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EP1910295A1 - Pyridocarboxamides substitues en tant qu'inhibiteurs de l'inhibiteur-1 de l'activateur du plasminogene (pai-1) - Google Patents

Pyridocarboxamides substitues en tant qu'inhibiteurs de l'inhibiteur-1 de l'activateur du plasminogene (pai-1)

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Publication number
EP1910295A1
EP1910295A1 EP06818239A EP06818239A EP1910295A1 EP 1910295 A1 EP1910295 A1 EP 1910295A1 EP 06818239 A EP06818239 A EP 06818239A EP 06818239 A EP06818239 A EP 06818239A EP 1910295 A1 EP1910295 A1 EP 1910295A1
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EP
European Patent Office
Prior art keywords
phenyl
substituents
salts
group
solvates
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06818239A
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German (de)
English (en)
Inventor
Stephan Siegel
Britta-Nicole FRÖHLEN
Christoph Gerdes
Mark Jean Gnoth
Julia Strassburger
Andreas Wilmen
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Bayer AG
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Bayer Healthcare AG
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Publication of EP1910295A1 publication Critical patent/EP1910295A1/fr
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Definitions

  • the invention relates to substituted pyridocarboxamides, a process for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases in humans and animals, in particular thrombotic diseases.
  • Plasminogen Activator Inhibitor-1 is the major regulatory component of the plasminogen plasmin system.
  • the fibrinolytic system encloses the proenzyme plasminogen, which is converted by the two plasminogen activators tPA and uPA into the active enzyme plasmin.
  • PAI-I is the major physiological inhibitor of both tissue-specific plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA).
  • tPA tissue-specific plasminogen activator
  • uPA urokinase-type plasminogen activator
  • One of the main tasks of plasmin in the fibrinolytic system is the breakdown of fibrin at the site of vascular injury.
  • the fibrinolytic system is not only responsible for the removal of fibrin from the circulation but is also involved in various other processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis.
  • Increased plasma levels of PAI-I are associated with a variety of conditions and conditions that interfere with the fibrinolytic system.
  • increased plasmatic PAI-I levels associated with thrombotic diseases characterized, for example, by the formation of a thrombus that locally impairs or loosens and embolizes vascular blood flow to block downstream blood flow (Krishnamurti, Blood, 69, 798 (1987 Reilly, Arterosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigations, 92, 2756 (1993); Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis, 24, 243 (1994); ).
  • Neutralizing antibodies of PAI-I activity result in an acceleration of endogenous fibrinolysis and perfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation, 85, 305 (1992)).
  • An object of the present invention is therefore to provide new PAI-I inhibitors for the treatment of thrombotic diseases in humans and animals.
  • WO 03/080060 and WO 03/080564 as PAI-I inhibitors for the treatment of thrombotic disorders.
  • WO 95/33750 discloses inter alia substituted pyridocarboxamides as corticotropin releasing factor (CRF) antagonists for the treatment of diseases of the central nervous system and
  • WO 03/061387 discloses methods for controlling algae using substituted pyridinecarboxamides.
  • the present invention relates to compounds of the formula
  • R 2, R 3, R 4 and R 5 independently represent hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C r C 4 alkyl, C r C 4 alkoxy, Ci-C 6 -alkylamino, C r C 4 -alkoxycarbonyl or C ⁇ alkylaminocarbonyl stand,
  • phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ⁇ alkyl, Ci C6 alkoxy, Ci-C 6 -alkylamino, Ci-C 6 alkylcarbonyl, Q-C ß alkoxycarbonyl and Ci-C ß alkylaminocarbonyl,
  • n is a number 0, 1, 2 or 3
  • R 1 is phenyl, wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, amino carbonyl, Ci-C 6 alkyl, Ci C6 alkoxy, Ci-C 6 -alkylamino, Ci-C ⁇ alkylcarbonyl, CpC 6 - alkoxycarbonyl, Ci-C ⁇ -alkylaminocarbonyl and Ci-C 6 alkylsulfonylamino,
  • Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts; the compounds of the formula (I) below and the salts, solvates and solvates of the salts thereof and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the of formula (I), compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from Ammonia or organic amines having 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methyl-mo ⁇ holin, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts)
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • Alkyl per se and "Alk” and "alkyl” in alkoxy, alkylamino, alkylcarbonyl, AlkylaminocarbonyU alkoxycarbonyl and alkylsulfonylamino are a linear or branched alkyl radical having usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkoxy is, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylamino is an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl N-methylamino.
  • C r C 4 alkylamino is, for example, a monoalkylamino radical having 1 to
  • Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, / er / -Butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents.
  • (C 1 -C 3 ) -Alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Examples which may be mentioned by way of example and by way of preference are: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, hexybutylaminocarbonyl, n-pentylaminocarbonyl, n-hexyl- aminocarbonyl, N, N-dimethylaminocarbonyl, N, N -diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.
  • Alkoxycarbonyl is, by way of example and by way of preference, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylsulfonylamino is by way of example and preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • Heteroaryl represents an aromatic, monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, O and ⁇ , by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, Pyrimidyl and pyridazinyl.
  • Halogen stands for fluorine, chlorine bromine and iodine.
  • radicals are substituted in the compounds according to the invention, the radicals may, unless otherwise specified, be mono- or polysubstituted or differently substituted. Substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 2 , R 3 , R 4 and R 5 independently of one another represent hydrogen, halogen, hydroxyl, amino,
  • Y is phenyl
  • phenyl may be substituted with 1 to 3 substituents, whereby the substituents are independently "selected from the group consisting of halogen,
  • n is a number 0 or 1
  • R 1 is phenyl
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, amino carbonyl, C r C 6 alkyl, C r C 6 alkoxy, C r C 6 alkylamino, C r C 6 alkylcarbonyl, C r C 6 - alkoxycarbonyl, Ci-C ⁇ -alkylaminocarbonyl and Ci-C 6 alkylsulfonylamino,
  • R 2 , R 3 , R 4 and R 5 are hydrogen
  • Y is phenyl
  • phenyl may be substituted by 1 to 2 substituents, the substituents being selected independently of one another from the group r consisting of halogen and C 1 -C 4 -alkoxy,
  • n is a number 0 or 1
  • R 1 is phenyl
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, methyl, methoxy and methylsulfonylamino,
  • R 2 and R 3 are hydrogen.
  • Another object of the present invention is a process for the preparation of the compounds of formula (I), characterized in that compounds of the formula
  • reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or acetonitrile, dimethyl sulfoxide being preferred.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or acetonitrile, dimethyl sulfoxide being preferred.
  • bases examples include alcoholates such as sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride or DBU, preferably sodium hydride.
  • alcoholates such as sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride or DBU, preferably sodium hydride.
  • R 1 has the meaning indicated above
  • the reaction is generally carried out in inert solvents, in the presence of a s michsreagenzes dehydra-, optionally in the presence of a base, preferably in a temperature range from -30 0 C to 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, halohydrocarbons such as dichloromethane or Trichloromethane, hydrocarbon such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate or organic bases
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • Suitable dehydrating here for example, carbodiimides such as N 1 N'-diethyl, N, N, dipropyl, N, N'-diisopropyl-, N, N'-dicyclohexylcarbodiimide, N- (3-dimethyl-aminoisopropyl) -N 'are ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1-1,2-dihydroquinoline, or propanephospho
  • the condensation is carried out with TBTU in the presence of diisopropylethylamine.
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as PAI-I inhibitors.
  • Another object of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably of thrombotic diseases.
  • the compounds of the invention are useful in the prophylaxis and / or treatment of thrombotic disorders such as venous and arterial thrombosis, pulmonary thrombosis, cerebral thrombosis, thromboembolism and deep venous thrombosis, or coronary heart disease, atrial fibrillation, pulmonary fibrosis, cystic fibrosis, thromboembolic complications, or stroke eg thrombotic stroke and thromboembolic stroke, or transient ischemic attacks, reocclusion and restenosis after coronary interventions (reocclusion and restenosis after percutaneous coronary interventions, reocclusion and restenosis after coronary bypass surgery), disseminated intravascular coagulation, or surgical intervention such as pulmonary embolism, apoplexy, vascular surgery , Vascular graft, stent patency, organ, tissue and cell implementation and transplantation, or cardiovascular diseases such as myocardial infarction, atherosclerotic plaque form ion,
  • the compounds of the invention can be used to support thrombolytic therapy, to influence wound healing, in the prevention and treatment of atherosclerotic vascular diseases, such as restenosis, coronary heart disease, cerebral ischemia and peripheral arterial occlusive diseases, heart failure, hypertension, inflammatory diseases , such as asthma, inflammatory lung disease, glomerulonephritis, inflammatory bowel disease, and rheumatic musculoskeletal disorders, degenerative diseases such as neurodegenerative diseases and osteoporosis.
  • atherosclerotic vascular diseases such as restenosis, coronary heart disease, cerebral ischemia and peripheral arterial occlusive diseases, heart failure, hypertension
  • inflammatory diseases such as asthma, inflammatory lung disease, glomerulonephritis, inflammatory bowel disease, and rheumatic musculoskeletal disorders
  • degenerative diseases such as neurodegenerative diseases and osteoporosis.
  • the compounds of the present invention may also be used to treat blood and blood products used for dialysis and storage of blood in the liquid phase, particularly for ex vivo platelet aggregation.
  • the present compounds may also be delivered to human plasma during chemical blood analysis under hospital conditions for the determination of ibrinolytic capacity.
  • the compounds of the present invention may also be used in combination with pro-thrombolytic, fibrinolytic and anticoagulant agents.
  • Another object of the present invention is the use of the compounds of the invention for the prophylaxis and / or treatment of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or treatment of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the prophylaxis and / or treatment of diseases, in particular the aforementioned diseases, using a cardiovascular effective amount of the compound of the invention.
  • Another object of the present invention are pharmaceutical compositions containing a erf ⁇ ndungs- proper compound in combination with one or more other active ingredients, in particular for the prophylaxis and / or treatment of the aforementioned diseases.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl
  • a further subject of the present invention are medicaments which comprise at least one compound according to the invention, preferably together with one or more inert non- contain toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above.
  • the compound of the invention in total amounts of about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight per 24 hours, optionally in the form of several individual doses to give the desired results.
  • a single dose contains the compound of the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.
  • Example IA Analogously to the instructions for the preparation of Example IA, 300 mg (2.06 mmol) of 2-fluoronicotinic acid are reacted with 254.6 mg (2.27 mmol) of 4-fluoroaniline to give the corresponding amide. Purification by preparative HPLC gives 419 mg (87% of theory) of product.
  • Example 6A Analogously to the instructions for the preparation of Example 6A, 150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid are reacted with 256.9 mg (1.56 mmol) of 3-trifluoromethylaniline to give the corresponding amide. After purification via preparative HPLC, 202 mg (68% of theory) of product are obtained.
  • Example 6A Analogously to the instructions for the preparation of Example 6A, 1000 mg (7.09 mmol) of 2-fluoro-4-pyridinecarboxylic acid are reacted with 792 mg (8.51 mmol) of aniline to give the corresponding amide.
  • the crude batch is mixed with saturated citric acid solution and extracted three times with methylene chloride. The combined organic phases are washed once with saturated sodium chloride solution and the solvent is completely removed. This gives 1.36 g (88% of theory) of product.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 2.89 g (12.34 mmol) of the 2-fluoronicotinamide from Example 2A with 2.05 g (14.81 mmol) of 4-hydroxybenzoic acid and Dissolved 1.234 g (30.85 mmol) of sodium hydride (60%) to the corresponding ether derivative in 100 ml of N-methylpyrrolidone. Recrystallization from methylene chloride gives 4.09 g (94% of theory) of product as a solid.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 80 mg (0.37 mmol) of the 2-fluoronicotinamide from Example 3A with 61.32 mg (0.44 mmol) 4-hydroxybenzoic acid and 37 mg (0.93 mmol) sodium hydride (60%) to the corresponding ether derivative in DMSO (4 ml) reacted. Purification by preparative HPLC gives 23.5 mg (19% of theory) of product.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 100 mg (0.352 mmol) of the isonicotinamide from Example 5 A with 58.3 mg (0.422 mmol) of 4-hydroxybenzoic acid and 35.2 mg (0.88 mmol) of sodium hydride (60%) to the corresponding ether derivative in 4 ml DMSO implemented. After purification via preparative HPLC, 91 mg (62% of theory) of product are obtained.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 37 mg (0.169 mmol) of the isonicotinic acid amide from Example 6A with 34.5 mg (0.203 mmol) of 3-fluoro-4-hydroxyphenyl-acetic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%) corresponding ether derivative in 4 ml of DMSO. After purification via preparative HPLC, 6 mg (9% of theory) of product are obtained.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 37 mg (0.169 mmol) of the isonicotinamide from Example 6A with 28 mg (0.203 mmol) of 4-hydroxybenzoic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%) to the corresponding ether derivative in 4 ml of DMSO implemented. Purification by preparative HPLC gives 39 mg (69% of theory) of product.
  • the identification of inhibitors of rat plasminogen activator inhibitor-1 (PAI-I) as well as the quantification of the efficacy of the substances described herein is carried out by means of plasma-based fibrinolysis tests.
  • the inhibition of the fibrinolytic system can be carried out either at the level of plasmin by ⁇ 2 -antiplasmin or ⁇ 2 -macroglobulin or at the level of the plasminogen activators by PAI-I.
  • the addition of human ⁇ -thrombin leads via several intermediates to form a Fibrinnetzes with three-dimensional structure.
  • the degradation of this fibrin network is carried out by means of the serine protease plasmin, which is previously formed by the plasminogen activator tPA from the inactive proenzyme plasminogen.
  • the activity of tPA is regulated by the plasminogen activator inhibitor-1 PAI-I.
  • PAI-I plasminogen activator inhibitor-1 PAI-I.
  • the inhibition of PAI-I leads to accelerated lysis of the fibrin network.
  • Test Procedure The rat recombinant plasminogen activator inhibitor-1 (PAI-1, Molecular Innovations Inc., MI, USA) (final concentration: 8.25 nM, 50 mM HEPES, pH 6.2, 50 mM NaCl, 0.1% PEG 6000) was incubated with the substance to be tested in a concentration range of 100 ⁇ M to 10 nM or the corresponding solvent for three minutes at room temperature in a 96-well microtiter plate. Human platelet-poor plasma (Blood Donor Service German Red Cross, Hagen, Germany) is diluted 1: 3 with buffer (150 mM NaCl, 20 mM HEPES, pH 7.4).
  • buffer 150 mM NaCl, 20 mM HEPES, pH 7.4
  • ⁇ l of the plasma / buffer mixture are added per batch to the protein / substance mixture. Subsequently, 8 ⁇ l of a mixture of calcium chloride (final concentration: 10 mM), human tissue plasminogen activator (tPA, final concentration: 7.5 nM, Chromogenix, Mölndal, Sweden) and ⁇ -thrombin (final concentration) are added. tration: 25nM; Kordia, Leiden, The Netherlands), mixed and transferred twice each 80 ul in a 384-well microtiter plate. The formation of a fibrin clot and its subsequent lysis are monitored by absorbance measurement at a wavelength of 405 nm. The measurement of the kinetics is performed over at least 3 hours at intervals of two minutes at 37 0 C (Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany).
  • the clot lysis time is the time at which absorption reached half the absorbance value between maximum and minimum absorbance
  • the determined CLT value in the absence of PAI-I is reported as "0% PAI -I activity "and defined as” 100% activity "in the presence of 8.25 nM
  • the CLT 50 value represents the concentration of test substance in which the clot lysis time was reduced by half.
  • Test procedure The substances are characterized with regard to their effect on tPA (tissue plasminogen activator) and urokinase.
  • tPA tissue plasminogen activator
  • urokinase tissue plasminogen activator
  • the PAI-I inhibitors with human tPA Sigma Aldrich Chemie GmbH, Taufmün, Germany, final concentration: 1 nM
  • human urokinase Sigma Aldrich Chemie GmbH, Taufmün, Germany, final concentration: 2.5 nM
  • a buffer with 50 mM TRIS pH 7.5, 140 mM NaCl and 0.1% PEG 6000 incubated for 10 min at RT.
  • the enzyme activities are measured as fluorescence increase by cleavage of specific peptide substrates (final concentration 10 ⁇ M, 444XF for tPA and 244XF for urokinase, American Diagnostica) in a SPECTRA Fluor Plus (Tecan, Switzerland). The highest substance concentration is 10 ⁇ M.
  • Test procedure The coagulation factors Factor X (FX), Factor Xa (FXa), Factor DCledge (FEKass), Factor VIIa (FVIIa), Factor XIa (FXIa) and Thrombin as well as the serine proteases plasmin and trypsin are used for the tests.
  • the generic fluorogenic substrates are the substrates designated I-1 100 (Boc-Ile-Glu-Gly-Arg-AMC), I-1575 (Boc-Glu (OBzl) -Ala-Arg-AMC HCl ), 1-1560 (Boc-Asp (OBzl) -Pro-Arg-AMC HCl), and I- 1275 (MeOSuc-Ala-Phe-Lys-AMC TFA). These substrates are all commercially available from Bachern (Bubendorf, Switzerland). All experiments are carried out in 50 millimolar (mM) Tris, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% BSA, at pH 7.4 and at room temperature. The final volume in all experiments is 100 microliter ( ⁇ l).
  • nM FXa 10 nM FXa with 5 ⁇ M of substrate 1-1 100, 0.3 nM FXIa with 5 ⁇ M 1-1575, 0.1 nM trypsin with 5 ⁇ M 1-1 100, 0.002 nM thrombin with 5 ⁇ M 1-1560, and 0.012 nM plasmin was spiked with 50 ⁇ M 1-1275.
  • 8.8 nM FDCass or 1 pM FVIIa are mixed with 9.5 nM FXa and 50 ⁇ M substrate 1-1100, respectively.
  • the test compounds are prepared as 10 millimolar (mM) solutions in dimethyl sulfoxide (DMSO).
  • the amidolytic activity of the enzymes is determined in a SPECTRA Fluor Plus (Tecan, Maennedorf, Switzerland) at the wavelengths 360 nm (absorbance) and 465 nm (emission).
  • the serine protease inhibitor 01 2 -antiplasmin is able, in addition to ⁇ 2 -macroglobulin, to inhibit the serine protease plasmin.
  • test procedure In a volume of ten microliters, human ⁇ 2 -antiplasmin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 50 nM, 50 mM TrisHCl pH 7.3, 200 mM NaCl, 0.2% BSA) with the substance to be tested a concentration range from 100 to 10 ⁇ M or the appropriate solvent for five minutes at room temperature in a 96-well microtiter plate. Ul 20 human plasmin (Merck Biosciences, Schwalbach / Taunus, Germany; final concentration: 5 nM) are plasmin per batch for ⁇ 2 -Anti- / substance mixture added and incubated for 15 minutes at 37 0 C.
  • the determined fluorescence value (emission at 465 nm) in the absence of ⁇ 2 -antiplasmin is defined as "0% inhibition” and that in the presence of 50 nM as "100% inhibition”.
  • the IC 50 value represents the concentration of test substance in which the emitted fluorescence has been reduced by half.
  • the serine protease inhibitor ⁇ r antitrypsin is able to inhibit the serine protease trypsin.
  • test Procedure In a volume of ten microliters, human oti-antitrypsin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 2 ⁇ M, 50 mM TrisHCl pH 7.3, 100 mM NaCl, 5 mM calcium chloride, 0.5% BSA) is added test substance in a concentration range of 100 to 10 uM or the corresponding solvent for five minutes at room temperature in a 96-well microtiter plate incubated.
  • human oti-antitrypsin Sigma-Aldrich Chemie GmbH, Taufmün, Germany, final concentration: 2 ⁇ M, 50 mM TrisHCl pH 7.3, 100 mM NaCl, 5 mM calcium chloride, 0.5% BSA
  • the fluorescence signal (Tecan Saphire, Tecantechnik GmbH, Crailsheim, Germany, extinction: 360 nm, emission: 465 nm, gain 50) is measured.
  • the IC 50 value represents the concentration of test substance in which the emitted fluorescence was reduced by half.
  • the compounds of the present invention can be tested in thrombosis models in which fibrinolysis is mediated via a PAI-I dependent mechanism (see: Clozel, J Cardiovasc Pharmacol 12: 520-5 (1998); Levi, Circulation 85: 305-12 ( Biemond, Circulation 91: 1 175-81 (1995); Friederich, Circulation 96: 916-21 (1997)). Furthermore, it is possible to characterize the compounds of the present invention with respect to their inhibition or reduction of PAI-I activity in vivo (compare: Crandall, BBRC 311: 904-908 (2003)).
  • test substances are dissolved in various formulation agents (eg, plasma, ethanol, DMSO, PEG400, etc.) or mixtures of these solubilizers and administered intravenously to male Wistar rats.
  • the applied doses are in the range of 0.1 to 1 mg / kg.
  • Blood samples are collected by means of a catheter or as killing plasma at different time points over an interval of up to 26 hours.
  • the quantitative determination of the substances in the test samples is carried out in plasma on calibration samples which are adjusted in plasma. Proteins contained in the plasma are removed by precipitation with acetonitrile.
  • the samples are separated by HPLC on a 2300 HTLC unit (Cohesive Technologies, Franklin, MA, USA) using reversed-phase columns.
  • HPLC system is coupled via a Turbo Ion Spray Interface to a Triple Quadropole Mass Spectrometer API 3000 (Applied Biosystems, Darmstadt, Germany).
  • the evaluation of the plasma concentration time course is carried out using a validated kinetics evaluation program.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules after drying with the magnesium stearate for 5 min. mixed.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the erf ⁇ ndungswasher compound is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is stirred for about 6 hours.
  • Intravenous solution Intravenous solution:
  • the compound of the present invention is dissolved in the water with stirring together with polyethylene glycol 400.
  • the solution is sterile-filtered (pore diameter 0.22 ⁇ m) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

La présente invention concerne des pyridocarboxamides substitués, un procédé pour les produire, et leur utilisation pour préparer un produit pharmaceutique qui sert à traiter et/ou prévenir des troubles chez l'homme et chez l'animal, en particulier des troubles thrombotiques.
EP06818239A 2005-07-22 2006-07-20 Pyridocarboxamides substitues en tant qu'inhibiteurs de l'inhibiteur-1 de l'activateur du plasminogene (pai-1) Withdrawn EP1910295A1 (fr)

Applications Claiming Priority (2)

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DE102005034262A DE102005034262A1 (de) 2005-07-22 2005-07-22 Substituierte Pyridocarboxamide II
PCT/EP2006/007148 WO2007028456A1 (fr) 2005-07-22 2006-07-20 Pyridocarboxamides substitues en tant qu'inhibiteurs de l'inhibiteur-1 de l'activateur du plasminogene (pai-1)

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EP1910295A1 true EP1910295A1 (fr) 2008-04-16

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RU2345770C1 (ru) * 2007-07-09 2009-02-10 Илья Николаевич Медведев Способ нормализации уровня ингибитора активатора плазминогена при метаболическом синдроме
RU2401093C1 (ru) * 2009-05-12 2010-10-10 Илья Николаевич Медведев Способ быстрой нормализации внутрисосудистой активности тромбоцитов у больных артериальной гипертонией с нарушением толерантности к глюкозе
RU2423096C2 (ru) * 2009-05-18 2011-07-10 Илья Николаевич Медведев Способ быстрой оптимизации содержания липидов в мембранах тромбоцитов у больных артериальной гипертонией с нарушением толерантности к глюкозе
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