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WO1997014417A1 - Antagonistes du recepteur de fibrinogene - Google Patents

Antagonistes du recepteur de fibrinogene Download PDF

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Publication number
WO1997014417A1
WO1997014417A1 PCT/US1996/016491 US9616491W WO9714417A1 WO 1997014417 A1 WO1997014417 A1 WO 1997014417A1 US 9616491 W US9616491 W US 9616491W WO 9714417 A1 WO9714417 A1 WO 9714417A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
alkyl
aryl
acetyl
alanine
Prior art date
Application number
PCT/US1996/016491
Other languages
English (en)
Inventor
Ben C. Askew
George D. Hartman
Mark E. Duggan
Steven D. Young
John H. Hutchinson
John S. Wai
Melissa S. Egbertson
Laura M. Vassallo
Laura A. Libby
Nathan C. Ihle
Amy E. Krause
Wasyl Halczenko
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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 GBGB9603371.7A external-priority patent/GB9603371D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002234967A priority Critical patent/CA2234967A1/fr
Priority to JP9515931A priority patent/JPH11513686A/ja
Priority to AU74322/96A priority patent/AU713247B2/en
Priority to EP96936505A priority patent/EP0866705A4/fr
Publication of WO1997014417A1 publication Critical patent/WO1997014417A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

  • the invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp IIb/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 IIb/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 IIb/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
  • fibrinogen fibrinogen, von Willebrand factor, and vitronectin.
  • Ruggeri et al. Proc. Nat'l Acad. Sci. U.S.A., 83, 5708-5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 ( 1984); Ginsberg et al., J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
  • a number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp IIb/IIIa 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 IIb/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • Gan et al. J. Biol. Chem., 263, 19827-19832 (1988).
  • 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 IIb/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
  • 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.
  • EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
  • 5,256,812 discloses compounds of the R 1 -A-(W) a -X-(CH 2 )b-(Y)c-B-Z-COOR wherein R 1 is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
  • 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.
  • Fibrinogen receptor antagonists of this invention have the formula:
  • Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the
  • the above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of such compound is another feature of this invention.
  • the invention also includes the use of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
  • Fibrinogen receptor antagonist compounds of Formula I are useful in a method of inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.
  • Fibrinogen receptor antagonists of this invention have the formula: X-Y-A-B-J and pharmaceutically acceptable salts, wherein X is a 5 or 6-membered monocyclic aromatic ring system containing
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-8 cycloalkyl, aryl, aryl C 1-8 alkyl, amino, amino C 1-8 alkyl, C 1-3 acylamino, C 1-3 acylamino C 1-8 alkyl, C 1-6 alkylamino, C 1-6 alkylamino C 1-8 alkyl, C 1-6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-6 alkyl, carboxy, carboxy 1-6 alkyl, C 1-3 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, carboxy C 1-6 alkyloxy, hydroxy, and hydroxy C 1-6 alkyl; Y, optionally present, is
  • CR 1 CR 2 (CH 2 ) 1-6 ,
  • p and q are integers independently chosen from 0-6, and wherein methylene units are unsubstituted or substituted with one or more groups chosen from R 1 and R 2 ; provided that when B is (CH 2 ) p , A must contain at least one heteroatom;
  • R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently chosen from: hydrogen,
  • aryl carbonyl C 1-6 alkyl, aryl carbonyl,
  • alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from R 1 and
  • R 12 is
  • Y is
  • n' is 1, 2, or 3; E is -CH- or -N-; G is -CH- or -N-; p and q are integers independently chosen from 0-6; and R 8 , R 10 , R 12 and R 2 are as previously defined.
  • R 12 is
  • Diasteromer B (16-5a) N-[3(R)-[2-(l -Pyridyl)ethyl-2-piperidone-1-yl]acetyl-3-(2-fluorophenyl)- ⁇ -alanine : Diasteromer B (16-5a) N-[3(R)-[2-(4-Pyridyl)ethyl]-2-piperidone-1-yl]acetyl-3-(2-fluorophenyl- ⁇ -alanine ethyl ester : Diasteromer A (16-6a)
  • 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 ⁇ 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca 2+ (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 IC 50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound. The following representative compounds were tested and found to have IC 50 values within the range of 0.08 and 64 ⁇ M.
  • 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:
  • 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
  • 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 about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-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, prop
  • 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, thiazole, and amino- and halogen- substituted derivatives thereof.
  • 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.
  • S sulfur
  • the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment.
  • a C 1-6 alkyl substituted with C 1-5 alkyl-carbonylamino is equivalent to
  • L- or D-amino acids suitable for compounds of the present invention include naturally occurring L- or D-amino acids include, for example, those naturally occurring L-amino acids present in humans, e.g., protein amino acids, including L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein amino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D-valine, D-asparagine, D-glutamate, D-ornithine,
  • 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.
  • intravenous bolus or infusion
  • intraperitoneal subcutaneous
  • 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 IIb/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
  • 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 IIb/IIIa on the platelet membranes and
  • 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.
  • 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
  • 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.
  • 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, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating 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.
  • novel compounds of the present invention were prepared according to the procedure of the following examples.
  • the most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
  • Compounds of the invention where X is a 9-membered polycyclic aromatic fused ring system can be prepared by reacting a substituted 5-membered ring starting material such as 2-amino-3-bromothiophene, 2-nitro-3-bromothiophene, 2-amino-3-bromopyrrole, and 2-amino-3-bromofuran, with an appropriate compound under suitable ring closure conditions to effect formation of the 9-membered fused ring system.
  • a substituted 5-membered ring starting material such as 2-amino-3-bromothiophene, 2-nitro-3-bromothiophene, 2-amino-3-bromopyrrole, and 2-amino-3-bromofuran
  • Compounds of the invention where X is a 10-membered polycyclic aromatic ring system can be prepared using a starting material such as naphthyridin (Hamada, Y. et al., Chem. Pharm. Bull. Soc, 1971, 19(9), 1857-1862), or by reacting an aminoaldehyde pyridine with a suitable ketone under suitable ring closure conditions to effect formation of the 10-membered fused ring system.
  • a starting material such as naphthyridin (Hamada, Y. et al., Chem. Pharm. Bull. Soc, 1971, 19(9), 1857-1862)
  • an aminoaldehyde pyridine with a suitable ketone under suitable ring closure conditions to effect formation of the 10-membered fused ring system.
  • an acid such as compound 1-8 can be reduced to its corresponding alcohol with borane, the alcohol converted to a bromide with carbon tetrabromide/phosphorous tribromide, and the bromide alkylated to form the final product.
  • the combined filtrate was transferred to a dry 5 L four-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, nitrogen inlet, cooling unit and a thermometer probe.
  • the solution was cooled to -10°C and n-butyllithium (1.6 M in hexane, 1.06 L, 1.695 mol) was slowly added over a 60 min period, keeping the internal temperature less than 0°C.
  • the mixture turned milky when ⁇ 50% of n-BuLi was charged.
  • n-Butyllithium could be charged over 2-4 h while maintaining the internal temperature ⁇ 5°C without
  • reaction mixture was stirred at 0-5°C for 1 h.
  • the reaction mixture was cooled to -10°C, and ethyl bromoacetate (283.1 g, 1.695 mol) was added over 15 min while maintaining the internal temperature less than 0°C. Ethyl bromoacetate could be charged over 0.5-1 h while maintaining the internal
  • reaction mixture was stirred at 0°C for 15 min and then allowed to warm to 23 °C and aged at this temperature for a 2 h period (or overnight if needed).
  • the reaction mixture was cooled to between -5 and 0°C and quenched into a solution of NaCl (170 g) in 2 N HCl (1.78 L), keeping the internal temperature less than 20°C.
  • the resulting aqueous phase had a pH of 6.
  • the mixture was transferred to a 12 L separatory funnel and the two layers were separated.
  • the aqueous layer was extracted with i-propyl acetate (3 ⁇ 1 L).
  • the combined organic layers were concentrated to near dryness and then azeotropically dried with acetonitrile (3 ⁇ 600 mL) (50°C, house vacuum).
  • the mixture was filtered to remove a small amount of NaCl after the azeotropic distillation.
  • the filter cake was washed with 500 mL acetonitrile.
  • the brown solution was used as is in the next step. Pure solid product was isolated by crystallization from isopropyl acetate/hexane.
  • the resulting mixture was cooled to -5-0°C, and 4-vinylpyridine (13.09 g, 124.2 mmol) was added dropwise over a 2 h period, while keeping the internal temperature below 0°C.
  • the reaction was aged at 0°C for 1-2 h, then quenched by slow addition (10 minutes) into a cold (0°C) solution of 1 N HCl (140 mL), while keeping the internal temperature ⁇ 20°C.
  • the final pH was 1.5-2.5.
  • the aqueous solution was extracted with toluene (2 ⁇ 150 mL). About 0.1% product remained in the aqueous layer after the extractions.
  • the combined organic layers were washed with saturated aqueous sodium bicarbonate (3 ⁇ 50 mL). Three washes were required to remove 95+% of Et 3 N•HI/NaI. Less than 0.5% of product was lost to the bicarbonate washes.
  • the resulting organics has a total volume of 460 mL and a KF of 5.1 mg/ mL.
  • the organic layer was azeotropically dried by distillation at
  • the combined filtrate was assayed to contain product al. It was concentrated in vacuo (50°C, 100 mBar). After distilling most of the solvent, the batch was flushed with IPA (3 ⁇ 100 mL) to give a final concentration of 25 wt% (86 g) in IPA. This solution was used as is in the next step.
  • reaction mixture was stirred for 2 h until complete consumption of a3 was observed as monitored by HPLC.
  • the mixture was cooled to 5-10°C, seeded with 50 mg of NaCl and then quenched by the slow addition of 36.6% aqueous hydrochloric acid (9.50 g, 95.36 mmol) over a 10 min period, while maintaining the internal temperature ⁇ 15°C.
  • the final pH was 5.45.
  • the combined filtrate contained acid a4 in quantitative yield as determined by HPLC analysis.
  • isopropyl alcohol (80.8 mL; KF ⁇ 0.1 mg/mL) were combined. The mixture was heated at 65°C for 15 min under a nitrogen atmosphere to dissolve all the solid. The resulting solution was allowed to cool to 20°C. When the solution reached 45°C, it was seeded with ⁇ 10 mg of 99.5% ee quinine salt 9-1. After stirring overnight, the mixture was cooled to 5-6°C and aged for 0.5-1 h.
  • the mixture was heated at reflux (83-85°C) for 5 h.
  • the filtrate was concentrated under vacuum at 45°C and flushed with toluene (3 ⁇ 300 mL) to remove water, followed by isopropyl alcohol (3 ⁇ 300 mL) to remove toluene.
  • the KF of the mixture should be less than 500 mg/mL after the flushes.
  • Isopropyl alcohol (750 mL) was added to the batch to give a final concentration of 3 mL IPA per gram of quinine salt.
  • the mixture was heated at 70-75°C for 15-30 min under a nitrogen atmosphere to dissolve all the solid.
  • the resulting solution was allowed to cool gradually to ambient.
  • the batch temperature reached 45°C, the mixture was seeded with 0.1 g of quinine salt 9-1.
  • the pyridine amide benzyl ester a7 solution in isopropyl acetate from last step was concentrated under vacuum (40°C pot temperature) to a volume of 8 L and then 10 L methanol was added and the solution concentrated again to 8 L (KF ⁇ 500 mg/mL).
  • the ester is hydrolyzed to form the corresponding acid 8-2.
  • bromoacetamide (0.035 g, 0.18 mmol), prepared from
  • Compound 1-13 was prepared from 1-6 and 2-5 as described for the preparation of 1-7.
  • Compound 1-15 was treated with H 2 and 10% Pd/Carbon as described for the preparation of 1-10 to give 1-16 as a white solid.
  • Neat 3-4 was heated to 100°C for 6 h under vacuum. The dark brown residue was chromatographed (silica gel, 10-20%
  • a solution of 5-2 (12 g, 57.6 mmol) in THF (100 mL) was cooled to -78°C and treated with n-butyllithium (2.1 M in hexanes, 55 mL, 115 mmol) to give a yellow solution.
  • the solution was warmed to 0°C for 0.5 h to give a yellow suspension which was re-cooled to -78°C and transferred via a wide-bore cannulla to a jacketed dropping funnel that had been pre-cooled to -78°C.
  • the impure product was purified by preparative HPLC (reverse phase, 95:5 0.1% TFA in H 2 O/0.1% TFA in CH 3 CN to 80-20 gradient) followed by column chromatography (25-35% isopropanol/CH 2 Cl 2 ) to give 6-3 as a white solid.
  • Ester 9-3 (125 mg, 0.24 mmol) was dissolved in 3 mL 50% aqueous THF, and 1 N LiOH (0.5 mL, 0.5 mmol) was added. After 2 h the reaction was concentrated. Flash chromatography (silica, 40:1:1 EtOH/H 2 O/NH 4 OH) provided acid (9-4) as a white solid.
  • Ester 9-3 (1.93 g, 3.78 mmol) was dissolved in 20 mL EtOH, 10% Pd/C (200 mg) was added, and the reaction was stirred under a balloon of H2 for 2 d. After filtering through Celite,
  • Ester 9-7 (300 mg, 0.64 mmol) and 1N NaOH (2.0 mL, 2.0 mmol) were combined in EtOH (4 mL). After stirring at ambient temperature for 1 h, the reaction was concentrated and purified by flash chromatography (silica, 10:1:1 EtOH/NH 4 OH/H 2 O) providing 9-8 as a white solid.
  • the protected picoline 5-2 (90 g, 0.43 mol) was dissolved in 3L THF under N 2 , cooled to -78°C, and n-Buli (1.6 M, 675 mL, 1.08 mol) was added during 30 min. The mixture was allowed to warm to RT for 1 h, then the resulting orange suspension was cooled to -78°C. Methyl 3-bromopropionate (79 g, 0.47 mol) was added during 2 min. After 15 min the cooling bath was removed and the mixture was allowed to warm to -20°C at which point it was quenched with 60 mL HO Ac in 250 mL THF. The solution was diluted with 2L EtOAc, washed with water, sat.
  • Acid 10-1 (667 mg, 2.38 mmol), and TEA (397 ⁇ L, 2.85 mmol) were combined in 12 mL THF, cooled to -78°C, and pivaloyl chloride (319 ⁇ g, 2.59 mmol) was added. After 10 min the reaction was warmed to 0°C for 1 h, then cooled to -78°C. In a second flask, 4(S)-benzyl-2-oxazolidinone (464 mg, 2.62 mmol) was dissolved in 6 mL THF, cooled to -78°C, and n-Buli (1.6 M, 1.64 mL, 2.62 mmol) was added.
  • the second solution was added to the first, and the mixture was warmed to 0°C for 1 h.
  • the reaction was diluted with EtOAc, washed with water, sat. NaHCO3, 10% KHSO 4 , and brine, dried (MgSO 4 ), filtered and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) provided 10-2 as a white solid.
  • Ti(i-PrO) 4 (2.19 mL, 7.37 mmol) was added to a solution of TiCl 4 (1M in CH 2 Cl 2 , 22.1 mL, 22.1 mmol) in 40 mL CH 2 Cl 2 at 0°C. After 15 min, DIPEA (5.15 mL, 30 mmol) was added and the solution turned deep red. After stirring for 10 min, a solution of the oxazolidinone 10-2 (2.6 g, 5.92 mmol) in 10 mL CH 2 Cl 2 was added, and after 1 h at 0°C, acrylonitrile (3.90 mL, 59 mmol) was added and the reaction was stirred at RT overnight. The reaction was diluted with EtOAc, washed with NaHCO 3 and brine, dried (MgSO 4 ), filtered and concentrated. Flash chromatography (silica, EtOAc then 2%
  • MeOH/EtOAc provided nitrile 10-3 as an orange gum.
  • Nitrile 10-3 (9.48 g, 24.2 mmol) was dissolved in 200 mL i-PrOH sat. with NH 3 . 5% Rh on alumina (10.69 g) was added, and the mixture was hydrogenated on a Parr shaker at 50 psi H 2 pressure.
  • reaction mixture was filtered through Celite, re-saturated with NH 3 , treated with fresh 5% Rh on alumina (3.00 g), and
  • Lactam 10-4 (246 mg, 1.12 mmol) was dissolved in 32 mL THF, cooled to -78°C, and NaHMDS (1M, 1.35 mL, 1.35 mmol) was added. After 15 min t-butyl bromoacetate (218 ⁇ l, 1.35 mmol) was added to the stirring suspension, and after 1 h the reaction was quenched by addition of water. After warming to RT the mixture was extracted with EtOAc (3x), the combined organic layers were washed with water and brine, dried (MgSO 4 ), filtered and concentrated. Flash
  • ester 10-7 (76 mg, 0.187 mmol), trifluoroacetic acid (2 mL), and CH 2 Cl 2 (2 mL) was stirred at ambient temperature for 20 minutes. The reaction mixture was then
  • Ester 10-9 (145 mg, 0.32 mmol) was dissolved in 3.5 mL EtOH, 10% Pd/C (100 mg) was added and the reaction was stirred under a balloon of H2 for 6 hrs. The mixture was filtered through celite and concentrated to an oil. Flash chromatography (silica, 50% EtOAc/10:1 :1 EtOH/ NH 4 OH/H 2 O) provided 10-10 as a white solid.
  • N,O-dimethylhydroxylamine HCl (0.51 g, 5.2 mmol) was added, and the reaction mixture was stirred at rt overnight.
  • the desired product 14-2 formed as a white crystalline solid (20.3 g, 94%) that was collected by filtration.
  • Bromine (5.03 mL, 97.5 mmol) was added to a chilled solution (45°C) of sodium hydroxide (21 g, 525 mmol) in water (300 mL) at such a rate as to keep the temperature below 0°C.
  • the solution was mixed for 10 min, then a cold (0°C) solution of N-p-toluene-sulfonyl-L-asparagine (14-2) (21.5 g, 75.0 mmol) in 40 mL of 10% NaOH was added in a single portion to the sodium hypobromite solution. This mixture was stirred with cooling for 20 min, then placed in an oil bath and heated at 80-90°C for 40 min.
  • Acid 14-3 (5.0 g, 19.4 mmol) was suspended in dioxane (100 ml) in a 1-L pressure bottle. The bottle was cooled to -15° and isobutylene (100 ml) was condenced into the dioxane. Concentrated H 2 SO 4 (5 ml) was added and the bottle sealed and stirred at room temperature for 36 h. The bottle was opened and the excess isobutylene carefully vented. The solution was diluted with etyl acetate (200 ml) and washed with 1N NaOH (200 ml). The organic layer was dried

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Abstract

Antagonistes du récepteur de fibrinogène présentant, par exemple, la structure de la formule (I), ou par exemple de la formule (II).
PCT/US1996/016491 1995-10-19 1996-10-15 Antagonistes du recepteur de fibrinogene WO1997014417A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002234967A CA2234967A1 (fr) 1995-10-19 1996-10-15 Antagonistes du recepteur de fibrinogene
JP9515931A JPH11513686A (ja) 1995-10-19 1996-10-15 線維素原受容体拮抗薬
AU74322/96A AU713247B2 (en) 1995-10-19 1996-10-15 Fibrinogen receptor antagonists
EP96936505A EP0866705A4 (fr) 1995-10-19 1996-10-15 Antagonistes du recepteur de fibrinogene

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US560295P 1995-10-19 1995-10-19
US60/005,602 1995-10-19
GBGB9603371.7A GB9603371D0 (en) 1996-02-16 1996-02-16 Fibrinogen receptor antagonists
GB9603371.7 1996-02-16

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Publication Number Publication Date
WO1997014417A1 true WO1997014417A1 (fr) 1997-04-24

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EP (1) EP0866705A4 (fr)
JP (1) JPH11513686A (fr)
AU (1) AU713247B2 (fr)
CA (1) CA2234967A1 (fr)
WO (1) WO1997014417A1 (fr)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5889023A (en) * 1996-05-10 1999-03-30 Merck & Co., Inc. Fibrinogen receptor antagonist
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
EP1080075A1 (fr) * 1998-03-23 2001-03-07 Aventis Pharmaceuticals Products Inc. Derives de piperididinyle et n-amidinopiperidinyle
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6211183B1 (en) 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
WO2001074774A1 (fr) 2000-04-05 2001-10-11 Daiichi Pharmaceutical Co., Ltd. Derives ethylenediamine
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6344450B1 (en) 1999-02-09 2002-02-05 Bristol-Myers Squibb Company Lactam compounds and their use as inhibitors of serine proteases and method
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
US7225170B1 (en) 2000-07-27 2007-05-29 Pitney Bowes Inc. Postage metering system for use with business reply mail
WO2007085357A1 (fr) * 2006-01-30 2007-08-02 Euro-Celtique S.A. Composes cyclo-uree utilises en tant que bloqueurs des canaux calciques
EP1950211A1 (fr) * 2005-11-18 2008-07-30 Eisai R&D Management Co., Ltd. Procede de production d'un derive cinnamamide
US7880009B2 (en) 2004-05-26 2011-02-01 Eisai R&D Management Co., Ltd. Cinnamide compound
US7897632B2 (en) 2006-03-09 2011-03-01 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
US8207155B2 (en) 2009-03-31 2012-06-26 Vanderbilt University Sulfonyl-azetidin-3-yl-methylamine amide analogs as GlyTl inhibitors, methods for making same, and use of same in treating psychiatric disorders
US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound

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US5051405A (en) * 1989-10-10 1991-09-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Anti-thrombotic peptides and pseudopeptides

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IL99538A0 (en) * 1990-09-27 1992-08-18 Merck & Co Inc Fibrinogen receptor antagonists and pharmaceutical compositions containing them
IL99537A (en) * 1990-09-27 1995-11-27 Merck & Co Inc Fibrinogen receptor antagonists and pharmaceutical compositions containing them
WO1992019595A1 (fr) * 1991-05-07 1992-11-12 Merck & Co., Inc. Antagonistes de recepteur de fibrinogene
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WO1994012181A1 (fr) * 1992-12-01 1994-06-09 Merck & Co., Inc. Antagonistes des recepteurs du fibrinogene
WO1995025101A1 (fr) * 1994-03-14 1995-09-21 Merck & Co., Inc. Ethylation pyridylique des lactames
AU7836594A (en) * 1994-03-14 1995-10-03 Merck & Co., Inc. Pyridyl ethylation of lactam derivatives
US5900422A (en) * 1994-12-22 1999-05-04 Smithkline Beecham Corporation Fibrinogen receptor antagonists

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US5037808A (en) * 1988-07-20 1991-08-06 Monsanto Co. Indolyl platelet-aggregation inhibitors
US5051405A (en) * 1989-10-10 1991-09-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Anti-thrombotic peptides and pseudopeptides

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5889023A (en) * 1996-05-10 1999-03-30 Merck & Co., Inc. Fibrinogen receptor antagonist
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6211183B1 (en) 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
EP1080075A1 (fr) * 1998-03-23 2001-03-07 Aventis Pharmaceuticals Products Inc. Derives de piperididinyle et n-amidinopiperidinyle
EP1080075A4 (fr) * 1998-03-23 2001-06-27 Aventis Pharm Prod Inc Derives de piperididinyle et n-amidinopiperidinyle
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
US6344450B1 (en) 1999-02-09 2002-02-05 Bristol-Myers Squibb Company Lactam compounds and their use as inhibitors of serine proteases and method
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
WO2001074774A1 (fr) 2000-04-05 2001-10-11 Daiichi Pharmaceutical Co., Ltd. Derives ethylenediamine
US7935824B2 (en) 2000-04-05 2011-05-03 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7192968B2 (en) 2000-04-05 2007-03-20 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7225170B1 (en) 2000-07-27 2007-05-29 Pitney Bowes Inc. Postage metering system for use with business reply mail
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
US7166586B2 (en) 2001-01-30 2007-01-23 Bristol Myers Squibb Co. Sulfonamide lactam inhibitors of FXa and method
US7880009B2 (en) 2004-05-26 2011-02-01 Eisai R&D Management Co., Ltd. Cinnamide compound
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
EP1950211A4 (fr) * 2005-11-18 2011-08-31 Eisai R&D Man Co Ltd Procede de production d'un derive cinnamamide
EP1950211A1 (fr) * 2005-11-18 2008-07-30 Eisai R&D Management Co., Ltd. Procede de production d'un derive cinnamamide
WO2007085357A1 (fr) * 2006-01-30 2007-08-02 Euro-Celtique S.A. Composes cyclo-uree utilises en tant que bloqueurs des canaux calciques
US8354434B2 (en) 2006-01-30 2013-01-15 Purdue Pharma L.P. Cyclourea compounds as calcium channel blockers
US7897632B2 (en) 2006-03-09 2011-03-01 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7973033B2 (en) 2006-03-09 2011-07-05 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound
US8207155B2 (en) 2009-03-31 2012-06-26 Vanderbilt University Sulfonyl-azetidin-3-yl-methylamine amide analogs as GlyTl inhibitors, methods for making same, and use of same in treating psychiatric disorders

Also Published As

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EP0866705A4 (fr) 1999-03-03
JPH11513686A (ja) 1999-11-24
CA2234967A1 (fr) 1997-04-24
EP0866705A1 (fr) 1998-09-30
AU7432296A (en) 1997-05-07
AU713247B2 (en) 1999-11-25

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