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WO2007008144A1 - Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa - Google Patents

Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa Download PDF

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Publication number
WO2007008144A1
WO2007008144A1 PCT/SE2006/000838 SE2006000838W WO2007008144A1 WO 2007008144 A1 WO2007008144 A1 WO 2007008144A1 SE 2006000838 W SE2006000838 W SE 2006000838W WO 2007008144 A1 WO2007008144 A1 WO 2007008144A1
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methyl
formula
oxo
chloro
compound
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PCT/SE2006/000838
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English (en)
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Emma Bratt
Kenneth Granberg
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Astrazeneca Ab
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Publication of WO2007008144A1 publication Critical patent/WO2007008144A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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

Definitions

  • the invention relates to novel heterocyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals.
  • the invention also relates to processes for the preparation of the heterocyclic derivatives, to their use, to pharmaceutical compositions comprising them, to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect, and to combinations comprising them.
  • Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation.
  • the protease known, as thrombin is the final protease in the cascade and Factor Xa is the preceding protease, which cleaves prothrombin to generate thrombin.
  • the compounds of the present invention possess activity useful in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebrovascular disease.
  • medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the rupture of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or on the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischemia and angina (including unstable angina).
  • the compounds of the invention are also useful as inhibitors of blood coagulation in an ex vivo situation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor
  • WO 98/21188 describes a range of Factor Xa inhibitors. Further particular examples of this type of compound including l-(5-chloroindol-2-ylsulphonyl)-4-[4-(6-oxo-lH- pyridazin-3-yl) benzoyl]piperazine are described in WO 99/57113. The applicants have found however, that by further derivatising the compounds of this type, enhanced properties may be obtained.
  • the present invention provides a compound of formula (I)
  • R 1 is hydrogen, C 1-3 alkyl, R 5 R 6 aminoCi- 5 alkyl, where R 5 and R 6 are each independently selected from hydrogen and C ⁇ alkyl, or
  • R 5 and R 6 may, together with the nitrogen to which they are attached, form a five- or six- membered heterocyclic ring, where said heterocyclic ring has 0 or 1 additional heteroatom;
  • R 3 is an indolyl
  • R 4 a hydrogen or a halogen; or a pharmaceutically acceptable salt thereof.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl” are specific for the straight chain version only. An analogous convention applies to other generic terms.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention encompasses any such optically active or racemic form which possesses Factor Xa inhibitory activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • tautomer or “tautomerism” refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, i.e. different tautomeric forms.
  • An example may be keto-enol tautomers.
  • the invention encompasses any such tautomeric forms which possesses Factor Xa inhibitory activity.
  • Compounds of the invention are potent inhibitors of Factor Xa, and may have improved selectivity over oxido squalene cyclase, better solubility and/or less cytochrome P 450 (CYP 45 o) inhibition and/or Caco2-permeability than some related compounds.
  • Caco2 is a cell line which mimics transport over the gut wall.
  • halogen fluoro, chloro, bromo, iodo
  • C 1-3 alkyl methyl, ethyl, propyl, isopropyl
  • C 1-4 alkyl methyl, ethyl, propyl, isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl
  • C 1-5 alkyl C 1-4 alkyl (as above), C h alky!
  • n- butyl isobutyl, pentyl, 2-pentyl, 3-pentyl, 2- methyl-1 -butyl, isopentyl, neopentyl, 3- methyl-2-butyI, 2-methyl-2-butyl.
  • a further embodiment of the invention discloses a compound of formula (I) wherein R 1 is C 1-3 alkyl, e.g. propyl, ethyl or methyl.
  • a compound of formula (I) wherein R 1 is R 5 R 6 aminoC 1 . 3 alkyl, where R 5 and R 6 are each independently selected from hydrogen and Ci -3 alkyl, e.g. propyl, ethyl or methyl, or R 5 and R 6 may, together with the nitrogen to which they are attached, form a six-membered heterocyclic ring, where said heterocyclic ring has 1 additional hetero oxygen.
  • R 1 is R 5 R 6 aminoC 1 . 3 alkyl, where R 5 and R 6 are each independently selected from hydrogen and Ci -3 alkyl, e.g. propyl, ethyl or methyl, or R 5 and R 6 may, together with the nitrogen to which they are attached, form a six-membered heterocyclic ring, where said heterocyclic ring has 1 additional hetero oxygen.
  • a further embodiment of the invention discloses a compound of formula (I) wherein one of
  • R is oxo
  • a further embodiment of the invention discloses a compound of formula (I) wherein R 3 is 2-indolyl or 6-indolyl.
  • a further embodiment of the invention discloses a compound of formula (I) which is 6- ⁇ 4-[S)-4-(3-chloro-lH-indole-6-sulfonyl)-2-methyl-6-sulfonyl)
  • a heterocyclic derivative of formula I, or pharmaceutically acceptable salt thereof may be prepared by any process known to be applicable to the preparation of related compounds, such as those described in WO 98/21188 and WO 99/57113. Such procedures are provided as a further feature of the invention and are illustrated by the following representative processes in which, unless otherwise stated any functional group, for example amino, aminoalkyl, carboxy, indolyl or hydroxy, is optionally protected by a protecting group which may be removed when necessary.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry and by reference to the processes used in the Examples.
  • the present invention provides a process for preparing a compound of formula (T) or a pharmaceutically acceptable salt thereof, which comprises the intramolecular reaction of an amino acid of formula (II), wherein the possible positioning of (R 2 ) n-1 corresponds to the possible positions of the corresponding (R 2 ) n- i in the - compound of formula (I), or a salt thereof, in the presence of a suitable base and a acid activating agent such as a carbodiimide.
  • a compound of formula (I) may be prepared by reaction of a compound of the formula (IH),
  • R 1 is as defined in relation to formula (I) and A is an activating group.
  • Suitable activating groups A include metalised derivatives, such as with zinc or tin, and borane derivatives.
  • the compound of formula (IV) is reacted with a compound of the formula (IH) to effect cross coupling where Z is triflate or a halo group, such as iodo, bromo or chloro.
  • a transition state metal catalyst such as palladium, for example Pd(PPh 3 ) 4 .
  • (V) may be prepared by reaction of a compound of the formula (VI),
  • X may be a halogen which is conveniently hydrolysed under mildly acidic conditions at - 50 °C - 200 0 C, or an alkoxy group which may be dealkylated using standard conditions found in the literature to give compounds of formula (V).
  • compounds of formula (I) are prepared by reaction a sulfonyl chloride derivative of formula (VII),
  • This reaction is carried out using a base such as iV,iV-dimethyl aminopyridine, diisopropylethyl amine in inert solvents, typically dichloromethane and N,N- dimethylformamide at a temperature in the range -50 0 C - IOO 0 C, conveniently at or near ambient temperature.
  • a base such as iV,iV-dimethyl aminopyridine, diisopropylethyl amine in inert solvents, typically dichloromethane and N,N- dimethylformamide
  • an optically active form of a compound of the formula (I) When an optically active form of a compound of the formula (I) is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure, for example by the formation of diastereomeric salts, use of chromatographic techniques, conversion using stereospecific enzymatic processes, or by addition of temporary extra chiral group to aid separation.
  • the invention also relates to a process for preparing a compound of formula (I) which process comprises either
  • A is an activating group
  • the compounds of the formula (I) are inhibitors of the enzyme
  • the FXa inhibitor potency was measured with a chromogenic substrate method, in a Plato 3300 robotic microplate processor (Rosys AG, CH-8634 Hombrechtikon, Switzerland), using 96-well, half-volume microtiter plates (Costar, Cambridge, MA, USA; Cat No 3690).
  • Stock solutions of test substance in DMSO (72 ⁇ L), 10 mmol/L, alternatively 1 mmol/L were diluted serially 1:3 (24 + 48 ⁇ L) with DMSO to obtain ten different concentrations, which were analyzed as samples in the assay, together with controls and blanks. As control sample melagatran was analysed.
  • test sample or DMSO for the blank were added, followed by 124 ⁇ L of assay buffer (0.05 mol/L Tris-hydrochloric acid pH 7.4 at 37 0 C, 5 mM CaCl 2 , ionic strength 0.15 adjusted with NaCl, 0.1 % bovine serum albumin, ICN Biomedicals, Inc, USA, lg/L) and 12 ⁇ L of chromogenic substrate solution (S-2765, Chromogenix, Molndal, Sweden) and finally 12 ⁇ L of FXa solution (human FXa, Haematologic Technologies Inc., Essec Junction, Vermont, USA), in buffer, was added, and the samples were mixed.
  • assay buffer 0.05 mol/L Tris-hydrochloric acid pH 7.4 at 37 0 C, 5 mM CaCl 2 , ionic strength 0.15 adjusted with NaCl, 0.1 % bovine serum albumin, ICN Biomedicals, Inc, USA, lg/L
  • chromogenic substrate solution S
  • K M 0.25 mmol/L
  • FXa 0.1 nmol/L The linear absorbance increase at 405 nm during 40 min incubation at 37 °C was used for calculation of percent inhibition for the test samples, as compared to references without inhibitor and/ or enzyme.
  • thrombin inhibitor potency was measured with a chromogenic substrate method developed in-house in principle as described in a) for FXa but using instead 0.3 mM of the chromogenic substrate solution S-2366 (Chromogenix., Molndal, Sweden) and 0.1 nmol/L human thrombin (Haematologic Technologies Inc., Essec Junction, Vermont, USA).
  • S-2366 Chromatologic Technologies Inc., Essec Junction, Vermont, USA.
  • Anticoagulant Activity An in vitro assay whereby human blood is collected and added directly to a sodium citrate solution (3.2 g/100 mL, 9 parts blood to 1 part citrate solution).
  • Plasma is prepared by centrifugation (1000 g, 15 minutes) and stored at -80 0 C.) and an aliquot was rapidly thawed at 37 °C on the day of the experiment and kept on ice before addition to the coagulometer cups.
  • Conventional prothrombin time (PT) tests are carried out in the presence of various concentrations of a test compound and the concentration of test compound required to double the clotting time is determined.
  • Thromborel ® S (Dade Behring, Liederbach, Germany) was reconstituted with 10 mL water. This solution was kept at 4 0 C and was used within one week. Before the experiment the solution was kept at 37 0 C for at least 30 minutes before start of the experiment.
  • the IC 50 is calculated from the curve of PTj/PT o versus the inhibitor concentration in plasma, id est three times the final assay concentration. d) An in vivo Measurement of Antithrombotic Activity
  • the abdoman is opened and the caval vein exposed.
  • the thrombotic stimulus is partial stasis to the caval vein and a piece of filter paper soaked with ferric chloride and superimposed to the external surface of the vein.
  • Thrombus size is determined as the thrombus wet weight at the end of the experiment. (Ref Thromb. Res. 2002;107:163-168).
  • a) Measurement of Factor Xa Inhibition the compounds of the Examples gave IC 50 values for inhibition of Factor Xa activity of less than 10 ⁇ M, indicating that the compounds of the invention are expected to possess useful therapeutic properties.
  • a feature of the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is a compound of the formula (I), or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • the invention also includes the use of such an active ingredient (i.e. a compound of the formula (I), or a pharmaceutically-acceptable salt thereof) in the production of a medicament for use in:-
  • an active ingredient i.e. a compound of the formula (I), or a pharmaceutically-acceptable salt thereof
  • the invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined hereinbefore.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula (I) will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine.
  • compounds of the formula (I) are useful in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated.
  • a compound of the formula (I) for such a purpose it will generally be administered so that a daily oral dose in the range, for example, 0.5 to 100 mg/kg body weight/day is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed, for example a dose for intravenous administration in the range, for example, 0.01 to 10 mg/kg body weight/day will generally be used.
  • lower doses will be employed, for example a daily dose in the range, for example, 0.1 to 10 mg/kg body weight/day.
  • a preferred dose range for either oral or parenteral administration would be 0.01 to 10 mg/kg body weight/day.
  • the compounds of formula (I) are primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including man, they are also useful whenever it is required to produce an anticoagulant, effect, for example during the ex vivo storage of whole blood or in the development of biological tests for compounds having anticoagulant properties.
  • the compounds of the invention may be administered as a sole therapy or they may be administered in conjunction with other pharmacologically active agents such as a thrombolytic agent, for example tissue plasminogen activator or derivatives thereof or streptokinase.
  • a thrombolytic agent for example tissue plasminogen activator or derivatives thereof or streptokinase.
  • the compounds of the invention may also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent or a known anti-hypertensive agent.
  • the compounds of the invention may also be combined and/or co-administered with any antithrombotic agent(s) with a different mechanism of action, such as one or more of the following: the anticoagulants unfractionated heparin, low molecular weight heparin, other heparin derivatives, synthetic heparin derivatives (e.g. fondaparinux), vitamin K antagonists, synthetic or biotechnological inhibitors of other coagulation factors than FXa (e.g.
  • thrombin synthetic thrombin, FVIIa, FXIa and FIXa inhibitors, and rNAPc2
  • the antiplatelet agents acetyls alicylic acid, ticlopidine and clopidogrel; thromboxane receptor and/or synthetase inhibitors; fibrinogen receptor antagonists; prostacyclin mimetics; phosphodiesterase inhibitors; ADP-receptor (P2X1 , P2Y1 , P2Y12 [P2T]) antagonists; and inhibitors of carboxypeptidase U (CPU or TAFIa) and inhibitors of plasminogen activator inhibitor-1 (PAI-I).
  • the compounds of the invention may further be combined and/or co-administered with thrombolytics such as one or more of tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), animal salivary gland plasminogen activators, and the like,. in the treatment of thrombotic diseases, in particular myocardial infarction.
  • tissue plasminogen activator naturally, recombinant or modified
  • streptokinase urokinase
  • prourokinase prourokinase
  • anisoylated plasminogen-streptokinase activator complex APSAC
  • animal salivary gland plasminogen activators and the like
  • the invention further relates to a combination comprising a compound of formula (I) and any antithrombotic agent(s) with a different mechanism of action.
  • Said antithrombotic agent(s) may be, for example, one or more of the following: the anticoagulants unfractionated heparin, low molecular weight heparin, other heparin derivatives, synthetic heparin derivatives (e.g. fondaparinux), vitamin K antagonists, synthetic or biotechnological inhibitors of other coagulation factors than FXa (e.g.
  • thrombin synthetic thrombin, FVIIa, FXIa and FIXa inhibitors, and rNAPc2
  • the antiplatelet agents acetylsalicylic acid, ticlopidine and clopidogrel; thromboxane receptor and/or synthetase inhibitors; fibrinogen receptor antagonists; prostacyclin mimetics; phosphodiesterase inhibitors; ADP-receptor (P2X1, P2Y1, P2Y12 [P2T]) antagonists; and inhibitors of carboxypeptidase U (CPU or TAFIa) and inhibitors of plasminogen activator inhibitor- 1 (PAI-I).
  • the invention further relates to a combination comprising a compound of formula (I) and thrombolytics, e.g. one or more of tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), animal salivary gland plasminogen activators.
  • tissue plasminogen activator natural, recombinant or modified
  • streptokinase urokinase
  • prourokinase prourokinase
  • anisoylated plasminogen-streptokinase activator complex APSAC
  • animal salivary gland plasminogen activators e.g. one or more of tissue plasminogen activator (natural, recombinant or modified)
  • APSAC anisoylated plasminogen-streptokinas
  • the invention also relates to a combination comprising a compound of formula (I) and thrombolytics, e.g. one or more of tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen- streptokinase activator complex (APSAC), animal salivary gland plasminogen activators, and the like, in the treatment of thrombotic diseases, in particular myocardial infarction.
  • tissue plasminogen activator naturally, recombinant or modified
  • streptokinase urokinase
  • prourokinase prourokinase
  • anisoylated plasminogen- streptokinase activator complex APSAC
  • animal salivary gland plasminogen activators and the like
  • Preparative reversed phase HPLC was performed using a Waters Prep LC 2000 with UV detection equipped with a 25 cm x 2 cm or 30 x 5 cm C8 or C18 columns from Kromasil.
  • Preparative chiral resolution using HPLC was performed using a Gilson 306 with UV detection equipped with either a Ciralpak AS (25 x 2 cm) (ester separations), a Chiralpak AD (25 x 2 cm) (amide separations) or a Chirobiotic R (25 x 2 cm) (carboxylic acid separation) column using 100 % methanol or methanol / acetic acid / triethyl amine 100 / 0.1 / 0.05. All chiral separations were performed at 40 0 C.
  • Triethyl amine was added and the reaction was stirred at room temperature for 1 hour 20 minutes. Water (0.5 mL) was added and the solution was purified by preparative HPLC using a gradient of acetonitrile 15 % acetonitrile-water phase containing 0.1 M ammonium acetate followed by flash chromatography using a gradient of methanol in dichloromethane containing 5 % triethylamine, to give the sub-title compound (176 mg, 56 % yield).
  • step C 6- ⁇ 4-[(S)-4-(l-Benzenesulfonyl-5-chloro-lH-indole-2-sulfonyl)-3-methyl-2-oxo- piperazin-l-ylmethyl]-phenyl ⁇ -2-methyl-2H- ⁇ yridazin-3-one (39 mg, 0.058 mmol) from step C was treated essentially as in example 3 step G to give the title compound (18 mg, 57 % yield).
  • the organic phase was washed two times with water, once with brine, dried (sodium sulfate) and evaporated.
  • the crude product was filtered through a silica column using ethyl acetate / heptane (60 : 40) as eluent.
  • the crude was further purified by preparative HPLC using a gradient of acetonitrile 1 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate to give a mixture of the sub-title compound and the corresponding boronic acid. The mixture was used without further purification (3.48 g).
  • 6-Chloro-2H-pyridazin-3-one (5.34 g, 40.8 mmol), 7.61 g of 4-(2-chloro-ethyl)- o morpholine hydrochloride (40.8 mmol) and 11.3 g of potassium carbonate (81.7 mmol) were added to a solution of 20 niL of acetonitrile, 10 mL of iV,iV-dimethylformamide and 0.5 mL of water.
  • the reaction mixture was heated with an oil bath at 116 0 C for 4 hours until LCMS showed the disappearance of 6-chloro-pyridazin-3-ol and the formation of the alkylated product.
  • hydrochloride salt was formed by adding 20 mL of 4 M aqueous hydrochloride solution and 20 mL of o methanol to the alkylation product until pH 2. The mixture was concentrated to get a solid residue, which was further purified by precipitation in hot ethanol. Finally, 4.23 g (37 %) of the sub-title product as a mono hydrochloride salt was obtained as colourless solids.
  • the vial was evacuated and filled with nitrogen, two times. 1,2-Dimethoxyethane / water / ethanol (3 mL, 7 : 3 : 2) was added and the vial was again evacuated and filled with nitrogen.
  • the reaction was heated at 150 °C for 100 seconds in a microwave oven.
  • the reaction mixture was filtered and purified by preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate, (C8-column) to give 72 mg of the sub-title compound after evaporation and freeze drying (47 % yield).
  • the crude product was further purified with preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile-water phase containing 0.1 M ammonium acetate, C8-column, to give the sub-title product (35 mg, 49 % yield) after evaporation and 0 freeze drying over night.
  • 6-Chloro-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one To a solution of 6-chloro-pyridazin-3-one (500 mg, 3.83 mmol) in 5 mL N,N- dimethylformamide was added 2-dimethylaminoethyl chloride hydrochloride (828 mg, 5.75 mmol), potassium carbonate (1.59 g, 11.5 mmol) and sodium iodide (632 mg, 4.21 mmol). The mixture was stirred over night at 65 0 C. The solvent was evaporated.
  • 1,2-Dimethoxyethane / water / ethanol (4 mL, 7 : 3 : 2) was added and the vial was again evacuated and filled with argon.
  • the reaction was heated at 150 °C for 80 seconds in a microwave oven.
  • the mixture was filtered and purified by preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate (C8-column) as eluent to give 138 mg (yield 79 %) of the desired sub-title compound after evaporation and freeze . drying.
  • the reaction was stirred at room temperature over night.
  • the reaction mixture was washed with 5 % hydrochloric acid and then ethyl acetate and water was added.
  • the organic phase was washed three times with water, once with brine, dried (sodium sulfate) and evaporated.
  • the crude was filtered on a silica column using ethyl acetate as eluent, the crude was further purified by preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate as eluent to give 155 mg (yield 33 %) of the sub-title compound after freeze drying.
  • the product was eluted with methanol and further purified by preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate as eluent to give 122 mg (yield 93 %) of the title product after freeze drying.
  • N-[(5-Chloro-lH-indol-2-yl)sulfonyl]-N-(2- ⁇ [4-(dihydroxyboryl)benzyl]- amino ⁇ ethyl)glycine 100 mg, 0.22 mmol
  • 3,6-dichloropyridazine 39.9 mg, 0.27 mmol
  • caesium carbonate 87 mg, 0.27 mmol
  • bis(triphenylphosphine)palladium(H)chloride (16 mg, 0.020 mmol) was added to a microwave vial.
  • the vial was evacuated and filled with nitrogen, three times.
  • 1,2-Dimethoxyethane / water / ethanol (2.5 mL, 7 : 3 : 2) was added.
  • the vial was again evacuated and filled with nitrogen.
  • the reaction was heated at 150 0 C for 100 seconds in a microwave oven. As the starting material was not consumed a small amount of catalyst was added and the vial was again evacuated. The reaction was heated again at 150 0 C for 100 seconds.
  • the crude was filtrated and purified by preparative HPLC using a gradient of acetonitrile / 5 % acetonitrile in water buffer containing 0.1 M ammonium acetate to give 27 mg of the sub-title product after freeze drying over night (yield 23 %).

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Abstract

L'invention concerne des composés de formule (I) [Formule chimique à insérer ici. Voir copie papier] où R1 est un hydrogène, un alkyle en C1-3, un R5R6amino(alkyle en C1-5), où R5 et R6 sont chacun indépendamment sélectionnés entre un hydrogène et un alkyle en C1-3 ou bien R5 et R6 peuvent, avec l'atome d'azote auquel ils sont attachés, former un hétérocycle à cinq ou six chaînons, ledit hétérocycle ayant 0 ou 1 hétéroatome supplémentaire ; n est 1 ou 2 ; chaque R2 est indépendamment sélectionné entre un hydrogène, un oxo et un alkyle en C1-3 ; R3 est un indolyle ; et R4 est un hydrogène ou un halogène ; ou un sel acceptable du point de vue pharmaceutique de ceux-ci, lesdits composés possédant des propriétés antithrombotiques et anticoagulantes et étant par conséquent utiles dans des procédés de traitement d'êtres humains ou d'animaux. L'invention concerne également des procédés pour la préparation des composés, leur utilisation, des compositions pharmaceutiques les comprenant, leur utilisation dans la fabrication de médicaments destinés à être utilisés dans la production d'un effet antithrombotique ou anticoagulant et des combinaisons les comprenant.
PCT/SE2006/000838 2005-07-08 2006-07-05 Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa WO2007008144A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0501619 2005-07-08
SE0501619-1 2005-07-08

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013188381A1 (fr) * 2012-06-12 2013-12-19 Abbvie Inc. Dérivés de pyridinone et de pyridazinone
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
EP3078378A1 (fr) 2015-04-08 2016-10-12 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057099A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation
WO2001007436A2 (fr) * 1999-07-28 2001-02-01 Aventis Pharmaceuticals Inc. Composes d'oxoazaheterocyclyle substitue
EP1104754A1 (fr) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
WO2002026734A1 (fr) * 2000-09-29 2002-04-04 Cor Therapeutics, Inc. Amides piperazine-2-un comme inhibiteurs du facteur xa
WO2005065688A1 (fr) * 2004-01-08 2005-07-21 Astrazeneca Ab Nouveau derives de 6-4{4-[1h-indole-2-sulphonyl)-piperazin-1-carbonyl-phenyl]}pyradizin-3-one

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation
WO1999057099A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
EP1104754A1 (fr) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
WO2001007436A2 (fr) * 1999-07-28 2001-02-01 Aventis Pharmaceuticals Inc. Composes d'oxoazaheterocyclyle substitue
WO2002026734A1 (fr) * 2000-09-29 2002-04-04 Cor Therapeutics, Inc. Amides piperazine-2-un comme inhibiteurs du facteur xa
WO2005065688A1 (fr) * 2004-01-08 2005-07-21 Astrazeneca Ab Nouveau derives de 6-4{4-[1h-indole-2-sulphonyl)-piperazin-1-carbonyl-phenyl]}pyradizin-3-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIA Z.J. ET AL.: "N,N-Dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines as potent factor Xa inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 2073 - 2078, XP003003221 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
WO2013188381A1 (fr) * 2012-06-12 2013-12-19 Abbvie Inc. Dérivés de pyridinone et de pyridazinone
US9561231B2 (en) 2012-06-12 2017-02-07 Abbvie Inc. Pyridinone and pyridazinone derivatives
EP3078378A1 (fr) 2015-04-08 2016-10-12 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
WO2016162472A1 (fr) 2015-04-08 2016-10-13 Vaiomer Utilisation d'inhibiteurs du facteur xa pour réguler la glycémie
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

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