WO2016146605A1 - Dérivés de phénylalanine substitués - Google Patents

Dérivés de phénylalanine substitués Download PDF

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Publication number
WO2016146605A1
WO2016146605A1 PCT/EP2016/055494 EP2016055494W WO2016146605A1 WO 2016146605 A1 WO2016146605 A1 WO 2016146605A1 EP 2016055494 W EP2016055494 W EP 2016055494W WO 2016146605 A1 WO2016146605 A1 WO 2016146605A1
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Prior art keywords
amino
mmol
salts
methyl
solvates
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PCT/EP2016/055494
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German (de)
English (en)
Inventor
Ulrike RÖHN
Manuel ELLERMANN
Susanne Röhrig
Robert Alan WEBSTER
Martina Victoria Schmidt
Adrian Tersteegen
Kristin BEYER
Martina SCHÄFER
Anja BUCHMÜLLER
Christoph Gerdes
Michael Sperzel
Jan Stampfuss
Alexander Hillisch
Jens Ackerstaff
Carsten TERJUNG
Astrid WENDT
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Bayer Pharma Aktiengesellschaft
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Publication of WO2016146605A1 publication Critical patent/WO2016146605A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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 substituted phenylalanine derivatives and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular blood loss in hyperfibrinolytic conditions, organ transplants or cardiac surgery, especially with cardiopulmonary bypass or as part of a fibrin sealant ,
  • Blood clotting is a protective mechanism of the organism that can rapidly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and hemostasis following vascular injury is essentially through the coagulation system, where an enzymatic cascade becomes more complex It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, one differentiates between the intrinsic and the extrinsic system in blood coagulation, which culminate in a final common pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two Ge since it is formed by Factor VIIa / Tissue Factor (extrinsic pathway) as well as the Tenase complex (intrinsic pathway) by reaction of Factor X. The activated serine protease Xa cleaves prothrombin to thrombin, which
  • a key component of the transition from initiation to amplification and propagation of coagulation is factor XIa.
  • Thrombin activated in positive feedback loops in addition to Factor V and Factor VIII and Factor XI to Factor XIa, which converts Factor IX to Factor IXa and on the thus generated Factor IXa / Factor VIIIa complex quickly larger amounts of Factor Xa produced. This triggers the production of large amounts of thrombin, which leads to strong thrombus growth and stabilizes the thrombus.
  • fibrinolysis Upon activation of plasminogen by tissue plasminogen activator (tPA), the active serine protease, plasmin, is formed which cleaves the polymerized fibrin and thus degrades the thrombus. This process is called fibrinolysis - with plasmin as the key enzyme.
  • tissue plasminogen activator tPA
  • PK plasma kallikrein
  • PK is a multifunctional trypsin-like serine protease for which several physiological substrates are known.
  • the PK-mediated release of bradykinin from high-molecular-weight kininogen leads to the release of t-PA, NO and prostacyclin from endothelial cells, thereby affecting fibrinolysis, blood pressure and inflammation.
  • antifibrinolytics In hyperfibrinolytic conditions, there is no sufficient closure of the wound, which results in severe, sometimes life-threatening bleeding. For the prevention and treatment of such bleeding, antifibrinolytics are available in the clinic. Antifibrinolytics inhibit specific steps of fibrinolysis. Indirect antifibrinolytics such as tranexamic acid inhibit the activation of plasminogen; Direct acting antifibrinolytic drugs block plasmin itself. Corresponding effects have been demonstrated with the plasminogen inhibitor tranexamic acid in various clinical studies.
  • W089 / 11852 describes inter alia substituted phenylalanine derivatives for the treatment of pancreatitis
  • WO 2007/070816 describes substituted thiophene derivatives as factor XIa inhibitors
  • JP 2014227401 describes substituted phenylalanine derivatives as factor XIa inhibitors.
  • the invention relates to compounds of the formula
  • R 12 is [(2iS) -1-methoxypropan-2-yl] amino, [(2iS) -1-hydroxypropan-2-yl] amino or
  • Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as the compounds of formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as it is in the compounds of formula (I), mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 82 Br, 123 I, 124 I, 129 I, and 131 I.
  • isotopic variants of a compound of the invention such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of the drug in the body; Because of the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and by the methods described below. Examples reproduced by appropriate isotopic modifications of the respective reagents and / or starting compounds are used.
  • 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 from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms 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 from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, V-methylmorpholine, arginine, lysine, ethylenediamine, V-methylpiperidine and choline.
  • 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.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • the enantiomers can either be separated directly after the coupling of the L-phenylalanine intermediates with the amine of the formula (VIII) or at a later intermediate of the synthesis or else the compounds according to the invention per se.
  • the separation of the enantiomers directly after the coupling of the L-phenylalanine intermediates with the amine of the formula (VIII) is preferred.
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • the end point of the line next to each of which represents a # does not represent a carbon atom or a CE group but is part of the bond to the atom to which R 1 is bonded ,
  • # is the point of attachment to the phenyl ring, and their salts, their solvates and the solvates of their salts.
  • R 12 is [(2iS) -1-methoxypropan-2-yl] amino, [(2iS) -1-hydroxypropan-2-yl] amino or
  • the invention further provides a process for the preparation of the compounds of the formula (I), or their salts, their solvates or the solvates of their salts, wherein
  • R 1 has the meaning given above, are reacted with an acid, or [B] the compounds of the formula
  • R 1 has the meaning given above, be reacted with an acid.
  • the reaction according to process [A] is generally carried out in inert solvents, preferably in a temperature range from room temperature to 60 ° C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, dioxane is preferred.
  • Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is hydrogen chloride in dioxane.
  • reaction according to method [B] is carried out as described for method [A].
  • the compounds of formula (III) are known or can be prepared by reacting compounds of formula (II) with a base.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols, such as methanol or ethanol, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents, such as dimethylformamide. Dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is a mixture of tetrahydrofuran and water.
  • Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or alcoholates such as potassium or sodium tert-butoxide, preferably sodium hydroxide or lithium hydroxide.
  • alkali metal hydroxides such as sodium, lithium or potassium hydroxide
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate
  • alcoholates such as potassium or sodium tert-butoxide, preferably sodium hydroxide or lithium hydroxide.
  • reaction generally takes place in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to reflux of the solvents under normal pressure.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. JV, JV-diethyl, V, V'-dipropyl, V, V'-diisopropyl, V, V'-dicyclohexylcarbodiimide, V- (3-dimethylamino-isopropyl) -V'-ethylcarbodiimide hydrochloride (EDC) ( optionally in the presence of pentafluoroquinol (PFP)), V-cyclohexylcarbodiimide-V'-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
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, V-methylmorpholine, A-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference is Diisopro- pylethylamin.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • organic bases such as trialkylamines, e.g. Triethylamine, V-methylmorpholine, A-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference is Diisopro- pylethylamin.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of the solvents, preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine.
  • the compound of formula (V) is known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula
  • R 1 has the meaning given above, be reacted with an acid.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to 60 ° C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, dioxane is preferred.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
  • ethers such as tetrahydrofuran or dioxane, dioxane is preferred.
  • Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is hydrogen chloride in dioxane.
  • the compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula
  • reaction is carried out as described for the reaction of compounds of the formula (IV) with the compound of the formula (V).
  • the compound of formula (VIII) is known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of formula (VII) are known or can be prepared by reacting compounds of the formula
  • X is bromine or iodine, with compounds of the formula
  • Q 1 is -B (OH) 2 , a boronic acid ester, preferably boronic acid pinacol ester, or -BF 3 ⁇ K + , can be reacted under Suzuki coupling conditions.
  • the reaction is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar.
  • catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine, tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphineferrocenyl) palladium (II) chloride, 1,3-bis (2,6-bis) diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl (chloro) - (1,3-dimesityl-l, 3-dihydro-2H-imidazol-2-ylidene) palladium, palladium (II) acetate / Dicyclohexyl- (2 ', 4
  • Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride or potassium phosphate, which may be present in aqueous solution, preference is given to additional reagents such as potassium acetate or a mixture of potassium acetate and sodium carbonate.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethylsulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is toluene, dimethylformamide or dimethyl sulfoxide.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide or dimethylacetamide
  • alkylsulfoxides such as dimethylsulfoxide, or N-
  • R 12 has the meaning given above
  • R 12 has the meaning given above
  • reaction generally takes place in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to reflux of the solvents under normal pressure.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. JV, JV-diethyl, V, V'-dipropyl, V, V'-diisopropyl, V, V'-dicyclohexylcarbodiimide, V- (3-dimethylamino-isopropyl) -V'-ethylcarbodiimide hydrochloride (EDC) ( optionally in the presence of pentafluoroquinol (PFP)), V-cyclohexylcarbodiimide-V'-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
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, V-methylmorpholine, A-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference is Diisopro- pylethylamin.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • organic bases such as trialkylamines, e.g. Triethylamine, V-methylmorpholine, A-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference is Diisopro- pylethylamin.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of the solvents, preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of the solvents, preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine.
  • the compounds of the formula (IIIa) are a subset of the compounds of the formula (III).
  • the compound of the formula (XI) is known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • the compounds of the formula (XII) are known or can be synthesized by known processes from the corresponding starting compounds.
  • the compounds of the invention show an unpredictable, valuable pharmacological activity spectrum and a good pharmacokinetic behavior. These are compounds which influence the proteolytic activity of the serine proteases plasmin, plasma kallikrein and factor XIa.
  • the compounds of the invention inhibit the enzymatic cleavage of substrates which play an essential role in the activation of the blood coagulation cascade and in fibrinolysis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, especially blood loss in hyperfibrinolytic conditions, organ transplants or cardiac surgery, especially with cardiopulmonary bypass or as part of a fibrin sealant.
  • Prophylaxis and / or treatment can reduce or eliminate severe perioperative blood loss. Strong bleeding occurs in severe surgery, such as. Coronary artery bypass graft surgery, organ transplantation or hysterectomy, as well as trauma, haemorrhagic shock, or postpartum hemorrhage.
  • extracorporeal circulation systems or filter systems such as, for example, heart lung machine, hemofiltration, hemodialysis, extracorporeal membrane oxygenation or ventricular support system, such as artificial heart, may occur.
  • Possible thrombotic complications induced by the activation of the intrinsic coagulation system in the extracorporeal circulation systems should be reduced with the compounds according to the invention.
  • the compounds of the invention can also be used as part of a fibrin sealant. Fibrin sealants are used in the bonding of wound edges instead of a traditional surgical suture and the closure of injured tissue, hemostasis, and to support and accelerate wound healing. Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis 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 treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients.
  • compositions containing a compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Lipid-lowering drugs in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor), simvastatin (Zocor), pravastatin (pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor) ;
  • Coronary / vasodilators in particular ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin II) receptor antagonists such as for example, embusartan, losartan, valsartan, irbesartan, candesartan, eprosartan and Temisarta, or ⁇ -adrenoceptor antagonists such as carvedilol,
  • ACE angiotensin converting enzyme
  • Alprenolol bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol, or alpha- 1 - adrenoceptor antagonists such as prazosin, bunazosin, doxazosin and terazosin, or diuretics such as hydrochlorothiazide, furosemide, Bumetanide, piretanide, torasemide, amiloride and dihydralazine, or calcium channel blockers such as verapamil and diltiazem, or dihydropyridine derivatives such as nifedipine (adalate) and nitrendipine (Bayotensin), or nitro preparations such as isosorbide-5-mononitrate, isosorbide dinit
  • Anticoagulant substances such as heparin (UFH), low molecular weight heparins (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675 / ORG42675; ⁇ As well as antiarrhythmics;
  • heparin UHF
  • LMWH low molecular weight heparins
  • Vasopressors such as norepinephrine, dopamine and vasopressin;
  • Inotropic therapy such as dobutamine
  • ⁇ Corticosteroids such as hydrocortisone and fludrocortisone
  • Recombinant human activated protein C such as Xigris
  • blood products such as red blood cell concentrates, platelet concentrates,
  • Combinations in the sense of the invention not only pharmaceutical forms containing all components (so-called. Fixed combinations) and combination packs containing the components separated from each other understood, but also simultaneously or temporally staggered applied components, if they are for prophylaxis and / or It is likewise possible to combine two or more active substances with one another, ie in each case in two or more combinations
  • the compounds according to the invention can have a systemic and / or local action be applied in a suitable manner, such as 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.
  • 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.
  • parenteral administration Preference is given to parenteral administration.
  • routes of administration are, for example, inhalant medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering 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 dodecylsulfate, 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
  • compositions containing at least one compound of the invention preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above.
  • Method 1 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> ⁇ 1.2 min 5% A -> 2.0 min 5% A Furnace: 50 ° C; Flow: 0.40 ml / min; UV detection: 208-400 nm.
  • Microwave The microwave reactor used was a Biotage TM initiator.
  • the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • Weaker salts can be converted to the corresponding chlorides by addition of some hydrochloride.
  • 6-Bromo-2-isopropyl-5-methyl-l_f / -benzimidazole 500 mg, 1.98 mmol
  • 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2' -bi-1, 3,2-dioxaborolane 602 mg, 2.37 mmol
  • potassium acetate 582 mg, 5.93 mmol
  • DMSO 8 ml
  • reaction mixture was stirred for 2 h at 120 ° C (oil bath), cooled to RT and 4-bromo-V- (but-tert-butoxycarbonyl) -L-phenylalanine (567 mg, 1.65 mmol) and degassed again with argon. Then, 2N aqueous sodium carbonate solution (2.47 ml, 4.94 mmol) and [l, l-bis (diphenylphosphino) ferrocene] dichloalladium dichloromethane complex (134.4 mg, 0.165 mmol) were added and the reaction became 3 h 110 ° C stirred in the microwave.
  • 6-Bromo-2-isopropyl-5-methyl-1 J f / -imidazo [4,5-b] pyridine 500 mg, 1.97 mmol
  • 4,4,4 ', 4', 5,5,5 '5'-Octamethyl-2,2'-bi-l, 3,2-dioxaborolane 600 mg, 2.36 mmol
  • potassium acetate 579 mg, 5.90 mmol
  • DMSO 8 ml
  • argon degassed and then [1,1 -Bis- (diphenylphosphino) ferrocene] -dichlo alladium-dichloromethane complex (80.3 mg, 0.098 mmol) was added.
  • reaction mixture was stirred for 2 h at 120 ° C (oil bath), cooled to RT and 4-bromo / V- (fer? -Butoxycarbonyl) -L-phenylalanine (564 mg, 1.64 mmol) and degassed again with argon. Then, 2N aqueous sodium carbonate solution (2.46 ml, 4.92 mmol) and [l, l-bis (diphenylphosphino) ferrocene] dichloalladium dichloromethane complex (134 mg, 0.164 mmol) were added and the reaction became 2 h 120 ° C stirred in the microwave.
  • 6-bromo-2-isopropyl-5-methyl-1,2-dihydro-3H-indazol-3-one 500 mg, 1.86 mmol
  • 4,4,4 ', 4', 5,5,5 ', 5'-Octamethyl-2,2'-bi-l, 3,2-dioxaborolane 566 mg, 2.23 mmol
  • potassium acetate 547 mg, 5.57 mmol
  • DMSO 8 ml
  • [1-, 1-bis (diphenylphosphino) ferrocene] -dichloroalladium dichloromethane complex 76 mg, 0.093 mmol.
  • reaction mixture was stirred for 2 h at 120 ° C (oil bath), cooled to RT and 4-bromo-V- (fer? -Butoxycarbonyl) -L-phenylalanine (532 mg, 1.55 mmol) and degassed again with argon. Then, 2N aqueous sodium carbonate solution (2.32 ml, 4.64 mmol) and [l, l-bis (diphenylphosphino) ferrocene] dichloalladium dichloromethane complex (126 mg, 0.16 mmol) were added and the reaction became 2 h 120 ° C stirred in the microwave.
  • Example 14A Methyl 3- ⁇ 5- [4- ( ⁇ N - [(trans-4- ⁇ [(fer-butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] -4- (2-isopropyl-5-methyl) 3-oxo-2,3-dihydro-l-f / -indazol-6-yl) -L-phenylalanyl ⁇ -amino) -phenyl] -4 - f / - 1, 2,4-triazol-3-yl ⁇ -2,2,3 , 3-tetrafluoropropanoate
  • N, N-diisopropylethylamine (6.3 ml, 36.3 mmol) and a 2,4,6-tripropyl-1,3, 5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in DMF, 21.2 ml, 36.3 mmol).
  • the reaction mixture was stirred for 3 h at reflux (oil bath temperature 85 ° C), then cooled to RT and diluted with ethyl acetate.
  • the organic phase was washed twice with water, once with dilute sodium bicarbonate solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. 7.5 g (87% of theory) of the title compound were obtained.
  • Example 18A Methyl 4 '- [(2iS) -2- ⁇ [( ⁇ '-5-4 - ⁇ [(fer-butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] amino ⁇ - 3-oxo-3 ( ⁇ 4- [3- (1,1,2,2-tetrafluoro-3-methoxy-3-oxopropyl) -H-1, 2,4-triazol-5-yl] -phenyl ⁇ -amino) -propyl] -2- methylbiphenyl-4-carboxylate
  • reaction mixture was made slightly acidic with 1 N hydrochloric acid and extracted twice with ethyl acetate.
  • the organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator to give 2.89 g (83% of theory) of the title compound.
  • reaction mixture was filtered through a Millipore filter and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient)). 50 mg (34% of theory) of the title compound were obtained (with about 25% without fert-butoxycarbonyl protective group).
  • the solution was adjusted to pH 5-6 with 1N hydrochloric acid, then frozen and lyophilized.
  • the residue was dissolved in dioxane (1 ml), treated with a 4 M hydrochloride solution in 1,4-dioxane (0.094 ml, 0.38 mmol) and stirred at RT overnight.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in DMSO / acetonitrile (about 3 ml).
  • the solution was filtered through a Millipore filter and purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).
  • the resulting substance was treated with 4 M hydrochloride solution in 1,4-dioxane (about 0.2 ml) and the mixture was lyophilized. 8.9 mg (43% of theory) of the title compound were obtained.
  • the solution was adjusted to pH 5-6 with 1N hydrochloric acid, then frozen and lyophilized.
  • the residue was dissolved in dioxane (1 ml), admixed with a 4 M hydrochloride solution in 1,4-dioxane (0.08 ml, 0.32 mmol) and stirred at RT overnight.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in DMSO / acetonitrile (about 3 ml).
  • the solution was filtered through a Millipore filter and purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).
  • a biochemical test system is used in which the reaction of a peptide factor Xla substrate is used to determine the enzymatic activity of human factor XIa.
  • Factor XIa from the peptic factor XIa substrate cleaves the C-terminal aminomethylcoumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.
  • Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 ⁇ assay buffer (50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin) and 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer) are added successively.
  • assay buffer 50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin
  • 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer
  • a biochemical test system is used in which the reaction of a peptidic plasmin substrate is used to determine the enzymatic activity of human plasmin. Plasmin separates from the peptic plasmin substrate the C-terminal aminomethylcoumarin (AMC), whose fluorescence is measured. The determinations are carried out in microtiter plates.
  • AMC C-terminal aminomethylcoumarin
  • Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells).
  • assay buffer 50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin
  • 20 ⁇ l plasmin from Kordia 20 ⁇ l plasmin from Kordia
  • the enzyme reaction is started by adding 20 ⁇ l of the plasmin substrate MeOSuc-Ala-Phe-Lys-AMC (150 ⁇ l in assay buffer) dissolved in assay buffer, incubated for 30 min at room temperature (22 ° C.) and then a fluorescence measurement was carried out (excitation: 360 nM, emission: 460 nM).
  • Plasma kallikrein inhibition of the substances according to the invention is a biochemical test system, in which the reaction of a peptidic plasma kallikrein substrate is used to determine the enzymatic activity of human plasma kallikrein.
  • Plasma kallikrein separates from the peptic plasma kallikrein substrate the C-terminal aminomethyl coumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.
  • Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 ⁇ of assay buffer (50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin) and 20 ⁇ human plasma kallikrein from Kordia (0.6 nM in assay buffer) are successively added. added.
  • assay buffer 50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin
  • Kordia 20 ⁇ human plasma kallikrein from Kordia (0.6 n
  • test substances are tested for their inhibition of other human serine proteases, such as factor Xa and trypsin.
  • factor Xa 1.3 nmol / l of Kordia
  • trypsin 83 mU / ml of Sigma
  • these enzymes are dissolved (50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) - aminomethane], 100 mmol / l sodium chloride, 0.1%> BSA [bovines Seramalbumin], 5 mmol / l calcium chloride, pH 7.4) and incubated for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide without test substance.
  • the enzymatic reaction is started by adding the appropriate substrates (5 ⁇ 1 / 1 Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin). After an incubation period of 30 min at 22 ° C, the fluorescence is measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test mixtures with test substance are compared with the test batches without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and IC50 values are calculated from the concentration-effect relationships. a.5) Determination of the anticoagulant effect
  • the anticoagulant activity of the test substances is determined in vitro in human and animal plasma (eg mouse, rat, rabbit, porcine and canine plasma).
  • human and animal plasma eg mouse, rat, rabbit, porcine and canine plasma.
  • blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9.
  • the blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 g. The supernatant is pipetted off.
  • the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.
  • the activated partial thromboplastin time is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercially available test kit (CK Perst from the company Diagnostica Stago).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by addition of a 25 mM aqueous calcium chloride solution and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a 1.5-fold prolongation of the aPTT. Action data from this test are listed in Table D below: Table D
  • Tissue factor (1 pM)
  • tPA tissue plasminogen activator
  • the antithrombotic activity of FXIa inhibitors is tested in an arterial thrombosis model.
  • the thrombus formation is triggered by chemical damage to a portion of the carotid artery in the rabbit. Simultaneously, the ear bleeding time is determined.
  • the vascular damage is produced by wrapping a piece of filter paper (10 mm x 10 mm) on a Parafilm® (25 mm x 12 mm) strip around the carotid artery without affecting the blood flow.
  • the filter paper contains 100 ⁇ . a 13% solution of ferrous chloride (Sigma) in water. After 5 minutes, the filter paper is removed and the vessel rinsed twice with aqueous 0.9% sodium chloride solution. 30 minutes after the injury, the carotid artery is dissected out in the area of the damage and any thrombotic material is removed and weighed.
  • the test substances are either administered intravenously via the femoral vein anesthetized or orally by gavage to the awake animals each 5 min or 2 h before damage.
  • the ear bleeding time is determined 2 minutes after the injury to the carotid artery.
  • the left ear is shaved and a defined section of 3 mm in length (blade Art.No. 10-150-10, Martin, Tuttlingen, Germany) is set parallel to the longitudinal axis of the ear. Care is taken not to injure any visible vessel. Any escaping blood is collected at 15-second intervals with accurately weighed pieces of filter paper without touching the wound directly.
  • the bleeding time is calculated as the time from placement of the incision to the time when no more blood is detectable on the filter paper.
  • the leaked blood volume is calculated after weighing the pieces of filter paper.
  • the determination of the antifibrinolytic action in vivo is carried out in hyper-fibrinolytic rats. Following anesthesia and catheterization of the animals, hyper-fibinolysis is initiated by infusion of tissue plasminogen activator (tPA) (8 mg / kg / h). 10 minutes after starting the tPA infusion, the substances are administered as iV bolus. After another 15 minutes, the tPA infusion is terminated and a tail transsection performed. The subaquale bleeding (37 ° C tempered physiological sodium chloride solution) is observed over 30 minutes and determines the bleeding time.
  • tissue plasminogen activator tPA
  • the substances according to the invention can, for example, be converted into pharmaceutical preparations as follows:
  • composition
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP) and 2 mg of magnesium stearate.
  • lactose monohydrate
  • corn starch 50 mg of corn starch
  • PVP polyvinylpyrrolidone
  • composition Composition:
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension. production:
  • the rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is about 6 h stirred.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • i.v. solution The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic sodium chloride solution, glucose solution 5% and / or polyethylene glycol 400 / water 30% m / m). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
  • a physiologically acceptable solvent e.g., isotonic sodium chloride solution, glucose solution 5% and / or polyethylene glycol 400 / water 30% m / m.

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Abstract

L'invention concerne des dérivés de phénylalanine substitués et des procédés pour les préparer et pour les utiliser pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, en particulier de l'hémorragie lors d'états hyperfibrinolytiques, lors de transplantations d'organes ou d'interventions de chirurgie cardiaque surtout avec pontage cardiopulmonaire ou comme partie intégrante d'une colle de fibrine.
PCT/EP2016/055494 2015-03-19 2016-03-15 Dérivés de phénylalanine substitués WO2016146605A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989011852A1 (fr) 1988-06-06 1989-12-14 Showa Denko Kabushiki Kaisha Agent de traitement de la pancreatite ou similaire
WO2007070816A2 (fr) 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Derives de thiophene en tant qu'inhibiteurs du facteur xia
JP2014227401A (ja) 2013-05-24 2014-12-08 大日本住友製薬株式会社 フェニルアラニン誘導体
WO2015044174A1 (fr) * 2013-09-26 2015-04-02 Bayer Pharma Aktiengesellschaft Dérivés de phénylalanine substitués servant de modulateurs du facteur xia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989011852A1 (fr) 1988-06-06 1989-12-14 Showa Denko Kabushiki Kaisha Agent de traitement de la pancreatite ou similaire
WO2007070816A2 (fr) 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Derives de thiophene en tant qu'inhibiteurs du facteur xia
JP2014227401A (ja) 2013-05-24 2014-12-08 大日本住友製薬株式会社 フェニルアラニン誘導体
WO2015044174A1 (fr) * 2013-09-26 2015-04-02 Bayer Pharma Aktiengesellschaft Dérivés de phénylalanine substitués servant de modulateurs du facteur xia

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