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WO1999006393A1 - Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant - Google Patents

Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1999006393A1
WO1999006393A1 PCT/EP1998/004705 EP9804705W WO9906393A1 WO 1999006393 A1 WO1999006393 A1 WO 1999006393A1 EP 9804705 W EP9804705 W EP 9804705W WO 9906393 A1 WO9906393 A1 WO 9906393A1
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WO
WIPO (PCT)
Prior art keywords
bisthien
thien
carbonyl
group
acetyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1998/004705
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English (en)
Inventor
Roberto Di Domenico
Gianpiero De Cillis
Bernhard König
Gerd Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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 Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Priority to AU88079/98A priority Critical patent/AU738104B2/en
Priority to EP98939643A priority patent/EP1000054A1/fr
Priority to BR9811577-4A priority patent/BR9811577A/pt
Priority to JP2000505151A priority patent/JP2001512116A/ja
Priority to CA002299045A priority patent/CA2299045A1/fr
Priority to KR1020007001086A priority patent/KR20010022500A/ko
Publication of WO1999006393A1 publication Critical patent/WO1999006393A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention concerns oligo-thiophenes, optionally linked to natural or synthetic aminoacids.
  • uPA urokinase-type plasminogen activator
  • ATF amino-terminai fragment
  • uPA is a multifunctional protein involved in tissue proteolysis, cellular migration, cellular proliferation and growth factor activation. uPA is released from cells as a virtually inactive pro-enzyme, pro-uPA.
  • the activation of the single-chain pro-uPA by plasmin (leading to the active two-chain form) is regulated by tight control mechanisms which are not completely understood yet.
  • Most of the uPA activities are confined to the cell surface and the pericellular environment. This is accomplished by binding to a specific, high- affinity receptor on the cell surface (uPAR). Both forms of uPA bind to uPAR with similar affinity. The binding interaction is mediated by the growth factor-like domain [S.A. Rabbani et al.. J. Biol. Chem., 267, 14151-56, 1992].
  • the uP A receptor is a three domain glycoprotein where each triplicated motif comprizes a cysteine rich consensus sequence of approximately 90 amino acids [M. Plough et al., J
  • uPAR is anchored to cell membrane by a glycosyi- phosphatidylinositol moiety (GPI anchor).
  • GPI anchor glycosyi- phosphatidylinositol moiety
  • uPAR binds uPA with K D values between 10 " 10 and 10 '9 M, depending on the experimental system.
  • the major determinants for uPA binding are located in the N-terminal domain 1.
  • uPAR can be cleaved by uPA and plasmin, liberating a water soluble domain 1 and by the action of phospholipase C, three domains uPAR (1+2+3) can be released from the cell surface. This latter form of uPAR is aiso water soluble because the GPI-anchor is missing.
  • the inhibition of uPA dependent phenomena can principally be approached in two ways, either by direct inhibition of the proteoiytic activity or by inhibition of uPA receptor binding.
  • the latter strategy has the potential of achieving greater specificity since inhibition might be localized to the pericellular environment.
  • the present invention concerns oligo-thiophenes with potent antagonistic activity.
  • Many bisthiophene and terthiophene derivatives seem to display interesting biological properties [Kagan, J. et al., J. Org. Chem., 48, 4317-20, 1983 and references cited therein]. Most notably they are toxic to nematodes and this effect can be greatly enhanced by the presence of ultraviolet light. The most carefully scrutinized of these compounds is ⁇ -terthienyl, a plant-derived natural product first recognized as phototoxin in the 1970s.
  • This compound showed photoenhanced activity against nematodes, microorganisms, algae, human erythrocytes, insect larvae and eggs, in addition to generating skin pigmentation, acting as herbicide and as a seed germination inhibitor. Photoactive antiviral and cytotoxic activities were also reported [(a) Cooper et al.,
  • uP A/uP AR system has been shown to be implicated in a variety of invasive biological processes such as tumor metastasis, trophoblast implantation, inflammation and angiogenesis. Therefore, uPAR antagonists should be able to block tumor invasiveness, metastasis and angiogenesis.
  • Formulations containing uPAR antagonists represent novel therapeutic treatments for a number of highly invasive and metastazising cancers where uPA and uPAR have been found to be consistently present at the invasive foci of the tumor [Dano et al., Proteolysis and Protein Turnover, eds. Barret + Bond, Portlan Press, 1994, London] (e.g. breast, lung, colon, ovarian cancers).
  • uPA and uPAR leveis in tumor tissue are prognostic factors in may types of cancers.
  • Inhibitors of plasmin generation by receptor bound uPA therefore have mechanism-based tumoristatic, anti-invasive, anti-metastatic, anti- angiogenic, anti-arthritic, anti-inflammatory, anti-osteoporotic, anti-retinopathic and contraceptive activities. These compounds are applied preferentially via the oral route, but also by i.v. or i.m. injections, nasal sprays or any other conventionally used application.
  • the present invention concerns oligo-thiophenes of the general formula (I):
  • B is a 2-thienyl or a phenyl group, which is substituted by an R group, or it is a natural or synthetic ammo acid, linked to the A group via its N-terminus
  • A-B is a -CH 2 CH -NH-A.A.-group, wherein the A. A.-group is a natural or synthetic amino acid residue, linked to the CH CH -NH-group via its carboxy-terminus;
  • R is hydrogen or a chlorine, bromine, iodine, fluorine, (C ⁇ -C4)alkyl, (d- C 4 )alkylene- COOR', (C,-C.)alkylene-NR' 2 or (C,- C 4 )alkylene-NHCOR' group; R' is hydrogen or a (C ⁇ -C 4 )alkyl group, isomers thereof, and salts thereof with pharmaceutically acceptable acids and bases.
  • a natural amino acid denotes one of the 20 ⁇ -amino acids which are the monomer units for polypeptides, for example Glycine, alanine, valine, leucine isoleucine, phenylalanine, tryptophan, proline, serine, threonine, tyrosine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, histidine, cysteine or methionine.
  • a synthetic amino acid consists of a compound comprising an amino group together with a carboxy group linked to the ⁇ -carbon atom.
  • Pharmaceutically acceptable salts of compounds of the present invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluensulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fiimarates and maieates. Salts may also be formed with bases, for example sodium, potassium, magnesium, and calcium salts.
  • Preferred compounds are those in which B is an amino acid or A-B is a group of formula
  • Particularly preferred compounds are those in which the aminoacid is triptophane.
  • Another object of the present invention is to provide a process for the preparation of the compounds of formula (I).
  • a further object of the present invention is the use of the compounds of formula (I) for the treatment of the diseases in which an inhibitor of the uPAR can be effective, in particular tumor and tumor metastasis or invaisveness, as well as pharmaceutical compositions containing a pharmacologically effective amount of one or more compounds of formula (I) in admixture with pharmaceutically suitable additives.
  • the transformation of the intermediate (II) into its acyl chloride is preferentially performed with thionyl chloride, which is used also as the solvent, at temperature between room temperature and the boiling temperature of the solvent.
  • the Friedel-Craft reaction is performed in an inert solvent and at a temperature ranging from -5°C and room temperature, using preferentially SnCU as the Lewis acid.
  • Suitable reaction conditions comprise the use of a base, preferentially an alkaline metal hydroxide, in water, an alcohol or mixtures thereof, at a temperature ranging from 0°C to room temperature.
  • the compounds of formula (I) in which A-B is a -CH 2 CH 2 -NH-A.A.-group can be prepared.
  • the -COCF 3 protecting group should be removed after the Friedel- Craft reaction and the intermediate so obtained should be condensed with a N-BOC- amino acid, previously activated through its carboxyi group.
  • the compounds of formula (I) are finally obtained after removal of the BOC protecting group.
  • the compounds of formula (I) in which B is a 2-thienyl or a phenyl group, which is substituted by an R group having the above meanings can be prepared by Friedel-Craft reaction of the intermediate of formula (II), activated in its carboxylic functionality as described above, with an intermediate of formula (VII):
  • A has the meanings shown above and B' is a 2-thienyl or a phenyl group, which is substituted by an R group as shown above.
  • the intermediates of formula (II) can be obtained by reaction of a bis-thiophene, substituted on one ring with the R substituents, with carbon dioxide and a strong base such as butyl lithium, at a temperature between -50°C and -20°C.
  • the starting products bis-thiophenes are commercially available or can be prepared according to procedures well known to one skilled in the art.
  • a suitable catalyst such as (PPh3) 3 RhCl.
  • the compounds of the invention were tested (ELISA test) as inhibitors of human urokinase (uPA) binding to its specific receptor uPAR mAk (BIO-R4), according to the procedure described in Biol. Chem. Hoppe-Seyler, 376, 587-94 (1995) by Rettenberger et al..
  • the assays are performed in Microtiterplates (96 wells). The following solutions are used: - washing buffer: PBS-buffer (without Mg 2+ and Ca 2+ ) + 0.05% Tween 20;
  • IP incubation buffer
  • the detection solution must be continously stirred.
  • testing substances are dissolved in DMSO. They are used in the test system with a highest concentration of 100 Tg ml. The solutions are prepared using
  • Table I BIO-R4 Assay - Inhibition of uPA binding to the specific uPAR receptor (BIO-R4) expressed as IC50 (mM)
  • the invention concerns pharmaceutical agents containing one or more compounds of formula (I).
  • the compounds of formula (I) are mixed in a known manner with suitable pharmaceutical carrier substances, aromatics, flavouring and dyes and are formed for example into tablets or coated tablets or they are suspended or dissolved in water or an oil such as e.g. olive oil with addition of appropriate auxiliary substances.
  • the substance of the general formula (I) can be administered orally or parenterally in a liquid or solid form.
  • Water is preferably used as the medium which contains the stabilizing agents, solubilizers and/or buffers which are usually used for injection solutions.
  • Such additives are for example tartrate or borate buffers, ethanol, dimethylsulfoxide, complexing agents (such as ethylendiaminotetraacetic acid), high moiucuiar polymers (such as liquid polyethylene oxide) for the regulation of the viscosity or polyethylene derivatives of sorbitol anhydrides.
  • Solid carrier substances are e.g. starch , lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular fatty acids (such as stearic acid), gelatin, agar- agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols).
  • Suitable formulations for the oral route can if desired contain flavourings and sweeteners.
  • the administered dose depends on the age, the health and the weight of the patient, the extent of the disease, the type of treatments which are possibly being carried out concurrently, the frequency of the treatment and the type of the desired effect.
  • the daily dose of the active compound is usually 0.1 to 50 mg/kg body weight. Normally 0.5 to 40 and preferably 1 to 20 mg/kg/day in one or several applications per day are effective in order to obtain the desired results.
  • the invention is further illustrated by the following examples.
  • a solution of bis-thiophene-2-carboxyiic acid (3 g; preparation 1) in 20 ml of thionyl chloride is heated at 50°C for 1 hour 30 minutes, then the unreacted thionyl chloride is evaporated off and the residue is treated three times with 10 ml of heptane and evaporated.
  • the residue is dissolved in methylene chloride and cooled at 0°C, then it is added drop wise with a solution of 2-(thien-2-yl)acetic acid, ethyl ester (2.19 g) in 5 ml of methylene chloride.
  • a solution of SnC (3 ml) in 10 ml of methylene chloride is subsequently added.
  • reaction mixture is kept at room temperature for 2 hours, then it is poured into 200 ml of 2 N hydrochloric acid.
  • aqueous phase is extracted with methylene chloride (3x150 ml) and the organic extracts are collected, dried over sodium sulfate and concentrated to dryness.
  • the residue (8 g) is purified by silica gel chromatography (eluent hexane ethyl acetate 8: 1) to give 3.62 of the product.
  • reaction mixture is kept under stirring at room temperature for 2 hours, then it is poured into 200 ml of 2 N hydrochloric acid and extracted with tetrahydrofuran (4 x 100 ml). The organic extracts are pooled, dried over sodium suifate and the solvent is evaporated under reduced pressure. 18 g of a black oil are obtained, which is purified by silica gel chromatography (eluant hexane/tetrahydrofuran 2 : 1). After recrystallization from hexane ( 100 mi) and drying under vacuum at 50°C, 4.3 g of the product are obtained, m.p. 168-170°C.
  • a suspension of 2.34 g of 2-[2-((2,2'-bisthien-5'-yl)carbonyl)thien-5-yl]acetic acid (preparation 5) and 1.74 g of carbonyldiimidazole in 150 ml of dry THF is kept at 40°C for 1 hour.
  • the mixture is cooled to 20°C and it is added dropwise with a solution of 2.45 g of triptophane ethyl ester in 10 ml of dry THF. After 2 hours the reaction mixture is concentrated to dryness, then it is dissolved in ethyl acetate, washed with water and extracted with 200 ml of chloroform.
  • Example 2 Synthesis of N-f2-r2-((2.2'-bisthien-5'-yl)carbonvi)thien-5- v ⁇ acetyl]triptophane
  • N-f2-r2-((2.2'-bisthien-5'-yl)carbonvi)thien-5- v ⁇ acetyl]triptophane A solution of 2.2 g of N-[2-[2-((2,2 , -bisthien-5'-yl)carbonyl)thien-5- yl]acetyl]triptophane, ethyl ester (example 1) in 320 ml of ethanol and 10 ml of water is cooled at 0°C, then it is added dropwise with 4.43 ml of 2 N sodium hydroxide.
  • reaction mixture is kept at room temperature for 1 hour, then it is poured into 100 ml of 2 N hydrochloric acid, extracted with ethyl acetate (3x100 ml), dried over sodium suifate and concentrated to dryness.
  • the residue (3 g) is purified by silica gel chromatography (eluent hexane ethyl acetate
  • reaction mixture is kept at room temperature for 4 hour, then further 0.3 ml of SnCU are added and the mixture is kept at room temperature overnight.
  • the reaction mixture is poured into 200 mi of 2 N hydrochloric acid, extracted with ethyl acetate (3x50 mi), dried over sodium suifate and concentrated to dryness.
  • the residue (1.3 g) is purified by silica gel chromatography (eluent hexane/ethyl acetate 5: 1, then pure ethyl acetate) to give 0.37 g of the product.
  • Example 5 Synthesis of 2- -.2-(.2.2'-bisthien-5'-yl)carbonyl.thien-5-yl]propanoyl]-4- fluorobenzene 1.06 g of bis-thiophene-2-carboxyiic acid (preparation 1) in 10 ml of thionyl chloride are heated at 50°C for 1 hour 30 minutes, then the mixture is concentrated to dryness.
  • the residue is purified by silica gel chromatography (eluant methylene chloride), to give, after crystallization from ethyl acetate/hexane mixture, 1 g of the product, m.p. 138-140°C.
  • Example 8 4-r2-r2-((2.2 , -bisthien-5'-yl .carbonyl .thien-5-yllethylam ⁇ nocarbonvn-2- aminobutanoic acid
  • the resulting dark solution is kept under stirring at room temperature overnight, then it is concentrated to dryness.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne les oligo-thiophènes représentés par la formule générale (I), dans laquelle A est un groupe -CH2-CO, -CH2CH2-CO- ou -CH=CH-CO-; B est un groupe 2-thiényle ou phényle, substitué par un groupe R, ou B est un acide aminé naturel ou synthétique, lié au groupe A via son extrémité N; ou A-B sont un groupe -CH2CH2-NH-A.A., le groupe A.A. étant un résidu acide aminé naturel ou synthétique lié au groupe CH2CH2-NH- via son extrémité carboxy; R est l'hydrogène ou un groupe chlorure, bromure, iodure, fluorure, alkyle C1-C4, alkylène C1-C4-COOR', alkylène C1-C4-NH2, alkylène C1-C4-NR'2 ou alkylène C1-C4-NHCOR', R' est l'hydrogène ou un groupe alkyle C1-C4. L'invention concerne également des isomères et des sels de ces derniers comprenant des acides et des bases pharmaceutiquement acceptables. L'invention concerne en outre l'utilisation des composés représentés par la formule (I) en tant qu'inhibiteurs de la liaison de uPA au récepteur uPAR spécifique, en particulier leur application en tant qu'agents antitumoraux et antimétastatiques.
PCT/EP1998/004705 1997-07-31 1998-07-28 Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant Ceased WO1999006393A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU88079/98A AU738104B2 (en) 1997-07-31 1998-07-28 Oligo-thiophenes useful as antimetastatic agents, a preparation thereof and pharmaceutical compositions containing them
EP98939643A EP1000054A1 (fr) 1997-07-31 1998-07-28 Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant
BR9811577-4A BR9811577A (pt) 1997-07-31 1998-07-28 Oligo-tiofenos úteis como agentes antimetastáticos, uma preparação dos mesmos e composições farmacêuticas que os contêm
JP2000505151A JP2001512116A (ja) 1997-07-31 1998-07-28 抗転移剤として有用なオリゴ−チオフェン類、その調製及びそれを含む医薬組成物
CA002299045A CA2299045A1 (fr) 1997-07-31 1998-07-28 Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant
KR1020007001086A KR20010022500A (ko) 1997-07-31 1998-07-28 항전이제로서 유용한 올리고-티오펜류, 그의 제조 및 그를함유하는 제약 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97113191.7 1997-07-31
EP97113191 1997-07-31

Publications (1)

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WO1999006393A1 true WO1999006393A1 (fr) 1999-02-11

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PCT/EP1998/004705 Ceased WO1999006393A1 (fr) 1997-07-31 1998-07-28 Oligo-thiophenes utiles comme agents antimetastatiques, preparation de ces oligo-thiophenes et compositions pharmaceutiques les contenant

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EP (1) EP1000054A1 (fr)
JP (1) JP2001512116A (fr)
KR (1) KR20010022500A (fr)
CN (1) CN1269797A (fr)
AR (1) AR020308A1 (fr)
AU (1) AU738104B2 (fr)
BR (1) BR9811577A (fr)
CA (1) CA2299045A1 (fr)
CO (1) CO4970718A1 (fr)
HR (1) HRP980420A2 (fr)
MA (1) MA26527A1 (fr)
TR (1) TR200000266T2 (fr)
WO (1) WO1999006393A1 (fr)
ZA (1) ZA986800B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015206A3 (fr) * 1998-09-16 2000-08-10 Max Planck Gesellschaft Esters de tryptophanyle et leurs derives n-acyle destines a la prevention et au traitement de maladies dues au procede d'oxydation ou amplifiees par ce dernier
WO2003051347A1 (fr) * 2001-12-19 2003-06-26 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Utilisation d'antagonistes de recepteurs d'urokinase afin de moduler les blessures de reperfusion ischemique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032190A2 (fr) * 1994-05-24 1995-11-30 Xenova Limited Composes pharmaceutiques de dicetopiperazine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032190A2 (fr) * 1994-05-24 1995-11-30 Xenova Limited Composes pharmaceutiques de dicetopiperazine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
E. LESCOT ET AL.: "Thiophen Derivatives. Part XIV. Some Problems of Substitution in the 2,2'-Bithienyl Series", JOURNAL OF THE CHEMICAL SOCIETY, 1959, LONDON, pages 3234 - 3237, XP002051010 *
J. KAGAN ET AL.: "Synthesis of alpha-Thiophene Oligomers via 1,3-Butadiyne", JOURNAL OF ORGANIC CHEMISTRY, vol. 48, 1983, EASTON US, pages 4317 - 4320, XP002051011 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015206A3 (fr) * 1998-09-16 2000-08-10 Max Planck Gesellschaft Esters de tryptophanyle et leurs derives n-acyle destines a la prevention et au traitement de maladies dues au procede d'oxydation ou amplifiees par ce dernier
WO2003051347A1 (fr) * 2001-12-19 2003-06-26 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Utilisation d'antagonistes de recepteurs d'urokinase afin de moduler les blessures de reperfusion ischemique

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Publication number Publication date
CO4970718A1 (es) 2000-11-07
JP2001512116A (ja) 2001-08-21
AR020308A1 (es) 2002-05-08
ZA986800B (en) 2000-01-31
MA26527A1 (fr) 2004-12-20
AU8807998A (en) 1999-02-22
KR20010022500A (ko) 2001-03-15
TR200000266T2 (tr) 2000-09-21
CA2299045A1 (fr) 1999-02-11
EP1000054A1 (fr) 2000-05-17
AU738104B2 (en) 2001-09-06
CN1269797A (zh) 2000-10-11
HRP980420A2 (en) 1999-04-30
BR9811577A (pt) 2000-08-29

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