WO2002057225A2 - Inhibiteurs de thrombine - Google Patents

Inhibiteurs de thrombine Download PDF

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Publication number
WO2002057225A2
WO2002057225A2 PCT/US2001/048673 US0148673W WO02057225A2 WO 2002057225 A2 WO2002057225 A2 WO 2002057225A2 US 0148673 W US0148673 W US 0148673W WO 02057225 A2 WO02057225 A2 WO 02057225A2
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WO
WIPO (PCT)
Prior art keywords
difluoro
amino
chloro
benzyl
oxo
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PCT/US2001/048673
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English (en)
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WO2002057225A3 (fr
Inventor
Harold G. Selnick
Kenneth E. Rittle
James C. Barrow
Philippe G. Nantermet
Donnette Staas
Matthew M. Morrissette
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Merck & Co., Inc.
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Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU2002246675A priority Critical patent/AU2002246675A1/en
Publication of WO2002057225A2 publication Critical patent/WO2002057225A2/fr
Publication of WO2002057225A3 publication Critical patent/WO2002057225A3/fr

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    • 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
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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.
  • 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.
  • the invention includes compounds having the following structure:
  • ring atom is selected from the group of heteroatoms consisting of N, O and S, wherein the ring carbons are unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with C, 4 alkyl, or
  • R 9 where R is hydrogen or C ⁇ _ 8 alkyl
  • Z is -(CH 2 ) 2 . 4 -, -CF 2 (CH 2 ) 1 . 3 -, or -(CH 2 ),. 3 S0 2 -;
  • X is CH or N;
  • R 1 is halogen;
  • R 2 is hydrogen or halogen; and R 3 and R 4 are independently selected from the group consisting of hydrogen, -C(0)R 5 , where R 5 is selected from the group consisting of OC(CH 3 ), OCH 3 , CH 3 ,
  • R 6 is phenyl; C ⁇ - 4 alkyl, C 3 . 7 cycloalkyl, -(CH 2 ) ⁇ . 2 R 7 , where R 7 is selected from the group consisting of C 3 . 7 cycloalkyl and phenyl, -S0 2 R 8 , where R 8 is C,. 4 alkyl.
  • R 1 is Cl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen
  • R 5 is selected from the group consisting of OC(CH 3 ), OCH 3 , CH 3 ,
  • R 7 is selected from the group consisting of cyclopropyl and phenyl, and -S0 2 CH 3 .
  • X is CH or N
  • Z is -CH 2 CH 2 -, -CF 2 CH 2 -, -CH 2 S02-;
  • R' is Cl
  • R 2 is hydrogen or Cl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, -C(0)OC(CH 3 ) 3 , -C(0)OCH 3 ,
  • 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; "halogen”, 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.
  • cycloC ⁇ - alkyl is intended to include non-heterocyclic saturated rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • aryl as used herein except where noted, represents a stable 6- to 10- membered mono- or bicyclic non-heterocyclic unsaturated ring system such as phenyl, or naphthyl.
  • the aryl ring can be unsubstituted or substituted with one or more of C ⁇ -4 lower alkyl; hydroxy; alkoxy; halogen; amino.
  • heterocycle or “heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl
  • methyl substituents may be represented by f— CH 3 or
  • the structures HN and H have equivalent meanings.
  • 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, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and 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) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood.
  • venous thromboembolism e.g. obstruction or occlusion of a vein by a detached thrombus
  • cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
  • 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.
  • 1,4-dioxane in a 2 L heavy- walled flask was added 84 mL (1.571 mol) concentrated sulfuric acid at ambient temperature.
  • the reaction mixture was chilled to -15 °C, and 580 mL isobutylene was condensed directly into the reaction vessel.
  • the sealed pressure flask was shaken mechanically at room temperature for 4 h (the pressure inside the flask rises to ca. 20 psi during this step).
  • the mixture was carefully quenched by slowly pouring it into a 0-5°C stirred mixture of 1.2 L tert-butyl methyl ether and 336 g (4.0 mol) solid sodium bicarbonate before slow dilution with 1.2 L ice- water.
  • the separated organic phase was washed with 0.8 L brine, dried with sodium sulfate, filtered concentrated in vacuo to give an oil, which was used without further purification.
  • Step A 2-(tert-butoxycarbonyl)-7-chloro-3,4-dihydro-2H-isoquinolin-l-one
  • 7-chloro-3,4-dihydroisoquinolin-l-one (11.6g, 12.6mMol) in 50mL of anhydrous N,N-dimethylformamide under inert atmosphere at ambient temperature was added diisopropylethylamine (17.0mL, 95.8mMol, 1.5eq), di-tert-butyl dicarbonate (15.33g, 70.26mMol, l.leq), and a catalytic amount of 4-(dimethylamino)pyridine.
  • Step B 2-(tert-butoxycarbonylaminoethyl)-5-chlorobenzyl alcohol
  • STEP B tert-Butyl 2-cyanobenzylcarbamate: To the THF layer from the previous step was diluted to a volume of 1.6 L, divided into two equal portions and each hydrogenated at 45psi in a Parr pressure bottle containing 6 g of 5% palladium on carbon (50% water by weight). A 5-10°C exotherm was observed within 30 min and shaking continued a total of 1.5 hr. The individual batches were filtered through celite, washed 2x with 100 mL fresh THF and the filtrates combined into a single portion.
  • Additional sodium borohydride and cobaltous chloride were added as needed to drive the reaction to completion. Typically, 2 x 7.5 g of additional sodium borohydride and 2 x 1 g portions of cobaltous chloride were added at 12 hour intervals.
  • the layers were allowed to settle and the clear upper THF layer was decanted from the black aqueous layer. The aqueous layer was washed with 750 mL fresh THF, the two THF layers combined and filtered through a pad of celite. The orange-yellow filtrate was concentrated to about 300 mL in vacuo, resulting in water layer with the product as an oily lower layer.
  • Step A 2-bromo-5-chlorobenzoate Through a solution of 2-bromo-chlorobenzoic acid (1 lg, 46J mmol) in methanol
  • Step D tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate To a solution of [2-(aminomethyl)-5-chlorophenyl]methanol in dichloromethane
  • Step C 2,2-Difluoro-2-(2-pyridyl)ethanol
  • ethyl difluoro-2-pyridylacetate 19.5 g (97 mmol) of ethyl difluoro-2-pyridylacetate in 200 mL of absolute ethanol at 0°C was added 4.42 g (116 mmol) of sodium borohydride in small portions. After 30 min, the reaction was quenched by the addition of 50 mL of sat. NH 4 C1. The reaction mixture was concentrated at reduced pressure and the residue partitioned between 500 mL of ethyl acetate and sat. NaHC0 3 .
  • Step G Ethyl N-(ethyl carboxymethyl)oxamate
  • ethyl glycine ⁇ Cl 38.4 g, 275 mmol
  • 1 ,2-dichloroethane 360 mL
  • triethylamine 77.0 mL, 550 mmol
  • the heterogenous mixture was cooled to 0 °C and ethyl oxalyl chloride (30.3 mL, 275 mol) was added dropwise over the course of 1 h.
  • the cooling bath was removed and the reaction was stirred at room temperature overnight.
  • the reaction was diluted with water (250 mL) and the layers separated.
  • aqueous layer was backwashed with 2 portions of dichloromethane (250 mL).
  • the combined organic layers were washed with water (250 mL), followed by brine (250 mL), dried over MgS0 4 and concentrated to give ethyl n-(ethyl carboxymethyl)oxamate_as an oil that was taken directly onto the next step.
  • Step J Ethyl 3-bromopyrazin(lH)-2-one-l -acetate
  • a solution of the hydroxypyrazinone (25.0 g, 126 mmol) and phosphorous oxybromide (37.9 g, 132 mmol) in 1,2-dichloroethane (250 mL) was heated to reflux. After 8 h the reaction mixture was treated with sat. aq. Na 2 C0 3 (250 mL) and stirred for lh. The mixture was diluted with water (100 mL) and dichloromethane (100 mL), the layers were separated and the aqueous layer was backwashed with EtOAc (3 x 200mL).
  • Step K Ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2-one-l-acetate
  • Step L Ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)-6-chloropyrazin(lH)-2-one-l-acetate
  • Step M 3-(2,2-Difluoro-2-(2-pyridylethylamino)-6-chloropyrazin(lH)-2-one-l -acetic acid
  • ethyl 3-(2,2-difluoro-2-(2- pyridylethylamino)-6-chloropyrazin(lH)-2-one-l-acetate was added 39 mL
  • Triphenylphosphine (7.72 g, 29.5 mmol) was added to a water bath cooled solution of 2,2-difluoro-2-(2-pyridyl-N-oxide)ethylazide (5.61 g, 28.1 mmol) in THF (90 mL). After 1 h water (10 mL) was added and the mixture was heated to 55 °C. Two hours after the addition of water, the heating bath was removed and the solution was allowed to stir overnight. The reaction was subsequently concentrated, diluted with EtO Ac (250 mL), and HCl (25 mL, 2.6M in EtO Ac) was added dropwise.
  • EtO Ac 250 mL
  • HCl 25 mL, 2.6M in EtO Ac
  • Step C Ethyl 3-(2,2-difluoro-2-(2-pyridyl-N-oxide-ethylamino)pyrazin(lH)-2-one-l-acetate
  • Step D Ethyl 3-(2,2-difluoro-2-(2-pyridyl-N-oxide-ethylamino)-6-chloropyrazin(lH)-2-one-l-acetate
  • Step E 3-(2,2-Difluoro-2-(2-pyridyl-N-oxide-ethylamino)-6-chloropyrazin(lH)-2-one-l-acetic acid
  • Step B l-(2- ⁇ [2-(Ammoniomethyl)benzyl]amino ⁇ -2-oxoethyl)-6-chloro-3-[(2,2-difluoro-2- pyridinium-2-ylethyl)amino]-2-oxo- 1 ,2-dihydropyrazin-4-ium trichloride:
  • EXAMPLE 10 1 -(2- ⁇ [2-(2- Ammonioethyl)benzyl]amino ⁇ -2-oxoethyl)-6-chloro-3-[(2,2-difluoro-2-pyridinium-2- ylethyl)amino]-2-oxo- 1 ,2-dihydropyrazin-4-ium trichloride:
  • EXAMPLE 20 l-[2-( ⁇ 2-[(Acetylamino)methyl]benzyl ⁇ amino)-2-oxoethyl]-6-chloro-3-[(2,2-difluoro-2-pyridinium-2- ylethyl)amino]-2-oxo-l,2-dihydropyrazin-4-ium bis(trifluoroacetate):
  • the title compound is prepared using a similar procedure as described for the synthesis of 6-chloro-3-[(2,2-difluoro-2-pyridinium-2-ylethyl)amino]-l- ⁇ 2-[(2- ⁇ [(methoxycarbonyl) aminojmethyl ⁇ benzyl)amino]-2-oxoethyl ⁇ -2-oxo-l,2-dihydropyrazin-4-ium bis(trifluoroacetate) in EXAMPLE 19 except acetic anhydride is substituted for methyl chloroformate: ⁇ N
  • EXAMPLE 22 6-Chloro-3-[(2,2-difluoro-2-pyridinium-2-ylethyl)amino]-l-(2- ⁇ [2-( ⁇ [(methylamino) carbonyl]amino ⁇ methyl)benzyl]amino ⁇ -2-oxoethyl)-2-oxo-l,2-dihydropyrazin-4-ium bis(trifluoroacetate):
  • the title compound is prepared using a similar procedure as described for the synthesis of 6-chloro-3-[(2,2-difluoro-2-pyridinium-2-ylethyl)amino]-l- ⁇ 2-[(2- ⁇ [(methoxycarbonyl) aminojmethyl ⁇ benzyl)amino]-2-oxoethyl ⁇ -2-oxo-l,2-dihydropyrazin-4-ium bis(trifluoroacetate) in EXAMPLE 19 except N-[2-(aminomethyl) benzy
  • STEP A tert-butyl 4-chloro-2-( ⁇ [(6-methyl-2-oxo-3-[(2-phenylethyl)amino]-l(2#)- pyrazinyl)acetyl]amino ⁇ methyl)benzylcarbamate
  • tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate To a stirred solution of tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate and [6-methyl-2- oxo-3-[(2-phenylethyl)amino]pyrazin-l(2/ )-yl]acetic acid (J. Med. Chem.
  • Step A 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2-n- propylaminomethyl-benzyl)-acetamide
  • N-(t- Butoxycarbonyl)-N-methyl-(2-aminomethyl)-benzylamine is prepared as follows: N-(t- Butoxycarbonyl)- 2-aminomethyl)-benzylamine sulfate (200 mg, 0.702 mmol) was partitioned between CHC1 3 and aqueous sodium bicarbonate. The combined organic layer was dried on sodium sulfate, concentrated in vacuo and azeotroped with benzene. To a solution of the resulting N-(t-
  • EXAMPLE 33A and 33B 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- ethylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2- oxo-2H-pyrazin-l-yl]-N-(2-diethylaminomethyl-benzyl)-acetamide
  • EXAMPLE 34A and 34B 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2-n- butylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2- oxo-2H-pyrazin-l-yl]-N-(2-bis-n-buthylaminomethyl-benzyl)-acetamide 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- n-butylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-
  • EXAMPLE 35A and 35B 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- isobutylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2- oxo-2H-pyrazin-l-yl]-N-(2-bis-isobutylaminomethyl-benzyl)-acetamide
  • EXAMPLE 36A and 36B 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- cyclopropylmethylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl- ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2-bis-cyclopropylmethylaminomethyl-benzyl)-acetamide
  • EXAMPLE 38A and 38B 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- phenethylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)- 2-oxo-2H-pyrazin-l-yl]-N-(2-bis-phenethylaminomethyl-benzyl)-acetamide 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2- phenethylaminomethyl-benzyl)-acetamide and 2-[6-chloro-3-(2,2-difluoro-2-pyr
  • Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
  • 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.
  • HMG CoA reductase inhibitors such as lovastatin, HMG CoA synthase inhibitors, etc.
  • atherosclerosis For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors.
  • 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 anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • Trypsin assays also contained 1 mM CaCl2- In assays wherein rates of hydrolysis of a p- nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance of p-nitroaniline.
  • p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm ⁇ M "1 .
  • 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 (V 0 ) or presence of inhibitor (Vj) were measured.
  • Vo/Vi 1 + [I]/Ki
  • 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.
  • compositions A-C Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compounds are prepared as illustrated below (compositions A-C).
  • Active I is compound 2-[6-chloro-3-(2,2-difluoro-2- pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2-cyclopentylaminomethyl-benzyl)-acetamide. Amount-(mg)
  • 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.
  • Active I, 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.
  • Intravenous formulations of compound 2-[6-chloro-3-(2,2-difluoro-2-pyridin-2-yl- ethylamino)-2-oxo-2H-pyrazin-l-yl]-N-(2-cyclopentylaminomethyl-benzyl)-acetamide (Active I) were prepared according to general intravenous formulation procedures.
  • compositions A-C are as follows:
  • 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 utiles dans l'inhibition de la thrombine et des occlusions thrombotiques associées ou un sel pharmaceutiquement acceptable desdits composés, lesquels sont représentés par la formule (I). Dans cette formule, R3 et R4 sont indépendamment choisis dans le groupe constitué par hydrogène, -C(O)R?5, où R5¿ est choisi dans le groupe constitué par OC(CH¿3?), OCH3, CH3, NHCH3 et OCH2R?6 (R6¿ étant phényle), alkyle C¿1-4?, cycloalkyle C3-7, -(CH2)1-2R?7, où R7¿ est choisi dans le groupe constitué par cycloalkyle C¿3-7? et phényle, et SO2R?8 (R8¿ étant alkyle C¿1-4?).
PCT/US2001/048673 2000-12-18 2001-12-14 Inhibiteurs de thrombine WO2002057225A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058826A1 (fr) * 2003-12-18 2005-06-30 Astrazeneca Ab Nouveaux composes de 5,6-dihydropyrin-2-one utiles en tant qu'inhibiteurs de thrombine
WO2006135323A1 (fr) * 2005-06-17 2006-12-21 Astrazeneca Ab Derives de 2-oxo-1,2,5,6-tetrahydropyridine inhibiteurs de thrombines
US7994343B2 (en) 2004-03-17 2011-08-09 Ranbaxy Laboratories Limited Process for the production of atorvastatin calcium in amorphous form

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866573A (en) * 1997-04-21 1999-02-02 Merck & Co., Inc. Pyrazinone thrombin inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866573A (en) * 1997-04-21 1999-02-02 Merck & Co., Inc. Pyrazinone thrombin inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058826A1 (fr) * 2003-12-18 2005-06-30 Astrazeneca Ab Nouveaux composes de 5,6-dihydropyrin-2-one utiles en tant qu'inhibiteurs de thrombine
US7994343B2 (en) 2004-03-17 2011-08-09 Ranbaxy Laboratories Limited Process for the production of atorvastatin calcium in amorphous form
WO2006135323A1 (fr) * 2005-06-17 2006-12-21 Astrazeneca Ab Derives de 2-oxo-1,2,5,6-tetrahydropyridine inhibiteurs de thrombines

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