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WO2007009635A1 - Derives de piperazine substitues par phenyle en tant qu'inhibiteurs pai-1 (inhibiteurs des activateurs du plasminogene 1) - Google Patents

Derives de piperazine substitues par phenyle en tant qu'inhibiteurs pai-1 (inhibiteurs des activateurs du plasminogene 1) Download PDF

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WO2007009635A1
WO2007009635A1 PCT/EP2006/006769 EP2006006769W WO2007009635A1 WO 2007009635 A1 WO2007009635 A1 WO 2007009635A1 EP 2006006769 W EP2006006769 W EP 2006006769W WO 2007009635 A1 WO2007009635 A1 WO 2007009635A1
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phenyl
substituents
mmol
salts
group
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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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Priority to JP2008521845A priority patent/JP2009501740A/ja
Priority to EP06762520A priority patent/EP1907363A1/fr
Publication of WO2007009635A1 publication Critical patent/WO2007009635A1/fr
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    • 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
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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 fibrino-1 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. So are z.
  • elevated plasmatic PAI-I levels are associated with thrombotic disorders characterized, for example, by the formation of a thrombus that locally impairs or detaches and vascularizes vascular blood flow to block downstream blood flow (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis 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 are independently hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C] -C 4 alkyl, C r C 4 alkoxy, Ci-C 6 -alkylamino, Q is C 4 -alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl,
  • 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 6 alkyl, Ci C6 alkoxy, Ci-C ⁇ alkylamino, Ci-C 6 alkylcarbonyl, C r C 6 alkoxycarbonyl and Ci-C ⁇ alkylaminocarbonyl,
  • n is a number 0, 1, 2 or 3
  • R 1 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl 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, CpCe-alkyl, Ci-C 6 -alkoxy, C ö alkylamino, Ci-C 6 alkylcarbonyl, Q
  • 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic 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 by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, 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 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, Alkylcarbonvh alkylaminocarbonyl, alkoxycarbonyl and alkylsulfonylamino stand for 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 1 -C 4 -alkylamino is, for example, a monoalkylamino radical
  • Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-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 dialkyl aminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, terf-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 is fluorine, chlorine, bromine and iodine.
  • the end point of the line next to each of which a * or # stands is not a carbon atom or a CK ⁇ group, but is part of the bond to the carbonyl group or to the Oxygen atom to which X is bonded.
  • 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 are independently hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, Ci-C4-alkyl, Ci-C 4 alkoxy, Ci-C6 alkylamino, Q C 4 alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl,
  • Y 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, aminocarbonyl, C r C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 -alkylamino, Ci-C 6 alkylcarbonyl, Ci-C ⁇ alkoxycarbonyl, and Ci-C ö alkylaminocarbonyl,
  • n stands for a number 0
  • 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,
  • R 2 , R 3 , R 4 and R 5 are hydrogen
  • Y is phenyl
  • phenyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen and C r C 4 alkoxy,
  • n stands for a number 0
  • 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
  • the 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, sodium hydride is preferred.
  • 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, sodium hydride is preferred.
  • R 1 has the meaning indicated above
  • the reaction is generally carried out in inert solvents, in the presence of a dehydrating reagent, if appropriate in the presence of a base, preferably in a temperature range from -3O 0 C to 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, 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 reagents for this purpose are, for example, carbodiimides, such as e.g. N, N-diethyl, N, N-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-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-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro
  • the condensation is carried out with TBTU in the presence of diisopropylethylamine.
  • the compounds of the formulas (III), (IV) and (V) are known per se to the person skilled in the art or can be prepared by customary processes known from the literature.
  • 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-1 inhibitors.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably 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 z.
  • 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 z.
  • 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 implantation and transplantation, or cardiovascular Diseases such as myocardial infarction, atherosclerotic plaque formation, myocardial infarction, stable angina pectoris and unstable angina pectoris, or chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, Alzheimers disease, bone loss induced by estrogen deficiency, diabetes, obesity, chronic periodontitis, lymphomas, diseases in conjunction with accumulation of extracellular matrix, inflammatory diseases such.
  • asthma septic shock, kidney disease, obesity, insulin resistance, diseases associated
  • the compounds according to the invention can be used to support thrombolytic therapy, to influence wound healing, in the prevention and treatment of atherosclerotic vascular diseases, such as e.g. Restenosis, coronary heart disease, cerebral ischaemias and peripheral arterial occlusive diseases, heart failure, hypertension, inflammatory diseases, e.g. Asthma, inflammatory lung disease, glomerulonephritis, inflammatory bowel disease, and rheumatic musculoskeletal disorders, degenerative diseases, e.g. neurodegenerative diseases and osteoporosis.
  • atherosclerotic vascular diseases such as e.g. Restenosis, coronary heart disease, cerebral ischaemias and peripheral arterial occlusive diseases, heart failure, hypertension, inflammatory diseases, e.g. Asthma, inflammatory lung disease, glomerulonephritis, inflammatory bowel disease, and rheumatic musculoskeletal disorders, degenerative diseases, e.g. neurodegenerative diseases and osteopo
  • 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 added to human plasma during chemical blood analysis under hospital conditions to determine fibrinolytic 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.
  • compositions containing a compound of the invention in combination with one or more other active ingredients are pharmaceutical compositions containing a compound of the invention 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, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic 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.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets to be applied films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), 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 dodecy
  • compositions containing at least one compound of the invention preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, and 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 single doses Achieve 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 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 175 mg (0.756 mmol) of 1- (3,4-dichlorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 236 mg (97% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 225 mg (0.756 mmol) of 1- [3,5-bis (trifluoromethyl) phenyl] piperazine to give the corresponding amide. Purification by preparative HPLC gives 215 mg (74% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 148.7 mg (0.756 mmol) of 1- (2-chlorophenyl) piperazine to give the corresponding amide. After purification via preparative HPLC, 208 mg (95% of theory) of product are obtained as an oil.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 141.6 mg (0.756 mmol) of 4-piperazin-1-yl-benzonitrile to give the corresponding amide. After purification via preparative HPLC, 201 mg (94% of theory) of product are obtained as solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 148.7 mg (0.756 mmol) of 1- (4-chlorophenyl) piperazine to give the corresponding amide. After purification via preparative HPLC, 190 mg (86% of theory) of product are obtained as solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.8 mg (0.756 mmol) of 1- (3,5-dichlorophenyl) piperazine to give the corresponding amide. After purification by preparative HPLC, 207 mg (85% of theory) of product are obtained as solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.8 mg (0.756 mmol) of 1- (2,3-dichlorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 218 mg (90% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.1 mg (0.756 mmol) of 1- [2- (trifluoromethyl) phenyl] piperazine to give the corresponding amide. Purification by preparative HPLC gives 223 mg (92% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 145.4 mg (0.756 mmol) of 1- (4-methoxyphenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 148 mg (67% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 188.4 mg (0.756 mmol) of 1- (4-methylphenyl) piperazine dihydrochloride to give the corresponding amide. However, 4.5 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 179 mg (87% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 248.2 mg (0.756 mmol) of N- (2-piperazin-1-ylphenyl) methanesulphonamide dihydrochloride to give the corresponding amide. However, 4.5 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 98 mg (27% of theory) of product as a solid.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid with 149.9 mg (0.78 mmol) of 1- (3-methoxyphenyl) piperazine to the corresponding Amide implemented. Purification by preparative HPLC gives 157 mg (68% of theory) of product as a resin.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 180.23 mg (0.78 mmol) of 1- (4-fluorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 199 mg (92% of theory) of product as an oil.
  • Example 3A Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 206.34 mg (0.78 mmol) of 1- [4-chloro-3- (trifluoromethyl) phenyl] piperazine to give the corresponding amide. After purification by preparative HPLC, 271 mg (99% of theory) of product are obtained as a resin.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.226 mmol) of the 2-fluoronicotinamide from Example 4A are reacted with 46.79 mg (0.339 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 77 mg (72% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.19 mmol) of the 2-fluoronicotinamide from Example 5A are reacted with 39.34 mg (0.285 mmol) 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 75 mg (73% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.25 mmol) of the 2-fluoronicotinamide from Example 6A are reacted with 51.8 mg (0.375 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 78 mg (71% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.258 mmol) of the 2-fluoronicotinamide from Example 7A are reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 71 mg (64% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.25 mmol) of the 2-fluoronicotinamide from Example 8A are reacted with 51.83 mg (0.375 mmol) 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 84 mg (77% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.266 mmol) of the 2-fluoronicotinamide from Example 9A are reacted with 46.8 mg (0.339 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification by preparative HPLC, 70 mg (66% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.266 mmol) of the 2-fluoronicotinamide from Example 10A are reacted with 46.8 mg (0.339 mmol) 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 73 mg (68% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.226 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 46.91 mg (0.34 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 51 mg (48% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.254 mmol) of the 2-fluoronicotinamide from Example 12A are reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 63 mg (54% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.258 mmol) of the 2-fluoronicotinamide from Example 13A are reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 66 mg (60% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.267 mmol) of the 2-fluoronicotinamide from Example 14A are reacted with 55.37 mg (0.4 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification by preparative HPLC, 76 mg (68% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 80 mg (0.254 mmol) of the 2-fluoronicotinamide from Example 15A are reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 2 mg (2% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 40 mg (0.106 mmol) of the 2-fluoronicotinamide from Example 16A are reacted with 21.9 mg (0.159 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 27 mg (49% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 46 mg (0.146 mmol) of the 2-fluoronicotinamide from Example 17A are reacted with 30.22 mg (0.219 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 17 mg (25% of theory) of product are obtained as solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 46 mg (0.152 mmol) of the 2-fluoronicotinamide from Example 18A are reacted with 31.42 mg (0.227 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 47 mg (74% of theory) of product are obtained.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 40 mg (0.11 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 26.5 mg (0.17 mmol) of 3-fluoro-4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 15 mg (26% of theory) of product as a solid.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 40 mg (0.113 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 29.3 mg (0.17 mmol) of 3-chloro-4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 18 mg (31% of theory) of product as a resin.
  • Example 3 Analogously to the instructions for the preparation of Example 3, 40 mg (0.113 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 28.6 mg (0.17 mmol) of vannilic acid to give the corresponding ether. After purification via preparative HPLC, 12 mg (21% of theory) of product are obtained as an oil.
  • the identification of inhibitors of the plasminogen activator inhibitor-1 (PAI-I) of the rat and the quantification of the effectiveness of the substances described herein is carried out using a plasma-based fibrinolysis.
  • the inhibition of the fibrinolytic system can take place 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.
  • 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: 25 nM, Kordia, Leiden, The Netherlands) were added, 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 IXass (FIXass), Factor VIIa (FVIIa), Factor XIa (FXlA) and thrombin as well as the serine proteases plasmin and trypsin are used for the tests.
  • the generic fluorogenic substrates are the substrates designated 1-1 100 (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 performed 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 substrate I-1100, 0.3 nM FXIa with 5 ⁇ M 1-1575, 0.1 nM trypsin with 5 ⁇ M 1-1100, 0.002 nM thrombin with 5 ⁇ M 1-1560, and 0.012 nM Plasmin 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 ⁇ 2 -antiplasmin is able, in addition to ⁇ 2 -macroglobulin, to inhibit the serine protease plasmin.
  • test procedure In a volume of ten microliters, human ct 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 in a concentration range of 100 to 10 ⁇ M or the corresponding solvent for five minutes at room temperature in a 96-well microtiter plate. 20 ⁇ l of human plasmin (Merck Biosciences, Schwalbach / Taunus, Germany, final concentration: 5 nM) are added per batch to the ⁇ 2 -antiplasmin / substance mixture and incubated for 15 minutes at 37 ° C.
  • human ct 2 -antiplasmin Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 50 nM, 50 mM TrisHCl pH 7.3, 200 mM NaCl, 0.2% BSA
  • 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 was reduced by half.
  • the serine protease inhibitor oci-antitrypsin is able to inhibit the serine protease trypsin.
  • test Procedure In a volume of ten microliters, human oci-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) with the 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 oci-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 determined fluorescence value (Emission at 465 nm). in the absence of oti-antitrypsin is defined as "0% inhibition” and that in the presence of 2 ⁇ M as "100% inhibition”.
  • 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: 1175-81 (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 mixed in various formulating agents (e.g., plasma, ethanol, DMSO, PEG400, etc.) or mixtures thereof
  • Solubilizers were dissolved and administered intravenously to male Wistar rats. The applied
  • Doses are in the range of 0.1 to 1 mg / kg. Blood samples are taken by means of a catheter or as
  • 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. Subsequently, the samples are analyzed by HPLC on a 2300 HTLC
  • 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 compound of 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 of the invention corresponds to 10 ml of oral suspension.
  • 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

L'invention concerne des pyrido-carboxamides substitués, un procédé pour leur production, ainsi que leur utilisation pour produire des médicaments servant à traiter et/ou à prévenir des maladies chez les hommes et les animaux, notamment des maladies thrombotiques.
PCT/EP2006/006769 2005-07-16 2006-07-11 Derives de piperazine substitues par phenyle en tant qu'inhibiteurs pai-1 (inhibiteurs des activateurs du plasminogene 1) Ceased WO2007009635A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002614939A CA2614939A1 (fr) 2005-07-16 2006-07-11 Derives de piperazine substitues par phenyle en tant qu'inhibiteurs pai-1 (inhibiteurs des activateurs du plasminogene 1)
JP2008521845A JP2009501740A (ja) 2005-07-16 2006-07-11 プラスミノーゲン活性化因子阻害因子−ｉ（ｐａｉ−ｉ）としてのフェニル置換ピペラジン誘導体
EP06762520A EP1907363A1 (fr) 2005-07-16 2006-07-11 Derives de piperazine substitues par phenyle en tant qu'inhibiteurs pai-1 (inhibiteurs des activateurs du plasminogene 1)

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DE102005033371A DE102005033371A1 (de) 2005-07-16 2005-07-16 Substituierte Pyridocarboxamide
DE102005033371.0 2005-07-16

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146648A1 (fr) 2008-06-04 2009-12-10 中国中化集团公司 Composés amides, leurs procédés de fabrication et leurs utilisations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040147502A1 (en) * 2002-12-17 2004-07-29 Bisacchi Gregory S. Beta lactam compounds and their use as inhibitors of tryptase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040147502A1 (en) * 2002-12-17 2004-07-29 Bisacchi Gregory S. Beta lactam compounds and their use as inhibitors of tryptase

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146648A1 (fr) 2008-06-04 2009-12-10 中国中化集团公司 Composés amides, leurs procédés de fabrication et leurs utilisations

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DE102005033371A1 (de) 2007-01-25
EP1907363A1 (fr) 2008-04-09
JP2009501740A (ja) 2009-01-22
CA2614939A1 (fr) 2007-01-25

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