WO1998042342A1 - Thrombin inhibitors - Google Patents

Thrombin inhibitors 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
French (fr)
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/en
Priority to AU65727/98A priority patent/AU728006B2/en
Priority to EP98911875A priority patent/EP0969840A4/en
Priority to JP54582598A priority patent/JP2001518932A/en
Publication of WO1998042342A1 publication Critical patent/WO1998042342A1/en

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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.

Abstract

A compound which inhibits human thrombin and has structure (I) or (II) or (III) and pharmaceutically acceptable salts thereof, wherein compounds such as (IV) are useful for inhibiting formation of blood platelet aggregates in blood in a mammal.

Description

TITLE OF THE INVENTION THROMBIN INHIBITORS
BACKGROUND OF THE INVENTION 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.
Edwards et al., J. Amer. Chem. Soc. (1992) vol. 114, pp. 1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase.
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. SUMMARY OF THE INVENTION
The invention relates to compounds of the formula:
Figure imgf000004_0001
and pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of
Figure imgf000004_0002
Figure imgf000004_0003
wherein
H
Figure imgf000004_0004
wherein
Ra and RD 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
Ra and RD, along with the carbon to which they are attached, form a C3-7 cycloalkyl ring or
Figure imgf000005_0001
where RlO is H or -OH, and RU is H or -OCH3, and
χl is selected from the group consisting of -OH
-NH2 -NHCH3, -NH(CH2)l-3CH3, 5 -NH(CH2)2-4θH,
-NH(CH2)l-3COOH,
-NH(CH2)l-3COOR6, where R6 is Cι_4alkyl,
Figure imgf000006_0001
where R? and R^ are independently hydrogen or
10 Ci-4alkyl,
7\
— NH(CH2)^CON D
where D is 1, 2, 3, or 4 carbon atoms unsubstituted or any 1, 2, 3, or 4 of which are substituted with OH, -NHSO2(CH2)l-3aryl, 15 -NH(CH2)1-3NH2,
-NHC3-7 cycloalkyl ring unsubstituted or substituted with -OH, -C(O)OH, or -C(O)ORc, where Rc is Ci-4 alkyl,
Figure imgf000006_0002
where
20
Y2 is O or NH, W4 is C or N, Z1 is C or N, and
R6 is -CH2OH or -N(CH3)2 provided that W4 and Z1 25 are not the same,
Figure imgf000006_0003
where
R7 is H or CH3, and R8 is H or O
II
— CNH(tBu)
Figure imgf000007_0001
Figure imgf000007_0002
-NHSO2-(CH2)l-2-NH-(CH2)2NH2
where R9 is H, NH2, or OH;
or
Figure imgf000008_0001
wherein B1 is a bond, O, -CH2-O-, or -O-CH2-;
W2 is hydrogen,
R1-,
RiOCCO)-,
R!C(0)-,
R1S02-, (Rl)2CH(CH2)0-4NHC(O)-,
(Rl)m(CH2)nNHqC(O)-, where n is 0-4, m is 1 or 2, wherein Rl is same or different, and q is 0 or 1, with the proviso that where n is 1-4, q is 1 and m is 1, and where n is 0, m is 1 or 2, and q is 0 or 1, and where n is 0, m is 2 and q is 0;
R! is
R17(CH2)t-, where t is 0-4, (R17)(OR17)CH(CH2)p-, where p is 1-4, (R17)2CH(CH2)r-, where r is 0-4 and each R17 can be the same or different, and wherein (Rl ' )2 can also form a ring with CH represented by C3.7 cycloalkyl, C7-12 bicylic alkyl, Clθ-16 tricylic alkyl, or a 5- to 7- membered mono- or bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, R170(CH2)p-, wherein p is 1-4; R2 and R 7 are independently selected from
-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
C3-7 cycloalkyl, C7.12 bicyclic alkyl, or
ClO-16 tricyclic alkyl;
X2 is CF2, CR^Rlβ wherein R 5 and Rl6 are independently hydrogen,
C3-7 cycloalkyl, 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
S(0)r, where r is 0-2; χ3 is hydrogen or halogen;
R3 and Rl° are independently selected from the group consisting of hydrogen, Ci-4 alkyl,
C3-7 cycloalkyl, or trifluor omethyl ;
B is selected from the group consisting of
C1-4 alkyl,
C3-.4 alkenyl, and
C3-4 alkynyl; X is selected from the group consisting of hydrogen, halogen, -CF3> -CH2CF3,
-C3-5 cyclolakyl, -CH2C3.5 cycloalkyl, and -C1-4 alkyl; Z is selected from the group consisting of hydrogen, -NH2, -Ci-4 alkylamino,
-Ci-4 alkanol, -Ci-4 alkyl; and
Y is selected from the group consisting of hydrogen, and
-Ci-7 alkyl,
-CH2CH2CH2CH2C3-6 cycloalkyl,
-CH2CH=CHCH2C3-6 cycloalkyl,
-CH2C≡CCH2C3.6 cycloalkyl, -CH2C≡CCH2CH2C3.6 cycloalkyl
-CH2CH2CH2CH2CH2C3.6 cycloalkyl,
-CH2CH=CHCH2CH2C3-6 cycloalkyl, and
-CH2COYI, wherein γ is selected from the group consisting of -OC1-7 alkyl,
-OH,
-Cl-6 alkyl,
-C3-6 cyclolalkyl,
-CH2C3-6 cycloalkyl, -CH2CH2C3-6 cycloalkyl,
-benzyl
-CH2benzyl
-NH2,
-NHC1-5 alkyl, -NHC1-4 alkylCF3,
-NHC2-4 alkanol,
-NHC2-4 alkylamino,
Figure imgf000011_0001
Figure imgf000012_0001
-rC
Figure imgf000012_0002
/=N.
B )
Figure imgf000012_0003
Figure imgf000013_0001
Figure imgf000013_0002
— N O
Figure imgf000014_0001
wherein Y2 is H, NH2 or OH,
Figure imgf000014_0002
wherein Y3 is H, NH2 or OH, and
Figure imgf000014_0003
wherein Y4 is hydrogen, and
Y5 is NH2 or OH, or H
Y5 is hydrogen, and Y4 is NH2 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.
DETAILED DESCRIPTION OF THE INVENTION
In one class of the invention, the compounds have the formula
Figure imgf000015_0001
and pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000016_0004
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
In one group of this class of the invention, the compounds have the formula
Figure imgf000021_0001
and pharmaceutically acceptable salts thereof, wherein
B is selected from the group consisting of:
-CH2CH =CH- , -CH2CH2CH2- , -CH2C ≡C- , and -CH2- ;
X is H,
-CH3, -Cl
Z is
H, -NH2, and
Y is selected from the group consisting of
hydrogen,
-CH2COOC(CH3)3
-CH2COOH,
-CH2CONHC(CH3)3 !
-CH2CONHCH2CH3!
-CH2CONH <]
-CH2CONHCH2 <]
-CHoCONH
Figure imgf000022_0001
Figure imgf000022_0002
-CH2CONHC(CH3)2CH2CH3,
-CH2CONHCH2C(CH3)3,
-CH2CONHCH2CF3,
-CHoCON 0
Figure imgf000023_0001
-CH2CONHCH2CH2OH, -CH2CONHCH2CH2NH2,
-CH2CONHC(CH3)2CH2NH2,
-CH2CONHCH2C(CH3)2NH2
-CH2COOC(CH3)3 .
Specific embodiments of the class include
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0003
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000029_0004
Figure imgf000029_0005
Figure imgf000030_0001
CONHBu
Figure imgf000030_0002
HEt
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000030_0005
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
-29-
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
CONHlBu
Figure imgf000032_0004
CONHlBu
Figure imgf000033_0001
Figure imgf000033_0002
CONHlBu
Figure imgf000033_0003
CONHlBu
Figure imgf000033_0004
CONHBu
Figure imgf000033_0005
10 COCteu
Figure imgf000034_0001
COOlBu
Figure imgf000034_0002
Figure imgf000034_0003
COCteu
Figure imgf000034_0004
Figure imgf000034_0005
10
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0003
Figure imgf000035_0004
-33-
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
Figure imgf000036_0004
-34-
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
Figure imgf000037_0004
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
-36-
Figure imgf000039_0001
Figure imgf000039_0002
NH2
Figure imgf000039_0003
Figure imgf000039_0004
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
Figure imgf000040_0004
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000041_0003
and pharmaceutically acceptable salts thereof.
Compounds of the present invention, which are thrombin inhibitors, are useful in anticoagulant therapy. 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. The term "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. Thus, 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. Furthermore, 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.
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. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
Furthermore, 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. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
For example, 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. 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. For a patient requiring 1000 mg 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. For a patient requiring 500 mg per day, 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. 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.
For instance, for oral administration in the form of a tablet or capsule, 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 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. For example, 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.
In vitro assay for determine proteinase inhibition
Assays of human a-thrombin and human trypsin were performed at 25°C in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCI, 0.1% PEG. 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 to measure (at 405 run) the time dependent appearance of p- nitroaniline. sar-PR-pna (sarcosine-Pro-Arg-p-nitroanilide) was used to assay human a-thrombin (Km=125 μM) and human trypsin (Km=59 μM). jD-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-lM-1.
In certain studies with potent inhibitors (K < 10 nM) where the degree of inhibition of thrombin was high, a more sensitive activity assay was employed. In this assay the rate of thrombin catalyzed hydrolysis of the fluorogenic substrate Z-GPR-afc (Cbz-Gly-Pro-Arg-7- amino-4-trifluoromethyl coumarin) (Km=27 μM) was determined from the increase in fluorescence at 500 nm (excitation at 400 nm) associated with production of 7-amino-4-trifluoromethyl coumarin. 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 (N0) or presence of inhibitor (N ) were measured. Assuming competitive inhibition, and that unity is negligible compared Km/[S], [I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of V0/Ni on [I] shown in equation 1.
No/Ni = 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.
Some abbreviations that may appear in this application are as follows.
Designation BOC (Boc) t-butyloxy carb onyl
HBT(HOBT or HOBt) 1-hydroxybenzotriazole hydrate BBC reagent benzotriazolyloxy-bis(pyrrolidino)- carbonium hexafluorophosphate
PyCIU l,l,3,3-bis(tetramethylene)- chlorouronium hexafluorophosphate
EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (BOC)2θ di-t-butyl dicarbonate
DMF dimethylformamide
Et3N or TEA triethylamine
EtOAc ethyl acetate
TFA trifluoroacetic acid DMAP dimethylaminopyridine
DME dimethoxyethane
BH3-THF Borane-tetrahydrofuran complex
D-Phe(3,4-Cl2) D-3,4-Dichlorophenylalanine
D-3,3-dicha D-3,3-Dicyclohexylalanine Pro Proline
Arg Arginine
Gly Glycine
D-3,3,-diphe D-3,3-Diphenylalanine
LAH lithium aluminum hydroxide Cy cyclohexyl
POCI3 phosphorous oxychloride
MeCN acetonitrile
BnEt3N+Cl- benzyl triethyl ammonium chloride
NaH sodium hydride DMF dimethylformamide
BrCH2COOtBu tert butyl bromoacetate
EtOH ethyl alcohol
Pd(C) palladium on activated carbon catalyst
CF3COOH trifluoroacetic acid DCM dichloromethane DIPEA diisopropylethylamine
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 term "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. The term "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. The term "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. The term "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 (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such 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, tosylate, and undecanoate. 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. Also, 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.
SCHEME 1
Figure imgf000050_0001
i) EDC coupling ii) deprotection
Figure imgf000050_0002
hydrogenation
Figure imgf000050_0003
Scheme 1 shows a general procedure for preparing compounds of the invention where B is a three carbon alkane or alkene moiety. In Scheme 1, 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
Boc20, Et3N
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
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
\ τ\ K K22CC0033,, B BrrCCHHg2CCC02 lBBuu
OH
HN τ.7. Nl DMF N^\ N
C02tBu 2:1 mixture
i) Chromatography ii) DPPA, DBU, DMF
N*.
Figure imgf000054_0001
CONHR
Figure imgf000054_0002
To form compounds of the invention with substituents X and Y at the 2- and 4- positions of the imidazole ring system, 4-methyl-5- imidazolemethanol is alkylated under basic conditions with an alkyl haloformate such as t-butylbromoacetate. Following chromatographic separation of the regioisomers, the major alcohol isomer is converted to the corresponding azide by treatment with diphenylphosphoryl azide and DBU.
Two different routes may be used to form a finished compound of the invention. In one, 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. Alternatively, 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.
Unless otherwise stated, all NMR determinations were made using 400 MHz field strength.
EXAMPLE I
Preparation of Boc-D-3,3-diphenylalanine-L-proline-N-(trαns-4- imidazoleallyl) amide
Figure imgf000056_0001
Step A: Boc-D-3.3-diphenylalanine-L-proline benzyl ester
To a solution of Boc-D-3,3-diphenylalanine (5.0 g, 14.6 mmol), L-proline benzyl ester (3.30 g 16.0 mmol) and HOBT (2.56 g 19.0 mmol) in DMF (150 ml) was added EDC (3.62 g, 19.0 mmol) and triethylamine (8.16 ml, 58 mmol). After stirring at room temperature overnight, the solvent was removed in vacuo and the resulting residue partitioned between chloroform and 1M citric acid. The aqueous layer was extracted with chloroform and the combined organics were washed with water, 10% Na2CO3 solution and dried over MgSO4. The solution was then filtered and the solvent removed in vacuo to give the title compound: lH NMR (CDCI3) d 1.20-1.90 (m, 4 H), 1.30 (s, 9 H), 2.80 (q, J =
6 Hz, 1 H), 3.70-3.80 (m, 1 H), 4.10-4.18 (m, 1 H), 4.35 (d, J = 11.5 Hz, 1 H)
5.03-5.28 (m, 4 H), 7.10-7.40 (m, 15 H).
Step B: Boc-D-3,3-diphenylalanine-L-proline
A solution of Boc-D-3,3-diphenylalanine-L-proline benzyl ester (8.0 g, 15.0 mmol) in ethanol (200 ml) was hydrogenated in the presence of 10% Pd/C (2.0 g) at atmospheric pressure for 24 h. The reaction mixture was then filtered through Celite and the nitrate concentrated in vacuo to give the title compound as a white solid: ^H
NMR (CDCI3) d 1.20-1.40 (m, 1 H), 1.35 (s, 9 H), 1.40-1.60 (m, 1 H), 1.70- 1.90 (m, 1 H), 2.21-2.30 (m, 1 H), 2.70 (q, J = 9 Hz, 1 H), 3.75 (br t, J = 9 Hz, 1 H), 4.16 (d, J = 9 Hz, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 4.97-5.18 (m, 2 H), 7.22-7.39 (m, 10 H).
Step C: Tmns-4-imidazoleacrylic acid methyl ester hydrochloride
A solution of £rans-4-imidazoleacrylic acid (20.0 g 145 mmol) in methanol (300 ml) was saturated with anhydrous HCl and the resulting solution was then refluxed for 90 min. After cooling to room temperature the solvent was removed in vacuo to give the title compound as a white solid: lH NMR (CD3OD) d 3.80 (s, 3 H), 6.61 (d, J =
16 Hz, 1 H), 7.60 (d, J = 16 Hz, 1 H), 7.92, (s, 1 H), 9.05, (s, 1 H).
Step D: Trans- l-trityl-4-imidazoleacrylic acid methyl ester
To a solution of raΛis-4-imidazoleacrylic acid methyl ester hydrochloride (20.0 g, 106 mmol) and triethylamine (44 ml, 318 mmol) in chloroform (500 ml) was added a solution of trityl chloride (29.5 g, 318 mmol) in chloroform (100 ml). The resulting suspension was stirred at room temperature for 24 h. The reaction mixture was then washed with water and dried over MgSO4. Filtration and removal of the solvent in vacuo to gave the title compound as a tan solid: ^H NMR (CDCI3) d 3.75 (s, 3 H), 6.54 (d, J = 16 Hz, 1 H) 7.03 (s, 1 H), 7.13-7.34 (m, 15 H) 7.46 (s, 1 H), 7.51 (d, J = 16 Hz 1 H).
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). After stirring at -45°C for 3 h, 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. The reaction was quenched with ethyl acetate, then saturated NH4CI and allowed to stir at room temperature overnight. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over MgSO4, filtered and the solvents removed in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate elution) to give the title compound: !H NMR (DMSO) d 4.03 (m, 2 H), 4.68 (t, J = 5 Hz, 1 H) 6.20-6.40 (m, 2 H), 6.89 (s, 1 H) 7.00-7.50 (m, 16 H).
Step F: Tra ns- l-trityl-4-imidazoleallyl azide DBU (5.4 ml 35.7 mmol) was added dropwise to a cooled
(0°C) solution of trans- l-trityl-4-imidazoleallyl alcohol (8.76 g, 23.8 mmol) and diphenylphosphoryl azide (7.7 ml, 35.7 mmol) in THF (300 ml). The reaction mixture was allowed to warm gradually to and then stirred at room temperature overnight. The solvent was then removed in vacuo and the resulting residue purified by flash chromatography on silica gel (2:1 hexane / ethyl acetate) to give the title compound: iH NMR (CDCI3) d
3.88 (d, J = 6 Hz, 2 H), 6.25-6.50 (m, 2 H), 6.79 (s, 1 H), 7.14-7.34 (m, 15 H), 7.40 (s, 1 H).
Step G: T'r s-l-trityl-4-imidazoleallylamine
A solution of trans- l-trityl-4-imidazoleallyl azide (6.4 g, 16.8 mmol) and triphenylphosphine (11.0 g, 42.0 mmol) in THF (100 ml) was heated to reflux for 2 h, after which water (1 ml) was added. The resulting solution was then heated at reflux for 24 h. After cooling to room temperature the solvent was removed in vacuo and the residue purified by flash chormatography on silica gel (19:1 chloroform / 10% NH4OH in MeOH) to give the title compound as white solid: lH NMR (CDCI3) d 1.50 (br s, 2 H), 3.41 (d, J = 5 Hz, 2 H), 6.30-6.48 (m, 2 H), 6.73 (s,
IH), 7.13-7.38 (m, 15 H), 7.40 (s, 1 H).
Step H: T'rαns-4-imidazoleallylamine dihvdrochloride
A solution of rans- l-trityl-4-imidazoleallylamine (1.0 g, 2.7 mmol) in IN HCl (50 ml) was heated to reflux for 30 min, cooled to room temperature and filtered. The filter cake was washed with water. Concentration of the filtrate in vacuo gave the title compound: ^H NMR
(DMSO) d 3.80 (br s, 2 H), 6.50-6.72 (m, 2 H), 7.81 (s, 1 H), 8.50 (br s, 3 H),
9.15 (s, 1 H). Step I: Boc-D-3,3-diphenylalanine-L-proline-N-( røns-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),
1.70-1.90 (m, 2 H), 2.90 (q, J = 6 Hz, 1 H), 3.75-3.85 (br m, 1 H), 3.90 (d, J = 6Hz, 2 H), 4.10 (d, J = 8 Hz, 1 H) 4.38 (d, J = 11 Hz, 1 H) 5.10 (d, J = 11 Hz, 1 H), 6.00-6.10 (br m, 1 H), 6.41 (d, J = 16 Hz, 1 H), 7.01 (s, 1 H) 7.20-7.45 (m, 10 H), 7.60 (s, 1 H); MS (FAB) 544 (M+l)+.
EXAMPLE II
Preparation of D-3,3-Diphenylalanine-L-proline-N-(trαns-4-imidazole allyl) amide
Figure imgf000059_0001
A solution of Boc-D-3,3-diphenylalanine-L-proline-N-( røtιs- 4-imidazoleallyl) amide (55 mg, 0.1 mmol) in 2:1 methylene chloride / TFA (30 ml) was stirred at room temperature for 4 h. The solvents were removed in vacuo and the residue was purified by preparative HPLC. iH NMR (CH3OD) d 1.10-1.37 (m, 2 H), 1.70-1.90 (br s, 2 H), 2.70-2.90 (br m, 1 H), 3.50-3.65 (br m, 1 H) 3.95 (br s, 2 H), 4.00-4.10 (br m, 1 H), 4.45 (d, J = 11.5 Hz, 1 H), 4.95 (d, J = 11.5 Hz, 1 H) 6.30-6.40 (m, 1 H), 6.58 (d, J = 16 Hz, 1 H), 7.25-7.70 (m, 11 H), 7.85 (s, 1 H); MS (FAB) 444 (M+l)+. EXAMPLE III
Preparation of D-3,3-Diphenylalanine-L-proline-N-(4-imidazolepropyl) amide
Figure imgf000060_0001
Step A: Boc-D-3,3-diphenylalanine-L-proline-N-(4-imidazole propyl) amide
A solution of Boc-D-3,3-diphenylalanine-L-proline-N-(-τα/ιs- 4-imidazoleallyl) amide (200 mg, 0.36 mmol) in ethanol (100 ml) containing 10% Pd/C (100 mg) was hydro enated at 45 psi for 24 h. The solution was subsequently filtered through Celite and the solvent removed in vacuo to give the title compound as a solid: *H NMR (CD3OD) d 1.28-1.65 (m, 3 H), 1.30 (s, 9 H), 1.70-1.87 (m, 3 H), 2.55 (t, J = 8 Hz, 2 H), 2.88 (q, J = 8 Hz, 1 H), 3.05-3.30 (m, 2 H), 3.70-3.80 (m, 1 H), 3.95- 4.05 (m, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 5.10 (d, J = 11.5 Hz, IH), 6.80 (s, 1 H), 7.19-7.42 (m, 10 H), 7.60 (s, 1 H).
Step B: D-3,3-Diphenylalanine-L-proline-N-(4-imidazolepropyl) amide
The title compound was prepared from Boc-D-3,3- diphenylalanine-L-proline-N-(4-imidazolepropyl) amide using the procedure of EXAMPLE II: iH NMR (CD3OD) d 1.22-1.35 (m, 2 H), 1.70-
1.95 (m, 4 H), 2.75-2.88 (m, 1 H), 2.78 (t, J = 8 Hz, 2 H), 3.12-3.33 (m, 2 H), 3.50-3.60 (m, 1 H), 4.00 (t, J = 7 Hz, 1 H), 4.42 (d, J = 12 Hz, 1 H), 4.99 (d, J = 12 Hz, 1 H), 7.25-7.62 (m, 11 H), 8.80 (s, 1 H); MS (FAB) 446 (M+l)+. EXAMPLE IV
Preparation of N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N- (-r- s-4-imidazoleallyl) amide
Figure imgf000061_0001
Step A: D-3.3-Diphenylalanine-L-proline benzyl ester
The title compound was prepared from Boc-D-3,3- diphenylalanine-L-proline benzyl ester using the procedure described for EXAMPLE II: iH NMR (CDC13) d 1.35-1.48 (m, 1 H), 1.70-1.83 (m, 3 H),
2.70-2.82 (m, 1 H), 3.50-3.60 (m, 1 H), 4.15-4.25 (m, 3 H), 5.15 (ab q, J = 32 and 12 Hz, 2 H), 7.12-7.40 (m, 15 H).
Step B: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline benzyl ester
A solution of benzylsulfonyl chloride (177 mg, 0.934 mmol) in methylene chloride (10 ml) was added dropwise to a solution of D-3,3- diphenylalanine-L-proline benzyl ester (200 mg, 0.47 mmol) in methylene chloride at -78°C. After stirring at -78°C for 45 min, triethylamine (0.13 ml, 0.93 mmol) was added and the reaction mixture was allowed to stir at -78°C for an additional 30 min. It was then warmed to room temperature for 24 h. The reaction mixture was washed with water, dried over MgSθ4, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (7:3 hexane / ethyl acetate). iH NMR (CDCI3) d 1.40-1.55 (m, 1 H),
1.55-1.77 (m, 1 H), 1.77-1.90 (m, 2 H), 2.70-2.80 (m, 1 H), 3.72-3.83 (m, 1 H), 4.10 (d, J = 11 Hz, 1 H), 4.15-4.25 (m, 1 H), 4.33 (d, J = 11 Hz, 1 H), 4.65 (d, J = 6 Hz 1 H), 5.10 (ab q, J = 56 and 14 Hz, 2 H), 5.10-5.19 (m, 1 H), 7.20- 7.41 (m, 20 H).
Step C: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline The title compound was prepared from N-benzylsulfonyl-D-
3,3-diphenylalanine-L-proline benzyl ester using the procedure described in EXAMPLE I, Step B: iH NMR (CDC13) d 1.30-1.53 (m, 2 H),
1.70-1.87 (m, 1 H), 2.07-2.17 (m, 1 H), 2.68 (q, J = 9 Hz, 1 H), 3.52-3.65 (m, 1 H), 3.95-4.15 (m, 3 H), 4.30 (d, J = 12 Hz, 1 H), 4.80-4.95 (m, 1 H), 5.00-5.12 (m, 1 H), 7.10-7.45 (m, 15 H).
Step D: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-
(trans- l-trityl-4-imidazoleall yl) amide
The title compound was prepared from N-benzylsulfonyl-D- 3,3-diphenylalanine-L-proline and trans- l-trityl-4-imidazoleallylamine using the procedure described in EXAMPLE 1, Step A: *H NMR (CDCI3) d 1.30-1.85 (m, 4 H), 2.02-2.15 (m, 1 H), 2.55-2.70 (m, 1 H), 3.60-4.27 (m, 5 H), 4.33 (d, J = 12 Hz, 1 H), 4.80-4.90 (m, 1 H), 4.95 (d, J = 12 Hz, 1 H), 6.15- 6.37 (m, 2 H), 6.70 (s, 1 H), 6.85 (t, J = 8 Hz, 1 H), 7.05-7.40 (m, 31 H).
Step E: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-
(trα/zs-4-imidazoleallyl) amide
N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-( røn.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. ^H NMR (CD3OD) d 1.40-1.50 (m, 1 H), 1.50-1.70 (m, 1 H), 1.70-1.90 (m, 2 H), 2.90-3.02 (m, 1 H), 3.72-3.83 (m, 2 H), 3.95-4.08 (m, 2 H), 4.21 (ab q, J = 16 and 2.7 Hz, 2 H), 4.34 (d, J = 11.5 Hz, 1 H), 5.06 (d, J = 11.5 Hz, 1 H), 6.22 (d oft, J = 16 and 6 Hz, 1 H), 6.50 (d, J = 16 Hz, 1 H), 7.10-7.60 (m, 16 H), 8.77 (s, 1 H); MS (FAB) 598 (M+l)+. EXAMPLE V
Preparation of N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N- (4-imidazolepropyl) amide
Figure imgf000063_0001
A solution of N-Benzylsulfonyl-D-3,3-diphenylalanine-L- proline-N-(tταns-4-imidazoleallyl) amide (55 mg, 0.092 mmol) in ethanol (50 ml) was hydrogenated at 40 psi in the presence of 10% Pd/C (50 mg) for 4 h. The solution was filtered through Celite and the solvent removed in vacuo. The product was purified by preparative HPLC. ^H NMR (CD3OD) d 1.40-1.90 (m, 6 H), 2.70 (t, J = 6 Hz, 2 H), 2.92-3.18 (m, 2 H),
3.20-3.30 (m, 1 H), 3.72-3.82 (br m, 1 H), 3.90-4.00 (m, 1 H), 4.20-4.38 (m, 3 H), 5.05 (d, J = 11.5 Hz, IH), 7.10-7.60 (m, 16 H), 8.60 (s, 1 H); MS (FAB) 600 (M+l)+.
EXAMPLE VI
Preparation of N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline-N-(trαns-4-imidazoleallyl) amide
Figure imgf000064_0001
Step A: N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline benzyl ester
To a solution of D-3,3-diphenylalanine-L-proline benzyl ester (200 mg, 0.47 mmol) in methylene chloride (20 ml) at -78°C was added dropwise a solution of chlorosulfonylacetic acid methyl ester (100 mg, 0.56 mmol) in methylene chloride (5 ml). The reaction was stirred at -78°C for 10 min and then triethylamine (0.13 ml, 0.93 mmol) was added. Stirring at -78°C was continued for an additional 5 min followed by warming to room temperature for 15 min. The reaction was quenched with water, dried over MgSO4, filtered and the solvent removed in vacuo.
The residue was purified by flash chromatography on silica gel (3:2 hexane / ethyl acetate). *H NMR (CDCI3) d 1.30-1.50 (m, 1 H), 1.60-1.82
(m, 3 H), 2.60-2.70 (m, 1 H), 3.60-3.70 (m, 1 H), 3.73 (s, 3 H), 4.00 (ab q, J = 108 and 16 Hz) 4.15-4.20 (m, 1 H), 4.35 (d, J = 12 Hz, 1 H), 5.00-5.20 (m, 3 H), 5.66 (d, J = 12 Hz, 1 H), 7.10-7.42 (m, 15 H). Step B: N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline
The title compound was prepared from N-methoxycarbonyl- methanesulfonyl-D-3,3-diphenylalanine-L-proline benzyl ester using the procedure described in EXAMPLE I, Step B. iH NMR (CDCI3) d 1.45-
1.55 (m, 2 H), 1.72-1.82 (m, 1 H), 2.02-2.10 (m, 1 H), 2.62-2.75 (m, 1 H), 3.68-3.72 (m, 1 H), 3.75 (s, 3 H), 3.92 (ab q, J = 75 and 14 Hz, 2 H), 4.10-4.18 (m, 1 H), 4.35 (d, J=12 Hz, 1 H), 5.07 (t, J = 12 Hz, 1 H), 5.80 (d, J = 12 Hz, 1 H), 7.20-7.42 (m, 10 H).
Step C: N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline-N-(-ταns-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
EXAMPLE I, Step A. iH NMR (CDCI3) d 1.40-1.90 (m, 3 H), 1.95-2.10 (m,
I H), 2.58-2.70 (q, J = 8 Hz, 1 H), 3.57-3.62 (m, 1 H), 3.65 (s, 3 H), 3.75-4.05 (m, 2 H), 3.98 (ab q, J = 65 and 15 Hz, 2 H), 4.10-4.18 (m, 1 H), 4.35 (d, J = 12 Hz, 1 H), 5.02 (d, J = 12 Hz, 1 H), 6.15-6.40 (m, 2 H), 6.65 (t, J = 6 Hz, 1 H), 6.75 (s, 1 H), 7.10-7.45 (m, 26 H).
Ste D: N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl- alanine-L-proline-N-(trαns-4-imidazoleal ) amide
The title compound was prepared from N-methoxycarbonyl- methanesulfonyl-D-3,3-diphenylalanine-L-proline-N-(trα«.s-l-trityl-4- imidazoleallyl) amide using the procedure described in EXAMPLE IV, Step E. !H NMR (CD3OD) d 1.30-1.50 (m, 1 H), 1.50-1.70 (m, 1 H), 1.70-
1.90 (m, 2 H), 2.82-2.95 (m, 1 H), 3.64 (s, 3 H), 3.62-3.78 (m, 1 H), 3.80-3.95 (m, 1 H), 3.95-4.19 (m, 4 H), 4.35 (d, 11.5 Hz, 1 H), 5.13 (d, J = 11.5 Hz, 1 H), 6.30 (d of t, J = 16 and 6 Hz, 1 H), 6.54 (d, J = 16 Hz, 1 H), 7.20-7.58 (m,
II H), 7.81 (t, J = 6 Hz, 1 H), 8.83 (s, 1 H); MS (FAB) 580 (M+l)+. EXAMPLE VII
Preparation of N-Methoxycarbonylmethanesulfonyl-D-3,3-diphenyl alanine-L-proline-N-(4-imidazolepropyl) amide
Figure imgf000066_0001
The title compound was prepared from N-methoxycarbonyl- methanesulfonyl-D-3,3-diphenylalanine-L-proline-N-(t:rans-4-imidazole- allyl) amide using the procedure of EXAMPLE III, Step A. The final product was purified by preparative HPLC. !H NMR (CD3OD) d 1.36-1.45
(m, 1 H), 1.55-1.70 (m, 1 H), 1.70-1.90 (m, 4 H), 2.70-2.80 (m, 2 H), 2.85-2.98 (m, 1 H), 3.10-3.20 (m, 1 H), 3.21-3.30 (m, 1 H), 3.68 (s, 3 H), 3.70-3.80 (m, 1 H), 3.92-3.99 (m, 1 H), 4.16 (s, 2 H), 4.34 (d, J = 11.5 Hz, 1 H), 5.13 (d, J = 11.5 Hz, 1 H), 7.22-7.55 (m, 11 H), 8.76 (s, 1 H); MS (FAB) 582 (M+l)+.
EXAMPLE VIII
Preparation of N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-( ταns-4-imidazoleallyl) amide
Figure imgf000067_0001
Step A: N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline benzyl ester
The title compound was prepared from D-3,3- diphenylalanine-L-proline benzyl ester and (lR)-(-)-10-camphorsulfonyl chloride using the procedure described in EXAMPLE IV, Step B: XH NMR (CDCI3) d 0.90 (s, 3 H), 0.95 (s, 3 H), 1.32-1.42 (m, 2 H), 1.70-1.78 (m,
2 H), 1.85 (d, J = 16 Hz, 1 H), 1.90-2.08 (m, 4 H), 2.35-2.48 (m, 1 H), 2.70 (q, J = 6 Hz, 1 H), 2.97 (d, J = 16 Hz, 1 H), 3.41 (d, J = 16 Hz, 1 H), 3.72-3.82 (m, 1 H), 4.10-4.17 (m, 1 H), 4.35 (d, J = 12 Hz, 1 H), 5.00-5.18 (m, 3 H), 6.57 (d, J = 12 Hz, 1 H), 7.10-7.45 (m, 15 H).
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. iH NMR (CDCI3) d 0.87
(s, 3 H), 0.93 (s, 3 H), 1.22-2.20 (m, 9 H), 2.35-2.45 (m, 1 H), 2.70 (q, J = 6 Hz, 1 H), 2.87 (d, J = 16 Hz, 1 H), 3.25 (d, J = 16 Hz, 1 H), 3.70-3.80 (m, 1 H), 4.05 (d, J = 10 Hz, 1 H), 4.37 (d, J = 12 Hz, 1 H), 5.08 (t, J = 12 Hz, 1 H), 6.50 (d, J = 12 Hz, 1 H) 7.17-7.42 (m, 10 H). Step C: N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-(tταns-l-trityl-4-imidazoleaHyl) amide
The title compound was prepared from N-[(1R)-10- camphorsulfonyl]-D-3,3-diphenylalanine-L-proline and trans- l-trityl-4- imidazoleallylamine using the procedure described in EXAMPLE I, Step
A. iH NMR (CDCI3) d 0.80 (s, 3 H), 0.88 (s, 3 H), 1.22-2.09 (m, 11 H), 2.28-
2.40 (m, 1 H), 2.65 (q, J = 9 Hz, 1 H), 2.75 (d, J = 16 Hz, 1 H), 3.50 (d, J = 16 Hz, 1 H), 3.62-3.78 (m, 1 H), 3.85-3.95 (m, 2 H), 4.22 (d, J = 9 Hz, 1 H), 4.35 (d, J = 12 Hz, 1 H), 4.98 (t, J = 12 Hz, 1 H), 6.15-6.40 (m, 2 H), 6.75 (s, 1 H), 6.85 (t, J = 6 Hz, 1 H), 7.10-7.47 (m, 26 H).
Step D: N-[(lR)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-(trαns-4-imidazoleallyl) amide __
The title compound was prepared from N-[(1R)-10- camphorsulfonyl]-D-3,3-diphenylalanine-L-proline-N-(trαns-l-trityl-4- imidazoleallyl) amide using the procedure described in EXAMPLE IV, Step E. iH NMR (CD3OD) d 0.80 (s, 3 H), 0.95 (s, 3 H), 1.30-2.10 (m, 11 H),
2.25-2.37 (m, 1 H), 2.85 (d, J = 15 Hz, 1 H), 2.98 (q, J = 7 Hz, 1 H), 3.35 (d, J = 15 Hz, 1 H), 3.75-3.90 (m, 2 H), 3.97-4.10 (m, 2 H), 4.32 (d, J = 11.5 Hz, 1 H), 5.09 (d, J = 11.5 Hz, 1 H), 6.28 (d of t, J = 16 and 6 Hz, 1 H), 6.53 (d, J = 16 Hz, 1 H), 7.20-7.60 (m, 11 H), 8.83 (s, 1 H); MS (FAB) 658 (M+l)+.
EXAMPLE IX
Preparation of N-[(lS)-10-Camphorsulfonyl]-D-3,3-diphenylalanine-L- proline-N-(-rαns-4-imidazoleallyl) amide
Figure imgf000069_0001
The title compound was prepared from D-3,3- diphenylalanine-L-proline benzyl ester and (lS)-(+)-10-camphorsulfonyl chloride using the procedure described for EXAMPLE VIII: XH NMR (CD3OD) d 0.83 (s, 3 H), 0.96 (s, 3 H), 1.25-2.40 (m, 11 H), 2.91 (d, J = 15 Hz,
1 H), 3.00 (q, J = 7 Hz, 1 H), 3.35 (d, J = 15 Hz, 1 H) 3.75-3.90 (m, 2 H), 4.00- 4.10 (m, 2 H), 4.33 (d, J = 11.5 Hz, 1 H), 5.05 (d, J = 11.5 Hz, 1 H), 6.30 (d of t, J = 16 and 6 Hz, 1 H), 6.51 (d, J = 16 Hz, 1 H) 7.20-7.60 (m, 11 H) 7.60-7.70 (m, 1 H), 8.83 (s, 1 H); MS (FAB) 658 (M+D+.
EXAMPLE X
Preparation of D-3,3-Diphenylalanine-L-homoproline-N-(trαns-4- imidazoleallyl) amide
Figure imgf000070_0001
Step A: Boc-L-homoproline benzyl ester
DBU (2.2 ml, 15 mmol) was added to a solution of Boc-L- homoproline (3 g, 13 mmol) in acetonitrile (30 ml). After stirring for 10 min, benzyl bromide (1.7 ml, 14 mol) was added and stirring was continued for 3 h. The solvent was then rotovapped off and the residue partitioned between ethyl acetate and water. The organic phase was washed with 1 M citric acid, water then 10% aqueous Na2CO3 and dried (Na2Sθ4). Concentration gave the title compound as a yellow oil (4 g). !H NMR (CDC13) d 1.19-1.68 (m, 15 H), 2.24 (br m, 1 H), 2.90-2.97 (br m, 1
H), 3.91-4.02 (br m, 1 H), 5.20 (br m, 2 H), 7.35 (m, 5 H).
Step B: L-Homoproline benzyl ester hydrochloride
Anhydrous HCl was bubbled through a cooled (0°C) solution of Boc-L-homoproline benzyl ester (3 g) in ethyl acetate (100 ml) for 10 min. The resulting mixture was allowed to warm gradually to room temperature over 4 h. The solution was then purged with argon and rotavapped down. Trituration of the residue with ether gave the title compound as a white solid (2.4 g). ^ NMR (CD3OD) d 1.55-1.92 (m, 6 H), 2.30 (br m, 1 H), 3.20 (br m, 1 H), 3.42 (br m, 1 H), 4.08 (br m, 1 H), 5.29 (br m, 2 H), 7.36-7.40 (m, 5 H). Step C: Boc-D-3,3-diphenylalanine-L-homoproline benzyl ester
The title compound was prepared from Boc-D-3,3-diphenyl- alanine and L-homoproline benzyl ester hydrochloride essentially according to the procedure described for EXAMPLE I, Step A. iH NMR (CDCI3) d 1.09-1.58 (m, 15 H), 2.05 (m, 1 H), 3.13 (br m, 1 H), 3.88 (br m, 1 H), 4.42 (br m, 1 H), 5.06 (br m, 1 H), 5.16 (m, 2 H), 5.55 (m, 1 H), 7.11-7.40 (m, 15 H).
Step D: Boc-D-3.3-diphenylalanine-L-homoproline A solution of Boc-D-3,3-diphenylalanine-L-homoproline benzyl ester (4.2 g, 7.8 mmol) in ethyl acetate (50 ml) was hydrogenated at 1 atm in the presence of 10% Pd/C (1 g) for 4 h. Removal of the catalyst by filtration through Celite and concentration of the filtrate in vacuo gave the title compound as a white solid (3.5 g). !H NMR (CDCI3) d 1.17-1.38 (m, 15 H), 2.15 (m, 1 H), 3.09 (m, 1 H), 3.84 (m, 1 H), 4.41 (m, 1 H), 5.15 (m, 1 H), 5.37 (m, 1 H), 7.17-7.40 (m, 10 H).
Step E: Boc-D-3,3-diphenylalanine-L-homoproline-N-(trαns-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. *H NMR (CDCI3) d 1.20- 1.34 (m, 15 H), 2.30 (m, 1 H), 3.02 (m, 1 H), 3.73 (m, 1 H), 3.85 (m, 1 H), 4.10 (m, 1 H), 4.38 (m, 1 H), 4.92 (m, 1 H), 5.19 (m, 2 H), 6.23-6.34 (m, 2 H), 6.70 (s, 1 H), 7.13-7.37 (m, 26 H).
Step F: D-3,3-diphenylalanine-L-homoproline-N-(trαns-4- imidazole-allyl) amide
Simultaneous removal of the protecting groups from Boc-D- 3,3-diphenylalanine-L-homoproline-N-(£rons-l-trityl-4-imidazoleallyl) amide was accomplished essentially according to the procedure described in EXAMPLE IV, Step E affording the title compound which was purified by preparative HPLC. *H NMR (CD3OD) d 0.24 (m, 1 H), 1.12-1.36 (m, 4 H), 2.03 (br d, J = 13.6 Hz, 1 H), 3.22 (m, 1 H), 3.74 (br d, J = 11.7 Hz, 1 H), 4.01 (m, 2 H), 4.44 (d, J = 11.3 Hz, 1 H), 4.95 (br s, 1 H), 5.34 (d, J = 11.3 Hz, 1 H), 6.35 (dt, J = 5.2, 16.2 Hz, 1 H), 6.47 (d, J = 16.2 Hz, 1 H), 7.25-7.64 (m, 11 H), 8.85 (d, J = 1.3 Hz, 1 H); MS (FAB) 458 (M+D+.
EXAMPLE XI
Preparation of D-3.3-Bis-(4'-methoxvphenvl)alanine-L-proline-N-(trαns- 4-imidazoleallyl) amide
Figure imgf000072_0001
Step A: Bis-(4-methoxyphenyl)methanol To a stirred solution of 4,4'-dimethoxybenzophenone (5.0 g,
20.6 mmol) in 1:1 THF / ethanol (100 ml) was added sodium borohydride (946 mg, 25 mmol) and the mixture stirred overnight at ambient temperature. Additional borohydride (200 mg) was added, and the mixture heated to 40°C for 1 h, cooled and quenched with acetone. The mixture was rotavapped to dryness, partitioned between EtOAc and cold 1M citric acid, the organic layer washed with 10% Na2CO3, brine, treated with activated carbon and concentrated to give the title compound as a colorless solid.
Step B: 3,3-Bis-(4'-methoxyphenyl)-2-nitropropionic acid ethyl ester
To a stirred (0°C) solution of bis-(4-methoxyphenyl)methanol (2.5 g, 10.2 mmol) and ethyl nitroacetate (2.26 ml, 20.4 mmol) in CH2CI2 (50 ml) under argon was added AICI3 (1.36 g, 10.2 mmol) in one portion. After 1 h, the reaction mixture was allowed to warm to approximately 10°C and poured into a mixture of ice and 2M HCl. The resulting mixture was stirred for 45 min, and the aqueous layer extracted with CH2C12* The combined organic layers were washed with 10% Na2Cθ3, dried over MgSO4, treated with activated carbon, and concentrated to give a reddish oil that was chromatographed (CHCI3 elution) to afford the title compound as a colorless oil.
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. The resulting residue was diluted with brine, basified with 2M NaOH and extracted with 3 portions of CH2CI2. The combined organic layers were dried over Na2SO4 and concentrated to give a colorless oil (2.62 g) that was dissolved in dioxane (50 ml) containing di-t-butyldicarbonate (2 g, 9.1 mmol). To this stirred solution under argon was added IM NaOH (9 ml) and stirred overnight at room temperature. The reaction mixture was concentrated and the residue partitioned between EtOAc and IM citric acid. The organic layer was washed with 10% Na2CO3, brine, dried over MgSO4 and concentrated to give a yellow oil that was chromatographed (1:4 to 2:3 ethyl acetate / hexanes) to provide the title compound as a colorless foam.
Step D: Boc-DL-3.3-bis-(4'-methoxyphenyl)alanine
To a stirred solution of Boc-DL-3,3-bis-(4'-methoxy- phenyl)alanine ethyl ester (2.32 g, 5.4 mmol) in dimethoxyethane (50 ml) was added IM LiOH (8.1 ml) and the mixture stirred overnight under argon. Additonal IM LiOH (4 ml) was added, and stirring continued for 48 h. The reaction mixture was concentrated by rotavap, the residue partitioned between IM citric acid and EtOAc, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2Sθ4 and concentrated by rotavap to give the title compound as a colorless foam. Step E: Boc-DL-3,3-bis-(4'-methoxyphenyl)alanine-L-proline benzyl ester
The title compound was prepared from Boc-DL-3,3-bis-(4'- methoxyphenyDalanine and L-proline benzyl ester essentially according to the procedure described for EXAMPLE I, Step A.
Step F: Boc-DL-3.3-bis-(4'-methoxyphenyl)alanine-L-proline
The title compound was prepared from Boc-DL-3,3-bis-(4'- methoxyphenyl)alanine-L-proline benzyl ester essentially according to the procedure described for EXAMPLE I, Step B.
Step G: Boc-DL-3,3-bis-(4'-methoxyphenyl)alanine-L-proline-N-
(trans- l-trityl-4-imidazoleallyl) amide The title compound was prepared from Boc-DL-3,3-bis-(4'- methoxyphenyl)alanine-L-proline and trans- l-trityl-4- imidazoleallylamine using the procedure described in EXAMPLE I, Step A .
Step H: D-3,3-Bis-(4'-methoxyphenyl)alanine-L-proline-N-(trαns-
4-imidazoleaIlyl) amide
The title compound was prepared from Boc-DL-3,3-bis-(4'- methoxyphenyl)alanine-L-proline-N-(trαns-l-trityl-4-imidazoleallyl) amide using the procedure described in EXAMPLE IV, Step E. The diastereomers were separated by preparative HPLC. The title compound is the less polar diastereomer. ^ NMR (CD3OD) d 1.30-1.42 (m, 1 H),
1.82 (br s, 3 H), 2.72-2.88 (m, 1 H), 3.50-3.63 (m, 1 H), 3.75 (s, 3 H), 3.81 (s, 3 H), 4.00 (br s, 2 H), 4.05-4.17 (m, 1 H), 4.34 (d, J = 11.2 Hz, 1 H), 6.35 (d oft, J = 16 and 6 Hz, IH), 6.58 (d J = 16 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8 Hz, 2 H), 7.20 (d J = 8.5 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.53 (s, 1 H), 8.86 (s, 1 H); MS (FAB) 504 M+D+. EXAMPLE XII
Preparation of D-3,3-Bis-(4'-methoxyphenyl)alanine-L-proline-N-(4- imidazolepropyl) amide
Figure imgf000075_0001
The title compound was prepared from D-3,3-bis-(4'- methoxyphenyl)alanine-L-proline-N-(trøns-4-imidazoleallyl) amide using the procedure described in EXAMPLE I, Step B. !H NMR (CD3OD) d 1.10-1.40 (br m, 2 H), 1.70-1.95 (br m, 4 H), 2.70-2.85 (br m, 3 H), 2.90-3.10 (br m, 2 H), 3.45-3.60 (br m, 1 H), 3.70 (br s, 3 H), 3.80 (br s, 3 H), 3.95-4.08 (br m, 1 H), 4.25-4.40 (br m, 1 H), 6.75-6.85 (br m, 2 H), 6.90- 7.05 (br m, 2 H), 7.10-7.22 (br m, 2 H), 7.30-7.37 (br m, 1 H), 7.42-7.53 (br m, 2 H), 8.75 (br s, 1 H); MS (FAB) 506 (M+l)+.
EXAMPLE XIII
Preparation of D-3,3-Diphenylalanine-L-proline-N-(trαns-5-methyl-4- imidazoleallyl) amide
Figure imgf000076_0001
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 NaHCθ3. Drying over Na2SO4 and removal of the solvent in vacuo gave a 1:1 mixture of the title compounds as a white powder. 1-trityl isomer ^H NMR (CDCI3) d 2.55 (s, 3 H), 7.12-7.38 (m, 15 H), 9.11 (s, 1 H); 3-trityl isomer !H NMR (CDCI3) d 1.83 (s, 3 H), 7.10-7.42 (m, 15 H), 10.02 (s, 1 H).
Step B: Trans- l-trityl-4-methyl-5-imidazoleacrylic acid methyl ester
A mixture of 1- and 3-trityl-4-methyl-5-imidazolecarbox- aldehyde (7 g, 20 mmol) and methyl
(triphenylphosphoranylidene)acetate (6.7 g, 20 mmol) in toluene (40 ml) was heated at reflux for 24 h. After cooling to room temperature, silica gel was added and the solvent removed in vacuo. The residue was transferred to a flash column and eluted with 3:2 hexane / ethyl acetate to give the title compound. XH NMR (CDCI3) d 1.58 (s, 3 H), 3.77 (s, 3 H), 6.59 (d, J = 15.3 Hz, 1 H), 7.13-7.16 (m, 6 H), 7.33-7.36 (m, 10 H), 7.57 (dd, J
= 0.4, 15.3 Hz, 1 H).
Step C: Trans- l-trityl-4-methyl-5-imidazoleall yl alcohol
A IM solution of DIBAL in methylene chloride (20 ml, 20 mmol) was added to a cooled (-78°C) solution of the ester (2.5 g, 6.1 mmol) in THF (30 ml). After stirring at -78°C for 30 min, the reaction mixture was stored at -25°C for 19 h. The reaction mixture was then warmed to 0°C and carefully quenched sequentially with methanol (1.4 ml) and IM sodium hydroxide (2.8 ml). After stirring for 10 min, 30% sodium potassium tartrate (7 ml) was added. The reaction mixture was then stirred until precipitation was complete. The precipitate was filtered off and washed well with ether and ethyl acetate. The filtrate was washed with brine and dried over Na2Sθ4. Filtration and concentration afforded the title compound as a crystalline foam. iH NMR (CDCI3) d 1.49 (s, 3 H), 4.30 (d, J = 5.1 Hz, 2 H), 6.46-6.57 (m, 2 H), 7.13-7.17 (m, 6 H), 7.29 (s, 1 H), 7.31-7.37 (m, 9 H).
Step D: Trans- l-trityl-4-methyl-5-imidazoleallyl azide
Trans- l-trityl-4-methyl-5-imidazoleallyl alcohol was converted to the corresponding azide essentially according to the procedure described for EXAMPLE I, Step F. H NMR (CDCI3) d 1.50 (s, 3 H), 3.93 (d, J = 6.2 Hz, 2 H), 6.40-6.51 (m, 2 H), 7.13-7.18 (m, 6 H), 7.29 (s, I H), 7.32-7.35 (m, 9 H).
Step E: Tmns-l-trityl-4-methyl-5-imidazoleallylamine
Trans- l-trityl-4-methyl-5-imidazoleallyl azide was converted to the corresponding amine essentially according to the procedure described for EXAMPLE I, Step G. !H NMR (CDCI3) d 1.48 (s, 3 H), 1.82 (br s, 2 H), 3.46 (d, J = 6.0 Hz, 2 H), 6.36 (d, J = 15.4 Hz, 1 H), 6.47 (m, 1 H), 7.12-7.18 (m, 6 H), 7.27 (s, 1 H), 7.31-7.37 (m, 9 H).
Step F: D-3,3-Diphenylalanine-L-proline-N-(frαns-5-methyl-4- imidazoleallyl) amide
Boc-D-3,3-diphenylalanine-L-proline was coupled to trans-1- trityl-4-methyl-5-iιmdazoleallylamine 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. 1-H NMR (CD3OD) d 1.18 (m, 1 H), 1.79 (m, 3 H), 2.42 (s, 3 H), 2.84 (m, 1 H), 3.58 (m, 1 H), 3.96-4.11 (m, 3 H), 4.45 (d, J = 11.4 Hz, 1 H), 4.99 (d, J = 11.4 Hz, 1 H), 6.25 (dt, J = 5.1, 16.3 Hz, 1 H), 6.55 (d, J = 16.3 Hz, 1 H), 7.27-7.60 (m, 10 H), 8.76 (s, 1 H); MS (FAB) 458 (M+D+.
EXAMPLE XrV
Preparation of D-3,3-Diphenylalanine-L-proline-N-(5-methyl-4- imidazolepropyl) amide
Figure imgf000078_0001
A solution of D-3,3-diphenylalanine-L-proline-N-(frαns-5- methyl-4-imidazoleallyl) amide (280 mg) in ethanol (10 ml) containing 5% Pd/C was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through Celite. The filtrate was concentrated and the residue purified by preparative HPLC to give the title compound. XH NMR (CD3OD) d 1.30 (m, 1 H), 1.73-1.87 (m, 5 H), 2.30 (s, 3 H), 2.71 (m, 2 H), 2.82 (m, 1 H), 3.22 (m, 2 H), 3.56 (m, 1 H), 4.01 (m, 1 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.98 (d, J = 11.5 Hz, 1 H), 7.27-7.62 (m, 10 H), 8.67 (s, 1 H); MS (FAB) 460 (M+l)+. EXAMPLE XV
Preparation of D-3,3-Diphenylalanine-L~proline-N-(4-imidazole- proparεryl) amide
Figure imgf000079_0001
Step A: N-Propargylphthalimide
A mixture of propargylamine (7 ml, 102 mmol) and phthalic anhydride (15 g, 101 mmol) in chloroform (200 ml) was heated together at 70°C overnight. Filtration gave a 1:1 mixture of the phthalimide and the acid-amide (20 g). This was suspended in THF (100 ml) and heated at 70°C until complete dissolution had been effected. Powdered 4A sieves (15 g) was added and the heating continued for 24 h. The reaction mixture was cooled and filtered through Celite washing the residue well with methanol. The filtrate was concentrated, redissolved in chloroform and then adsorbed onto silica gel and chromatographed (8:1:1 to 7:1.5:1.5 hexane / chloroform / ethyl acetate) to give the title compound as a white solid. !H NMR (CDCI3) d 2.23 (m, 1 H), 4.47 (m, 2 H), 7.75 (m, 2 H), 7.88 (m, 2 H).
Step B: 4.5-Diodoimidazole
A solution of iodine (49.5 g, 195 mmol) and sodium iodide (53.5 g, 360 mmol) in water (350 ml) was added dropwise over 3 h to a solution of imidazole (6.8 g, 100 mmol) and sodium carbonate (23 g, 220 mmol) in water (650 ml). After an additional 3 h, the diiodide was filtered off and washed well with water. Drying yielded a cream colored solid which was recrystallized from aqueous acetone with the aid of decolorizing carbon. !H NMR (CD3OD) d 7.75 (s, 1 H).
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 A suspension of N-propargylphthalimide (450.9 mg, 2.4 mmol) and l-trityl-4-iodoimidazole (875.5 mg, 2 mmol) in diethylamine (20 ml) was heated to 55°C. Dissolution was incomplete. Bis triphenyl- phosphinepalladium dichloride (15.6 mg) and 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). It was washed with saturated NaHCθ3 and water then dried (1:1 Na2Sθ4 / K2CO3). Concentration, adsorption onto silica gel and chromatography (5:4:1 ethyl acetate / hexane / chloroform) gave the title compound as a cream powder. iH NMR (CDCI3) d 4.65 (s, 2 H), 7.01 (s, 1 H), 7.10 (m, 6 H), 7.33 (m, 10 H), 7.72 (m, 2 H), 7.86 (m, 2 H).
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
D-3,3-Diphenylalanine-L-proline and l-trityl-4-imidazole- propargylamine were coupled essentially according to the procedure for Example I, Step A then the protecting groups were removed essentially according to the procedure of Example IV, Step E. H NMR (CD3OD) d 1.30-1.39 (m, 1 H), 1.77 (m, 3 H), 2.79 (m, 1 H), 3.56 (m, 1 H), 4.06 (m, 1 H), 4.25 (dd, J = 17.9 Hz, 2 H), 4.44 (d, J = 11.4 Hz, 1 H), 4.98 (d, J = 11.4 Hz, 1 H), 7.27-7.70 (m, 11 H), 8.78 (s, 1 H); MS (FAB) 442 (M+l)+.
EXAMPLE XVI
Preparation of N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-(4- imidazolepropargyl) amide
Figure imgf000082_0001
Step A: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-(l- trityl-4-imidazolepropargyl) amide
The title compound was prepared from N-benzylsulfonyl-D- 3,3-diphenylalanine-L-proline and l-trityl-4-imidazolepropargylamine using the procedure described in EXAMPLE I, Step A.
Step B: N-Benzylsulfonyl-D-3,3-diphenylalanine-L-proline-N-(4- imidazolepropargyl) amide The title compound was prepared from N-benzylsulfonyl-D-
3,3-diphenylalanine-L-proline-N-(l-trityl-4-imidazolepropargyl) amide using the procedure described in EXAMPLE IV, Step E. iH NMR (CD3OD) d 1.40-1.50 (m, 1 H), 1.50-1.68 (m, 1 H), 1.72-1.90 (m, 2 H), 2.95-
3.05 (m, 1 H), 3.72-3.82 (m, 1 H), 4.00-4.08 (m, 1 H), 4.10-4.18 (m, 2 H), 4.24 (d, J = 2.7 Hz, 2 H), 4.33 (d, J = 11.7 Hz, 1 H), 5.07 (d, J = 11.2 Hz, 1 H), 7.15-7.58 (m, 16 H), 8.07 (m, 1 H), 8.72 (s, 1 H); MS (FAB) 596 (M+l)+ EXAMPLE XVII
Preparation of D-3,3-diphenylalanine-L-homoproline-N-(4-imidazole- propargyl) amide
Figure imgf000083_0001
Step A: Boc-D-3,3-diphenylalanine-L-homoproline-N-(l-trityl-4- imidazolepropargyl) amide
The title compound was prepared from Boc-D-3,3- diphenylalanine-L-homoproline and l-trityl-4-imidazolepropargylamine using the procedure described in EXAMPLE I, Step A.
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
(m, 1 H), 3.62-3.80 (m, 1 H), 4.25 (s, 2 H), 4.41 (d, J = 11.5 Hz, 1 H), 5.34 (d, J = 11.5 Hz, 1 H), 7.20-7.65 (m, 11 H), 8.46 (br s, 1 H); MS (FAB) 456 (M+l)+ EXAMPLE XVIII
Preparation of D-3,3-Diphenylalanine-L-proline-N-(5-methyl-4- imidazole-propargyl) amide
Figure imgf000084_0001
Step A: 4-Iodo-5-methylimidazole
To a solution of 4-methylimidazole (8.20 g, 100 mmol) and sodium carbonate (21.2 g, 200 mmol) in water (650 ml) was added a solution of sodium iodide (26.5 g, 180 mmol) and iodine (25.4 g, 100 mmol) in water (350 ml) over 90 min at room temperature. The reaction was stirred a furthur 30 min and filtered. The resulting white solid was washed with water and dried in vacuo at 50°C. !H NMR (CD3OD) d 2.20
(s, 3 H), 4.86 (br s, 1 H), 7.57 (s, 1 H).
Step B: l-Boc-4-iodo-5-methylimidazole
A suspension of 4-iodo-5-methylimidazole (4.16 g, 20 mmol) and di-t-butyldicarbonate (5.24 g, 24 mmol) in methylene chloride (100 ml) containing triethylamine (4.0 ml, 28.7 mmol) was stirred at room temperature until homogeneity was achieved (2 h). The reaction mixture was then washed well with water, dried (Na2SO4) and concentrated. The residue was chromatographed (5:1 hexane / ethyl acetate) to afford the title compound as a crystalline white solid. ^H NMR (CDCI3) d 1.62 (s, 9 H), 2.43 (s, 3 H), 8.00 (s, 1 H). Step C: l-Boc-5-methyl-4-imidazolepropargyl phthalimide
A miture of l-Boc-4-iodo-5-methylimidazole (936.8 mg, 3 mmol), copper (I) iodide (30 mg) and bis triphenylphosphinepalladium- dichloride (217.5 mg, 0.3 mmol) in triethylamine (30 ml) was heated at 60°C for 10 min. There was incomplete dissolution of the catalyst. N- Propargylphthalimide (651.4 mg, 3.5 mmol) was added and the heating continued. Most of the solids went in then triethylamine hydroiodide was gradually deposited. After 4 h more alkyne (384.5 mg) was added. After 1 h the reaction mixture became difficult to stir and was then evaporated to dryness. The residue was redissolved in chloroform and adsorbed onto silica gel. Chromatography (5:4:1 ethyl acetate / hexane / chloroform) gave the title compound. iH NMR (CDCI3) d 1.61 (s, 9 H), 2.46 (s, 3 H), 4.70 (s, 2 H), 7.74 (m, 2 H), 7.89 (m, 2 H), 7.91 (s, 1 H).
Step D: 5-Methyl-4-imidazolepropargylamine
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. iH ΝMR (CD3OD) d 1.32 (m, 1 H), 1.77 (m, 3 H), 2.39 (s, 3 H), 2.79 (m, 1 H), 3.57 (m, 1 H), 4.06 (m, 1 H), 4.27 (dd, J = 17.9 Hz, 2 H), 4.45 (d, J = 11.4 Hz, 1 H), 4.98 (d, J = 11.4 Hz, 1 H), 7.26-7.60 (m, 10 H), 8.75 (s, 1 H); MS (FAB) 456 (M+l)+. EXAMPLE XIX
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(4-methylene- carboxamidopropylimidazolyl)-2-pyridinone
Figure imgf000086_0001
Step A: 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone
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. The residue was partitioned between 1:1 methylene chloride / chloroform and cold 1:1 brine / IM citric acid. There was partial formation of an emulsion. The aqueous phase was washed once with ether and the combined organics filtered through Celite to break up the colloid. The filtrate was washed with 1:1 saturated NaHCO3 / 10% aqueous Na2CO3 solution and dried (Na2SO4). Concentration in vacuo gave a tan solid. Methanol was added to the crude product to give a slurry which was then filtered. The residue was washed with methanol until the filtrate was clear. Drying gave the title compound as an off-white powder. A further crop was obtained by evaporating the washings and chromatographing the residue (7:1.5:1.5 ethyl acetate / hexanes / chloroform): ^ NMR (CDCI3) d 2.29 (s, 3H, CH3), 5.20 (s, 2 H, PI1CΗ2), 6.06 (d, J = 7.6 Hz, pyridinone-5- H), 7.32-7.43 (m, 5 H, Ph), 7.67 (br s, 1 H, CbzNH), 8.03 (br d, pyridinone- 4-H). Step B: 3-Benzyloxycarbonylamino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyridinone
Sodium hydride (5.3 g, 220 mmol) was added proportionwise to a well stirred slurry of 3-benzyloxycarbonylamino-6-methyl-2- pyridinone (53 g, 200 mmol) in THF (300 ml) at 0°C. By the end of the addition a brown solution had resulted. t-Butyl bromoacetate (45 ml, 270 mmol) was then added. Within minutes NaBr started separating out. After 1 h a thick white precipitate had formed. The reaction was stirred for an additional hour (bath temperature then 15°C) then the THF was rotovapped off. The residue was partitioned between THF / methylene chloride (600 ml / 100 ml) and half saturated brine (200 ml). The organic phase was dried (Na2SO4), filtered and concentrated. The resulting cream colored solid was triturated with hexane to give of N-alkylated material as a white microcrystalline solid: iH NMR (CDCI3) d 1.47 (s, 9 H), 2.25 (s, 3 H), 4.75 (s, 2 H), 5.19 (s, 2 H), 6.09 (d, J = 7.8 Hz), 7.30-7.40 (m, 5 H), 7.75 (br s, 1 H), 7.94 (br d, 1 H).
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. The solid residue was triturated with ether to give the title compound as a pale yellow crystalline solid: iH NMR (CDCI3) d 1.46 (s, 9 H, t-Bu), 2.18 (s, 3 H, Me), 4.02 (br s, 2 H, NH2), 4.74 (s, 2 H, CEtø), 5.90 (d, J = 7.3 Hz, 1 H, pyridinone H-5), 6.47 (d, J = 7.3 Hz, 1 H, pyridinone H-4).
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. This gave the title compound as an off-white solid: !H NMR (CDCI3) d 1.51 (s, 9 H, t- Bu), 2.26 (s, 3 H, Me), 4.31 (s, 2 H, PI1CΗ2), 4.75 (s, 2 H, NCH2), 6.01 (d, J = 7.7 Hz, 1 H, pyridinone H-5), 7.22-7.34 (m, 7 H, remaining H).
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. The mixture was degassed with argon and filtered to give the title compound as a pink solid: ^H NMR (CD3OD) d 2.32 (s, 3 H, Me), 4.43 (s, 2 H, PI1CΗ2), 4.89 (s, 2 H, NCH2), 6.14 (d, J = 7.7 Hz, 1 H, pyridinone H-5), 7.28-7.33 (m, 6 H, remaining H).
Step F: 3-Benzyls fonylamino-6-methyl-l-(trαns-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. iH NMR (CDCI3) d 2.40 (s, 3 H), 4.00 (t, J = 6 Hz, 2 H), 4.30 (s, 2 H),
4.68 (s, 2 H), 6.02 (d, J = 8 Hz, 1 H), 6.20-6.40 (m, 2 H), 6.60 (t, J = 6 Hz, 1 H), 6.73 (s, 1 H), 7.08-7.40 (m, 21 H), 8.02 (s, 1 H).
Step G: 3-Benzylsulfonylamino-6-methyl- l-(trαns-4-methylene- carboxamidoallylimidazolyl)-2-pyridinone
The title compound was prepared from 3-benzylsulfonyl- amino-6-methyl- l-(trans- l-trityl-4- methylenecarboxamidoallylimidazolyl)-2-pyridinone using the procedure described in EXAMPLE IV, Step E. iH NMR (CD3OD) d 2.35 (s, 3 H), 4.05 (br m, 2 H), 4.45 (s, 2 H), 4.85 (s, 2 H), 6.19 (d, J = 8 Hz, 1 H), 6.38 (d of t, J = 16 and 6 Hz, 1 H), 6.58 (br d, J = 16 Hz, 1 H), 7.20-7.37 (m, 6 H), 7.52 (s, 1 H), 8.60 (t, J = 6 Hz, 1 H), 8.81 (s, 1 H).
Step H: 3-Benzylsulfonylamino-6-methyl-l-(4-methylenecarbox amido-propylimidazolyl)-2-pyridinone
The title compound was prepared from 3-benzylsulfonyl- amino-6-methyl-l-(trαns-4-methylenecarboxamidoallylimidazolyl)-2- pyridinone using the procedure described in EXAMPLE I, Step B. ^H NMR (CD3OD) d 1.15-1.40 (m, 2 H), 1.89 (t, J = 6.6 Hz, 2 H), 2.33 (s, 3 H), 2.77 (t, J = 7 Hz, 2 H), 4.43 (s, 2 H), 4.79 (s, 2 H), 6.16 (d, J = 7.3 Hz, 1 H), 7.15-7.40 (m, 7 H), 8.71 (s, 1 H); MS (FAB) 444 (M+l)+.
EXAMPLE XX
Preparation of 3-Benzylsulfonylaιmno-6-methyl-l-(4-methyl-5- methylene-carboxamidomethylimidazolyl)-2-pyridinone
Figure imgf000089_0001
Step A: l-Trityl-4-methyl-5-imidazolemethanol A solution of 4-methyl-5-imidazolemethanol hydrochloride
(6.0 g, 40 mmol), trityl chloride (12.3 g, 44 mmol), and triethylamine (16.4 ml, 120 mmol) in chloroform (200 ml) was stirred at room temperature overnight. The reaction mixture was washed with water, dried over MgSO4, filtered and the solvents removed in vacuo. The crude material was purified by flash chromatography (24:1 CHCI3 / MeOH). !H NMR (CDCI3) d 1.42 (s, 3 H), 3.80 (br s, 1 H), 4.55 (s, 2 H), 7.10-7.40 (m, 16 H).
Step B: 5-Azidomethyl-4-methyl-l-tritylimidazole
To a solution of l-trityl-4-methyl-5-imidazolemethanol (3.7 g, 10 mmol) and DPPA (3.0 ml, 13 mmol) in THF (100 ml) was added DBU (2.0 ml, 13 mmol). The resulting solution was heated to 60°C for 2 h. The solvents were removed in vacuo and the residue purified by flash chromatography (2:1 hexane / ethyl acetate) to give of the title compound. 4ϊ NMR (CDC13) d 1.42 (s, 3 H), 4.22 (s, 2 H), 7.10-7.35 (m, 16 H).
Step C: l-Trityl-4-methyl-5-imidazolemethylamine
To a solution of 5-azidomethyl-4-methyl-l-tritylimidazole (3.0 g, 7.9 mmol) in THF (70 ml) was added triphenylphosphine (5.18 g, 19.8 mmol). The resulting solution was refluxed for 1.5 h then water (5 ml) was added. Refluxing was continued for an additional 24 hours. After cooling to room temperature, the solvents were removed in vacuo and the crude reaction mixture was purified by chromatography on silica gel (19:1 chloroform / 10% NH4OH in methanol) to give of the title compound. !H NMR (CDCI3) d 1.40 (s, 3 H), 1.70 (br s, 2 H), 3.70 (s, 2 H), 7.10-7.35 (m, 16 H).
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),
4.78 (s, 2 H), 6.01 (d, J = 8 Hz, 1 H), 6.85-7.05 (br s, 1 H), 7.10-7.35 (m, 22 H).
Step E: 3-Benzylsulfonylamino-6-methyl-l-(4-methyl-5-methyl-ene- carboxamidomethylimidazolyl)-2-pyridinone
The title compound was prepared from 3-benzylsulfonyl- amino-6-methyl-l-(l-trityl-4-methyl-5-methylenecarboxamidomethyl- imidazolyl)-2-pyridinone using the procedure described in EXAMPLE TV, Step E. iH NMR (CD3OD) d 2.31 (s, 3 H), 2.34 (s, 3 H), 4.40 (s, 2 H),
4.42 (s, 2 H), 4.80 (s, 2 H), 6.16 (d, J = 7 Hz, 1 H), 7.20-7.35 (m, 6 H), 8.65 (s, I H); MS (FAB) 430 (M+l)+. EXAMPLE XXI
Preparation of 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-(4- methyl-5-methylenecarboxamidomethylimidazolyl)-2-pyridinone
Figure imgf000091_0001
Step A: Sodium 4- chlorobenzylthio sulfate
To a solution of 4-chlorobenzyl chloride (10.0 g, 62 mmol) in 1:1 methanol / water (100 ml) was added sodium thiosulfate (9.81 g, 62 mmol). The resulting solution was then refluxed for 24 h. After cooling to room temperature, the solvents were removed in vacuo and the residue triturated with ether to give the title compound as a white solid. !H NMR (CD3OD) d 4.25 (s, 2 H), 7.32 (q, J = 33, 9 Hz, 4 H).
Step B: 4-Chlorobenzylsulfonyl chloride
Chlorine gas was slowly bubbled through a cooled (0°C) solution of sodium 4-chlorobenzylthiosulfate (11.2 g, 56 mmol) in acetic acid (100 ml) to which ice (10 g) had been added. Additional ice was added as necessary to maintain the temperature <10°C. After 0.5 h the addition of chlorine was stopped and the resulting yellow solution was allowed to stir at 0°C for 1 h. The solution was then extracted with ether and the organics washed twice with cold 5% sodium bisulfite solution. Drying over MgSO4, filtration and removal of the solvents in vacuo gave the title compound as a white solid. iH NMR (CDCI3) d 4.82 (s, 2 H), 7.45 (m, 4 H).
Step C: 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone
To a solution of 3-amino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyridinone (600 mg, 2.5 mmol) in pyridine (50 ml) was added 4-chlorobenzylsulfonyl chloride (830 mg, 3.75 mmol). The resulting red solution was stirred at room temperature overnight. The solvents were removed in vacuo and the crude material purified by preparative HPLC. iH NMR (CDCI3) d 1.51 (s, 9 H), 2.27 (s, 3 H), 4.27 (s, 2 H), 4.75 (s, 2 H), 6.03 (d, J = 8 Hz, 1 H), 7.17-7.30 (m, 4 H), 7.35 (d, J = 8 Hz, 1 H).
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
(s, 2 H), 6.12 (d, J = 7.6 Hz, 1 H), 7.29 (s, 4 H), 7.34 (d, J = 7.8 Hz, 1 H).
Step E: 3-(4-Chlorobenzylsulfonylamino)-6-methyl-l-(l-trityl-4- methyl-5-methylenecarboxamidomethylimidazolyl)-2- pyridinone
The title compound was prepared from 3-(4-chlorobenzyl- sulfonylamino)-6-methyl- l-methylenecarboxy-2-pyridinone and l-trityl-4- methyl-5-imidazolemethylamine using the procedure described in EXAMPLE I, Step A. *H NMR (CDCI3) d 1.40 (s, 3 H), 2.39 (s, 3 H), 4.25- 4.35 (m, 4 H), 4.78 (s, 2 H), 6.01 (d, J = 8 Hz, 1 H), 6.85-7.05 (br s, 1 H), 7.10- 7.35 (m, 22 H).
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),
4.43 (s, 2 H), 4.46 (s, 2 H), 4.81 (s, 2 H), 6.17 (d, J = 8 Hz, 1 H), 7.20-7.30 (m, 4 H), 7.35 (d, J = 7.5 Hz, 1 H), 8.68 (s, 1 H); MS (FAB) 464 (M+l)+. EXAMPLE XXII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l'-t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethyl-imidazolyl)-2- pyridinone
COOlBu
Figure imgf000093_0001
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. This solution was washed well with cold water and dried over sodium sulfate. Filtration and concentration gave a cream colored solid (16 g) which was determined by NMR analysis to be a 2:1 mixture of l-t-butoxycarbonyl-methyl-4-methyl-5-hydroxvmethylimidazole and 3-t- butoxycarbonyl-methyl-4-methyl-5-hydroxymethylimidazole respectively. The two isomers displayed very similar mobility on TLC but were separable by careful gradient elution chromatography on silica gel (99:1 to 19:1 chloroform / methanol): N-1 isomer ^ NMR (CDCI3) d 1.46 (s, 9 H), 2.23 (s, 3 H), 4.55 (s, 2 H), 4.63 (s, 2 H), 7.35 (s, 1 H); N-3 isomer iH NMR (CDCI3) d 1.48 (s, 9 H), 2.17 (s, 3 H), 4.47 (s, 2 H), 4.56 (s, 2 H), 7.39 (s, 1 H). Step B: l-t-Butoxycarbonylmethyl-4-methyl-5-azidomethylimidazole
A solution of l-t-butoxycarbonylmethyl-4-methyl-5-hydroxy- methylimidazole (4.61 g, 20 mmol) in DMF (100 ml) was cooled to 0°C and treated sequentially with diphenylphosphoryl azide (5.4 ml, 25 mmol) and DBU (3.7 ml, 25 ml). The resulting solution was allowed to warm gradually to room temperature and was then stirred there overnight. The DMF was rotavapped off, the residue dissolved in a minimum quantity of methylene chloride and the resulting solution diluted several fold with ether and ethyl acetate. This solution was washed sequentially with IM citric acid, water, 10% sodium carbonate, brine and then dried over magnesium sulfate. Filtration and concentration gave an oil which was purified by flash chromatography (19:1 chloroform / methanol) to give the title compound as an oil: !H NMR (CDCI3) d 1.48 (s, 9 H), 2.27 (s, 3 H), 4.28 (s, 2 H), 4.56 (s, 2 H), 7.43 (s, 1 H).
Step C: l-t-Butoxycarbonylmethyl-4-methyl-5- aminomethylimidazole
A solution of l-t-butoxycarbonylmethyl-4-methyl-5-azido- methylimidazole (2.9 g) in ethyl acetate (100 ml) containing 10% palladium on carbon (1.5 g) was stirred at room temperature under an atmosphere of hydrogen for 3 h. After removal of the catalyst by filtration through Celite, the filtrate was concentrated to give the amine as a colorless oil: !H NMR (CD3OD) d 1.48 (s, 9 H), 2.19 (s, 3 H), 3.69 (s, 2 H), 4.81 (s, 2 H), 7.49 (s, 1 H).
Step D: 3-Benzylsulfonamino-6-methyl-l-(l-t-butoxycarbonylmethyl-
4-methyl-5-methylenecarboxamidomethylimidazolyl)-2- pyridinone
The title compound was prepared from 3-benzylsulfonyl- amino-6-methyl-l-methylenecarboxy-2-pvridinone and 1-t-butoxy- carbonylmethyl-4-methyl-5-aminomethylimidazole essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 1.41 (s, 9 H, t-Bu), 2.36 (s, 3 H, pyridinone Me), 2.37 (s, 3 H, imidazole Me), 4.27 (s, 2 H, PhCH2), 4.36 (d, J = 5.7 Hz, 2 H, imidazoleCH2N), 4.51 (s, 2 H, pyridinoneNCH2), 4.86 (s, 2 H, imidazoleNCH2), 6.06 (d, J = 7.9 Hz, 1 H, pyridinone H5), 7.15-7.26 (m, 6 H, Ph and pyridinone He), 8.08 (br s, 1 H, SO2NH), 8.28 (br s, 1 H, CONH), 8.48 (s, 1 H, imidazole Etø); MS (FAB) 544 (M+D+.
EXAMPLE XXIII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l-carboxymethyl-4- rnethvI-5-rnethylenecarboxamidoπιethylimidazolyl)-2-pyridinone
Figure imgf000095_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-t-butoxycarbonylmethyl-4-methyl-5- methylenecarboxamido-methylimidazolyl)-2-pyridinone essentially according to the procedure of EXAMPLE XXI, Step D: *H NMR (CD3OD) d 2.31 (s, 3 H), 2.41 (s, 3 H), 4.44 (s, 2 H), 4.46 (m, 2 H), 4.73 (s, 2 H), 5.17 (s, 2 H), 6.13 (d, J = 7 Hz, 1 H), 7.30 (m, 6 H), 8.74 (br s, 1 H), 8.81 (s, 1 H); MS (FAB) 488 (M+l)+. EXAMPLE XXIN
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l-t-butylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)- 2-pyridinone
CONHlBu
Figure imgf000096_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and t- butylamine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 1.33 (s, 9 H), 2.32 (s, 3 H), 2.39 (s, 3 H), 4.41 (m, 2 H), 4.45 (s, 2 H), 4.75 (s, 2 H), 4.99 (s, 2 H), 6.15 (d, J = 7.5 Hz, 1 H), 7.26- 7.34 (m, 6 H), 7.89 (br s, 1 H), 8.67 (br t, 1 H), 8.74 (s, 1 H); MS (FAB) 544 (M+l)+.
EXAMPLE XXV
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l- ethylaminocarbonyl-methyl-4-methyl-5- methylenecarboxamidomethylimidazolyl)-2-pyridinone
CONHEt
Figure imgf000096_0002
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and ethylamine hydrochloride essentially according to the procedure of EXAMPLE I, Step A: 1-3 NMR (CD3OD) d 1.13 (t, J = 7.3 Hz, 3 H), 2.32 (s, 3 H), 2.39 (s, 3 H), 3.26 (m, 2 H), 4.43 (m, 2 H), 4.45 (s, 2 H), 4.75 (s, 2 H), 5.05 (s, 2 H), 6.15 (d, J = 7.7 Hz, 1 H), 7.26-7.34 (m, 6 H), 8.25 (br s, 1 H), 8.64 (br t, 1 H), 8.77 (s, 1 H); MS (FAB) 515 (M+l)+.
EXAMPLE XXVI
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l-cyclopropylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)-2- pyridinone
Figure imgf000097_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and cyclopropylamine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 0.72 (m, 4 H), 2.32 (s, 3 H), 2.40 (s, 3 H), 2.70 (m, 1 H), 4.43 (m, 2 H), 4.45 (s, 2 H), 4.74 (s, 2 H), 5.02 (s, 2 H), 6.15 (d, J = 7.7 Hz, 1 H), 7.24-7.36 (m, 6 H), 8.39 (br s, 1 H), 8.67 (br t, 1 H), 8.76 (s, 1 H); MS (FAB) 527 (M+l)+.
EXAMPLE XXVII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-(l-cyclopropylmethyl- aminocarbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazolyl)-2-pyridinone
Figure imgf000098_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and cyclopropylmethylamine essentially according to the procedure of EXAMPLE I, Step A: *H NMR (CD3OD) d 0.20 (d, J = 4.7 Hz, 2 H), 0.49 (d, J = 6.9 Hz, 2 H), 0.96 (br m, 1 H), 2.31 (s, 3 H), 2.39 (s, 3 H), 3.07 (d, J = 7 Hz, 2 H), 4.43 (s, 2 H), 4.44 (s, 2 H), 4.74 (s, 2 H), 5.07 (s, 2 H), 6.15 (d, J 7.9 Hz, 1 H), 7.28 (m, 6 H), 8.77 (s, 1 H); MS (FAB) 541 (M+D+.
EXAMPLE XXVIII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(l,l-dimethylpropyl- aminocarbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl- imidazolyll-2-pyridinone
Figure imgf000099_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and t- amylamine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 0.85 (t, J = 7.5 Hz, 3 H), 1.28 (s, 6 H), 1.70 (q, J = 7.5 Hz, 2 H), 2.32 (s, 3 H), 2.38 (s, 3 H), 4.40 (s, 2 H), 4.44 (s, 2 H), 4.75 (s, 2 H), 5.01 (s, 2 H), 6.15 (d, J = 7.7 Hz, 1 H), 7.28 (m, 6 H), 7.78 (s, 1 H), 8.74 (s, 1 H); MS (FAB) 557 (M+l)+.
EXAMPLE XXIX
Preparation of 3-Benzylsulfonylamino-6-methyl- 1-( 1-t-butylmethylamino- carbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl-imidazolyl]- 2-pyridinone
Figure imgf000100_0001
Step A: l-CarboxymethvI-4-methyl-5-azidomethylimidazole
The title compound was prepared from 1-t-butoxycarbonyl- methyl-4-methyl-5-azidomethylimidazole using the procedure described in EXAMPLE XXI, Step D. !H NMR (CD3OD) d 2.43 (s, 3 H), 4.61 (s, 2 H),
5.13 (s, 2 H), 8.94 (s, 1 H).
Step B: l-t-Butylmethylaminocarbonylmethyl-4-methyl-5- azidomethylimidazole
The title compound was prepared from l-carboxymethyl-4- methyl-5-azidomethylimidazole and t-butylmethylamine using the procedure described in EXAMPLE I, Step A. iH NMR (CDCI3) d 0.84 (s, 9 H), 2.30 (s, 3 H), 3.05 (d, J = 6.4 Hz, 2 H), 4.35 (s, 2 H), 4.62 (s, 2 H), 5.45 (br s, 1 H), 7.50 (s, 1 H).
Step C: l-t-Butylmethylaminocarbonylmethyl-4-methyl-5- aminomethylimidazole
A solution of l-t-butylmethylaminocarbonylmethyl-4- methyl-5-azidomethylimidazole (400 mg) and 10% Pd/C ( 400 mg) in ethyl acetate (60 ml) was hydrogenated at atmospheric pressure for 4 h. The solution was filtered through Celite and the solvents removed in vacuo to give the title compound. iH NMR (CDCI3) d 0.80 (s, 9 H), 1.61 (br s, 2 H), 2.23 (s, 3 H), 2.99 (d, J = 6.1 Hz, 2 H), 3.86 (s, 2 H), 4.63 (s, 2 H), 7.50 (s, 1 H).
Step D: 3-Benzylsulfonylamino-6-methyl-l-(l-t-butylmethylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazoιyl)-2-pyridinone
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-methylenecarboxy-2-pvridinone and 1-t- butylmethylamino-carbonylmethyl-4-methyl-5-aminomethylimidazole essentially according to the procedure of EXAMPLE I, Step A: *H NMR (CD3OD) d 0.90 (s, 9 H), 2.31 (s, 3 H), 2.39 (s, 3 H), 3.04 (d, J = 6.1 Hz, 2 H), 4.43 (m, 4 H), 4.88 (s, 2 H), 5.12 (s, 2 H), 6.15 (d, J = 7.5 Hz, 1 H), 7.26-7.34 (m, 6 H), 8.25 (br s, 1 H), 8.71 (br t, 1 H), 8.77 (s, 1 H); MS (FAB) 557 (M+l)+.
EXAMPLE XXX
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(2,2,2-trifluoroethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl- imidazolvn-2-pyridinone
Figure imgf000101_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxvmethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and 2,2,2- trifluoroethylamine hydrochloride essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 2.30 (s, 3 H), 2.39 (s, 3 H), 3.95 (q, J = 9.1 Hz, 2 H), 4.41 (s, 2 H), 4.44 (s, 2 H), 4.74 (s, 2 H), 5.16 (s, 2 H), 6.14 (d, J = 7.5 Hz, 1 H), 7.26-7.31 (m, 6 H), 8.77 (s, 1 H); MS (FAB) 569 (M+l)+.
EXAMPLE XXXI
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(N-morpholino- carbonylmethyl)-4-methyl-5-methylenecarboxamidomethylimidazolyl]-2 pyridinone
Figure imgf000102_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and morpholine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 2.32 (s, 3 H), 2.40 (s, 3 H), 3.40 (d, J = 4.4 Hz, 2 H), 3.57 (d, J = 16.3 Hz, 2 H), 3.63 (dd, J = 5.4 Hz, 4 H), 4.45 (s, 2 H), 4.46 (s, 2 H), 4.70 (s, 2 H), 5.25 (s, 2 H), 6.14 (d, J = 7.5 Hz, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 7.32 (m, 5 H), 8.64 (br t, 1 H), 8.71 (s, 1 H); MS (FAB) 557 (M+l)+.
EXAMPLE XXXII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(3-hydroxyazetidine- l-carbonylmethyl)-4-methyl-5-methylenecarboxamidomethylimidazolyl]- 2-pyridinone
Figure imgf000103_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and 3- hydro xyazeti dine essentially according to the procedure of EXAMPLE X, Step Y: iH NMR (CD3OD) d 2.31 (s, 3 H), 2.39 (s, 3 H), 3.82 (m, 1 H), 4.03 (m, 1 H), 4.24 (m, 1 H), 4.42 (m, 1 H), 4.44 (s, 6 H), 4.50 (m, 1 H), 4.73 (s, 2 H), 5.04 (s, 2 H), 6.15 (d, J = 7.7 Hz, 1 H), 7.30 (m, 6 H), 8.72 (s, 1 H); MS (FAB) 543 (M+l)+.
EXAMPLE XXXIII
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(2-hydroxyethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl- imidazolyll-2-pyridinone
Figure imgf000104_0001
The title compound was prepared from 3- benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone and hydroxyethylamine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 2.30 (s, 3 H), 2.38 (s, 3 H), 3.34 (t, J = 5 Hz, 2 H), 3.61 (t, J = 5.5 Hz, 2 H), 4.44 (s, 4 H), 4.74 (s, 2 H), 5.06 (s, 2 H), 6.15 (d, J = 7.5 Hz, 1 H), 7.28 (m, 6 H), 8.76 (s, 1 H); MS (FAB) 531 (M+l)+.
EXAMPLE XXXIV
Preparation of 3-Benzylsulfonylamino-6-methyl-l-[l-(2-aminoethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl- imidazolyll-2-pyridinone
Figure imgf000105_0001
Step A: Bocaminoethylamine
A solution of di-t-butyl dicarbonate (6.98 g, 32 mmol) in dioxane (50 ml) was added in a slow dropwise manner to a cooled (0°C) solution of ethylenediamine (2.2 ml, 32 mmol) in dioxane (30 ml). Upon completion of the addition, the reaction mixture was stirred overnight at room temperature. After filtration to remove a white precipitate, the filtrate was concentrated. The residue was partitioned between water and methylene chloride. The organic phase was dried (Na2Sθ4) and concentrated to give the title compound as an oil which partially crystallized. iH NMR (CDCI3) d 1.45 (s, 9 H), 2.80 (m, 2 H), 3.16 (m, 2 H).
Step B: 3-Benzylsulfonylamino-6-methyl-l-[l-(2-aminoethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarbox- amidomethylimidazoIyll-2-pyridinone
3-Benzylsulfonamino-6-methyl-l-(l-carboxymethyl-4- methyl-5-methylenecarboxamidomethylimidazolyl)-2-pyridinone and Bocamino-ethylamine were coupled essentially according to the procedure of EXAMPLE I, Step A. Removal of the Boc protecting group according to the procedure of EXAMPLE XXI, Step D gave the title compound: iH NMR (CD3OD) d 2.32 (s, 3 H), 2.39 (s, 3 H), 3.04 (t, J = 5.7 Hz, 2 H), 4.49 (s, 2 H), 4.51 (s, 2 H), 4.76 (s, 2 H), 5.12 (s, 2 H), 5.31 (t, J = 5.7 Hz, 2 H), 6.15 (d, J = 7.5 Hz, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 7.34 (m, 5 H), 8.77 (s, 1 H); MS (FAB) 531 (M+l)+.
EXAMPLE XXXV
Preparation of 3-(4-Chlorobenzylsulfonylamino)-6-methyl- 1-( 1-t-butyl- aminocarbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazolyl)-2-pyridinone
CONHlBu
Figure imgf000106_0001
The title compound was prepared from 3-(4-chlorobenzyl- sulfonylamino)-6-methyl-l-methylenecarboxy-2-pyridinone and 1-t- butylaminocarbonylmethyl-4-methyl-5-aminomethylimidazole using the procedure described in EXAMPLE I, Step A. XH NMR (CD3OD) d 1.33 (s,
9 H), 2.32 (s, 3 H), 2.39 (s, 3 H), 4.40 (br s, 2 H), 4.44 (s, 2 H), 4.75 (s, 2 H), 5.00 (s, 2 H), 6.15 (d, J = 7.8 Hz, 1 H), 7.20-7.35 (m, 5 H), 7.93 (br s, 1 H), 8.70 (br m, 1 H), 8.77 (s, 1 H); MS (FAB) 577 (M+l)+.
EXAMPLE XXXVI
Preparation of 3-Benzylsulfonylamino-6-propyl-l-(l-t-butylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)-2; pyridinone
Figure imgf000107_0001
Step A: b-N.N-Dimethylaminoethenylcvclopropyl ketone
A mixture of cyclopropyl methyl ketone (5.88 ml, 59 mmol) and N,N-dimethylformamide dimethyl acetal (7.83 ml, 59 mmol) was heated in the presence of a catalytic quantity of p-toluenesulfonic acid for 48 h. The resulting crude sample of the title compound (a pale yellow oil) was used in subsequent reactions without further purification: ^H NMR (CDCI3) d 0.74 (m, 2 H), 1.00 (m, 2 H), 1.75 (m, 1 H), 3.48 (s, 3 H), 3.50 (s, 3 H), 5.20 (d, 1 H), 7.55 (d, 1 H).
Step B: 6-Cyclopropyl-3-nitro-2-pyridinone
A mixture of crude b-N,N- dimethylaminoethenyl cyclopropyl ketone (12 g, < 86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight. Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound: *H NMR (CDCI3) d 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H), 6.02 (br d, J = 8.0 Hz, 1 H), 8.41 (d, J = 8.0 Hz, 1 H). Step C: 3-Amino-6-propyl-2-pyridinone
A mixture of 6-cyclopropyl-3-nitro-2-pyridinone (2 g, 13.3 mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (100 ml) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed by filtration through a bed of Celite and the filtrate concentrated to yield product as a white microcrystalline solid. iH NMR (CDCI3) d 0.94 (t, J = 7.3 Hz, 3 H), 1.67 (m, 2 H), 2.49 (t, J = 7.5 Hz, 2 H), 4.00 (br s), 5.88 (d, J = 7.1 Hz, 1 H), 6.59 (d, J = 7.1 Hz, 1 H).
Step D: 3-Benzyloxycarbonylamino-6-propyl-2-pyridinone
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and IN NaOH at 0°C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 h then at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi- solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium carbonate (12 ml) and cooled to 0°C. Benzyl chloroformate (1.5 ml, 10.5 mmol) was once again added and after stirring for 0.5 h, the reaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave the title compound as a white powder: iH NMR (CDCI3) d 0.96 (t, J = 7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J = 7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J = 7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H), 8.05 (br d, J = 5.3 Hz, 1 H).
Ste E 3-Benzyloxycarbonylamino-6-propyl-l-(t-butylmethylene- carboxy)-2-pyridinone
Solid 3-benzyloxycarbonylamino-6-propyl-2-pyridinone (2.64 g, 9.3 mmol) was added in small portions to a suspension of sodium hydride (269 mg, 11.2 mmol) in THF (30 ml) at 0°C. The reaction mixture was the stirred at room temperature for 20 min by which time an almost completely homogeneous solution had been obtained. Tert- butyl-bromo acetate (2.2 ml, 14.9 mmol) was then added. Within minutes a white precipitate started forming. Stirring was continued overnight, then the THF was evaporated in vacuo. Ice was carefully added to the residue to destroy any unreacted sodium hydride. Brine was added and the resulting miture was extracted with 2:1:1 ethyl acetate / ether / chloroform and the combined extracts were dried over magnesium sulfate. Filtration and evaporation of the filtrate gave a cream solid which was purified by flash column chromatography eluting with 3:1:1 hexane / chloroform / ethyl acetate. This gave the title compound as a white crystalline solid: iH NMR (CDCI3) d 1.00 (t, J = 7.3 Hz, 3 H), 1.48 (s, 9 H), 1.64 (m, 2 H), 2.46 (t, J = 7.6 Hz, 2 H), 4.72 (s, 2 H), 5.20 (s, 2 H), 6.08 (d, J = 7.7 Hz, 1 H), 7.31-7.40 (m, 4 H), 7.77 (s, 1 H), 7.97 (br d, J = 7.0 Hz, 1 H).
Step F: 3-Amino-6-propvl-l-(t-butvlmethvlenecarboxv)-2-pyridinone
3-Benzyloxycarbonylamino-6-propyl-l-(t-butylmethylene- carboxy)-2-pyridinone (2.38 g, mmol) was dissolved in a 1:1 mixture of ethyl acetate and ethanol (100 ml) and then stirred in the presence of 20% palladium hydroxide on carbon (800 mg) under an atmosphere of hydrogen for 2 h. The catalyst was removed by filtration through Celite and the filtrate concentrated to give the title compound as an orange oil: iH NMR (CDCI3) d 0.98 (t, J = 7.3 Hz, 3 H), 1.47 (s, 9 H), 1.57 (m, 2 H), 2.40 (t, J = 7.7 Hz, 2 H), 4.73 (s, 2 H), 5.91 (d, J = 7.3 Hz, 1 H), 6.55 (d, J = 7.3 Hz, 1 H).
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. The organic layer was dried (Na2SO4) and evaporated in vacuo to give a red solid which was purified by flash chromatography (2:1:1 hexane / chloroform / ethyl acetate) to give the desired product as a mustard crystalline solid: !H NMR (CDCI3) d 1.03 (t, J = 7.3 Hz, 3 H), 1.51 (s, 9 H), 1.63 (m, 2 H), 2.46 (t, J = 7.7 Hz, 2 H), 4.32 (s, 2 H), 4.73 (s, 2 H), 5.99 (d, J = 7.7 Hz, 1 H), 7.22-7.32 (m, 5 H), 7.35 (d, J = 7.7 Hz, 1 H).
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. After 4 h at room temperature the mixture was degassed with nitrogen and filtered to give the title compound as a pale pink solid: XH NMR (CDCI3) d 1.02 (t, J = 7.3 Hz, 3 H), 1.63 (m, 2 H), 2.57 (t, J = 7.7 Hz, 2 H), 4.44 (s, 2 H), 4.85 (s, 2 H), 6.11 (d, J = 7.7 Hz, 1 H), 7.26-7.33 (m, 5 H), 7.34 (d, J = 7.7 Hz, 1 H).
Step I: l-Carboxymethyl-4-methyl-5-azidomethylimidazole
The title compound was prepared from 1-t-butoxycarbonyl- methyl-4-methyl-5-azidomethylimidazole using the procedure described in EXAMPLE XXI, Step D. iH NMR (CD3OD) d 2.43 (s, 3 H), 4.61 (s, 2 H),
5.14 (s, 2 H), 8.97 (s, 1 H).
Step J: l-t-Butylaminocarbonylmethyl-4-methyl-5-azidomethyl- imidazole
The title compound was prepared from l-carboxymethyl-4- methyl-5-azidomethylimidazole and tert -butylamine using the procedure described in EXAMPLE I, Step A. iH NMR (CDCI3) d 1.32 (s,
9 H), 2.29 (s, 3 H), 4.31 (s, 2 H), 4.48 (s, 2 H), 5.25 (br s, 1 H), 7.47 (s, 1 H). Step K: l-t-Butylaminocarbonylmethyl-4-methyl-5-aminomethyl- imidazole
A solution of l-t-butylaminocarbonylmethyl-4-methyl-5- azidomethylimidazole (1.27 g, 5.4 mmol) and 10σ/c Pd/C (700 mg) in ethyl acetate (100 ml) was hydrogenated at atmospheric pressure for 5 h. The catalyst was removed by filtration through Celite and the solvents removed in vacuo to give the title compound. ^H NMR (CDCI3) d 1.27 (s,
9 H), 2.23 (s, 3 H), 3.83 (s, 2 H), 4.50 (s, 2 H), 7.08 (br s, 1 H), 7.46 (s, 1 H).
Step L: 3-Benzylsulfonamino-6-propyl- 1-( 1-t-butylaminocarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimida- zolyl)-2-pyridinone
The title compound was prepared from 3-benzylsulfonyl- amino-6-propyl-l-methylenecarboxy-2-pyridinone and 1-t-butylamino- carbonylmethyl-4-methyl-5-aminomethylimidazole essentially according to the procedure of EXAMPLE I, Step A: !H NMR (CD3OD) d 1.00 (t, J = 7.4 Hz,3 H), 1.32 (s, 9 H),1.61 (m, 2 H), 2.38 (s, 3 H), 2.56 (t, J = 7.7 Hz, 2 H), 4.41 (d, J = 3.9 Hz, 2 H), 4.44 (s, 2 H), 4.72 (s, 2 H), 4.99 (s, 2 H), 6.13 (d, J = 7.7 Hz, 1 H), 7.26-7.34 (m, 6 H), 8.74 (s, 1 H); MS (FAB) 571 (M+l)+.
EXAMPLE XXXVII
Preparation of 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl- l-(l'-t-butoxycarbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazolyl)-2-pyridinone
COOlBu
Figure imgf000111_0001
Step A: 2-Tetrahvdropyranylmethanethioacetate
To a solution of 2-bromomethyltetrahydropyran (10.5 g, 59 mmol) in THF (100 ml) was added potassium thioacetate (7.35 g, 65 mmol). The resulting suspension was refluxed for 48 h. After cooling to room temperature, the solvents were removed in vacuo and the residue dissolved in chloroform and washed with water. The organics were dried over MgSO4, filtered and the solvents removed in vacuo. The crude product was purified by chromatography (9:1 hexane / ethyl acetate). ^H NMR (CDC13) d 1.21-1.40 (m, 1 H), 1.45-1.60 (m, 3 H), 1.73 (br d, J = 14 Hz,
1 H), 1.80-1.90 (m, 1 H), 2.35 (s, 3 H), 2.81-2.95 (m, 1 H), 3.01-3.15 (m, 1 H), 3.35-3.45 (m, 2 H), 3.95-4.07 (m, 1 H).
Step B: 2-Tetrahvdropyranylmethane sulfonyl chloride
The title compound was prepared from 2-tetrahydropyranyl- methanethioacetate using the procedure described in EXAMPLE XXI, Step B. !H NMR (CDCI3) d 1.35-1.50 (m, 1 H), 1.50-1.70 (m, 3 H), 1.75 (br d, J = 14 Hz, 1 H), 1.83-1.95 (m, 1 H) 3.42-3.57 (m, 1 H), 3.70-3.80 (m, 1 H), 3.90-4.12 (m, 3 H).
Step C: 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl-.l
(t-butylmethylenecarboxy)-2-pyridinone
The title compound was prepared from 2-tetrahydropyranyl- methanesulfonyl chloride and 3-amino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyridinone using the procedure described in EXAMPLE XXI, Step C. !H NMR (CDCI3) d 1.25-1.48 (m, 4 H), 1.45 (s, 9 H), 1.62 (br d, J =
14 Hz, 1 H), 1.78-1.85 (m, 1 H), 2.25 (s, 3 H), 3.00-3.10 (m, 1 H), 3.25-3.35 (m, 1 H), 3.35-3.45 (m, 1 H), 3.80-3.87 (m, 1 H), 3.87-3.95 (m, 1 H), 4.75 (s, 2 H), 6.05 (d, J = 8 Hz, 1 H), 7.45 (d, J = 8 Hz, 1 H) 7.49 (s, 1 H).
Step D: 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl-ji methylenecarboxy-2-pyridinone
The title compound was prepared from 3-(2-tetrahydro- pyranylmethanesulfonylamino)-6-methyl-l-(t-butylmethylenecarboxy)-2- pyridinone using the procedure described in EXAMPLE XXI, Step D. ^H NMR (CD3OD) d 1.25-1.58 (m, 4 H), 1.63 (br d, J = 14 Hz, 1 H), 1.75-1.85
(m, 1 H), 2.32 (s, 3 H), 3.17-3.40 (m, 3 H), 3.75-3.90 (m, 2 H), 4.90 (s, 2 H), 6.22 (d, J = 8 Hz, 1 H), 7.50 (d, J = 7.5 Hz, 1 H). Step E: 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl- 1-
(l'-t-butoxvcarbonvlmethvl-4-methvl-5-methvlene-carbox- amidomethylimidazolyl)-2-pyridinone
The title compound was prepared from 3-(2-tetrahydro- pyranylmethanesulfonylamino)-6-methyl-l-methylenecarboxy-2- pyridinone and l-t-butoxycarbonylmethyl-4-methyl-5-aminomethyl- imidazole using the procedure described in EXAMPLE I, Step A. iH NMR (CD3OD) d 1.20-1.58 (m, 4 H), 1.50 (s, 9 H), 1.65 (br d, J = 14 Hz, 1
H), 1.72-1.87 (m, 1 H), 2.31 (s, 3 H), 2.40 (s, 3 H), 3.16-3.40 (m, 3 H), 3.75- 3.87 (m, 2 H), 4.41 (s, 2 H), 4.75 (s, 2 H), 5.12 (s, 2 H), 6.22 (d, J = 7.3 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 1 H), 8.80 (s, 1 H); MS (FAB) 552 (M+l)+.
EXAMPLE XXXVIII
Preparation of 3-(2-Tetrahydropyranylmethanesulfonylamino)-6-methyl- l-( -t-butylaminocarbonylmethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyl)-2-pyridinone
CONHteu
Figure imgf000113_0001
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. ^H NMR (CD3OD) d 1.20-1.40 (m, 2 H), 1.30 (s, 9 H), 1.40-1.60 (m, 2 H), 1.65 (br d, J = 14 Hz, 1 H), 1.75-1.90 (m, 1 H), 2.33 (s, 3 H), 2.39 (s, 3 H), 3.15- 3.40 ( , 3 H), 3.75-3.87 (m, 2 H), 4.40 (s, 2 H), 4.76 (s, 2 H), 5.00 (s, 2 H), 6.24 (d, J = 7.6 Hz, IH), 7.46 (d, J = 7.6 Hz, 1 H), 7.95 (br s, 1 H), 8.70 (m, 1 H), 8.78 (s, 1 H) MS (FAB) 551 (M+l)+.
-Ill- EXAMPLE XXXIX
Preparation of 3-(2-Tetrahydropyranmethanesulfonylamino)-6-propyl- 1- (l'-t-butylaminocarbonylmethyl)-4-methyl-5-methylenecarboxamido- methylimidazolyl)-2-pyridinone
CONHlBu
Figure imgf000114_0001
The title compound was prepared using the procedure described for Example XXXVI by substituting 2- tetrahydropyranmethane-sulfonyl chloride for benzylsulfonyl chloride in Step G. iH NMR (CD3OD) d 1.00 (t, J = 7.2 Hz, 3 H), 1.34 (s, 9 H), 2.39 (s, 3
H), 2.58 (t, J = 7.6 Hz, 2 H), 3.83 (d, J = 10.5 Hz, 2 H), 4.39 (s, 2 H), 4.74 (s, 2 H), 5.01 (s, 2 H), 6.24 (d, J = 7.6 Hz, IH), 7.50 (d, J = 7.6 Hz, 1 H), 8.78 (s, 1 H); MS (FAB) 579 (M+l)+.
EXAMPLE XL
Preparation of 3-Cyclohexylmethanesulfonylamino-6-methyl-l-(l'-t- butyl-aminocarbonylmethyl-4-methyl-5-methylenecarboxamidomethyl- imidazolyl)-2-pyridinone
CONHlBu
Figure imgf000115_0001
Step A: Sodium cvclohexylmethanethiosulfate
The title compound was prepared from bromomethyl- cyclohexane using the procedure described in EXAMPLE XXI, Step A. iH NMR (CDCI3) d 0.90-1.05 (m, 2 H), 1.15-1.39 (m, 3 H), 1.60-1.80 (m, 4
H), 1.85 (br d, J = 12 Hz, 2 H) 2.95 (d, J = 7 Hz, 2 H).
Step B: Cvclohexylmethanesulfonyl chloride The title compound was prepared from sodium cyclohexyl- methanethiosulfate using the procedure described in EXAMPLE XXI, Step B. iH NMR (CDCI3) d 1.10-1.42 (m, 5 H), 1.62-1.80 (m, 3 H), 1.97 (br d, J = 12 Hz, 2 H), 2.15-2.30 (m, 1 H), 3.75 (d, J = 6 Hz, 2 H).
Step C: 3-Cyclohexanemethylsulfonylamino-6-methyl-l-(t-butyl- methylenecarboxy)-2-pyridinone
The title compound was prepared from cyclohexylmethane- sulfonyl chloride and 3-amino-6-methyl-l-(t-butylmethylenecarboxy)-2- pyridinone using the procedure described in EXAMPLE XXI, Step C. ^H NMR (CDCI3) d 0.95-1.37 (m, 5 H), 1.45 (s, 9 H), 1.58-1.95 (m, 6 H), 2.27 (s,
3 H), 2.95 (d, J = 7 Hz, 2 H), 4.77 (s, 2 H), 6.10 (d, J = 8 Hz, 1 H), 7.20 (s, 1 H), 7.45 (d, J = 8 Hz, 1 H). Step D: 3-Cyclohexanemethylsulfonylamino-6-methyl- 1-methylene- carboxy-2-pyridinone
The title compound was prepared from 3- cyclohexanemethyl-sulfonylamino-6-methyl-l-(t- butylmethylenecarboxy)-2-pyridinone using the procedure described in
EXAMPLE XXI, Step D. iH NMR (CD3OD) d 0.95-1.40 (m, 5 H), 1.60-1.75
(m, 3 H), 1.85-1.95 (m, 3 H), 2.35 (s, 3 H), 2.97 (d, J = 6 Hz, 2 H), 4.90 (s, 2 H), 6.22 (d, J = 8 Hz, 1 H), 7.43 (d, J = 8 Hz, 1 H).
Step E: 3-Cyclohexylmethanesulfonylamino-6-methyl-l-(l'-t-butyl- aminocarbonylmethyl-4-methyl-5-methylenecarboxamido- methylimidazolyl)-2-pyridinone
The title compound was prepared from 3- cyclohexanemethyl-sulfonylamino-6-methyl-l-methylenecarboxy-2- pyridinone and l-t-butyl-aminocarbonylmethyl-4-methyl-5- aminomethylimidazole using the procedure described in EXAMPLE I, Step A. iH NMR (CD3OD) d 0.95-1.42 (m, 5 H), 1.34 (s, 9 H), 1.60-1.75 (m,
3 H), 1.81-1.98 (m, 3 H), 2.33 (s, 3 H), 2.39 (s, 3 H), 3.00 (d, J = 5.6 Hz, 2 H), 4.40 (s, 2 H), 4.74 (s, 2 H), 5.00 (s, 2 H) 6.24 (d, J = 7.4 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.95 (br s, 1 H), 8.75 (br m, 1 H), 8.78 (s, 1 H); MS (FAB) 549 (M+l)+.
EXAMPLE XLI
Preparation of 3-Pentanesulfonylamino-6-methyl-l-(l'-t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethyl-imidazolyl)-2- pyridinone
COOlBu
Figure imgf000117_0001
Step A: Pentane sulfonyl chloride
The title compound was prepared from 1-pentanethiol using the procedure described in EXAMPLE XXI, Step B. Ice water was used as the solvent instead of ice water / acetic acid. ^H NMR (CDCI3) d 0.95
(t, J = 7 Hz, 3 H), 1.32-1.45 (m, 4 H), 1.95-2.10 (m, 2 H), 3.60-3.70 (m, 2 H).
Step B: 3-Pentanesulfonylamino-6-methyl-l-(t-butylmethylene- carboxy)-2-pyri din on e
The title compound was prepared from pentanesulfonyl chloride and 3-amino-6-methyl-l-(t-butylmethylenecarboxy)-2-pyridinone using the procedure described in EXAMPLE XXI, Step C. It was purified by chromatography (2:1 hexane / ethyl acetate). ^H NMR (CDCI3) d 0.85 (t, J = 7 Hz, 3 H), 1.20-1.40 (m, 4 H), 1.45 (s, 9 H), 1.74-1.86
(m, 2 H), 2.25 (s, 3 H), 2.98-3.05 (m, 2 H), 4.75 (s, 2 H), 6.08 (d, J = 8 Hz, 1 H), 7.20 (s, 1 H), 7.45 (d, J = 8 Hz, 1 H).
Step C: 3-Pentanesulfonylamino-6-methyl-l-methylenecarboxy-2- pyridinone
The title compound was prepared from 3-pentanesulfonyl- amino-6-methyl-l-(t-butylmethylenecarboxy)-2-pyridinone using the procedure described in EXAMPLE XXI, Step D. iH NMR (CD3OD) d 0.85
(t, J = 7 Hz, 3,H), 1.22-1.40 (m, 4 H), 1.70-1.82 (m, 2 H), 2.35 (s, 3 H), 3.02- 3.12 (m, 2 H), 4.87 (s, 2 H), 6.25 (d, J = 8 Hz, 1 H), 7.47 (d, J = 8 Hz, 1 H). Step D: 3-Pentanesulfonylamino-6-methyl-l-(l'-t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimida- zolyl)-2-pyridinone
The title compound was prepared from 3-pentanesulfonyl- amino-6-methyl-l-methylenecarboxy-2-pyridinone and 1-t-butoxy- carbonylmethyl-4-methyl-5-aminomethylimidazole using the procedure described in EXAMPLE I, Step A. iH NMR (CD3OD) d 0.89 (t, J = 6.8 Hz,
3 H), 1.25-1.40 (m, 4 H), 1.49 (s, 9 H), 1.70-1.81 (m, 2 H), 2.31 (s, 3 H), 2.40 (s, 3 H), 3.08-3.18 (m, 2 H), 4.41 (s, 2 H), 4.76 (s, 2 H), 5.11 (s, 2 H), 6.23 (d, J = 7.6 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 8.81 (s, 1 H); MS (FAB) 524 (M+l)+.
EXAMPLE XLII
Preparation of 3-(2-Phenethylamino)-6-methyl-l-(l'-t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)pyraz- inone
COOlBu
Figure imgf000118_0001
Step A: N-(l-Cvanoethyl)glvcine benzyl ester hydrochloride
TMSCN (4.27 ml, 32 mmol) was added cautiously (reaction is exothermic) to a stirred solution of glycine benzyl ester (5.3 g, 32 mmol, prepared from the HCl salt by partitioning between EtOAc and NaHCO3 solution) and acetaldehyde (1.8 ml, 32 mmol) in methylene chloride (11 ml). After 4 h the volatiles were removed in vacuo and the residue was taken up in EtOAc and was washed with brine, dried (Na2S04) and evaporated in vacuo to an oil. The oil was redissolved in EtOAc and 9.9 M HCl in EtOH (38.4 mmol) was added to give a crystalline precipitate which was isolated by filtration and washing with EtOAc, to give the title compound: iH NMR (CDCI3) d 1.49 (d, J = 7.1 Hz, 3 H, CH3), 3.54 (d, J = 17.3 Hz, 1 H, CHAHB), 3.64 (d, J = 17.3 Hz, 1 H, CHAHB), 3.74 (q, J = 7.0 Hz, 1 H, a-CH), 5.18 (s, 2 H, CH2O), 7.36 (s, 5 H, Ph).
Step B: l-Benzyloxycarbonylmethyl-3,5-dichloro-6- methylpyrazinone
A stirred mixture of oxalyl chloride (9.3 ml, 107 mmol) and N-(l-cyanoethyl)glycine benzyl ester hydrochloride (6.8 g, 26.7 mmol) in 1,2-dichlorobenzene (25 ml) was heated to 100°C for 15 h. The excess reagent was evaporated in vacuo and the residue was purified by flash chromatography (eluting first with hexanes to remove the dichlorobenzene, then with 3:2 hexanes / ethyl acetate) to give a solid which was triturated with 1:1 hexanes / ethyl acetate to give the title compound as a pale green crystalline solid: ^H NMR (CDCI3) d 2.35 (s, 3 H, CH3), 4.88 (s, 2 H, CH2), 5.24 (s, 2 H, CH2), 7.38 (m, 5 H, Ph).
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. After 2 h the reaction was cooled, diluted with EtOAc (the product is sparingly soluble), washed with 10% citric acid solution and brine, dried (Na2Sθ4) and evaporated in vacuo to give the title compound as a crystalline solid. ^H NMR (CDCI3) d 2.21 (s, 3 H, CH3), 2.93 (t, J = 7.1 Hz, 2 H, PI1CΗ2), 3.67 (q, J = 7.1 Hz, 2 H, CH2NH), 4.79 (s, 2 H, CH2), 5.21 (s, 2 H, CH2), 6.10 (br t, 1 H), 7.20-7.39 (m, 10 H, 2 Ph).
Step D: 3-(2-Phenethylamino)-5-chloro-6-methyl-l-(methylene- carboxy)pyrazinone
Water (1 ml) was added to a stirred solution of 3-(2- phenethylamino)-5-chloro-6-methyl-l-(benzyloxycarbonylmethyl)- pyrazinone (436 mg) in 1:1 THF / MeOH (6 ml) and LiOH.H2θ was added to the resulting mixture. After 2 h, the reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 10% KHSO4 solution to give a cloudy mixture which was extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid: ^H NMR (DMSO-d6) d 2.19 (s, 3 H, Me), 2.84 (t, J = 7.0 Hz, 2 H, PI1CH2), 3.45 (q, J = 7.0 Hz, 2 H, CH2NH), 4.70 (s, 2 H, CH2CO2), 7.18-7.31 (m, 5 H, Ph), 7.46 (br s, 1 H, NH).
Step E: 3-(2-Phenethylamino)-6-methyl-l-methylenecarboxy- pyrazinone
3-(2-Phenethylamino)-5-chloro-6-methyl-l-(methylene- carboxy)pyrazinone (13.4 g, 41.6 mmol) was added to a stirred solution of potassium hydroxide (7.28 g, 110 mmol, assuming 15% water in the pellets) in water (600 ml). After degassing the resulting solution with argon, 10% Pd/C (6.3 g) was added and the mixture then stirred under a balloon of hydrogen. After 16 h, HPLC analysis showed that 1% of the starting material remained. The mixture was filtered through Celite and the filtrate was adjusted to pH 2 with 3N KHSO4 solution. The resulting precipitate was collected by filtration and washed with water. Drying for 16 h at 0.5 mm Hg gave the title compound as a crystalline solid: iH NMR (DMSO-dβ) d 2.11 (s, 3 H, Me), 2.87 (t, J = 7.6 Hz, 2 H, PI1CH2), 3.53 (br s, 2 H, CH2NH), 4.68 (s, 2 H, CH2CO2), 6.68 (s, 1 H, pyrazinone H-5), 7.20-7.31 (m, 5 H, Ph), 8.16 (br s, 1 H, NH).
Step F: 3-(2-Phenethylamino)-6-methyl-l-( -t-butoxycarbonyl- methyl-4-methyl-5- methylenecarboxamidomethylimidazolvD-pyrazinone The title compound was prepared from 3-(2- phenethylamino)-6-methyl-l-methylenecarboxypyrazinone and 1-t- butoxycarbonylmethyl-4-methyl-5-aminomethylimidazole essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 1.44 (s, 9 H), 2.18 (s, 3 H), 2.19 (s, 3 H), 2.92 (t, J = 7.1 Hz, 2 H), 3.60 (m, 2 H), 4.33 (d, J = 5.5 Hz, 2 H), 4.55 (d, J = 10.8 Hz, 4 H), 5.93 (t, J = 5.7 Hz, 1 H), 6.73 (s, 1 H), 7.2 (m, 1 H); MS (FAB) 495 (M+l)+. EXAMPLE XLIII
Preparation of 3-(2-Phenethylamino)-6-methyl-l-(l'-t-butylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)- pyrazinone
CONHlBu
Figure imgf000121_0001
Step A: 3-(2-Phenethylamino)-6-methyl-l-(l-carboxymethyl-4- methyl-5- methylenecarboxamidomethylimidazolvDpyrazinone The title compound was prepared from 3-(2- phenethylamino)-6-methyl-l-(l'-t-butoxycarbonyl-methyl-4-methyl-5- methylenecarbox-amidomethylimidazolyl)pyrazinone essentially according to the procedure of EXAMPLE XXI, Step D: iH NMR (CD3OD) d 2.16 (s, 3 H), 2.41 (s, 3 H), 2.99 (t, J = 7.1 Hz, 2 H), 3.67 (t, J = 7.1 Hz, 2 H), 4.47 (m, 2 H), 4.68 (s, 2 H), 5.15 (s, 2 H), 6.56 (s, 1 H), 7.21-7.33 (m, 5 H), 8.84 (s, 1 H).
Step B: 3-(2-Phenethylamino)-6-methyl-l-(l'-t-butylaminocarbonyl- methyl-4-methyl-5- methylenecarboxamidomethylimidazolvD-pyrazinone
The title compound was prepared from 3-(2- phenethylamino)-6-methyl-l-(l-carboxymethyl-4-methyl-5- methylenecarboxamidomethyl-imidazolyDpyrazinone and t-butylamine essentially according to the procedure of EXAMPLE I, Step A: iH NMR (CD3OD) d 1.36 (s, 9 H), 2.17 (s, 3 H), 2.39 (s, 3 H), 2.98 (t, J = 7.4 Hz, 2 H), 3.60 (t, J = 7.4 Hz, 2 H), 4.42 (m, 2 H), 4.70 (s, 2 H), 4.99 (s, 2 H), 6.59 (s, 1 H), 7.21-7.33 (m, 4 H), 7.97 (br s, 1 H), 8.78 (s, 1 H); MS (FAB) 495 (M+l)+. EXAMPLE XLIN
Preparation of 3-(2-Pyridylethylamino)-6-methyl-l-( -t-butoxycarbonyl- methyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)pyrazinone
Figure imgf000122_0001
The title compound was prepared according to the procedure described for EXAMPLE XLII by substituting 2-(2- aminoethyDpyridine for 2-phenethylamine in Step C: *H ΝMR (CD3OD) d 1.45 (s, 9 H), 2.12 (s, 3 H), 2.20 (s, 3 H), 3.08 (t, J = 7.0 Hz, 2 H), 3.69 (t, J = 7.0 Hz, 2 H), 4.32 (s, 2 H), 4.62 (s, 2 H), 4.79 (s, 2 H), 6.66 (s, 1 H), 7.25 (m, 1 H), 7.35 (d, J = 4.0 Hz, 1 H), 7.52 (s, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 8.44 (d, J = 4.0 Hz, 1 H); MS (FAB) 495 (M+l)+.
EXAMPLE XLN
Preparation of 3-(2-Pyridylethylamino)-6-methyl-l-(l'-t-butylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)- pyrazinone
Figure imgf000122_0002
The title compound was prepared according to the procedure described for EXAMPLE XLIV by substituting 1-t- butylmethylamino-carbonylmethyl-4-methyl-5-aminomethylimidazole for l-t-butoxycarbonyl-methyl-4-methyl-5-aminomethylimidazole in Step F: iH NMR (CD3OD) d 1.35 (s, 9 H), 2.15 (s, 3 H), 2.38 (s, 3 H), 3.82 (t, J = 6.8 Hz, 2 H), 3.82 (t, J = 6.8 Hz, 2 H), 4.41 (d, J = 3.7 Hz, 2 H), 4.69 (s, 2 H), 4.87 (s, 2 H), 4.99 (s, 2 H), 6.66 (s, 1 H), 7.77 (t, J = 6.50 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.98 (s, 1 H), 8.68 (d, J = 5.7 Hz, 1 H), 8.78 (s, 1 H); MS (FAB) 495 (M+l)+.
EXAMPLE XLVI
Preparation of 3-(2-Phenethylamino)-6-methyl-l-(l'-t-butylmethylamino- carbonylmethyl-4-methyl-5-methylenecarboxamidomethylimidazolyl)- pyrazinone
Figure imgf000123_0001
The title compound was prepared according to the procedure described for EXAMPLE XLIII by substituting 1-t- butylmethylamino-carbonylmethyl-4-methyl-5-aminomethylimidazole for l-t-butoxycarbonyl-methyl-4-methyl-5-aminomethylimidazole in Step F: iH NMR (CD3OD) d 0.93 (s, 9 H), 2.17 (s, 3 H), 2.39 (s, 3 H), 2.99 (t, J = 7.5 Hz, 2 H), 3.07, (d, J = 6.1 Hz, 2 H), 3.68 (t, J = 7.5 Hz, 2 H), 4.43 (s, 2 H), 4.71 (s, 2 H), 5.12 (s, 2 H), 6.56 (s, 1 H), 7.22-7.34 (m, 6 H), 8.34 (br t, 1 H), 8.82 (s, 1 H); MS (FAB) 508 (M+l)+.
EXAMPLE XLVII
Preparation of 3-(2-Phenethylamino)-6-methyl-l-[l'-(2,2,2-trifluoroethyl- aminocarbonylmethyl)-4-methyl-5-methylenecarboxamidomethyl- imidazolyllpyrazinone
Figure imgf000124_0001
The title compound was prepared according to the procedure described for EXAMPLE XLIII by substituting l-(2,2,2- trifluoroethyl-aminocarbonylmethyl)-4-methyl-5-aminomethylimidazole (prepared according to the procedure for EXAMPLE XXIX, Steps A to C by substituting 2,2,2-trifluoroethylamine hydrochloride for t-butylmethyl- amine in Step B) for l-t-butoxycarbonylmethyl-4-methyl-5-aminomethyl- imidazole in Step F: iH NMR (CD3OD) d 2.16 (s, 3 H), 2.41 (s, 3 H), 2.98 (t, J = 7.4 Hz, 2 H), 3.65 (t, J = 7.4 Hz, 2 H), 4.43 (s, 2 H), 4.68 (s, 2 H), 5.17 (s, 2 H), 6.59 (s, 1 H), 7.23-7.33 (m, 4 H), 8.83 (s, 1 H); MS (FAB) 520 (M+l)+.
EXAMPLE XLVIII
Preparation of 3-(2-Phenethylamino)-6-methyl-l-[l'-(3-piperidineamino)- carbonylmethyl]-4-methyl-5-methylenecarboxamido-methylimidazolyl]- pyrazinone
Figure imgf000124_0002
Step A: 3-Hvdroxy-N-t-butoxycarbonylpiperidine
Di-t-butyldicarbonate (21 g, 96 mmol) was added to a mixture of 3-hyroxypiperidine hydrochloride (12 g, 87 mmol) and triethylamine (24.5 ml, 176 mmol) in methylene chloride (500 ml) at 0°C. After stirring for 2 h, the reaction mixture was washed well with water and dried (MgSO4). Concentration gave the title compound. ^H NMR (CDCI3) d 1.46 (s, 9 H), 1.60-1.89 (m, 4 H), 3.04-3.16 (m, 2 H), 3.52 (br s, 1 H), 3.73 (m, 2 H).
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. iH NMR (CDCI3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).
Step C: 3-Azido-N-t-butoxycarbonylpiperidine Lithium azide (1.35 g, 27.6 mmol) was added to a solution of
3-methanesulfonyloxy-N-t-butoxycarbonylpiperidine (1.54 g, 5.51 mmol) in DMF (20 ml) and the resulting mixture heated at 60°C for 48 h. Removal of the solvent in vacuo and chroma to graphic purification (3:1 hexane / ethyl acetate) of the residue afforded the title compound. ^H NMR (CDCI3) d 1.46 (s, 9 H), 1.75 (m, 2 H), 1.96 (m, 2 H), 3.13 (br s, 1 H),
3.46 (m, 2 H), 3.57 (m, 2 H).
Step D: 3-Amino-N-t-butoxycarbonylpiperidine
A solution of 3-azido-N-t-butoxycarbonylpiperidine (850 mg) in ethyl acetate (50 ml) was hydrogenated in the presence of 10% Pd/C
(550 mg) at atmospheric pressure for 2.5 h. The reaction mixture was then filtered through Celite and the filtrate concentrated in vacuo to give the title compound. 4ϊ NMR (CDCI3) d 1.46 (s, 9 H), 1.66-2.05 (m, 4 H),
2.57 (br s, 1 H), 2.78 (m, 4 H), 3.80 (br d, 2 H). Step E: l-r(N-t-butoxvcarbonyl-3-piperidineamino)carbonvl-methyll-
4-methyl-5-azidomethylimidazole
The title compound was prepared from l-carboxymethyl-4- methyl-5-azidomethylimidazole and 3-amino-N-t- butoxycarbonylpiperidine using the procedure described in EXAMPLE I,
Step A. iH NMR (CDCI3) d 1.45 (s, 9 H), 1.53 (br m, 2 H), 1.63 (m, 1 H),
1.80 (br m, 1 H), 2.28 (s, 3 H), 3.23-3.49 (br m, 4 H), 3.95 (br s, 1 H), 4.32 (dd, J = 14.6, 21.4 Hz, 2 H), 4.57 (s, 2 H), 7.47 (s, 1 H).
Step F: l-[(N-t-butoxycarbonyl-3-piperidineamino)carbonyl-methyTJ
4-methyl-5-aminomethylimidazole
A solution of l-[(N-t-butoxycarbonyl-3-piperidine- amino)carbonylmethyl]-4-methyl-5-azidomethylimidazole (3.77 g) in ethanol (100 ml) was hydrogenated in the presence of 20% Pd(OH)2/C (850 mg) at atmospheric pressure for 5 h. The reaction mixture was then filtered through Celite and the filtrate concentrated in vacuo to give the title compound.
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
The title compound was prepared from 3-(2- Phenethylamino)-6-methyl-l-[l'-(N-t-butoxycarbonyl-3- piperidineamino)carbonylmethyl]-4-methyl-5- methylenecarboxamidomethylimidazolyl]pyrazinone using the procedure described in EXAMPLE XXI, Step D. XH NMR (CD3OD) d 1.63-2.04 (m, 4 H), 2.16 (s, 3 H), 2.40 (s, 3 H), 2.99 (m, 4 H), 3.30 (m, 2 H), 3.66 (m, 2 H), 4.05 (br s, 1 H), 4.44 (m, 2 H), 4.68 (s, 2 H), 5.12 (m, 2 H), 6.59 (s, 1 H), 7.20-7.32 (m, 5 H), 8.81 (s, 1 H); MS (FAB) 521 (M+l)+.
EXAMPLE XLIX
Tablet Preparation
Tablets containing 100.0, 200.0, and 300.0 mg, respectively, of 3-Benzylsulfonylamino-6-methyl- l-[l-(2-hydroxyethyl- aminocarbonylmethyl)-4-methyl-5- methylenecarboxamidomethylimidazolyl]-2-pyridinone (example XXXIII) active compound are prepared as illustrated below:
Ingredient Amount-mg
Active compound 100.0 200.0 300.0
Microcrystalline cellulose 160.0 150.0 200.0
Modified food corn starch 20.0 15.0 10.0
Magnesium stearate 1.5 1.0 1.5
All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 100.0, 200.0, and 300.0 mg, respectively, of active ingredient per tablet. EXAMPLE L
An intravenous dosage form of the above-indicated active compound is prepared as follows:
Active compound 0.5-10.0mg
Sodium Citrate 5-50mg
Citric Acid l-15mg
Sodium Chloride l-8mg
Water for Injection (USP) q.s. to 1 L
Utilizing the above quantities, 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.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula
Figure imgf000129_0001
and pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of
Figure imgf000129_0002
Figure imgf000129_0003
wherein
H
Figure imgf000129_0004
wherein Ra and Rfo 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, Cχ-4 alkyl unsubstituted or substituted with CH3 or C3..7 cycloalkyl, aryl, substituted aryl with one or two substituents selected from C1-4 alkyl, Cχ-4 alkoxy, methylenedioxy, halogen or hydroxy, C3-7 cycloalkyl, C9-10 bi cycloalkyl, or Ra and R , along with the carbon to which they are attached, form a C3..7 cycloalkyl ring or
Figure imgf000130_0001
where R^O is H or -OH, and R11 is H or -OCH3, and
χl is selected from the group consisting of
-OH -NH2
-NHCH3,
-NH(CH2)1-3CH3,
-NH(CH2)2-4θH,
-NH(CH2)l-3COOH,
-NH(CH2)l-3COOR6, where R6 is C1.4a-.kyl, where R ' and R° are independently hydrogen or Ci_4alkyl,
7
— NH(CH2)^CO N D
10 where D is 1, 2, 3, or 4 carbon atoms unsubstituted or any 1, 2, 3, or 4 of which are substituted with OH, -NHSO2(CH2)l-3aryl, -NH(CH2)l-3NH2, 15 -NHC3.7 cycloalkyl ring unsubstituted or substituted with -OH, -C(O)OH, or -C(O)ORc, where Rc is
C1-4 alkyl,
Figure imgf000131_0002
where
20 Y2 is O or NH,
W4 is C or N, Z1 is C or N, and
R6 is -CH2OH or -N(CH3)2 provided that W4 and Z1 are not the same,
25
Figure imgf000131_0003
where
R7 is H or CH3, and R8 is H or O
II
— CNH(tBu)
Figure imgf000132_0001
-NHSO2-(CH2)l-2-NH-(CH2)2NH2
where R9 is H, NH2, or OH;
or
Figure imgf000132_0002
wherein B* is a bond, O, -CH2-O-, or -O-CH2-;
W2 is hydrogen, R1-,
R1OC(O)-, R!C(0)-, R1Sθ2-,
(Rl)2CH(CH2)0-4NHC(O)-, (Rl)m(CH2)nNHqC(O)-, where n is 0-4, m is 1 or 2, wherein Rl is same or different, and q is 0 or 1, with the proviso that where n is 1-4, q is 1 and m is 1, and where n is 0, m is 1 or 2, and q is 0 or 1, and where n is 0, m is 2 and q is 0;
R! is
R17(CH2)t-, where t is 0-4, (R17)(OR17)CH(CH2)p-, where p is 1-4, (R17)2CH(CH2)r-, where r is 0-4 and each R 7 can be the same or different, and wherein (R^7)2 can also form a ring with CH represented by C3-7 cycloalkyl, C7-I2 bicylic alkyl, Ciθ-16 tricylic alkyl, or a 5- to 7- membered mono- or bicyclic heterocyclic ring which can be saturated or unsaturated, and which contains from one to three heteroatoms selected from the group consisting of N, O and S, R17O(CH2)p-, wherein p is 1-4;
R2 and R-^7 are independently selected from -phenyl, unsubstituted or substituted with one or more of
C1-4 alkyl, Cl-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, -Cχ-7 alkyl, unsubstituted or substituted with one or more of hydroxy,
COOH, amino, aryl,
C3-7 cycloalkyl, heteroaryl, or heterocycloalkyl, -CF3
C3-7 cycloalkyl, C7-12 bicyclic alkyl, or C10-I6 tricyclic alkyl;
X2 is
CF2, CR15,R16 wherein Rl5 and Rl6 are independently hydrogen, C3-7 cycloalkyl,
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
S(O)r, where r is 0-2;
χ3 is hydrogen or halogen; R3 and Rl8 are independently selected from the group consisting of hydrogen, Ci-4 alkyl, C3-7 cycloalkyl, or trifluor omethyl ;
B is selected from the group consisting of
C1-4 alkyl, C3-4 alkenyl, and C3.4 alkynyl;
X is selected from the group consisting of hydrogen, halogen,
-CF3,
-CH2CF3,
-C3-5 cyclolakyl,
-CH2C3-5 cycloalkyl, and -C1-4 alkyl;
Z is selected from the group consisting of hydrogen, -NH2,
-Ci-4 alkylamino, -Ci-4 alkanol, -Cχ-4 alkyl; and Y is selected from the group consisting of hydrogen, and -C1-7 alkyl,
-CH2CH2CH2CH2C3-6 cycloalkyl, -CH2CH=CHCH2C3-6 cycloalkyl, -CH2C≡ CCH2C3_6 cycloalkyl, -CH2C≡ CCH2CH2C3.6 cycloalkyl. -CH2CH2CH2CH2CH2C3-6 cycloalkyl,
-CH2CH=CHCH2CH2C3-6 cycloalkyl, and -CH2COYI, wherein γl is selected from the group consisting of
-OC1.7 alkyl, -OH,
-Cl-6 alkyl,
-C3-6 cyclolalkyl,
-CH2C3-6 cycloalkyl,
-CH2CH2C3-6 cycloalkyl, -benzyl
-CH2benzyl
-NH2,
-NHC1-5 alkyl, -NHC1-4 alkylCF3, -NHC2-4 alkanol,
-NHC2-4 alkylamino,
Figure imgf000136_0001
Figure imgf000136_0002
Figure imgf000137_0001
N=
-Λ )
Figure imgf000137_0002
Ή-
Figure imgf000137_0003
— N o
Figure imgf000138_0001
wherein Y2 is H, NH2orOH,
Figure imgf000138_0002
wherein Y3 is H, NH2 or OH, and
Figure imgf000138_0003
wherein Y4 is hydrogen, and
Y5isNH2orOH,orH
Y5 is hydrogen, and Y4isNH2orOH.
2. A compound of claim 1 having the formula
Figure imgf000139_0001
Z or Z or Z and pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of
Figure imgf000140_0001
Figure imgf000140_0002
Figure imgf000140_0003
Figure imgf000140_0004
Figure imgf000141_0001
Figure imgf000141_0002
Figure imgf000141_0003
Figure imgf000142_0001
Figure imgf000142_0002
Figure imgf000142_0003
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000143_0003
Figure imgf000144_0001
Figure imgf000144_0002
Figure imgf000144_0003
3. A compound of claim 2 having the formula
Figure imgf000145_0001
and pharmaceutically acceptable salts thereof, wherein
B is selected from the group consisting of:
-CH2CH =CH- ,
-CH2CH2CH2- ,
-CH2C ≡ C- , and
-CH2- ;
X is
H,
-CH3,
-Cl
Z is
H,
-NH2, and
Y is selected from the group consisting of
hydrogen,
-CH2COOC(CH3)3
-CHoCOOH,
-CH2CONHC(CH3)3 !
-CH2CONHCH2CH3,
-CH2CONH <j
-CH2CONHCH2 <]
Figure imgf000146_0001
-CH2CONHC(CH3)2CH2CH3, -CH2CONHCH2C(CH3)3,
-CH2CONHCH2CF3,
-CH2CON 0
Figure imgf000147_0001
-CH2CONHCH2CH2OH, -CH2CONHCH2CH2NH2,
-CH2CONHC(CH3)2CH2NH2,
-CH2CONHCH2C(CH3)2NH2
-CH2COOC(CH3)3 .
The compound of Claim 3 selected from the group consisting of:
Figure imgf000147_0002
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000149_0003
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000150_0003
Figure imgf000151_0001
Figure imgf000151_0002
Figure imgf000151_0003
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000153_0001
Figure imgf000153_0002
Figure imgf000153_0003
Figure imgf000153_0004
r COOlBu N
Figure imgf000153_0005
N
Figure imgf000154_0001
Figure imgf000154_0002
05 CONHEt
Figure imgf000154_0003
Figure imgf000154_0004
Figure imgf000154_0005
Figure imgf000155_0001
Figure imgf000155_0002
Figure imgf000155_0003
Figure imgf000155_0004
-153-
Figure imgf000156_0001
Figure imgf000156_0002
Figure imgf000156_0003
CONHlBu
Figure imgf000156_0004
CONHlBu
Figure imgf000157_0001
COOlBu
Figure imgf000157_0002
Figure imgf000157_0003
Figure imgf000157_0004
CONHlBu
Figure imgf000157_0005
10 cocteu
Figure imgf000158_0001
COOlBu
Figure imgf000158_0002
Figure imgf000158_0003
COOlBu
Figure imgf000158_0004
CONHlBu
Figure imgf000158_0005
Figure imgf000159_0001
Figure imgf000159_0002
Figure imgf000159_0003
Figure imgf000159_0004
-157-
Figure imgf000160_0001
Figure imgf000160_0002
Figure imgf000160_0003
Figure imgf000160_0004
-158-
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000161_0003
Figure imgf000161_0004
-159-
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000162_0004
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000163_0003
Figure imgf000163_0004
Figure imgf000164_0001
Figure imgf000164_0002
Figure imgf000164_0003
Figure imgf000164_0004
Figure imgf000165_0001
Figure imgf000165_0002
Figure imgf000165_0003
and pharmaceutically acceptable salts thereof.
5. A composition for inhibiting thrombin in blood comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.
6. A method for inhibiting thrombin in blood in a mammal comprising administering to the mammal a composition of Claim 5.
7. A method for inhibiting formation of blood platelet aggregates in blood in a mammal comprising administering to the mammal a composition of Claim 5.
8. A method for inhibiting formation of fibrin in blood in a mammal comprising administering to the mammal a composition of
Claim 5.
9. A method for inhibiting thrombus formation in blood in a mammal comprising administering to the mammal a composition of Claim 5.
10. A method for inhibiting thrombin in stored blood comprising administering to the mammal a composition of Claim 5.
11. The use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin, and inhibiting formation of blood platelet aggregates, in a mammal.
PCT/US1998/005486 1997-03-24 1998-03-20 Thrombin inhibitors WO1998042342A1 (en)

Priority Applications (4)

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CA002283704A CA2283704A1 (en) 1997-03-24 1998-03-20 Thrombin inhibitors
AU65727/98A AU728006B2 (en) 1997-03-24 1998-03-20 Thrombin inhibitors
EP98911875A EP0969840A4 (en) 1997-03-24 1998-03-20 Thrombin inhibitors
JP54582598A JP2001518932A (en) 1997-03-24 1998-03-20 Thrombin inhibitors

Applications Claiming Priority (8)

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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
GBGB9716872.8A GB9716872D0 (en) 1997-08-08 1997-08-08 Thrombin Inhibitors
GB9716872.8 1997-08-08
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JP2001518932A (en) 2001-10-16
AU728006B2 (en) 2001-01-04

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