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WO2003051347A1 - Utilisation d'antagonistes de recepteurs d'urokinase afin de moduler les blessures de reperfusion ischemique - Google Patents

Utilisation d'antagonistes de recepteurs d'urokinase afin de moduler les blessures de reperfusion ischemique Download PDF

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Publication number
WO2003051347A1
WO2003051347A1 PCT/EP2002/014478 EP0214478W WO03051347A1 WO 2003051347 A1 WO2003051347 A1 WO 2003051347A1 EP 0214478 W EP0214478 W EP 0214478W WO 03051347 A1 WO03051347 A1 WO 03051347A1
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Prior art keywords
ischemia
par
urokinase receptor
reperfusion injury
modulate
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Ceased
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PCT/EP2002/014478
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English (en)
Inventor
Désiré COLLEN
Peter Carmeliet
Hugo Van Aken
Gregor Theilmeier
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Vlaams Instituut voor Biotechnologie VIB
Desire Collen Research Foundation vzw
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Vlaams Instituut voor Biotechnologie VIB
Desire Collen Research Foundation vzw
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Priority to AU2002358158A priority Critical patent/AU2002358158A1/en
Publication of WO2003051347A1 publication Critical patent/WO2003051347A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a method of prevention and/or treatment of ischemia-reperfusion injury.
  • the invention indicates the importance of the urokinase receptor (u- PAR) in the pathogenesis following ischemia. Consequently, the use of selective inhibitors of u-PAR are beneficial for the prevention and/or treatment of patients suffering from reperfusion injury in the heart, in organ transplantation and in the brain.
  • u- PAR urokinase receptor
  • Peri-operative myocardial ischemia causes serious morbidity and mortality for over 5 million patients each year. Once Ml occurs, the prognosis of the patient is dramatically altered: post-operative recovery times are lengthened, while non-cardiac complications are increased. Notably, 20 to 30% of those patients who experience new onset Ml, will suffer fatal myocardial infarctions or dysrhythmias within 6 years. Patients who have required CPR, have a poor prognosis. Only 4-33% of the approximately 750.000 resuscitated Americans per year survive to hospital discharge. A large proportion of deaths are associated with the "post-resuscitation" syndrome, characterized by multi- organ damage.
  • Regional Ml and global ischemia share features of hypoxia-induced endothelial cell (EC) damage and ensuing reperfusion injury:
  • EC hypoxia-induced endothelial cell
  • Global ischemia after cardiac arrest results in diffuse EC damage, with increased plasma levels of soluble thrombomodulin and adhesion molecules, as well as enhanced expression of P-selectin and ICAM-1 in the brain.
  • the latter is particularly relevant, since clinical outcome after global ischemia is inversely correlated with the extent of neurologic damage that is in part due to reperfusion.
  • transient ischemia induces long-lasting changes in excitatory synaptic transmission in CA1 hippocampal neurons.
  • Anoxic longterm synaptic potentiation is considered by some, an early marker of delayed neuronal death induced by transient ischema.
  • tissue repair is initiated with an inflammatory response characterized by influx of leukocytes.
  • Murine models of Ml both transient and permanent, have recently been well characterized and provide reliable means to study myocardial wound healing and ventricular remodelling that closely reflect these processes in man.
  • Transient ischemia induces myocyte damage and microvascular endothelial cell (EC) activation.
  • EC microvascular endothelial cell
  • tissue repair is initiated by an inflammatory response characterized by influx of leukocytes and platelets.
  • Leukocyte/platelet/EC interactions are tightly regulated by adhesion molecules.
  • Members of the selectin family and their ligands mediate tethering and rolling events of leukocytes and platelets on the EC surface.
  • ICAM-1 and VCAM-1 immunoglobulin superfamily
  • ICAM-1 and VCAM-1 immunoglobulin superfamily
  • ICAM-1 and VCAM-1 immunoglobulin superfamily
  • integrins engage members of the immunoglobulin superfamily, ICAM-1 and VCAM-1 , on EC.
  • Inflammatory cells such as monocytes and polymorphonuclear cells (PMNs) are, partly through platelets, recruited to clear damaged tissue. This is followed by mesenchymal cell division, migration, matrix synthesis and eventual ventricular remodelling.
  • PMNs polymorphonuclear cells
  • u-PAR urokinase receptor
  • u-PAR has been recognized to also play a pivotal role in integrin activation and cell signalling in leukocyte-EC interactions in vitro. And indeed, in vivo it has been shown that disruption of the u-PAR gene markedly reduces integrin-mediated recruitment of PMNs to inflamed peritoneum ((May AE, Kanse SM, Lund LR, Gisler RH, Imhof BA, Preissner KT. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo J Exp Med. 1998 Sep 21 ; 188(6):1029-37).
  • Ischemia-reperfusion injury in the heart is a complex biological process with many factors involved but the present invention surprisingly shows that mice lacking a functional u-PAR gene (u-PAR "A mice) exhibit a significantly smaller infarction after 30 minutes ischemia and 3 or 24 hours reperfusion compared to wild type mice.
  • u-PAR "A mice mice lacking a functional u-PAR gene
  • the data show that reducing u-PAR-mediated integrin activation is a useful therapeutic target for the treatment of myocardial ischemia and/or infarction.
  • the present invention shows that the urokinase receptor is a target for the prevention and/or the treatment of ischemia-reperfusion injury.
  • At least one urokinase receptor inhibitor can be used for the preparation of a medicament to prevent and/or to treat ischemia-reperfusion injury.
  • a pharmaceutical composition comprising urokinase receptor inhibitors can be applied to prevent and/or to treat reperfusion injury.
  • Urokinase receptor inhibitors are described in the art and comprise cyclic peptidomimetics, alkoxyalkylidenecoumarones, peptide inhibitors, oligothiophenes, porphyrins, bis(carbamoylphenyl)methanes, oligonucleotides encoding peptide inhibitors of urokinase receptor activity, sulfonic acid sulfonylamino N-(heteroaralkyl)- azaheterocyclylamide compounds, 2-alkylidene hydroxycumaranone and these inhibitors are described in WO 2001005811 , EP 1026165, WO 2000001802, WO 9906393, EP 792647, WO 9846731 , WO 9806386, US 6030940, US 5679782, US 5656726, WO 9428014, WO 9735969, US 6281227 and US 6200989 which are described in WO
  • Ischemia-reperfusion injury refers to injury that occurs when the flow of blood to a region of the body is temporarily halted (ischemia) and then re-established (reperfusion). Ischemia-reperfusion injury can occur as a consequence of disease processes or surgical interventions associated with temporary interruption of blood flow. Such surgical procedures include adult and pediatric cardiac surgery procedures, peripheral vascular surgical procedures, neurosurgical procedures, i.e. brain arterial aneurysm resection and clipping, repair of certain aortic aneurysms and organ transplantation.
  • ischemia- reperfusion injury is manifested by such complications as for example pulmonary dysfunction, including adult respiratory distress syndrome, renal dysfunction, consumptive coagulopathies including thrombocytopenia, fibrin deposition into the microvasculature and disseminated intravascular coagulopathy.
  • pulmonary dysfunction including adult respiratory distress syndrome, renal dysfunction, consumptive coagulopathies including thrombocytopenia, fibrin deposition into the microvasculature and disseminated intravascular coagulopathy.
  • pulmonary dysfunction including adult respiratory distress syndrome, renal dysfunction, consumptive coagulopathies including thrombocytopenia, fibrin deposition into the microvasculature and disseminated intravascular coagulopathy.
  • pulmonary dysfunction including adult respiratory distress syndrome, renal dysfunction, consumptive coagulopathies including thrombocytopenia, fibrin deposition into the microvasculature and disseminated intravascular coagulopathy.
  • hepatic dysfunction including acute hepatocellular damage and necrosis
  • gastrointestinal dysfunction including hemorrh
  • Ischemia-reperfusion injury can also occur in the brain because of a stroke.
  • myocardial ischemia occurs when myocard blood flow is interrupted for a period of more than 2 minutes.
  • Reperfusion occurs when blood flow is restored leukocytes are recruited to the tissue and inflammatory mediators as well as oxygen radicals are generated at an increased rate in reperfused formerly ischemic myocardium.
  • the end result is myocardial cell death, the extent of which is dependent on the duration of the ischemic insult and on the intensity of the subsequent reperfusion injury.
  • the histological changes are characterized by cell swelling, calcium deposition, and contraction band formation.
  • at least one urokinase receptor inhibitor can be used for the preparation of a medicament to prevent and/or to treat ischemia-reperfusion injury that occurs in the heart and is caused by a myocard infarct.
  • At least one urokinase receptor inhibitor can be used for the preparation of a medicament to prevent and/or to treat ischemia-reperfusion injury that occurs in the brain and is caused by a stroke.
  • At least one urokinase receptor inhibitor can be used for the preparation of a medicament to prevent and/or to modulate ischemia-reperfusion injury that occurs during an organ transplant.
  • the term 'medicament to treat' relates to a composition comprising inhibitors as described above and a pharmaceutically acceptable carrier or excipient (both terms can be used interchangeably) to treat or to prevent diseases as described herein.
  • the administration of an inhibitor as described above or a pharmaceutically acceptable salt thereof may be by way of oral, inhaled or parenteral administration.
  • the active compound may be administered alone or preferably formulated as a pharmaceutical composition.
  • An amount effective to treat disorders described herein depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.01 to 50 mg for example 0.01 to 10 mg, or 0.05 to 2 mg of urokinase receptor antagonist or a pharmaceutically acceptable salt thereof.
  • Unit doses will normally be administered continuously or once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range of 0.0001 to 1 mg/kg; thus a suitable total daily dose for a 70 kg adult is 0.01 to 50 mg, for example 0.01 to 10 mg or more usually 0.05 to 10 mg. It is greatly preferred that the compound or a pharmaceutically acceptable salt thereof is administered in the form of a unit-dose composition, such as a unit dose oral, parenteral, or inhaled composition.
  • a unit-dose composition such as a unit dose oral, parenteral, or inhaled composition.
  • compositions are prepared by admixture and are suitably adapted for oral, inhaled or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories or aerosols.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • compositions for inhalation are presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns, for example between 1 and 5 microns, such as between 2 and 5 microns.
  • a favored inhaled dose will be in the range of 0.05 to 2 mg, for example 0.05 to 0.5 mg, 0.1 to 1 mg or 0.5 to 2 mg.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the active compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.
  • small amounts of bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • mice Twelve week old gender-matched mice (bw: 23 ⁇ 4 g) were barbiturate-anesthetized, intubated and ventilated with isoflurane in O 2 . Temperature and blood pressure were maintained constant. The left anterior descending coronary artery (LAD) was ligated over PE10 tubing for 30 minutes to induce myocardial ischemia with reperfusion (Ml/R). Reperfusion times were 3 or 24 hours. Mice were NaCI-perfused and after the ligation had been re-tied coomassie blue was injected via a carotid artery catheter to planimetrically detect the area at risk (AAR). Infarcted tissue was measured by lack of TTC staining.
  • AAR area at risk
  • PMN polymorphnuclear leukocytes
  • Murine peptides are not suitable for these studies because 1. integrin binding may be species-dependent, and 2. immune responses to the "foreign" peptides might confound the data.
  • canine and porcine u-PAR cDNAs are traditionally cloned - hybridization of commercial canine and porcine cDNA phagemid libraries with human and/or murine probes, followed by isolation of positive clones, confirmation by DNA sequencing, subcloning and expression for functional evaluation.
  • a model of Ml/R, in chronically instrumented, awake dogs has been established in our tea ⁇ -29. We will, for practical and ethical reasons, adapt this model to the pig. We monitor the corresponding polypeptides that are protective in mice are active in the larger animal models.

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Abstract

L'invention se rapporte à un procédé de traitement et/ou de modulation des blessures de reperfusion ischémique. Plus particulièrement, cette invention porte sur un nouveau rôle négatif du récepteur d'urokinase dans la pathogénèse de l'ischémie du myocarde. Par conséquent, l'utilisation d'inhibiteurs sélectifs de u-PAR sont utiles au traitement de patients souffrant de maladies coronariennes ischémiques.
PCT/EP2002/014478 2001-12-19 2002-12-18 Utilisation d'antagonistes de recepteurs d'urokinase afin de moduler les blessures de reperfusion ischemique Ceased WO2003051347A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002358158A AU2002358158A1 (en) 2001-12-19 2002-12-18 Use of urokinase receptor antagonists to modulate ischemiareperfusion injury

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01204998.7 2001-12-19
EP01204998 2001-12-19

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WO2003051347A1 true WO2003051347A1 (fr) 2003-06-26

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028014A2 (fr) * 1993-05-28 1994-12-08 Chiron Corporation Peptides inhibiteurs de l'activite des recepteurs d'urokinase
EP0792647A1 (fr) * 1996-02-27 1997-09-03 Roche Diagnostics GmbH Porphyrines comme antagonistes du récepteur de l'activateur du plasminogène du type urokinase
WO1997035969A2 (fr) * 1996-03-28 1997-10-02 Chiron Corporation Ligands peptidiques du recepteur de l'urokinase
WO1997041844A1 (fr) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Combinaisons de composes angiostatiques
DE19635352A1 (de) * 1996-08-12 1998-02-19 Boehringer Mannheim Gmbh Bisaryltetracarbonsäurederivate und diese enthaltende Arzneimittel
US5756492A (en) * 1996-09-09 1998-05-26 Sangstat Medical Corporation Graft survival prolongation with porphyrins
WO1999006393A1 (fr) * 1997-07-31 1999-02-11 Roche Diagnostics Gmbh Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant
US6030940A (en) * 1995-07-31 2000-02-29 Chiron Corporation Peptide analog inhibitors of urokinase receptor activity
US6200989B1 (en) * 1997-07-31 2001-03-13 Hoffmann-La Roche Inc. 2-alkylidene hydroxycumaranone derivatives

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028014A2 (fr) * 1993-05-28 1994-12-08 Chiron Corporation Peptides inhibiteurs de l'activite des recepteurs d'urokinase
US6030940A (en) * 1995-07-31 2000-02-29 Chiron Corporation Peptide analog inhibitors of urokinase receptor activity
EP0792647A1 (fr) * 1996-02-27 1997-09-03 Roche Diagnostics GmbH Porphyrines comme antagonistes du récepteur de l'activateur du plasminogène du type urokinase
WO1997035969A2 (fr) * 1996-03-28 1997-10-02 Chiron Corporation Ligands peptidiques du recepteur de l'urokinase
WO1997041844A1 (fr) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Combinaisons de composes angiostatiques
DE19635352A1 (de) * 1996-08-12 1998-02-19 Boehringer Mannheim Gmbh Bisaryltetracarbonsäurederivate und diese enthaltende Arzneimittel
US5756492A (en) * 1996-09-09 1998-05-26 Sangstat Medical Corporation Graft survival prolongation with porphyrins
WO1999006393A1 (fr) * 1997-07-31 1999-02-11 Roche Diagnostics Gmbh Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant
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