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WO1998042342A1 - Inhibiteurs de thrombine - Google Patents

Inhibiteurs de thrombine Download PDF

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Publication number
WO1998042342A1
WO1998042342A1 PCT/US1998/005486 US9805486W WO9842342A1 WO 1998042342 A1 WO1998042342 A1 WO 1998042342A1 US 9805486 W US9805486 W US 9805486W WO 9842342 A1 WO9842342 A1 WO 9842342A1
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WO
WIPO (PCT)
Prior art keywords
methyl
cycloalkyl
alkyl
nmr
mmol
Prior art date
Application number
PCT/US1998/005486
Other languages
English (en)
Inventor
Richard C. A. Isaacs
Adel M. Naylor-Olsen
Bruce D. Dorsey
Christina L. Newton
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 GBGB9716872.8A external-priority patent/GB9716872D0/en
Priority claimed from GBGB9800214.0A external-priority patent/GB9800214D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002283704A priority Critical patent/CA2283704A1/fr
Priority to EP98911875A priority patent/EP0969840A4/fr
Priority to AU65727/98A priority patent/AU728006B2/en
Priority to JP54582598A priority patent/JP2001518932A/ja
Publication of WO1998042342A1 publication Critical patent/WO1998042342A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two amino acids
    • 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
    • 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.
  • 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.
  • the invention relates to compounds of the formula:
  • R a and R D are independently selected from hydrogen, a heterocyclic group which is 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 three 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, Ci-4 alkyl unsubstituted or substituted with CH3 or C3-7 cyclo alkyl, aryl, substituted aryl with one or two substituents selected from C1-4 alkyl, Ci-4 alkoxy, methylenedioxy, halogen or hydroxy, C3-7 cycloalkyl, C9-10 bicycloalkyl, or
  • R a and R D along with the carbon to which they are attached, form a C3-7 cycloalkyl ring or
  • RlO is H or -OH
  • RU is H or -OCH3
  • ⁇ l is selected from the group consisting of -OH
  • D is 1, 2, 3, or 4 carbon atoms unsubstituted or any 1, 2, 3, or 4 of which are substituted with OH, -NHSO 2 (CH2)l-3aryl, 15 -NH(CH2)1-3NH 2 ,
  • Y 2 is O or NH
  • W 4 is C or N
  • Z 1 is C or N
  • R 6 is -CH2OH or -N(CH3)2 provided that W 4 and Z 1 25 are not the same,
  • R7 is H or CH3, and R 8 is H or O
  • R 9 is H, NH2, or OH
  • B 1 is a bond, O, -CH2-O-, or -O-CH2-;
  • W 2 is hydrogen
  • -phenyl unsubstituted or substituted with one or more of C1-4 alkyl, Ci-4 alkoxy, halogen, hydroxy, COOH, or CONH2, naphthyl, biphenyl, a 5- to 7- membered mono- or a 9- to 10-membered bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to four heteroatoms selected from the group consisting of N, O and S, -Ci-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, C3-7 cycloalkyl, heteroaryl, or heterocycloalkyl, -CF3
  • X2 is CF 2 , CR ⁇ Rl ⁇ wherein R 5 and Rl6 are independently hydrogen,
  • 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 are joined to form a four to seven membered cycloalkyl ring unsubstituted or substituted with hydroxy, amino or aryl, or
  • R3 and Rl° are independently selected from the group consisting of hydrogen, Ci-4 alkyl,
  • B is selected from the group consisting of
  • X is selected from the group consisting of hydrogen, halogen, -CF 3> -CH2CF3,
  • Z is selected from the group consisting of hydrogen, -NH 2 , -Ci-4 alkylamino,
  • Y is selected from the group consisting of hydrogen
  • ⁇ is selected from the group consisting of -OC1-7 alkyl
  • Y 2 is H, NH 2 or OH
  • Y 3 is H, NH 2 or OH
  • Y 5 is NH 2 or OH, or H
  • Y 5 is hydrogen, and Y 4 is NH 2 or OH.
  • the invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
  • the compounds have the formula
  • the compounds have the formula and pharmaceutically acceptable salts thereof, wherein
  • B is selected from the group consisting of:
  • -CH 2 CH CH- , -CH 2 CH 2 CH 2 - , -CH 2 C ⁇ C- , and -CH 2 - ;
  • Y is selected from the group consisting of
  • 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. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems
  • 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- methacrylami de-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 0.1 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day and most preferably 1-20 mg/kg/day.
  • the most preferred doses will range from about 0.01 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.
  • intranasal form can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
  • oral tablets can be prepared which contain an amount of active compound of between 100 and 500 mg, e.g. 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 100 and 1000 mg active compound per day.
  • two tablets containing 250 mg of active compound can be administered in the morning and two tablets containing 250 mg of active compound can again be administered in the evening.
  • one tablet containing 250 mg of active compound can be administered in the morning and one tablet containing 250 mg of active compound can again be administered in the evening.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers 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.
  • Specific embodiments of compounds of the invention inhibit thrombin with a Ki range of less than 1.0 nM according to in vitro measurements.
  • a Thermomax 96-well plate reader was used to measure (at 405 run) the time dependent appearance of p- nitroaniline.
  • sar-PR-pna sarcosine-Pro-Arg-p-nitroanilide
  • K m 125 ⁇ M
  • jD-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-lM-1.
  • 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 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 (N 0 ) or presence of inhibitor (N ) were measured.
  • the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
  • 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, methane sulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, to
  • 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 dicyclohexyl amine 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
  • Scheme 1 shows a general procedure for preparing compounds of the invention where B is a three carbon alkane or alkene moiety.
  • imidazole-4-acrylic acid methyl ester is protected as its trityl derivative by treatment with trityl chloride in the presence of triethylamine.
  • Reduction of the ester with lithium aluminum hydride affords the corresponding alcohol which is then converted to an azide using DBU and diphenylphosphoryl azide.
  • the allyl azide is then reduced to the corresponding allyl amine using the standard Staudinger reduction/hydrolysis protocol.
  • the resulting amine is then coupled to A- COOH via routine EDC coupling techniques. Removal of the protecting groups under acidic conditions followed by hydrogenation of the double bond as necessary afforded compounds of the invention.
  • Scheme 2 shows a procedure for preparing compounds of the invention where B includes an alkyne.
  • 4-Methylimidazole was iodinated under basic conditions and then protected as its Boc derivative. Following bis triphenylphosphinepalladium dichloride and copper iodide mediated coupling to N-propargylphthalimide the protecting groups were removed via treatment with hydrazine. The resulting imidazole propargylamine is coupled to A-COOH via a standard EDC coupling to form a compound of the invention.
  • SCHEME 3
  • 4-methyl-5- imidazolemethanol is alkylated under basic conditions with an alkyl haloformate such as t-butylbromoacetate.
  • an alkyl haloformate such as t-butylbromoacetate.
  • the azido functionality is first reduced in the presence of hydrogen and palladium on carbon and the resulting amine coupled to the A-COOH via standard EDC methodology.
  • the t-butyl group is then removed under acidic conditions and the compound of the invention secured via EDC coupling to the requisite amine.
  • the azidomethylimidazole t-butyl ester is first deprotected under acidic conditions and the resulting acid coupled to an amine using EDC. Reduction of the azide and EDC coupling to the A- COOH affords the compound of the invention.
  • Step A Boc-D-3.3-diphenylalanine-L-proline benzyl ester
  • Step B Boc-D-3,3-diphenylalanine-L-proline
  • Step C Tmns-4-imidazoleacrylic acid methyl ester hydrochloride
  • Step D Trans- l-trityl-4-imidazoleacrylic acid methyl ester
  • Step E Trans- l-trityl-4-imidazoleallyl alcohol
  • a 1M solution of LAH in ether (30 ml, 30 mmol) was added dropwise to a cooled (-45°C) solution of -rc s-l-trityl-4-imidazoleacrylic acid methyl ester (23 g, 58.3 mmol) in THF (300 ml).
  • additional 1M LAH solution (30 ml) was added.
  • Stirring was continued at -45 °C for 1 h, then the solution was warmed to and stirred at 0°C for 30 min.
  • Step F Tra ns- l-trityl-4-imidazoleallyl azide DBU (5.4 ml 35.7 mmol) was added dropwise to a cooled
  • Step G T'r s-l-trityl-4-imidazoleallylamine
  • Step I Boc-D-3,3-diphenylalanine-L-proline-N-( r ⁇ ns-4- imidazoleallyl) amide
  • Boc-D-3,3-diphenylalanine-L-proline and trans-4- imidazoleallylamine dihydrochlori.de were coupled using essentially the same procedure described in EXAMPLE I, Step A except that no citric acid wash was preformed. The final compound was purified by preparative HPLC. iH NMR (CH3OD) d 1.23 (s, 9 H), 1.40-1.65 (m, 2 H),
  • Step A Boc-D-3,3-diphenylalanine-L-proline-N-(4-imidazole propyl) amide
  • Step B D-3,3-Diphenylalanine-L-proline-N-(4-imidazolepropyl) amide
  • Step A D-3.3-Diphenylalanine-L-proline benzyl ester
  • Step B N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline benzyl ester
  • Step C N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline The title compound was prepared from N-benzylsulfonyl-D-
  • Step D N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-
  • Step E N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-
  • N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-( r ⁇ n.s- l-trityl-4-imidazoleallyl) amide (180 mg, 0.2 mmol) was dissolved in 2:1 methylene chloride / TFA (75 ml). Triethyl silane was then added dropwise until the bright yellow color had disappeared. The reaction was allowed to stir at room temperature overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC.
  • Step A N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline benzyl ester
  • Step B N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline
  • Step C N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline-N-(- ⁇ ns-l-trityl-4-imidazoleallyl) amide
  • the title compound was prepared from N-methoxycarbonyl- methanesulfonyl-D-3,3-diphenylalanine-L-proline and trans- l-trityl-4- imidazoleallylamine essentially using the procedure described in
  • Step A N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline benzyl ester
  • Step B N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline
  • the title compound was prepared from N-[(1R)-10- camphorsulfonyl]-D-3,3-diphenylalanine-L-proline benzyl ester using the procedure described in EXAMPLE I, Step B.
  • Step C N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-(t ⁇ ns-l-trityl-4-imidazoleaHyl) amide
  • Step D N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-(tr ⁇ ns-4-imidazoleallyl) amide __
  • Step A Boc-L-homoproline benzyl ester
  • Step B L-Homoproline benzyl ester hydrochloride
  • Step D Boc-D-3.3-diphenylalanine-L-homoproline
  • ethyl acetate 50 ml
  • Pd/C 10% Pd/C
  • Step E Boc-D-3,3-diphenylalanine-L-homoproline-N-(tr ⁇ ns-l- trityl-4-imidazoleallyl) amide Boc-D-3,3-diphenylalanine-L-homoproline was coupled to trans- l-trityl-4-imidazoleallylamine essentially according to the procedure described for EXAMPLE I, Step A.
  • Step F D-3,3-diphenylalanine-L-homoproline-N-(tr ⁇ ns-4- imidazole-allyl) amide
  • Step A Bis-(4-methoxyphenyl)methanol To a stirred solution of 4,4'-dimethoxybenzophenone (5.0 g,
  • Step B 3,3-Bis-(4'-methoxyphenyl)-2-nitropropionic acid ethyl ester
  • Step C Boc-DL-3.3-bis-(4'-methoxyphenyl)alanine ethyl ester
  • Amalgamated zinc was prepared by treating zinc dust ( 11.4 g) with 2M HCl (83 ml) for 5 min and then decanting the supernatant. To this was then added a solution of 3,3-bis-(4'-methoxyphenyl)-2- nitropropionic acid ethyl ester (3.0 g, 8.3 mmol) in 1:1 THF / CH3OH ( 166 ml), followed by the addtion of 2M HCl (43 ml). This mixture was heated at reflux under argon for 2 h, cooled to approximately 40 °C, filtered through a glass-fiber filter and concentrated by rotavap.
  • Step D Boc-DL-3.3-bis-(4'-methoxyphenyl)alanine
  • Step F Boc-DL-3.3-bis-(4'-methoxyphenyl)alanine-L-proline
  • Step G Boc-DL-3,3-bis-(4'-methoxyphenyl)alanine-L-proline-N-
  • Step H D-3,3-Bis-(4'-methoxyphenyl)alanine-L-proline-N-(tr ⁇ ns-
  • Step A 1- and 3-Trityl-4-methyl-5-imidazolecarboxaldehvde
  • Trityl chloride 28 g, 100 mmol was added to a cooled (0°C) solution of 4-methyl-5-imidazolecarboxaldehyde (10 g, 91 mmol) and triethylamine (16 ml, 115 mmol) in methylene chloride (300 ml). After stirring for 30 min, the reaction mixture was warmed to room temperature and stirred there for 2 h. The reaction mixture was then washed well with water and saturated NaHC ⁇ 3. Drying over Na2SO4 and removal of the solvent in vacuo gave a 1:1 mixture of the title compounds as a white powder.
  • Step B Trans- l-trityl-4-methyl-5-imidazoleacrylic acid methyl ester
  • Step C Trans- l-trityl-4-methyl-5-imidazoleall yl alcohol
  • Step D Trans- l-trityl-4-methyl-5-imidazoleallyl azide
  • Step F D-3,3-Diphenylalanine-L-proline-N-(fr ⁇ ns-5-methyl-4- imidazoleallyl) amide
  • Boc-D-3,3-diphenylalanine-L-proline was coupled to trans-1- trityl-4-methyl-5-i ⁇ mdazoleallylamine essntially according to the procedure described for EXAMPLE I, Step A then the protecting groups were simultaneously removed essentially according to the procedure of EXAMPLE IV, Step E.
  • Step B 4.5-Diodoimidazole
  • Step C 4-Iodoimidazole A hot saturated solution of the diodide (12 g) in ethanol (60 ml) was mixed together with a solution of sodium thiosulfate (29 g) in water (10 ml). A white precipitate separated. The resulting mixture was heated at 100 °C for 24 h. then cooled and filtered. The filtrate was evaporated and the residue boiled three times with chloroform (400 ml portions) each time followed by a hot filtration. Concentration of the filtrate gave 4-iodoimidazole as a white solid. H NMR (CD3OD) d 7.20 (s, 1 H), 7.63 (s, 1 H).
  • Step D l-Trityl-4-iodoimidazole Trityl chloride (3.8 g, 13.6 mmol) was added to a cooled (0°C) solution of 4-iodoimidazole (2.25 g, 11.6 mmol) and triethylamine (2 ml, 14.3 mmol) in methylene chloride (25 ml). After stirring for 30 min the reaction mixture was warmed to room temperature and stirred ther for 2 h. The reaction mixture was washed well with water and saturated NaHCO3 then dried (Na2SO4). Concentration gave the product as a white solid. !H NMR (CDCI3) d 6.92 (s, 1 H), 7.08-7.20 (m, 6 H), 7.28-7.40 (m, 10 H).
  • Step E l-Trityl-4-imidazolepropargyl phthalimide
  • N-propargylphthalimide 450.9 mg, 2.4 mmol
  • l-trityl-4-iodoimidazole 875.5 mg, 2 mmol
  • diethylamine 20 ml
  • Bis triphenyl- phosphinepalladium dichloride (15.6 mg)
  • copper (I) iodide (a smidgen) were added and heating continued overnight.
  • the reaction mixture was cooled and the solvent rotavapped off. The residue was redissolved in methylene chloride and ether (twice the volume).
  • Step F l-Trityl-4-imidazolepropargylamine Hydrazine monohydrate (3 ml) was added to a suspension of the phthalimido compound (734.2 mg, 1.5 mmol) in ethanol (15 ml). The bulk of the starting material dissolved. The reaction mixture was heated at 80°C for 2 h. It was then cooled and rotavapped down. After azeotroping with toluene the residue was adsorbed onto silica gel and purified by flash chromatography (19:1 to 9:1 chlorofrom / 10% NH4OH in methanol) to give the amine as a white solid.
  • iH NMR (CDCI3) d 3.60 (s, 2 H), 6.98 (s, 1 H), 7.13 (m, 6 H), 7.35 (m, 9 H), 7.39 (s, 1 H).
  • Step G D-3,3-Diphenylalanine-L-proline-N-(4-imidazolepro pargyl) amide
  • Step A N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-(l- trityl-4-imidazolepropargyl) amide
  • Step B N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-(4- imidazolepropargyl) amide
  • the title compound was prepared from N-benzylsulfonyl-D-
  • Step A Boc-D-3,3-diphenylalanine-L-homoproline-N-(l-trityl-4- imidazolepropargyl) amide
  • Step B D-3,3-Diphenylalanine-L-homoproline-N-(4-imidazole- propargyl) amide
  • the title compound was prepared from Boc-D-3,3- diphenylalanine-L-homoproline-N-(l-trityl-4-imidazolepropargyl) amide using the procedure described in EXAMPLE IV, Step E.
  • iH NMR (CD3OD) d 0.20 (m, 1 H), 0.80-1.40 (m, 4 H), 1.95-2.05 (m, 1 H), 3.18-3.30
  • Step B l-Boc-4-iodo-5-methylimidazole
  • the phthaloyl group was removed from l-Boc-5-methyl-4- imidazolepropargyl phthalimide as for EXAMPLE XV, Step F with the exception that the reaction was run at room temperature.
  • the Boc group was labile under these conditions. iH NMR (CD3OD) d 2.25 (s, 3 H), 3.62 (s, 2 H), 4.95 (br s, 2 H), 7.47 (s, 1 H).
  • Step E D-3 ,3-Diphenylalanine-L-proline-N-(5-methyl-4- imidazole-propargyl) amide
  • Boc-D-3,3-diphenylalanine-L-proline and 5-methyl-4- imidazolepropargylamine were coupled essentially according to the procedure for EXAMPLE I, Step A then the Boc group was removed essentially according to the procedure of EXAMPLE IN, Step E.
  • DPPA (70 ml, 320 mmol) was added to a stirred solution of 2- hydroxy-6-methylpyridine-3-carboxylic acid (49 g, 320 mmol) and triethylamine (45 ml, 320 mmol) in dry dioxane (500 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (45 ml, 320 mmol) and benzyl alcohol (32 ml, 310 mmol) were added and the solution was refluxed for a further 24 h. The reaction was concentrated in vacuo to remove most of the volatiles.
  • Step C 3-Amino-6-methyl-l-(t-butylmethylenecarboxy)-2- pyridinone
  • a mixture of 3-benzyloxycarbonylamino-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone (10 g, 27 mmol) and Pearlman's catalyst (2 g) in 4:1 ethanol/water (250 ml) was shaken in a Parr apparatus under H2 (50 psi) for 3 h.
  • the reaction mixture was filtered through Celite and evaporated in vacuo.
  • Step D 3-Benzylsulfonylamino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyridinone
  • Benzyl sulfonyl chloride (5.2 g, 27 mmol) was added to a solution of 3-amino-6-methyl-l-(t-butylmethylenecarboxy)-2-pyridinone (6 g, 25 mmol) in pyridine (50 ml) at 0°C and as the resulting solution was stirred a thick precipitate formed. After 1 h the reaction mixture was evaporated in vacuo to a thick paste. This was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give a yellow solid which triturated first with hexane then ether.
  • Step E 3-Benzylsulfonylamino-6-methyl-l-methylenecarboxy-2- pyridinone
  • HCl gas was bubbled through a stirred suspension of 3- benzylsulfonylamino-6-methyl-l-(t-butylmethylenecarboxy)-2-pyridinone (7.5 g, 19 mmol) in ethyl acetate (250 ml) at 0°C until a solution had formed which was saturated with HCl. After 1 h at room temperature a thick suspension had formed.
  • Step F 3-Benzyls fonylamino-6-methyl-l-(tr ⁇ ns-l-trityl-4- methylenecarboxamidoallylimidazolyl)-2-pyridinone
  • the title compound was prepared from 3-benzylsulfonyl- amino-6-methyl- l-methylenecarboxy-2-pyridinone and trans- l-trityl-4- imidazoleallylamine using the procedure described in EXAMPLE I, Step A.
  • Step G 3-Benzylsulfonylamino-6-methyl- l-(tr ⁇ ns-4-methylene- carboxamidoallylimidazolyl)-2-pyridinone
  • Step H 3-Benzylsulfonylamino-6-methyl-l-(4-methylenecarbox amido-propylimidazolyl)-2-pyridinone
  • Step A l-Trityl-4-methyl-5-imidazolemethanol A solution of 4-methyl-5-imidazolemethanol hydrochloride
  • Step B 5-Azidomethyl-4-methyl-l-tritylimidazole
  • Step C l-Trityl-4-methyl-5-imidazolemethylamine
  • Step D 3-Benzylsulfonylamino-6-methyl- 1-( l-trityl-4-methyl-5- methylenecarboxamidomethylimidazolyl)-2-pyridinone
  • the title compound was prepared from 3-benzylsulfonyl- amino-6-methyl-l-methylenecarboxy-2-pyridinone and l-trityl-4-methyl- 5-imidazolemethylamine using the procedure described in EXAMPLE I, Step A.
  • iH NMR (CDCI3) d 1.40 (s, 3 H), 2.39 (s, 3 H), 4.25-4.35 (m, 4 H),
  • Step E 3-Benzylsulfonylamino-6-methyl-l-(4-methyl-5-methyl-ene- carboxamidomethylimidazolyl)-2-pyridinone
  • Step A Sodium 4- chlorobenzylthio sulfate
  • Step C 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone
  • Step D 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-methylene- carboxy-2-pyridinone
  • Hydrogen chloride gas was bubbled through a suspension of 3-(4-chlorobenzylsulfonylamino)-6-methyl-l-(t-butyl-methylenecarboxy)- 2-pyridinone (850 mg, 2.0 mmol) in ethyl acetate (100 ml) that had been cooled to 0°C. After 15 min the addition of HCl gas was stopped and the solution warmed to room temperature for 1 h. The mixture was then purged with nitrogen and the solvent removed in vacuo to give the title compound as a solid. iH NMR (CH3OD) d 2.33 (s, 3 H), 4.43 (s, 2 H), 4.88
  • Step E 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-(l-trityl-4- methyl-5-methylenecarboxamidomethylimidazolyl)-2- pyridinone
  • Step F 3-(4-Chlorobenzylsulfonylamino-6-methyl-l-(4-methyl-5- methylenecarboxamidomethylimidazolyl)-2-pyridinone
  • the title compound was prepared from 3-(4-chlorobenzyl- sulfonylamino-6-methyl-l-(l-trityl-4-methyl-5-methylenecarboxamido- methyl-imidazolyl)-2-pyridinone using the procedure described in EXAMPLE IV, Step E.
  • iH NMR (CD3OD) d 2.33 (s, 3 H), 2.35 (s, 3 H),
  • Step A l-t-Butoxycarbonylmethyl-4-methyl-5-hydroxymethyl- imidazole t-Butyl bromoacetate (35 ml, 240 mmol) was added to a mixture of 4-methyl-5-imidazolemethanol hydrochloride (30 g, 200 mmol) and potassium carbonate (80 g, 580 mmol) in N,N- dimethylformamide (500 ml) and the resulting heterogenous mixture stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the DMF was then removed in vacuo from the filtrate. The residue was dissolved in a minimum quantity of methylene chloride and the resulting solution diluted several fold with ether and ethyl acetate.
  • Step C l-t-Butoxycarbonylmethyl-4-methyl-5- aminomethylimidazole
  • Step D 3-Benzylsulfonamino-6-methyl-l-(l-t-butoxycarbonylmethyl-
  • Step A l-CarboxymethvI-4-methyl-5-azidomethylimidazole
  • Step B l-t-Butylmethylaminocarbonylmethyl-4-methyl-5- azidomethylimidazole
  • Step C l-t-Butylmethylaminocarbonylmethyl-4-methyl-5- aminomethylimidazole
  • Step D 3-Benzylsulfonylamino-6-methyl-l-(l-t-butylmethylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazo ⁇ yl)-2-pyridinone
  • Step B 3-Benzylsulfonylamino-6-methyl-l-[l-(2-aminoethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarbox- amidomethylimidazoIyll-2-pyridinone
  • Step A b-N.N-Dimethylaminoethenylcvclopropyl ketone
  • Step D 3-Benzyloxycarbonylamino-6-propyl-2-pyridinone
  • Step F 3-Amino-6-propvl-l-(t-butvlmethvlenecarboxv)-2-pyridinone
  • Step G 3-Benzylsulfonylamino-6-propyl-l-(t-butylmethylene- carboxy)-2-pyridinone
  • Benzylsulfonyl chloride (880 mg, 4.6 mmol) was added to a solution of 3-amino-6-propyl-l-(t-butylmethylenecarboxy)-2-pyridinone (1.1 g, 4.1 mmol) in pyridine (20 ml) at 0°C and as the resulting solution was stirred a thick precipitate formed. After 1 h the reaction mixture was evaporated in vacuo to a thick paste. This was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution.
  • Step H 3-Benzylsulfonylamino-6-propyl-l-methylenecarboxy-2- pyridinone
  • HCl gas was bubbled through a stirred suspension of 3- benzylsulfonylamino-6-propyl-l-(t-butylmethylenecarboxy)-2-pyridinone (1.1 g, 2.8 mmol) in ethyl acetate (20 ml) at 0°C until a solution had formed which was saturated with HCl.
  • Step I l-Carboxymethyl-4-methyl-5-azidomethylimidazole
  • Step J l-t-Butylaminocarbonylmethyl-4-methyl-5-azidomethyl- imidazole
  • Step K l-t-Butylaminocarbonylmethyl-4-methyl-5-aminomethyl- imidazole
  • Step L 3-Benzylsulfonamino-6-propyl- 1-( 1-t-butylaminocarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimida- zolyl)-2-pyridinone
  • Step B 2-Tetrahvdropyranylmethane sulfonyl chloride
  • Step C 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl-.l
  • Step D 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl-j i methylenecarboxy-2-pyridinone
  • the title compound was prepared from 3-(2-tetrahydro- pyranylmethanesulfonylamino)-6-methyl-l-methylenecarboxy-2- pyridinone and l-t-butylaminocarbonylmethyl-4-methyl-5-aminomethyl- imidazole using the procedure described in EXAMPLE I, Step A.
  • Step A Sodium cvclohexylmethanethiosulfate
  • Step B Cvclohexylmethanesulfonyl chloride
  • the title compound was prepared from sodium cyclohexyl- methanethiosulfate using the procedure described in EXAMPLE XXI, Step B.
  • Step C 3-Cyclohexanemethylsulfonylamino-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone
  • Step E 3-Cyclohexylmethanesulfonylamino-6-methyl-l-(l'-t-butyl- aminocarbonylmethyl-4-methyl-5-methylenecarboxamido- methylimidazolyl)-2-pyridinone
  • Step B 3-Pentanesulfonylamino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyri din on e
  • Step C 3-Pentanesulfonylamino-6-methyl-l-methylenecarboxy-2- pyridinone
  • Step D 3-Pentanesulfonylamino-6-methyl-l-(l'-t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimida- zolyl)-2-pyridinone
  • Step A N-(l-Cvanoethyl)glvcine benzyl ester hydrochloride
  • Step B l-Benzyloxycarbonylmethyl-3,5-dichloro-6- methylpyrazinone
  • Step C 3-(2-Phenethylamino)-5-chloro-6-methyl- l-(benzyloxy- carbonylmethyl )p yrazinone
  • 2-Phenethylamine (0.38 ml, 3.0 mmol) was added to a stirred mixture of l-benzyloxycarbonylmethyl-3,5-dichloro-6- methylpyrazinone (327 mg, 1.00 mmol) in EtOAc (2 ml) and the resulting mixture was heated to reflux under argon.
  • Step D 3-(2-Phenethylamino)-5-chloro-6-methyl-l-(methylene- carboxy)pyrazinone
  • Step E 3-(2-Phenethylamino)-6-methyl-l-methylenecarboxy- pyrazinone
  • Step F 3-(2-Phenethylamino)-6-methyl-l-( -t-butoxycarbonyl- methyl-4-methyl-5- methylenecarboxamidomethylimidazolvD-pyrazinone
  • Step A 3-(2-Phenethylamino)-6-methyl-l-(l-carboxymethyl-4- methyl-5- methylenecarboxamidomethylimidazolvDpyrazinone
  • Step B 3-(2-Phenethylamino)-6-methyl-l-(l'-t-butylaminocarbonyl- methyl-4-methyl-5- methylenecarboxamidomethylimidazolvD-pyrazinone
  • Step B 3-Methanesulfonyloxy-N-t-butoxycarbonylpiperidine
  • Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0°C. After stirring for 1 h, the reaction mixture was washed with staurated NaHCO3 and dried (Na2SO4). Concentration gave the title compound.
  • Step C 3-Azido-N-t-butoxycarbonylpiperidine Lithium azide (1.35 g, 27.6 mmol) was added to a solution of
  • Step E l-r(N-t-butoxvcarbonyl-3-piperidineamino)carbonvl-methyll-
  • Step F l-[(N-t-butoxycarbonyl-3-piperidineamino)carbonyl-methyTJ
  • Step G 3-(2-Phenethylamino)-6-methyl-l-[l'-(N-t-butoxycarbonyl-3- piperidineamino)carbonylmethyl]-4-methyl-5-methylene- carboxamidomethylimidazolyllpyrazinone
  • the title compound was prepared from 3-(2- phenethylamino)-6-methyl-l-methylenecarboxypyrazinone and l-[(N-t- butoxycarbonyl-3-piperidineamino)carbonylmethyl]-4-methyl-5- aminomethylimidazole using the procedure described in EXAMPLE I, Step A.
  • Step H 3-(2-Phenethylamino)-6-methyl-l-[l'-(3-piperidineamino)- carbonylmethyl]-4-methyl-5-methylenecarboxamidomethyl- imidazolyllpyrazinone
  • 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.

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Abstract

L'invention concerne un composé inhibant la thrombine humaine et ayant la structure (I) ou (II) ou (III), ainsi que des sels pharmaceutiquement acceptables dudit composé (IV), caractérisé en ce que des composés tels que sont utiles pour inhiber la formation d'agrégats de plaquettes dans le sang d'un mammifère.
PCT/US1998/005486 1997-03-24 1998-03-20 Inhibiteurs de thrombine WO1998042342A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002283704A CA2283704A1 (fr) 1997-03-24 1998-03-20 Inhibiteurs de thrombine
EP98911875A EP0969840A4 (fr) 1997-03-24 1998-03-20 Inhibiteurs de thrombine
AU65727/98A AU728006B2 (en) 1997-03-24 1998-03-20 Thrombin inhibitors
JP54582598A JP2001518932A (ja) 1997-03-24 1998-03-20 トロンビン阻害薬

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US4154397P 1997-03-24 1997-03-24
US60/041,543 1997-03-24
US4756197P 1997-05-22 1997-05-22
US60/047,561 1997-05-22
GB9716872.8 1997-08-08
GBGB9716872.8A GB9716872D0 (en) 1997-08-08 1997-08-08 Thrombin Inhibitors
GBGB9800214.0A GB9800214D0 (en) 1998-01-06 1998-01-06 Throbin inibitors
GB9800214.0 1998-01-06

Publications (1)

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WO1998042342A1 true WO1998042342A1 (fr) 1998-10-01

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AU (1) AU728006B2 (fr)
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WO (1) WO1998042342A1 (fr)

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JP2001518932A (ja) 2001-10-16
AU728006B2 (en) 2001-01-04
CA2283704A1 (fr) 1998-10-01
EP0969840A1 (fr) 2000-01-12
EP0969840A4 (fr) 2001-02-28
AU6572798A (en) 1998-10-20

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