[go: up one dir, main page]

WO2007008145A1 - 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

Info

Publication number
WO2007008145A1
WO2007008145A1 PCT/SE2006/000839 SE2006000839W WO2007008145A1 WO 2007008145 A1 WO2007008145 A1 WO 2007008145A1 SE 2006000839 W SE2006000839 W SE 2006000839W WO 2007008145 A1 WO2007008145 A1 WO 2007008145A1
Authority
WO
WIPO (PCT)
Prior art keywords
salkyl
formula
compound according
alkyl
hydrogen
Prior art date
Application number
PCT/SE2006/000839
Other languages
English (en)
Inventor
Kosrat Amin
Kenneth Granberg
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2007008145A1 publication Critical patent/WO2007008145A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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.
  • the antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa.
  • 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.
  • Certain heterocyclic derivatives possess Factor Xa inhibitory activity.
  • Many of the compounds of the present invention also possess the advantage of being selective Factor Xa inhibitors, that is the enzyme Factor Xa is inhibited strongly at concentrations of test compound which do not inhibit or which inhibit to a lesser extent the enzyme thrombin which is also a member of the blood coagulation enzymatic cascade.
  • 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.
  • 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).
  • myocardial infarction the rupture of atherosclerotic plaques
  • venous or arterial thrombosis venous or arterial thrombosis
  • coagulation syndromes vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery
  • vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery
  • 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 Xa and in which coagulation is detrimental.
  • 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 , R and R are independently selected from carbon and nitrogen, and where at least one of R 1 , R 2 and R 3 is nitrogen
  • A is a single bond or a double bond; n is 0, 1, 2 or 3; each R 4 is independently selected from hydrogen, Ci. 3 alkyl, hydroxy, oxo and thioxo;
  • R 5 is hydrogen or oxo; m is O, 1, 2 or 3; each R 6 is independently selected from hydrogen, Ci-salkyl, oxo, carboxy, cyano, tetrazolyl, hydroxyQ-salkyl, carboxyQ.salkyl, Q.salkylcarboxy, Q.salkoxyoxod-salkyl, carbamoyl, C 1-5 alkylcarbamoyl, di(C 1-5 alkyl)carbamoyl, -CONR 80 (CH 2 ) x S(O) p R 9 , -CONH(CH 2 ) q NR 10 R ⁇ , -Ci.salkyl-Y 1 , -COOCHR 17 R 18 and -CON R 17 R 18 , wherein x represents an integer 0 to 4; p is 0, 1 or 2; q represents an integer 2 to 4;
  • R 80 represents hydrogen or Q ⁇ alkyl
  • R 9 represents Q-salkyl or phenyl
  • R 80 and R 9 may together form a Q.salkylene group
  • R 10 and R 11 independently represent hydrogen, Q.salkyl, phenyl, C 1-5 alkylphenyl, S(O) P R 9 , COR 12 or a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from nitrogen, oxygen and sulphur;
  • R 12 represents hydrogen, C h alky! or phenyl;
  • Y 1 represents S(O) p R 9 , NHS(O) 2 R 9 , NHCOR 13 , O(CH 2 ) r R 14 , azetidino, pyrrolidin-1- yl, piperidino, morpholino, thiamorpholino, 1-oxothiamorpholino, 1,1-dioxothiamorpholino, piperazin-1-yl or C ⁇ alkylamino,
  • R 13 represents Q.salkyl, phenyl or Q ⁇ alkylphenyl; r represents an integer 1 to 4; when r represents an integer 2 to 4, R 14 represents hydroxy, Q.salkylalkoxy, carboxy, Ci-salkoxycarbonyl, S(O) P R 9 or NR 15 R 16 ; and when r represents 1, R 14 represents carboxy or Ci-salkoxycarbonyl; wherein any phenyl group within R 6 is independently substituted by 0, 1 or 2 substituents selected from halogeno, trifluoromethyl, cyano, Q.salkyl and C 1-S aIkOXy;
  • R 15 and R 16 independently represent hydrogen or Q.salkyl;
  • R 17 and R 18 are independently selected from hydrogen, C 1-6 alkyl, C 4-7 cycloalkyl, C 2-6 alkenyl,
  • R 17 and R 18 may form along with the carbon to which they are attached a 4- ,5- , 6- or 7- membered carbocyclic ring which contains 0, 1 or 2 heteroatoms selected from nitrogen, oxygen and sulphur, or R 17 and R 18 may form along with the nitrogen to which they are attached a 4- ,5- , 6- or 7- membered heterocyclic ring which contain in addition to the nitrogen atom present 0, 1 or 2 additional heteroatoms selected from nitrogen, oxygen 1 *7 1 J?
  • each R , R or any of said rings formed by R and R is independently substituted by 0, 1 or 2 substituents selected from hydroxy, amino, carboxy, C 1-5 alkoxycarbonyl, oxo, Q ⁇ alkyl, hydroxyQ.salkyl, Q.salkoxyQ.salkyl, carboxyCi-salkyl, Ci-salkoxyoxoQ.ealkyl, and carbamoylC 1-5 alkyl; R 7 is carbon or nitrogen; pi is O, 1 or 2; and each R is independently selected from hydrogen and 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.
  • 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 450 ) inhibition and/or Caco2-permeability than some related compounds.
  • Caco2 is a cell line which mimics transport over the gut wall.
  • oxoQ.salkyl C 1-4 alkyl (as above), C 1-3 alkyl (as above), n- butyl, isobutyl, pentyl, 2-pentyl, 3-pentyl, 2- methyl-1 -butyl, isopentyl, neopentyl, 3- methyl-2-butyl, 2-methyl-2-butyl; for C 1-3 alkoxy: methoxy, ethoxy, propoxy, isopropoxy; for C 1-4 alkoxy: C 1-3 alkoxy (as above), n-butoxy, secbutoxy, isobutoxy, terbutoxy; for Ci.salkoxy: C 1-4 alkoxy (as above), C 1-3 alkoxy (as above), pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-l- butoxy, isopentoxy, neopentoxy, 3-methyl-2- butoxy, 2-methyl-2-butoxy; for 4- , 5- , 6-
  • oxido denotes a ⁇ O-group (ion)
  • carbamoyl denotes a H 2 N-C(O)-group.
  • a compound of formula (I) wherein one or two of R 1 , R 2 and R 3 is/are nitrogen.
  • a further embodiment of the invention discloses a compound of formula (I) wherein both R 2 and R 3 are nitrogen.
  • a further embodiment of the invention discloses a compound of formula (I) where one of R 4 is oxo.
  • a compound of formula (I) is disclosed where one of R 4 is C 1-3 alkyl, e.g methyl.
  • a compound of formula (I) is disclosed where one or two of R 4 is/are hydrogen. In a further embodiment of the invention a compound of formula (I) is disclosed where one of R 4 is hydroxy.
  • each R 6 is independently selected from hydrogen, Q.salkyl, oxo, carboxy, cyano, tetrazolyl, hydroxyQ.salkyl, carboxyQ.salkyl, Q.salkylcarboxy, Q.salkoxyoxoCi-salkyl, carbamoyl, C 1-5 alkylcarbamoyl, di(C 1-5 alkyl)carbamoyl, -CONR 80 (CH 2 ) x S(O) p R 9 , -CONH(CH 2 ) q NR 10 R ⁇ , -Q.salkyl-Y 1 , -COOCHR 17 R 18 and -CON R 17 R 18 .
  • each R 6 is independently selected from hydrogen, Q-salkyl, oxo, carboxy,
  • each R 6 is independently selected from hydrogen, Q.salkyl and oxo.
  • a compound of formula (T) is disclosed wherein R 7 is nitrogen.
  • a further embodiment of the invention discloses a compound of formula (I) wherein at least one of R is halogen, e.g. chloro or bromo.
  • a further embodiment of the invention discloses a compound of formula (I) which is
  • the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the reaction, conveniently in the presence of a suitable base, of an amine of formula (II) or a salt thereof, W
  • a suitable reactive derivative of an acid of the formula (HT) is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate or with an activated amide such as l,r-carbonyldiimidazole; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as iV-hydroxybenzotriazole or N-hydroxysuccinimide; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an
  • reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, and at a temperature in the range, for example, -78 0 C to 150 0 C, conveniently at or near ambient temperature.
  • a suitable base such as, for example, an alkali or alkaline earth metal carbonate
  • a suitable inert solvent or diluent for example methylene chloride
  • R groups, n, p, pi and m are as defined above in relation to formula (I) and A 1 is halogen, with corresponding halogen succinimide in an inert solvent like dichloromethane or N, N-dimethylformamide at a temperature in the range -50 0 C - 100 0 C, conveniently at or near ambient temperature.
  • R-groups, A, n and m are as defined above in relation to formula (T).
  • This reaction is carried out using a base such as ⁇ iV-dimethyl aminopyridine, diisopropylethyl amine in inert solvents, typically dichloromethane and N 1 N- dimethylformamide at a temperature in the range -50 °C - 100 0 C, conveniently at or near ambient temperature.
  • a base such as ⁇ iV-dimethyl aminopyridine, diisopropylethyl amine in inert solvents, typically dichloromethane and N 1 N- dimethylformamide
  • a pharmaceutically-acceptable salt of a compound of the formula (I) When a pharmaceutically-acceptable salt of a compound of the formula (I) is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
  • 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
  • the compounds of the formula (I) are inhibitors of the enzyme Factor Xa.
  • the effects of this inhibition may be demonstrated using one or more of the standard procedures set out hereinafter: -
  • 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 °C, 5 mM CaCl 2 , ionic strength 0.15 adjusted with NaCl, 0.1 % bovine serum albumin, ICN Biomedicals, Inc, USA, IgFL) 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 °C, 5 mM CaCl 2 , ionic strength 0.15 adjusted with NaCl, 0.1 % bovine serum albumin, ICN Biomedicals, Inc, USA, IgFL
  • chromogenic substrate solution S-2765,
  • the linear absorbance increase at 405 nm during 40 min incubation at 37 0 C was used for calculation of percent inhibition for the test samples, as compared to references without inhibitor and/ or enzyme.
  • the 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). c) Measurement of Anticoagulant Activity
  • Plasma is prepared by centrifugation (1000 g, 15 minutes) and stored at -80 0 C.) and an aliquot was rapidly thawed at 37 0 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 D S (Dade Behring, Liederbach, Germany) was reconstituted with 10 mL water.
  • the IC 5O is calculated from the curve of PTjZPT 0 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 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:-
  • 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. As mentioned above, 0 compounds of the formula (I) are useful in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated. In using 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 5 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 o 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 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 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.
  • the formed solid material was filtered off and washed with water and diethyl ether.
  • the aqueous filtrate was extracted with dichloromethane and the organic phase was dried (sodium sulfate) and concentrated.
  • the evaporated residue plus the filtered material was subjected to flash column chromatography (dichloromethane / methanol 100 : 4) to give 11 mg (34 %) of the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I), où R1, R2 et R3 sont indépendamment sélectionnés entre un carbone et un azote, au moins l'un de R1, R2 et R3 étant un azote ; A est une simple liaison ou une double liaison , n est 0, 1, 2 ou 3 ; chaque R4 est indépendamment sélectionné entre un hydrogène, un alkyle en C1-3, un hydroxy, un oxo et un thioxo ; R5 est un hydrogène ou un oxo ; m est 0, 1, 2 ou 3 ; chaque R6 est indépendamment sélectionné entre un hydrogène, un alkyle en C1-5, un oxo, un carboxy, un cyano, un tétrazolyle, un hydroxy(alkyle en C1-5), un carboxy(alkyle en C1-5), un (alkyl en C1-5)carboxy, un (alcoxy en C1-5)oxo(alkyle en C1-5), un carbamoyle, un (alkyl en C1-5)carbamoyle, un di(alkyl en C1-5)carbamoyle, un groupe -CONR80(CH2)xS(O)pR9, -CONH(CH2)qNR10R11, -(alkyl en C1-5 )-Y1, -COOCHR17R18 et -CON R17R18 ; R7 est un carbone ou un azote ; p1 est 0, 1 ou 2 ; chaque R8 est indépendamment sélectionné entre un hydrogène et 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/SE2006/000839 2005-07-08 2006-07-05 Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa WO2007008145A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0501620-9 2005-07-08
SE0501620 2005-07-08

Publications (1)

Publication Number Publication Date
WO2007008145A1 true WO2007008145A1 (fr) 2007-01-18

Family

ID=37637408

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2006/000839 WO2007008145A1 (fr) 2005-07-08 2006-07-05 Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa

Country Status (1)

Country Link
WO (1) WO2007008145A1 (fr)

Cited By (3)

* 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
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 (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021188A1 (fr) * 1996-11-08 1998-05-22 Zeneca Limited DERIVES HETEROCYCLIQUES INHIBANT LE FACTEUR Xa
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO1999057099A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
EP1031563A1 (fr) * 1997-09-30 2000-08-30 Daiichi Pharmaceutical Co., Ltd. Derives sulfonyle
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation
WO2000078749A1 (fr) * 1999-06-19 2000-12-28 Astrazeneca Uk Limited Derives de sulfonamide comme inhibiteur du facteur xa
WO2001017990A1 (fr) * 1999-07-24 2001-03-15 Astrazeneca Uk Limited Derives heterocycliques inhibiteurs du facteur xa
EP1104754A1 (fr) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
WO2001095931A1 (fr) * 2000-06-10 2001-12-20 Astrazeneca Ab PRODUIT COMBINE CONTENANT DU MELAGATRAN ET UN INHIBITEUR DU FACTEUR Xa
WO2002026734A1 (fr) * 2000-09-29 2002-04-04 Cor Therapeutics, Inc. Amides piperazine-2-un comme inhibiteurs du facteur xa
WO2002026720A2 (fr) * 2000-09-29 2002-04-04 Millennium Pharmaceuticals, Inc. INHIBITEURS DE FACTOR Xa A BASE DE PIPERAZINE

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021188A1 (fr) * 1996-11-08 1998-05-22 Zeneca Limited DERIVES HETEROCYCLIQUES INHIBANT LE FACTEUR Xa
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
EP1031563A1 (fr) * 1997-09-30 2000-08-30 Daiichi Pharmaceutical Co., Ltd. Derives sulfonyle
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO1999057099A1 (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
WO2000078749A1 (fr) * 1999-06-19 2000-12-28 Astrazeneca Uk Limited Derives de sulfonamide comme inhibiteur du facteur xa
WO2001017990A1 (fr) * 1999-07-24 2001-03-15 Astrazeneca Uk Limited Derives heterocycliques inhibiteurs du facteur xa
WO2001095931A1 (fr) * 2000-06-10 2001-12-20 Astrazeneca Ab PRODUIT COMBINE CONTENANT DU MELAGATRAN ET UN INHIBITEUR DU FACTEUR Xa
WO2002026734A1 (fr) * 2000-09-29 2002-04-04 Cor Therapeutics, Inc. Amides piperazine-2-un comme inhibiteurs du facteur xa
WO2002026720A2 (fr) * 2000-09-29 2002-04-04 Millennium Pharmaceuticals, Inc. INHIBITEURS DE FACTOR Xa A BASE DE PIPERAZINE

Cited By (4)

* 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
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

Similar Documents

Publication Publication Date Title
JP4390833B2 (ja) 閉塞性気道疾患の処置のための新規ヒダントイン誘導体
JP4053597B2 (ja) 置換ｎ―［（アミノイミノメチル又はアミノメチル）フェニル］プロピルアミド
ES2219894T3 (es) Derivados heterociclicos que inhiben el factor xa.
US20080214495A1 (en) Heterocyclic Sulfonamide Derivatives as Inhibitors of Factor Xa
JP6441830B2 (ja) カテプシンｃの置換２−アザ−ビシクロ［２．２．１］ヘプタン−３−カルボン酸（シアノ−メチル）−アミド阻害剤
US20090012087A1 (en) New Aza-Bicyclohexane Compounds Useful As Inhibitors Of Thrombin
JP2007523927A (ja) Ｘａ因子阻害剤としてのピロール誘導体
US20080221063A1 (en) Heterocyclic Sulfonamide Derivatives As Inhibitors Of Factor Xa
JP2002513790A (ja) Ｘａ因子を阻害する複素環誘導体
RU2376301C2 (ru) Новые производные гидантоина в качестве ингибиторов металлопротеиназ
RU2283306C2 (ru) Пиперидин- и пиперазинзамещенные n-гидроксиформамиды в качестве ингибиторов металлопротеиназ
RU2378269C2 (ru) Новые производные гидантоина в качестве ингибиторов металлопротеиназ
US20080004317A1 (en) Compounds
WO2007008145A1 (fr) Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa
US7648992B2 (en) Hydantoin derivatives for the treatment of obstructive airway diseases
WO2007008144A1 (fr) Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa
US20080200431A1 (en) Heterocyclic Sulfonamide Derivatives as Inhibitors of Factor Xa
HUP0105102A2 (hu) Xa-faktort gátló hatású heterociklusos vegyületek és ezeket tartalmazó gyógyszerkészítmények
US7419979B2 (en) Derivatives of 6-{4-[4-(1H-indole-2-sulphonyl)-piperazin-1-carbonyl-phenyl]}pyradizin-3-one
JP2006519188A (ja) 第Ｘａ因子阻害剤としてのエチニル誘導体
CZ2000293A3 (cs) Heterocyklické deriváty, které inhibují faktor Xa

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06747990

Country of ref document: EP

Kind code of ref document: A1