WO1999011267A1 - Inhibiteurs de thrombine a base de pyrazinone - Google Patents

Inhibiteurs de thrombine a base de pyrazinone Download PDF

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Publication number
WO1999011267A1
WO1999011267A1 PCT/US1998/018417 US9818417W WO9911267A1 WO 1999011267 A1 WO1999011267 A1 WO 1999011267A1 US 9818417 W US9818417 W US 9818417W WO 9911267 A1 WO9911267 A1 WO 9911267A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
halogen
cycloalkyl
unsubstituted
hydroxy
Prior art date
Application number
PCT/US1998/018417
Other languages
English (en)
Inventor
Philip E. Sanderson
Terry A. Lyle
Bruce D. Dorsey
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 GBGB9801005.1A external-priority patent/GB9801005D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002301520A priority Critical patent/CA2301520A1/fr
Priority to EP98946835A priority patent/EP1017393A4/fr
Priority to JP2000508369A priority patent/JP2001514227A/ja
Priority to AU93767/98A priority patent/AU746024B2/en
Publication of WO1999011267A1 publication Critical patent/WO1999011267A1/fr

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Classifications

    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • 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

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 a-keto carboxyl derivatives.
  • the invention includes compounds 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 compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a compound 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 compounds 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.
  • 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:
  • R 2 (COOR3)(CH2)r, where r is 1-4; R 2 and Rl4 are independently phenyl, unsubstituted or substituted with one or more of C1.4 alkyl, Ci-4 alkoxy, halogen, hydroxy, COOH, CONH2, CH2OH, CO2R', where R' is Cl-4 alkyl, or SO2NH2, naphthyl, biphenyl, a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring contains from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic or non- heterocyclic ring is unsubstituted or substituted with halogen, Cl-4 alkyl, or hydroxy, Ci-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, halogen, amino,
  • R3 IS hydrogen, Ci-4 alkyl, C3-7 cycloalkyl, or trifluor omethyl ;
  • X is hydrogen or halogen
  • A is chosen from one of the following radicals:
  • ⁇ l and ⁇ 2 are independently hydrogen, Cl-4 alkyl, Cl-4 alkoxy,
  • R4 is hydrogen
  • 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, -ZCH2CO2H, -ZCH2CO2CH3, -ZCH2R 14 ,
  • RlO and R ⁇ are independently hydrogen, C3.7 cycloalkyl, aryl, heteroaryl, heterocycloalkyl,
  • Ci-4 alkyl unsubstituted or substituted with one or more of: hydroxy,
  • RlO and RU are joined to form a four to seven membered cycloalkyl or heterocycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl or disubstituted with hydroxy, wherein Z is O, S or CH2;
  • R5 is hydrogen, halogen
  • Rl is hydrogen, phenyl, unsubstituted or substituted with one or more of Cl-4 alkyl, Cl-4 alkoxy, halogen, hydroxy, COOH, CONH2, naphthyl, biphenyl, 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, Cl-4 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, heteroaryl, or heterocycloalkyl, CF3,
  • R ⁇ is Cl-4 alkyl and X is H.
  • ⁇ l and ⁇ 2 are independently hydrogen, halogen or Cl-4 alkyl; or
  • R is hydrogen
  • RlO and R ⁇ are independently hydrogen, C3-7 cycloalkyl, heteroaryl, heterocycloalkyl,
  • Ci-4 alkyl substituted with amino, or RlO and R ⁇ are joined to form a four to seven membered cycloalkyl or heterocycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl or disubstituted with hydroxy,
  • W is Rl.
  • R 1 is
  • R 2 CF2C(R 12 )2, or (R 2 CH2)(R 2 CH2)CH;
  • R 2 is phenyl, unsubstituted or substituted with one or more of Cl-4 alkyl, Cl-4 alkoxy, halogen, hydroxy, or SO2NH2, a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring contains from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic or non-heterocyclic ring is unsubstituted or substituted with halogen, Cl-4 alkyl or hydroxy, C3-7 cycloalkyl, unsubstituted, monosubstituted or disubstituted with halogen, CF3, or Ci-7 alkyl, unsubstituted or substituted with halogen or C3-7
  • R3 is CH3, or CH2CH3
  • Inhibitory activity of compounds of the invention is represented by "*”, indicating Ki greater than or equal to 1 nM, or "**”, indicating Ki less than 1 nM. Values are as determined according to the in vitro assay described later in the specification.
  • 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.
  • the compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
  • 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[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl, 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 Ci-4 lower alkyl; hydroxy; alkoxy; halogen; amino.
  • heteroaryl refers to a 5- to 7- membered unsaturated ring containing 1 or 2 heteroatoms selected from O, N, or S.
  • heterocycle or "heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7 -membered mono- or bicyclic or stable 9- 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.
  • Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated.
  • Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups.
  • Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms.
  • the 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, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimid
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, 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, camphor sulf onate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulf onate, 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.
  • 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 extracorporeal circulation systems.
  • Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g.
  • obstruction or occlusion of a vein by a detached thrombus obstruction or occlusion of a lung artery by a detached thrombus
  • cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
  • arterial thrombosis e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery
  • atherosclerosis e.g. arteriosclerosis characterized by irregularly distributed lipid deposits
  • Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the invention are useful for maintaining patency of indwelling catheters.
  • cardiogenic thromboembolism examples include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.
  • arterial thrombosis examples include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.
  • Atherosclerosis examples include arteriosclerosis.
  • devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal 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 Corporation.
  • 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 phospholipids, 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 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1- 0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
  • an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day.
  • a suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
  • the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day.
  • Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.
  • a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g.
  • 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg.
  • an 80 kg patient receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day.
  • Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. Consideration should be given to the solubility of the drug in choosing an The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
  • the compounds can also 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 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.
  • Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
  • Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
  • the thrombin inhibitors can also be co-administered with suitable anti-platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis.
  • fibrinogen receptor antagonists e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis
  • anticoagulants such as aspirin
  • thrombolytic agents such as plasminogen activators or streptokinase
  • 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.
  • Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional antiplatelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • Step B 2-amino-5-cvano-3.6-dimethylpyridine ( 1-2)
  • Step D 3-(2-Phenethylamino)-6-methyl-l-(2-amino-3,6-dimethyl-
  • Step A Benzyl-N-(l-cvanoethyl)glvcine hvdrochloride (5-1)
  • Step B l-Benzyloxycarbonylmethyl-3,5-dichloro-6- methylpyrazinone (5-2) A stirred mixture of oxalyl chloride (40.4 mL, 463 mmol) and 5 ⁇ l (29.51 g, 116 mmol) in 1,2-dichlorobenzene 110 mL) was heated to 100°C for 15 h.
  • 2-Cyclobutylethylamine hydrochloride (95 mg, 0.7 mmol) was added to a stirred mixture of 5 ⁇ (208 mg, 0.636 mmol) and sodium hydrogen carbonate (112 mg, 1.34 mmol) in water (0.66 mL) and toluene (1.27 mL) and the resulting two phase mixture was heated to 80°C. After 4 h the reaction was cooled and partitioned between methylene chloride and 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give 5 ⁇ as a crystalline solid.
  • Step D 3-(2-Cyclobutylethylamino)-5-chloro-6-methyl-l- carboxymethylpyrazinone (5-4) __
  • Step E 3-(2-Cyclobutylethylamino)-6-methyl-l- carboxymethylpyrazinone (5-5)
  • Step F 3-(2-Cyclobutylethylamino)-6-methyl-l-(2-amino-6- methyl-5-methylcarboxamidomethylpyridinyl)-pyrazinone dihvdrochloride (5-6)
  • Step B N-(Ethoxycarbonylmethyl)-N'-(2-oxo-l-propyl) oxamide ilzZ ⁇
  • Step C l-(Ethoxycarbonylmethyl)-3-hydroxy-6-methyl- pyrazinone (7-3)
  • a solution of 3.43 g (14.9 mmol) of 7z2, 1.15 mL (14.9 mmol) of TFA and 2.104 mL (14.9 mmol) of trifluoroacetic anhydride in 60 mL of acetic acid was heated to 80°C under a slow stream of Ar for 7h.
  • an additional 766 ⁇ L (9.9 mmol) of TFA and 1.4 mL (9.9 mmol) of trifluoroacetic anhydride were added and the reaction mixture was heated for an additional 24 h.
  • Step D 3-Bromo- l-(ethoxycarbonylmethyl)-6-methylpyrazinone
  • Step F 2.2-Difluoro-2-phenylethylamine (7-6) Following the procedures described in Middleton and
  • Step G 3-(2,2-Difluoro-2-phenylethylamino)-l- (ethoxycarbonylmethyl)-6-methylpyrazinone (7-7 )
  • Step H 3-(2,2-Difluoro-2-phenylethylamino)-l-(2-amino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-6- methylpyrazinone bis-TFA salt (7-8)
  • Step A 3-[2-(3-Fluorophenyl)ethylamino]-l-(benzyloxy- carbonylmethyl)-5-chloro-6-methylpyrazinone (8-1)
  • Step B 3-[2-(3-Fluorophenyl)ethylamino]-l-carboxy ⁇ ethyl-6-methyI pyrazinone (8-2)
  • Step C 3-[2-(3-Fluorophenyl)ethylamino]-l-(2-amino-6-methyl-
  • Step C 5.6-Cyclopentenopyridine-2-carboxylic acid (9-3)
  • Step F 2-Chloromethyl-5.6-cvclopentenopyridine(9-6)
  • Step I 3-[2-(5,6-Cyclopenteno-2-pyridyl)ethyl]-l-(2-amino-6-methyl- 5-methylenecarboxamidomethylpyridinyl)-6- methylpyrazinone tris-TFA salt (9-9)
  • Step C 3- ⁇ 2-[6-(l,4-Benzomoxan)]ethylamino ⁇ -5-chloro-6- methyl- l-(benzyloxycarbonylmethyl)-pyrazinone ( 10-3 )
  • Step E 3- ⁇ 2-[6-(l,4-Benzodioxan)]ethylamino ⁇ -6-methyl-l-(2-amino-
  • Step A l-[3,4-(methylenedioxy)phenyl]-l-cyclopropane- methylamine(12-l)
  • Step B 3- ⁇ l-[3,4-(methylenedioxy)phenyl]-l-cyclopropane- methylamino ⁇ -5-chloro-6-methyl-l- (benzyloxycarbonylmethyl)-pyrazinone ( 12-2)
  • Step C 3- ⁇ l-[3,4-(methylenedioxy)phenyl]-l-cyclopropane- methylamino ⁇ -6-methyl-l-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyD-pyrazinone dihvdrochloride (12-3)
  • EDC # HC1 (0.109 g, 0.567 mmol) was added to a stirred mixture of carboxylic acid (from above), 2-amino-5-aminomethyl-6-methylpyridine dihydrochloride (0.119 g, 0.567 mmol), HOBfH2 ⁇ (0.076 g, 0.567 mmol) and triethylamine (0.22 g, 2.16 mmol) in dry DMF (5 mL). After 16 h, the volatiles were evaporated in vacuo and the residue was partitioned between ethyl acetate and 1 M HCl solution.
  • Example 14-1 was prepared from l-benzyloxy-carbonylmethyl-3,5- dichloro-6-methylpyrazinone and 1-phenyl-l-cyclopropanemethylamine (which was prepared from 1-phenyl-l-cyclopropanecarbonitrile using the procedure of Example 12, Step A and then using the procedure of Example 5).
  • the final step provided two compounds which were separated by reverse phase preparative HPLC using a gradient elution of water (0.1% TFA) and acetomtrile (0.1% TFA), 95:5 to 55:45 over lh.
  • the first compound to elute was 3-(l-phenyl-l-cyclopropanemethylamino)-6- methyl-l-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)- pyrazinone followed by the titled compound.
  • the appropriate fractions were concentrated and then partitioned between saturated NaHCO3 and
  • Step A 1.3-Dicvclopropyl-2-propanol (16-1).
  • Step B 1.3-Dicvclopropyl-2-propyl methanesulfonate (16-2)
  • Step C 1.3-Dicvclopropyl-2-propyl azide (16-3)
  • Step E 3-(l-Cyclopropylmethyl-2-cyclopropylethylamino)-l-(2-amino- 6-methvl-5-methvlenecarboxamidomethvlpvridinvl)-6-methylpyrazin(lH)- 2-one (16-5)
  • Step B 3-(2-Cyclobutyl-2,2-difluoroethylamino)-6-methyl- l-(2- amino-6-methyl-5-methylcarboxamidomethylpyridinyl)- pyrazinone dihvdrochloride (18-2) 18-2 was prepared as the bis-HCl salt from 18-1 using the procedures of Example 5, Steps C-F as a tan solid: MS (FAB) 421 (M+l) + .
  • p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm"lM"l.
  • Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4-trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 K m 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 (Vo) or presence of inhibitor (V were measured. Assuming competitive inhibition, and that unity is negligible compared K m /[S], [I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of V 0 /Vi on [I] shown in equation 1.
  • V 0 Vi 1 + [I]/Ki (1)
  • 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 compounds of the invention against human thrombin, represented by Ki is less than 24 nM. These are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1000 nM.
  • Inhibitory activity of compounds of the invention is shown above.
  • compositions A-I Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compounds are prepared as illustrated below (compositions A-I).
  • Active I is 3-(2-Cyclobutyl-2,2-difluoroethylamino)-6- methyl-l-(2-amino-6-methyl-5-methylcarboxamidomethylpyridinyl)- pyrazinone dihydrochloride;
  • Active II is 3-[2-(3-Fluorophenethylamino)]- 6-methyl-l-(2-amino-3,6-dimethyl-5-methylcarboxamidomethyl- pyridinyl)-pyrazinone_dihydrochloride;
  • Active III is 3-(2- Phenethylamino)-6-methyl-l-(2-amino-3,6-dimethyl-5- methylcarboxamidomethylpyridinyD-pyrazinone dihydrochloride; and
  • Active IV is 3-(
  • Modified food corn starch 37.25 4.25 8.5 37.25 4.25 8.5 37.25 4.25 8.5 37.25 4.25 8.5
  • All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • compositions of 3-(2,2-difluoro-2- phenylethylamino)-l-(2-amino-3,6-dimethyl-5- methylenecarboxamidomethylpyridinyl)-6-methylpyrazin(lH)-2-one tablets are shown below:
  • Active IV, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 ⁇ m) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water-soluble polymers and pigment.
  • Tablet preparation via dry granulation Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.
  • Intravenous formulations of 3-(2,2-difluoro-2- phenylethylamino)-l-(2-amino-3,6-dimethyl-5- methylenecarboxamidomethylpyridinyl)-6-methylpyrazin(lH)-2-one were prepared according to general intravenous formulation procedures.
  • compositions A-C are as follows:
  • Component A B C Component A B C .
  • buffer acids such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.

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Abstract

L'invention concerne des composés aptes à inhiber la thrombine et les occlusions thrombotiques associées, lesquels composés ont la structure (a), par exemple, la structure (17-1).
PCT/US1998/018417 1996-04-23 1998-09-03 Inhibiteurs de thrombine a base de pyrazinone WO1999011267A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002301520A CA2301520A1 (fr) 1997-09-05 1998-09-03 Inhibiteurs de thrombine a base de pyrazinone
EP98946835A EP1017393A4 (fr) 1997-09-05 1998-09-03 Inhibiteurs de thrombine a base de pyrazinone
JP2000508369A JP2001514227A (ja) 1997-09-05 1998-09-03 ピラジノン系トロンビン阻害薬
AU93767/98A AU746024B2 (en) 1996-04-23 1998-09-03 Pyrazinone thrombin inhibitors

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US5805897P 1997-09-05 1997-09-05
US60/058,058 1997-09-05
GBGB9801005.1A GB9801005D0 (en) 1998-01-16 1998-01-16 Pyrazinone thrombin inhibitors
GB9801005.1 1998-01-16

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Cited By (36)

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US6147078A (en) * 1998-05-19 2000-11-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
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
WO2000069834A1 (fr) * 1999-05-19 2000-11-23 Pharmacia Corporation Pyrazinones d'heteroaryle et d'aryle polycyclique substituees utiles a l'inhibition selective de la coagulation en cascade
WO2000075134A1 (fr) * 1999-06-04 2000-12-14 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
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
WO2001038323A1 (fr) * 1999-11-23 2001-05-31 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
WO2001077079A2 (fr) * 2000-04-05 2001-10-18 Pharmacia Corporation Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation
WO2001079195A2 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Nouveaux inhibiteurs de thrombine de type non covalent
WO2001079262A1 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Inhibiteurs de la thrombine a base de derives de pyrazinone et pyridinone
WO2001087854A1 (fr) * 2000-05-18 2001-11-22 Pharmacia Corporation Aryle polycyclique substitute et pyrazinones d'heteroaryle utilises dans l'inhibition selective de la coagulation
WO2001092234A1 (fr) * 2000-06-01 2001-12-06 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
WO2002006248A2 (fr) * 2000-07-17 2002-01-24 3-Dimensional Pharmaceuticals, Inc. Pyrazinones oxyguanidines cycliques comme inhibiteurs de protease
WO2002009711A1 (fr) * 2000-07-28 2002-02-07 Merck & Co., Inc. Inhibiteurs de thrombine
US6376499B1 (en) 1998-10-30 2002-04-23 Merck & Co., Inc. Thrombin inhibitors
WO2002046160A2 (fr) * 2000-12-06 2002-06-13 Merck & Co., Inc. Procede de preparation d'un inhibiteur de thrombines
US6444811B1 (en) 1999-07-19 2002-09-03 Merck Frosst Canada & Co. Pyrazinones, compositions containing such compounds and methods of use
US6458952B1 (en) 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6534510B2 (en) 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
US6610692B1 (en) 1998-10-30 2003-08-26 Merck & Co., Inc. Thrombin 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
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
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
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
EP1586565A1 (fr) * 1999-05-19 2005-10-19 Pharmacia Corporation Pyrazinones d'hétéroaryle et d'aryle polycyclique substituées utiles à l'inhibition selective de la coagulation en cascade
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
US7026324B2 (en) * 2001-02-09 2006-04-11 Merck & Co., Inc. Thrombin inhibitors
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
US7700523B2 (en) 1997-05-23 2010-04-20 Gendaq Limited Nucleic acid binding polypeptide library

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US7700523B2 (en) 1997-05-23 2010-04-20 Gendaq Limited Nucleic acid binding polypeptide library
US6147078A (en) * 1998-05-19 2000-11-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
EP1589029A3 (fr) * 1998-06-11 2006-01-18 Johnson & Johnson Pharmaceutical Research & Development L.L.C. Inhibiteurs de protéase à base de pyrazine
US6514978B2 (en) 1998-06-11 2003-02-04 3-Dimensional Pharmaceuticals, Inc. Thromboresistant materials incorporating pyrazinone protease inhibitors
US6204263B1 (en) 1998-06-11 2001-03-20 3-Dimensional Pharmaceuticals, Inc. Pyrazinone protease inhibitors
US6180627B1 (en) 1998-08-14 2001-01-30 Pfizer Inc. Antithrombotic agents
US6610692B1 (en) 1998-10-30 2003-08-26 Merck & Co., Inc. Thrombin inhibitors
US6376499B1 (en) 1998-10-30 2002-04-23 Merck & Co., Inc. Thrombin inhibitors
US6458952B1 (en) 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils 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
WO2000069834A1 (fr) * 1999-05-19 2000-11-23 Pharmacia Corporation Pyrazinones d'heteroaryle et d'aryle polycyclique substituees utiles a l'inhibition selective de la coagulation en cascade
EP1586565A1 (fr) * 1999-05-19 2005-10-19 Pharmacia Corporation Pyrazinones d'hétéroaryle et d'aryle polycyclique substituées utiles à l'inhibition selective de la coagulation en 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
US6867217B1 (en) 1999-05-19 2005-03-15 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
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
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
AU775229B2 (en) * 1999-05-19 2004-07-22 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones 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
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
JP2010150275A (ja) * 1999-06-04 2010-07-08 Merck Sharp & Dohme Corp ピラジノントロンビン阻害剤
US6455532B1 (en) 1999-06-04 2002-09-24 Merck & Co., Inc. Pyrazinone thrombin inhibitors
WO2000075134A1 (fr) * 1999-06-04 2000-12-14 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
US6444811B1 (en) 1999-07-19 2002-09-03 Merck Frosst Canada & Co. Pyrazinones, compositions containing such compounds and methods of use
US6387911B1 (en) 1999-11-23 2002-05-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
WO2001038323A1 (fr) * 1999-11-23 2001-05-31 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
US6852761B2 (en) 2000-03-13 2005-02-08 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes 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
US6534510B2 (en) 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
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
WO2001077079A2 (fr) * 2000-04-05 2001-10-18 Pharmacia Corporation Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation
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
WO2001077079A3 (fr) * 2000-04-05 2002-04-11 Pharmacia Corp Pyridones polycycliques 4-aryl et heteroaryl substituees utiles pour l'inhibition selective de la cascade de coagulation
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
WO2001079195A2 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Nouveaux inhibiteurs de thrombine de type non covalent
WO2001079262A1 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Inhibiteurs de la thrombine a base de derives de pyrazinone et pyridinone
WO2001079195A3 (fr) * 2000-04-14 2002-05-16 Corvas Int Inc Nouveaux inhibiteurs de thrombine de type non covalent
US6506754B1 (en) 2000-04-14 2003-01-14 Corvas International, Inc. Non-covalent thrombin inhibitors
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
WO2001087854A1 (fr) * 2000-05-18 2001-11-22 Pharmacia Corporation Aryle polycyclique substitute et pyrazinones d'heteroaryle utilises dans l'inhibition selective de la coagulation
WO2001092234A1 (fr) * 2000-06-01 2001-12-06 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
US6521625B2 (en) 2000-06-01 2003-02-18 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6476016B2 (en) 2000-07-17 2002-11-05 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
WO2002006248A3 (fr) * 2000-07-17 2002-04-04 Dimensional Pharm Inc Pyrazinones oxyguanidines cycliques comme inhibiteurs de protease
WO2002006248A2 (fr) * 2000-07-17 2002-01-24 3-Dimensional Pharmaceuticals, Inc. Pyrazinones oxyguanidines cycliques comme inhibiteurs de protease
US7030110B2 (en) 2000-07-17 2006-04-18 Ortho-Mcneil Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
WO2002009711A1 (fr) * 2000-07-28 2002-02-07 Merck & Co., Inc. 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
US6828338B2 (en) 2000-11-20 2004-12-07 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
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
WO2002046160A2 (fr) * 2000-12-06 2002-06-13 Merck & Co., Inc. Procede de preparation d'un inhibiteur de thrombines
WO2002046160A3 (fr) * 2000-12-06 2003-03-06 Merck & Co Inc Procede de preparation d'un inhibiteur de thrombines
US7026324B2 (en) * 2001-02-09 2006-04-11 Merck & Co., Inc. Thrombin inhibitors
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds 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

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JP2001514227A (ja) 2001-09-11
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