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WO1992013552A1 - Peptides inhibant l'aggregation et contenant un amide ou un ester aromatique - Google Patents

Peptides inhibant l'aggregation et contenant un amide ou un ester aromatique Download PDF

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Publication number
WO1992013552A1
WO1992013552A1 PCT/US1992/000999 US9200999W WO9213552A1 WO 1992013552 A1 WO1992013552 A1 WO 1992013552A1 US 9200999 W US9200999 W US 9200999W WO 9213552 A1 WO9213552 A1 WO 9213552A1
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WIPO (PCT)
Prior art keywords
asp
gly
phenylamide
mmol
nhr
Prior art date
Application number
PCT/US1992/000999
Other languages
English (en)
Inventor
Fadia El-Fehail Ali
William Edward Bondinell
Thomas Wen-Fu Ku
James Martin Samanen
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP4506448A priority Critical patent/JPH06505978A/ja
Publication of WO1992013552A1 publication Critical patent/WO1992013552A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • a thrombus is the result of processes which initiate the coagulation cascade. It is composed of an aggregation of platelets enmeshed in a polymeric network of fibrin. This process is normally initiated as a consequence of tissue injury and has the effect of slowing or preventing blood flow in a vessel. Etiological factors which are not Girectly related to tissue injury, such as atherosclerotic plaque, inflammation of the blood vessels (phlebitis) and septicemia, may also initiate thrombus formation. In some instances, the inappropriate formation of a thrombus, and subsequent decrease in blood flow, may have pathological consequences, such as stroke, pulmonary embolism and heart disease.
  • EP 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation.
  • the cyclic peptides reported are formed via a disulfide bridge between two cysteinyl residues.
  • Other linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in EP-A 0 341 915.
  • One compound disclosed therein is Ac-Arg-Gly-Asp-NHCH 2 CH 2 Ph.
  • the instant invention provides compounds in which the carboxy terminus of the peptide is substituted with an aryl alcohol or aryl amine to form an aryl ester or amide.
  • the compounds of this invention inhibit the binding of GP-IIbllla to fibrinogen and are surprisingly potent.
  • A is absent, Asn, Gin, Ala, Pro or Abu;
  • Ar-C 1-4 alkyl Het, Het-C 1-4 alkyl, Ar-(CH 2 ) p CH(Ar) (CH 2 ) P or Ar-C 3-7 cycloalkyl;
  • Ar is phenyl or phenyl substituted by one to three C 1-6 alkyl, trifluoromethyl, halogen, R'O or R'S; and is a five or six-membered, mono or bicyclic ring containing one or two nitrogen atoms;
  • This invention discloses acyclic peptide-like compounds comprising the sequence Gly-Asp and having an aryl ester or amide moiety attached directly to the carboxy group of Asp.
  • the compounds of this invention inhibit platelet aggregation and are believed to interact with the GPIIb-IIIa receptor and other adhesion proteins.
  • the attachment of an aryl group to the Asp residue confers increased activity for inhibition of platelet aggregation.
  • D is the preferred value of m is
  • W is -NHR', m is preferably 0-3 for para, 2-4 for meta, and 3-5 for an ortho orientation.
  • a para orientation is generally
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the- t-butyloxycarbonyl radical
  • Fmoc refers to the
  • Coupling reagents as used herein denote reagents which may be used to form peptide bonds.
  • Typical coupling reagents are carbodiimides, activated anhydrides and esters and acyl halides.
  • Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.
  • ⁇ -R' substituted derivatives of the amino acids of this invention which may be denoted as ( ⁇ -R')AA, indicate amino acids which are mono-substituted on the ⁇ -amino group by R', wherein R* is C 1-6 alkyl or Ar(CH 2 )n.
  • R' is methyl or benzyl.
  • R' is preferably methyl.
  • a combination of solid phase and solution synthesis may be used, as in a convergent synthesis in which di-, tri-, tetra-, or penta-peptide fragments may be prepared by solid phase synthesis and either coupled or further modified by solution synthesis.
  • Solution phase synthesis is generally preferred for the smaller peptides of this invention.
  • the reactive functional groups of the sidechains of each synthetic fragment, amino acid or peptide are suitably protected as known in the peptide art.
  • the Boc, Cbz or Fmoc group may be used for protection of an amino group, especially an ⁇ -amino group.
  • the Boc group is generally preferred for protection of the ⁇ -amino group.
  • a t-Bu, cHex or benzyl ester may be used for the protection of the side chain carboxyl of Asp or Glu.
  • a benzyl group or suitably substituted benzyl group is used to protect the mercapto group of cysteine, or other thiol containing residues; or the hydroxyl of serine or threonine.
  • the tosyl group may be used for protection of the imidazolyl group of His, and tosyl or nitro group for protection of the guanidino nitrogen of Arg.
  • a suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ⁇ -amino group of lysine.
  • the phthaloyl group may also be used for the protection of the ⁇ -amino group of lysine. Suitable substitution of the
  • Solid phase methods for instance when Y bears a carboxyl group which may be attached to a resin, the peptide, or a convenient fragment thereof, is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide.
  • Solid phase synthesis is begun by covalently attaching the carboxyl group of the appropriately protected Y residue, such as Boc-NH-Y, to a suitable resin, such as a benzhydrylamine resin (BHA), methylbenzhydrylamine resin (MBHA), chloromethyl resin (CMR), hydroxymethyl resin (HMR) or SASRIN resin, as is generally set forth in U.S. Patent No. 4,244,946 and Gisin, Helv. Chem.
  • a BHA or MBHA support resin is used if the carboxy terminus of the product peptide is to be a carboxamide.
  • a CMR or HMR support is generally used if the carboxy terminus of the product peptide is to be a carboxyl group, although this may also be used to produce a
  • the completed peptide may then be deblocked and/or split from the carrying resin in any order.
  • the peptide may be attached to a CMR or HMR via the ⁇ -carboxyl group of Asp.
  • the synthesis is begun by coupling the aryl amine or aryloxy group, via solution phase synthesis, to an appropriately sidechain-protected aspartic acid residue.
  • the side chain carboxyl group is then selectively deprotected and coupled to a chloromethyl resin (CMR).
  • CMR chloromethyl resin
  • a benzyl ester is a suitable sidechain protecting group which is selectively deprotected by hydrogenation.
  • the amino group is
  • Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants, thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in wliich one or more amino acids have been added, deleted or substituted or in which one or more or functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator with the fibrin binding domain of another plasminogen activator or fibrin binding molecule.
  • a variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use.
  • the fibrinolytic and the peptide may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
  • both agents When both agents are provided in solution form, they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
  • the platelet aggregation inhibitor may be in an i.v. injectable form, or infusion bag linked in series, via tubing, to the fibrinolytic agent in a second infusion bag.
  • a patient can receive an initial bolus-type injection or infusion, of the peptide inhibitor followed by an infusion of the fibrinolytic agent.
  • Boc-Gly-Asp(O-cHex)-(2-methylthio)phenylamide (21) (770 mg) was treated with 50% TFA solution in methylene chloride (5 mL) for 60 min at room temperature. The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA. The residue was triturated with ether to yield the TFA salt of the title compound (609.5 mg).
  • Boc-N ⁇ MeArg(Tos)-Gly-Asp(O-cHex)-(2-methylthio)-phenylamide (23) (920 mg) was treated with 50% TFA solution in methylene chloride (5 mL) for 60 min at room temperature The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA, and triturated with ether to yield the TFA salt of the title compound (635.5 mg).
  • the mixture was degassed and filtered through a pad of
  • Boc-Gly-Asp(O-cHex)-phenylamide (496 mg, 1.11 mmol) was dissolved in 5 mL 4N HCl/dioxane and stirred at room temperature
  • Example 1Kb The protected peptide of Example 1Kb (200 mg, 254 nmol) was treated with 5 mL anhydrous HF at 0° for 1 h. The HF was removed in vacuo and the residue was dissolved in glacial acetic acid and lyophilized to yield the crude peptide salt (135 mg, 87%). 100 mg was filtered and purified by gel filtration (Sephadex ® G-10, 10% acetic acid). The appropriate fractions were pooled and lyophilized to yield the title compound (25 mg).
  • Boc-Asp(O-cHex)-(4-chloro)phenylamide (1.44 g, 3.4 mmol) was treated with 50% TFA solution in methylene chloride (10 mL) for 45 min at room temperature. The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA. The product was
  • Boc-Asp (O-cHex) 0.883 g, 2.8 mmol
  • THF 10 mL
  • N-methylmorpholine 0.34 mL, 3.1 mmol
  • isobutylchloroformate 0.40 mL, 3.1 mmol
  • Boc-Asp(O-cHex)-(4-benzyloxycarbonyl)phenylamide (1.1 g, 2.1 mmol) was treated with 50% TFA/methylene chloride (20 mL) for 90 min at room temperature. The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA. The product was
  • Boc-Arg(Tos)-Gly-Asp(O-Bzl)-phenylamide (220 mg, 0.287 mmol) was treated with 50% TFA/methylene chloride (10 mL) at room temperature for 4 H. The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA. The residue was treated with HCl-dioxane and evaporated several times from toulene and dried under vacuum to yield the titled compound as its hydrochloride salt.
  • Boc-Asp(O-Bzl)-(N-methyl)phenylamide (0.91 g, 2.2 mmol) at 0°C was added a solution of trifluoroacetic acid (8 mL) in CH 2 CI 2 (8 mL). After stirring at 0°C for 45 min, the mixture was concentrated under reduced pressure and treated azeotropically with toluene several times. To the residue was added a solution of 20% phosgene in toluene (42 mL). The resulting mixture was heated at reflux for 15 min, then allowed to cool to room temperature and concentrated under reduced pressure. The residue was treated azeotropically with toluene, and used without further purification. e) Boc-Arg(NO 2 )-NHNHCO-Asp(O-Bzl)-(N-methyl)phenylamide
  • Example 25(f) To a solution of the compound of Example 25(f) (150 mg, 0.22 mmol) in MeOH (30 mL) was added glacial acetic acid (0.3 mL) and 10% palladium on activated carbon (19 mg). The resulting mixture was hydrogenated at 46 psi H 2 for 3 h, at which time thin layer chromatographic analysis indicated only the presence of starting material. The mixture was degassed and additional 10% palladium on activated carbon (90 mg) was added. The reaction mixture was hydrogenated (46 psi) overnight at which time thin layer chromatographic analysis again indicated only the presence of starting material. The mixture was filtered through a pad of Celite ® and
  • Boc-D-Arg(Tos)-(N-methyl)phenylamide (2.3 g,4.4 mmol) was treated with 50% TFA in methylene chloride (20 mL) at room temperature for 1 h. The solvent was removed and the residue was evaporated several times from methylene chloride to eliminate traces of TFA. The residue was triturated with ether and used in the next step without further purification.
  • Triethylamine (1.3 mL, 9.3 mmol) was added to a cold solution of D-Arg(Tos)-(N-methyl)phenylamide in methylene chloride (5 mL). This was followed by the addition of methyl malonylchloride (500 ⁇ L, 4.7 mmol). The reaction mixture was allowed to warm to room temperature and stirring was
  • Example 29 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
  • D5W dextrose in water
  • a capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 3 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
  • Example 30 Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 3 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet.

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Abstract

L'invention se rapporte à des composés de la formule D-E-Asp-Q-Y où Q représente NH, NCH3 ou O; Y représente phényle, naphtyle, ou Het, non substitué ou substitué par un à trois alkyle C1-6, trifluorméthyle, halogène, OR', SR', (CH2)nAr, CONR1R2, CO2R2, CO2R2 or R4R4N; D représente (A) ou (B); W représente NHR', NR'C(=NH)NHR', NR'C(=NH)R' ou (C=NH)NHR'; U représente CO, SO2, NHCO, (CH2)n, SO2NH, NHSO2 or OC(=O); V représente H, R', R4R5N, R4R5NCO, R'O, Y-NR', X-A-B-NR' ou (C); A est absent ou représente Asn, Gln, Ala, Pro or Abu; B représente un acide aminé D- ou L- chosi à partir de Arg, HArg, NArg, (Me2)Arg, (Et2)Arg, Abu, Ala, Gly, His, Orn, Lys, Phg ou un dérivé substitué par α-R', Dtc, Tpr ou Pro; E représnte Gly, Sar, CH2CO ou NHCO; R' représente H, alkyle C1-6 ou Ar(CH2)p; X représente R4R4N, R4R5N-CO ou H; R1 et R2 représentent H, alkyle C1-6 ou(CH2)pAr; R4 représente H ou alkyle C1-6; R5 représente R6, R6CO, R6OCO, R6OCH(R6')CO, R6NHCH(R6')CO, R6SCH(R6')CO, R6SO2 ou R6SO; R6 et R6' représentent H, alkyle C1-6, cycloalkyle C3-7, Ar, Ar-alkyle C1-4, Het, Het-alkyle C1-4, Ar-(CH2)pCH(Ar)(CH2p ou Ar-cycloalkyle C3-7; Ar représente phényle ou phényle substitué par un à trois alkyle C1-6, trifluorométhyle, halogène, R'O ou R'S; et (C) représente un noyau mono ou bicyclique à cinq ou six éléments, contenant un ou deux atomes d'azote; m vaut (1) 0-4 lorsque W représente N'-(C=NH)NHR', (2) 0-5 lorsque W représente (C=NH)NHR' ou NR'(C=NH)R'; ou (3) 0-6 lorsque W représente NHR'; n vaut 0-2; p vaut 0-3; q vaut (1) 1-4 lorsque W représente NR'-(C=NH)NHR'; (2) 2-5 lorsque W représente (C=NH)NHR' ou NR'(C=NH)R'; ou (3) 3-6 lorsque W représente NHR'. L'invention se rapporte aussi à un sel pharmaceutiquement acceptable de ces composés, lesquels inhibent efficacement l'agrégation plaquettaire, ainsi qu'à des compositions pharmaceutiques favorisant une telle activité et à un procédé servant à inhiber l'agrégation plaquettaire.
PCT/US1992/000999 1991-02-05 1992-02-05 Peptides inhibant l'aggregation et contenant un amide ou un ester aromatique WO1992013552A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4506448A JPH06505978A (ja) 1991-02-05 1992-02-05 芳香族エステルまたはアミドを含有する抗凝集性ペプチド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65052791A 1991-02-05 1991-02-05
US650,527 1991-02-05

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WO1992013552A1 true WO1992013552A1 (fr) 1992-08-20

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Cited By (23)

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WO1993024448A1 (fr) 1992-06-03 1993-12-09 Fuji Photo Film Co., Ltd. Derive d'acides amines et son utilisation
FR2693107A1 (fr) * 1992-07-01 1994-01-07 Chauvin Laboratoire Moyens pour la prévention de la cataracte secondaire.
EP0584066A1 (fr) * 1991-04-11 1994-03-02 Rhone-Poulenc Rorer International (Holdings) Inc. Derives peptidiques et pseudopeptidiques antithrombotiques
WO1994022907A1 (fr) * 1993-03-26 1994-10-13 Hoechst Aktiengesellschaft Nouveaux derives d'uree, leur preparation et leur utilisation
EP0677043A1 (fr) * 1992-12-29 1995-10-18 Smithkline Beecham Corporation Composes inhibant l'aggregation des plaquettes
US5494922A (en) * 1993-06-28 1996-02-27 Zeneca Limited Allophanic acid derivatives
US5556977A (en) * 1993-03-29 1996-09-17 Zeneca Limited Heterocyclic derivatives
US5563141A (en) * 1993-03-29 1996-10-08 Zeneca Limited Heterocyclic compounds
US5576334A (en) * 1993-06-28 1996-11-19 Zeneca Limited Acylurea derivatives
US5602155A (en) * 1995-01-17 1997-02-11 G. D. Searle & Co. Platelet aggregation inhibitors
US5612373A (en) * 1993-06-28 1997-03-18 Zeneca Limited Certain diacyl hydrazine derivatives
US5639765A (en) * 1995-01-17 1997-06-17 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss
US5652242A (en) * 1993-03-29 1997-07-29 Zeneca Limited Heterocyclic derivatives
US5672585A (en) * 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
US5750754A (en) * 1993-03-29 1998-05-12 Zeneca Limited Heterocyclic compounds
US5753659A (en) * 1993-03-29 1998-05-19 Zeneca Limited Heterocyclic compouds
US5763408A (en) * 1992-06-03 1998-06-09 Fuji Photo Film Co., Ltd. Amino acid derivatives and application thereof
US5780303A (en) * 1990-04-06 1998-07-14 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US6017877A (en) * 1990-04-06 2000-01-25 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US6326403B1 (en) * 1998-07-15 2001-12-04 Merck Patent Gesellschaft Mit Diacylhydrazine derivatives as integrin inhibitors
WO2002066421A1 (fr) 2001-02-21 2002-08-29 Provincia Italiana Della Congregazione Dei Figli Dell'immacolata Concezione - Istituto Dermopatico Dell'immacolata Molecules non peptidiques analogue rgd possedant des effets anti-adhesion, anti-migration et anti-proliferation.
US6521594B1 (en) 1990-04-06 2003-02-18 La Jolla Cancer Research Foundation Method and composition for treating thrombosis

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EP1162194A1 (fr) * 2000-06-06 2001-12-12 Aventis Pharma Deutschland GmbH Dérivés de (thio)-urée inhibiteurs du facteur VIIa, procédé de leur préparation et leur utilisation

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EP0341915A2 (fr) * 1988-05-09 1989-11-15 Smithkline Beecham Corporation Peptides antiagrégatifs

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WO1989000515A1 (fr) * 1987-07-22 1989-01-26 Zahnradfabrik Friedrichshafen Ag Selecteur de vitesses servocommande
EP0341915A2 (fr) * 1988-05-09 1989-11-15 Smithkline Beecham Corporation Peptides antiagrégatifs

Non-Patent Citations (1)

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Title
See also references of EP0570507A4 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6521594B1 (en) 1990-04-06 2003-02-18 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5780303A (en) * 1990-04-06 1998-07-14 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US6017877A (en) * 1990-04-06 2000-01-25 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5672585A (en) * 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
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EP0570507A1 (fr) 1993-11-24
EP0570507A4 (en) 1994-09-21

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