+

WO1998031670A1 - Inhibiteurs de thrombine - Google Patents

Inhibiteurs de thrombine Download PDF

Info

Publication number
WO1998031670A1
WO1998031670A1 PCT/US1998/000875 US9800875W WO9831670A1 WO 1998031670 A1 WO1998031670 A1 WO 1998031670A1 US 9800875 W US9800875 W US 9800875W WO 9831670 A1 WO9831670 A1 WO 9831670A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
mammal
mmol
amino
Prior art date
Application number
PCT/US1998/000875
Other languages
English (en)
Inventor
Philip E. Sanderson
Terry A. Lyle
Craig Coburn
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 GBGB9704209.7A external-priority patent/GB9704209D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU59613/98A priority Critical patent/AU722429B2/en
Priority to CA002277929A priority patent/CA2277929A1/fr
Priority to JP53457498A priority patent/JP2001508796A/ja
Priority to EP98902807A priority patent/EP0971891A4/fr
Publication of WO1998031670A1 publication Critical patent/WO1998031670A1/fr

Links

Classifications

    • 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
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 a-keto carboxyl derivatives.
  • Thrombin inhibitors described in prior publications contain sidechains of arginine and lysine. These structures show low selectivity for thrombin over other trypsin-like enzymes. Some of them show toxicity of hypotension and liver toxicity.
  • European Publication 601 459 describes sulfonamido heterocyclic thrombin inhibitors, such as N-[4-[(aminoimino- methyl)amino]butyl]-l-[N-(2-naphthalenylsulfonyl)-L-phenylalanyl]-L- prolinamide.
  • WO 94/29336 describes compounds which are useful as thrombin inhibitors.
  • WO 96/18644 describes heterocyclic derivatives as thrombin inhibitors.
  • the invention relates to compounds of the formula:
  • Rl 7 0(CH2)p-, wherein p is 1-4;
  • R2, Rl4 and Rl ⁇ are independently selected from -phenyl, unsubstituted or substituted with one or more of C1-4 alkyl,
  • Ci-4 alkyl unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, heteroaryl, or heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl, or
  • Rl5 and Rl6 a re joined to form a four to seven membered cycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl, or
  • R 3 is hydrogen
  • A is chosen from one of the following radicals:
  • R ⁇ -X is not Ci-4 alkyl, C3-7 cycloalkyl, or trifluoromethyl
  • R 4 is hydrogen, Ci-4 alkyl, Ci-4 alkoxy, halogen, -OCH2CF3,
  • -SO2NH2, -(CH2)1-4S0 2 R 6 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,
  • R9 is H or C 1-4 alkyl
  • RIO and RU are independently hydrogen, C3-7 cycloalkyl, aryl, heteroaryl, heter o cy cl oalkyl ,
  • Z is O, S or CH2;
  • R 5 is hydrogen, halogen
  • R 2 and Rl3 are independently hydrogen
  • Ci-4 linear or branched alkyl or alkoxy, C3-7 cycloalkyl, halogen, or trifluoromethyl;
  • 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 atrial fibrillation, deep venous thrombosis, pulmonary embolism, cardiac thromoembolism and associated stroke in patients with atrial fibrillation, mechanical heart valves, or recent myocardial infarction with decreased left ventricular function, disseminated intravascular coagulation, ocular build up of fibrin, unstable angina, refractory angina, transient ischemic attacks, thrombotic stroke, embolic stroke, 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.
  • W is hydrogen, -Ci-4 alkyl, -C3-7cycloalkyl, -SO2C1-7 alkyl, or -(CH2) n COOH, where n is 1-4;
  • A is chosen from one of the following radicals:
  • W is hydrogen, -SO2CH3, or
  • R 2 is -CH3
  • A is chosen from one of the following radicals:
  • 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.
  • 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.
  • the compounds 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 compounds 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 compounds 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 compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds 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 compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • a 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.
  • the dosage regimen utilizing the compounds 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 compounds when used for the indicated effects, will range between about 0.001 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.1-20 mg/kg/day.
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/minute during a constant rate infusion.
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
  • 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.
  • oral tablets can be prepared which contain an amount of active compound of between 1 and 500 mg, e.g. 1, 10, 100, 200, 300, 400 or 500 mg.
  • active compound typically, a patient in need of thrombin inhibitor compound, depending on weight and metabolism of the patient, would be administered between about 20 and 500 mg active compound per day.
  • two tablets containing 125 mg of active compound can be administered in the morning and two tablets containing 125 mg of active compound can again be administered in the evening.
  • one tablet containing 100 mg of active compound can be administered in the morning and one tablet containing 100 mg of active compound can again be administered in the evening.
  • one tablet containing 5 mg of active compound can be administered in the morning and one tablet containing 5 mg of active compound can again be administered in the evening.
  • An i.v. formulation can be administered to patients requiring parenteral administration, such as hospitalized patients who are fasted (e.g. perioperative patients) and certain patients with indwelling catheters.
  • parenteral administration such as hospitalized patients who are fasted (e.g. perioperative patients) and certain patients with indwelling catheters.
  • an i.v. formulation having 100 mg/ml active ingredient, at pH 4 could be administered twice a day at a dose of 0.5 ml/kg.
  • the compounds 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.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds can also be co-administered with suitable anti-coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • suitable anti-coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • the compounds enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • the compounds may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter. They may also be combined with heparin, aspirin, or warfarin.
  • 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 ⁇ 0.5 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.
  • 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.
  • HBT(HOBT or HOBt) 1-hydroxybenzotriazole hydrate BBC reagent benzotriazolyloxy-bis(pyrrolidino)- carbonium hexafluorophosphate
  • 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.
  • alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like.
  • alkenyl means straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like.
  • alkynyl means straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
  • Cycloalkyl means a cyclic, saturated ring containing 3 to 8 carbon atoms, e.g., cyclopropyl, cyclohexyl, etc.
  • Halogen means chloro, bromo, fluoro or iodo.
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from O, N, and S, e.g. phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.
  • the pharmaceutically-acceptable salts of the compounds of the invention 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, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos
  • 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 and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl and stearyl
  • Step A Starting 2,4-dihydroxy-3-nitropyridine is reacted with a dehydrating chloride source, for example phosphorous oxychloride, in Step A to give the 4-chloropyridine.
  • a dehydrating chloride source for example phosphorous oxychloride
  • Step B This is reacted in Step B with a thiol in the presence of a base such as triethylamine, and is then alkylated in Step C with an acetate equivalent such as t-butylbromoacetate.
  • a dehydrating chloride source for example phosphorous oxychloride
  • the ester may be deprotected by a strong acid such as TFA in Step D and the resulting carboxylic acid coupled in Step E with the appropriate amine, in this case cyclopropyl-(2-aminomethyl-4-chlorophenoxy)-acetamide (a method for the preparation of this class of amines is shown below) and the nitro group reduced in Step F by a reducing agent such as stannous chloride to give the final product.
  • a strong acid such as TFA in Step D
  • the resulting carboxylic acid coupled in Step E with the appropriate amine in this case cyclopropyl-(2-aminomethyl-4-chlorophenoxy)-acetamide (a method for the preparation of this class of amines is shown below) and the nitro group reduced in Step F by a reducing agent such as stannous chloride to give the final product.
  • Step F EDC, EtNH 2 .HCI HOBT, NMM, DMF
  • Step D Ethyl-(2-t-Butoxycarbonylaminomethyl-4-Chlorophen- oxy)-Acetate
  • Step E 2-t-Butoxycarbonylaminomethyl-4-Chlorophenoxyacetic Acid
  • 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.
  • 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-methylmorpholine (0.396 ml, 3.6 mmol) in DMF (4 ml) and the mixture was stirred for 16 h.
  • Step G Ethyl-(2-Aminomethyl-4-Chlorophenoxy)-Acetamide
  • Ethyl-(2-t-butoxycarbonylaminomethyl-4-chlorophenoxy)- 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 A The product of METHOD 1, Step A is alkylated with an acetate equivalent such as ethyl bromoacetate in Step A which is then reacted with the thiol in Step B.
  • the ester is then hydrolysed in Step C with lithium hydroxide and the resulting carboxylic acid is coupled with the appropriate amine, in this case 5-aminomethyl-2-t- butoxycarbonylamino-6-methylpyridine (a method for the preparation of this amine is shown below) in Step D.
  • the nitro group is reduced in Step E with hydrogen in the presence of a catalyst such as palladium on carbon and the BOC group removed by a strong acid such as HC1 in Step F to give the final product.
  • METHODS 1 and 2 Modifications of METHODS 1 and 2 will allow different W, R2, R3 and A groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
  • the starting pyridine in Step A can have as its side chain at the 6-position, ethyl, isopropyl, cyclopropyl, trifluoromethyl, and the like, to achieve the different operable values of R ⁇ .
  • the thiol in Step B can have as its R ⁇ group, benzyl, cyclopropylmethyl, and the like, to achieve the different operable values of R 2 .
  • An appropriate choice of the amine in the coupling step will allow the different operable values of A to be achieved.
  • W groups may be introduced by such methods as alkylation, acylation or sulfonylation of the products of METHOD 1, Step F and METHOD 2, Step E. Obvious variations and modifications of the method to produce similar and obvious variants thereof, will be apparent to one skilled in the art.
  • Step B in this case where R 2 is benzyl, is reduced in Step A with a reducing agent such as iron in acetic acid to give the amine.
  • a reducing agent such as iron in acetic acid
  • the ester is then hydrolysed and coupled with the appropriate amine, in this case 2-amino-5-aminomethyl-6- methylpyridine (a method for the preparation of this amine is shown below) in Step B to give the final product.
  • Step A is reacted with a sulfinate salt in this case were R 2 is cyclopropylmethyl in a solvent such as ethanol or DMF in Step A to give the sulfone.
  • the nitro group may be reduced in Step B with hydrogen in the presence of a catalyst such as palladium on carbon, the ester hydrolysed in Step C and the resulting carboxylic acid coupled to with the appropriate amine, in this case 2- amino-5-aminomethyl-6-methylpyridine, in Step D to give the final product.
  • Sulfinate salts used in the preparation of compound of the invention may be generated from the sulfinic acids. They may also be generated by a number of other methods, including the reductive cleavage of 2-sulfonylbenzothiazoles, the reaction of organometallics with sulfur dioxide, the reduction of sulfonyl chlorides, the oxidation of thiols and the cleavage of phthalimidomethyl sulfones.
  • Modifications of this method will allow different W, R 2 , R ⁇ and A groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
  • the starting pyridinone in Step A can have as its side chain at the 6-position, ethyl, isopropyl, cyclopropyl, trifluoromethyl, and the like, to achieve the different operable values of R ⁇ .
  • the sulfinate in Step A can have as its R 2 group, benzyl, cyclopentyl, and the like, to achieve the different operable values of R 2 .
  • An appropriate choice of the amine in Step D will allow the different operable values of A to be achieved.
  • the product of METHOD 2, Step B, in this case where R 2 is benzyl, may be oxidized with a suitable oxidizing agent such as OXONE® or a peracid such as mCPBA to give the sulfone which may be further manipulated, for example by the procedures of METHOD 4, Steps B-D, to give the products of the invention.
  • a suitable oxidizing agent such as OXONE® or a peracid such as mCPBA
  • the starting 2-hydroxy-3-nitropyridine is alkylated with an acetate equivalent such as t-butyl bromoacetate in Step A to give the pyridinone.
  • This is reacted with an organomagnesium reagent, in this case cyclohexylmethyl magnesium bromide, in Step B.
  • the resulting lactam is oxidised in Step C with an oxidising agent such as DDQ or nickel peroxide to regenerate the pyridinone.
  • the t-butyl group is removed using a strong acid such as HC1 in Step D and the resulting carboxylic acid coupled with the appropriate amine, in this case 2-BOC- amino-5-aminomethyl-6-methylpyridine in Step E.
  • the nitro group is reduced in Step F by hydrogenation using a catalyst such as palladium on carbon and the the BOC group is removed in Step G with a strong acid such as TFA to give the final product.
  • the starting acid is esterified in Step A and is alkylated with t-butyl bromoacetate in Step B.
  • the resulting pyridinone is reacted with an organomagnesium reagent, in this case benzyl magnesium chloride, in Step C and the lactam is oxidised in Step D with an oxidising agent such as DDQ or nickel peroxide to regenerate the pyridinone.
  • an organomagnesium reagent in this case benzyl magnesium chloride
  • the lactam is oxidised in Step D with an oxidising agent such as DDQ or nickel peroxide to regenerate the pyridinone.
  • the t-butyl group is removed using a strong acid such as TFA in Step E and the resulting carboxylic acid coupled with the appropriate amine, in this case 2-BOC-amino-5-aminomethyl-6-methylpyridine in Step F.
  • the ethyl ester is hydrolysed with lithium hydroxide in Step G and the acid was rearranged to the isocyanate via the acyl azide using DPPA and a base such as triethylamine followed by heating in Step H.
  • the intermediate isocyanate is then reacted with benzyl alcohol in the presence of a base to give the CBZ derivative.
  • the CBZ group was removed by hydrogenolysis in Step I using a catalyst such as palladium and the amine is then sulfonylated in Step J, in this case with methane sulfonyl chloride, in the presence of a base such as pyridine.
  • the BOC group is removed in Step K with a strong acid such as TFA to give the final product.
  • METHODS 6 and 7 will allow different W, R 2 , R3 and A groups contemplated by the scope of the broad claim below to be present by the use of an appropriate reagent or appropriately substituted starting material in the indicated synthetic step.
  • the starting pyridine can have as its side chain at the 6- position, ethyl, isopropyl, cyclopropyl, trifluoromethyl, and the like, to achieve the different operable values of R3.
  • Different operable values of R . may be acheived by the appropriate choice of the organometallic reagent.
  • An appropriate choice of the amine in the coupling step will allow the different operable values of A to be achieved.
  • W groups may be introduced by such methods as alkylation, acylation or sulfonylation of the products from METHOD 6, Step F, and METHOD 7, Step I. Obvious variations and modifications of the method to produce similar and obvious variants thereof, will be apparent to one skilled in the art.
  • Amide couplings 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.
  • Step B Ethyl 6-methyl-l-(t-butyl acetate)pyridin[lH]-2-one-3- carboxylate (1-2)
  • Step C Ethyl 4-benzyl-3,4-dihydro-6-methyl-l-(t-butyl acetate)pyridinriHl-2-one-3-carboxylate (1-3) To a stirred -78° solution of 1.0 g (3.39 mmol) of ethyl 6-me- thyl-l-(t-butyl acetate )pyridin-2-one-3-carboxylate in 20 mL of anhydrous THF was added a 2M THF solution of benzylmagnesium chloride dropwise. After stirring for 15 min at -78, the reaction was stored in the freezer (approx. -15 °C) overnight.
  • Step D Ethyl 4-benzyl-6-methyl-l-(t-butyl acetate)pyridin[lH]-2- one-3-carboxylate (1-4)
  • Step E Ethyl 4-benzyl-6-methyl-l-carboxymethylpyridin[lH]-2- one-3-carboxylate (1-5)
  • Step F 4-Benzyl-3-(ethoxycarbonyl)-6-methyl-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl) pyridin[lH]-2-one
  • Step G 4-Benzyl-3-carboxy-6-methyl- l-(2-t-butyloxycarbonylamino-
  • Step H 4-Benzyl-3-(benzyloxycarbonylamino)-6-methyl-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl) pyridin[lH]-2-one
  • Step I 4-Benzyl-3-amino-6-methyl-l-(2-t-butyloxycarbonylamino-6- methyl-5-methylenecarboxamidomethylpyridinyl) pyridinriHl-2-one (1-9)
  • Step J 4-Benzyl-3-(methanesulfonylamino)-6-methyl-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl) pyridin[lH]-2-one
  • Step I The product from Step I was dissolved in 3 mL of pyridine, cooled in an ice bath and treated with 28 ⁇ L (0.36 mmol) of methane sulfonyl chloride dropwise. The cold bath was allowed to expire over a 2.5 h period, the reaction concentrated at reduced pressure, partitioned between CHCI3 and 1M citric acid.
  • Step K 4-Benzyl-3-methanesulfonylamino-6-methyl-l-(2-amino-
  • Step A 4-Chloro-2-hvdroxy-6-methyl-3-nitropyridine (II- 1) POC13 (7.6 mL, 81.4 mmol) was added to a solution of 2,4- dihydroxy-6-methyl-3-nitropyridine (Fluka, 3.15 g, 18.5 mmol) and BnEt3NCl (16.8 g, 74 mmol) in MeCN (65 mL). The resulting solution was stirred at 40° C for 30 min then was heated at reflux for 1 h. After evaporation of the solvent, water (70 mL) was added and the mixture was stirred at room temperature for 16 h. The precipitate which formed was filtered and washed with hexane to afford II-l as a yellow solid.
  • IH NMR (DMSO-d6) d 2.25 (s, 3H), 6.45 (s, IH).
  • Step B 2-Hvdroxy-6-Methyl-3-Nitro-4-Thiophenylpyridine (II-2)
  • Step C l-(t-Butyl-Methylenecarboxy)-6-Methyl-3-Nitro-4-
  • Step D 1- Methylenecarboxy-6-Methyl-3-Nitro-4-Thiophenyl-2-
  • Step F 3-Amino-6-Methyl-4-Thiophenyl-l-[Cyclopro ⁇ yl-(2- Methylenecarboxamidomethyl-4-Chlorophenoxy)- Acetamidol-2-Pyridinone (II-6) To a solution of 6-methyl-3-nitro-4-thiophenyl-l-[cyclopropyl-
  • Step A 4-Chloro-6-methyl-3-nitro-l-(ethyl-methylenecarboxy)-2- pyridinone (IH-1)
  • Step B 4-IsopropyltMo-6-methyl-3-mtro-l-(ethyl- methylenecarboxy)-2-pyridinone (III-2)
  • Step C 4-Isopropylthio-6-methyl-3-nitro- l-methylenecarboxy-2- pyridinone (III-3)
  • Step D 4-Isopropylthio-6-methyl-3-nitro-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone ⁇ iH]
  • Step F 3-Amino-4-isopropylthio-6-methyl-l-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone
  • Step C 4-Cyclopropylmethylsulfonyl-6-methyl-3-nitro-l-(ethyl- methylenecarboxy)-2-pyridinone (IV-3 )
  • Step D 3-Amino-4-cyclopropylmethylsulfonyl-6-methyl- l-(ethyl- methylenecarboxy)-2 -pyridinone (IV-4)
  • Step E 3-Amino-4-cyclopropylmethylsulfonyl-6-methyl-l- methylenecarboxy-2-pyridinone (IN-5)
  • Lithium hydroxide hydrate (84 mg, 2.0 mmol) was added to a stirred mixture of 3-amino-4-cyclopropylmethylsulfonyl-6-methyl-l- (ethyl-methylenecarboxy)-2-pyridinone (the product from Step D) in 2:2:1 methanol/THF/water (10 mL). After 2 h a thick white precipitate formed. The mixture was acidified with 1 M HC1 to give a clear solution which was partitioned between methylene chloride and brine. The brine was re-extracted with methylene chloride and the combined organic layers were dried (Na2S04) and evaporated in vacuo to give a crystalline solid.
  • Step F 3-Amino-4-cyclopropylmethylsulfonyl-6-methyl-l-(2-amino- ⁇ -methyl- ⁇ -methylenecarboxamidomethylpyridinyl)- ⁇ pyridinone (IV-6)
  • ⁇ -Methylmorpholine (0.187 mL, 1.70 mmol) was added to a stirred mixture of 3-amino-4-cyclopropylmethylsulfonyl-6-methyl-l- methylenecarboxy-2-pyridinone (120 mg, 0.40 mmol), 2-amino-5- aminomethyl-6-methylpyrinine dihydrochloride (84 mg, 0.40 mmol), EDC.HC1 (96 mg, 0.50 mmol) and HOBT.H20 (68 mg, 0.50 mmol) in DMF (2 mL).
  • Step A Lithium cyclopropylsulfinate (V-l)
  • V-l was prepared by a modification of the method of Crowell et. al. (J. Med. Chem. 1989, 32, 2436).
  • a solution of cyclopropyl bromide (1.73 mL, 21.6 mmol) in dry diethyl ether (4 mL) was added dropwise to a stirred slurry of 30% lithium dispersion in mineral oil (1.0 g) in dry ether (8 mL) at 0° C (internal T ⁇ 5° C) under nitrogen. After 3 h, an excess of sulfur dioxide was blown on to the surface of the mixture to give a thick white precipitate.
  • the solvent was evaporated in vacuo and absolute ethanol (50 mL) was added cautiously.
  • Step B 4-Cyclopropylsulfonyl-6-methyl-3-nitro-l-(ethyl- methylenecarboxy)-2-pyridinone (V-2)
  • Glacial acetic acid was added dropwise to a solution of the crude lithium cyclopropylsulfinate from Step A (448 mg) in absolute ethanol (2 mL) to give a solution pH 4-5 (moist pH paper).
  • 4-Chloro-6- methyl-3-nitro-l-(ethyl-methylenecarboxy)-2-pvridinone (137 mg, 0.50 mmol) was added to give solution.
  • Over 1 h a thick precipitate forms which was collected by filtration, washing with ethanol, and dried at 0.5 mm Hg to give V-2 as a yellow solid which was used without purification in the next step.
  • Step C 3-Amino-4-cyclopropylsulfonyl-6-methyl-l-(2-amino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone (V-3)
  • V-3 was prepared from 4-cyclopropylsulfonyl-6-methyl-3- nitro-l-(ethyl-methylenecarboxy)-2-pyridinone using the procedures of
  • VI- 1 was prepared from bromomethylcyclobutane using the procedures of Example IV, Steps A - F.
  • EXAMPLE VII EXAMPLE VII
  • VII-2 may be prepared from 4-benzylthio-6- methyl-3-nitro-l-(ethyl-methylenecarboxy)-2-pyridinone by oxidation with OXONE® to give 4-benzylsulfonyl-6-methyl-3-nitro-l-(ethyl- methylenecarboxy)-2-pyridinone (VII- 1). followed by the use of the procedures of Example IV, Steps D-F:
  • Step A 6-Methyl-3-nitro-4-phenylsulfonyl-l-(ethyl- methylenecarboxy)-2-pyridinone (VIII- 1 )
  • Step B 3-Amino-4-phenylsulfonyl-6-methyl-l-(2-amino-6-methyl- 5-methylenecarboxamidomethylpyridinyl)-2-pyridinone
  • VIII-2 was prepared, as the free base, from 6-methyl-3- nitro-4-phenylsulfonyl-l-(ethyl-methylenecarboxy)-2-pyridinone using the procedures of Example IV, Steps D - F.
  • IX- 1 was prepared as the HC1 salt from 4-chloro-6-methyl-3- nitro-l-(ethyl-methylenecarboxy)-2-pyridinone and sodium thienylsufinate [which was prepared by the method of Crowell et. al. (J. Med. Chem. 1989, 32, 2436)] using the procedure of Example VIII.
  • Step A 3-Amino-4-benzylthio-6-methyl- l-(ethyl-methylenecarboxy)-
  • Step B 3-Amino-4-benzylthio-6-methyl-l-(2-amino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-2-pyridinone (X-2)
  • X-2 was prepared, as the free base, from 3-amino-4- benzylthio-6-methyl-l-(ethyl-methylenecarboxy)-2-pyridinone using the procedures of Example IV, Steps E and F.
  • Step A l-(t-Butyl methylenecarboxy)-6-Methyl-3-nitro- pyridin[lHl-2-one (XI- 1)
  • Step B l-(t-Butyl methylenecarboxy)-4-cyclohexylmethyl-3,4- dihvdro-6-methyl-3-nitro-Pyridin[lHl-2-one (XI-2)
  • XI-2-one l-(t-Butyl methylenecarboxy)-4-cyclohexylmethyl-3,4- dihvdro-6-methyl-3-nitro-Pyridin[lHl-2-one (XI-2)
  • Step C l-(t-Butyl methylenecarboxy)-4-cyclohexylmethyl-6- methyl-3-nitro-pyridinriHl-2-one (XI-3)
  • Step D l-Methylenecarboxy-4-cyclohexylmethyl-6-methyl-3- nitro-pyridinriHl-2-one (XI-4)
  • Step E 4-Cyclohexylmethyl-6-methyl-3-nitro-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-pvridin[lH]-2- one (XI-5)
  • Step F 3-Amino-4-cyclohexylmethyl-6-methyl-l-(2-t- butyloxycarbonylamino-6-methyl-5- methylenecarboxamidomethylpyridinyl)-pyridin[lH]-2- one (XI-6)
  • the product from Step D was dissolved in 18 mL of ethanol, 2 mL of water, 1 mL of acetic acid and hydrogenated at 50 psi using 32 mg of 20% Pd(OH)2 on carbon overnight.
  • the catalyst was removed by filtration, concentrated at reduced pressure and the residue partitioned between CHC13 and 10% Na2C ⁇ 3.
  • the organic layer was dried over Na2S04 and the solvents removed at reduced pressure to give XI-6 as a yellow oil:
  • Step G 3- Amino-4-cyclohexylmethyl-6-methyl- l-(2-amino-6- methyl-5-methylenecarboxamidomethylpyridinyl)-2- pyridinone (XI-7)
  • the product from Step F was dissolved in 5 mL of CH2C12 and treated with 5 mL of TFA under Ar for lh, concentrated at reduced pressure and purified by gradient elution preparative HPLC using a C- 18 stationary phase and 0.1% aqueous TFA/CH3CN as the mobile phase.
  • 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 10.0, 25.0, and 50.0 mg, respectively, of active ingredient per tablet.
  • An intravenous dosage form of the above-indicated active compound is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à un composé qui est un inhibiteur de la thrombine d'origine humaine et qui est représenté par la formule (a) ou par la formule (b).
PCT/US1998/000875 1997-01-22 1998-01-16 Inhibiteurs de thrombine WO1998031670A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU59613/98A AU722429B2 (en) 1997-01-22 1998-01-16 Thrombin inhibitors
CA002277929A CA2277929A1 (fr) 1997-01-22 1998-01-16 Inhibiteurs de thrombine
JP53457498A JP2001508796A (ja) 1997-01-22 1998-01-16 トロンビン阻害薬
EP98902807A EP0971891A4 (fr) 1997-01-22 1998-01-16 Inhibiteurs de thrombine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3614997P 1997-01-22 1997-01-22
US60/036,149 1997-01-22
GBGB9704209.7A GB9704209D0 (en) 1997-02-28 1997-02-28 Thrombin inhibitors
GB9704209.7 1997-02-28

Publications (1)

Publication Number Publication Date
WO1998031670A1 true WO1998031670A1 (fr) 1998-07-23

Family

ID=26311088

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/000875 WO1998031670A1 (fr) 1997-01-22 1998-01-16 Inhibiteurs de thrombine

Country Status (5)

Country Link
EP (1) EP0971891A4 (fr)
JP (1) JP2001508796A (fr)
AU (1) AU722429B2 (fr)
CA (1) CA2277929A1 (fr)
WO (1) WO1998031670A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018762A1 (fr) * 1998-09-28 2000-04-06 Merck & Co., Inc. Inhibiteurs de la thrombine
FR2786482A1 (fr) * 1998-11-27 2000-06-02 Synthelabo Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique
WO2000073302A1 (fr) * 1999-05-27 2000-12-07 3-Dimensional Pharmaceuticals, Inc. Oxazaheterocycles comme inhibiteurs de protease
WO2000075134A1 (fr) * 1999-06-04 2000-12-14 Merck & Co., Inc. Inhibiteurs de thrombine a base de pyrazinone
WO2001087842A1 (fr) * 2000-05-18 2001-11-22 Pharmacia Corporation Pyridones aryle et heteroaryle polycycliques substituees utilisees pour l'inhibition selective de la cascade de coagulation
WO2002012207A1 (fr) * 2000-08-04 2002-02-14 3-Dimensional Pharmaceuticals, Inc. Inhibiteurs de protease a base d'oxyguanidine cyclique
US6387911B1 (en) 1999-11-23 2002-05-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6403583B1 (en) 1998-12-23 2002-06-11 Patrick Y. S. Lam Thrombin or factor Xa 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
US6476016B2 (en) 2000-07-17 2002-11-05 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease 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
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
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
EP1055683A4 (fr) * 1998-02-17 2007-07-25 Nippon Kayaku Kk Nouveau derive d'acetamide et son utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033974A1 (fr) * 1995-04-27 1996-10-31 The Green Cross Corporation Composes heterocycliques amides et leur utilisation medicinale

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0804464B1 (fr) * 1994-12-13 2002-05-08 Corvas International, Inc. Derives aromatiques heterocycliques utilisables comme inhibiteurs d'enzymes
CA2224437A1 (fr) * 1995-06-27 1997-01-16 Merck & Co., Inc. Inhibiteurs de la thrombine a base de pyridinone
EP0923372A4 (fr) * 1996-02-22 2001-09-05 Merck & Co Inc Inhibiteurs de pyridinone thrombine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033974A1 (fr) * 1995-04-27 1996-10-31 The Green Cross Corporation Composes heterocycliques amides et leur utilisation medicinale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0971891A4 *

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1055683A4 (fr) * 1998-02-17 2007-07-25 Nippon Kayaku Kk Nouveau derive d'acetamide et son utilisation
EP1117660A4 (fr) * 1998-09-28 2002-01-09 Merck & Co Inc Inhibiteurs de la thrombine
US6117888A (en) * 1998-09-28 2000-09-12 Merck & Co., Inc. Thrombin inhibitors
WO2000018762A1 (fr) * 1998-09-28 2000-04-06 Merck & Co., Inc. Inhibiteurs de la thrombine
FR2786482A1 (fr) * 1998-11-27 2000-06-02 Synthelabo Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique
WO2000032574A1 (fr) * 1998-11-27 2000-06-08 Sanofi-Synthelabo Nouveaux derives de 2-pyridone, leur preparation et leur application en therapeutique
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
US6664255B1 (en) 1999-05-19 2003-12-16 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
US6870056B1 (en) 1999-05-19 2005-03-22 Pharmacia Corporation Substitituted 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
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils 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
US6653316B1 (en) 1999-05-19 2003-11-25 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
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
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
AU761982B2 (en) * 1999-06-04 2003-06-12 Merck Sharp & Dohme Corp. Pyrazinone thrombin inhibitors
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
US6387911B1 (en) 1999-11-23 2002-05-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
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
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
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
WO2001087842A1 (fr) * 2000-05-18 2001-11-22 Pharmacia Corporation Pyridones aryle et heteroaryle polycycliques substituees utilisees pour l'inhibition selective de la cascade de coagulation
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
WO2002012207A1 (fr) * 2000-08-04 2002-02-14 3-Dimensional Pharmaceuticals, Inc. Inhibiteurs de protease a base d'oxyguanidine cyclique
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
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
US6828338B2 (en) 2000-11-20 2004-12-07 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines 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
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

Also Published As

Publication number Publication date
EP0971891A4 (fr) 2000-04-19
EP0971891A1 (fr) 2000-01-19
JP2001508796A (ja) 2001-07-03
AU722429B2 (en) 2000-08-03
CA2277929A1 (fr) 1998-07-23
AU5961398A (en) 1998-08-07

Similar Documents

Publication Publication Date Title
AU722429B2 (en) Thrombin inhibitors
US5869487A (en) Pyrido 3,4-B!pyrazines for use as thrombin inhibitors
US5744486A (en) Pyridinone thrombin inhibitors
EP0934064B1 (fr) Inhibiteurs de thrombine
AU720616B2 (en) Pyridinone thrombin inhibitors
US5629324A (en) Thrombin inhibitors
US5792779A (en) Pyridinone thrombin inhibitors
EP0835109A1 (fr) Inhibiteurs de la thrombine a base de pyridinone
US6534510B2 (en) Thrombin inhibitors
EP0820453A1 (fr) Inhibiteurs de thrombine
US6117888A (en) Thrombin inhibitors
AU709088B2 (en) Thrombin inhibitors
US5798377A (en) Thrombin inhibitors
US6017934A (en) Thrombin inhibitors
US5792761A (en) Thrombin inhibitors
AU741766B2 (en) Thrombin inhibitors
EP0949921B1 (fr) Inhibiteurs de la thrombine
CA2374654A1 (fr) Inhibiteurs de la thrombine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GE GW HU ID IL IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998902807

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2277929

Country of ref document: CA

Ref country code: CA

Ref document number: 2277929

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1998 534574

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 59613/98

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 1998902807

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 59613/98

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1998902807

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载