WO2013151719A2 - Dérivés oxazolidinone fluorés - Google Patents

Dérivés oxazolidinone fluorés Download PDF

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Publication number
WO2013151719A2
WO2013151719A2 PCT/US2013/031405 US2013031405W WO2013151719A2 WO 2013151719 A2 WO2013151719 A2 WO 2013151719A2 US 2013031405 W US2013031405 W US 2013031405W WO 2013151719 A2 WO2013151719 A2 WO 2013151719A2
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Prior art keywords
compound
chf
ocf
ochf
och
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PCT/US2013/031405
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WO2013151719A3 (fr
Inventor
Mark E. Duggan
Takeru Furuya
D. Scott Edwards
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Scifluor Life Sciences, Llc
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Publication of WO2013151719A2 publication Critical patent/WO2013151719A2/fr
Publication of WO2013151719A3 publication Critical patent/WO2013151719A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents

Definitions

  • Thromboembolic disorders are a group of disorders characterized by inflammation of the veins and formation of blood clots (thrombus). The disorders develop as a result of changes in the venous blood flow (it becomes sluggish) due to infection, damage, or increased coagulability (blood clotting) of the blood. Thromboembolic disease can be a serious complication of surgery. Rivaroxaban, also known as (S)-5-chloro-N- ⁇ [2-oxo-3-[4- (3 -oxomorpholin-4-yl)
  • phenyl]oxazolidin-5-yl]methyl ⁇ thiophene-2-carboxamide is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto®. In the United States, it is marketed by Janssen Pharmaceutica. It is an orally active direct factor Xa inhibitor.
  • U.S. Patent Nos. 7,157,456; 7,592,339; and 7,585,860 describe rivaroxaban and its use.
  • a compound of the invention refers to a compound(s) disclosed herein e.g., a compound(s) of the invention includes a compound(s) of any of the formulae described herein including formulae I, II, III, IV, V, VI, VII, VIII, ⁇ , X, XI, or XII and/or a compound(s) explicitly disclosed herein.
  • a compound(s) of the invention includes a compound(s) of any of the formulae described herein including formulae I, II, III, IV, V, VI, VII, VIII, ⁇ , X, XI, or XII and/or a compound(s) explicitly disclosed herein.
  • pharmaceutical or “pharmaceutically acceptable” when used herein as an adjective, means substantially non- toxic and substantially non-deleterious to the recipient.
  • pharmaceutical formulation it is further meant that the carrier, solvent, excipient(s) and salt must be compatible with the active ingredient of the formulation (e.g. a compound of the invention). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
  • Some of the compounds of the present invention may exist in unsolvated as well as solvated forms such as, for example, hydrates.
  • Solvate means a solvent addition form that contains either a stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 0, such combination being able to form one or more hydrate. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges.
  • Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state.
  • Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of salts of the compounds of the invention
  • the compounds described herein can have asymmetric centers.
  • salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid
  • organic carboxylic or sulphonic acids such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
  • salts with customary bases such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
  • any variable e.g. , X
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • X at each occurrence is selected independently from the definition of X.
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds within a designated atom' s normal valency.
  • treat is meant decreasing the symptoms, markers, and/or any negative effects of a condition in any appreciable degree in a patient who currently has the condition.
  • treatment may be administered to a subject who exhibits only early signs of the condition for the purpose of decreasing the risk of developing the disease, disorder, and/or condition.
  • prevention refers to any method to partially or completely prevent or delay the onset of one or more symptoms or features of a disease, disorder, and/or condition. Prevention may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • subject means a human or animal (in the case of an animal, more typically a mammal). In one aspect, the subject is a human.
  • a fluorinated derivative is a derivative compound that the same chemical structure as the original compound, except that at least one atom is replaced with a fluorine atom or with a group of atoms containing at least one fluorine atom.
  • the problem to be solved by the present invention is the identification of novel compounds for the treatment and/or prevention of diseases or disorders that are influenced by positively inhibiting factor Xa e.g., thromboembolic disorders.
  • drugs for thromboembolic disorders are available, these anti-coagulant drugs are often not suitable for patients for a variety of reasons. Many of the available anti-coagulant drugs are associated with bleeding complications.
  • side effects of the anti-coagulant rivaroxaban include coughing up blood, nosebleeds, unusual weakness and blood in the urine. Additional adverse effects of rivaroxaban include back pain, itching, and headaches. Patients on rivaroxaban also have been known to have elevated liver enzymes, elevated bilirubin levels, and low blood platelets.
  • the present invention provides the solution of new fluorinated oxazolidinone derivatives for the treatment and/or prevention of diseases and disorders.
  • the fluorinated compounds described herein have the advantage of providing improved potency, selectivity, tissue penetration, half-life, and/or metabolic stability.
  • the present invention relates to novel fluorinated oxazolidinone derivatives and their use.
  • the present invention relates the synthesis of fluorinated oxazolidinone derivatives.
  • one or more hydrogen atoms are replaced with F or a group of atoms selected from CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F;
  • one or more hydrogen atoms are replaced with F or a group of atoms selected from CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F;
  • one or more hydrogen atoms are replaced with a group of atoms selected from CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F;
  • one or more hydrogen atoms are replaced with a group of atoms selected from CF 3 , CHF 2 , and CH 2 F;
  • one or more hydrogen atoms are replaced with a group of atoms selected from OCF 3 , OCHF 2 , and OCH 2 F;
  • chlorine atom is replaced with F or a group of atoms selected from CF 3 , CHF 2 ,
  • the chlorine atom is replaced with a group of atoms selected from CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F;
  • the chlorine atom is replaced with a group of atoms selected from CF 3 , CHF 2 , and CH 2 F;
  • the chlorine atom is replaced with a group of atoms selected from OCF 3 , OCHF 2 , and OCH 2 F;
  • one heteroatom is replaced with a group of atoms selected from CF 2 , CHF, CH(CF 3 ), CH(OCF 3 ), CH(OCHF 2 ),and CH(OCH 2 F);
  • the heteroatom is an oxygen atom and said oxygen atom is replaced with a group of atoms selected from CF 2 , CHF, CH(CF 3 ), CH(OCF 3 ), CH(OCHF 2 ), and CH(OCH 2 F);
  • u) the oxygen atom of the morpholinone ring is replaced with a group of atoms selected from CF 2 , CHF, CH(CF 3 ), CH(OCF 3 ), CH(OCHF 2 ), and CH(OCH 2 F);
  • the oxygen atom of the morpholinone ring is replaced with a group of atoms selected from CF 2 , CHF, and CH(CF 3 );
  • the oxygen atom of the morpholinone ring is replaced with a group of atoms selected from CH(OCF 3 ), CH(OCHF 2 ), and CH(OCH 2 F);
  • T is F
  • T is CF 3 ;
  • T is CHF 2 ;
  • T is CH 2 F
  • T is OCF 3 ;
  • T is OCHF 2 ;
  • T is OCH 2 F
  • X is F
  • X is F and W is O;
  • X is F, W is O, and n is 1;
  • n 2 and one X is F and the remaining X is H, and W is O.
  • n 0 and W is CF 2 ;
  • n 0 and W is CHF.
  • a-15 the combination of any one of classes a-1, a-2, a-3, a-4, a-5, a-6, or a-7 with classes a-8, a-9, a-10, a-11, a- 12, a-13, or a- 14.
  • the invention provides a compound of formula V:
  • X is F, W is O, and n is 1;
  • n 2, each X is F, and W is O;
  • n 2 X is F and the remaining X is H, and W is O;
  • n 0 and W is CF 2 ;
  • n 0 and W is CHF.
  • the compounds is a pharmaceutically acceptable salt
  • each X 1 and X 2 is independently selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 ,and OCH 2 F; and W is selected from O, CF 2 , CHF, CH(CF 3 ), CH(OCF 3 ), CH(OCHF 2 ), and CH(OCH 2 F), provided that when W is O, then X 1 and X 2 are not both H.
  • the invention provides a compound of formula VIII:
  • each X 1 and X 2 is independently selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F; and W is selected from O, CF 2 , CHF, CH(CF 3 ),
  • X 1 and X 2 is independently selected from H, F, CF 3 , CHF 2 , and CH 2 F, provided that X 1 and X 2 are not both H;
  • c-5 W is CF 2 ;
  • the invention provides a compound of formula IX: (IX) or a pharmaceutically acceptable salt or solvate thereof, wherein each X 1 and X 2 is independently selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F, provided that X 1 and X 2 are not both H.
  • each X 1 and X 2 is independently selected from H, F, CF 3 , CHF 2 , and CH 2 F, provided that X 1 and X 2 are not both H;
  • the compounds is a pharmaceutically acceptable salt
  • each W 1 and W 2 are selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F.
  • each W 1 and W 2 is independently selected from H, F, CF 3 , CHF 2 , and CH 2 F;
  • W 1 and W 2 are both F; and e-5) each W 1 and W 2 is independently selected from H, OCF 3 , OCHF 2 , and OCH 2 F.
  • the compounds is a pharmaceutically acceptable salt
  • T is selected from F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , and OCH 2 F.
  • T is F
  • T is CF 3 ;
  • T is CH 2 F
  • T is CHF 2 ;
  • T is OCF 3 ;
  • T is OCHF 2 ;
  • T is OCH 2 F.
  • T is CF 3 , CHF 2 , or CH 2 F;
  • T is F or CF 3 ;
  • T is OCF 3 , OCHF 2 , or OCH 2 F
  • the compound is the free base; f-12) the compounds is a pharmaceutically acceptable salt;
  • the compound is a hydrate.
  • the invention provides compound 1, 2, or 3. In one aspect, the invention provides a pharmaceutically acceptable salt of compound 1, 2, or 3. In one aspect, the invention provides a solvate of compound 1, 2, or 3. In one aspect, the invention provides a hydrate of compound 1, 2, or 3.
  • the present invention relates to pharmaceutical compositions comprising one of the compounds of the invention as an active ingredient.
  • the invention provides a pharmaceutical composition comprising at least one compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, or XII or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier or excipients.
  • the invention provides a pharmaceutical composition comprising compound 1, 2, or 3 or a
  • the present invention also comprehends deuterium labeled compounds, which are identical to those recited in formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, or XII but for the fact that one or more hydrogen atoms is replaced by a deuterium atom having an abundance of deuterium at that position that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • a compound of the invention has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium
  • a compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the invention.
  • substitution with heavier deuterium i.e., 3 ⁇ 4, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the present invention relates to a method of synthesizing a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of the invention can be synthesized using a variety of methods known in the art.
  • the schemes and description below depict general routes for the preparation of a compound of the invention.
  • Scheme 1 outlines a retrosynthetic analysis for preparing compounds of the invention.
  • a B The retrosynthesis is directed to compounds of formula III. It is understood that formulae IV, VI, VII, VIII, IX, X, XI, and XII are subsets of formula III. Thus, preparations described for a compound of formula III can also be applied for the preparation of a compound of formulae IV, VI, VII, VIII, IX, X, XI, and XII.
  • the retrosynthesis in Scheme 1 depicts two possible routes to compounds of formula III.
  • Scheme 2 shows the preparation of Compound A.
  • Compound D is coupled to Compound E.
  • Compounds D and E can be coupled via a palladium coupling reaction between the secondary amine of Compound D and the group Y on Compound E.
  • Y is e.g., a halogen.
  • Step 1 after the coupling reaction, the position adjacent to the nitrogen atom is oxidized to form a carbonyl to produce Compound F.
  • the oxidation step can be carried out using ruthenium oxide and sodium iodate.
  • the nitro group of Compound F is reduced to produce Compound A.
  • the Step 2 reduction can be carried out using palladium catalyzed hydrogenation conditions.
  • Scheme 3 shows the preparation of Compound B.
  • Compound G is coupled to Compound H.
  • the amine of Compound G can be coupled to the carboxylic acid of Compound H using HATU and iPr 2 NEt in DMF.
  • Step 3 after the coupling reaction, the primary hydroxyl group is converted to a leaving group (LG) to form Compound B.
  • LG leaving group
  • leaving group formation can be carried out using HBr, Ac 2 0 in MeOH and AcOH.
  • Scheme 4 shows the final step for the preparation of a compound of formula III.
  • the nucleophilic primary amine of Compound A displaces the leaving group on Compound B.
  • leaving group displacement can be carried out using 2,4,6- collidine, EtOH, Nal in toluene.
  • the oxazolidine group is formed to produce a compound of formula III.
  • the oxazolidinone group can be formed using CDI.
  • Compounds A-l and B-l are coupled.
  • Compounds A-l and B-l are coupled in pyridine.
  • Compounds A-l and B-l are commercially available compounds.
  • Deuterium labeled compounds can be prepared using any of a variety of art- recognized techniques.
  • deuterium labeled compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, or XII of this invention can generally be prepared by carrying out the procedures described above and/or in the Examples described herein, by substituting a readily available deuterium labeled reagent for a non-deuterium labeled reagent.
  • the present invention relates to methods for the use of compounds of the invention.
  • the compounds of the invention have a useful pharmacological activity spectrum and are therefore particularly suitable for the prophylaxis and/or treatment of disorders.
  • compounds of the invention act in particular as anticoagulants and can therefore be employed in medicaments for the prophylaxis and/or therapy of thromboembolic disorders.
  • thromboembolic disorders include, in particular, serious disorders such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusion disorders, pulmonary embolisms or deep venous thromboses.
  • compounds of invention are suitable for treating disseminated intravascular coagulation (DIC).
  • compounds of the invention are also suitable for the prophylaxis and/or treatment of atherosclerosis and arthritis, and additionally also for the prophylaxis and/or treatment of Alzheimer's disease and cancer.
  • compounds of the invention act in particular as selective inhibitors of the blood coagulation factor Xa and do not inhibit, or only inhibit at considerably higher concentrations, other serine proteases as well, such as thrombin, plasmin or trypsin.
  • inhibitors of the blood coagulation factor Xa in which the IC 50 values for the factor Xa inhibition are lower by a factor of 100, preferably by a factor of 500, in particular by a factor of 1000, than the IC 50 values for the inhibition of other serine proteases, in particular thrombin, plasmin and trypsin, are referred to as being "selective.”
  • compounds of the invention can furthermore be used for preventing coagulation ex vivo, for example for banked blood or biological samples which contain factor Xa.
  • the invention provides medicaments and pharmaceutical compositions comprising at least one compound of the invention together with one or more
  • compositions can be used for the indications mentioned above.
  • the invention provides a method for the prophylaxis and/or treatment of disorders of the human or animal body, in particular of the abovementioned disorders, using the compounds of the invention.
  • the invention provides a method for preventing blood coagulation in vitro, in particular in banked blood or biological samples which contain factor Xa, which method is characterized in that compounds of the invention.
  • the invention provides a method of treating or preventing a thromboembolic disorder in a subject comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for preventing thromboembolism in a subject comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the method prevents venous thromboembolism.
  • the method prevents pulmonary embolism.
  • the method prevents deep vein thrombosis.
  • the invention provides a method of preventing a disorder due to thrombus formation selected from the group consisting of myocardial infact, unstable angina, stroke, transitory ischaemic attacks, peripheral anterial occlusive disorders, pulmonary embolisms and deep vein thromboses in a subject comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the disorder is stroke.
  • the disorder is myocardial infarct.
  • the disorder is unstable angina.
  • the disorder is peripheral arterial occlusive disorder.
  • the disorder is pulmonary embolism.
  • the disorder is deep venous thrombosis.
  • the invention provides a method of treating a disorder selected from the group consisting of myocardial infarct, unstable angina, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms, and deep venous thromboses in a subject comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the method treats pulmonary embolism.
  • the method treats deep vein thrombosis.
  • the method treats myocardial infarct.
  • the method treats stroke.
  • the invention provides a method of treating or preventing disorders, wherein the disorders are influenced positively by inhibition of factor Xa in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method of treating disseminated intravascular coagulation (DIC) in a subject, comprising administering to the subject in need thereof an effective amount of any compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • DIC disseminated intravascular coagulation
  • the invention provides a method of treating or preventing disorders such as atherosclerosis, arthritis, Alzheimer's disease or cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the disorder is atherosclerosis.
  • the invention provides method for preventing the coagulation of blood in vitro, in particular in the case of banked blood or biological samples containing factor Xa, characterized in that a compound of the invention is added.
  • the invention provides a method for inhibiting thrombus formation in a subject comprising administering to the subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the subject has a throembolism.
  • the thromboembolism is a venous thromboembolism.
  • the veneous thromboembolism comprises pulmonary embolism.
  • the veneous thromboembolism comprises deep vein thrombosis.
  • the invention provides a medical device containing a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the device is a stent.
  • All customary administration forms are suitable for administration of the compounds according to the invention. Administration is preferably carried out orally, lingually, sublingually, buccally, rectally or parenterally (i.e. bypassing the intestinal tract, that is intravenously, intraarterially, intracardially, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly).
  • oral and intravenous administration are suitable.
  • oral administration is suitable.
  • the compounds of the invention can be converted in a known manner into the customary formulations, such as tablets, sugar-coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of from about 0.1 to 95% by weight, preferably from 0.5 to 90% by weight, in particular from 1 to 85% by weight, of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
  • the formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it being possible, for example if the diluent used is water, optionally to use organic solvents as auxiliary solvents.
  • intravenous administration amounts from approximately 0.001 to 10 mg/kg, preferably approximately 0.01 to 10 mg/kg, in particular approximately 0.1 to 8 mg/kg, of body weight to achieve effective results.
  • oral administration amounts from approximately 0.01 to 50 mg/kg, preferably approximately 0.1 to 10 mg/kg, in particular approximately 0.5 to 8 mg/kg, of body weight to achieve effective results.
  • the compounds of the invention are distinguished in particular by the fact that a greater therapeutic range is achieved by the selective inhibition of factor Xa. For the patient, this means a lower risk of bleeding, and for the treating physician, this means that the patient is easier to adjust. Moreover— owing to the mechanism— the onset of action is more rapid.
  • Example 4 Testing for anti-coagulation activity
  • the compounds of the present invention were tested for anti-coagulation activity in whole human blood by measuring prothrombin time (PT) and activated partial
  • thromboplastin time as follows.
  • Syringes were prepared with 2mL of trisodium citrate (3.8%, w/v). Blood was collected into the syringes to a final volume of 20mL. Samples were centrifuged at 3000rpm for 15 minutes. The plasma samples were then transferred to appropriately labeled tubes.
  • test items were diluted to a concentration of 30 mM with DMSO for the first experiment. They were then stored at -20°C in the dark. During the second experiment, the test items were thawed and then further diluted to obtain final concentrations of 3 ⁇ , 1 ⁇ , 0.3 ⁇ and 0.1 ⁇ in plasma and 1% (w/v) DMSO.
  • Samples were incubated for 10 minutes at 37 C and then assayed for PT and APTT using the Instrumentation Laboratory ACL Advance Coagulometer. The samples were analyzed in triplicate. Quality control material was run throughout the analysis and all values obtained were within the laboratory criteria.
  • the mean CT2 obtained for PT was 1.97 ⁇ with SD of 0.37 ⁇ .
  • the CT2 obtained for APTT was 5.37 ⁇ with SD of 0.62 ⁇ .
  • the mean CT2 obtained for PT was 7.75 ⁇ with SD of 1.79 ⁇ .
  • the mean CT2 obtained for APTT was 17.26 ⁇ with SD of 2.84 ⁇ .
  • the mean CT2 obtained for PT was 0.90 ⁇ with SD of 0.06 ⁇ .
  • the mean CT2 obtained for APTT was 2.70 ⁇ with SD of 0.20 ⁇ .

Abstract

La présente invention concerne des composés fluorés et leur utilisation dans le domaine de la coagulation du sang. L'invention concerne plus particulièrement de nouveaux dérivés oxazolidinone fluorés du rivaroxaban et leurs sels ou solvates pharmaceutiquement acceptables ainsi que leur utilisation en tant que composés actifs du point de vue médicinal dans le traitement et la prévention de divers troubles.
PCT/US2013/031405 2012-04-05 2013-03-14 Dérivés oxazolidinone fluorés WO2013151719A2 (fr)

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US201261620623P 2012-04-05 2012-04-05
US61/620,623 2012-04-05
US201261697695P 2012-09-06 2012-09-06
US61/697,695 2012-09-06

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Cited By (1)

* Cited by examiner, † Cited by third party
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US11154558B2 (en) * 2016-04-15 2021-10-26 Adams Pharmaceuticals LLC Prevention of atherosclerotic events with direct factor Xa inhibitors

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