WO1994022885A1 - Composes anticoagulants - Google Patents

Composes anticoagulants Download PDF

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Publication number
WO1994022885A1
WO1994022885A1 PCT/CA1994/000161 CA9400161W WO9422885A1 WO 1994022885 A1 WO1994022885 A1 WO 1994022885A1 CA 9400161 W CA9400161 W CA 9400161W WO 9422885 A1 WO9422885 A1 WO 9422885A1
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WO
WIPO (PCT)
Prior art keywords
disaccharide
sodium salt
anticoagulant
oso
integer
Prior art date
Application number
PCT/CA1994/000161
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English (en)
Inventor
Robert Kisilvesky
Walter A. Szarek
Alan R. Giles
Michael E. Nesheim
Original Assignee
Queen's University At Kingston
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.)
Filing date
Publication date
Application filed by Queen's University At Kingston filed Critical Queen's University At Kingston
Priority to EP94909884A priority Critical patent/EP0691976A1/fr
Publication of WO1994022885A1 publication Critical patent/WO1994022885A1/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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • 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
    • 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
    • A61K47/54—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 compound
    • A61K47/549—Sugars, nucleosides, nucleotides or 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
    • A61K47/54—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 compound
    • A61K47/55—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61K47/54—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 compound
    • A61K47/555—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 compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/08—Polysaccharides
    • 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

Definitions

  • This invention relates to novel pharmaceutical compositions for use as blood anticoagulants. More particularly this invention relates to pharmaceutical compositions which inhibit Factor IXa in the blood coagulation cascade, and to compositions which may be used to render material surfaces anticoagulative, such as prosthetic implant surfaces and artificial devices and blood carrying devices such as tubing, prosthetic heart valves, and extracorporeal devices such as renal dialysis machines. BACKGROUND OF INVENTION
  • Heparin and polysaccharide derivatives thereof have long been used for selective anticoagulation activity both in vivo and in vitro.
  • Heparin is a sulfate-containing polysaccharide which can be extracted from bovine and porcine lung and intestinal mucosa.
  • Heparin is not, however, a pure compound but is a mixture of polysaccharides with a continuous distribution of molecular weights in the range 1,500 to 30,000 daltons. The activity thereof is somewhat variable, depending on the source and molecular weight. This can cause problems, such as risk of bleeding complications, because different patients react very differently to a given dosage.
  • Heparin is not orally active and must be given parenterally.
  • M is hydrogen or a salt of an alkali metal, alkaline earth metal, ammonium, tri(loweralkyl)amine (C 1 -C 6 ), piperidine, pyrazine, alkanolamine (C r C 6 ) and cycloalkanolamine ( - ); and n is 2-10, which are used to inhibit the complement system of warm blooded animals.
  • “Complements” refer to a complex group of proteins in blood and other body fluids that, working together with antibodies or other factors, play an important role as mediators of immune, allergic, immunochemical and/or immunopathological reactions.
  • Complement inhibitors can be used therapeutically for such non-immunologic diseases as paroxysmal nocturnal haemoglobinuria and hereditary angio-neurotic edema. While activation of the complement system may also accelerate blood clotting, there is no evidence that inhibition thereof would have any anticoagulant activity and, indeed, the opposite is probably the case. In this series of compounds, however, the anomeric hydroxyl group is not blocked but may be sulfated. It has now been found that sulfated and sulfonated oligosaccharides preferably having blocked anomeric centers, surprisingly exhibit anticoagulant properties specific to inhibition of Factor IXa. OBJECT OF INVENTION
  • Another object of this invention is to provide a composition and method for producing antithrombotic surfaces for implanted prostheses, extracorporeal devices, laboratory equipment and the like.
  • a disaccharide containing at least one sulfur based anion which exhibits antithrombotic properties specific to inhibition of Factor IXa.
  • an anticoagulant preparation comprising a pharmaceutically effective amount of a disaccharide containing at least one sulfur based anion, which exhibits antithrombotic properties specific to inhibition of Factor IXa, and a pharmaceutically acceptable carrier therefor.
  • Figure 1 is a sketch illustrating the blood coagulation cascade
  • Figure 2 is a sketch similar to Figure 1 but showing the blood coagulation cascade in a simplified form
  • Figure 3 is a graph showing APTT prolongation at various concentrations of test compounds in plasma.
  • Figure 4 is a graph illustrating Factor IXa clotting time with increasing concentrations of selected inhibitors
  • Figure 5 is a graph illustrating Factor X activation versus concentration of inhibitor #3
  • Figure 6 is a graph illustrating Factor X intrinsic fluorescence versus concentration of inhibitor #3
  • Figure 7 is a graph illustrating Factor IXa fluorescence versus concentration of inhibitor #3
  • Figure 8 is a graph illustrating Factor X activation and intrinsic fluorescence versus concentration of inhibitor #3; and Figure 9 is a graph illustrating Factor X activation and Factor Ixa intrinsic fluorescence versus concentration of inhibitor #3.
  • Sulfated compounds of the present invention fall into two groups namely non- reducing disaccharides having a general formula:
  • R 1 is H or (CH 2 OSO “ 3 M + )n, n is an integer from 1-6,
  • R 2 is OSO " 3 M + and M is selected from NH 4 , trialkylammonium, cyclic ammonium, alkali metals and alkaline earth metals, and R is
  • 2-Picoline was fractionally distilled to remove the water azeotrope and the collected "dry" picoline was dried over CaH 2 and re-distilled.
  • the solvent was stored in a sealed flask until used.
  • the flask was placed in an oil bath held at 45°C and brisk stirring was begun.
  • the dropping funnel was charged with chlorosulfonic acid (16 mL, 240.7 mmol) and the top of the funnel was fitted with a calcium chloride drying tube.
  • the chlorosulfonic acid was carefully dripped into the 2-picoline over 1.5 h.
  • the bath temperature was raised to 60°C, and powdered sucrose (10.0 g, 29.2 mmol) was added, rinsing the sides of the joint and the flask clean with a small amount of dry 2-picoline from a dry pipette. Stirring was continued for 1-1.5 hours more, to afford a viscous purple solution.
  • the tan powder was dissolved in water (60 Ml). The solution was decolorized and filtered; the filtrate was added to a separatory funnel, and the Ph was adjusted to 8.5 with concentrated aqueous ammonium hydroxide. A 500-M1 Erlenmeyer flask was fitted with a mechanical stirrer, and ethanol (300 Ml) was added. The product solution was slowly dripped into the vigorously stirred ethanol over 2 h. A white precipitate was formed, which was collected by filtration, washed with absolute ethanol, and then with acetone. The product was dried in vacuo. yield 27.5 g (84%); mp 155-158°C (dec).
  • Sucrose octasulfate ammonium salt (10 g) prepared in Example 1 was dissolved in water (50 Ml), and the Ph was raised to 9.0 with 20% w/v aqueous sodium hydroxide. Ethanol (95%) was added to the solution with vigorous mechanical stirring, until an oily precipitate was formed. Scratching of the precipitate eventually caused solidification, and the solid was collected by filtration. This was dissolved in a minimum amount of water, the solution was filtered, and the Ph of the filtrate was adjusted to 9 with 20% sodium hydroxide. Alcohol was added, with vigorous stirring, to form a fine powder. When addition was complete, the suspension was stirred for several hours more.
  • 2-picoline • S0 3 complex was prepared at 45°C from chlorosulfonic acid (15.4 mL, 232 mmol) and 2-picoline (990 mL). The temperature was raised to 60°C, and methyl 3-D lactoside (10.00 g, 28.06 mmol) was added. The mixture was stirred at 60°C for lh before being cooled. The solution was chilled in an ice-water bath, as half concentrated ammonium hydroxide solution (75 mL) was added. Ethanol (95%, 500 mL) was added with vigorous stirring. This procedure caused separation of an oily material, which was allowed to settle.
  • Methyl 0-D-lactoside heptasulfate ammonium salt (12 g, 11.6 mmol), as prepared by Example 4, was dissolved in water (60 Ml), and the solution was filtered. The Ph of the filtrate was adjusted to 8 with 20% w/v sodium hydroxide solution. While the aqueous solution was being vigorously stirred, 95% ethanol (150 Ml) was added. This procedure caused separation of an oily material. The supernatant was decanted, the oily residue was dissolved in water (100 Ml) and the solution was freeze-dried. The resulting powder was dissolved again in water (100 Ml) and the solution was freeze-dried. The powdery product was dried 24 h in vacuo at 60°C. Yield 10.41 g (84%); mp 167-174°C (dec).
  • compositions produced according to Example 5, Example 3 and Example 2, and sucrose (MW360) as a control were designated compounds 1, 2, 3 and 4, respectively for blind screening tests of their anticoagulation properties.
  • Each compound was added to human plasma at increasing concentrations and the Activated Partial Thromboplastin Time (APTT), Prothrombin Time (PT) and Thrombin Clotting Time (TCT) were measured using standard protocols (Figure 3).
  • Compound 4 showed no anticoagulant activity but in the case of compounds 1, 2 and 3 the TCT and PT remained the same as the control, while the APTT showed a dose related response by prolongation of APTT.
  • a male NZW rabbit was anesthetized and a stomach tube placed so that the test solution, sucrose octasulfate at 200 mg/kg body weight, could be administered in a 200 mg/ml water.
  • the infusions were well tolerated. Blood samples were drawn from the left ear vein via a 21 gauge butterfly needle immediately pre- infusion and then at 1, 5, 10, 20, 46, 70, 123, 182 and 240 minutes post infusion (injected
  • the blood samples were collected into 1/lOth volume of buffered citrate and also into pediatric EDTA tubes for cell counts.
  • the citrated samples were centrifuged to obtain platelet-poor plasma and frozen. Complete blood counts were performed on a
  • Teknika Teknika was added and incubated for 3 minutes at 37°C. 100 ⁇ l 25 mM CaCl 2 was then added and the time to clotting was then measured with a stopwatch.
  • a standard line was constructed by adding known amounts of test material to citrated normal rabbit plasma. The prolongation of the APTT (in seconds) was plotted against the concentration of anticoagulant and the prolongation of each of the test samples was read as apparent activity from this line.
  • the APTT is simply a measure of blood coagulation in the overall blood coagulation cascade and no inferences as to where the inhibitor is active can be drawn.
  • the PT is a measure of the activation of Factor X to Factor Xa (prothrombinase) and activation of prothrombin to thrombin via the extrinsic pathway
  • the TCT is a measure of the conversion of fibrinogen to fibrin by thrombin alone.
  • the anticoagulant activity of the test compounds is confined to the inhibition of one or more components of the intrinsic pathway, i.e defined by the activation of Factor XII to Xlla, and/or XI to XIa and/or IX to IXa, and subsequent action of IXa.
  • Respective aliquots of human blood plasma were mixed, in vitro, with 15 ⁇ g ml of purified bovine Factor XIa (Enzyme Research Labs Inc.), or 300 ng/ml of purified human Factor IXa (Enzyme Research Labs Inc.), or 9 ng/ml purified human Factor Xa
  • This assay is described by Nesheim et al. in Biochemistry 18:996-1003 (1979) and was designed to measure prothrombin activating potential of prothrombinase (see Figure 1) contained within highly purified components. Activation of prothrombin was monitored with a freshly prepared fluorescent thrombin inhibitor DAP A. Reaction mixtures consisted of purified bovine prothrombin (1.4 ⁇ M) in tris-buffered saline (TBS) pH 7.4, consisting of 2 mM CaCl 2 and 3 ⁇ M DAPA at ambient temperature.
  • TBS tris-buffered saline
  • the reaction was started with the addition of purified bovine factor Xa to a final concentration of 5 nM.
  • This assay was performed to determine Factor X activating potential of an activating enzyme complex comprising highly purified components.
  • Reaction mixtures consisted of 0.5 ⁇ M purified human factor X in HEPES buffered saline (HBS) pH 7.4, containing 5 mM CaCl 2 , 10 ⁇ M PCPS vesicles and 0.2 mM chromogenic substrate S- 2222.
  • HBS HEPES buffered saline
  • F.VIII(rF.VIII) purified recombinant F.VIII(rF.VIII) to a final concentration of 2.5 nM followed by thrombin (1 nM final to activate the rF.VIII).
  • the anticoagulant test compounds were added in a 2 ⁇ l volume and the reaction initiated with the addition of purified human F.IXa (1.4 nM final). The cleavage of S-2222 by F.Xa was monitored at 405 nM and the slopes plotted vs the concentration of inhibitor.
  • Binding of the anticoagulant compounds to and/or induction of conformational changes in the individual components of the tenase complex was analyzed by changes in intrinsic fluorescence. Samples at 22°C were excited at a wavelength of 280 nm at a slit width of 1 nm and emission was measured at 340 nm.
  • the buffer used was HEPES-buffered saline (HBS) pH 7.4 containing 5 mM CaCl 2 and 0.01% Tween®- 80 and was filtered through a 0.2 ⁇ filter.
  • Purified proteins were tested as follows: recombinant F.VIII at a concentration of 55 nM, purified F.X at a concentration of 600 nM and purified F.IXa/3 at a concentration of 200 nM. Concentrated solutions of the
  • test compounds were prepared in a solution containing the protein to be tested. Aliquots of these solutions were added to a cuvette containing a solution of the test protein at the same concentration. After each addition, intrinsic fluorescence of the protein was measured. The inclusion of the protein in the concentrated solution eliminated the need to correct for dilution of the protein during the titration and thereby allowed highly accurate measurements of small relative changes in fluorescence. Titrations of anticoagulants covered the concentration range of 0.1 to 30 ⁇ M. The change in intrinsic fluorescence induced by the addition of anticoagulant was expressed as a ratio relative to initial fluorescence intensity obtained in the absence of the compound.
  • Anticoagulant compound 3 caused no change with rF.VIII, a decrease in intrinsic fluorescence with F.X ( Figure 6) and an increase with FIXa ( Figure 7).
  • the change in F.X did not saturate with increasing concentrations of compound 3 and the concentration of compound 3 required to produce half-maximal change in intrinsic fluorescence was much higher than the concentration of compound 3 that produced half-maximal anticoagulant activity in the tenase assay ( Figure 8).
  • the increases in intrinsic fluorescence induced by compound 3 on F.IXa/3 were saturable, with the concentration to produce half-maximal response virtually identical to that for the anticoagulant activity (Figure 9). No changes were induced by compound 4.
  • Compounds 1 and 2 were subsequently assayed and found to have very similar values to those obtained for 3.
  • compositions for administration to a patient parenterally may be administered parenterally in the form of a sterile aqueous solution
  • the dosage of the compounds of this invention can be readily calculated on a weight per kilogram of body weight basis designed to elevate the APTT into the therapeutic range, given that for heparin an APTT of 55-70 seconds can be achieved at a dosage rate of 0.2 - 0.3 units heparin/ml plasma.
  • the invention does, however, also contemplate the treatment of surfaces which come into contact with blood in vivo, extraco ⁇ oreally or in vitro so as to render them anticoagulative.
  • silicones and silicone rubbers in addition to many other materials, have been used to manufacture many medical devices, such as implants and equipment to transport or transfer blood, i.e. tubing, in which blood comes into contact with the silicone surface.
  • Silicones are inert to human tissue and the body is able to tolerate silicone materials without undue adverse effects.
  • blood tends to coagulate when in contact with silicone surfaces and this has been seen as a serious shortcoming to the extended use of such materials.
  • Heparin coated surfaces have been suggested in the past to overcome this shortcoming, but there
  • SUB is considerable difficulty in bonding heparin to a silicone surface.
  • One of the few effective methods involves exposing the heparin-coated surface to ionizing radiation.
  • Another method described in U.S. patent 3,508,959, involves sulfonating a partially cured silicone rubber by coating the rubber with an organosilane or organosiloxane and curing the rubber so as to sulfonate the surface thereof.
  • silicone and other surfaces such as metals, glass and plastics materials with which blood comes into contact, may be activated by reacting the surface with a chemical linking agent, to which a selected compound of the present invention is then chemically attached.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
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  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Biochemistry (AREA)
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  • Biotechnology (AREA)
  • Crystallography & Structural Chemistry (AREA)
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Abstract

On a démontré qu'une série de disaccharides sulfatés, dotés de centres anomères bloqués, présentent des propriétés anticoagulantes du sang spécifiques de l'inhibition du facteur IXa, et qu'on peut les utiliser in vivo pour inhiber la coagulation de façon extra-corporelle, ou in vitro pour recouvrir des surfaces qui entrent en contact avec du sang, afin d'inhiber la formation de caillots sur ces surfaces.
PCT/CA1994/000161 1993-03-29 1994-03-29 Composes anticoagulants WO1994022885A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94909884A EP0691976A1 (fr) 1993-03-29 1994-03-29 Composes anticoagulants

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3784493A 1993-03-29 1993-03-29
US08/037,844 1993-03-29
US20186194A 1994-02-24 1994-02-24
US08/201,861 1994-02-24

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996039129A1 (fr) * 1995-06-06 1996-12-12 Queen's University At Kingston Procede permettant d'accroitre le depot de plaques amyloides
US6391300B1 (en) * 1996-05-16 2002-05-21 The Trustees Of Columbia University In The City Of New York Method for inhibiting thrombosis in a patient whose blood is subjected to extracorporeal circulation
WO2008031509A1 (fr) 2006-09-13 2008-03-20 Sanofi-Aventis Dérivés d'isosérine utilisés comme inhibiteurs du facteur de coagulation ixa
WO2008031508A1 (fr) 2006-09-13 2008-03-20 Sanofi-Aventis Dérivés de tartrate utilisés comme inhibiteurs du facteur de coagulation ixa
WO2009049370A1 (fr) * 2007-10-16 2009-04-23 Progen Pharmaceuticals Limited Nouveaux dérivés d'oligosaccharides sulfatés
US9011519B2 (en) 2008-02-21 2015-04-21 Edoardo Camenzind Implantable medical device including a protection/retaining layer for an active ingredient or drug, in particular a water-soluble one
CN106572650A (zh) * 2014-06-10 2017-04-19 生物马特里卡公司 在环境温度下稳定凝血细胞
WO2017207931A1 (fr) 2016-06-01 2017-12-07 Hexacath Dispositif formant catheter d'infusion pour traiter au moins une obstruction partielle ou totale dans un conduit, tel que conduit corporel
US9999217B2 (en) 2010-07-26 2018-06-19 Biomatrica, Inc. Compositions for stabilizing DNA, RNA, and proteins in blood and other biological samples during shipping and storage at ambient temperatures
WO2019113645A1 (fr) 2017-12-15 2019-06-20 The Australian National University Composés pour le traitement et la prévention de pathologies médiées par l'histone extracellulaire
US10568317B2 (en) 2015-12-08 2020-02-25 Biomatrica, Inc. Reduction of erythrocyte sedimentation rate
WO2020172698A1 (fr) * 2019-02-25 2020-09-03 The Australian National University Composés pour traiter et prévenir des complications associées au net
CN114436858A (zh) * 2020-11-03 2022-05-06 江苏开元药业有限公司 一种药用辅料的三乙胺盐的制备方法
CN116813675A (zh) * 2023-08-23 2023-09-29 北京远大九和药业有限公司 一种化合物晶型及其制备、组合物和用途

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EP0048231A1 (fr) * 1980-09-15 1982-03-24 Kabi AB Oligosaccharides ayant une activité anti-coagulante
EP0230023A2 (fr) * 1985-12-24 1987-07-29 Marion Merrell Dow Inc. Compositions pharmaceutiques pour l'amélioration de la guérison des blessures
EP0351314A2 (fr) * 1988-07-11 1990-01-17 Terumo Kabushiki Kaisha Matériau et instrument médical
EP0479093A1 (fr) * 1990-10-03 1992-04-08 F. Hoffmann-La Roche Ag Dérivés oligosaccharides et leurs utilisations comme médicaments
EP0504645A2 (fr) * 1991-03-13 1992-09-23 F. Hoffmann-La Roche Ag Utilisation d'oligosaccharides sulphatés pour le traitement des maladies artériosclérotiques et pour la prévention de la resténose

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US8263621B2 (en) 2006-09-13 2012-09-11 Sanofi Tartrate derivatives for use as coagulation factor IXa inhibitors
WO2008031509A1 (fr) 2006-09-13 2008-03-20 Sanofi-Aventis Dérivés d'isosérine utilisés comme inhibiteurs du facteur de coagulation ixa
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US9999217B2 (en) 2010-07-26 2018-06-19 Biomatrica, Inc. Compositions for stabilizing DNA, RNA, and proteins in blood and other biological samples during shipping and storage at ambient temperatures
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