier which may be solid, semisolid or liquid, or as a capsule, and such compositions constitute a further aspect of the invention.
  • the compounds may also be used as such without carrier and in a form of an aqueous solution for injection.
  • pharmaceutical preparations there may be mentioned tablets, drops, solutions and suppositories.
  • the active substance usually constitutes from 0.05 to 99% by weight of the preparation, for example from 0.1 to 50% for preparations intended for oral administration.
  • the active constituents can be admixed with a solid pulverulent or other carrier, for example lactose, saccharose, sorbitol, mannitol, starch, such as potatoe starch, corn starch, amylopectin, a cellulose derivative or gelatin and may also include lubricants, such as magnesium or calcium stearate, or polyethylene glycol waxes compressed to form tablets or cause for dragees.
  • a solid pulverulent or other carrier for example lactose, saccharose, sorbitol, mannitol, starch, such as potatoe starch, corn starch, amylopectin, a cellulose derivative or gelatin and may also include lubricants, such as magnesium or calcium stearate, or polyethylene glycol waxes compressed to form tablets or cause for dragees.
  • Liquid preparations for oral application can be in the form of elixires, syrups or suspensions, for example solutions containing from 0.1 to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerol, propylene, glycol and optionally other additives of a conventional character.
  • the dose by which the active constituents are administered may vary within wide limits and depend on different factors, such as the severity of the disorder, the age and the weight of the patient and can be individually adjusted. As a conceivable range for the quantity of active constituents that may be administered per day there may be mentioned from 0.1 to 2000 mg or from 1 mg to 2000 mg.
  • the present invention has also for an object to provide a method for therapeutic treatment of mammals including man, and in this treatment a therapeutically active amount of a substance or a composition in accordance with the invention is administered.
  • the present invention also includes a process for identification or quantification of the compound I or residues of native biological material from mammals including man.
  • antibodies are used the generation of which has been induced by the compound I as defined above.
  • the invention furthermore includes a process for the purification of acceptor structures of bacteria, and in this purification the affinity between compound I and the acceptor structures of the bacteria is utilized.
  • the invention covers a process for performing desinfection on surfaces, a compound I being applied on to the surface and then removed with bacteria adhering thereto.
  • Chitosan hydrochloride was prepared from chitin by alkaline N-deacetylation according to Barker et al. (Ref.2). Chitosan was partially hydrolyzed using aqueous hydrochloric acid and their N-acetylated (Ref. 2). N-acetylated oligosaccharides were separated using gel chromatography (Saphadex G15) and hplc (C-18 column, CH 3 CN/H 2 O system). The following oligosaccharides were isolated and characterized:
  • the purity of the oligosaccharides I-VII was checked by hplc.
  • the oligosaccharides gave expected p.m.r. spectra (500 Mhz . Bruker) and correct sugar and methylation analyses (Refs. 3,4) in accordance with structure.
  • oligosaccharides were prepared using trifluoroacetolysis (Refs. 5,6) from the oligosaccharides I-VIII according to the following general technique.
  • the oligosaccharides (I-VIII) (100 mg) were treated with trifluoroacetic acid/trifluoracetic anhydride (TFA/TFAA) (1:100; v/v; 20 ml) at 100°C for 48 hours. After cooling the reaction mixture was evaporated to dryness. The residue was dissolved in methanol (20 ml) and the resulting solution was evaporated to dryness. The residue was dissolved in globial acetic acid (10 ml) and water (10 ml) was added. The mixture was heated at 100°C for 4 hours and evaporated to dryness. The crude product was gel chr ⁇ matographed on Sephadex G15 (2x100 cm) using water as eluant.
  • TFA/TFAA trifluoroacetic acid/trifluoracetic anhydride
  • Shifts are given relative to acetone (2.225 ppm. 20°C) for H 1 and relative to external TFA (-78.500 ppm, 20°C).
  • the oligosaccharide (I-II) (100 mg) was treated with TFA/TFAA (1:100, v/v, 20 ml) at 100°C for 30 min. After work-up (see above) the product was purified by hplc (C-18 column, CH 3 CN/H 2 O) . Typical yield of purified product was 40 mg. The purity and identity of the products was corraborated by p.m.r. and F 19 n.m.r.
  • the oligosaccharide (XVII-XVIII) (50 mg) was dissolved in 1M ammonia in methanol/water (1:4, v/v) and was left at 20°C for 18 h. The reaction mixture was evaporated to dryness. The yield was 80% .
  • XIX and XX was treated with different anhydrides in pyridine to substitute all hydrocyl and aminogroups.
  • the O- and N-acylated compounds were de-O-acylated with ammonia in methanol/water.
  • the oligosaccharide (XIX-XX) (50 mg) was treated with (RCO) 2 O (10-fold excess) in pyridine (20 ml) at 100°C for 2h. The reaction mixture was evaporated to dryness. The residue was treated with 1M ammonia in methanol/water (3:1, v/v) for 18h arid the reaction mixture was evaporated to dryness. The crude product was purified using hplc (C-18 column, CH 3 CN/H 2 O) .
  • XXV ⁇ -D-GNAcp-(1-4)-D-GNPHT
  • microtitre plates (Limbo Sc. Comp. Inc. ) were used. 25 ⁇ l of bacterial suspension were titrated in PBS by two-step titre steps, 25 ⁇ l of 1% erythrocyte suspension being then added. The haemagglutination titre was determined after incubation of the plates for 2-4 hours in room temperature.
  • RPMI 1640 Flow Ltd
  • Oligosaccharides which were tested for their ability of preventing adhesion of S.saprophyticus to urinary epithelial cells were dissolved in RPMI 1640 to a concentration of 5 mg/ml.
  • 1 ml of the oligosaccharide solution was incubated with 0.1 ml bacterial suspension at 37°C for 30 minutes.
  • Urinary epithelial cells were incubated with the bacterial suspension incubated in advance as described above with oligosaccharide solution for 45 minutes at 37°C.
  • As a control there was used a bacterial suspension preincubated with 1 ml RPMI 1640.
  • Incubated samples were filtrated through a 12 ⁇ filter and washed 3 times with PBS.
  • the filter was pressed against microscope slides for a few seconds, the slides being then fixed in methanol for 10 minutes.
  • the slides were dried in air and coloured with acridine orange for 2 minutes.
  • the slides were washed, dried in air and studied in fluorescence microscope. The number of bacteria per cell was counted. In each experiment 50 cells were counted.
  • Example 4 Preparation of compositions containing the structural element in at least bivalent state and covalently linked to a macromolecular carrier.
  • composition was made starting from oligosaccharides having a free reducing end.
  • the reactions used are well known and, therefore, they are only diagrammatically illustrated (in the scheme SR represents the structural element without the sugar residue constituting the reducing terminal, and MB represents a macromolecular carrier).
  • compositions containing the structural element according to the invention in at least bivalent association without covalent bond.
  • a glycolipid containing the said structural element is linked by a hydrophobic interaction to lipophilic (hydrophobic) gels, polymers or particles, for example octylsepharose, plastics and latex surfaces.
  • a Manufacture of monoclonal antibodies by hybridoma technique.
  • Balb/c-mice are immunized with a composition according to the invention.
  • the spleen from hyper immunized animals is harvested and a cell suspension is prepared by mechanical comminution of the tissue. After gradient centrifugation to obtain a pure cell preparation the cells are fused by means of polyethylene glycol (PEG, average molecular weight 1500) with established B-myeloma cell lines from Balb/c-mice according to known technique.
  • PEG polyethylene glycol
  • the cells After cloning the hybridoma cells generating the antibody sought, the cells are propagated on a large scale, the culture medium supernatants being harvested and the antibodies thereof being purified in a conventional manner.
  • ELISA enzyme-linked immunosorbent assay
  • Mammals are immunized with an oligosaccharide protein or polymer composition according to the invention.
  • Antibodies are isolated from the hyperimmune serum of the mammal and purified in accordance with conventional techniques.
  • Example 7 Diagnostic test for identification of bacteria having acceptor structures showing specificity towards the structural element according to the invention.
  • Bacteria are incubated with sheep erythrocytes to agglutinate same.
  • bacteria are incubated with sheep erythrocytes together with the structural element according to the invention at such concentration as to totally inhibit haemagglutination.
  • Haemagglutination and inhibition of haemagglutination is performed according to Example 1. Positive haemagglutination of sheep erythoryctes and complete inhibition of haemagglutination after addition of oligosaccharide verifies the fact that the bacteria possess acceptor structure.
  • b Bacteria are incubated with sheep erythrocytes to agglutinate same.
  • bacteria are incubated with sheep erythrocytes together with the structural element according to the invention at such concentration as to totally inhibit haemagglutination.
  • Haemagglutination and inhibition of haemagglutination is performed according to
  • Bacteria are incubated with a composition wherein the said structural element is covalently or by other association in multivalent form linked to a particular matrix according to Example 3 or 4. Incubation is carried out on microscope slides for 10-15 minutes, the preparation being then studied in a microscope. If the bacteria posses acceptor structure the particles are covered by bacteria. Where the reaction is negative the particles are free from bacteria. c. Bacteria are mixed with a composition according to claim 4 or 5 on microscope slides positive reaction resulting in agglutination of particles covered with the said structural element.
  • Example 8 Purification of bacteria or acceptor structures a.
  • a composition according to Example 3 or 4 above is arranged in the form of a column.
  • a mixture of bacteria is then passed through the column, bacteria possessing acceptor structures being maintained by interaction with the receptor structures of the column.
  • the column can be eluted with buffer containing a receptor-active structural element according to the invention and this results in elusion of bacteria having acceptor structures in a pure form.
  • the acceptor structure can be obtained in a pure form.
  • Bacteria or acceptor structures can be used for the manufacture of vaccines or for determination of antibody in for example body fluids, such as blood, urine or mother's milk.
  • composition for use for desinfection Composition for use for desinfection
  • a 0.1% by weight aqueous solution of the compounds I or XV is prepared and applied by using a cotton pad on a surface infected by S.saprophvticus. The solution results in effective removal of the bacterium from the surface.
  • Lymphocytes isolated from peripheral blood drained from normal donors have the ability of exerting a cytotoxic, i.e. cell killing activity against certain types of cells in culture.
  • a cytotoxic i.e. cell killing activity against certain types of cells in culture.
  • K-562 a human leukemia cell line called K-562 as a target cell for such cytolytic activity.
  • K-562 cells intracellularly labelled with radioactive chromium are incubated with effector cells (lymphocytes) for 4 hours at 37°C.
  • the cytotoxic effect is measured as the quantity of isotope released in relation to remaining isotope in the target cells.
  • the assays were carried out in capped polystyren tubes (12x75 mm) at 4°C . To each tube was added 3x10 6 rabbit hepatocytes in modified Dulbecco's Eagle's medium and 1x10 -10 M 125 I-asialofetuin and different concentrations of oligosaccharide in a total volume of 1 ml. The tubes were rotated slowly at 4°C for 4h, after which time duplicate samples (200 ⁇ l) were taken, transferred into 400 ⁇ l centrifuge tubes containing 150 ⁇ l of silicone/mineral oil (4:1, v/v) and centrifuged for 10s in an Eppendorf centrifuge. The cell pellet at the bottom of the tube was counted for radioactivity in a Packard-counter. The 50% inhibition value was determined from the observed inhibition curve and the values are shown in Table 3. Table 3

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  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Composé pour usage thérapeutique ou diagnostique, caractérisé par la formule (I) où R1 et R2 sont indivisiblement de l'hydrogène, un alkyle inférieur, un acyle ou forment ensemble un amide ou une amine cycliques; où R3 et R4 sont indivisiblement de l'hydrogène, un alkyle, un résidu organique; et où n est >=2, les résidus des monomères individuels du composé (I) étant indépendants les uns des autres quant à la structure. Sont également décrits une composition contenant ce composé et des procédés d'utilisation du composé et de la composition, respectivement.
PCT/SE1986/000131 1985-04-01 1986-03-25 Derives d'hydrates de carbone et leurs compositions pour usage diagnostique ou therapeutique, et leurs procede d'utilisation WO1986005789A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8501613A SE8501613D0 (sv) 1985-04-01 1985-04-01 Foreningar for terapeutisk eller diagnostisk anvendning jemte forfarande for terapeutisk behandling
SE8501613-7 1985-04-01

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WO1986005789A1 true WO1986005789A1 (fr) 1986-10-09

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EP (1) EP0217912A1 (fr)
AU (1) AU5668286A (fr)
SE (1) SE8501613D0 (fr)
WO (1) WO1986005789A1 (fr)

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FR2640628A1 (fr) * 1988-12-16 1990-06-22 Commissariat Energie Atomique Oligosaccharides lies (beta)-(1 -> 6) en particulier des 2-acetamido-2-desoxy-glucoses ou - galactoses et leur preparation
WO1990011069A1 (fr) * 1989-03-20 1990-10-04 Parfums Christian Dior Procede de preparation de compose ligand-recepteur
FR2663636A1 (fr) * 1990-06-26 1991-12-27 Centre Nat Rech Scient Procede de fonctionnalisation d'un oligonucleotide.
WO1992011015A1 (fr) * 1990-12-21 1992-07-09 Microcarb Inc. Utilisation de phospholipides de cellules hotes pour inhiber la colonisation microbienne
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
EP0535668A1 (fr) * 1991-10-04 1993-04-07 Nihon Medi-Physics Co., Ltd. Agent d'imagerie diagnostique
DE10221055A1 (de) * 2002-05-10 2003-11-27 Hemoteq Gmbh Verfahren zur hämokompatiblen Beschichtung von Oberflächen
US8784862B2 (en) 2002-05-09 2014-07-22 Hemoteq Ag Compounds and method for coating surfaces in a hemocompatible manner
US9290515B2 (en) 2011-10-04 2016-03-22 Shionogi & Co., Ltd Cephem derivative having catechol group

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WO1990011069A1 (fr) * 1989-03-20 1990-10-04 Parfums Christian Dior Procede de preparation de compose ligand-recepteur
FR2645741A1 (fr) * 1989-03-20 1990-10-19 Dior Christian Parfums Procede pour fixer un produit sur la membrane d'un keratinocyte au moyen d'une liaison ligand-recepteur, procede de preparation d'un tel produit, produit obtenu, composition cosmetique ou pharmaceutique le contenant et son procede de preparation
US5286629A (en) * 1989-03-20 1994-02-15 Parfums Christian Dior Method of binding a product to the membrane of a keratinocyte by means of a ligand-receptor bond, method of preparing such a product, product obtained, cosmetic or pharmaceutical composition in which it is present and its method of preparation
FR2663636A1 (fr) * 1990-06-26 1991-12-27 Centre Nat Rech Scient Procede de fonctionnalisation d'un oligonucleotide.
WO1992000315A1 (fr) * 1990-06-26 1992-01-09 Centre National De La Recherche Scientifique (Cnrs) Procede de fonctionnalisation d'un oligonucleotide
WO1992011015A1 (fr) * 1990-12-21 1992-07-09 Microcarb Inc. Utilisation de phospholipides de cellules hotes pour inhiber la colonisation microbienne
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
US5271924A (en) * 1991-10-04 1993-12-21 Nihon Medi-Physics Co., Ltd. Low molecular weight polysaccharide complexes for nuclear magnetic resonance imaging
EP0535668A1 (fr) * 1991-10-04 1993-04-07 Nihon Medi-Physics Co., Ltd. Agent d'imagerie diagnostique
US5352431A (en) * 1991-10-04 1994-10-04 Nihon Medi-Physics Co., Ltd. Low molecular weight polysaccharide complexes for X-ray imaging
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DE10221055A1 (de) * 2002-05-10 2003-11-27 Hemoteq Gmbh Verfahren zur hämokompatiblen Beschichtung von Oberflächen
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US9290515B2 (en) 2011-10-04 2016-03-22 Shionogi & Co., Ltd Cephem derivative having catechol group

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