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WO2016173948A1 - Indazolopyrimidinones comme inhibiteurs de la fibrinolyse - Google Patents

Indazolopyrimidinones comme inhibiteurs de la fibrinolyse Download PDF

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Publication number
WO2016173948A1
WO2016173948A1 PCT/EP2016/059052 EP2016059052W WO2016173948A1 WO 2016173948 A1 WO2016173948 A1 WO 2016173948A1 EP 2016059052 W EP2016059052 W EP 2016059052W WO 2016173948 A1 WO2016173948 A1 WO 2016173948A1
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Prior art keywords
group
substituted
formula
butyl
compound
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Inventor
Manuel ELLERMANN
Gaelle VALOT
Yolanda Cancho Grande
Jorma Hassfeld
Tom KINZEL
Johannes KÖBBERLING
Kristin BEYER
Susanne Röhrig
Michael Sperzel
Jan Stampfuss
Imke Meyer
Maria KÖLLNBERGER
Nils Burkhardt
Karl-Heinz Schlemmer
Christian Stegmann
Joachim Schuhmacher
Matthias Werner
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present application relates to novel substituted indazolopyrimidinones, to processes for their preparation, the compounds for use alone or in combinations in a method for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the present invention also relates to medicaments comprising the compounds according to the invention for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding (HMB), postpartum hemorrhage, hemorrhagic shock, trauma, surgery, transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.
  • HMB heavy menstrual bleeding
  • Bleeding is the common clinical hallmark in hereditary and acquired hemostatic disorders, trauma, surgery, stroke, heavy menstrual bleeding, HMB (also termed menorrhagia), postpartum hemorrhage, and liver diseases.
  • HMB also termed menorrhagia
  • the fibrinolytic system is activated by the deposition of fibrin and assists in the maintenance of an open lumen in damaged blood vessels. A balance between the formation and lysis of fibrin is required to maintain and remold the hemostatic seal during several days in which the injured vessel wall is repaired.
  • Fibrinolysis is the physiological mechanism that dissolves clots.
  • the fibrinolytic system comprises plasminogen, the circulating inactive precursor of plasmin, a potent serine protease involved in the dissolution of fibrin blood clots.
  • Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are the two major plasminogen activators expressed in many cell types and tissues (Levi JH, Lancet 2010, 376, 9734, 3-4). Plasminogen binds to lysine residues on the surface of fibrin and is converted to plasmin by an activator released from endothelial cells - tPA - that simultaneously binds to fibrin.
  • plasmin generation and activity are also modulated by multiple inhibitors that include plasminogen activator inhibitor (PAI-1), thrombin- activatable fibrinolysis inhibitor (TAFI) and cb-antiplasmin (Cesarman-Maus G, Hajjar KA, Br J Haematol 2005; 129: 307-21).
  • PAI-1 plasminogen activator inhibitor
  • TAFI thrombin- activatable fibrinolysis inhibitor
  • cb-antiplasmin Cesarman-Maus G, Hajjar KA, Br J Haematol 2005; 129: 307-21.
  • Activators of fibrinolysis can be therapeutically used to dissolve blood clots in thrombotic conditions like myocardial infarction or ischemic stroke, to avoid degradation of the surrounding tissue (Flemming M, Melzig MF, J Pharm Pharmacol. 2012, 64(8): 1025-39).
  • fibrinolysis can be, and is successfully and safely used in the management of bleeding. After extensive tissue injury that occurs with trauma or surgery, the equilibrium is shifted and fibrinolysis is considered to be an important contributor to bleeding and coagulopathy.
  • many studies reported the use of antifibrinolytic agents to decrease bleeding and need for allogeneic transfusions.
  • Antifibrinolytics are a safe and effective proven concept for reducing blood loss and rebleeding, without increased risk for thrombotic events, for example in the management of hemostatic disorders like hemophilia and von Willebrand's disease, in heavy menstrual bleeding, HMB (also called menorrhagia) and in different surgical conditions.
  • antiplasmin may be used for treating synovitis and cartilage damage following hemarthrosis in patients with underlying hemostatic disorders including hemophilia and von Willebrand's disease (L. Nieuwenhuizen L, Roosendaal G, Masterbergen SC, Coeleveld K, Biesma DH, Lafeber FPJG, and Schuthens, REG, J Thrombosis and Haemostasis 2013, 12: 237-245).
  • hemophilia and von Willebrand's disease L. Nieuwenhuizen L, Roosendaal G, Masterbergen SC, Coeleveld K, Biesma DH, Lafeber FPJG, and Schuthens, REG, J Thrombosis and Haemostasis 2013, 12: 237-245
  • a further potential area of use of antifibrinolytics is the treatment of nosebleed caused by trauma and other causes, also coupled with underlying hemostatic disorders including hemophilia and von Willebrand's disease.
  • Antifibrinolytics have also been successfully applied to the treatment of hereditary angioedema, where a reduction in the number and severity of attacks of edema in patients treated with tranexamic acid could be demonstrated (Dunn CJ, Goa KL, Drugs 1999, 57(6): 1005-1032).
  • Abnormal uterine bleeding (AUB) may be diagnosed when a woman experiences a change in her menstrual blood loss (MBL), or the degree of MBL or vaginal bleeding pattern differs from that experienced by the age-matched general female population (National Collaborating Centre for Women's and Children's Health (NCCWCH): National Institute for Clinical Excellence (NICE) guidelines. CG44 Heavy Menstrual Bleeding: full guideline. 24 January 2007).
  • AUB presents a spectrum of abnormal menstrual bleeding patterns that includes irregular, heavy or prolonged menstrual bleeding or an altered bleeding pattern. AUB may be associated with ovulatory or anovulatory cycles. Terms in use are dysfunctional uterine bleeding (DUB), heavy menstrual bleeding (HMB) or menorrhagia (abnormally heavy menstrual bleeding at regular intervals which may also be prolonged), metrorrhagia (uterine bleeding at irregular intervals, particularly between the expected menstrual periods), and metromenorrhagia (combination of both).
  • DAB dysfunctional uterine bleeding
  • HMB heavy menstrual bleeding
  • metrorrhagia uterine bleeding at irregular intervals, particularly between the expected menstrual periods
  • metromenorrhagia combination of both.
  • AUB is one of the most frequent gynecological disorders observed by general practitioners and gynecologists. AUB is an exclusion diagnosis; an organic cause should always be ruled out. Organic causes of AUB include benign uterine neoplasia, especially cervical and endometrial polyps and myoma's, adenomyosis, and malignancies of the cervix and endometrium.
  • HMB Heavy menstrual bleeding, HMB (also called menorrhagia) is widely defined in the medical literature as blood loss (MBL) of 80 mL or more per menstrual period
  • MBL blood loss
  • heavy menstrual bleeding is defined as menstrual blood loss of 60 ml or more per cycle, for example 60 to 80 ml per cycle, in particular more than 80 ml per cycle.
  • heavy menstrual bleeding should be defined for clinical purposes as excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life, and which can occur alone or in combination with other symptoms. Any interventions should aim to improve quality of life measures.
  • the global prevalence rate of heavy menstrual bleeding based on 18 epidemiological studies, ranges from 4% to 52% (Fraser IS, Langham S, Uhl-Hochgraeber K. Health-related quality of life and economic burden of abnormal uterine bleeding.
  • hemostatic disorders for example hereditary or acquired hemostatic disorders, such as hemophilia and von Willebrand's disease, platelet disorders/dysfunctions like Glantzmann's thrombasthenia and thrombocytopenia as well as PAI-1 deficiency, are potential causes of heavy menstrual bleeding. Menstruation and ovulation are unique hemostatic challenges that occur monthly in women of reproductive age. Integral hemostatic systems are required to control excessive bleeding during these events. While men with mild hereditary hemostatic disorders are often asymptomatic, women suffer a significant morbidity and impaired quality of life mainly with menstrual-related bleedings. Heavy menstrual bleeding is often the presenting symptom of an underlying hemostatic disorder and can be the only bleeding symptom in women.
  • Tranexamic acid is approved for the treatment of heavy menstrual bleeding and a variety of surgical hemorrhagic conditions. Very high, multiple doses of tranexamic acid are required and the most commonly reported drug-related adverse events after oral administration are gastrointestinal, like nausea, vomiting, diarrhea and dyspepsia (Wellington K, Wagstaff AJ, Drugs 2003, 63 (13): 1417- 1433), (Dunn CJ, Goa KL, Drugs 1999, 57(6): 1005-1032).
  • WO 2006/023000 Al pertains to modified release oral tranexamic acid formulations and methods of treatment herewith.
  • WO 2010/117323 Al and WO 2012/047156 Al pertain to isoxazol-3(2H)-one analogs as plasminogen inhibitors and their use in the treatment of fibrinolysis related diseases, including hereditary hemostatic disorders, stroke, heavy menstrual bleeding and liver diseases.
  • the compounds described in WO 2010/117323 Al and WO 2012/047156 Al are structurally unrelated to the compounds of the present invention.
  • WO 2012/080237 pertains to substituted pyrimido[l,2-B]indazoles and their use as modulators of the PI3K/AKT pathway for the treatment of cancer.
  • the compounds of formula (I-A) or (I-B) according to the present invention are structurally distinct from the compounds of formula (I) of WO 2012/080237.
  • the present invention provides compounds of the general formula (I- A)
  • R is selected from hydrogen and C1-C5 alkyl; R 2 is selected from the group consisting of
  • -CO-NR 3 R 4 wherein selected from the group consisting of hydrogen and C 1 -C4 alkyl; selected from the group consisting of C1-C4 alkyl, wherein the C1-C4 alkyl may be substituted with C3-C6 cycloalkyl or phenyl, wherein the phenyl may be substituted with one, two or three halogen substituents
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl may be substituted with one, two or three methyl substituents, or
  • N, R 3 , and R 4 together form a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one, two or three halogen substituents;
  • R 5 is selected from the group consisting of C 1 -C4 alkyl, wherein the C 1 -C4 alkyl may be substituted with one, two or three substituents independently of one another selected from the group consisting of halogen, amino, hydroxyl, C1-C4 alkoxy,
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, and N-oxo,
  • R 7 is selected from the group consisting of hydrogen and C 1 -C4 alkyl; is selected from the group consisting of hydrogen, C 1 -C4 alkyl, wherein the C 1 -C4 alkyl may be substituted with one, two or three substituents independently of one another selected from hydroxyl, halogen, dimethylamino and C1-C4 alkoxy, or with one substituent selected from phenyl, furanyl, and pyridinyl phenyl, wherein the phenyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl and C1-C4 haloalkyl, and C3-C6 cycloalkyl, or R 7 , and R 8 together form a 5- to 6-membered N-heterocycle;
  • R 11 is selected from the group consisting of 6-membered N-heteroaryl, wherein the 6-membered N-heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, halogen, cyano, and C1-C4 alkoxy, and -SO2-R 12 , wherein R 12 is selected from the group consisting of C1-C4 alkyl and phenyl; and its salts, solvates, and solvates of the salts.
  • the present invention provides compounds of the general formula (I-B)
  • R 1 and R 2 are as defined above and its salts, solvates, and solvates of the salts.
  • Compounds according to the invention are the compounds of the formulae (I-A) or (I-B) and their salts, solvates and solvates of the salts, the compounds included in the formulae (I-A) or (I-B) of the formulae mentioned in the following and their salts, solvates and solvates of the salts, and the compounds included in the formulae (I-A) or (I-B) and mentioned in the following as embodiment examples and their salts, solvates and solvates of the salts, where the compounds included in the formulae (I-A) or (I- B) and mentioned in the following are not already salts, solvates and solvates of the salts.
  • the term "x acid" in any of the formulae does not indicate any defined stoichiometric ratio of acid and the respective compound.
  • the term “x acid” denotes different ratios of the compound to the acid, such as 10: 1 to 1: 10, 8: 1 to 1 :8, 7: 1 to 1:7, 5: 1 to 1:5, 4.5: 1 to 1 :4.5, 4: 1 to 1 :4, 3.5: 1 to 1 : 3.5, 3: 1 to 1:3, 2.5: 1 to 1 : 2.5, 2: 1 to 1:2, 1.5: 1 to 1: 1.5, and 1:1.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds of formula (I-A) or (I-B) according to the invention are also included.
  • Physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, benzoic acid, oxalic acid, ascorbic acid, and salicylic acid.
  • mineral acids e.g. salts of mineral acids, carboxylic acids and sulphonic acids
  • Physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention also include salts of conventional bases, such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g.
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenedi amine, and N- methylpiperidine.
  • physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention include salts of hydrochloric acid, sulphuric acid, maleic acid, acetic acid, trifluoroacetic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, oxalic acid, ascorbic acid, salicylic acid, and lysine.
  • physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention include salts of hydrochloric acid, sulphuric acid, maleic acid, acetic acid, trifluoroacetic acid, tartaric acid, ascorbic acid, and salicylic acid.
  • physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention include salts of hydrochloric acid, and trifluoroacetic acid.
  • the physiologically acceptable salts of the compounds of formula (I-A) or (I-B) according to the invention are the salts of hydrochloric acid.
  • the terms “heavy menstrual bleeding, HMB” and “menorrhagia” are interchangeable.
  • the term “medical intervention” includes medical interventions associated with bleeding, such as surgery and transplantation.
  • the definition of the term “medical intervention” also includes minor medical interventions that may cause bleeding, such as tooth extractions, periodontal (gum) surgery, dental implant placement, biopsies, e.g. dental, prostatic, and urinary biopsies, and the removal of urinary stones.
  • Solvates in the context of the invention are designated as those forms of the compounds of formula (I-A) or (I-B) according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • the compounds of formula (TA) or (TB) according to the invention can exist in different stereoisomeric forms depending on their structure, i.e. in the form of configuration isomers or optionally also as conformation isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their particular mixtures.
  • the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, in particular HPLC chromatography on an achiral or chiral phase.
  • the compounds of formula ( A) or (TB) according to the invention can occur in tautomeric forms
  • the present invention includes all the tautomeric forms.
  • stereoisomeric forms of the compounds of formula (TA) or (TB) or (IV) according to the invention are compounds of the formulae (TA) or (TB) as defined above, and compounds of the formula (IV) as defined below, wherein the substituent R 1 has the meaning of C 1 -C4 alkyl.
  • Formula (TA), wherein the substituent R 1 has the meaning of C 1 -C5 alkyl comprises the following trans-isomers:
  • the present invention comprises all possible stereoisomeric forms, also in cases where no stereoisomerism is indicated.
  • the compounds of formulae (I-A), (I-B), and (IV), wherein the substituent R 1 has the meaning of C 1 -C5 alkyl are present as mixtures of cis- and trans- isomers.
  • the compounds of formulae (I-A), (I-B), and (IV), wherein the substituent R 1 has the meaning of C 1 -C5 alkyl are present as mixtures of cis- and trans- isomers, wherein more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, more than 97%, more than 98%, or more than 99%, of the compounds of formulae (I-A), (I-B), and (IV) are present as trans- isomer.
  • the compounds of formulae (I-A), (I-B), and (IV), wherein the substituent R 1 has the meaning of C 1-C5 alkyl are present as the enantiomerically pure trans-isomers.
  • the present invention also encompasses all suitable isotopic variants of the compounds of formula (I-A) or (I-B) according to the invention.
  • An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the invention may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
  • the incorporation of isotopes for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds of formula (I-A) or (I-B) according to the invention may therefore in some cases also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds of formula (I-A) or (I-B) according to the invention can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
  • the present invention moreover also includes prodrugs of the compounds of formula (I-A) or (TB) according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds of formula (I-A) or (TB) according to the invention during their dwell time in the body.
  • Alkyl in the context of the invention represents a straight-chain or branched alkyl radical having the number of carbon atoms stated in each case.
  • the following may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n- pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 3- methyl-3-ethylpropyl.
  • Haloalkyl in the context of the invention represents an alkyl radical as defined above being mono- or polyhalogenated up to the maximum possible number of substituents.
  • the halogen atoms can be identical or different.
  • halogen represents fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.
  • Cycloalkyl or carbocycle in the context of the invention represents a monocyclic saturated alkyl radical having the number of ring carbon atoms stated in each case.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl The following may be mentioned by way of example and by way of preference: fluoro methyl, difluoromethyl, trifluoro methyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, 3-methyl-3-fluorethyl- 1 -fluorpropyl.
  • Cycloalkyl or carbocycle in the context of the invention represents a monocyclic saturated alkyl radical having the number of ring carbon atoms stated in each case.
  • Cycloalkylalkyl in the context of the invention represents a monocyclic saturated cycloalkyl radical being as defined above, attached to an alkyl group, being as defined above.
  • the following may be mentioned by way of example and by way of preference: cyclopropyl-methyl, cyclopropyl-ethyl, cyclopropyl-propyl, cyclopropyl-isopropyl, cyclopropyl-butyl, cyclopropyl-isobutyl, cyclopropyl- 1- methylpropyl, cyclopropyl-ieri-butyl, cyclobutyl-methyl, cyclobutyl-ethyl, cyclobutyl-propyl, cyclobutyl-isopropyl, cyclobutyl-butyl, cyclobutyl-isobutyl, cyclobutyl- 1 -methylpropyl, cyclobutyl- tert-
  • Bridged bi- and tri-cycloalkyl in the context of the invention include Cs— C12, or C7-C12, or Cs, groups. Bicyclic and tricyclic groups may be fused or bridged. Examples include: bicyclo-[2,2,l]-heptyl, methylbicyclo-[2,2,l]-octyl, bicyclo-[3,3,0] -octyl, bicyclo- [2,2,2] -octyl, bicyclo-[3,2,l]-octyl, bicyclo- [4,3,0]-nonyl, bicyclo-[3,3,l]-nonyl, and tricyclo[3.3.1.1 3 ' 7 ]decan (adamantanyl).
  • a 10- 18 membered annelated aryl in the context of the invention represents a bi- to tricyclic aromatic cycle.
  • this may be naphthalenyl.
  • a 10-18 membered annelated heteroaryl in the context of the invention represents a bi- to tricyclic aromatic heterocycle which has a total of 10 to 18 ringatoms in two or three rings, and which contains up to six identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • this may be benzimidazole.
  • 3- to 6-membered heterocycloalkyl in the context of the invention represents a monocyclic saturated heterocycloalkyl radical which has a total of 3 to 6 ring atoms, which contains one or two ring heteroatoms from the group consisting of N, O, S, SO and SO 2 and which is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • azetidinyl oxetanyl, oxythianyl, oxoimidazolidinyl, oxazolidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl, diazepanyl, and hexahydro-l,4-diazepinyl.
  • 3- to 6-membered heterocycloalkyl- alkyl in the context of the invention represents a heterocycloalkyl radical being as defined above, attached to an alkyl group, being as defined above.
  • the following may be mentioned by way of example and by way of preference: azetidinylmethyl, oxetanylmethyl, oxythianylmethyl, oxoimidazolidinylmethyl, oxazolidinylmethyl, pyrrolidinylmethyl, pyrazolidinylmethyl, tetrahydrofuranylmethyl, thiolanylmethyl, piperidinylmethyl, piperazinylmethyl, tetrahydropyranylmethyl, tetrahydrothiopyranylmethyl, morpholinylmethyl, thiomorpholinylmethyl, hexahydroazepinylmethyl, diazepanylmethyl, hexahydro-lmethyl,4-diazepinyl, azetidin
  • a cyclic amine in the context of the invention represents a 5 to 7 membered heterocycle which contains one or two ring nitrogen atoms and zero or one ring oxygen atom and is attached via a ring nitrogen atom.
  • the following may be mentioned by way of example: morpholinyl, piperidinyl, piperazinyl, diazepanyl, pyrrolidinyl, aziridinyl, and azetidinyl.
  • Alkenyl in the context of the invention represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one double bond.
  • Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
  • the following may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Haloalkoxy in the context of the invention represents an alkoxy radical as defined above being mono- or polyhalogenated up to the maximum possible number of substituents.
  • the halogen atoms can be identical or different.
  • halogen represents fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.
  • Alkoxy alky 1 in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms as defined above, attached to an alkyl group, being as defined above.
  • the following may be mentioned by way of example and by way of preference: methoxy-methyl, methoxy-ethyl, methoxy -propyl, methoxy-isopropyl, methoxy -butyl, methoxy-isobutyl, methoxy- 1-methylpropyl, methoxy-ieri-butyl, ethoxy-methyl, ethoxy-ethyl, ethoxy-propyl, ethoxy-isopropyl, ethoxy-butyl, ethoxy-isobutyl, ethoxy- 1 -ethylpropyl, ethoxy-ieri-butyl, n-propoxy-methyl, n-propoxy-ethyl, n-propoxy-propyl,
  • Alkylester in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms as defined above, which is attached to a carboxy group.
  • Alkylamino in the context of the invention includes mono- and dialkylamino and represents an amino group wherein one or two hydrogen atoms are substituted with alkyl radicals.
  • a 5 to 6-membered Heteroaryl in the context of the invention represents a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • a 5 to 6-membered N-Heteroaryl in the context of the invention represents a subgroup of 5 to 6- membered Heteroaryl and represents a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, which contains up to three ring nitrogen atoms and is attached via a ring carbon atom or, if appropriate, a ring nitrogen atom.
  • heterocycle heterocycle
  • pyrrolyl pyrazolyl, imidazolyl, triazolyl, including 1,2,4- and 1,2,3- triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, including 1,2,3-, 1,2,4-, and 1,3,5- triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine, bromine, or fluorine.
  • radicals in the compounds of formula (I-A) or (I-B) according to the invention are substituted, the radicals may, unless specified otherwise, be mono- or polysubstituted. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.
  • treatment includes the inhibition, delay, arrest, amelioration, attenuation, limitation, reduction, suppression, reversal or cure of a disease, a condition, a disorder, an injury and a health impairment, of the development, course or the progression of such states and/or the symptoms of such states.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention In the context of the present invention, the terms “prevention”, “prophylaxis” or “precaution” are used synonymously and refer to the avoidance or reduction of the risk to get, to contract, to suffer from or to have a disease, a condition, a disorder, an injury or a health impairment, a development or a progression of such states and/or the symptoms of such states.
  • the treatment or the prevention of a disease, a condition, a disorder, an injury or a health impairment may take place partially or completely.
  • the compounds of the formulae (TA) or (TB) are defined as follows: R 1 is selected from hydrogen and C 1-C5 alkyl;
  • R 2 is selected from the group consisting of (a) -CO-NR 3 R 4 , wherein
  • R 3 is selected from the group consisting of hydrogen and C 1 -C4 alkyl
  • R 4 is selected from the group consisting of C1-C4 alkyl, wherein the C1-C4 alkyl is substituted with C3-C6 cycloalkyl or phenyl, wherein the phenyl may be substituted with one, two or three halogen substituents
  • 5- or 6-membered heterocyclyl wherein the 5- or 6-membered heterocyclyl may be substituted with one, two or three methyl substituents, phenyl, wherein the phenyl is substituted independently from each other with one, two or three halogen or methyl substituents
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl is substituted with one, two or three methyl substituents, or
  • N, R 3 , and R 4 together form a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one, two or three halogen substituents;
  • R 5 is selected from the group consisting of C 1 -C4 alkyl, wherein the C1-C4 alkyl is substituted with one, two or three substituents independently of one another selected from the group consisting of halogen, amino, hydroxyl, C1-C4 alkoxy,
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl is substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, and N-oxo,
  • 10- to 18-membered annelated aryl or heteroaryl, or adamantanyl wherein the 10- to 18-membered annelated aryl or heteroaryl, or adamantanyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl,
  • R 6 is selected from the group consisting of C1-C4 alkyl and C3-C6 cycloalkyl
  • R 7 is selected from the group consisting of hydrogen and C1-C4 alkyl
  • R 8 is selected from the group consisting of hydrogen, C 1 -C4 alkyl, wherein the C 1 -C4 alkyl may be substituted with one, two or three substituents independently of one another selected from hydroxyl, halogen, dimethylamino, C1-C4 alkoxy, phenyl, furanyl, and pyridinyl phenyl, wherein the phenyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl and C1-C4 haloalkyl, and C3-C6 cycloalkyl, or
  • N, R 7 , and R 8 together form a 5- to 6-membered N-heterocycle
  • (c) wherein is selected from the group consisting of-(CH2) m -, wherein m is selected from 2, 3 and 4; and wherein R 9 may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl;
  • R 11 is selected from the group consisting of 6-membered N-heteroaryl, wherein the 6-membered N-heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, halogen, cyano, and C1-C4 alkoxy, and -SO2-R 12 , wherein R 12 is selected from the group consisting of C1-C4 alkyl and phenyl; and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 is selected from the group consisting of methyl, wherein the methyl may be substituted with cyclohexyl or phenyl, wherein the phenyl may be substituted with one fluorine substituent, ethyl, iso-propyl, tert-butyl, sec -butyl, 1,1,1-trifluoroethyl, cyclohexyl, cyclopentyl, phenyl, wherein the phenyl may be substituted with one substituent selected from fluorine, chlorine and methyl, oxanyl, and pyridinyl wherein the pyridinyl may be substituted with one methyl substituent; or N, R 3 , and R 4 together form a piperidinyl, azetidinyl, morpholinyl or pyrrolidinyl, wherein the azetidinyl may be substituted with two fluorine
  • R 5 is selected from the group consisting of methyl, ethyl, iso-propyl, propyl, butyl, sec-butyl, tert-butyl, butenyl, trifluoromethyl, 1-amino-ethyl, 2-hydroxy-ethyl, 1-hydroxy-ethyl, methoxy-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, the phenyl being optionally substituted with one, two or three fluorine substituents, or optionally substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, methyl, and trifluoromethyl, or optionally substituted with one substituent selected from piperidine, trifluoromethoxy, methoxy, ethyl, butyl, tert-butyl, nitro, cyano, and hydroxyl, pyrimidinyl, pyrazinyl,
  • R 5 is -O-R 6 , wherein R 6 is selected from the group consisting of methyl, iso-propyl, butyl, sec -butyl, and cyclohexyl; or is -NR 7 R 8 , wherein
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, methoxy ethyl, 1,1,1-trifluoroethyl, propyl, iso-propyl, dimethylamino-propyl, butyl, iso-butyl, tert-butyl, furanylmethyl, pyridinylmethyl, benzyl, phenyl, the phenyl being optionally substituted with methyl, and cyclohexyl, or
  • N, R 7 , and R 8 together form a piperazinyl, piperidinyl, or pyrrolidinyl;
  • R may be substituted with one substituent selected from fluorine and hydroxyl, and wherein one carbon atom of R 10 may have two substituents which, together with the carbon atom to which they are jointly attached, form a 4-membered heterocycle or wherein two carbon atoms of R 10 may have two substituents which, together with the two carbon atoms to which they are attached, form a 5- to 6-membered aliphatic cycle; and
  • R 11 is selected from the group consisting of pyrimidinyl and pyridinyl wherein pyrimidinyl and pyridinyl may be substituted with one or two substituents independently of one another selected from methyl, and fluorine, or may be substituted with one substituent selected from trifluoromethyl, cyano, and methoxy, and -SO2-R 12 , wherein R 12 is selected from the group consisting of methyl and phenyl; and salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R 1 is hydrogen
  • R 2 is selected from the group consisting of (a) -CO-NR 3 R 4 , wherein
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 is selected from the group consisting of methyl, wherein the methyl is substituted with cyclohexyl or phenyl, wherein the phenyl may be substituted with one fluorine substituent, ethyl, iso-propyl, tert-butyl, sec -butyl, 1,1,1-trifluoroethyl, cyclohexyl, cyclopentyl, phenyl, wherein the phenyl may be substituted with one substituent selected from fluorine, chlorine and methyl, oxanyl, and pyridinyl wherein the pyridinyl is substituted with one methyl substituent; or
  • N, R 3 , and R 4 together form a piperidinyl, azetidinyl, morpholinyl or pyrrolidinyl, wherein the azetidinyl may be substituted with two fluorine substituents;
  • R 5 is selected from the group consisting of butenyl, trifluoromethyl, 1-amino-ethyl, 2- hydroxy-ethyl, 1-hydroxy-ethyl, methoxy-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, the phenyl being substituted with one, two or three fluorine substituents, or being substituted with one or two substituents independently selected from the group consisting of fluorine, chlorine, methyl, and trifluoromethyl, or being substituted with one substituent selected from piperidine, trifluoromethoxy, methoxy, ethyl, butyl, tert-butyl, nitro, cyano, and hydroxyl, pyridinyl, the pyridinyl being substituted with one or two substituents independently selected from methyl and trifluoromethyl, or being substituted with one substituent selected from methoxy and N-oxo
  • R 5 is -O-R 6 , wherein
  • R 6 is selected from the group consisting of methyl, iso-propyl, butyl, sec-butyl, and cyclohexyl;
  • R 7 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, methoxy ethyl, 1,1,1-trifluoroethyl, propyl, iso-propyl, dimethylamino-propyl, butyl, sec-butyl, tert-butyl, furanylmethyl, pyridinylmethyl, benzyl, phenyl, the phenyl being optionally substituted with methyl , and cyclohexyl, or
  • N, R 7 , and R 8 together form a piperazinyl, piperidinyl, or pyrrolidinyl;
  • R is selected from the group consisting of pyrimidinyl and pyridinyl wherein pyrimidinyl and pyridinyl may be substituted with one or two substituents independently of one another selected from methyl and fluorine, or may be substituted with one substituent selected from trifluoromethyl, cyano, and methoxy, and -SO 2 -R 12 , wherein R 12 is selected from the group consisting of methyl and phenyl; and salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows: R 1 is hydrogen and R 2 is as defined above, and its salts, solvates, and solvates of the salts.
  • R 1 is selected from hydrogen and C1-C5 alkyl
  • R 3 is selected from the group consisting of hydrogen and C 1 -C4 alkyl
  • R 4 is selected from the group consisting of C1-C4 alkyl, wherein the C1-C4 alkyl may be substituted with C3-C6 cycloalkyl or phenyl, wherein the phenyl may be substituted with one, two or three halogen substituents
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl may be substituted with one, two or three methyl substituents, or
  • N, R 3 , and R 4 together form a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one, two or three halogen substituents; and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R is selected from hydrogen and C1-C5 alkyl
  • R 5 is selected from the group consisting of C 1 -C4 alkyl, wherein the C 1 -C4 alkyl may be substituted with one, two or three substituents independently of one another selected from the group consisting of halogen, amino, hydroxyl, C1-C4 alkoxy,
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, and N-oxo,
  • R 5 is -O-R 6 , wherein
  • R 6 is selected from the group consisting of C1-C4 alkyl and C3-C6 cycloalkyl; or R 5 is -NR 7 R 8 , wherein
  • R 7 is selected from the group consisting of hydrogen and C 1 -C4 alkyl
  • R 8 is selected from the group consisting of hydrogen, C1-C4 alkyl, wherein the C 1 -C4 alkyl may be substituted with one, two or three substituents independently of one another selected from hydroxyl, halogen, dimethylamino and C 1 -C4 alkoxy, or with one substituent selected from phenyl, furanyl, and pyridinyl phenyl, wherein the phenyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl and C1-C4 haloalkyl, and C3-C6 cycloalkyl, or
  • N, R 7 , and R 8 together form a 5- to 6-membered N-heterocycle, and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R 1 is selected from hydrogen and C1-C5 alkyl
  • R 11 is selected from the group consisting of 6-membered N-heteroaryl, wherein the 6-membered N-heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, halogen, cyano, and C1-C4 alkoxy, and -SO2-R 12 , wherein R 12 is selected from the group consisting of C1-C4 alkyl and phenyl; and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R 3 is selected from the group consisting of hydrogen and C 1 -C4 alkyl
  • R 4 is selected from the group consisting of C 1 -C4 alkyl, wherein the C1-C4 alkyl is substituted with C3-C6 cycloalkyl or phenyl, wherein the phenyl may be substituted with one, two or three halogen substituents
  • 5- or 6-membered heterocyclyl wherein the 5- or 6-membered heterocyclyl may be substituted with one, two or three methyl substituents, phenyl, wherein the phenyl is substituted independently from each other with one, two or three halogen or methyl substituents
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl is substituted with one, two or three methyl substituents, or
  • N, R 3 , and R 4 together form a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one, two or three halogen substituents; and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R is selected from hydrogen and C1-C5 alkyl
  • R 5 is selected from the group consisting of C 1 -C4 alkyl, wherein the C 1 -C4 alkyl is substituted with one, two or three substituents independently of one another selected from the group consisting of halogen, amino, hydroxyl, C1-C4 alkoxy,
  • 5- or 6-membered heteroaryl wherein the 5- or 6-membered heteroaryl is substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, and N-oxo,
  • 10- to 18-membered annelated aryl or heteroaryl, or adamantanyl wherein the 10- to 18-membered annelated aryl or heteroaryl, or adamantanyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl, or
  • R 5 is -O-R 6 , wherein
  • R 6 is selected from the group consisting of C1-C4 alkyl and C3-C6 cycloalkyl; or R 5 is -NR 7 R 8 , wherein
  • R 7 is selected from the group consisting of hydrogen and C 1 -C4 alkyl
  • R 8 is selected from the group consisting of hydrogen, C1-C4 alkyl, wherein the C 1 -C4 alkyl is substituted with one, two or three substituents independently of one another selected from hydroxyl, halogen, dimethylamino, C 1 -C4 alkoxy, phenyl, furanyl, and pyridinyl phenyl, wherein the phenyl may be substituted with one, two or three substituents independently of one another selected from C1-C4 alkyl and C1-C4 haloalkyl, and C3-C6 cycloalkyl, or
  • N, R 7 , and R 8 together form a 5- to 6-membered N-heterocycle; and its salts, solvates, and solvates of the salts.
  • the compounds of the formulae (I- A) or (I-B) are defined as follows:
  • R 1 is selected from hydrogen and C1-C5 alkyl
  • R 11 is selected from the group consisting of 6-membered N-heteroaryl, wherein the 6-membered N-heteroaryl may be substituted with one, two or three substituents independently of one another selected from the group consisting of Ci- C4 alkyl, C1-C4 haloalkyl, halogen, cyano, and C1-C4 alkoxy, and -SO2-R 12 , wherein R 12 is selected from the group consisting of C1-C4 alkyl and phenyl; and its salts, solvates, and solvates of the salts.
  • the definitions of radicals indicated specifically in the respective combinations of radicals are replaced as desired irrespective of the particular combinations indicated for the radicals also by definitions of radicals of other combinations.
  • the invention furthermore provides a process for preparing the compounds of the formula (IV)
  • R 1 has the meaning given above
  • R 6 represents an amino protective group
  • R 13 is bromine or cyano, wherein a compound of the formula (II)
  • reaction sequence described above is a regioselective process.
  • regioselective process within the meaning of the invention is defined as a process that yields a compound of formula (IV) wherein less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1 % or 0% of the compound of formula (IV) is present as the regioisomer of the compound of formula (IV) shown below
  • the compound of formula (IV) is isolated from the mixture of regioisomers.
  • Suitable amino protective groups (substituent R 6 ) in formulae (ITA), (ITB), and (IV) are tert- butoxycarbonyl (Boc), removed by a concentrated strong acid, benzyloxycarbonyl (Cbz), removed by hydrogenolysis, methyl or ethylcarbamate, removed by TMSI in CHCI 3 or HBr in AcOH, Trimethylsilylethyl carbamate (Teoc), removed by fluoride, p-Methoxybenzyl carbamate (Moz or MeOZ), removed by hydrogenolysis, 9-Fluorenylmethyl carbamate (F-moc), removed by a base, and optionally substituted benzyl or benzylamine, removed by hydrogenolysis.
  • Preferred for use as amino protective group is ieri-butoxycarbonyl (Boc).
  • the amino protective group R 6 is ieri-butoxycarbonyl (Boc).
  • the condensation process (II) + (III) -> [(V)] -> (IV) can be carried out in one single step without isolation of the intermediate (V), in two separate steps by changing the reaction conditions for the formation of (V) from (ITB) and (III) and the formation of (IV) from (V) but without purification of the intermediate (V), or in two separate steps involving the purification of intermediate (V). Preference is given to a procedure with two separate steps without purification of the intermediate.
  • the compounds of formulae (II) and (III) are reacted in a first step to a compound of formula (V).
  • the compound of formula (V) is reacted in a second step to the compound of formula (IV) without separation and purification of the intermediate (V).
  • the solvent is changed between the first and the second step.
  • Suitable solvents for the process steps (II) + (III) -> (V) are, for example, aliphatic alcohols such as methanol, ethanol, iso-propanol, l-methoxy-2-propanol or ieri-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulph- oxide, -dimefhyl
  • Suitable solvents for the process steps (V) -> (IV) are, for example, aliphatic alcohols such as methanol, ethanol, iso-propanol, l-methoxy-2-propanol or ieri-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulph- oxide, -dimefhylformamide, -
  • the process (II) + (III) -> (V) may proceed in the absence of a base, in the presence of organic bases such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • Inorganic bases include alkali metal or alkali earth metal phosphates and carbonates such as potassium phosphate, potassium carbonate, cesium carbonate, sodium phosphate, or calcium carbonate. Preference is given to reacting the compounds of formulae (II-B) and (III) in the absence of a base.
  • the compounds of formulae (II-B) and (III) are reacted in the absence of a base.
  • the condensation process (V) -> (IV) may proceed in the absence of a base, in the presence of organic bases such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • Inorganic bases include alkali metal or alkali earth metal phosphates and carbonates such as potassium phosphate, potassium carbonate, cesium carbonate, sodium phosphate, or calcium carbonate. Preference is given to reacting the compound of formula (V) to the compound of formula (IV) in the presence of potassium phosphate.
  • the compound of formula (V) is reacted to the compound of formula (IV) in the presence of a base, in particular in the presence of potassium phosphate.
  • a base in particular in the presence of potassium phosphate.
  • the reaction is carried out in the presence of a base.
  • the process (II) + (III) -> (V) is generally carried out in a temperature range of 0 °C to 100 °C, preferably from 40°C to 80°C.
  • the compounds of formulae (II) and (III) are reacted at a temperature of 0 °C to 100 °C, preferably of 40°C to 80°C.
  • the process (V) -> (IV) is generally carried out in a temperature range of 0 °C to 150 °C, preferably from 60 °C to 130 °C.
  • the compound of formula (V) is reacted to a compound of formula (IV) at a temperature of 0 °C to 150 °C, preferably of 60°C to 130°C.
  • R 6 is an acid cleavable amino protective group, such as ieri-butoxycarbonyl
  • the compound of the formula (IV) obtained in reaction [A] or [B] is reacted to the compound of the formula (TB) by addition of an acid.
  • This reaction is carried out in a suitable solvent, e.g. dioxane.
  • salts of formula (TB) may be transformed to the respective free bases of formula (I- A) by any way known to the person skilled in art.
  • the compound of formula (TB) may be reacted to the compound of formula (TA) by treating the compound of formula (TB) with a base.
  • bases are ammonia, sodium hydroxide, NaHCCb, and Na 2 CC>3. This may also be achieved by a suitable chromatographic method by using a basic eluent.
  • the acid used to obtain the compound of the formula (TB) from the compound of the formula (IV) is selected from hydrochloric acid, trifluoroacetic acid, acetic acid, sulphuric acid, maleic acid, tartaric acid, ascorbic acid, and salicylic acid.
  • the compound of the formula (I-A) is obtained from the compound of formula (IV) by cleaving the amino protective group of the compound of formula (IV) for example by hydrogenation. Examples for this reaction are the cleavage of benzyloxycarbonyl (Cbz), and of optionally substituted benzyl.
  • the invention furthermore provides a process for preparing a compound of the formula (TB) as defined above, wherein a compound of formula (XIII)
  • R 1 is as defined above and R 6 represents an acid cleavable amino protective group
  • R 6 represents an acid cleavable amino protective group
  • a compound of the formula H-R 14 wherein R 14 is defined as R 2 above, with the proviso that R 14 is not -CO-NR 3 R 4 , wherein the compound of formula H-R 14 is reacted in an inert solvent, in the presence of a base, and in the presence of a catalyst, optionally in the presence of a ligand to give a compound of formula (VI-A)
  • R 14 of formula (I-B) is defined as R 2 above, with the proviso that R 14 is not -CO-NR 3 R 4 R 2 .
  • reactions in process (XIII) (VI-A) are generally carried out in an inert solvent, in the presence of a base, and in the presence of a catalyst, optionally in the presence of a ligand.
  • reactions in process (XIII) (VI-A) are generally carried out in an inert solvent, in the presence of a base, and in the presence of a catalyst, optionally in the presence of a ligand, preferably at elevated temperature and at atmospheric pressure.
  • Suitable solvents for reactions in process (XIII) (VI-A) are, for example, aliphatic alcohols such as methanol, ethanol, iso-propanol, l-methoxy-2-propanol, 2-methyl-2-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halo- genated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichlor- oethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulph
  • reaction in process (XIII) (VI-A) may proceed in the absence of a base, or in the presence of organic bases such as metal alcoholates, such as sodium tert-butoxide, potassium tert-butoxide, and metal amides, such as Lithium diisopropyl amide or Lithium bis(trimethylsylyl)amide, or amines such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • organic bases such as metal alcoholates, such as sodium tert-butoxide, potassium tert-butoxide, and metal amides, such as Lithium diisopropyl amide or Lithium bis(trimethylsylyl)amide, or amines such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • Inorganic bases include alkali metal or alkali earth metal phosphates and carbonates such as potassium phosphate, potassium carbonate, cesium carbonate, sodium phosphate, or calcium carbonate. Preference is given to using tripotassium phosphate or sodium tert-butoxide.
  • the reactions in process (XIII) (VI- A) are generally carried out in a temperature range from 0 °C to 200 °C. Heating options include conventional heating below the boiling point of the solvent, under reflux, or above the boiling point of the solvent in a closed vial, or in a closed vial with the aid of a microwave reactor. Preference is given to heating the reaction to 60-110 °C.
  • the reactions in process (XIII) (VI- A) can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 25 bar). In general, the reactions are carried out at atmospheric pressure.
  • Suitable catalysts for the reactions in the process (XIII) (VI-A) are usually copper and palladium catalyst, for example, Copper(I) iodide, Copper(II) diacetate, Copper(I) oxide, Palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), Tetrakis(triphenylphosphine)palladium(0), Bis(triphenylphosphine)palladium(II) dichloride, [1,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), l,3-Bis(2,6-diisopropylphenyl)imidazol-2- ylidene ( 1 ,4-naphthoquinone)palladium(0) dimer, Methanesulfonato [2-(di- 1 -adamant
  • Suitable ligands for the reactions in process (XIII) are usually amino and phosphor ligands, for example, 2,2,6,6-Tetramethyl-3,5-heptanedione, N-methyl-2-(methylamino)ethylamine, (+)- Pyrrolidine-2-carboxylic acid, 1,10-Phenanthroline, (+)-trans-l,2-Diaminocyclohexane, N V'- Dimethylethylenediamine, 2-(Di- l-adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl- 1,1'- biphenyl (AdBrettPhos), 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl- 1 , 1 '-biphenyl (BrettPhos), 2-(Di-ieri-butyl
  • the invention furthermore provides a process for preparing a compound of the formula (TB) as defined above, wherein R 2 is -NH-CO-R 5 , and R 5 is as defined above, and wherein a compound of formula
  • R 2 is -NH-CO-R 5 , and R 5 is as defined above.
  • the compounds of formulae (XIII) and tert-butyl carbamate are reacted in a first step to a compound of formula (VII) in an inert solvent, in the presence of a base, and in the presence of a catalyst, optionally in the presence of a ligand.
  • the compounds of formulae (XIII) and tert-butyl carbamate are reacted in a first step to a compound of formula (VII) in an inert solvent, in the presence of a base, and in the presence of a catalyst, optionally in the presence of a ligand, preferably at elevated temperature and atmospheric pressure.
  • Suitable solvents are, for example, aliphatic alcohols such as methanol, ethanol, iso-propanol, 1- methoxy-2-propanol, 2-methyl-2-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulph- oxide, ⁇ , ⁇ -dimethylformamide, N,N-di
  • the step may proceed in the absence of a base,or in the presence of organic bases such as metal alcoholates, such as sodium tert-butoxide, potassium tert-butoxide, and metal amides, such as Lithium diisopropylamide or Lithium bis(trimethylsylyl)amide, or amines such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • organic bases such as metal alcoholates, such as sodium tert-butoxide, potassium tert-butoxide, and metal amides, such as Lithium diisopropylamide or Lithium bis(trimethylsylyl)amide, or amines such as triethylamine or diisopropylethylamine, or in the presence of inorganic bases.
  • organic bases such as metal alcoholates, such as sodium tert-butoxide, potassium tert-butoxide, and metal amides, such as Lithium diisoprop
  • the step is generally carried out in a temperature range from 0 °C to 200 °C.
  • Heating options include conventional heating below the boiling point of the solvent, under reflux, or above the boiling point of the solvent in a closed vial, or in a closed vial with the aid of a microwave reactor. Preference is given to heating the reaction to 50-70 °C.
  • the step can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 25 bar). In general, the reactions are carried out at atmospheric pressure.
  • Suitable catalysts for the step are usually copper and palladium catalyst, for example, Copper(I) iodide, Copper(II) diacetate, Copper(I) oxide, Palladium(II) acetate, Bis(dibenzylideneacetone)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), Tetrakis(triphenylphosphine)palladium(0), Bis(triphenylphosphine)palladium(II) dichloride, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), l,3-Bis(2,6-diisopropylphenyl)imidazol-2- ylidene ( 1 ,4-naphthoquinone)palladium(0) dimer, Methanesulfonato [2-(di- 1 -adamantylphosphino)-3,6- dime
  • Suitable ligands for the step are usually amino and phosphor ligands, for example, 2,2,6,6-Tetramethyl- 3,5-heptanedione, N-methyl-2-(methylamino)ethylamine, (+)-Pyrrolidine-2-carboxylic acid, 1,10- Phenanthroline, (+)-trans-l,2-Diaminocyclohexane, /V,/V'-Dimethylethylenediamine, 2-(Di-l- adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl- 1, 1 '-biphenyl (AdBrettPhos), 2- (Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l,l '-biphenyl (BrettPhos), 2-(Oi-tert- butylphosphin
  • the compound of formula (VII) is reacted in a second step to the compound of formula (VIII) in the presence of an acid, a solvent, preferably at room temperature and atmospheric pressure.
  • the step can partially result in a cleavage of protecting group R 6 .
  • the compound of formula (VIII) is isolated from this mixture.
  • Suitable solvents for the process steps (VII) -> (VIII) are, for example, aliphatic alcohols such as methanol, ethanol, iso-propanol, l-methoxy-2-propanol or ieri-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulph- oxide, -dimethylformamide, /V
  • Suitable acids for the process step are, for example, mineral acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, organic acids, such as acetic acid, trifluoroacetic acid, sulfonic acids, such as para-toluenesulfonic acid, trifluorsulfonic acid, methylsulfonic acid. It is also possible to use mixtures of the acids mentioned. The acids can also be used as solutions in solvents of the type mentioned above. Preference is given to using hydrochloric acid or hydrochloric acid dissolved in 1,4-dioxane.
  • the process (VII) -> (VIII) is generally carried out in a temperature range of -78 °C to 150 °C, preferably from 10 °C to 30 °C.
  • the reaction in process (VIII) -> (IX) is generally effected in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably within a temperature range from 0°C to the reflux of the solvents at atmospheric pressure.
  • Suitable dehydrating reagents here are, for example, carbodiimides, for example NN'-diethyl-, ⁇ , ⁇ '- dipropyl-, /V,/V'-diisopropyl- and A ⁇ /V'-dicyclohexylcarbodiimide, /V-(3-dimethylaminoisopropyl)-/V'- ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N- cyclohexylcarbodiimide- '-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l,2-oxazolium 3- sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlor
  • Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, -mefhylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
  • alkali metal carbonates for example sodium carbonate or potassium carbonate
  • sodium hydrogencarbonate or potassium hydrogencarbonate or organic bases
  • organic bases such as trialkylamines, for example triethylamine, -mefhylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
  • 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, dimethyl sulphoxide, acetonitrile or pyridine, or mixtures of the solvents, preference being given to dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulphoxide, acetonitrile or pyridine, or mixtures of the solvents, preference being given to dimethylformamide.
  • the invention furthermore provides a process for preparing a compound of the formula (TB) as defined above, in which R 2 is -CO-NR 3 R 4 , and R 3 and R 4 are as defined above, wherein a compound of formula
  • R 3 and R 4 are as defined above, and R 3 and R 4 together with N-CO form R 2 .
  • the reaction in process (X) -> (XI) is generally effected in solvents, in the presence of a base, preferably within a temperature range from 0°C to the reflux of the solvents at atmospheric pressure.
  • Suitable solvents for the process step are, for example, water, or aliphatic alcohols such as methanol, ethanol, iso-propanol, l-methoxy-2-propanol or ieri-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene or chlorobenzene, or other solvents such as acetonitrile, pyridine, dimethyl sulphoxide,
  • Bases are alkali hydroxides, such as sodium hydroxide or potassium hydroxide or caesium hydroxide. Bases can also be used as solutions in water. Preference is given to sodium hydroxide.
  • the reaction in process (XI) -> (XII) is generally effected in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably within a temperature range from 0°C to the reflux of the solvents at atmospheric pressure.
  • Suitable dehydrating reagents here are, for example, carbodiimides, for example ⁇ , ⁇ '-diet yl-, ⁇ , ⁇ '- dipropyl-, /V,/V'-diisopropyl- and A ⁇ /V'-dicyclohexylcarbodiimide, /V-(3-dimethylaminoisopropyl)-/V'- ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N- cyclohexylcarbodiimide- '-propyloxymefhyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l,2-oxazolium 3- sulphate or 2-tert-butyl-5-methyl-iso
  • Bases are, for example, alkali metal carbonates, for example sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, or organic bases such as trialkylamines, for example triethylamine, -mefhylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
  • alkali metal carbonates for example sodium carbonate or potassium carbonate
  • sodium hydrogencarbonate or potassium hydrogencarbonate or organic bases
  • organic bases such as trialkylamines, for example triethylamine, -mefhylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preference being given to diisopropylethylamine.
  • 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, dimethyl sulphoxide, acetonitrile or pyridine, or mixtures of the solvents, preference being given to dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulphoxide, acetonitrile or pyridine, or mixtures of the solvents, preference being given to dimethylformamide.
  • the present invention also provides compounds of the formula (VII)
  • the present invention also provides compounds of the formula (VIII)
  • the present invention also provides compounds of the formula (XII)
  • R 3 and R 4 are as defined above, and R 3 and R 4 together with N-CO form R 2 .
  • the preparation processes described can be illustrated in an exemplary manner by the synthesis schemes below (Scheme 1).
  • Suitable amino protecting groups (substituent R 6 ) in formulae (II-A), (II-B), (IV) and (V) are tert- butoxycarbonyl (Boc), removed by a concentrated strong acid, benzyloxycarbonyl (Cbz), removed by hydrogenolysis, methyl or ethylcarbamate, removed by TMSI in CHCh or HBr in AcOH, Trimethylsilylethyl carbamate (Teoc), removed by fluoride, p-Methoxybenzyl carbamate (Moz or MeOZ), removed by hydrogenolysis, 9-Fluorenylmethyl carbamate (F-moc), removed by a base, and optionally substituted benzyl or benzylamine, removed by hydrogenolysis.
  • Preferred for use as amino protective group is ieri-butoxycarbonyl (Boc).
  • the amino protective group R 6 is selected from tert- butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). Preferred for use as amino protective group is tert- butoxycarbonyl (Boc).
  • the reaction can also be carried out without protecting the amino group.
  • R 6 is hydrogen. According to an embodiment of the invention, the reaction is carried out without protecting the amino group. In this embodiment, R 6 is hydrogen.
  • the compounds of formula (I-A) or (TB) according to the invention have useful pharmacological properties and can be employed for the prevention and treatment of disorders in humans and animals.
  • the compounds of formula (TA) or (TB) according to the invention open up a further treatment alternative and are therefore an enrichment of pharmacy.
  • the compounds of formula ( A) or (TB) according to the invention bring about an inhibition of clot lysis (fibrinolysis), lead to an increase in clot stability (clot firmness) and thereby to a reduction of bleeding, re-bleeding and blood loss. These effects are due to direct inhibition of plasminogen, the central precursor of plasmin, a potent serine protease involved in the dissolution of fibrin blood clots.
  • the compounds of formula (I-A) or (I-B) according to the invention are suitable for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention are also suitable for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention are also suitable for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary rare hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention are also suitable for the treatment and/or prophylaxis of hereditary or acquired hemostatic disorders, hereditary or acquired hemostatic disorders, and rare hemostatic disorders.
  • hereditary or acquired hemostatic disorders comprises von Willebrand's disease, platelet disorders/dysfunctions like Glantzmann's thrombasthenia and thrombocytopenia, and vitamin K deficiency, PAI-1 deficiency, mild and moderate hemophilia, including hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and hemophilia C (factor XI deficiency), symptomatic carriers of hemophilia and other hereditary hemostatic disorders, autoimmune disorders that lead to the formation of antibodies against the coagulation factor, blood cancers, bone marrow diseases, infections, kidney failure, liver disease, medications, medications, including heparin, low molecular weight heparin, and coumarin derivatives, like warfarin, accidental injuries and surgical interventions leading to massive blood loss and resulting in a critical reduction in the level of coagulation factors which can lead to additional non-surgical bleeding complications (e.g.
  • coagulopathic bleeding acquired von Willebrand syndrome (AVWS), characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders.
  • VWF von Willebrand factor
  • mild hemophilia is defined as a level of clotting factor activity of the respective deficient factor of 5% to 50% of the normal level
  • moderate hemophilia is defined as a level of clotting factor activity of the respective deficient factor of 1% to 5% of the normal level.
  • hereditary or acquired hemostatic disorders is defined as pathological processes resulting in abnormal bleeding or clotting.
  • the term underlying hereditary rare hemostatic disorders is defined as hemostatic disorders caused by hereditary disorders, that are less common than e.g. hemophilia A and B or von Willebrand disease.
  • Rare hemostatic disorders include deficiency of fibrinogen, prothrombin, factors V, combined factors V+VIII, factor VII, factor X, factor XI or factor XIII.
  • the compounds of formula (I-A) or (I-B) according to the invention can be used in a wide range of hemorrhagic conditions like upper gastrointestinal bleeding, hemorrhages caused by antifibrinolytics, and gynecological bleeding indications including heavy menstrual bleeding (HMB, also termed menorrhagia), placental bleeding, postpartum hemorrhage and conisation of the cervix.
  • HMB also termed menorrhagia
  • menorrhagia menorrhagia
  • menorrhagia menorrhagia
  • menstrual blood loss 60 ml or more per cycle, for example 60 to 80 ml per cycle, in particular more than 80 ml per cycle.
  • heavy menstrual bleeding is defined for clinical purposes as excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life, and which can occur alone or in combination with other symptoms.
  • the compounds of formula (I-A) or (I-B) according to the invention can be used in heavy menstrual bleeding (HMB, also termed menorrhagia) caused by underlying hemostatic disorders, for example hereditary or acquired hemostatic disorders, such as von Willebrand's disease, platelet disorders/dysfunctions like Glantzmann's thrombasthenia and thrombocytopenia, and vitamin K deficiency, PAI-1 deficiency, mild and moderate hemophilia, including hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and hemophilia C (factor XI deficiency), symptomatic carriers of hemophilia and other hereditary hemostatic disorders, such as deficiency of fibrinogen, prothrombin, factors V, combined factors V+VIII, factor VII, factor X, factor XI, or factor XIII, autoimmune disorders, blood cancers, bone marrow diseases, infections, kidney failure, liver disease,
  • the compounds of formula (I-A) or (I-B) according to the invention can also be used for reducing peri- and postoperative blood loss and rebleeding during and after different surgical interventions, including cardiovascular surgery, including coronary artery bypass surgery, spinal surgery, trauma surgery, transplantation, including orthotopic liver transplantation, and hysterectomy, as well as transfusion requirements in patients with or without underlying hemostatic disorders.
  • the compounds of formula (I-A) or (I-B) according to the invention can be used for the prevention of recurrence of bleeding in patients after elective minor surgery like prostatic surgery including prostatectomy and transurethral prostatic surgery, gynaecological surgery, urinary surgery, otolaryngological (ENT) surgery including tonsillectomy, and adenoidectomy, oral surgery, and dental surgery, in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (I-A) or (I-B) according to the invention can also be used for treatment and/or prophylaxis of acute and recurrent bleeding in patients with liver diseases, including patients with end-stage liver diseases in patients with or without underlying hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention can also be used for treatment and/or prophylaxis of acute and recurrent bleeding in patients with trauma and/or traumatic hyphaema, hemorrhagic stroke, acute promyelocytic leukaemia, and to block plasmin-induced proteolysis which may be of biological relevance during athero-thrombosis and inflammatory states, cancer and other diseases in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention can also be used for the treatment and/or prophylaxis of hereditary or acquired hemostatic disorders in patients including von Willebrand's disease, platelet disorders/dysfunctions like Glantzmann's thrombasthenia and thrombocytopenia, and vitamin K deficiency, PAI-1 deficiency, mild and moderate hemophilia, including hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and hemophilia C (factor XI deficiency), symptomatic carriers of hemophilia and other hereditary hemostatic disorders, such as deficiency of fibrinogen, prothrombin, factors V, combined factors V+VIII, factor VII, factor X, factor XI or factor XIII, autoimmune disorders, blood cancers, bone marrow diseases, infections, kidney failure, liver disease, medications, medications, including heparin, low molecular weight heparin, and coumarin
  • the compounds of the present invention can be used either alone as monotherapy or in combination with other therapies to address a hemostatic disorder.
  • co-administration of one or more compounds of the invention with a plasma-derived or recombinant coagulation factor such as factor Vila, factor VIII, factor IX or desmopressin is believed useful for treating hemophilia.
  • the compounds of formula (TA) or (TB) according to the invention can also be used for treating synovitis, wherein the synovitis may be associated with cartilage damage and is associated with hemarthrosis in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention can also be used for the treatment of nosebleed (epistaxis) caused by trauma or other causes in patients with or without underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (TA) or (TB) according to the invention can also be used for the treatment and/or prophylaxis of hereditary or acquired hemostatic disorders in patients.
  • the present invention further relates to the use of the compounds of formula (I-A) or (I-B) according to the invention for the treatment and/or prophylaxis of diseases, in particular the aforementioned diseases.
  • An embodiment of the present invention is also a compound of formula (I-A) or (I-B) according to the invention for use in a method for the treatment and/or prophylaxis of diseases.
  • An embodiment of the present invention is also a compound of formula (I-A) or (I-B) according to the invention for use in a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders.
  • An embodiment of the present invention is also a compound of formula (I-A) or (I-B) according to the invention for use in a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders.
  • An embodiment of the present invention is also a compound of formula (I-A) or (I-B) according to the invention for use in a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, including otolaryngological, cardiovascular, and spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis.
  • a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, including otolaryngological, cardiovascular, and spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis.
  • An embodiment of the present invention is also a compound of formula (I-A) or (I-B) according to the invention for use in a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, including otolaryngological, cardiovascular, and spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis.
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention in combination with an inert, non-toxic, pharmaceutically suitable auxiliary.
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention in combination with a further active compound selected from the group consisting of Factor VIII, Factor IX, Factor Vila, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCCs), ⁇ -aminocaproic acid, ethamsylate, paraaminobutyl benzoic acid, tranexamic acid, desmopressin, danazol, combined oral contraceptive pills (COCPs), progestin intrauterine system, glucocorticoid receptor agonists, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • a further active compound selected from the group consisting of Factor VIII, Factor IX, Factor Vila, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCCs), ⁇ -aminocaproic acid
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention as described above for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders.
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention as described above for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders.
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention as defined above for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic surgery, gynaecological surgery, cardiovascular surgery, spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.
  • a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic
  • An embodiment of the present invention is also a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention as defined above for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic surgery, cardiovascular surgery, spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.
  • a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic surgery, cardiovascular surgery, spinal surgery, liver or lung transplant
  • An embodiment of the present invention is also a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders in humans and animals using an effective amount of at least one compound of the formula (I- A) or (I-B) according to the invention or a medicament comprising a compound of the formula (I-A) or (I-B) according to the invention as defined above.
  • An embodiment of the present invention is also a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders in humans and animals using an effective amount of at least one compound of the formula (I- A) or (I-B) according to the invention or a medicament comprising a compound of the formula (I- A) or (I-B) according to the invention as defined above.
  • An embodiment of the present invention is also a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired hemostatic disorders in humans and animals using an effective amount of at least one compound of the formula (I- A) or (I-B) according to the invention or a medicament comprising a compound of the formula (I-A) or (I-B) according to the invention as defined above, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic surgery, cardiovascular surgery, spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.
  • a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagi
  • An embodiment of the present invention is also a method for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with underlying hereditary or acquired hemostatic disorders in humans and animals using an effective amount of at least one compound of the formula (I-A) or (I-B) according to the invention or a medicament comprising a compound of the formula (I-A) or (I-B) according to the invention as defined above, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, otolaryngological surgery, dental surgery, urinary surgery, prostatic surgery, cardiovascular surgery, spinal surgery, liver or lung transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.
  • a disease or medical intervention selected from the group consisting of heavy menstrual bleeding, postpartum hemorrhage, hemorrhagic shock
  • the compound of formula (I-A) or (I-B) need not be, but is optionally administered with one or more agents currently used to prevent or treat the disorder in question.
  • the effective amount of such other agents depends on the amount of compound of the invention present, the type of disorder or treatment. These are generally used in the same dosages and with administration routes as used hereinbefore or about from 1 to 99% of the heretofore employed dosages.
  • the present invention further relates to medicaments containing at least one of the compounds of formula (TA) or (TB) according to the invention and one or more further active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases.
  • Suitable combination active substances we may mention for example and preferably: Factor VIII, Factor IX, Factor Vila, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCCs), ⁇ -aminocaproic acid, ethamsylate, paraaminobutyl benzoic acid, tranexamic acid, desmopressin, danazol, combined oral contraceptive pills (COCPs), progestin intrauterine systems, glucocorticoid receptor agonists, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with the coagulation factor commonly known as Factor VIII, any derivatives, fragments, muteins or conjugates thereof.
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with the coagulation factor commonly known as Factor IX, any derivatives, fragments, muteins or conjugates thereof.
  • the coagulation factor commonly known as Factor IX, any derivatives, fragments, muteins or conjugates thereof.
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with the coagulation factor commonly known as Factor Vila, any derivatives, fragments, muteins or conjugates thereof.
  • the coagulation factor commonly known as Factor Vila
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with activated prothrombin complex concentrates (aPCCs) or prothrombin complex concentrates (PCCs).
  • aPCCs activated prothrombin complex concentrates
  • PCCs prothrombin complex concentrates
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with antifibrinolytic agents such as, by way of example and preferably, ⁇ -aminocaproic acid, ethamsylate, paraaminobutyl benzoic acid, and tranexamic acid.
  • antifibrinolytic agents such as, by way of example and preferably, ⁇ -aminocaproic acid, ethamsylate, paraaminobutyl benzoic acid, and tranexamic acid.
  • the compounds of formula (TA) or (TB) according to the invention are administered in a combination with desmopressin.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in a combination with danazol.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in combination with combined oral contraceptive pills (COCPs) such as, by way of example and preferably, combinations of an estrogen, for example the synthetic estrogen ethinylestradiol or the natural estrogens estradiol and estradiolderivatives, preferably estradiolester, such as estradiolvalerate and estradiolhydrate, and a gestagen for example progesterone, trimegestone, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, chlormadinone acetate, nestorone, levonorgestrel, norgestimate, desogestrel, ethonogestrel (3-Ketodesogestrel), nomegestrol acetate (NOMAC), norethisterone acetate (NETA), drospirenone, gestodene, dienogest,
  • COCPs such
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in combination with intrauterine devices, including progestine impregnated intrauterine devices, e.g. LNG-IUS levonorgestrel intrauterine system.
  • intrauterine devices including progestine impregnated intrauterine devices, e.g. LNG-IUS levonorgestrel intrauterine system.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in combination with a glucocorticoid receptor agonist, such as, by way of example and preferably, Cortisol, cortisone, hydrocortisone, prednisone, methyl-prednisolone, prednylidene, deflazacort, fluocortolone, triamcinolone, dexamethasone or betamethasone.
  • a glucocorticoid receptor agonist such as, by way of example and preferably, Cortisol, cortisone, hydrocortisone, prednisone, methyl-prednisolone, prednylidene, deflazacort, fluocortolone, triamcinolone, dexamethasone or betamethasone.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), such as by way of example and preferably acetylsalicylic acid, diclofenac, flurbiprofen, ibuprofen, indomethacin, mefenamic acid, meclofenamic acid, and naproxen.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in combination with analgesics, such as by way of example and preferably, acetaminophen, acetanilide, aminobenzoic acid, antipyrine, calcium or choline salicylate, codeine, phenatecin, phenyltoloxamine citrate, salicylamide, sodium salicylate, and sodium para-aminobenzoate.
  • analgesics such as by way of example and preferably, acetaminophen, acetanilide, aminobenzoic acid, antipyrine, calcium or choline salicylate, codeine, phenatecin, phenyltoloxamine citrate, salicylamide, sodium salicylate, and sodium para-aminobenzoate.
  • An embodiment of the invention is also a medicament, comprising a compound of the formula (I-A) or (I-B) as defined above in combination with a further active compound selected from the group consisting of Factor VIII, Factor IX, Factor Vila, activated prothrombin complex concentrates (aPCC) or prothrombin complex concentrates (PCCs), ⁇ -aminocaproic acid, ethamsylate, paraaminobutyl benzoic acid, tranexamic acid, desmopressin, danazol, hormonal treatments, including combined oral contraceptive pills (COCPs), progestin intrauterine system, glucocorticoid receptor agonists, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • COCPs oral contraceptive pills
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • An embodiment of the invention is also a medicament as defined above for the treatment and/or prophylaxis of hereditary or acquired hemostatic disorders, trauma, surgery, stroke, heavy menstrual bleeding, including heavy menstrual bleeding in women with underlying hemostatic disorders, postpartum hemorrhage, liver diseases, and hereditary angioedema.
  • An embodiment of the invention is also a method for the treatment and/or prophylaxis of hereditary or acquired hemostatic disorders, trauma, surgery, stroke, heavy menstrual bleeding, including heavy menstrual bleeding in women with underlying hemostatic disorders, postpartum hemorrhage, liver diseases, and hereditary angioedema in humans and animals using an effective amount of at least one compound of the formula (I-A) or (I-B) as defined above or a medicament as defined above.
  • the present invention further relates to medicaments that contain at least one compound of formula (I- A) or (I-B) according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and use thereof for the aforementioned purposes.
  • the compounds of formula (TA) or (I-B) according to the invention may be effective after systemic and/or local administration. For this purpose they can be applied in a suitable way, e.g. by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, or otic administration or as implant or stent.
  • the compounds of formula (TA) or (I-B) according to the invention can be administered in suitable dosage forms.
  • tablets uncoated or coated tablets, for example with enteric coatings or coatings with delayed dissolution or insoluble coatings, which control the release of the compound formula (TA) or (I-B) according to the invention
  • tablets or films/wafers that disintegrate rapidly in the oral cavity films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, are suitable for oral administration.
  • Parenteral administration can take place avoiding an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar
  • absorption e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal
  • Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders are suitable, among others, as dosage forms for parenteral application.
  • Intravenous administration can take place for example by bolus administration or by continuous infusion.
  • Inhaled pharmaceutical forms including powder inhalers, nebulizers
  • nasal drops nasal solutions or nasal sprays
  • tablets films/wafers or capsules for lingual, sublingual or buccal application, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents for example are suitable for other routes of administration.
  • the compounds of formula (I-A) or (I-B) according to the invention can be administered in the form of nasal drops, nasal solutions or nasal sprays for the treatment and/or prophylaxis of acute and recurrent nosebleed in patients, in particular in patients with underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (I-A) or (I-B) according to the invention can be administered in the form of patches soaked with the compounds of formula (I-A) or (I-B) according to the invention and applied to the wound for the treatment and/or prophylaxis of acute and recurrent bleeding in patients, in particular in patients with underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered intra-muscular, rectal or transvaginal for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with trauma and other forms of acute bleeding, in particular in patients with underlying hereditary or acquired hemostatic disorders.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered in form of a swish and swallow or a lozenge for the treatment and/or prophylaxis of acute and recurrent mouth bleeding in patients, in particular in patients with underlying hereditary or acquired hemostatic disorders.
  • a swish and swallow route of administration is defined as the administration of a liquid substance to the oral mucosa by swishing the drug inside the mouth for a certain amount of time then allowed to be swallowed. The drug action is both topical and systemic.
  • the compounds of formula (TA) or (TB) according to the invention can also be used in vitro or ex vivo to inhibit fibrinolysis, for example for in vitro/ex vivo assays, to inhibit fibrinolysis in blood and plasma products, to pretreat catheters and other medicinal devices and equipment, for surface coatings or in biological samples.
  • the compounds of formula (TA) or (TB) according to the invention can be transformed to the aforementioned dosage forms. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable auxiliaries.
  • auxiliaries include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g.
  • liquid polyethylene glycols such as sodium dodecyl sulphate, polyoxysorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • colorants e.g. inorganic pigments, for example iron oxides
  • taste and/or odour correctants for example sodium dodecyl sulphate, polyoxysorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • colorants e.g. inorganic pigments, for example iron oxides
  • An embodiment of the invention are pharmaceutical compositions comprising at least one compound of formula (I-A) or (I-B) according to the invention, preferably together with at least one inert, non-toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the above cited purposes.
  • the appropriate dosage of a compound of the invention (when used alone or in combination with other agents) will depend on the type of disease to be treated, the type of compound, the severity and course of the disease, whether the compound is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the compound, and the discretion of the attending physician.
  • the compound is suitably administered to the patient at one time or over a series of treatments.
  • 0.1 ⁇ g/kg to 100 mg/kg of the compound is an initial candidate dosage for administration to the patient, whether for example, by one or more separate administrations, or by continuous infusion.
  • a typical daily dosage might range from about 0.1 ⁇ g kg to 100 mg kg or more, depending on the factors mentioned above.
  • the treatment is sustained until a desired suppression of disease symptoms occurs.
  • An initial higher loading dose, followed by one or more lower doses may be administered.
  • other dosing regimen may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice or three times a day. According to a further embodiment, the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice a day. According to a further embodiment, the compounds of formula (I-A) or (I-B) according to the invention are administered orally once a day. For the oral administration, a rapid release or a modified release dosage form may be used.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice or three times a day on 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 days per month.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice or three times a day on 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 consecutive days per month.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice or three times a day on 3 or 4 or 5 or 6 or 7 days per month.
  • the compounds of formula (I-A) or (I-B) according to the invention are administered orally once or twice or three times a day on 3 or 4 or 5 or 6 or 7 consecutive days per month.
  • Instrument MS Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; column : Waters BEH C18 1.7 ⁇ 50 x 2.1 mm; solvent A: 1 1 water + 0.01 mol Ammonium formiate, solvent B: 1 1 Acetonitrile; gradient: 0.0 min 95% A ⁇ 0.1 min 95% A ⁇ 2.0 min 15% A ⁇ 2.5 min 15% A ⁇ 2.51 min 10% A ⁇ 3.0 min 10% A; oven: 40°C; flows: 0.5 ml/min; UV-detection: 210 nm.
  • a mixture of potassium carbonate (124 mg, 0.89 mmol), di-ieri-butyl[2',4',6'-tri(propan-2-yl)biphenyl-2- yl]phosphane ( iBu-XPhos) (38 mg, 0.089 mmol), allylpalladium(II) chloride dimer (8 mg, 0.022 mmol), methanesulfonamide (51 mg, 0.54 mmol), 1.8 ml acetonitrile and tert-b tyl 4-(10-bromo-2-oxo- l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l-carboxylate (200 mg, 0.45 mmol) was stirred for 15min at RT before being placed into a pre-heated bath at 80 °C.
  • the mixture was stirred 2 h at 60 °C under argon. After cooling to RT, the mixture was stirred with a 10% aqueous solution of 2-hydroxypropane-l,2,3-tricarboxylic acid. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were then concentrated and purified by preparative HPLC (gradient acetonitrile/water with 0.1 % trifluoroacetic acid). Evaporation of the combined product fractions yielded the title compound. The obtained amout was 152 mg (100 % purity, 72 % of theory).
  • tert-butyl 4 10-(tert-butylcarbamoyl)-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl]piperidine-l- carboxylate
  • the obtained amout was 125 mg (63 % purity, 46 % of theory).
  • the obtained amout was 82.6 mg (100 % purity, 47 % of theory).
  • the obtained amout was 71.0 mg (100 % purity, 41 % of theory).
  • the obtained amout was 120 mg (96 % purity, 72 % of theory).
  • the obtained amout was 76.6 mg (92 % purity, 48 % of theory).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 2,6-dimethylpyridin-3-amine 102 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 4-methylpyrimidin-2-amine 91.5 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • pyrimidin-2-amine 79.7 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 3-methylpyridin-2-amine 84 ⁇ , 840 ⁇ mol
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 2-aminopyridine-3-carbonitrile 99.9 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 3-fluoropyridin-2-amine 94.0 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 3,5-difluoropyridin-2-amine 109 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 150 mg, 335 ⁇
  • 6-methylpyridin-2-amine 90.7 mg, 838 ⁇
  • Tripotassium phosphate 99.6 mg, 469 ⁇
  • tBuBrettPhos 9.75 mg, 20.1 ⁇
  • tBuBrettPhos Pd G3 (17.2 mg, 20.1 ⁇ ) were dissolved in tert-Butanol (3.0 ml, 31 mmol).
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 200 mg, 447 ⁇
  • 4,6-dimethylpyridin-2-amine 137 mg, 1.12 mmol
  • Tripotassium phosphate 133 mg, 626 ⁇
  • tBuBrettPhos 13.0 mg, 26.8 ⁇
  • tBuBrettPhos Pd G3 22.9 mg, 26.8 ⁇
  • tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate 200 mg, 447 ⁇
  • 5-fluoropyridin-2-amine 125 mg, 1.12 mmol
  • Tripotassium phosphate 133 mg, 626 ⁇
  • tBuBrettPhos 13.0 mg, 26.8 ⁇
  • tBuBrettPhos Pd G3 22.9 mg, 26.8 ⁇

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Abstract

La présente invention concerne de nouvelles piperidinylpyrazolopyrimidinones substituées, des procédés pour leur préparation, les composés étant destinés à être utilisés seuls ou dans des associations dans une méthode pour le traitement et/ou la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie d'un saignement aigu et récurrent chez des patients présentant ou non des troubles hémostatiques héréditaires ou acquis sous-jacents, le saignement étant associé à une maladie ou à une intervention médicale choisie dans le groupe constitué par une ménorragie, une hémorragie postpartum, un choc hémorragique, un traumatisme, une opération chirurgicale, une transplantation, un accident vasculaire cérébral, des maladies hépatiques, un œdème de Quincke héréditaire, un saignement de nez, ainsi qu'une synovite et une lésion cartilagineuse à la suite d'une hémarthrose.
PCT/EP2016/059052 2015-04-30 2016-04-22 Indazolopyrimidinones comme inhibiteurs de la fibrinolyse Ceased WO2016173948A1 (fr)

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WO2022018256A1 (fr) * 2020-07-24 2022-01-27 Université Grenoble Alpes Composés pour le traitement de l'hémophilie

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US10668071B2 (en) * 2013-11-05 2020-06-02 Bayer Pharma Aktiengesellschaft (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
WO2022018256A1 (fr) * 2020-07-24 2022-01-27 Université Grenoble Alpes Composés pour le traitement de l'hémophilie
FR3112684A1 (fr) * 2020-07-24 2022-01-28 Université Grenoble Alpes Composés pour le traitement de l’hémophilie

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