WO1998025601A1 - Antagonistes de recepteurs du fibrinogene - Google Patents

Antagonistes de recepteurs du fibrinogene Download PDF

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Publication number
WO1998025601A1
WO1998025601A1 PCT/US1997/022622 US9722622W WO9825601A1 WO 1998025601 A1 WO1998025601 A1 WO 1998025601A1 US 9722622 W US9722622 W US 9722622W WO 9825601 A1 WO9825601 A1 WO 9825601A1
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Prior art keywords
alkyl
aryl
carboxy
mammal
alkyloxy
Prior art date
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PCT/US1997/022622
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English (en)
Inventor
Melissa S. Egbertson
Laura M. Vassallo
George D. Hartman
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Merck & Co., Inc.
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
Priority claimed from GBGB9702834.4A external-priority patent/GB9702834D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97952350A priority Critical patent/EP0957908A4/fr
Priority to AU55981/98A priority patent/AU719495B2/en
Priority to CA002274029A priority patent/CA2274029A1/fr
Priority to JP52691998A priority patent/JP2001506633A/ja
Publication of WO1998025601A1 publication Critical patent/WO1998025601A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • 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
    • C07D333/26—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 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the invention relates generally to inhibition of the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp ⁇ b/IIIa fibrinogen receptor site.
  • Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IHa receptor site is known to be essential for normal platelet function.
  • platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
  • agonists such as thrombin, epinephrine, or ADP
  • arginine-glycine- aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits.
  • integrins structurally related receptors
  • the authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
  • Cheresh in Proc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987) describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothelial cells that is structurally similar to the Ilb IIIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
  • a number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp ⁇ b/ffla complex.
  • Huang et al, J. Biol Chem., 262, 16157-16163 (1987); Huang et al, Biochemistry, 28, 661- 666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
  • Echistatin is another compound which has high affinity for the gp Ilb/ ⁇ ia complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/ ⁇ ia receptor.
  • U.S. Patent No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
  • WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • W09111458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
  • WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle.
  • U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
  • EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
  • EP 437 367 discloses linear polypeptide fibrinogen receptor antagonists.
  • U.S. Patent No. 5,256,812 discloses compounds of the R l-A-(W) a -X-(CH2)b-(Y)c- B-Z-COOR wherein Rl is a guanidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
  • W09412181 describes fibrinogen receptor antagonists such as bipheny lcarboxamides .
  • a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli.
  • Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
  • Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
  • the above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective amount of such compound to a mammal, preferably a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective amount of such compound is another feature of this invention.
  • Aryl 1 and Aryl ⁇ are independently selected from a 6-membered monocyclic aromatic ring system containing 0, 1 , 2, 3, or 4 nitrogen or sulfur atoms, wherein the carbon atoms of the Aryl 1 ring system are either unsubstituted or substituted with R2a, and wherein the carbon atoms of the Aryl2 ring system are either unsubstituted or substituted with R2b;
  • R2a and R2b are independently selected from hydrogen Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl-, Cl-6 alkylcarboxy -, Cl-6 alkylcarboxy Cl-6 alkyl-, oxo,
  • n and n are integers independently chosen from 0-6, p is an integer chosen from 1-6, and R 3 is selected from the group consisting of hydrogen, hydroxyl,
  • R6, R7, R8, and R9 are independently chosen from:
  • Cl-6 alkylamino- amino Cl-6 alkyl-, Cl-6 alkylamino Cl-6 alkyl-, arylamino-, aryl Cl-6 alkylamino-, arylamino Cl-6 alkyl-, aryl Cl-6 alkylamino Cl-6 alkyl-, amino Cl-6 alkyl-, Cl-6 dialkylamino-,
  • groups may be unsubstituted or substituted with one or more substituents selected from Rl and R2a;
  • RlO is chosen from
  • R2a and R2b are independently selected from the group consisting of hydrogen Cl-6 alkyl, carboxy,
  • Rl, R5, R3a an d R3b a re independently selected from the group consisting of hydrogen, hydroxyl,
  • R7 is arylsulfonylamino-, aryl Cl-6 alkylsulfonylamino-, arylsulfonylamino Cl_6 alkyl-, aryl Cl-6 alkylsulfonylamino Cl-6 alkyl-, Cl-8 alkylsulfonylamino-, Cl -8 alkylsulfonylamino Cl-6 alkyl-, C3-8 cycloalkylsulfonylamino-, thienylsulfonylamino-, or
  • R7 is arylsulfonylamino-, C3-8 cycloalkylsulfonylamino-, thienylsulfonylamino-, or
  • ADP-stimulated platelet aggregation assay used to determine inhibition associated with the compounds claimed in the instant invention, human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
  • Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
  • the reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested.
  • the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
  • the reaction is then allowed to proceed for at least 2 minutes.
  • the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
  • the IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
  • composition l__ was tested and found to have an IC50 of less than 50 nM.
  • pharmaceutically acceptable salts shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate
  • Prodrugs such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • anti-coagulant shall include heparin, and warfarin.
  • thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
  • platelet anti-aggregation agent shall include agents such as aspirin and dipyridamole.
  • alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like, straight or branched alkene containing 2 to.
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from O, N, and S, e.g., phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, and thiazole.
  • alkyloxy or “alkoxy” include an alkyl portion where alkyl is as defined above, e.g., methyloxy, propyloxy, and butyloxy.
  • arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
  • arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienyhnethyl, thienylethyl, and thienylpropyl.
  • alkylaryl examples include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
  • halogen includes fluorine, chlorine, iodine and bromine.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • BOP Benzotriazol- 1 -yloxytris(dimethylamino) ⁇ hosphonium, hexafluorophosphate
  • EDC 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Oxone Potassium peroxymonosulfate
  • LDA Lithium diisopropylamide
  • the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non- toxic amount of the compound desired can be employed as an anti- aggregation agent.
  • Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
  • Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physiol., 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg kg/day) to about 100 mg/kg/day and preferably 0.01 - 100 mg/kg/day and most preferably 0.01 -20 mg/kg/day.
  • oral dosages for an adult patient are, for example, 1 mg, 10 mg or 100 mg.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in divided doses of two, three, or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non- toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn- sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy- ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention can also be co- administered with suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin. Coadministration includes administration together or separately in order to achieve beneficial thrombosis prevention or thrombolysis.
  • suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, or warfarin.
  • Coadministration includes administration together or separately in order to achieve beneficial thrombosis prevention or thrombolysis.
  • a solution of di-tert-butyl dicarbonate (BOC20, Aldrich, 72.3g, 331 mmol) in CHCI3 (100 mL) was added dropwise and the pH of the reaction monitored closely with a pH meter. Additional 1 N NaOH was added as needed to maintain the pH of the solution >12 throughout the addition of the BOC2O. After addition was complete TLC showed starting material remaining.
  • the acid chloride was dissolved in CHCI3 (100 mL), cooled to 0°C in a jacketed addition funnel, then added dropwise to a 0°C slurry of 1-2 (19.6g, 83.3 mmol), and pyridine (29 mL, 250 mmol) in CHCI3 (500 mL). The resulting slurry was stirred for one hour, then treated with 1 L of 10% KHSO4. The resulting precipitate was collected by filtration, then re-suspended in H2O, refiltered and washed with water and dried under vacuum to give 1-5 as a white solid. Rf(5% MeOH/CHC13 saturated with NH3) 0.65.
  • N-[4-(tert-butoxycarbonylaminoiminomethyl)phenyl]terephthalamic acid 1-6 A suspension of 1-5 (9.78g, 2.12 mmol) in MeOH (1 10 mL) and THF (250 mL) was treated with 1 N NaOH solution (42.4 mL, 8.48 mmol) to give a yellow suspension that was stirred at room temperature overnight. The pH of the solution was adjusted to -7 and the MeOH and THF carefully removed under vacuum. The resulting aqueous slurry was diluted with H2 ⁇ and acidified with 10% KHSO4. A white solid precipitated and was collected by filtration, washed with water and Ethyl Acetate and dried under vacuum at 50°C to give l__ as a white solid.
  • Another example of a compound of the invention is
  • Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound 2(S)-benzenesulfonylamino-3-[4-(4- carbamimidoylphenylcarbamoyl)benzoylamino]-propionic acid are prepared as illustrated below:
  • All of the active compound, cellulose, and a portion of the com starch are mixed and granulated to 10% com starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the com starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • An intravenous dosage form of the above-indicated active compound is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
  • a pharmaceutical composition was prepared at room temperature using 2(S)-benzenesulfonylamino-3-[4-(4- carbamimidoylphenylcarbamoyl)benzoylamino]-propionic acid, a citrate buffer, and sodium chloride, to obtain a concentration of 0.25 mg/ml.
  • 800 grams of water was introduced into a standard pharmaceutical mixing vessel.
  • 0.25 grams of (3(R)-[(2-Amino-4- pyridyl)ethyl]-2-piperidon-l-yl)acetic- ⁇ -alanine was dissolved in the water.
  • 2.7 grams sodium citrate and 0.16 grams citric acid were added to obtain a finished citrate concentration of 10 mM.
  • 8 grams of sodium chloride was added.
  • 200 grams of water was then added to achieve the desired final concentrations of ingredients.
  • the resulting aqueous formulation had the following concentrations:
  • the finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C. Prior to compound administration, the concentrated formulation is diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml and transferred to an infusion bag.
  • compound ⁇ __ was orally administered to a dog. Blood samples were drawn at various intervals over a 6 hour period and subjected to the ADP- stimulated platelet aggregation assay.
  • Compound __ was shown to have a profound oral profile with regard to platelet aggregation over time. According to the ADP extent measurement of percent inhibition of platelet aggregation, a dose of 0.2 mg/kg p.o. provided 100% inhibition over a period of 6 hours.
  • Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
  • Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and thromboemboli.
  • Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I) et certains de leurs sels pharmaceutiquement admis, tels que ceux représentés par la formule spécifique (II).
PCT/US1997/022622 1996-12-13 1997-12-09 Antagonistes de recepteurs du fibrinogene WO1998025601A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97952350A EP0957908A4 (fr) 1996-12-13 1997-12-09 Antagonistes de recepteurs du fibrinogene
AU55981/98A AU719495B2 (en) 1996-12-13 1997-12-09 Fibrinogen receptor antagonists
CA002274029A CA2274029A1 (fr) 1996-12-13 1997-12-09 Antagonistes de recepteurs du fibrinogene
JP52691998A JP2001506633A (ja) 1996-12-13 1997-12-09 フィブリノーゲン受容体拮抗薬

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3288896P 1996-12-13 1996-12-13
US60/032,888 1996-12-13
GB9702834.4 1997-02-12
GBGB9702834.4A GB9702834D0 (en) 1997-02-12 1997-02-12 Fibrinogen receptor antagonists

Publications (1)

Publication Number Publication Date
WO1998025601A1 true WO1998025601A1 (fr) 1998-06-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/022622 WO1998025601A1 (fr) 1996-12-13 1997-12-09 Antagonistes de recepteurs du fibrinogene

Country Status (5)

Country Link
EP (1) EP0957908A4 (fr)
JP (1) JP2001506633A (fr)
AU (1) AU719495B2 (fr)
CA (1) CA2274029A1 (fr)
WO (1) WO1998025601A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof

Citations (3)

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Publication number Priority date Publication date Assignee Title
US5039805A (en) * 1988-12-08 1991-08-13 Hoffmann-La Roche Inc. Novel benzoic and phenylacetic acid derivatives
US5563158A (en) * 1993-12-28 1996-10-08 The Dupont Merck Pharmaceutical Company Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists
US5648368A (en) * 1992-12-01 1997-07-15 Merck & Co., Inc. Fibrinogen receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5039805A (en) * 1988-12-08 1991-08-13 Hoffmann-La Roche Inc. Novel benzoic and phenylacetic acid derivatives
US5648368A (en) * 1992-12-01 1997-07-15 Merck & Co., Inc. Fibrinogen receptor antagonists
US5563158A (en) * 1993-12-28 1996-10-08 The Dupont Merck Pharmaceutical Company Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICAL CHEMISTRY LETTERS, 1994, Vol. 4, No. 15, EGBERTSON et al., "Non-Peptide Fibrinogen Receptor Antagonists. 3. Design and Discovery of a Centrally Constrained Inhibitor", pages 1835-1840. *
CURRENT PHARMACEUTICAL DESIGN, 1995, Vol. 1, ZABLOCKI et al., "Fibrinogen Receptor Antagonists", pages 533-558. *
See also references of EP0957908A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof

Also Published As

Publication number Publication date
JP2001506633A (ja) 2001-05-22
EP0957908A1 (fr) 1999-11-24
EP0957908A4 (fr) 2003-03-12
AU5598198A (en) 1998-07-03
AU719495B2 (en) 2000-05-11
CA2274029A1 (fr) 1998-06-18

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