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WO2003011222A2 - Inhibiteurs de la thrombine - Google Patents

Inhibiteurs de la thrombine Download PDF

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Publication number
WO2003011222A2
WO2003011222A2 PCT/US2002/024219 US0224219W WO03011222A2 WO 2003011222 A2 WO2003011222 A2 WO 2003011222A2 US 0224219 W US0224219 W US 0224219W WO 03011222 A2 WO03011222 A2 WO 03011222A2
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WO
WIPO (PCT)
Prior art keywords
benzyl
mmol
chloro
tricyclo
pentaene
Prior art date
Application number
PCT/US2002/024219
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English (en)
Other versions
WO2003011222A3 (fr
Inventor
Philippe G. Nantermet
Harold G. Selnick
James C. Barrow
Christina L. Newton
Original Assignee
Merck & Co., Inc.
Newton, Randall, C.
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
Application filed by Merck & Co., Inc., Newton, Randall, C. filed Critical Merck & Co., Inc.
Priority to AU2002322802A priority Critical patent/AU2002322802A1/en
Publication of WO2003011222A2 publication Critical patent/WO2003011222A2/fr
Publication of WO2003011222A3 publication Critical patent/WO2003011222A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems

Definitions

  • Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
  • European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
  • Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a- keto carboxyl derivatives.
  • the invention includes compounds for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a compound for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
  • Compounds of the invention are useful as thrombin inhibitors and have therapeutic value in for example, preventing coronary artery disease.
  • the invention includes compounds having the following structure:
  • R 1 is aryl, C ⁇ -4 alkyl, or C 3-7 cycloalkyl;
  • R >2 is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, halogen, or CN;
  • R 3 is hydrogen, C 1-4 alkyl, C 3- cycloalkyl, halogen or CN;
  • R 4 is hydrogen, C 1-4 alkyl or -ZCOOH, wherein Z is C 1-4 alkyl;
  • A is selected from the group consisting of a) — (CHz X 1 — where X 1 is O or CH 2j
  • Y 1 is O, S, SO, SO 2 or NR 5
  • X 2 is O or CH 2
  • Y 2 is O, S, SO, SO 2 or NR 5
  • X 3 is O or CH 2
  • X is O or CH 2 , provided that when X is O, n and m are independently 1, 2 or 3, and that when ⁇ is CH 2 , n is 1, 2 or 3, and m is 2 or 3, or e) I— (CH 2 ) n -NR 5 -C(O)-(CH 2 ) m -X 5
  • X is O or CH 2 , provided that when X is O, n and m are independently 1, 2 or 3, and when X is CH 2 , n is 1, 2 or 3 and m is 2 or 3;
  • R 5 is hydrogen, C ⁇ -4 alkyl or -ZOOH, where Z is C 1-4 alkyl.
  • R is hydrogen or halogen and R 3 is hydrogen or halogen.
  • R 2 is hydrogen or CI and R 3 is hydrogen or
  • R 1 is phenyl or cyclopropyl.
  • R 4 is hydrogen, methyl, ethyl, or - CH 2 COOH.
  • R 5 is hydrogen, methyl or ethyl.
  • A is selected from the group consisting of -(CH 2 ) 4 -O-, -(CH 2 ) 3 -O-, -(CH 2 ) 5 -O-, -(CH 2 ) 6 -O-,
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • the compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "halogen”, as used herein, means fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
  • cycloC3_7alkyl is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • aryl as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system such as phenyl, or naphthyl.
  • the aryl ring can be unsubstituted or substituted with one or more of C1 -.4 lower alkyl; hydroxy; alkoxy; halogen; amino.
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3- ⁇ henylpropionate, picrate, pivalate, propionate, succinate, sulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • Thrombin Inhibitors Therapeutic Uses- Method of Using Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebro vascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
  • Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g.
  • obstruction or occlusion of a vein by a detached thrombus obstruction or occlusion of a lung artery by a detached thrombus
  • cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
  • arterial thrombosis e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery
  • atherosclerosis e.g. arteriosclerosis characterized by irregularly distributed lipid deposits
  • Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin HI deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the invention are useful for maintaining patency of indwelling catheters.
  • cardiogenic thromboembolism examples include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.
  • arterial thrombosis examples include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease.
  • compounds of the invention are useful for maintaining patency in arteriovenous cannulas.
  • atherosclerosis examples include arteriosclerosis.
  • devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems
  • the thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non- toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
  • the thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
  • the thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl- aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the thrombin inhibitors when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
  • an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day.
  • a suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
  • the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day.
  • Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.
  • a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g.
  • 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg.
  • an 80 kg patient receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day.
  • Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. Consideration should be given to the solubility of the drug in choosing an The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
  • the compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
  • thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds claimed in this invention can be prepared according to the following general procedures.
  • scheme 1 ethyl oxalyl chloride is converted in four steps to the bromopyrazinone 1.
  • Addition of an -(azidomethyl)-alkylamine hydrochloride to bromopyrazinone 1, followed by chlorination of the pyrazinone and reduction of the azide to the corresponding amine gives access to aminomethyl derivatives of type 2.
  • Alkylation of aminomethyl derivatives of type 2 with tertbutylbromoacetate followed by hydrolysis with aqueous LiOH leads to acids of type 3.
  • Acylation of aminomethyl derivatives of type 2 with allyl chloroformate followed by hydrolysis with aqueous LiOH leads to acids of type 4.
  • phenols of type 5 can be converted to bromides of type 6 by alkylation with dibromide intermediates.
  • Alkylation of aminomethyl derivatives of type 2 with bromides of type 6 leads to Boc-amino ester derivatives of type 7. Removal of the Boc group, followed by hydrolysis of the ester and cyclization under EDC / HO At conditions provides macrocycles of type 8.
  • Scheme 3 illustrates an alternative preparation of ethyl bromide derivative 9 from phenol 5, via alkylation with ethyl bromoacetate, reduction and bromination of the resulting primary alcohol.
  • Alkylation of 2-mercaptoethanol with bromide 9 followed by bromination affords bromides of type 10.
  • Alkylation of aminomethyl derivatives of type 2 with bromides of type 10 leads to Boc-amino ester derivatives of type 11. Removal of the Boc group, followed by hydrolysis of the ester and cyclization under EDC / HOAt conditions provides macrocycles of type 12.
  • Scheme 4 illustrates the preparation of macrocycle 15 with an amide type linker.
  • Alylation of alkylglycine ethyl ester with bromide 9 followed by ester hydrolysis leads to acid 13.
  • EDC/HOAt coupling of acid 13 to aminomethyl derivative 2 provides intermediate 14 which can be cyclized to 15 following the same procedure as described in the previous schemes.
  • Scheme 5 illustrates an alternative mode of macrocyclization.
  • Amine 16 can be prepared by akylation of bromide 9.
  • EDC/HOAt coupling of acid 3 to benzylaminel derivative 16 provides intermediate 17 which can be cyclized to 18 after tertbutyl removal.
  • Scheme 6 illustrates an alternative mode of coupling between the pyrazinone derivative and the phenolic derivative.
  • Aldehyde 19 is obtained from phenol 5 using the following three steps sequence: alkylation with a bromoester, reduction of the ester and oxidation to the corresponding aldehyde.
  • Reductive amination with aminomethyl derivative 2 provides the intermediates of type 20.
  • this alternative mode of linker introduction was found to be more efficient than the original bromide alkylation procedure utilized in schemes 2 and 3. Macrocyclization of intermediate 20 to macrocycle 21 is accomplished using the same sequence as described earlier.
  • Scheme 7 illustrates the preparation of aldehyde 22 and its attachment to the pyrazinone core via reductive amination as described in scheme 6, followed by macrocyclization to 24, as described before.
  • Scheme 8 illustrates the preparation of macrocycles of type 28 which present an amino type linker.
  • Alkylation of a primary amine of type 25 with a bromoester followed by Boc protection and conversion of the ester to the corresponding aldehyde leads to aldehyde derivatives of type 26.
  • Reductive amination with aminomethyl derivative 2 and macrocyclization provides macrocycles of type 28.
  • Scheme 9 illustrates yet another mode of macrocyclization which utilizes Grubbs type olefin metathesis (Grubbs, R. H., Chang, S. Tetrahedron, 1998, 54, 4413-4450).
  • Allyl derivative 29 is prepared from phenol 5 and allyl bromide.
  • Coupling of acid 4 and amine 29 under EDC HOAt conditions leads to bis-olefin derivative 30 which is converted to an E/Z mixture of macrocycles of type 31 via Grubbs olefin metathesis.
  • Hydrogenation on Pd/C provides derivatives of type 32.
  • Scheme 10 illustrates further modifications of the previously described macrocycles.
  • Dehalogenation with hydrogen provides derivatives of type 33 and 34.
  • Reductive alkylation leads to amino derivatives of type 35.
  • a carboxymethyl group can be attached to afford structures of type 36.
  • Step B preparation of (S)-[3-(l-Aminomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo- 2H-pyrazin-l-yl] -acetic acid ethyl ester
  • reaction mixture is concentrated in vacuo and purified by flash chromatography (silica gel, 20% diethyl ether in hexane to 45%) to give (S)-[3-(l-Azidomethyl-2-phenyl-ethylamino)-2-oxo- 2H-6-chloro-pyrazin-l-yl] -acetic acid ethyl ester (5.6 g) as a thick syrup.
  • Step A preparation of [3-(l-(S)-Benzyl-2- ⁇ 4-[2-(tert-butoxycarbonylamino-methyl)- 4-chloro-phenoxy] -butylamino ⁇ -ethylamino)-6-chloro-2-oxo-2H-pyrazin- 1 -yl] -acetic acid ethyl ester
  • reaction mixture is diluted with EtOAc, washed with water and aqueous LiCl (x3), dried on sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 10% EtOAc in hexane to 20%) to give [2-(4-Bromo- butoxy)-5-chloro-benzyl]-carbamic acid tert-butyl ester (1.13 g).
  • Step B cyclization to 19-(S)-Benzyl-8,24-dichloro-12-oxa-l,4,17,20,22-pentaaza tricyclo[19.3.1.0(6,ll)] pentacosa-6(ll),7,9,21, 23-pentaene-3,25-dione dihydrochloride
  • the dihydrochloride salt is obtained by treatment of a solution of the free base in CH 2 C1 2 with 2N HCl in Et O.
  • the crude material is purified by reverse phase preparative HPLC (5% to 95% CH 3 CN in water containing 0.1 % TFA, C18 PRO YMC 20x150 mm) to provide after extraction and hydrochloride preparation under standard conditions (S)-19-Benzyl-8- chloro-12-oxa-l,4,17,20,22-pentaaza tricyclo[19.3.1.0(6,ll)] pentacosa-6(ll),7,9,21, 23-pentaene-3,25-dione dihydrochloride.
  • EXAMPLE 8 (S)-18-Benzyl-8,23-dichloro-12-oxa-l,4,16,19,21-pentaaza tricyclo[18.3.1.0(6,11)] tetracosa-6(l 1),7,9,20, 22-pentaene-3,24-dione
  • (S)-18-Benzyl-8,23-dichloro-12-oxa-l,4,16,19,21-pentaaza tricyclo[18.3.1.0(6,ll)] tetracosa-6(ll),7,9,20, 22-pentaene-3,24-dione is prepared from [2-(3-Bromo-propoxy)-5-chloro-benzyl]-carbamic acid tert-butyl ester (prepared from (5-Chloro-2-hydroxy-benzyl)-carbamic acid tert-butyl ester and 1,3- dibromopropane) and (S)-[3-(l-Aminomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo- 2H-pyrazin-l-yl] -acetic acid ethyl ester, using a similar procedure as described in example 5.
  • [21.3.1.0(6,ll)]-heptacosa-6(ll),7,9,23, 25-pentaene-3,27-dione is prepared from [2- (6-BiOmo-hexoxy)-5-chloro-benzyl]-carbamic acid tert-butyl ester (prepared from (5- Chloro-2-hydroxy-benzyl)-carbamic acid tert-butyl ester and 1,6-dibromohexane) and (S)-[3-(l-Aminomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo-2H-pyrazin-l-yl]-acetic acid ethyl ester, using a similar procedure as described in example 5.
  • EXAMPLE 12 (S)-19-Benzyl-17-Methyl-8,24-dichloro-12-oxa-l,4,17,20,22-pentaaza tricyclo[19.3.1.0(6,11)] pentacosa-6(ll),7,9,21, 23-pentaene-3,25-dione bis TFA salt
  • EXAMPLE 16 (S)-20-Cyclopropylmethyl-18-Methyl-8,25-dichloro-12-oxa-l,4,18,21,23-pentaaza tricyclo[20.3.1.0(6, 11)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione bis TFA salt
  • EXAMPLE 17 (S)-20-Cyclopropylmethyl-8 ,25-dichloro- 12, 15-dioxa- 1 ,4, 18 ,21 ,23-pentaaza tricyclo[20.3.1.0(6,11)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione
  • Step A Preparation of ⁇ 5-Chloro-2-[2-(2-hydroxy-ethoxy)-ethoxy]-benzyl ⁇ -carbamic acid tert-butyl ester
  • reaction mixture is concentrated in vacuo, diluted with CH 2 C1 2 , washed with water, concentrated in vacuo and purified by flash chromatography (silica gel, 20% EtOAc in hexane to 70%) to give ⁇ 5-Chloro-2-[2-(2-hydroxy-ethoxy)-ethoxy]-benzyl ⁇ -carbamic acid tert-butyl ester (0.6 g) as a colorless oil.
  • Step B Preparation of ⁇ 3-[2-(2- ⁇ 2-[2-(tert-Butoxycarbonylamino-methyl)-4-chloro- phenoxy] -ethoxy ⁇ -ethylamino)- 1 -cyclopropylmethyl-ethylamino] -6-chloro-2-oxo-2H- pyrazin-1-yl ⁇ -acetic acid ethyl ester
  • reaction mixture is allowed to warm to room temperature, is diluted with CH 2 C1 2 , washed with water, dried on sodium sulfate, and concentrated in vacuo to give ⁇ 5-Chloro-2-[2-(2- oxo-ethoxy)-ethoxy] -benzyl ⁇ -carbamic acid tert-butyl ester which is selectiveely used in the next step without further purification.
  • reaction mixture is stirred at room temperature for 50 min, diluted with CH C1 2 , washed with aqueous sodium bicarbonate, dried on sodium sulfate, concentrated in vacuo, and purified by flash chromatography (silica gel, 1% MeOH containibg 10% NH OH in CH 2 C1 2 to 5%) to give ⁇ 3-[2-(2- ⁇ 2-[2-(tert-Butoxycarbonylarmno-methyl)- 4-chloro-phenoxy] -ethoxy ⁇ -ethylamino)- 1 -cyclopropylmethyl-ethylamino] -6-chloro- 2-oxo-2H-pyrazin-l-yl ⁇ -acetic acid ethyl ester (193 mg).
  • Step C cyclization to (S)-20-Cyclopropylmethyl-8,25-dichloro-12,15-dioxa- 1,4,18,21,23-pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene- 3,26-dione
  • EXAMPLE 18 (S)-20-Benzyl-8,25-dichloro-12,15-dioxa-l,4,18,21,23-pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione
  • EXAMPLE 19 15-Ethyl- 20(S)-Benzyl-8,25-dichloro-12-oxa-l,4,15,18,21,23-hexaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,16,26-trione bis TFA salt
  • reaction mixture is diluted with EtOAc, washed with water and aqueous LiCl (x3), dried on sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 30% EtOAc in hexane to 50%) to give (2- ⁇ 4-[(2-Allyloxy-5-chloro-benzylcarbamoyl)-methyl]-5-chloro-3-oxo- 3,4-dihydro-pyrazin-2-ylamino ⁇ -3-phenyl-propyl)-carbamic acid allyl ester (100 mg) as a white foam.
  • MS ES+ M+l 600.3.
  • EXAMPLE 21 (S)-21-Benzyl-8,26-dichloro-12,17-dioxa-l,4,19,22,24-pentaaza tricyclo- [21.3.1.0(6,11)] heptacosa-6(ll),7,9, 23, 25-pentaene-3,18,27-trione TFA salt and (S)-21-Benzyl-8-chloro-12,17-dioxa-l,4,19,22,24-pentaaza tricyclo-[21.3.1.0(6,ll)] heptacosa-6(ll),7,9,23, 25-pentaene-3,18,27-trione TFA salt
  • EXAMPLE 26 (S)-20-Benzyl- 18-methyl-25-chloro- 12-oxa- 1 ,4, 18 ,21 ,23-pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione dihydrochloride
  • (S)-20-Benzyl-18-methyl-25-chloro-12-oxa-l,4,18,21,23-pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione dihydrochloride is prepared from (S)-20-Benzyl-25-chloro-12-oxa -1,4,18,21,23- pentaaza tricyclo[20.3.1.0(6, 11)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione dihydrochloride and formaldehyde using a similar procedure as described in example 12.
  • (S)-20-Benzyl-18-carboxymethyl-25-chloro-12-oxa-l,4,18,21,23- pentaaza tricyclo[20.3.1.0(6, 11)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione dihydrochloride is prepared from (S)-20-Benzyl-25-chloro-12-oxa -1,4,18,21,23- pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione dihydrochloride and tert-butyl bromoacetate using a similar procedure as described in example 2 followed by tert-butyl removal in TFA.
  • EXAMPLE 30 (S)-20-Benzyl-18-methyl-25-chloro-12,15-dioxa-l,4,18,21,23-pentaaza tricyclo[20.3.1.0(6,ll)] hexacosa-6(ll),7,9,22, 24-pentaene-3,26-dione .2
  • tert-Butyl 2-(aminomethyl benzylcarbamate hemisulfate To a 3 L, 3 neck flask fitted with a thermocouple, a condenser and nitrogen inlet was added 3 g (23 mmol) of cobaltous chloride, then 1200 mL of THF followed by 59 g (254 mmol) of tert-butyl 2-cyanobenzylcarbamate and 600 mL of ice-water. To the light pink solution at 15°C was added 26 g (684 mmol) of sodium borohydride in portions as follows. The initial 3 g of sodium borohydride resulted in a vigorous hydrogen gas evolution and formation of a black suspension.
  • the batch temperature reached 35°C within 2 hr, and was maintained at this temperature with a heating mantle. Additional sodium borohydride and cobaltous chloride were added as needed to drive the reaction to completion. Typically, 2 x 7.5 g of additional sodium borohydride and 2 x 1 g portions of cobaltous chloride were added at 12 hour intervals. Once complete, the layers were allowed to settle and the clear upper THF layer was decanted from the black aqueous layer. The aqueous layer was washed with 750 mL fresh THF, the two THF layers combined and filtered through a pad of celite.
  • the orange-yellow filtrate was concentrated to about 300 mL in vacuo, resulting in water layer with the product as an oily lower layer.
  • the mixture was extracted with 2 x 250 mL ethyl acetate and the combined extracts reacted with 24 g (200 mmol) of solid sodium hydrogensulfate. A solid formed immediately, and the slurry was stirred for 30 min, filtered and washed with 2 x 100 mL ethyl acetate to give 62 g of a white powder.
  • the powder was slurried in 175 mL water, cooled to 0°C, filtered, washed with 2 x 40 mL cold water and the solid dried in a vacuum oven at 55°C for 24 hr to give 46 g (64% yield from tert-butyl 2-cyanobenzylcarbamate) of tert-butyl 2- (aminomethyl)benzylcarbamate hemisulfate salt as a white powder.
  • Step B Preparation of [2-(tert-Butoxycarbonylamino-methyl)-benzyl]-(4-hydroxy- butyl)-carbamic acid dimethyl-ethyl ester
  • tert-Butyl 2-(aminomethyl)benzylcarbamate hemisulfate (1 g, 3.5 mmol) is partitioned betwwen aqueous NaHCO 3 and CH 2 C1 2 to obtain the free base from the organic layer after back extraction with CH 2 C1 2 .
  • a solution of tert-Butyl 2-(aminomethyl) benzylcarbamate free base (3.5 mmol) in DMF (10 ml) is added ethyl 4-bromo- butyrate (602 ul, 4.2 mmol) and the reaction mixture is stirred at 70 °C for 18 h.
  • reaction mixture is allowed to cool down to room temperature, dilute with EtOAc, washed with water, aqueous NaHCO 3 and aqueous LiCl, dried on Na 2 SO , concentrated in vacuo and purified by flash chromatography (silica gel, 1% MeOH containibg 10% NH 4 OH in CH 2 C1 2 to 10%) to give 4-[2-(tert-Butoxycarbonylamino- methyl)-benzylamino] -butyric acid ethyl ester (912 mg) contaminated with the bis- alkylation product.
  • reaction mixture is concentrated in vacuo and purified by flash chromatography (silica gel, 5% EtOAc in hexane to 40%) to give 4- ⁇ tert-Butoxycarbonyl-[2-(tert-butoxycarbonylamino- methyl)-benzyl] -amino ⁇ -butyric acid ethyl ester (669 mg) as a colorless oil.
  • Step C Reductive alkylation and cyclization toward (S)-20-Benzyl-25-chloro- 1,4,13,18,21,23-hexaaza tricyclo[20.3.1.0(6, 11)] hexacosa-6(ll),7,9,22, 24-pentaene- 3,26-dione tris TFA salt
  • Step A Preparation of tert-Butyl [2-(aminomethyl)phenyl] acetate
  • 2-Bromomethylphenylacetic acid To a solution of 97.0 g (0.646 mol) o-tolylacetic acid in 1.75 L carbon tetrachloride was added 115.0 g (0.646 mol) N-bromosuccinimide and 3.4 g (0.021 mol) 2,2 -azobisisobutyronitrile. The mixture was heated at reflux under a nitrogen atmosphere for 4 h. After the mixture was cooled to 0-5 °C for 30 min, the solids were removed by filtration and washed with a small portion of carbon tetrachloride.
  • Step B Preparation of (2- ⁇ 2-[tert-Butoxycarbonyl-(3-hydroxy-propyl)-amino]-ethyl ⁇ - benzyl)-carbamic acid tert-butyl ester
  • reaction mixture is concentrated in and purified by flash chromatography (silica gel, 30% EtOAc in hexane to 65%) to give (2- ⁇ 2-[tert- Butoxycarbonyl-(3-hydroxy-propyl)-amino]-ethyl ⁇ -benzyl)-carbamic acid tert-butyl ester (439 mg) as a thick oil.
  • Step C reductive alkylation and cyclization toward (S)-20-Benzyl-25-chloro- 1,4,14,18,21,23-hexaaza tricyclo[20.3.1.0(6,11)] hexacosa-6(ll),7,9,22, 24-pentaene- 3,26-dione tris hydrochloride
  • Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
  • Mannitol, microcrystallme cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
  • the thrombin inhibitors can also be co-administered with suitable antiplatelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis.
  • fibrinogen receptor antagonists e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis
  • anticoagulants such as aspirin
  • thrombolytic agents such as plasminogen activators or streptokinase
  • thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
  • Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • Trypsin assays also contained 1 mM CaCl2- In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance of p-nitroaniline.
  • p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm' ⁇ M" 1.
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V 0 ) or presence of inhibitor (N were measured.
  • the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of N 0 /Ni on [I] shown in the following equation.
  • 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.
  • Active I is compound (S)-19-Benzyl-8,24-dichloro-12-oxa-l,4,17,20,22-pentaaza tricyclo[19.3.1.0(6,11)] pentacosa-6(ll),7,9,21, 23-pentaene-3,25-dione dihydrochloride .
  • All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • compositions of compound (S)-19-Benzyl-8,24-dichloro- 12-oxa-l,4,17,20,22-pentaaza tricyclo[19.3.1.0(6,11)] pentacosa-6(ll),7,9,21, 23- pentaene-3,25-dione dihydrochloride (Active I) tablets are shown below:
  • Active I, mannitol and microcrystallme cellulose were sieved through mesh screens of specified size (generally 250 to 750 ⁇ m) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water-soluble polymers and pigment.
  • a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size.
  • the granules are then mixed with magnesium stearate and tabletted as stated above.
  • compositions A-C are as follows:
  • Narious other buffer acids such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.

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Abstract

L'invention concerne des composés utiles pour inhiber la thrombine et les occlusions thrombotiques associées, représentés par la formule (I), par exemple un composé de formule (II).
PCT/US2002/024219 2001-07-27 2002-07-23 Inhibiteurs de la thrombine WO2003011222A2 (fr)

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US10208068B2 (en) 2011-08-05 2019-02-19 Bristol-Myers Squibb Company Macrocycles as factor XIa inhibitors
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