EP1286982A2 - Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites - Google Patents

Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites

Info

Publication number
EP1286982A2
EP1286982A2 EP01941787A EP01941787A EP1286982A2 EP 1286982 A2 EP1286982 A2 EP 1286982A2 EP 01941787 A EP01941787 A EP 01941787A EP 01941787 A EP01941787 A EP 01941787A EP 1286982 A2 EP1286982 A2 EP 1286982A2
Authority
EP
European Patent Office
Prior art keywords
compound
salt
acid
acetic acid
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01941787A
Other languages
German (de)
English (en)
Inventor
Luc Antoine
Pascal Bouquel
Alfio Borghese
Matthew Fisher
Hugo Gorissen
Joseph A. Jakubowski
Vien V. Khau
Michael Martinelli
Alain Merschaert
Michael Paal
Gerd Ruhter
Carine Rypens
Theo Schotten
Wolfgang Stenzel
Jean-Pierre Van Hoeck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1286982A2 publication Critical patent/EP1286982A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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

Definitions

  • this invention relates to novel processes for coupling amino substituted 2-chromane derivatives and benzoyl derivatives via an amide bond, which are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors.
  • the invention relates to processes for producing such compounds from chiral intermediates to provide desired enantiomers, and methods for using the compounds as platelet aggregation inhibitors.
  • the bicyclic starting material is a resolved single enantiomer
  • the loss of 64% of the enantiomer in the coupling step is very expensive.
  • the carbonyl nitrile derivative may be substituted by various groups as described in U.S. Patent 5,731 ,324, such as halogen, see for example, Scheme 17 on pages 77-78, wherein 2-fluoro-4-cyano benzoic acid is coupled with a tetralone compound.
  • novel processes for producing amino substituted bicyclic compounds such as racemic, (6-amino-chroman-2-yl)acetic acid esters, and resolving such bicyclic compounds into either the R or S enantiomer.
  • novel processes for producing amidino-substituted benzoyl compounds wherein the phenyl ring may be substituted with lower (C,-C 6 ) alkyl, lower alkoxy, -halo (Cl, F, Br, I), and the like, which are intermediates for coupling with bicyclic compounds to produce therapeutic agents, or are themselves therapeutic agents, for disease states in mammals that have disorders caused by or impacted by platelet dependent narrowing of the blood supply.
  • a coupling process for coupling a benzoyl derivative salt with an amine salt of a bicyclic compound to form such therapeutic agents is also provided.
  • the compounds produced by the coupling reactions are all effective therapeutic agents for inhibition of platelet aggregation. It has surprisingly been found, however, that the S enantiomer form, an example of which is shown below, generally has greater activity than the R enantiomer form.
  • R is hydrogen or halogen, and R 1 is hydrogen or alky!; wherein said compound is present in pure, substantially pure or enriched form.
  • R is fluorine and R., is ethyl.
  • a pharmaceutical formulation comprising one of the compounds above and a pharmaceutically acceptable carrier, excipient or diluent.
  • Other embodiments involve using the above compounds or pharmaceutical formulations to inhibit platelet aggregation or to treat a mammal suffering from any of a variety of conditions characterized by platelet aggregation or thrombosis formation.
  • R is an alkyl group.
  • the process comprises reactions (a) through (d) below:
  • the process comprises (a) and (b) as follows: (a) reacting 4-cyano-2-R-benzoic acid with lithium bis(trimethylsilyl)amide in a suitable solvent such as anhydrous THF to form 4-amidino-2-R-benzoic acid as follows:
  • step (b) reacting the 4-amidino-2-R-benzoic acid from step (a) with hydrochloric acid in a suitable solvent such as dimethylformamide to form the product as follows:
  • the method comprises (a) through (c) below:
  • the salt of the 4-amidino-2-benzoyl halide and the salt of the bicyclic intermediate compound are as follows:
  • esters shown are primarily ethyl esters, other esters may be made, either by use of different solvents and/or reagents in the initial formation reactions or by transesterification.
  • any amino substituted bicyclic compound useful for making platelet aggregation inhibitor compounds may be utilized for the coupling reaction step, examples of such bicyclic compounds can be found at pages 5-6 of U.S. patent 5,731 ,324, the entire disclosure of which is hereby incorporated by reference.
  • a bicyclic free amino-substituted acetic acid ester compound (described as a dark oil) having the following formula:
  • one or both of the amino group and the ester group of the acetic acid side chain can be modified with a group which can be utilized to resolve the R and S enantiomers.
  • the ester group can be reacted resolved with a conventional camphor sulfonic acid derivative, a dibenzoyl tartaric acid derivative, (L) or (D) alaninol, and the like, for example) to produce a desired enantiomer.
  • the amino group can be protected by converting the it to an acetamido group, as follows:
  • the racemic ethyl (6-acetamidochroman-2-yl)acetate is converted to the free acid by reaction with a base such as sodium hydroxide and neutralized with an acid such as hydrochloric acid.
  • a base such as sodium hydroxide
  • an acid such as hydrochloric acid.
  • the free acid is then reacted with a slight excess of 1/2 mole of (L) or (D) alaninol per mole of racemate in the presence of methanol.
  • One of the enantiomers will preferentially react with the alaninol and crystallize out (depending upon whether (L) or (D) alaninol is used as the reactant).
  • the crystalline salt can be rinsed by an appropriate solvent such as isopropyl alcohol and may be further purified by recrystallization in an appropriate solvent such as methanol or a mixture of isopropanol and ethanol, and the like. This procedures and the optional recrystallization result in an enriched, essentially pure, or pure crystalline composition of the alaninol salt of either the (R) or (S) enantiomer.
  • Both the alaninol and the amino protecting group can be removed from the crystalline alaninol salt by heating the salt in an appropriate solvent in the presence of an acid.
  • the acid is sulfuric acid and the solvent is absolute ethanol.
  • the mixture is neutralized with an appropriate base (such as sodium hydrogen carbonate and the like) in the presence of an appropriate solvent (such as toluene and the like).
  • an appropriate solvent such as toluene and the like.
  • the aqueous layer can be separated from the organic layer and the aqueous layer extracted with toluene.
  • an acid halide can be added to precipitate the amino halide salt from the toluene solvent as follows:
  • the halide salt can optionally be recrystallized in an appropriate solvent such ethanol, ethyl acetate, ethanol/isopropyl alcohol, and the like to produce a higher enantiomeric purity.
  • an appropriate solvent such as ethanol, ethyl acetate, ethanol/isopropyl alcohol, and the like.
  • the crude enantiomer is heated in absolute alcohol or denatured absolute alcohol (no methanol) or the like, and recrystallized. If the preferred enantiomer remains in the solvent, the solvent can be evaporated to yield the more pure form of the single enantiomer halide salt.
  • HCI solution are utilized for the esterification and to cause the amino group to form a hydrochloride salt, but other esters such as the methyl or propyl ester may likewise be envisioned.
  • the purity of the enantiomer my be optionally improved by recrystallization, HPLC or the like.
  • the preferred solvent for recrystallization is methanol or isopropyl alcohol or a mixture.
  • the acidic alcoholic solutions may be added to the free acid R or S enantiomer compound to form the 2-carboxylic acid ethyl ester (or another ester) and an excess of HCI is then utilized to produce the hydrochloride salt of the amino group.
  • the amino halide salt of the bicyclic compound thus produced can be utilized in a coupling reaction with a carbonyl compound or a halide salt of a carbonyl compound to provide a carboxamide coupled compound, as described in greater detail below.
  • any basic substituted carbonyl group useful for making platelet aggregation inhibitor compounds may be utilized for the coupling reaction step.
  • preferred carbonyl derivative compounds are those in U.S. patent 5,731 ,324, particularly at pages 17-20, and more preferably, are the substituted or unsubstituted amidino-benzoyl or amidino thiophenoyl derivatives. Even more preferably, the carbonyl derivative is an amidino benzoyl derivative, which is optionally substituted by a halogen atom.
  • Such compounds include those selected from the group consisting of 4- amidinobenzoic acid, 4-amidino-2-fluorobenzoicacid, 4-amidino-2-bromobenzoic acid, 4- amidino-2-iodobenzoic acid and 4-amidino-2-chlorobenzoic acid.
  • 4-amidino-2-fluorobenzoic acid which is readily obtained from the nitrile shown in Scheme 17, pages 77-78, by converting the cyano group to a carbamidoyl group using procedures described in the patent 5,731 ,324.
  • the acid halide of the coupled 4-carbamidoyl-2-halobenzoic acid can be made as follows:
  • the acid halide for coupling is 4-amidino-2-fluorobenzoyl chloride or 4- amidinobenzoyl halide.
  • any salt of an aminobicyclic compound and any basic substituted carbonyl group that are useful for coupling to make platelet aggregation inhibitor compounds may be utilized for the coupling reaction step.
  • the above described ethyl (R or S) (6-aminochroman-2- yl)acetate hydrochloride and 4-amidino-2-fluorobenzoyl chloride will be utilized.
  • the acyl chloride is suspended in anhydrous acetonitrile and stirred.
  • a suspension of the bicyclic amino hydrochloride salt in pyridine and anhydrous acetonitrile is added rapidly with stirring at about 10 to about 40 degrees centigrade (preferably at about 20°C) and stirring is continued for about 10-30 minutes (preferably for about 15 minutes) to result in coupling.
  • This coupling step may be illustrated as follows:
  • the solid obtained from the coupling step illustrated above can be filtered, washed with anhydrous acetonitrile and dried at about 40 °C to about 60 °C (preferably at about 50°C) under reduced pressure.
  • the solid can be further purified by recrystallized in an appropriate solvent
  • the recrystallization solvent may be water or a lower alcohol such as ethanol, propanol, isopropanol.
  • a mixed alcohol solvent/anti-solvent can be used as the recrystallization solvent, an example would be ethanol/isopropanol in a ratio of about 1 :1 to about 1 :6, preferably about 1 :5, which may be optimized by simple testing.
  • patent 5,731 ,324 may be used as potent therapeutic agents therapeutic agents for disease states in mammals which have disorders that are due to platelet dependent narrowing of the blood supply, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.
  • such (S) and (R) enantiomers are provided in pure, substantially pure or enriched form as therapeutic agents for treating such disorders, and pharmaceutical compositions comprising an effective amount of such compounds.
  • a method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of either the (S) and (R) enantiomers of ethyl (6-(4- amidino-2-fluorobenzoyl)amino-chroman-2-yl)acetate, the free acid, or other esters and salts thereof.
  • the compounds disclosed herein find utility as intermediates for producing therapeutic agents or as therapeutic agents for disease states in mammals which have disorders that are due to platelet dependent narrowing of the blood supply, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.
  • Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex llb/llla. When a platelet is activated by an agonist such as thrombin the GP llb/llla binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation. Thus, intermediate compounds for producing compounds that effective in the inhibition of platelet aggregation and reduction of the incidence of clot formation are useful intermediate compounds.
  • the compounds produced according to the methods disclosed herein may used as intermediates for producing therapeutic compounds or as compounds that may be administered in combination or in concert with other therapeutic or diagnostic agents.
  • the compounds produced by the intermediates according to the disclosure herein may be co-administered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or . warfarin.
  • the compounds produced from the intermediates according to preferred embodiments may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Such compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects.
  • Such compounds can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the starting materials used in above processes are commercially available from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may be readily synthesized by known procedures, for example, by using procedures such as indicated above.
  • Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated, or is well-known in literature available in the art. Further, the above procedures of the processes described herein may be carried out on a commercial scale by utilizing reactors and standard scale-up equipment available in the art for producing large amounts of compounds in the commercial environment. Such equipment and scale-up procedures are well-known to the ordinary practitioner in the field of commercial chemical production.
  • amino or acid functional groups may be protected by blocking groups to prevent undesired reactions with the amino group during certain procedures.
  • blocking groups are well known in the art.
  • the compounds according to preferred embodiments may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this disclosure and are presently contemplated. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
  • a number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
  • Diagnostic applications of compounds according to preferred embodiments disclosed herein will typically utilize formulations such as solution or suspension.
  • preferred compounds according to the present disclosure may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions for injectable or parenteral administration, and the like, or incorporated into shaped articles.
  • Subjects in need of treatment (typically mammalian) using the compounds according to the present disclosure can be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
  • Formulations of the compounds disclosed herein are prepared for storage or administration by mixing the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counter ions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such as
  • Dosage formulations of the present compounds to be used for parenteral administration are preferably sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods known to those skilled in the art. Formulations are preferably stored in lyophilized form or as an aqueous solution.
  • the pH of the preparations are preferably between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts.
  • While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds according to the present disclosure are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
  • the compounds according to the present disclosure may 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 lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds according to the present disclosure may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled.
  • the compounds may also be coupled with suitable polymers as targetable drug carriers.
  • suitable polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the platelet aggregation inhibitors disclosed herein 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.
  • Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound presently disclosed, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • a typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg.
  • the compounds disclosed herein may be administered several times daily, and other dosage regimens may also be useful.
  • about 0.5 to 500 mg of a compound or mixture of compounds, as the free acid or base form or as a pharmaceutically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent.
  • a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice.
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compounds may be used alone or in combination, or in combination with other therapeutic or diagnostic agents.
  • the compounds disclosed herein may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds disclosed herein can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the preferred compounds disclosed herein are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use.
  • Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.
  • abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
  • PTCA percutaneous transluminal coronary angioplasty
  • abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism.
  • Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life- threatening thrombi occurring throughout the microvasculature leading to -widespread organ failure.
  • the compounds disclosed herein, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-
  • Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the compounds disclosed herein can be added to or contacted with any medium containing or suspected to contain factor llb/llla, and the like, in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.
  • material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.
  • the solution was stirred for at least one hour at room temperature.
  • the solvents were distilled off under reduced pressure (at T ⁇ 35°C ), until the volume of the residue was about 65 L.
  • the mixture was cooled down to room temperature and 40.65 Kg of toluene was added.
  • the mixture was stirred for about 15 minutes.
  • the organic phase was separated and the aqueous layer was extracted with 19.9 kg of toluene.
  • the pH of the aqueous phase was reduced to 2 ⁇ pH ⁇ 3 by slow addition of the 25.3 Kg of 2 N aqueous hydrochloric acid.
  • the suspension was stirred for at least 1 hour at room temperature.
  • reaction mixture was stirred for 30 minutes after addition, after which TLC analysis indicated that the reaction was not yet complete.
  • An additional 50 g (0.6 mole) of pyridine and 50 g (0.45 mole) of acetyl chloride were added and the reaction stirred for 30 more minutes before it was quenched by the addition of 4 L of water. After stirring for 15 minutes, the organic layer was separated. The aqueous layer was extracted with 1 L of toluene and the combined toluene extracts were washed with 2 L of water. After removal of most of the toluene by distillation under reduced pressure (T ⁇ 55°C) until most of the solvent was eliminated.
  • the mixture was cooled down to room temperature and 6 L of toluene was added. The mixture was stirred for about 15 minutes. The organic phase was separated and the aqueous layer was extracted with 2 x 2 L of toluene. The pH of the aqueous phase was reduced to 2 ⁇ pH ⁇ 3 by slow addition of about 2.75 L of 2 N aqueous hydrochloric acid.
  • Examples 4-8 were repeated with essentially the same results except that L- alaninol was reacted with the racemic chromane acetic acid and the (R) enantiomer was obtained in enriched form with essentially the same yields.
  • the organic phase was concentrated to minimum stirrable volume under reduced pressure while keeping the temperature below 40°C 29 L of toluene was added under vacuum and distillation was continued until the volume was about 12 L, while maintaining the temperature below 50°C.
  • the reaction mixture was then cooled to about 19°C and 1.45 L of 6.2 M hydrochloric acid in ethyl alcohol was slowly added in order to maintain the temperature between 10 and 20°C.
  • the crystals were maturated under stirring for at least 16 h at the same temperature, filtered and washed with 6 L of toluene.
  • a second clean and dry reaction vessel was obtained, which was purged with nitrogen and all reactions in this vessel were conducted under nitrogen.
  • Stir to effect a homogeneous suspension for coupling keep under nitrogen and transfer to a transfer vessel for adding to the reaction vessel of (a) above containing the preheated acetonitrile suspension of the benzoic acid chloride salt (may also be transferred by conduit from the second reaction vessel to the first while avoid moisture contact).
  • the 590 g of crude product was dissolved in 3 L of absolute ethanol at reflux.
  • the solution was cooled to from about 70 to about 80°C and passed through a polishing filter to remove any particulates.
  • the solution was concentrated by removing 1790 g of ethanol under reduced pressure, and 3.7 L of preheated isopropyl alcohol (preheated to 60°C) was added to the reaction mixture to provide a recrystallization ratio of about 1.5 mL of ethanol and 7.5 mL isopropyl alcohol per gram of crude product.
  • the solution was cooled to ambient temperature and filtered.
  • reaction vessel A clean and dry reaction vessel was obtained, which was purged with nitrogen and all reactions in this vessel were conducted under nitrogen.
  • the suspension was stirred for 10 minutes, and then 1.17 L (1.69 Kg, 13.34 moles, 1.5 eq) of oxalyl chloride was added at ambient temperature.
  • 140 mL 130 g, 1.7 moles, 0.2 eq
  • the reaction was cooled back to room temperature and the yellow product was filtered off, washed with 10 L of acetonitrile, and dried at 50°C under vacuum for 10 hours to provide 3.25 Kg of crude product.
  • the 3.25 Kg of crude product was dissolved in 20 L of absolute ethanol with refluxing and then the insolubles were removed by filtration.
  • the filtrate was concentrated to 4.5 L of ethanol and 22 L of hot isopropyl alcohol (about 60°C) was added.
  • the resultant solution was slowly cooled to room temperature with stirring.
  • Example 17 The procedures of Example 17 were followed substantially except that ethyl (2R)- (6-aminochroman-2-yl)acetate hydrochloride salt (> 97 ee produced as in Examples 14 or
  • the (2S) enantiomer was greater than 15 times more active than the (2R>2S, 97.5%/2.5%) enantiomer. Further the (2S) enantiomer was 200% more active than the racemate.
  • the corresponding esters, such as the ethyl ester, were found to be substantially less active than the free acid forms.
  • ester forms are converted in vivo into the active free acid forms of the drug that were utilized in the fibrinogen binding assay in the above paragraph.
  • the ester forms are good prodrug forms of the free acids.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention porte sur des procédés permettant de fixer des dérivés amino substitués de 2-chromanyle à des dérivés de benzoyle par l'intermédiaire d'une liaison amide, et sur des intermédiaires servant à l'obtention d'inhibiteurs de l'agrégation plaquettaire et d'inhibiteurs puissants de l'agrégation plaquettaire. L'invention porte également sur des procédés d'obtention de ces composés à partir d'intermédiaires chiraux pour produire les énantiomères désirés, et sur des méthodes d'utilisation desdits composés comme inhibiteurs de l'agrégation plaquettaire.
EP01941787A 2000-06-02 2001-06-01 Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites Withdrawn EP1286982A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US20876200P 2000-06-02 2000-06-02
US208762P 2000-06-02
PCT/US2001/017765 WO2001094333A2 (fr) 2000-06-02 2001-06-01 Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites

Publications (1)

Publication Number Publication Date
EP1286982A2 true EP1286982A2 (fr) 2003-03-05

Family

ID=22775949

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01941787A Withdrawn EP1286982A2 (fr) 2000-06-02 2001-06-01 Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites

Country Status (4)

Country Link
EP (1) EP1286982A2 (fr)
JP (1) JP2003535856A (fr)
AU (1) AU2001275115A1 (fr)
WO (1) WO2001094333A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2571452T3 (es) * 2012-01-10 2016-05-25 Lilly Co Eli Compuesto antagonista de leucotrieno B4

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5273982A (en) * 1990-03-09 1993-12-28 Hoffmann-La Roche Inc. Acetic acid derivatives
JPH08511538A (ja) * 1993-06-09 1996-12-03 スミスクライン・ビーチャム・コーポレイション 二環式フィブリノゲン拮抗物質
US5731324A (en) * 1993-07-22 1998-03-24 Eli Lilly And Company Glycoprotein IIb/IIIa antagonists
US6117910A (en) * 1994-12-13 2000-09-12 Smithkline Beecham Corporation Bicyclic fibrinogen antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0194333A2 *

Also Published As

Publication number Publication date
AU2001275115A1 (en) 2001-12-17
WO2001094333A2 (fr) 2001-12-13
WO2001094333A3 (fr) 2002-06-06
JP2003535856A (ja) 2003-12-02

Similar Documents

Publication Publication Date Title
CA2627086C (fr) Nouveaux sels pharmaceutiques et polymorphes d'un inhibiteur du facteur xa
CA2667488C (fr) Procedes de synthese de sels pharmaceutiques d'un inhibiteur du facteur xa
EP1273575B1 (fr) Derives de diazepane ou sels desdits composes
US6545054B1 (en) Alkenyl and alkynyl compounds as inhibitors of factor Xa
CN100509799C (zh) 一种合成非手性，非肽类的抗凝血酶抑制剂的方法
EP0804431B9 (fr) ANTAGONISTES DE LA GLYCOPROTEINE IIb/IIIa
EP1633718A2 (fr) Compositions et procedes d'inhibition du facteur de croissance transformant beta (tgf-$g(b))
EP1332131A2 (fr) Derives d'acide utiles comme inhibiteurs de serines proteases
EP0822934A1 (fr) Derives d'amidinotetrahydropyridylalanine presentant une activite antithrombotique
AU2002231235A1 (en) Acid derivatives useful as serine protease inhibitors
US6903227B2 (en) Synthesis of 2-acyl substituted chromanes and intermediates thereof
JP2002514578A (ja) ２−フタルイミジノグルタル酸の類似体および血管新生の阻害剤としてのそれらの使用
WO2005030706A1 (fr) Derive carboxamide du type amide
US6756403B2 (en) Methods for producing chiral chromones, chromanes, amino substituted chromanes and intermediates therefor
WO2001094333A2 (fr) Procedes de couplage de composes de benzoyle et de derives bicycliques amino substitues, et compositions enantiomeriquement pures ou enrichies en etant faites
WO2001094334A1 (fr) Methodes de separation de chromanes chiraux (2s) et (2r)
US20040014994A1 (en) Method for resolving chiral (2s) and (2r) chromanes
CN117164566B (zh) 一种氧代哒嗪类化合物及其制备方法和用途
CN117164565B (zh) 一种氧代嘧啶类化合物及其制备方法和用途
CN117164564B (zh) 氧代哒嗪类化合物及其制备方法和用途
CN117164563B (zh) 氧代嘧啶类化合物及其制备方法和用途
WO2001092249A2 (fr) Synthese chirale et achirale de chromanes substitues par 2-acyle et leurs derives
JPH05507932A (ja) イミダゾピリジンｐａｆ拮抗薬
US20040225137A1 (en) Methods for producing amino substituted chromanes and intermediates thereof
US20040044225A1 (en) Chiral and achiral synthesis of 2-acyl substituted chromanes and their derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021219

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20031002

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040213