WO1999045939A1 - Fibrinogen receptor antagonists - Google Patents
Fibrinogen receptor antagonists Download PDFInfo
- Publication number
- WO1999045939A1 WO1999045939A1 PCT/US1999/004911 US9904911W WO9945939A1 WO 1999045939 A1 WO1999045939 A1 WO 1999045939A1 US 9904911 W US9904911 W US 9904911W WO 9945939 A1 WO9945939 A1 WO 9945939A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- mammal
- inhibiting
- fibrinogen
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- 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
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 Ilb/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/IIIa 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.
- 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/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
- these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the GP Ilb/IIIa complex.
- 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/IIIa 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.
- WO9111458 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 Rl-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.
- WO9412181 describes fibrinogen receptor antagonists such as biphenylcarboxamides.
- 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.
- R 1 a 5, 6 or 7 membered nonaromatic ring, having 1, 2 or 3 nitrogen atoms and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl, or disubstituted on the carbon and nitrogen atoms with Rl and 2, where R and R ⁇ are independently selected from the group consisting of hydrogen, halogen, Ci-io alkyl, C3-8 cycloalkyl, aryl, aryl Ci-8 alkyl, amino, amino Ci-8 alkyl,
- n is an integer from 1 to 8;
- R ⁇ i IS hydrogen, Cl-8 alkyl, aryl, aryl Cl-6 alkyl-,
- R3 and R ⁇ are independently selected from the group consisting of
- Ci-10 alkyl are independently selected from hydrogen, halogen, Ci-10 alkyl,
- 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.
- One class of compounds of the invention includes those having the formula
- X is NH2, or
- Cl-6 alkoxy Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl,
- n is an integer from 1 to 8;
- ⁇ 11- R3 and R ⁇ are independently selected from the group consisting of
- a group of this class of compounds includes those having the formula
- n 3, 4, 5, or 6;
- a subgroup of this group of compounds of the invention includes those consisting essentially of
- 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 ( ⁇ g/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 1S The IC50 1S
- compositions i, ii, and iii shown above were tested and found to have an IC50 of less than 5000 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.
- terapéuticaally 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 be any substance that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
- 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 about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., ethynyl
- 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, thienylmethyl, 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.
- 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 intramuscular 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 300 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.
- doses of compounds of the invention will range from about 0.001 ⁇ g/kg/minute and 1 mg/kg/minute, during a constant rate of infusion, e.g., 0.1, 0.15, and 0.2 ⁇ g/'kg/minute.
- an intravenous composition having 0.05 mg/ml of active ingredient can be administered at rates of 0.002, 0.003 or 0.004 ml/kg/min, respectively.
- Compositions of the invention containing higher concentrations of active ingredients should be administered at correspondingly lower rates.
- 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
- 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 poly ethyl eneoxide-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.
- 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. To be administered in the form of a transdermal delivery system, the dosage
- ⁇ 19- administration will, or course, be continuous rather that intermittent throughout the dosage regime.
- Novel compounds of the present invention were prepared according to the procedures shown below which illustrate the general synthetic procedures in Scheme 1 and Scheme 2.
- Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound 3-[2-(4-Amino-butyrylamino)-acetylamino]-2(S)- benzenesulfonylamino-propionic acid (1-7) are prepared as illustrated below:
- Active Compound (1-7) 25.0 50.0 100.0
- All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
- the resulting granulation is sieved, dried and blended with the remainder of the corn 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.
- Intravenous formulations 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 3-[2-(4-amino-butyrylamino)-acetylamino]-2(S)- benzenesulfonylamino-propionic acid, a citrate buffer, and sodium chloride, to obtain a concentration of 0.25 mg/ml.
- 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.
- Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
- -28- arteries arterial grafts, carotid endaterectomy
- 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 the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002322743A CA2322743A1 (en) | 1998-03-09 | 1999-03-05 | Fibrinogen receptor antagonists |
EP99909869A EP1061934A1 (en) | 1998-03-09 | 1999-03-05 | Fibrinogen receptor antagonists |
JP2000535353A JP2002506039A (en) | 1998-03-09 | 1999-03-05 | Fibrinogen receptor antagonist |
AU28976/99A AU742197B2 (en) | 1998-03-09 | 1999-03-05 | Fibrinogen receptor antagonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7737498P | 1998-03-09 | 1998-03-09 | |
US60/077,374 | 1998-03-09 | ||
GBGB9814737.4A GB9814737D0 (en) | 1998-07-07 | 1998-07-07 | Fibrinogen receptor antagonists |
GB9814737.4 | 1998-07-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999045939A1 true WO1999045939A1 (en) | 1999-09-16 |
Family
ID=26313986
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/004911 WO1999045939A1 (en) | 1998-03-09 | 1999-03-05 | Fibrinogen receptor antagonists |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1061934A1 (en) |
JP (1) | JP2002506039A (en) |
AU (1) | AU742197B2 (en) |
CA (1) | CA2322743A1 (en) |
WO (1) | WO1999045939A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001074774A1 (en) | 2000-04-05 | 2001-10-11 | Daiichi Pharmaceutical Co., Ltd. | Ethylenediamine derivatives |
US9814672B2 (en) * | 2007-03-09 | 2017-11-14 | Susan T. Laing | Echogenic vehicle for clinical delivery of plasminogen activator and other fibrin-binding therapeutics to thrombi |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4474764A (en) * | 1981-10-13 | 1984-10-02 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | 3-Amino-2-hydroxy-4-phenylbutanoic acid derivatives and pharmaceutical composition containing the same |
-
1999
- 1999-03-05 JP JP2000535353A patent/JP2002506039A/en not_active Withdrawn
- 1999-03-05 EP EP99909869A patent/EP1061934A1/en not_active Withdrawn
- 1999-03-05 WO PCT/US1999/004911 patent/WO1999045939A1/en not_active Application Discontinuation
- 1999-03-05 CA CA002322743A patent/CA2322743A1/en not_active Abandoned
- 1999-03-05 AU AU28976/99A patent/AU742197B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4474764A (en) * | 1981-10-13 | 1984-10-02 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | 3-Amino-2-hydroxy-4-phenylbutanoic acid derivatives and pharmaceutical composition containing the same |
Non-Patent Citations (9)
Title |
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HANABUSA K., ET AL.: "FUNCTIONAL MONOMERS AND POLYMERS, 64 SYNTHESIS OF POLY-SS-ALANINE FROM SS-ALANINE, SS-ALANYL-SS-ALANINE, AND SS-ALANYL-SS-ALANYL-SS- ALANINE 4-DODECANOYL-2-NITROPHENYL ESTERS.", ANGEWANDTE MAKROMOLEKULARE CHEMIE. APPLIED MACROMOLECULARCHEMISTRY AND PHYSICS., WILEY VCH, WEINHEIM., DE, vol. 84., no. 1299., 1 January 1980 (1980-01-01), DE, pages 97 - 104., XP002918993, ISSN: 0003-3146, DOI: 10.1002/apmc.1980.050840107 * |
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