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WO1999004796A1 - Antagonistes du recepteur de fibrinogene - Google Patents

Antagonistes du recepteur de fibrinogene Download PDF

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Publication number
WO1999004796A1
WO1999004796A1 PCT/US1998/015288 US9815288W WO9904796A1 WO 1999004796 A1 WO1999004796 A1 WO 1999004796A1 US 9815288 W US9815288 W US 9815288W WO 9904796 A1 WO9904796 A1 WO 9904796A1
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WO
WIPO (PCT)
Prior art keywords
compound
acid
pharmaceutically acceptable
carbonylpiperadino
phenylamino
Prior art date
Application number
PCT/US1998/015288
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English (en)
Inventor
Dirk Heerding
James M. Samanen
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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 JP51008299A priority Critical patent/JP2002509547A/ja
Priority to AU85103/98A priority patent/AU8510398A/en
Priority to CA002297909A priority patent/CA2297909A1/fr
Priority to EP98935967A priority patent/EP1001777A4/fr
Publication of WO1999004796A1 publication Critical patent/WO1999004796A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • 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

Definitions

  • This invention relates to novel compounds which inhibit platelet aggregation, pharmaceutical compositions containing these compounds and methods of using the compounds.
  • GPIIb-IIIa platelet receptor complex which is a member of a family of adhesion receptors referred to as integrins. It has been found that frequently the natural ligands of integrin receptors are proteins which contain an Arg-Gly-Asp sequence. Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GPIIb-IIIa receptor, possess an Arg-Gly-Asp (RGD in single letter amino acid code) sequence in their primary structure.
  • these proteins are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets.
  • Fibronectin, vitronectin and thrombospondin are RGD-containing proteins which have also been demonstrated to bind to GPIIb-IIIa.
  • Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
  • Linear and cyclic peptides which bind to vitronectin and contain an RGD sequence are disclosed in WO 89/05150 (PCT US88/04403).
  • 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.
  • Other linear and cyclic peptides are reported in EP-A 0 341 915.
  • the peptide like structures of such inhibitors often pose problems, such as in drug delivery, metabolic stability and selectivity.
  • Inhibitors of the fibrinogen receptor which are not constructed of natural amino acid sequences are disclosed in EP-A 0 372,486, EP-A 0 381 033 and EP-A 0 478 363.
  • WO 92/07568 discloses fibrinogen receptor antagonists which mimic a conformational ⁇ -turn in the RGD sequence by forming a monocyclic seven-membered ring structure.
  • novel fibrinogen receptor antagonists e.g., inhibitors of the GPIIb-IIIa protein
  • the present invention discloses novel compounds. These compounds inhibit the GPIIb-IIIa receptor and inhibit platelet aggregation.
  • this invention is a compound as described hereinafter in formula (I).
  • This invention is also a pharmaceutical composition for inhibiting platelet aggregation or clot formation, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
  • This invention is further a method for inhibiting platelet aggregation in a mammal in need thereof, which comprises internally administering an effective amount of a compound of formula (I).
  • this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I).
  • This invention is also a method for treating stroke, transient ischemia attacks, or myocardial infarction.
  • This invention discloses a compound which inhibits platelet aggregation.
  • the compound of the instant invention is believed to interact favorably with the GPIIb-IIIa receptor.
  • this compound is believed to inhibit the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa, and may interact with other adhesion proteins via antagonism of a putative RGD binding site.
  • the compound of this invention is a compound of formula (I):
  • This compound is 4-[(4-(l- piperizinyl)phenyl)aminocarbonyl]-l-piperidine-l-phenylacetic acid or a pharmaceutically acceptable salt thereof.
  • prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • prodrugs are, for example, compounds of formula (II):
  • this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
  • the meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • the preferred compound of this invention is 4-[(4-(l-piperizinyl)- phenyl)aminocarbonyl]-l-piperidine-l-phenylacetic acid or a pharmaceutically acceptable salt thereof.
  • This invention also includes the following compounds which are useful in the methods of the instant invention:
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Ph refers to the phenyl radical
  • Bzl refers to the benzyl radical
  • Me refers to methyl
  • Et refers to ethyl
  • Ac refers to acetyl
  • Alk refers to C ⁇ _6alkyl
  • Nph refers to 1- or 2-naphthyl
  • cHex refers to cyclohexyl.
  • DMAP refers to dimethylaminopyridine
  • DIEA refers to diisopropylethyl amine
  • EDC refers to N- ethyl-N'(dimethylaminopropyl)-carbodiimide
  • HOBt refers to 1-hydroxybenzotriazole
  • THF refers to tetrahydrofuran
  • DMF refers to dimethyl formamide
  • Pd/C refers to a palladium on carbon catalyst
  • TEA refers to triethylamine
  • TFA refers to trifluoroacetic acid.
  • the compounds of formula (I) are generally prepared by reacting a compound of the formula (III) with a compound of the formula (IV):
  • R' is an amine protecting group
  • R" is a C ⁇ alkyl group and X is OH or chloro; and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
  • a suitably protected amine, such as 1-1 is reacted with a commercially available suitable bromoester, such as 1-2, in a polar aprotic solvent, such as THF, to give the substitution product.
  • a polar aprotic solvent such as THF
  • additional base such as triethyl amine
  • the reaction may heated to reflux to increase the rate of reaction.
  • the benzyl ester is removed by standard methods, such as hydrogenation over palladium, to give the corresponding carboxylic acid 1-3.
  • a suitable protecting group such as t-butoxycarbonyl
  • THF a suitable solvent
  • Many other protecting group schemes can be devised for this compound and can be found in such volumes as Greene, "Protective Groups in Organic Synthesis” (published by Wiley-Interscience).
  • the nitro group is then reduced by standard methods, such as hydrogenation over palladium catalyst, to give the corresponding amine 1-5.
  • the carboxylic acid 1-3 is activated in situ by standard methods, such as EDC, and reacted with amine 1-5 in a suitable solvent, such as pyridine, to give the resulting amide 1-6.
  • a suitable solvent such as pyridine
  • Saponification of the methyl ester is carried out using a base, such as NaOH, in a suitable polar solvent, such as EtOH,to give the corresponding carboxylic acid.
  • a suitable polar solvent such as EtOH
  • Removal of the t- butoxycarbonyl group from nitrogen is accomplished by strong acid, such as trifluoroacetic acid, in a suitable solvent, such as CH 2 C1 , to give the final compound 1-7.
  • the compounds of the instant invention are prepared as described in Scheme I or by processes analogous to those described described in Scheme I. Furthermore, the compounds of the instant invention are prepared as described in Examples 1-8 hereinafter. Acid addition salts of the compound of this invention are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li+ , Na+, K+ , Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
  • This invention provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier. Accordingly, the compound of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compound of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the compound of this invention may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compound of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the compound of this invention may be used in vitro to inhibit the aggregation of platelets in blood and blood products, e.g., for storage, or for ex vivo manipulations such as in diagnostic or research use.
  • This invention also provides a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, which comprises the internal administration of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Indications for such therapy include acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, dissecting anurysm, transient ischemia attack (TIA), stroke and other infarct-related disorders, and unstable angina.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • post-operative and post- partum trauma cardiopulmonary bypass surgery
  • incompatible blood transfusion abruptio placenta
  • thrombotic thrombocytopenic purpura TTP
  • snake venom immune diseases
  • the compound of this invention may be useful in a method for the prevention of metastatic conditions, the prevention or treatment of fungal or bacterial infection, inducing immunostimulation, treatment of sickle cell disease, and the prevention or treatment of diseases in which bone resorption is a factor.
  • the compound of formula (I) is administered either orally or parenterally to the patient, in a manner such that the concentration of drug in the plasma is sufficient to inhibit platelet aggregation, or other such indication.
  • the pharmaceutical composition containing the compound is administered at a dose between about 0.2 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • parenteral administration is preferred.
  • an intravenous infusion of the peptide in 5% dextrose in water or normal saline is most effective, although an intramuscular bolus injection may be sufficient.
  • oral administration of a capsule or tablet, or a bolus intramuscular injection is suitable.
  • the compound of this invention is administered one to four times daily at a level of about 0.4 to about 50 mg/kg to achieve a total daily dose of about 0.4 to about 200 mg/kg/day.
  • This invention further provides a method for inhibiting the reocclusion of an artery or vein following fibrinolytic therapy, which comprises internal administration of a compound of formula (I) and a fibrinolytic agent. It has been found that administration of an peptide in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion.
  • fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
  • Plasminogen activators are a well known group of fibrinolytic agents.
  • 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 which 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.
  • Other illustrative variants include tPA molecules in which one or more glycosylation sites have been altered.
  • plasminogen activators are variants of tPA in which the primary amino acid sequence has been altered in the growth factor domain so as to increase the serum half-life of the plasminogen activator.
  • tPA Growth factor variants are disclosed, e.g., by Robinson et al., EP-A 0 297 589 and Browne et al., EP-A 0 240 334.
  • Other variants include hybrid proteins, such as those disclosed in EP 0 028 489, EP 0 155 387 and EP 0 297 882, all of which are incorporated herein by reference.
  • Anistreplase is a preferred hybrid protein for use in this invention.
  • Fibrinolytic agents may be isolated from natural sources, but are commonly produced by traditional methods of genetic engineering. Useful formulations of tPA, SK, UK and pUK are disclosed, for example, in
  • the fibrinolytic agent may be formulated in an aqueous, buffered, isotonic solution, such as sodium or ammonium acetate or adipate buffered at pH 3.5 to 5.5. Additional excipients such as polyvinyl pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene, glycol, mannitol and sodium chloride may also be added. Such a composition can be lyophilized.
  • the pharmaceutical composition may be formulated with both the compound of formula (I) and fibrinolytic in the same container, but formulation in different containers is preferred.
  • both agents are provided in solution form they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
  • Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and other infarct-related disorders.
  • the compound of formula (I) is administered just prior to, at the same time as, or just after parenteral administration of tPA or other fibrinolytic agent. It may prove desirable to continue treatment with the peptide for a period of time well after reperfusion has been established to maximally inhibit post-therapy reocclusion.
  • the effective dose of tPA, SK, UK or pUK may be from 0.5 to 5 mg/kg and the effective dose of the compound of this invention may be from about 0.1 to 25 mg/kg.
  • a kit for convenient administration of the inhibitor and the fibrinolytic agent at the same or different times, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the inhibitor for parenteral administration, as described above, and an effective amount of tPA, or other fibrinolytic agent, for parenteral administration, as described above.
  • kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution.
  • 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 compound of this invention 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 inhibitor followed by an infusion of the fibrinolytic agent.
  • the pharmacological activity of the compound of this invention is assessed by its ability to inhibit the binding of 3 H-SK&F 107260, a known RGD-fibrinogen antagonist, to the GPIIbllla receptor; its ability to inhibit platelet aggregation, in vitro, and its ability to inhibit thrombus formation in vivo.
  • a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen.
  • Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a proteimphospholipid ratio of 1 :3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min.
  • the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
  • the GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.
  • GPIIb-IIIa The binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H]-SK&F- 107260 as an RGD-type ligand.
  • the binding assay was performed in a 96-well filtration plate assembly (Millipore Corporation, Bedford, MA) using 0.22 um hydrophilic durapore membranes.
  • the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
  • Various concentrations of unlabeled benzadiazapines were added to the wells in quadruplicate.
  • [ 3 H]-SK&F- 107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H]-SK&F- 107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
  • Inhibition of platelet aggregation was determined following the procedure described in Nichols, et al., Thrombosis Research, 75, 143 (1994). Blood was drawn from the antecubital vein of normal human volunteers who had not taken a cyclooxygenase inhibitor within the previous 14 days into a plastic syringe containing one part 3.8% trisodium citrate to nine parts blood. Platelet rich plasma was prepared by centrifuging the blood at 200 g for 10 min at RT. The platelet rich plasma was drawn off and the remaining blood was centrifuged at 2400 g for 5 min at RT to make platelet poor plasma.
  • Platelet count was measured with a model ZB 1 Coulter Counter (Coulter Electronics Inc., Hialeah, FL) and was adjusted to 300,000/ ⁇ l using platelet poor plasma. Platelet aggregation was studied in a Chrono-Log model 400VS Lumi Aggregometer (Chrono-Log, Havertown, PA) using platelet rich plasma stirred at 1200 r.p.m.and maintained at 37°C, with platelet poor plasma as the 100% transmission standard.
  • Concentration-response curves for the ability of compounds to inhibit platelet aggregation measured as the maximum change in light transmission, induced by a maximal concentration of adenosine diphosphate (10 ⁇ M) were constructed and the IC50 was determined as the concentration of antagonist required to produce 50% inhibition of the response to the agonist.
  • Nuclear magnetic resonance spectra were obtained using either a Bruker AM 250 or Bruker AC 400 spectrometer. Chemical shifts are reported in parts per milliom ( ⁇ ) downfield from the internal standard tetramethylsilane. Mass spectra were taken on either VG 70 FE or VG ZAB HF instruments using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, New Jersey. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
  • Reverse phase flash chromatography was carried out on YMC-Gel (S20-120A) reverse phase silica gel. Radial chromatography was caried out on a Chrmoatotron (Model 8924; Harrison Research Company, Palo Alto, CA). All other materials and solvents were obtained from commercial sources and were used without further purification.
  • Benzyl alcohol (2.40 mL, 23.2 mmol)
  • EDC (2.23 g, 11.6 mmol
  • DMAP (0.09 g, 0.74 mmol) were added to a solution of this material in CH 2 C1 2 (30 mL) at RT. After 5 days, the reaction was diluted with CH 2 C1 2 and washed with IN HC1, sat.
  • Example 1(b) To the material obtained from Example 1(b) (0.80g, 2.50 mmol) in CH 2 C1 (10 mL) was added trifluoroacetic acid (10 mL) at RT. When the gas evolution ceased (approx. 45 min.) the solvent was removed under vacuum. The residue was dissolved in THF (20 mL) and Et3N (1.05 mL, 7.53 mmol) and ethyl alpha- bromophenylacetic acid (0.91 g, 3.74 mmol) was added. After heating the reaction at reflux for 18 h, the reaction was cooled to RT and the solvent was removed under reduced pressure.
  • Example 1(c) To the compound of Example 1(c) (0.84 g, 2.20 mmol) in EtOH (10 mL) was added 10% Pd/C (0.20 g). The reaction vessel was flushed with hydrogen and then fitted with a hydrogen filled balloon. After lh, the hydrogen was vented and the catalyst was removed by filtration through celite. The filter cake was rinsed with EtOH and the combined organic filtrates were concentrated to give 0.62 g of the desired product as a clear oil. To the compound of Example 1(a) (0.72 g, 2 34 mmol) in EtOH (10 mL) was added 10% Pd/C (0.21 g). The reaction vessel was flushed with hydrogen and then fitted with a hydrogen filled balloon.
  • Example 1(e) (Chiralpak AD, 4.6 x 250 mm, 1.0 mL. min, 90: 10:0.1 :0.1 hexane/ethanol/trifluoroacetic acid/diethylamine, UV detection at 220 nm).
  • the material prepared above gave 60 mg of the desired material as an off-white powder.
  • Example 1(c) In a manner analogous to Example 1(c), the material from Example 1(b) and methyl 2-bromo-2-(4-methoxyphenyl)acetate gives methyl 2- [4- (benzyloxycarbonyl)piperadino]-2-(4-methoxyphenyl)acetate
  • Example 4(a) the compound of Example 4(a) and the compound of Example 1(a) gives 4-[(4-(4-t-butoxycarbonyl-l- piperizinyl)phenyl)aminocarbonyl]- 1 -piperidine- 1 -(4-methoxyphenyl)acetic acid, methyl ester.
  • Example 4(b) In a manner analogous to the preparation of Example 1(e), the compound of Example 4(b) gives the title compound.
  • Example 8(a) The material from Example 8(a) is dissolved in CH 2 C1 2 and trifluoroacetic acid is added. The reaction is stirred at RT until the gas evolution ceases. The solvent is removed under reduced pressure and the residue is dissolved in THF and Et3N. Methyl 2-bromo-2-(4-nitrophenyl)acetate is added and the reaction is heated at reflux for 18 h. The solvent is removed under reduced pressure after allowing the reaction to cool to RT. The desired material is isolated by flash chromatography.
  • Tetrakistriphenylphosphine palladium is added and the reaction is heated to 60 °C. When the reaction is complete, it is allowed to cool to RT and filtered through a pad of celite. The solvent is removed under vacuum.
  • a hydrogenation vessel is charged with EtOH, 10% Pd/C and the compound from Example 1(a).
  • the reaction vessel is fitted with a hydrogen-filled balloon.
  • the hydrogen is vented and the catalyst is removed by filtration through a bed of celite.
  • the solvent is removed by filtration and the residue is dissolved in pyridine.
  • the material obtained above and EDC are added to the pyridine solution.
  • the solvent is removed under reduced pressure and the product is isolated by flash chromatography.
  • Example 9 In a manner analogous to the preparation of Example 1(e), the compound of Example 8(c) gives the title compound.
  • Oral Dosage Unit Composition A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
  • 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 1 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 concerne un composé représenté par la formule (I) ou un de ses sels acceptable sur le plan pharmaceutique, servant à inhiber efficacement l'agrégation des plaquettes, des compositions pharmaceutiques permettant de mettre en application cette activité, ainsi qu'un procédé servant à inhiber l'agrégation des plaquettes.
PCT/US1998/015288 1997-07-25 1998-07-23 Antagonistes du recepteur de fibrinogene WO1999004796A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP51008299A JP2002509547A (ja) 1997-07-25 1998-07-23 フィブリノーゲンレセプターアンタゴニスト
AU85103/98A AU8510398A (en) 1997-07-25 1998-07-23 Fibrinogen receptor antagonists
CA002297909A CA2297909A1 (fr) 1997-07-25 1998-07-23 Antagonistes du recepteur de fibrinogene
EP98935967A EP1001777A4 (fr) 1997-07-25 1998-07-23 Antagonistes du recepteur de fibrinogene

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5378897P 1997-07-25 1997-07-25
US60/053,788 1997-07-25
US6354597P 1997-10-28 1997-10-28
US60/063,545 1997-10-28

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US09445489 A-371-Of-International 1999-12-08
US09/840,358 Continuation US20010014682A1 (en) 1997-07-25 2001-04-23 Fibrinogen receptor antagonists

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WO1999004796A1 true WO1999004796A1 (fr) 1999-02-04

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PCT/US1998/015288 WO1999004796A1 (fr) 1997-07-25 1998-07-23 Antagonistes du recepteur de fibrinogene

Country Status (6)

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EP (1) EP1001777A4 (fr)
JP (1) JP2002509547A (fr)
AU (1) AU8510398A (fr)
CA (1) CA2297909A1 (fr)
CO (1) CO4970784A1 (fr)
WO (1) WO1999004796A1 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069143A (en) * 1994-12-20 2000-05-30 Smithkline Beecham Corporation Fibrinogen receptor antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts Service (C A S); 1 January 1900 (1900-01-01), XP002913748, Database accession no. 127-220673 *
Chemical Abstracts Service (C A S); 1 January 1900 (1900-01-01), XP002913749, Database accession no. 127-176437 *
See also references of EP1001777A4 *

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Publication number Publication date
JP2002509547A (ja) 2002-03-26
EP1001777A4 (fr) 2002-10-09
EP1001777A1 (fr) 2000-05-24
AU8510398A (en) 1999-02-16
CA2297909A1 (fr) 1999-02-04
CO4970784A1 (es) 2000-11-07

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