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WO1997030708A1 - Inhibiteurs de pyridinone thrombine - Google Patents

Inhibiteurs de pyridinone thrombine Download PDF

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Publication number
WO1997030708A1
WO1997030708A1 PCT/US1997/002408 US9702408W WO9730708A1 WO 1997030708 A1 WO1997030708 A1 WO 1997030708A1 US 9702408 W US9702408 W US 9702408W WO 9730708 A1 WO9730708 A1 WO 9730708A1
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WO
WIPO (PCT)
Prior art keywords
blood
compound
alkyl
pharmaceutically acceptable
inhibiting
Prior art date
Application number
PCT/US1997/002408
Other languages
English (en)
Inventor
Philip E. Sanderson
Terry A. Lyle
Joseph P. Vacca
William C. Lumma
Stephen F. Brady
Thomas J. Tucker
Original Assignee
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 GBGB9605643.7A external-priority patent/GB9605643D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP09530260A priority Critical patent/JP2000512616A/ja
Priority to AU21274/97A priority patent/AU720616B2/en
Priority to EP97906633A priority patent/EP0923372A4/fr
Publication of WO1997030708A1 publication Critical patent/WO1997030708A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
  • European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
  • Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or -keto carboxyl derivatives.
  • the invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
  • the invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin, and inhibiting formation of blood platelet aggregates, in a mammal
  • Compounds of the invention are useful as thrombin inhibitors and have therapeutic value in for example, preventing coronary artery disease, and have the following structure:
  • (R2)2CH(CH2)r where r is 0-4 and each R 2 can be the same or different, and wherein (R ⁇ )2 can also form a ring with CH represented by C3-7 cycloalkyl, C7.12 bicylic alkyl, Cl ⁇ -16 tricylic alkyl, or a 5- to 7- membered mono- or bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, R 2 0(CH2) ⁇ -, wherein p is 1-4, or R2(COOR3)(CH2)r-, where r is 1 -4;
  • R 2 and R 14 are independently selected from
  • Cl-4 alkyl C3-7 cycloalkyl, C7-12 bicyclic alkyl, or Cl ⁇ -16 tricyclic alkyl;
  • R3 and R3" are independently Cl-4 alkyl, C3-7 cycloalkyl, or trifluoromethyl
  • R4 is hydrogen, Cl-4 alkyl, Cl-4 alkoxy, halogen,
  • a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to four heteroatoms selected from the group consisting of N, O and S, -XCH2CO2H, -XCH2CO2CH3,
  • R9 is H or Cl-4 alkyl
  • R 10 and R 1 1 are independently hydrogen, C3-7 cycloalkyl, aryl, heteroaryl, heterocycloalkyl,
  • Cj-4 alkyl unsubstituted or substituted with one or more of hydroxy, COOH, amino, dialkylamino, aryl, heteroaryl, or heterocycloalkyl, or R 10 and R 1 1 are joined to form a four to seven membered cycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl, or
  • X is O, S or CH2;
  • R5 is hydrogen, halogen, Cl-4 alkyl
  • W is Rl or RlS ⁇ 2-
  • Rl is R 2 (CH2)r, or (R2)2CH(CH2)r, phenyl-CH2S ⁇ 2, or diphenyl-CHS ⁇ 2-
  • Rl is phenyl-CH2S02, or diphenyl-CHS ⁇ 2.
  • R3 is Cl-4 alkyl.
  • R ⁇ is methyl and R3 ' is hydrogen.
  • R5 is chlorine
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • a racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "Halo”, as used herein, means fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, single negatively- charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
  • C3-7cycloalkyl is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • C7-12 bicyclic alkyl is intended to include bicyclo[2.2. l]heptyl (norbornyl), bicyclo[2.2.21octyl, 1 , 1 ,3-trimethyl- bicyclo[2.2.1]heptyl (bornyl), and the like.
  • aryl as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system such as phenyl, or naphthyl.
  • the aryl ring can be unsubstituted or substituted with one or more of Cl-4 lower alkyl; hydroxy; alkoxy; halogen; amino.
  • heterocycle or “heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazoiidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, mo ⁇ holin
  • the pharmaceutical ly-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extraco ⁇ oreal circulation systems
  • the thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, 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. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
  • the thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Co ⁇ oration.
  • the thrombin inhibitors 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 phosphohpids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the thrombin inhibitors 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.
  • biodegradable polymers useful in achieving controlled release of a drug
  • 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 dosage regimen utilizing the thrombin inhibitors 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 thrombin inhibitors when used for the indicated effects, will range between about 0.1 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day and most preferably 1 -20 mg/kg/day.
  • a suitably prepared medicament for once a day administration would thus contain between 9 mg and 9 g, preferably between 90 mg and 9 g, and most preferably between 90 mg and 1.8 g, e.g. lOOmg, 500 mg and 1 g.
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
  • individual medicament strengths can be, for example, 25 mg, 33 mg or 50 mg, .
  • the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • they 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 than intermittent throughout the dosage regime.
  • thrombin inhibitors are typically administered as active ingredients 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, elixers, 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, distintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be inco ⁇ orated 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 thrombin inhibitors can also be co-administered with suitable anti -coagulation agents, including, but not limited to, fibrinogen receptor antagonists, heparin, aspirin, or warfarin, or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • suitable anti -coagulation agents including, but not limited to, fibrinogen receptor antagonists, heparin, aspirin, or warfarin, or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
  • Amide couplings e.g., Step F in Scheme 1, to form the compounds of this invention can be performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3- dimethyl-aminopropyl) carbodiimide.
  • reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3- dimethyl-aminopropyl) carbodiimide.
  • Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester.
  • solution phase amide couplings are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
  • 4-Chlorosalicaldehyde is condensed with hydroxylamine hydrochloride in ethanolic aqueous sodium carbonate solution.
  • the oxime is reduced by hydrogenation over a catalyst such as rhodium and the amine is protected as its BOC derivative under standard conditions.
  • the phenol is alkylated in Step D with an acetate equivalent such as ethylbromoacetate and the resulting ester is hydrolysed with lithium hydroxide.
  • the product carboxylic acid is coupled to an amine such as ethylamine in Step F, and the BOC group is removed by strong acid.
  • the amine is coupled to the product of Scheme 1 , Step E to give the final product.
  • Step F EDC, EtNH 2 .HCI HOBT, NMM, DMF
  • Step A A method for preparing compounds which are derivatives of 3-amino-4-trifluoromethyl-2-pyridinone is illustrated in Scheme 3.
  • 1,1 ,1 trifluoro-2,4-pentanedione is condensed with nitroacetamide in ethanolic diethylamine to give 2-hydroxy-6-methyl- 3-nitro-4-trifluoromethylpyridine.
  • This is alkylated in Step B with an acetate equivalent such as t-butyl bromoacetate in THF using sodium hydride as a base and the nitro group is reduced in Step C by hydrogenation using a catalyst such as palladium on carbon.
  • a catalyst such as palladium on carbon.
  • DPPA (35.6 ml, 165 mmol) was added to a stirred solution of 2-hydroxy-6-methylpyridine-3-carboxylic acid (22.97 g, 165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 165 mmol) were added and the solution was refluxed for a further 24 h. The reaction was concentrated in vacuo to remove most of the volatiles.
  • Step B 3-Benzyloxycarbonylamino-6-methyl- 1 -(t-butyl- methylenecarboxy -2-pyridinone
  • Step C 3-Amino-6-methyl-l-(t-butyl-methylenecarboxy)-2- pyridinone
  • Step D 3-Benzy lsulfonylamino-6-methyl- 1 -(t-butyl- methylenecarboxyV2-pyridinone
  • Benzylsulfonyl chloride (3.15 g, 16.5 mmol) was added to a stirred solution of 3-amino-6-methy 1- 1 -(t-butyl-methylenecarboxy)-2- pyridinone (3.55 g, 14.9 mmol) in pyridine (30 ml) at 0°C and as the resulting solution was stirred a thick precipitate formed. After lh the reaction mixture was evaporated in vacuo to a paste which was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution.
  • HCl gas was bubbled through a stirred suspension of 3- benzylsulfonylamino-6-methyl-l-(t-butyl-methylenecarboxy)-2- pyridinone (5.70 g, 14.52 mmol) in ethyl acetate (60 ml) at 0°C until a solution had formed which was saturated with HCl. After 1.5 h at RT a thick suspension had formed.
  • Step F 3-Benzylsulfonylamino-6-methyl- 1 -(N-2,5-Dichloro benzyl-acetamidoV2-pyridinone EDC Hydrochloride (48 mg, 0.25 mmol) was added to a stirred mixture of 3-benzylsulfonylamino-6-methyl-l -methy lenecarboxy- 2-pyridinone (70 mg, 0.21 mmol), HOBT (34 mg, 0.25 mmol), 2,5- dichlorobenzylamine (44 mg, 0.25 mmol) and triethylamine (0.070 ml, 0.50 mmol) in DMF (2.5 ml) and the mixture was stirred for 16 h.
  • Step C N-t-Butoxycarbonyl-2-Hvdroxy-5-Chlorobenzylamine
  • 2-hydroxy-5-chlorobenzy lamine (1.22 g, 4.77 mmol assuming the bisulfate salt), (BOC)2 ⁇ (1.56 g, 7.16 mmol) and N- methylmo ⁇ holine (1.05 ml, 9.54 mmol) in DMF (10 ml) was stirred for 5 h at r.t.
  • the reaction was partitioned between water and ethyl acetate and the organic layer was washed with 5% KHSO4 solution (2 times), sodium hydrogen carbonate solution and brine, dried (Na2S ⁇ 4) and evaporated in vacuo to a solid.
  • Step D Ethyl-(2-t-Butoxycarbonylaminomethyl-4-Chlorophen- oxyVAcetate
  • Step D The product from Step D was suspended in 1 :1 : 1 methanol/THF/ water (9 ml) and lithium hydroxide hydrate (126 mg, 3.0 mmol) was added. After 16 h the volatiles were removed in vacuo and the solution was diluted with water and was washed with ethyl acetate, adding sufficient brine to disperse the emulsion.
  • Step F Ethyl-(2-t-Butoxycarbonylaminomethyl-4-Chlorophen- oxyVAcetamide
  • EDC Hydrochloride (249 mg, 1.3 mmol) was added to a stirred mixture of 2-t-butoxycarbonylaminomethyl-4-chloro- phenoxyacetic acid (316 mg, 1.0 mmol), HOBT (176 mg, 1.3 mmol), ethylamine hydrochloride (106 mg, 1.3 mmol) and N-methylmo ⁇ holine (0.396 ml, 3.6 mmol) in DMF (4 ml) and the mixture was stirred for 16 h.
  • Step G Ethyl-(2-Aminomethyl-4-ChlorophenoxyVAcetamide
  • Ethyl-(2-t-butoxycarbonylaminomethyl-4-chloro ⁇ henoxy)- acetamide from Step F was dissolved in 2: 1 methylene chloride/TFA (3 ml) and after 15 min the solvent was evaporated in vacuo. The residue was dissolved in water and the solution was washed with methylene chloride (twice). The aqueous layer was then basified with saturated sodium carbonate solution and NaCl was added to saturation.
  • Step H 3-Benzylsulfonylamino-6-methyl- 1 -[Ethyl-(2-Methyl- enecarboxamidomethyl-4-Chlorophenoxy)-Acetamide DCC (103 mg, 0.50 mmol) was added to a stirred solution of ethyl-(2-aminomethyl-4-chlorophenoxy)-acetamide (137 mg, 0.57 mmol) and 3-benzylsulfonylamino-6-methyl- 1 -methylenecarboxy-2-pyridinone (168 mg, 0.0.50 mmol) in methylene chloride (3 ml).
  • the crude product was purified by flash column chromatography on silica (eluting with 3:1 hexanes/acetone followed by a methanol/chloroform gradient, 2-4% methanol) to give the title compound as a crystalline solid, m.p.
  • the crude product was purified by flash column chromatography on silica (eluting with 3:1 hexanes/acetone followed by a methanol/chloroform gradient, 2-5% methanol) to give the title compound as a crystalline solid, m.p.
  • EDC Hydrochloride (236 mg, 1.23 mmol) was added to a stirred mixture of 3-benzylsulfonylamino-6-methyl- 1 -methylenecarboxy- 2-pyridinone (415 mg, 1.23 mmol), HOBT (167 mg, 1.23 mmol), 2- hydroxy-5-chlorobenzylamine (195 mg, the product of Step B, Example B) and NMM (0.136 ml, 1.23 mmol) in DMF (1.2 ml) and the mixture was stirred for 3 h. The reaction was diluted with ethyl acetate and was washed with water, dried (Na2S ⁇ 4) and evaporated in vacuo to a solid.
  • the crude product was purified by flash column chromatography on silica (ethylacetate/hexanes/2% acetic acid gradient, 50-80% ethyl acetate), to give the title compound as a crystalline solid, m.p.
  • the crude product was purified by flash column chromatography on silica (eluting with 3:1 hexanes/acetone followed by 50% ethyl acetate/hexanes) to give a crystalline solid which was triturated with methylene chloride to give the title compound as a crystalline solid, m.p.
  • the crude product was purified by flash column chromatography on silica (eluting with 3:1 hexanes/acetone followed by an ethyl acetate/hexanes gradient, 60-100% ethyl acetate) to give a crystalline solid which was triturated with methanol to give the title compound as a solid, m.p.
  • Trypsin assays also contained 1 mM CaCl2- In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance of p- nitroaniline.
  • -Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm" 1 M- 1.
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V 0 ) or presence of inhibitor (Vi) were measured.
  • the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
  • the inhibitory activity of each of the following compounds against human thrombin, represented by Ki is less than 15 nM. These are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1800 nM.
  • Rats (8-10/group) were randomized to continuous intravenous infusions of saline or test compound administered via the tail vein at a rate of 0.028 ml/min. Treatment infusions were initiated 60 min before the placement of a 3 mm square piece of Whatman No. 1 filter paper saturated with 35% FeCl3 onto the exposed carotid artery distal to the flow probe. Treatment infusions were continued for an additional 90 minutes after the application of FeCl3 (total infusion duration 150 minutes) if thrombotic occlusions did not occur, or were terminated 30 minutes after thrombotic occlusion of the vessel. Time to occlusion was defined as the time from application of FeCl3 to thrombotic occlusion of the vessel.
  • 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 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.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés utiles pour inhiber la thrombine et les occlusions thrombotiques associées, de la structure représentée par la formule (I) et, par exemple, la formule (II).
PCT/US1997/002408 1996-02-22 1997-02-18 Inhibiteurs de pyridinone thrombine WO1997030708A1 (fr)

Priority Applications (3)

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JP09530260A JP2000512616A (ja) 1996-02-22 1997-02-18 ピリジノントロンビンインヒビター
AU21274/97A AU720616B2 (en) 1996-02-22 1997-02-18 Pyridinone thrombin inhibitors
EP97906633A EP0923372A4 (fr) 1996-02-22 1997-02-18 Inhibiteurs de pyridinone thrombine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1205896P 1996-02-22 1996-02-22
US60/012,058 1996-02-22
GBGB9605643.7A GB9605643D0 (en) 1996-03-18 1996-03-18 Pyridinone thrombin inhibitors
GB9605643.7 1996-03-18

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WO1997030708A1 true WO1997030708A1 (fr) 1997-08-28

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JP (1) JP2000512616A (fr)
AU (1) AU720616B2 (fr)
CA (1) CA2245811A1 (fr)
WO (1) WO1997030708A1 (fr)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026926A1 (fr) * 1997-11-26 1999-06-03 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines et alcoxyguanidines et leur utilisation en tant qu'inhibiteurs de protease
EP0971891A4 (fr) * 1997-01-22 2000-04-19 Merck & Co Inc Inhibiteurs de thrombine
WO2000069826A1 (fr) * 1999-05-19 2000-11-23 Pharmacia Corporation Pyridones aryle et heteroaryle polycycliques substituees utilisees pour l'inhibition selective de la cascade de coagulation
WO2000073302A1 (fr) * 1999-05-27 2000-12-07 3-Dimensional Pharmaceuticals, Inc. Oxazaheterocycles comme inhibiteurs de protease
FR2795072A1 (fr) * 1999-06-15 2000-12-22 Adir Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6180627B1 (en) 1998-08-14 2001-01-30 Pfizer Inc. Antithrombotic agents
US6204263B1 (en) 1998-06-11 2001-03-20 3-Dimensional Pharmaceuticals, Inc. Pyrazinone protease inhibitors
EP1039907A4 (fr) * 1997-12-01 2001-09-19 Merck & Co Inc Inhibiteurs de thrombine
WO2001079195A3 (fr) * 2000-04-14 2002-05-16 Corvas Int Inc Nouveaux inhibiteurs de thrombine de type non covalent
US6403583B1 (en) 1998-12-23 2002-06-11 Patrick Y. S. Lam Thrombin or factor Xa inhibitors
US6420397B1 (en) 1999-07-09 2002-07-16 3-Dimensional Pharmaceuticals, Inc. Heteroaryl protease inhibitors and diagnostic imaging agents
US6458952B1 (en) 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6469029B1 (en) 1999-09-13 2002-10-22 3-Dimensional Pharmaceuticals, Inc. Azacycloalkanone serine protease inhibitors
US6476016B2 (en) 2000-07-17 2002-11-05 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
WO2003048155A1 (fr) * 2001-12-04 2003-06-12 University Of Ljubljana Inhibiteurs de thrombine
US6624180B2 (en) 2000-11-20 2003-09-23 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
US6635637B2 (en) 2000-08-04 2003-10-21 Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine protease inhibitors
CN1125051C (zh) * 1997-11-26 2003-10-22 三维药物公司 杂环氨基胍和烷氧基胍及其作为蛋白酶抑制剂的用途
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6660885B2 (en) 2000-03-13 2003-12-09 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6686484B2 (en) 2000-04-17 2004-02-03 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
US6693121B2 (en) 2000-04-05 2004-02-17 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6875791B2 (en) 2000-04-05 2005-04-05 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
FR2867780A1 (fr) * 2004-03-19 2005-09-23 Servier Lab Nouveaux derives de 4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrazine-6-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US7067540B2 (en) 2002-02-14 2006-06-27 Pharmacia Corporation Substituted pyridinones
US7105559B2 (en) 2001-10-03 2006-09-12 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
KR100854584B1 (ko) 2006-03-20 2008-08-27 주식회사 엘지생명과학 피리다지논, 피리미돈 또는 피리돈 구조를 포함하는선택적인 트롬빈 억제제

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WO2021181653A1 (fr) * 2020-03-13 2021-09-16 三菱電機株式会社 Structure de panneau de porte d'ascenseur

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EDWARDS P. D., ET AL.: "DESIGN, SYNTHESIS, AND KINETIC EVALUATION OF A UNIQUE CLASS OF ELASTASE INHIBITORS, THE PEPTIDYL ASPIRE-KETOBENZOXAZOLES, AND THE X-RAY CRYSTAL STRUCTURE OF THE COVALENT COMPLEX BETWEEN PORCINE PANCREATIC ELASTASE AND AC-ALA-PRO-VAL-2-BENZOXAZOLE.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 114., no. 05., 1 January 1992 (1992-01-01), US, pages 1854 - 1863., XP002915297, ISSN: 0002-7863, DOI: 10.1021/ja00031a046 *
See also references of EP0923372A4 *

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0971891A4 (fr) * 1997-01-22 2000-04-19 Merck & Co Inc Inhibiteurs de thrombine
US6472399B2 (en) 1997-11-26 2002-10-29 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
US6566379B1 (en) 1997-11-26 2003-05-20 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
US6706021B2 (en) 1997-11-26 2004-03-16 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
WO1999026926A1 (fr) * 1997-11-26 1999-06-03 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines et alcoxyguanidines et leur utilisation en tant qu'inhibiteurs de protease
US7029654B2 (en) 1997-11-26 2006-04-18 Ortho-Mcneil Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
US7402586B2 (en) 1997-11-26 2008-07-22 Ortho-Mcneil Pharmaceutical, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
US6350764B2 (en) 1997-11-26 2002-02-26 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
CN1125051C (zh) * 1997-11-26 2003-10-22 三维药物公司 杂环氨基胍和烷氧基胍及其作为蛋白酶抑制剂的用途
US6245763B1 (en) 1997-11-26 2001-06-12 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
US6037356A (en) * 1997-11-26 2000-03-14 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
EP1039907A4 (fr) * 1997-12-01 2001-09-19 Merck & Co Inc Inhibiteurs de thrombine
US6204263B1 (en) 1998-06-11 2001-03-20 3-Dimensional Pharmaceuticals, Inc. Pyrazinone protease inhibitors
US6514978B2 (en) 1998-06-11 2003-02-04 3-Dimensional Pharmaceuticals, Inc. Thromboresistant materials incorporating pyrazinone protease inhibitors
US6180627B1 (en) 1998-08-14 2001-01-30 Pfizer Inc. Antithrombotic agents
US6602871B2 (en) 1998-12-23 2003-08-05 Bristol-Myers Squibb Pharma Company Thrombin or factor Xa inhibitors
US6403583B1 (en) 1998-12-23 2002-06-11 Patrick Y. S. Lam Thrombin or factor Xa inhibitors
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6458952B1 (en) 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
MY138303A (en) * 1999-05-19 2009-05-29 Monsanto Co Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
AU771928B2 (en) * 1999-05-19 2004-04-08 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
EA005367B1 (ru) * 1999-05-19 2005-02-24 Фармация Корпорейшн Замещенные пиридоны, их применение, композиция и способ ингибирования тромботических состояний и способы профилактики и лечения
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6870056B1 (en) 1999-05-19 2005-03-22 Pharmacia Corporation Substitituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
WO2000069826A1 (fr) * 1999-05-19 2000-11-23 Pharmacia Corporation Pyridones aryle et heteroaryle polycycliques substituees utilisees pour l'inhibition selective de la cascade de coagulation
WO2000073302A1 (fr) * 1999-05-27 2000-12-07 3-Dimensional Pharmaceuticals, Inc. Oxazaheterocycles comme inhibiteurs de protease
US6326492B1 (en) 1999-05-27 2001-12-04 3-Dimensional Pharmaceuticals, Inc. Heterocyclic protease inhibitors
FR2795072A1 (fr) * 1999-06-15 2000-12-22 Adir Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1069132A1 (fr) * 1999-06-15 2001-01-17 Adir Et Compagnie Dérivés bicycliques d'amino-pyrazinones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US6420397B1 (en) 1999-07-09 2002-07-16 3-Dimensional Pharmaceuticals, Inc. Heteroaryl protease inhibitors and diagnostic imaging agents
US6962942B2 (en) 1999-09-13 2005-11-08 3-Dimensional Pharmaceuticals, Inc. Azacycloalkanone serine protease inhibitors
US6469029B1 (en) 1999-09-13 2002-10-22 3-Dimensional Pharmaceuticals, Inc. Azacycloalkanone serine protease inhibitors
US6660885B2 (en) 2000-03-13 2003-12-09 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
US6852761B2 (en) 2000-03-13 2005-02-08 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
US6693121B2 (en) 2000-04-05 2004-02-17 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade
US6875791B2 (en) 2000-04-05 2005-04-05 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
US6916847B2 (en) 2000-04-05 2005-07-12 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
WO2001079195A3 (fr) * 2000-04-14 2002-05-16 Corvas Int Inc Nouveaux inhibiteurs de thrombine de type non covalent
US6686484B2 (en) 2000-04-17 2004-02-03 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
US7030110B2 (en) 2000-07-17 2006-04-18 Ortho-Mcneil Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
US6476016B2 (en) 2000-07-17 2002-11-05 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
US6635637B2 (en) 2000-08-04 2003-10-21 Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine protease inhibitors
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6951872B2 (en) 2000-11-06 2005-10-04 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6624180B2 (en) 2000-11-20 2003-09-23 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US6828338B2 (en) 2000-11-20 2004-12-07 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
US7105559B2 (en) 2001-10-03 2006-09-12 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
WO2003048155A1 (fr) * 2001-12-04 2003-06-12 University Of Ljubljana Inhibiteurs de thrombine
US7524871B2 (en) 2001-12-04 2009-04-28 University Of Ljubljana, Faculty Of Pharmacy Thrombin inhibitors
US7067540B2 (en) 2002-02-14 2006-06-27 Pharmacia Corporation Substituted pyridinones
US7629363B2 (en) 2002-02-14 2009-12-08 Pfizer Inc Diaryl substituted pyridinones
EP1593682A3 (fr) * 2004-03-19 2006-01-18 Les Laboratoires Servier Dérivés de 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US7498330B2 (en) 2004-03-19 2009-03-03 Les Laboratories Servier 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds
FR2867780A1 (fr) * 2004-03-19 2005-09-23 Servier Lab Nouveaux derives de 4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrazine-6-carboxamides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
KR100854584B1 (ko) 2006-03-20 2008-08-27 주식회사 엘지생명과학 피리다지논, 피리미돈 또는 피리돈 구조를 포함하는선택적인 트롬빈 억제제

Also Published As

Publication number Publication date
EP0923372A4 (fr) 2001-09-05
CA2245811A1 (fr) 1997-08-28
JP2000512616A (ja) 2000-09-26
AU720616B2 (en) 2000-06-08
EP0923372A1 (fr) 1999-06-23
AU2127497A (en) 1997-09-10

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