WO2017153231A1 - N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation - Google Patents

N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation Download PDF

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WO2017153231A1
WO2017153231A1 PCT/EP2017/054866 EP2017054866W WO2017153231A1 WO 2017153231 A1 WO2017153231 A1 WO 2017153231A1 EP 2017054866 W EP2017054866 W EP 2017054866W WO 2017153231 A1 WO2017153231 A1 WO 2017153231A1
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formula
fluorine
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compound
methyl
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German (de)
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Hartmut Beck
Tobias THALER
Raimund Kast
Mark Meininghaus
Carsten TERJUNG
Hideki MIYATAKE ONDOZABAL
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present application relates to novel substituted N-cyclo-2-arylisoquinolinone-4-carboxamide derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for treatment and / or disease prevention, in particular for the treatment and / or prevention of fibrotic and inflammatory diseases.
  • Prostaglandin F2alpha belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid. After release from membrane phospholipids by A2 phospholipases, the arachidonic acid is oxidized by cyclooxygenases to the prostaglandin H2 (PGH2), which is further converted to PGF2a by PGF synthase. To a much lesser extent PGF2a can also be formed enzymatically from other prostaglandins such as PGE2 or PGD2 [Watanabe et al., J. Biol. Chem. 1985, 260, 7035-7041]. PGF2a is not stored, but released immediately after synthesis, causing its effects locally.
  • PGF2a is an unstable molecule (ti 2 ⁇ 1 minute) which rapidly rearranges enzymatically into the lung, liver and kidney to an inactive metabolite, 15-ketodihydro PGF2a [Basu et al, Acta Chem. Scand. 1992, 46, 108-1 10]. 15-Ketodihydro- PGF2a is detectable in large quantities in plasma and later in urine both under physiological and pathophysiological conditions.
  • the biological effects of PGF2a come about through the binding and activation of a membrane-bound receptor, the PGF2a receptor or the so-called FP receptor.
  • the FP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains.
  • the mouse and rat FP receptors could also be cloned [Abramovitz et al, J. Biol. Chem. 1994, 269, 2632-2636; Sugimoto et al, J. Biol. Chem. 1994, 269, 1356-1360; Kitanaka et al, Prostaglandins 1994, 48, 31-41].
  • FPA isoforms of the FP receptor
  • the FP receptor is the least selective, since PGD2a and PGD2 and PGE2 bind with nanomolar affinities [Woodward et al., Pharmacol. Rev. 2011, 63, 471-538]. Stimulation of the FP receptor leads primarily to Gq-dependent activation of phospholipase C, resulting in release of calcium and activation of diacylglycerol-dependent protein kinase C (PKC). The elevated intracellular calcium level leads to calmodulin-mediated stimulation of myosin-linked chain kinase (MLCK).
  • MLCK myosin-linked chain kinase
  • the FP receptor can also activate the Rho / Rhokinase signal transduction cascade via G12 / G13 and alternatively stimulate the Raf / MEK / MAP signaling pathway via Gi coupling [Woodward et al, Pharmacol. Rev. 2011, 63, 471-538].
  • PGF2a is involved in the regulation of numerous physiological functions such as ovarian function, embryonic development, changes in the lining of the uterus, uterine contraction, luteolysis and the induction of labor and delivery. PGF2a is also synthesized in the endometrium in epithelial cells where it stimulates cellular proliferation [Woodward et al., Pharmacol. Rev.
  • PGF2a is a potent stimulator of smooth muscle, vascular and bronchoconstriction and is involved in acute and chronic inflammatory processes [Basu, Mol. Cells 2010, 30, 383-391]. It was shown that 15-keto-dihydro-PGF2a, a stable metabolite of PGF2a, could be systemically detected in patients with rheumatoid arthritis, psoriatic arthrosis and osteoarthrosis. In kidney PGF2a is involved in water absorption, natriuresis and diuresis. In the eyes, PGF2a regulates the intraocular pressure.
  • PGF2a also plays an important role in bone metabolism: prostaglandin stimulates the sodium-dependent transport of inorganic phosphate into osteoblasts and increases the release of interleukin-6 and vascular endothelial growth factor (VEGF) into osteoblasts; In addition, PGF2a is a potent mitogen and survival factor for osteoblasts [Agas et al., J. Cell Physiol. 2013, 228, 25-29].
  • PGF2a / FP receptor plays a multifactorial role in endometallic adenocarcinomas (Yang et al., 2013 J Recept Signal Transduct, 33 (1): 14-27 / Increased expression of the FP receptor in progenitor cells of oligodendrocytes (OPCs) may be a marker for damage to oligodendrocyte and active myelin (Soldan et al., Neurology 2015, 84).
  • FP receptor-deficient mice and treatment with the FP antagonist AI-8810 have been shown to have significant neuroprotective effects after cerebral artery occlusion (Kim et al., 2012, Neurobiol Disease 48, 58-65).
  • PGF2a FP receptor activation is involved in various cardiovascular dysfunctions such as myocardial fibrosis, myocardial infarction and hypertension [Zhang et al., Frontiers in Pharmacol. 2010, 1, 1-7; Ding et al., Int. J. Biochem. Cell.
  • PGF2a 15-keto-dihydro-PGF2a in humans with living conditions at increased cardiovascular risk, such as in smokers (Helmersson et al., 2005 Atherosclerosis 181, 201-207), obesity (Sinaiko et al., 2005 Circulation 1 1 1, 1985-91), Type I diabetes (Basu et al., 2005), and Type II diabetes (Helmersson et al., 2004, Circulation 109, 1729-1734). (Zhang et al., Frontiers in Pharmacol 2010, 1: 1-7).
  • PGF2a receptor participates in joint inflammation and in the regulation of the signaling cascade of the bone morphogenetic protein (BMP) and promotes the differentiation of chondrocytes [Kim et al., Biochim. Biophys. Acta, 2015, 1853, 500-512]. More stable analogues of PGF2a have been developed for estrus synchronization and for influencing human reproductive functions, as well as for reducing intraocular pressure for the treatment of glaucoma [Basu, Mol. Cells 2010, 30, 383-391]. In the latter application, as a side effect the stimulation of hair growth, eg that of eyelashes, by the chemically more stable PGF2a analogues such as latanoprost was observed.
  • the genes of the FP receptor are expressed in human hair follicles of the scalp (Khidhir et al., J Invest Dermatol, 2009, Abstr 607). These findings suggest that the FP receptor is involved in the regulation of hair growth, and also in diseases such as, e.g. Hirsutism may be involved.
  • FP - / - mice bleomycin administration showed a significant reduction in hydroxyproline content as well as decreased induction of profibrotic genes in lung tissue.
  • the function of the lung in FP - / - mice was significantly improved compared to the wild-type mice.
  • PGF2a stimulates proliferation and collagen production via the FP receptor. Since this occurs independently of the profibrotic mediator TGF ⁇ , the PGF2a / FP receptor signaling cascade represents an independent pathway in the development of pulmonary fibrosis [Oga et al., Nat. Med. 2009, 15, 1426-1430].
  • the FP receptor plays an important role in many diseases, injuries and pathological changes whose genesis and / or progression is associated with inflammatory events and / or proliferative and fibroproliferative tissue and vascular remodeling. These may be, in particular, diseases and / or damage to the lung, the cardiovascular system or the kidney, or it may be a blood disorder, a cancerous disease or other inflammatory diseases.
  • idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome (BOS), chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis are inflammatory and fibrotic diseases and lung damage to be named in this connection.
  • Diseases and damages of the cardiovascular system in which the FP receptor is involved are, for example, tissue changes after a myocardial infarction and in heart failure.
  • Kidney diseases include kidney failure and kidney failure.
  • a disease of the blood is, for example, sickle cell anemia.
  • tissue degradation and remodeling in cancer processes are the invasion of cancer cells into the healthy tissue (metastasis) and the reformation of supplying blood vessels (neo-angiogenesis).
  • Other inflammatory diseases in which the FP receptor plays a role are, for example, osteoarthritis and multiple sclerosis.
  • Idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis is a progressive lung disease that, if left untreated, leads to an average death within 2.5 to 3.5 years after diagnosis. Patients are usually older than 60 years of age at the time of diagnosis, and men are more likely to be affected than women. Of the Onset of IPF is insidious and characterized by an increased shortness of breath and dry irritated cough. IPF belongs to the group of idiopathic interstitial pneumonias (IIP), a heterogeneous group of lung diseases characterized by varying degrees of fibrosis and inflammation, which are distinguished by clinical, imaging and histologic criteria.
  • IIP idiopathic interstitial pneumonias
  • IPF idiopathic pulmonary fibrosis
  • idiopathic pulmonary fibrosis is of particular importance due to its frequency and its aggressive nature [Ley et al, Am. J. Respir. Cht. Care Med. 2011, 183, 431-440].
  • IPF can be either sporadic or familial. The causes are currently not clear. In recent years, however, numerous indications have been found that chronic damage to the alveolar epithelium results in the release of profibrotic cytokines / mediators, followed by increased fibroblast proliferation and increased collagen fiber formation, resulting in patchy fibrosis and the typical honeycomb structure of the Lung comes [Strieter et al., Chest 2009, 136, 1364-1370].
  • Pulmonary hypertension is a progressive lung disease that, if left untreated, leads to death on average within 2.8 years of diagnosis.
  • chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value ⁇ 20 mmHg).
  • mPAP pulmonary arterial mean pressure
  • the pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels.
  • Chronic PH neo- muscularizes primarily non-muscularized pulmonary vessels, and the vascular musculature of already muscularized vessels increases in size.
  • idiopathic (or primary) pulmonary arterial hypertension is a very rare disease
  • secondary pulmonary hypertension is widespread and it is currently believed that PH is the third most common cardiovascular disease Disease group after coronary heart disease and systemic hypertension is [Naeije, in: AJ Peacock et al. (Eds.), Pulmonary Circulation.
  • New combination therapies are one of the most promising future treatment options for the treatment of pulmonary hypertension.
  • the exploration of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; E. B. Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733].
  • new therapeutic approaches which can be combined with the therapy concepts already on the market, could form the basis of a more efficient treatment and thus bring a great advantage for the patients.
  • pulmonary hypertension includes both primary and secondary subforms (NPAHPH), as defined by the Dana Point classification according to their respective etiology [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and Their treatment, 3 rd edition, Hodder Arnold Publ, 201 1, 197-206. Hoeper et al., J. Am. Coli. Cardio!., 2009, 54 (1), Suppl. S, S85- S96].
  • group 1 includes pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively).
  • PAH also includes persistent pulmonary hypertension in newborns and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medications (eg Appetite suppressants), with diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy.
  • APAH pulmonary arterial hypertension
  • diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
  • other diseases such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, and sple
  • Group 2 of the Dana Point classification summarizes PH patients with causative left ventricular disease, such as ventricular, atrial or valvular disease.
  • Group 3 includes forms of pulmonary hypertension associated with a lung disease, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and / or hypoxemia (eg sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, plant-related Malformations) are associated.
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung disease
  • IPF pulmonary fibrosis
  • hypoxemia eg sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, plant-related Malformations
  • Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, eg in thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or in non-thrombotic embolization (eg as a result of tumor diseases, parasites, foreign bodies).
  • CTEPH proximal and distal pulmonary arteries
  • non-thrombotic embolization eg as a result of tumor diseases, parasites, foreign bodies.
  • Rarer forms of pulmonary hypertension such as in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in Group 5.
  • Bronchiolitis obliterans syndrome is a chronic rejection reaction after lung transplantation. Within the first five years after lung transplantation, approximately 50-60% of all patients are affected and over 90% of patients within the first nine years [Estenne et al., Am. J. Respir. Crit. Care Med. 2003, 166, 440-444]. The cause of the disease is not clear. Despite many advances in the treatment of transplant patients, BOS case numbers have barely changed in recent years. BOS is the most important long-term complication of lung transplants and is considered the main reason that survival rates are still significantly lower than those of other organ transplants. BOS is an inflammatory event associated with changes in the lung tissue, especially those affecting the small airways.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea.
  • COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of over-45s are affected.
  • the object of the present invention is to identify and provide novel substances which are potent, chemically and metabolically stable, non-prostanoid antagonists of the FP receptor and are suitable as such for the treatment and / or prevention, in particular of fibrotic and inflammatory diseases.
  • WO 95/32948-A1, WO 96/02509-A1, WO 97/19926-A1 and WO 2000/031038-A1 disclose 2-arylquinoline-4-carboxamides as NK 3 - or dual NK 2 / NK 3 - Antagonists are known which are suitable for the treatment of diseases of the lung and the central nervous system.
  • WO 2016/004035 discloses 2-arylquinoline-4-carboxamides as TSH receptor agonists which can be used to treat dysfunctions and malignant thyroid changes.
  • WO 2000/064877 discloses quinoline-4-carboxamide derivatives. which can be used as NK 3 antagonists for the treatment of various diseases, including the lungs and the central nervous system.
  • quinoline derivatives are disclosed as sirtuin modulators, which can be used for the treatment of various diseases.
  • WO 2011/153553-A2 various bicyclic heteroaryl compounds are claimed as kinase inhibitors for the treatment of particular cancers.
  • WO 2013/074059 A2 lists various quinoline-4-carboxamide derivatives which can serve as inhibitors of cytosine deaminases for enhancing a DNA transfection of cells.
  • WO 2013/164326-A1 discloses ⁇ / 3-diphenylnaphthalene-1-carboxamides as agonists of the EP2 prostaglandin receptor for the treatment of respiratory diseases.
  • WO 2014/117090-A1 various 2-aryl quinoline derivatives are described as inhibitors of metalloenzymes.
  • WO 2012/122370-A2 discloses quinoline-4-carboxamide derivatives which can be used for the treatment of autoimmune and cancer diseases.
  • the present invention relates to compounds of the general formula (I)
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • R 7 is hydrogen or (C 1 -C 4 ) -alkyl which may be substituted up to three times by fluorine,
  • R 8 is (C 1 -C 4 ) -alkyl which may be substituted by hydroxy, methoxy or ethoxy or up to three times by fluorine
  • n is the number 0, 1 or 2
  • G is CR G or N
  • R D and R E independently of one another are hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy
  • R G is hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl
  • R 1 is halogen, up to five times fluorine-substituted (C 1 -C 4 ) -alkyl, up to three times fluorine-substituted methoxy, (trifluoromethyl) sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl, or cyclobutyl,
  • R 2 , R 3 and R 4 independently of one another represent hydrogen, halogen or up to three times fluorine-substituted methyl
  • R 5 is halogen, up to five times fluorine-substituted (C 1 -C 4 ) -alkyl, up to three times fluorine-substituted methoxy, hydroxyl, methylsulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl which may be substituted up to three times by fluorine,
  • R 10 is (C 1 -C 4 ) -alkyl, which may be substituted up to three times by fluorine, or phenyl
  • R 11A and R 11 B independently of one another denote hydrogen or (C 1 -C 4 ) -alkyl which may be substituted up to three times by fluorine,
  • Ar is phenyl which may be substituted up to three times, identically or differently, by fluorine, chlorine, methyl substituted up to three times by fluorine and methoxy substituted up to three times by fluorine, or by thienyl which is mono- or di-methyl or may simply be substituted by chlorine or bromine, or represents thiazolyl or pyridyl, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts, solvates and solvates of the salts encompassed by formula (I) and also those of the formula (I) encompassed, hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds encompassed by formula (I) below are not already salts, solvates and solvates of the salts.
  • Compounds of the invention are also N-oxides of the compounds of formula (I) and their salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include, in particular, the salts derived from customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris (hydroxymethyl) aminomethane, choline (2-hydroxy-N, N, N-trimethylethanamine), procaine, dicyclohexylamine , Dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.
  • customary bases such as,
  • physiologically acceptable salts of the compounds of the invention also include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and pamoic.
  • mineral acids e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, n
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers as well as their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform insulate components in a known manner.
  • chromatographic methods are used, in particular HPLC chromatography on achiral or chiral separation phases.
  • separation may also be via diastereomeric salts using chiral amine bases.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 129 l and 131 1.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • Such modifications of the compounds according to the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by generally customary methods known to the person skilled in the art, for example by the methods described below and the instructions reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the invention.
  • esters which can be hydrolyzed in physiological media, under the conditions of the biological tests described hereinafter, and in particular enzymatically or chemically in vivo to the free carboxylic acids, as the biologically predominantly active compounds.
  • esters (C 1 -C 4 ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred. Particularly preferred are methyl, ethyl or tert-butyl esters.
  • (C 1 -C 4) -alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • (C 1 -C 4 ) -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
  • alkoxy radical having 1 to 4 carbon atoms.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • Y is a group of the formula -C (H) (OH) - or -CHF-,
  • n is the number 0 or 2
  • R D is hydrogen or fluorine
  • G is CR G or N, in which
  • R G is hydrogen, fluorine or chlorine
  • R 4 independently of one another represent hydrogen, chlorine or methyl
  • R 5 is fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl,
  • Ar is phenyl which may be mono- or di-substituted by fluorine, thienyl which may be mono- or di-substituted by methyl or simply by chlorine or bromine, or by a group of the formula
  • # 3 represents the point of attachment to the quinoline ring
  • R 12 is chlorine or methyl
  • R 13 is chlorine or methoxy
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • R 8 is methyl or trifluoromethyl
  • n is the number 0 or 2
  • G is CR G or N, in which
  • R G is hydrogen, fluorine or chlorine
  • R 1 is chlorine, bromine, iodine, methyl, tert-butyl, difluoromethyl, trifluoromethyl, trimethylsilyl, ethynyl or cyclopropyl,
  • R 2 is hydrogen
  • R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl
  • R 3 and R 4 are in each case hydrogen
  • R 5 is fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl,
  • Ar represents phenyl, which may simply be substituted by fluorine,
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • R 1 is bromine
  • R 2 , R 3 and R 4 are hydrogen
  • R 5 is methyl, cyclopropyl or chlorine
  • Ar is phenyl
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • R 1 is bromine
  • R 2 , R 3 and R 4 are hydrogen
  • R 5 is methyl, cyclopropyl or chlorine
  • Ar is phenyl
  • a particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula
  • # 1 represents the point of attachment to R 6 .
  • # 2 represents the point of attachment to the nitrogen atom
  • R A is fluorine
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 1 is bromine
  • R 2 , R 3 and R 4 are each hydrogen
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 5 is methyl
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Ar is phenyl
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • radicals which are mentioned as being preferred, particularly preferred and very particularly preferred apply both to the compounds of the formula (I) and, correspondingly, to all intermediates.
  • Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that either
  • T is an ester protective group, in particular (C 1 -C 4 ) -alkyl, benzyl or 4-methylphenylsulfonylethyl, by ester cleavage to a compound of formula (IA)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , Q and Ar have the meanings given above, and the compounds according to the invention thus obtained are optionally converted with the corresponding (i) solvents and / or (ii) acids or bases into their solvates, salts and / or solvates of the salts.
  • Inert solvents for process steps (III) -> (IB), (IV) -> (IC), (IV) -> (ID), (IV) -> (I-E), (IV) -> (lF ), (V) -> (LG), (VI) -> (lH) and (VII) -> (lJ) are - depending on the method used - for example, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran , Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane,
  • Suitable bases for process steps (IV) -> (IC), (IV) -> (ID) and (IV) -> (IF) are - depending on the process used - conventional inorganic or organic bases.
  • These include preferably alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) - amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, / V-diisopropylethylamine, pyridine, 4-N, / V-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] non- 5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, / V-diisopropyl-ethylamine, pyridine, 4- / V, / V-dimethylaminopyridine, 1, 5 -Diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4- diazabicyclo [2.2.2] octane (DABCO ®) or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , Preference is given to pyridine for process step (IV) -> (IC), DBU for process steps (IV) -> (I-
  • the reactions mentioned are generally carried out, depending on the reactivity of the participating reactants, in a temperature range of 0 ⁇ bi s + 140 ⁇ .
  • the process steps (III) -> (IB) and (VI) -> (IH) are preferably in a temperature range of 80 ° carried out to 140 ⁇ .
  • Process steps (IV) -> (IC), (IV) -> (ID), (IV) -> (IE), (IV) -> (IF), (V) -> (LG) and (VII) -> (lJ) are preferably carried out in a temperature range of CC to 60 ⁇ .
  • the reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • some process steps may preferably be carried out under an argon atmosphere.
  • suitable ester protecting groups T are generally all protective groups known to the person skilled in the art, for example (C 1 -C 4 ) -alkyl, suitably substituted methyl, such as methylthiomethyl (MTM), tetrahydropyranyl (THP), 2- ( Trimethylsilyl) ethoxymethyl (SEM), benzyloxymethyl (BOM), phenacyl and N-phthalimidomethyl, suitable 2-substituted ethyl, such as 4-methylphenylsulfonylethyl (TSE), 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl and 2- ( 2 '-pyridyl) ethyl (PET), allyl, benzyl, appropriately substituted benzyl such as diphenylmethyl (DPM), bis (ortho-nitrophenyl) methyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl,
  • the cleavage of the ester is carried out by customary methods by treating the ester in an inert solvent with an acid or base, wherein in the latter variant, the initially formed salt of the carboxylic acid by subsequent treatment with acid in the free carboxylic acid is transferred.
  • the ester cleavage is preferably carried out with an acid.
  • Methyl and ethyl esters are preferably cleaved by means of a base.
  • benzyl esters can also be cleaved off by hydrogenation (hydrogenolysis) in the presence of a suitable catalyst, for example palladium on activated carbon.
  • Silyl esters can be obtained by treatment with acids or fluorides, e.g. Tetrabutylammonium fluoride are cleaved.
  • suitable inert solvents for these reactions are water and the organic solvents customary for ester cleavage.
  • these include in particular alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetonitrile, N, / V-dimethylformamide or dimethylsulfoxide. It is also possible to use mixtures of these solvents.
  • Suitable bases are the inorganic bases customary for a hydrolysis reaction. These include in particular alkali metal or alkaline earth metal hydroxides such as lithium, sodium, potassium or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preference is given to using aqueous lithium hydroxide solution or sodium hydroxide solution (sodium hydroxide solution).
  • Suitable acids for ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • hydrochloric acid or trifluoroacetic acid are used.
  • the ester cleavage is usually carried out in a temperature range from -20 ⁇ to + 100 ⁇ , preferably at 0 ⁇ C to +80 ⁇ C.
  • Suitable azide compounds include, for example, sodium azide, trimethylsilyl azide, dialkylaluminum azide and hydrazoic acid.
  • the reaction can be carried out with the addition of an additive or catalyst such as tributyltin oxide, tributyltin chloride, ammonium halide, copper sulfate, nickel ferrite (NiFe 2 0 4 ) or other metal compounds such as copper, zinc, zirconium, scandium salts or with the addition of acetic acid become.
  • reaction step (III) -> (IB) is preferably carried out either with sodium azide and ammonium chloride in DMF or with trimethylsilyl azide and di-butyltin oxide in toluene.
  • Suitable additives for process step (IV) -> (I-D) are DBU or other amine bases, such as triethylamine or diisopropylethylamine.
  • Suitable additives for process step (IV) -> (I-E) are Lewis acids such as, for example, silica gel or boron trifluoride diethyl etherate.
  • ⁇ /, ⁇ / '- thiocarbonyldiimidazole can alternatively be replaced by chlorocarbonyl sulfenyl chloride.
  • phosgene or suitable phosgene analogues are used.
  • Suitable phosgen analogues for process steps (IV) -> (IF) and (V) -> (IG) are, for example, diphosgene, phenyl chloroformate, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 2-ethylhexyl chloroformate, 2-ethylcyclohexyl chloroformate, triphosgene, diphenyl carbonate, Dimethyl carbonate or diethyl carbonate.
  • the process step (VI) -> (lH) is preferably carried out with (phenylsulfonyl) acetonitrile in N, ND ⁇ methyl formamide (DMF) and a solution of sodium azide in water, [cf. Tetrahedron Letters 2012, 53 (1), 59-63].
  • the amide formation in process step (VII) -> (lK) is usually carried out in the presence of a larger excess of the amine component of the formula (VIII), optionally with the addition of a customary tertiary amine base as auxiliary base, such as triethylamine, DIPEA, N- Methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine or 4- ⁇ /, ⁇ / -dimethylaminopyridine (DMAP).
  • a customary tertiary amine base such as triethylamine, DIPEA, N- Methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine or 4- ⁇ /, ⁇ / -dimethylaminopyridine (DMAP).
  • Inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, toluene, Xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), N, N-di
  • mixtures of such solvents can be used.
  • the preferred solvents differ depending on R 9 . If R 9 is hydrogen, the reaction of the compound of the formula (VII) preferably takes place in water, tetrahydrofuran, 1,4-dioxane, methanol or ethanol or a mixture of these solvents. If R 9 is one of the substituents other than hydrogen, preference is given to using tetrahydrofuran or dichloromethane. The reaction is usually carried out at a temperature of 0 ⁇ to + 40 ⁇ .
  • reaction is preferably carried out using sodium hydride as base in tetrahydrofuran or N, N-dimethylformamide as an inert solvent at a temperature of 0 ⁇ C to +80 ⁇ C.
  • the coupling reaction (IX) + (XII) -> (II) [amide formation] can be carried out with the aid of a condensation or activating agent or via the intermediate of a carboxylic acid chloride or carboxylic imidazolide obtainable from (IX).
  • Carbodiimides such as ⁇ /, ⁇ / '- diethyl, ⁇ /, ⁇ /' - dipropyl, ⁇ /, ⁇ / '- diisopropyl-, ⁇ /, ⁇ /' - dicyclohexylcarbodiimide are suitable as such condensation or activating agents.
  • DCC or ⁇ / (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as ⁇ , ⁇ '-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl 5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, ⁇ -chloroeneamines as in 1 -Chlorine- N, N, 2-trimethylprop-1 -ene-1-amine, 1, 3,5-triazine derivatives such as 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4 methylmorpholinium chloride, phosphorus compounds such as n-prop
  • inert solvents for the stated coupling reactions are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl ) ethers, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile , Pyridine, dimethyl sulfoxide, 1,4-d
  • N, / V-dimethylformamide is used.
  • the couplings are generally carried out in a temperature range from 0 ⁇ to +1 10 ⁇ , preferably at + 20 ⁇ to +80 ⁇ C.
  • the carboxylic acid imidazolides themselves are prepared by reaction of (IX) with ⁇ /, ⁇ / '- carbonyldiimidazole (CDI) at elevated temperature (+ 60 ⁇ to + 150 ⁇ ) in a correspondingly higher-boiling solvent such as N, / V-dimethylformamide (DMF). available.
  • CDI carbonyldiimidazole
  • DMF N, / V-dimethylformamide
  • the preparation of the acid chloride (IA) -> (VII) is carried out in a conventional manner by treating a carboxylic acid of formula (IA) with oxalyl chloride or thionyl chloride in an inert solvent such as dichloromethane, trichloromethane or 1,2-dichloroethane, optionally with a small amount on N, / V-dimethylformamide as a catalyst.
  • the reaction is generally carried out at a temperature of 0 ⁇ to + 30 "C.
  • compounds of formula (III) can be prepared under similar reaction conditions directly via amide coupling of a compound of formula (IX) with a compound of formula (XIII) (Scheme 1 b).
  • compounds of formula (III-A) or (VI-A) can be prepared via a nucleophilic substitution reaction of a haloaromatic of formula (XV) or via a palladium-catalyzed coupling reaction of a haloaromatic of formula (XVI) with a quinolinecarboxamide of formula (XIV) (Scheme 2).
  • the process step (XIV) + (XVI) -> (VI-A) takes place in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers, such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di-n-butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as tert-butanol or amyl alcohols or other solvents, such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), dimethylacetamide (DMA), toluene or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned.
  • ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di-n-butyl ether, glycol dimethyl
  • the process step (XIV) + (XVI) -> (VI-A) is carried out in the presence of a suitable palladium catalyst.
  • suitable palladium catalysts are palladium on activated carbon, palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, Bis (acetonitrile) palladium (II) chloride, [1, 1 'bis (diphenylphosphino) ferrocene] dichloropalladium (II), optionally in combination with additional phosphorous such as 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl (BINAP), (2-biphenyl) di-tert-butylphosphine, dicyclohexyl [2 ', 4', 6
  • precatalysts such as chloro- [2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-1,1-biphenyl] [2- (2-aminoethyl) -phenyl] palladium (II) (BrettPhos precatalyst), optionally in conjunction with additional phosphine ligands such as 2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-1, 1'-biphenyl (BrettPhos) use [see , eg SL Buchwald et al., Chem.
  • Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide, alkali metal or alkaline earth metal phosphates such as potassium phosphate, alkali metal alcoholates such as sodium or potassium ferric butylate and sodium methoxide, alkali phenolates such as sodium phenolate, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide or organic amines such as 1, 5-diazabicyclo [4.3.0] non -5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).
  • a suitable base include preferably alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali
  • the process step (XIV) + (XVI) -> (VI-A) is generally carried out in a temperature range from 0 ⁇ to + 200 ⁇ , preferably at + 10 ⁇ to + 150 ⁇ .
  • the reactions can also be carried out in closed vessels (microwave tubes) in a microwave apparatus.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, working at atmospheric pressure or in closed vessels (microwave tubes) below or above the boiling point of the solvent used.
  • the process step (XIV) + (XV) -> (III-A) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or other solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), ⁇ /, ⁇ / '- dimethylpropyleneurea (DMPU), N-methyl-pyrrolidone (NMP) or acetonitrile.
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • DMPU dimethylformamide
  • NMP N-methyl-pyrrolidone
  • the process step (XVI) + (XVII) -> (II-A) takes place in the presence of a suitable base, for example sodium hydride, and generally runs in a temperature range from -20 ° C to 50 ° C.
  • the subsequent substitution step is generally carried out in a temperature range from 20 ⁇ to 150 ⁇ .
  • Compounds of formula (IV) can be prepared by reacting compounds of formula (III) with hydroxylammonium chloride in the presence of bicarbonate; compounds of formula (VI) can be prepared by reacting compounds of formula (III) with diisobutylaluminum hydride (DIBAL-H) (Scheme 3).
  • DIBAL-H diisobutylaluminum hydride
  • the benzoyl chloride derivatives of the formula (XVII) are reacted with aromatic amines (Ar-NH 2 ), typically with the aid of a base such as pyridine, triethylamine or N, / V-diisopropylethylamine, to give amides of the formula (XVIII).
  • aromatic amines Ar-NH 2
  • a base such as pyridine, triethylamine or N, / V-diisopropylethylamine
  • the amide of formula (XVIII) may also be prepared by an amide coupling, starting from the carboxylic acid corresponding to (XVIII).
  • the transformation (XVIII) -> (XX) is carried out by reaction with an acylacetic acid ester of the formula (XIX), or another suitable ester such as methyl, ethyl or benzyl ester with the addition of / - proline, copper iodide or cesium carbonate as the catalyst or with the addition of a suitable palladium catalyst.
  • the subsequent cyclization to compounds of formula (XXI) is accomplished by the addition of molecular sieve, a Lewis acid such as aluminum chloride or boron trifluoride, or other dehydrating conditions.
  • the resulting ester of formula (XXI) is converted by the addition of TFA or other acid such as hydrochloric acid (eg, in 1, 4-dioxane) in the free carboxylic acid of formula (IX).
  • TFA or other acid such as hydrochloric acid (eg, in 1, 4-dioxane) in the free carboxylic acid of formula (IX).
  • hydrochloric acid eg, in 1, 4-dioxane
  • the compounds of the formula (XII) are commercially available or their preparation is described in the literature, or they can, starting from other commercially available compounds, be prepared by methods known to the person skilled in the art and known from the literature.
  • the amine functionality of the compounds of the formula (XII) can also be represented by the known Curtius rearrangement from the corresponding carboxylic acid azide (Scheme 6).
  • the carboxylic acid is first reacted with sodium azide to form the acid azide.
  • the carboxylic acid can be reacted with diphenylphosphoryl azidate (DPPA) under basic conditions, for example with triethylamine as the base, and in the presence of an alcohol such as tert-butanol or benzyl alcohol at elevated temperatures [cf. J. Am. Chem. Soc., 1972, 94 (17), 6203-6205].
  • DPPA diphenylphosphoryl azidate
  • the resulting protected amines can then be deprotected, usually in the case of a Boc protecting group by acid hydrolysis with addition of e.g. Hydrochloric acid or trifluoroacetic acid or in the case of a Z-protecting group by hydrogenation to the corresponding amine.
  • the temperature range in the Curtius rearrangement is typically in the range + 40 ⁇ bi s + 120 ⁇ . Inert solvents such as toluene or THF may be added. Other variants of the rearrangement of carboxylic acid to the amine are readily available to those skilled in the relevant literature.
  • transformations are carried out by customary methods familiar to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of organometallic compounds (eg Grignard compounds or organolithium), oxidation and reduction reactions, hydrogenation, Halogenation (eg fluorination, bromination), dehalogenation, amination, alkylation and acylation, the formation of carboxylic acid esters, carboxylic acid amides and sulfonamides, the ester cleavage and hydrolysis and the introduction and removal of temporary protecting groups.
  • reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of organometallic compounds (eg Grignard compounds or organolithium), oxidation and reduction reactions, hydrogenation, Halogenation (eg fluorination, bromination), dehalogenation, amination, alkylation and acylation, the formation of carboxylic acid esters, carb
  • the compounds according to the invention have valuable pharmacological properties and can be used for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention are potent, chemically and metabolically stable antagonists of the FP receptor and are therefore suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which in the course of an inflammatory event and / or a tissue or vascular remodeling FP receptor is involved.
  • these include, in particular, diseases such as the group of interstitial idiopathic pneumonia, including idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia Pneumonia, desquamative interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other unknown interstitial lung diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans - Syndrome (BOS), chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin De (AATD), pulmonary emphysema (eg, cigarette smoke induced lung emphy
  • IPPF id
  • the compounds of the present invention may further be used for the treatment and / or prevention of asthmatic diseases of varying severity with intermittent or persistent history (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma) of various types Forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, cough and cold sores (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and seasonal, allergic rhinitis, eg hay fever) and of polyps.
  • intermittent or persistent history refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma
  • bronchitis chronic bronchitis, infectious bronchitis, eosin
  • the compounds according to the invention can furthermore be used for the treatment and / or prevention of cardiovascular diseases, such as, for example, hypertension, cardiac insufficiency, coronary heart disease, stable and unstable angina pectoris, renal hypertension, peripheral and cardiac vascular diseases, arrhythmias, arrhythmias Atria and ventricles, as well as conduction disorders such as grade I-III atrio-ventricular blockages, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, tsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional Extrasystoles, sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, a
  • cardiac failure encompasses both acute and chronic manifestations of cardiac insufficiency as well as specific or related forms of the disease, such as acute decompensated heart failure, right heart failure, Left heart insufficiency, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy, congenital heart defects, heart valve defects, cardiac insufficiency with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, Pulmonalklappeninsuffizi- enz, combined heart valve defects , Myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy,
  • kidney diseases in particular renal insufficiency and kidney failure.
  • renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immune complex-induced kidney disease, toxicology-induced nephropathy, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome.
  • kidney cancer which diagnostically, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrate ions of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamylsynthetase, altered urinosmolarity or urine level, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis.
  • renal enzymes e.g. Glutamylsynthetase, altered urinosmolarity or urine level, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis.
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (eg hypercalemia, hyponatremia) and disorders in the bone and carbohydrate. Metabolism.
  • sequelae of renal insufficiency such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (eg hypercalemia, hyponatremia) and disorders in the bone and carbohydrate. Metabolism.
  • the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, such as benign prostatic syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes (LUTS). , neurogenic overactive bladder (OAB), incontinence such as mixed, urgency, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.
  • BPS benign prostatic syndrome
  • BPH benign prostate hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorders
  • LUTS lower urinary tract syndromes
  • OAB neurogenic overactive bladder
  • incontinence such as mixed, urgency, stress or overflow incontinence
  • MUI UUI, SUI, OUI
  • pelvic pain as well as erectile dysfunction and female sexual dysfunction.
  • the compounds of the invention may also be used to treat disorders of the
  • the compounds of the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis ), Pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, osteoarthritis, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases, and inflammatory ocular diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammation
  • IBD chronic intestinal inflammation
  • Crohn's disease chronic intestinal inflammation
  • ulcerative colitis ulcerative colitis
  • Pancreatitis peritonitis
  • cystitis cystitis
  • urethritis prostatitis
  • the compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, Morphaea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitororetinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin.
  • the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.
  • anemias such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.
  • the compounds of the invention are also useful in the treatment of cancers, such as skin cancers, brain tumors, breast cancers, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, and of malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.
  • cancers such as skin cancers, brain tumors, breast cancers, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract
  • malignant tumors of the lymphoproliferative system such as Hodgkin's and Non-Hodgkin's Lymphoma.
  • the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidaemias (Hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolaemia), xanthomatosis, Tangier's disease, obesity (obesity), obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-obesity).
  • lipid metabolism disorders and dyslipidaemias Hepolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolaemia), xanthomatosis, Tangier's disease, obesity (obesity), obesity, metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-obesity).
  • Insulin-dependent diabetes gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy
  • diseases of the gastrointestinal tract and the abdomen glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis
  • diseases of the central nervous system and neurodegenerative disorders stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy .
  • dermatitis abacribus dermatitis actinica
  • dermatitis allergica dermatitis ammoniacalis
  • dermatitis artefacta dermatitis autogenica
  • dermatitis atrophicans dermatitis calorica
  • dermatitis combustionis dermatitis congelationis
  • dermatitis cosmetica dermatitis escharotica
  • exfoliative dermatitis dermatitis gangrenosis
  • dermatitis haemostatica dermatitis herpetiformis
  • dermatitis lichenoides dermatitis linearis
  • dermatitis maligna medermecotoxic dermatitis
  • dermatitis palmaris et plantaris dermatitis parasitaria
  • the compounds of the invention are particularly suitable for the treatment and / or prevention of interstitial lung diseases, especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), inflammatory and fibro - skin and eye diseases and fibrotic diseases of the internal organs.
  • interstitial lung diseases especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), inflammatory and fibro - skin and eye diseases and fibrotic diseases of the internal organs.
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • Another object of the present invention is thus the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sGC soluble guanylate cyclase
  • sGC soluble guanylate cyclase
  • Prostacyclin analogs and IP receptor agonists such as, for example, and preferably louprost, beraprost, treprostinil, epoprostenol, or selexipag;
  • Endothelin receptor antagonists such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan;
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors, such as by way of example and preferably Ninte-danib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, Sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;
  • MMPs matrix metalloproteases
  • stromelysin a matrix metalloproteases
  • collagenases a subset of cells
  • gelatinases a matrix metalloproteases
  • aggrecanases a subset of cells
  • MMP-12 metallo-elastase
  • Antagonists of growth factors, cytokines and chemokines by way of example and preferably antagonists of TGF- ⁇ , CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;
  • Rho kinase inhibiting compounds such as exemplified and preferably Fasudil, Y-27632, SLx-21 19, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • the energy metabolism of the heart affecting compounds such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;
  • anti-obstructive agents such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically applied ⁇ -adrenergic receptor agonists ( ⁇ -mimetics) and the inhaled anti-muscarinergen substances; anti-inflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, pirfenidone or etanercept; antifibrotic agents, such as, by way of example and by way of illustration, adenosine A2b receptor antagonists, sphingosine 1-phosphate receptor 3 (S1 P3) antagonists, autotaxine inhibitors, lysophosphatidic acid receptor
  • antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances; hypotensive agents, by way of example and with preference from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, ⁇ -receptor blockers, ⁇ -receptor blockers , Mineralocorticoid receptor antagonists and diuretics;
  • lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR -a, PPAR- ⁇ and / or PPAR-8 agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; and or
  • Chemotherapeutic agents as described e.g. used for the treatment of neoplasms of the lungs or other organs.
  • the compounds according to the invention are administered in combination with a ⁇ -adrenergic receptor agonist such as, by way of example and by way of preference, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.
  • a ⁇ -adrenergic receptor agonist such as, by way of example and by way of preference, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.
  • the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • an anti-muscarinergic substance such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.
  • a corticosteroid such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, by way of example and preferably tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, ⁇ -receptor blocker, ⁇ -receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with a cti receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a ⁇ -receptor blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a ⁇ -receptor blocker by way of example and preferably propranolol, atenolol, timolol, pin
  • the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin all-antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone, eplerenone or finerenone.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth- azon, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trich
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-a- , PPAR- ⁇ and / or PPAR-8 agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • cholesterol absorption inhibitors polymeric bile acid adsorbents
  • the compounds according to the invention are administered in combination with a CETP inhibitor such as, by way of example and by way of preference, Torcetrapib (CP-529 414), JJT-705 or CETP-vaccine (Avant).
  • a CETP inhibitor such as, by way of example and by way of preference, Torcetrapib (CP-529 414), JJT-705 or CETP-vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist, by way of example and by preference.
  • a thyroid receptor agonist by way of example and by preference.
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implants, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implants, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-.gamma.-agonist, by way of example and preferably pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-8 agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • AS BT IBAT
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one inventive compound are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicines including powder inhalers, nebulizers, metered aerosols
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg patches)
  • milk pastes, foams, powdered powders, Implants or stents.
  • oral and parenteral administration in particular oral, intravenous and intrapulmonary (inhalative) administration.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others.
  • Carrier substances for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Carrier substances for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • the amount is generally about 0.1 to 50 mg per inhalation.
  • the compounds according to the invention can be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain sufficiently basic or acid functionalities.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • Purity specifications usually refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the aid of the 1 H NMR spectrum. Compounds may still contain residual solvents, which was not necessarily taken into account in the indication of purity. If no purity is specified, it is either a 100% purity according to automatic peak integration in the LC / MS chromatogram or the purity was not explicitly determined.
  • the 1 H NMR data of selected examples are noted in part in the form of 1 H NMR peaks.
  • For each signal peak first the ⁇ value in ppm and then the signal intensity in round brackets are listed.
  • the ⁇ value signal intensity number pairs of different signal peaks are listed separated by commas.
  • the peak list of an example therefore has the form: ⁇ (intensity i), ⁇ 2 (intensity 2 ), ..., ⁇ (intensity), ..., ⁇ ⁇ (intensity).
  • the intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities compared to other signals. For broad signals, multiple peaks or the center of the signal and their relative intensity can be shown compared to the most intense signal in the spectrum.
  • the lists of the 1 H NMR peaks are similar to the classical 1 H NMR prints and thus usually contain all the peaks listed in a classical NMR interpretation. In addition, they can, like classical 1 H-NMR prints solvent signals, signals from stereoisomers of the target compounds, which are also the subject of the invention, and / or show peaks of impurities.
  • the peaks of stereoisomers of the target compounds and / or peaks of impurities usually have on average a lower intensity than the peaks of the target compounds (for example with a purity of> 90%). Such stereoisomers and / or impurities may be typical of the particular production process. Their peaks can thus help to detect the reproduction of our manufacturing process by "by-product fingerprints.”
  • An expert calculating the peaks of the target compounds by known methods can isolate the peaks of the target compounds as needed, using additional intensity filters if necessary. This isolation would be similar to peak-picking in the classical 1 H NMR interpretation.
  • Example 1 Exemplary embodiments: Example 1
  • the PGF2a-induced calcium flux was used in FP-expressing CHEM1 cells (Millipore, HTS093C).
  • 3000 cells in 25 ⁇ M complete medium [DMEM F12, 10% FCS, 1 .35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX TM, 2% sodium bicarbonate, 1% Pen / Strep, 1% 100x nonessential amino acids] are added per well seeded a 384 multi-well plate (Greiner, TC plate, black with a clear bottom) and incubated at 37 ⁇ / 5% CO 2 for 24 hours.
  • DMEM F12, 10% FCS, 1 .35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX TM, 2% sodium bicarbonate, 1% Pen / Strep, 1% 100x nonessential amino acids are added per well seeded a 384 multi-well plate (Greiner, TC plate, black with a clear bottom) and incubated at 37 ⁇ / 5% CO 2 for 24 hours.
  • the medium Prior to measurement, the medium is passed through 30 ⁇ M Fluo-8 AM loading buffer [calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4), 2 mM CaCl 2 2 , 1 x SmartBlock (CANDOR Bioscience GmbH), 4.5 mM Probenecid, 5 ⁇ M Fluo-8 AM, 0.016% Pluronic®, 0.04% Brilliant black] and incubated at 37 ⁇ C / 5% C0 2 for 30 minutes.
  • the test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with calcium-free Tyrode / 2 mM CaCl 2 . 10 ⁇ of the prediluted substance solution are added to the Fluo-8 loaded cells and incubated at 37 ⁇ / 5% C0 2 for 10 minutes.
  • the FP receptor is activated by addition of 20 ⁇ 3 nM (final concentration) of PGF2a in calcium-free Tyrode / 2 mM CaCl 2 / 0.04% Brilliant black, and the calcium flux is determined by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds in a fluorescence meter (FLIPR Tetra®, Molecular Devices).
  • FP receptor binding assay human recombinant prostanoid FP receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0. The performance of this test is commercially available (Eurofins Panlabs, catalog # 268510). 80 ⁇ g of membrane are incubated with 1 nM [ 3 H] -PGF2a for 60 minutes at 25 °. The amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding is determined in the presence of 1 ⁇ cloprostenol. The membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -PGF2a.
  • Substances are tested for inhibitory activity at a concentration of 10 ⁇ or in the form of a dose-response curve [Ref. : Abramovitz et al., J. Biol. Chem. 1994, 269 (4): 2632].
  • human recombinant prostanoid CRTH2 receptors expressed in CHO-K1 cells are used in modified Tris-HCl buffer, pH 7.4.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 268030).
  • 4 ⁇ g of membrane are incubated with 1 nM [ 3 H] -PGD2 for 120 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed. Non-specific binding becomes determined in the presence of 1 ⁇ PGD2.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] PGD2.
  • Substances are tested for inhibitory activity at a concentration of 10 ⁇ or in the form of a dose-response curve [Lit .: Wright et al., Br. J. Pharmacol. 1998, 123 (7): 1317; Sharif et al., Br. J. Pharmacol. 2000, 131 (6): 1025].
  • human recombinant prostanoid EP1 receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 2681 10).
  • 14 ⁇ g of membrane are incubated with 1 nM [ 3 H] -PGE2 for 60 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed.
  • Non-specific binding is determined in the presence of 10 ⁇ PGE2.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -PGE2.
  • Substances are tested for inhibitory activity at a concentration of 10 ⁇ or in the form of a dose-response curve [Lit .: Abramovitz et al., Biochim. Biophys. Acta 2000, 1483 (2): 285; Funk et al., J. Biol. Chem. 1993, 268 (35): 26767].
  • human recombinant prostanoid EP2 receptors expressed in HEK293 cells are used in modified MES / KOH buffer, pH 6.0.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 268200).
  • 25 mg / ml membrane are incubated with 4 nM [ 3 H] -PGE2 for 120 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed.
  • Non-specific binding is determined in the presence of 10 ⁇ PGE2.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -PGE2.
  • human recombinant prostanoid EP3 receptors expressed in HEK293 cells are used in modified MES buffer, pH 6.0.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 268310).
  • 3 ⁇ g of membrane are incubated with 0.5 nM [ 3 H] -PGE2 for 120 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed.
  • Non-specific binding is determined in the presence of 10 ⁇ PGE2.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -PGE2.
  • Substances are tested for inhibitory activity at a concentration of 10 ⁇ or in the form of a dose-response curve [Lit .: Schmidt et al., Eur. J. Biochem. 1995, 228 (1): 23].
  • human recombinant prostanoid IP receptors expressed in HEK293 cells are used in modified HEPES buffer, pH 6.0.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 268600).
  • 15 ⁇ g of membrane are incubated with 5 nM [ 3 H] -loprotect for 60 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed. Unspecific binding is determined in the presence of 10 ⁇ l of lloprost.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -loprostone.
  • human recombinant prostanoid TP receptors expressed in HEK-293 EBNA cells are used in modified Tris / HCl buffer, pH 7.4.
  • the performance of this test is commercially available (Eurofins Panlabs, catalog # 285510).
  • 18.4 ⁇ g of membrane are incubated with 5 nM [ 3 H] -SQ-29,548 for 30 minutes at 25 °.
  • the amount of membrane protein can vary from lot to lot and is adjusted as needed.
  • Non-specific binding is determined in the presence of 1 ⁇ SQ-29,548.
  • the membranes are filtered, washed and then measured to determine the specific binding of [ 3 H] -SQ-29,548.
  • Substances are tested for inhibitory activity at a concentration of 10 ⁇ or in the form of a dose-response curve [Ref. : Saussy Jr. et al., J. Biol. Chem. 1986, 261: 3025; Hedberg et al., J. Pharmacol. Exp. Ther. 1988, 245: 786].
  • DP-expressing CHEM1 cells (Millipore, HTS091 C): 3000 cells in 25 ⁇ M complete medium [DMEM, 4.5 g / l glucose, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 0.25 mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin] are incubated per well of a 384 multititer plate (Greiner, Co.). Plate, black with a clear bottom) and incubated at 37 ⁇ / 5% C0 2 for 24 hours.
  • DMEM complete medium
  • FCS 1% 100x non-essential amino acids
  • 10 mM HEPES 0.25 mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ⁇ / 5% CO 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • EP1-expressing CHEM1 cells (Millipore, HTS099C): 3000 cells in 25 ⁇ M complete medium [DMEM, 4.5 g / l glucose, 10 % Heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 0.25 mg / ml geneticin (G418), 100 U / ml penicillin and streptomycin] are per well of a 384 multititer plate (Greiner, TC Plate, black with a clear bottom) and incubated at 37 ⁇ / 5% C0 2 for 24 hours.
  • DMEM 4.5 g / l glucose
  • 10 % Heat-inactivated FCS 1% 100x non-essential amino acids
  • 10 mM HEPES 0.25 mg / ml geneticin (G418), 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ⁇ / 5% C0 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • EP2-expressing CHEM9 cells (Millipore, HTS185C): 3000 cells in 25 ⁇ l plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are added to each well of a 384 multititer plate (Greiner, TC plate, black with clear bottom ) and incubated at 37 ⁇ / 5% C0 2 for 24 hours.
  • DMEM 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ⁇ / 5% C0 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • EP3 splice variant 6
  • CHEM1 cells (Millipore, HTS092C): 3000 cells in 25 ⁇ l plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin] are incubated per well of a 384 multititer plate (Greiner, Co.). Plate, black with a clear bottom) and incubated at 37 ⁇ / 5% C0 2 for 24 hours.
  • DMEM 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° C / 5% CO 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • EP4-expressing CHEM1 cells (Millipore, HTS142C): 3000 cells in 25 ⁇ plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are per well of a 384-Multititerplatte (Greiner, TC plate, black with clear soil) and incubated at 37 ⁇ / 5% CO 2 for 24 hours.
  • DMEM 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x non-essential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ° C / 5% C0 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • EP4 agonism measurement in a fluorescence meter 10 ⁇ the prediluted substance-solution is added to the loaded with calcium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 ⁇ / 5% CO 2 for 10 minutes.
  • EP4- measurement of the EP4 receptor in the FLIPR Tetra ® is prepared by adding 20 ⁇ -26 nM (2 x EC50, final concentration) PGE2 activated in, for example, calcium-free Tyrode / 2 mM CaCl 2 and the calcium Flux determined by measuring the fluorescence at Ex.
  • IP-expressing CHEM1 cells (Millipore, HTS131 C): 3000 cells in 25 ⁇ plating medium [DMEM, 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin) are each well of a 384 multititer plate (Greiner, TC plate, black with clear Soil) and incubated at 37 ⁇ / 5% C0 2 for 24 hours.
  • DMEM 4.5 g / l glucose, 4 mM glutamine, 10% heat-inactivated FCS, 1% 100x nonessential amino acids, 10 mM HEPES, 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ⁇ / 5% C0 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3 , pH 7.4) / 2 mM CaCl 2 prediluted.
  • IP agonism measurement are in one Fluorescence meter (FLIPR Tetra ® , Molecular Devices) 10 ⁇ the prediluted substance solution added to the Caicium dye-loaded cells and determines the calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 ⁇ / 5% C0 2 for 10 minutes.
  • fluorescent meter FLIPR Tetra ® , Molecular Devices
  • IP antagonism measurement of IP receptor in the FLIPR Tetra ® is prepared by adding 20 ⁇ -106 nM (2 x EC50, final concentration) iloprost in, for example, calcium-free Tyrode / 2 mM CaCl 2 activated and the calcium Flux determined by measuring the fluorescence at Ex.
  • TP-expressing CHEM1 cells (Millipore, HTS081 C): 3000 cells in 25 ⁇ plating medium [DMEM, 10% heat-inactivated FCS , 100% non-essential amino acids, 10 mM HEPES, 0.25 mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin] are per well of a 384 multititer plate (Greiner, TC plate, black with clear bottom ) and incubated at 37 ⁇ / 5% CO 2 for 24 hours.
  • DMEM 10% heat-inactivated FCS , 100% non-essential amino acids
  • 10 mM HEPES 0.25 mg / ml Geneticin (G418), 100 U / ml penicillin and streptomycin
  • the medium Prior to measurement, the medium is replaced with 30 ⁇ M Calcium Dye Loading Buffer (FLIPR Calcium Assay, Molecular Devices) and incubated at 37 ⁇ / 5% CO 2 for 60 minutes.
  • the test substance is prepared in DMSO at various concentrations as a dose response curve (starting concentration 10 mM, dilution factor 3.16) and 1:50 with, for example, calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl 2 , 4.8 mM NaHCO 3, pH 7.4) / 2 mM CaC prediluted.
  • TP-agonism measurement in a fluorescence meter FLIPR Tetra ®, Molecular Devices
  • FLIPR Tetra ® Fluorescence meter
  • Molecular Devices For the TP-agonism measurement in a fluorescence meter (FLIPR Tetra ®, Molecular Devices) is added 10 ⁇ the prediluted substance solution to the loaded Caicium dye cells and calcium flux by measuring the fluorescence at Ex. 470 nm / Em. 525 nm for 120 seconds. Thereafter, the cells are incubated at 37 ⁇ / 5% CO 2 for 10 minutes.
  • For the TP antagonism measurement of TP-receptor in the FLIPR Tetra ® is prepared by adding 20 ⁇ -88 nM (2 x EC50, final concentration) U46619 in, for example, calcium-free Tyrode / 2 mM CaC activated and the calcium flux determined by measuring the fluorescence at Ex.
  • Bleomycin-induced lung fibrosis in the mouse or rat is a widely used animal model of pulmonary fibrosis.
  • Bleomycin is a glycopeptide antibiotic used in oncology for the treatment of testicular tumors, Hodgkin's and non-Hodgkin's tumors. It is eliminated renally, has a half-life of about 3 hours and, as a cytostatic, influences different phases of the division cycle [Lazo et al., Cancer Chemother. Biol. Response Modif. 15, 44-50 (1994)]. Its anti-neoplastic effect is based on an oxidative damaging effect on DNA [Hay et al., Arch. Toxicol. 65, 81-94 (1991)].
  • the lung tissue is particularly endangered in comparison with bleomycin, since so-called cysteine hydrolases, which lead to inactivation of bleomycin in other tissues, are only present in small numbers.
  • ARDS acute respiratory distress syndrome
  • Administration of bleomycin may be single or multiple, intratracheal, inhalative, intravenous or intraperitoneal.
  • the treatment of the animals with the test substance starts on the day of the first application of bleomycin or therapeutically 3-14 days later and extends over a period of 2-6 weeks.
  • a bronchioalveolar lavage is performed to assess cell content and pro-inflammatory and pro-fibrotic markers as well as lung function measurements and histological assessment of pulmonary fibrosis.
  • DQ12 quartz induced lung fibrosis is a widely used animal model of pulmonary fibrosis [Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)].
  • DQ12 quartz is a highly active quartz that breaks or grinds. Intratracheal or inhaled administration of DQ12-quartz leads to alveolar proteinosis in mice and rats followed by interstitial pulmonary fibrosis. The animals receive a single or multiple intratracheal or inhaled instillation of DQ12 quartz.
  • the treatment of the animals with the test substance starts on the day of the first instillation of the silicate or therapeutically 3-14 days later and extends over a period of 3-12 weeks.
  • a bronchioalveolar lavage is performed to determine cell content and pro-inflammatory and pro-fibrotic markers as well as lung function measurements and histological assessment of pulmonary fibrosis.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used.
  • Orally administrable suspension :
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. i.v. Lösunq:
  • the compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution).
  • a physiologically acceptable solvent e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Abstract

L'invention concerne de nouveaux dérivés de N-cyclo-2-arylisochinolinon-4-carboxamides substitués, des procédés de préparation de ces composés, leur utilisation seuls ou dans des combinaisons pour le traitement et/ou la prévention de maladies, et leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prévention de maladies, notamment pour le traitement et/ou la prévention de maladies fibrotiques et inflammatoires.
PCT/EP2017/054866 2016-03-09 2017-03-02 N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation WO2017153231A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861111A (zh) * 2021-11-23 2021-12-31 浙江工业大学 N-芳基-4-硫(硒)乙基多元环并[c]-1-吡啶酮衍生物及其合成方法和应用
WO2023165591A1 (fr) * 2022-03-03 2023-09-07 Immuther Pharmatech (Shanghai) Co., Ltd. Composés et leurs utilisations utilisés en tant qu'antagonistes de lpar5

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032948A1 (fr) 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1996002509A1 (fr) 1994-07-14 1996-02-01 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes de la neurokinine 3 (nk3)
WO1997019926A1 (fr) 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2000031038A1 (fr) 1998-11-20 2000-06-02 Smithkline Beecham S.P.A. Derives de quinoline utilises comme ligands des recepteurs nk-2 et nk-3
WO2000064877A1 (fr) 1999-04-26 2000-11-02 Neurogen Corporation 2-aminoquinolinecarboxamides: ligands de recepteurs de la neurokinine
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
US20020128233A1 (en) * 2000-09-14 2002-09-12 Burk Robert M. Interheteroaryl 7-oxabicyclic [2.2.1]heptane oxazoles as prostaglandin F2alpha antagonists
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2006094237A2 (fr) 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Modulateurs de la sirtuine a base d'acridine et de quineoline
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2011153553A2 (fr) 2010-06-04 2011-12-08 The Regents Of The University Of California Méthodes et compositions pour l'inhibition de kinases
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2012122370A2 (fr) 2011-03-08 2012-09-13 Eutropics Pharmaceuticals, Inc. Compositions et méthodes utiles dans le traitement de maladies
WO2013074059A2 (fr) 2010-11-05 2013-05-23 Regents Of The University Of Minnesota Modulateurs de la cytosine désaminase pour l'amélioration de la transfection d'adn
US20130165665A1 (en) * 2011-12-21 2013-06-27 Allergan, Inc. Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response
WO2013164326A1 (fr) 2012-05-03 2013-11-07 Takeda Gmbh Nouveaux agonistes du récepteur ep2
WO2014117090A1 (fr) 2013-01-28 2014-07-31 Viamet Pharmaceuticals, Inc. Composés inhibiteurs de métalloenzyme
WO2016004035A1 (fr) 2014-07-01 2016-01-07 Icahn School Of Medicine At Mount Sinai Dérivés 2-aryl-4-quinoléinecarboxamide pour le traitement de maladies de la thyroïde

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032948A1 (fr) 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1996002509A1 (fr) 1994-07-14 1996-02-01 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes de la neurokinine 3 (nk3)
WO1997019926A1 (fr) 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2000031038A1 (fr) 1998-11-20 2000-06-02 Smithkline Beecham S.P.A. Derives de quinoline utilises comme ligands des recepteurs nk-2 et nk-3
WO2000064877A1 (fr) 1999-04-26 2000-11-02 Neurogen Corporation 2-aminoquinolinecarboxamides: ligands de recepteurs de la neurokinine
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
US20020128233A1 (en) * 2000-09-14 2002-09-12 Burk Robert M. Interheteroaryl 7-oxabicyclic [2.2.1]heptane oxazoles as prostaglandin F2alpha antagonists
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2006094237A2 (fr) 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Modulateurs de la sirtuine a base d'acridine et de quineoline
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2011153553A2 (fr) 2010-06-04 2011-12-08 The Regents Of The University Of California Méthodes et compositions pour l'inhibition de kinases
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2013074059A2 (fr) 2010-11-05 2013-05-23 Regents Of The University Of Minnesota Modulateurs de la cytosine désaminase pour l'amélioration de la transfection d'adn
WO2012122370A2 (fr) 2011-03-08 2012-09-13 Eutropics Pharmaceuticals, Inc. Compositions et méthodes utiles dans le traitement de maladies
US20130165665A1 (en) * 2011-12-21 2013-06-27 Allergan, Inc. Compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response
WO2013164326A1 (fr) 2012-05-03 2013-11-07 Takeda Gmbh Nouveaux agonistes du récepteur ep2
WO2014117090A1 (fr) 2013-01-28 2014-07-31 Viamet Pharmaceuticals, Inc. Composés inhibiteurs de métalloenzyme
WO2016004035A1 (fr) 2014-07-01 2016-01-07 Icahn School Of Medicine At Mount Sinai Dérivés 2-aryl-4-quinoléinecarboxamide pour le traitement de maladies de la thyroïde

Non-Patent Citations (90)

* Cited by examiner, † Cited by third party
Title
"Citation of NMR Peaklist Data within Patent Applications", RESEARCH DISCLOSURE DATABASE NUMBER 605005, 1 August 2014 (2014-08-01), Retrieved from the Internet <URL:http://www.researchdisclosure.com/searching-disclosures>
"Pulmonary Circulation. Diseases and their treatment", 2011, HODDER ARNOLD PUBL., pages: 3
ABRAMOVITZ ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1483, no. 2, 2000, pages 285
ABRAMOVITZ ET AL., J. BIOL. CHEM., vol. 269, 1994, pages 2632 - 2636
ABRAMOVITZ ET AL., J. BIOL. CHEM., vol. 269, no. 4, 1994, pages 2632
AGAS ET AL., J. CELL PHYSIOL., vol. 228, 2013, pages 25 - 29
AIHARA ET AL., PLOS ONE, vol. 8, 2013, pages 1 - 6
ARMSTRONG ET AL., BR. J. PHARMACOL., vol. 97, no. 3, 1989, pages 657
BASTIAANSEN ET AL., ARTHRITIS RHEUM., vol. 65, 2013, pages 2070 - 2080
BASTIEN ET AL., J. BIOL. CHEM., vol. 269, no. 16, 1994, pages 11873
BASU ET AL., ACTA CHEM. SCAND., vol. 46, 1992, pages 108 - 110
BASU, MOL. CELLS, vol. 30, 2010, pages 383 - 391
BEHR ET AL., EUR. RESPIR. J., vol. 31, 2008, pages 1357 - 1367
BOIE ET AL., EUR. J. PHARMACOL., vol. 340, no. 2-3, 1997, pages 227
BOIE ET AL., J. BIOL. CHEM., vol. 269, no. 16, 1994, pages 12173
C. H. XIAO ET AL., CIRCULATION, vol. 104, 2001, pages 2210 - 2215
C. R. KENNEDY ET AL., NAT. MED., vol. 5, 1999, pages 217 - 220
CARLSON ET AL., MULT. SCLEROSIS, vol. 23, no. 11, 2015, pages 467 - 468
D. MONTANA; G. SIMONNEAU ET AL.: "Pulmonary Circulation. Diseases and their treatment", 2011, HODDER ARNOLD PUBL., pages: 197 - 206
D. STOLZ ET AL., EUR. RESPIR. J., vol. 32, 2008, pages 619 - 628
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 October 2012 (2012-10-22), XP002768351, Database accession no. 1401585-50-9 *
DAVIS ET AL., BR. J. PHARMACOL., vol. 130, no. 8, 2000, pages 1919
DING ET AL., INT. J. BIOCHEM. & CELL BIOL., vol. 44, 2012, pages 1031 - 1039
DING ET AL., INT. J. BIOCHEM. CELL. BIOL., vol. 44, 2012, pages 1031 - 1039
DING ET AL., J. MOL. MED., vol. 6, 2014, pages 629 - 640
E. B. ROSENZWEIG, EXPERT OPIN. EMERGING DRUGS, vol. 11, 2006, pages 609 - 619
ESTENNE ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 166, 2003, pages 440 - 444
F. USHIKUBI ET AL., NATURE, vol. 395, 1998, pages 281 - 284
FUNK ET AL., J. BIOL. CHEM., vol. 268, no. 35, 1993, pages 26767
G. A. FITZGERALD, N. ENGL. J. MED., vol. 351, 2004, pages 1709 - 1711
GHOFRANI ET AL., HERZ, vol. 30, 2005, pages 296 - 302
HASSAN J. ET AL., CHEM. REV., vol. 102, 2002, pages 1359 - 1469
HAY ET AL., ARCH. TOXICOL., vol. 65, 1991, pages 81 - 94
HEDBERG ET AL., J. PHARMACOL. EXP. THER., vol. 245, 1988, pages 786
HELMERSSON ET AL., ATHEROSCLEROSIS, vol. 181, 2005, pages 201 - 207
HELMERSSON ET AL., CIRCULATION, vol. 109, 2004, pages 1729 - 1734
HOEPER ET AL., J. AM. COLL. CARDIOL.,, vol. 54, no. 1, 2009, pages S85 - S96
I. BLANCO ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 181, 2010, pages 270 - 278
J. AM. CHEM. SOC., vol. 94, no. 17, 1972, pages 6203 - 6205
JOHNSTON ET AL., AM J OPHTHALMOL, 1997, pages 124 - 544,547
K. HANASAKI ET AL., BIOCHEM. PHARMACOL., vol. 38, 1989, pages 2967 - 2976
K. WATANABE ET AL., CANCER RES., vol. 59, 1999, pages 5093 - 5096
K. YOSHIDA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 99, 2002, pages 4580 - 4585
KANNO ET AL., ARTHRITIS RHEUM., vol. 65, 2013, pages 492 - 502
KHIDHIR ET AL., J INVEST DERMATOL, 2009
KIM ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1853, 2015, pages 500 - 512
KIM ET AL., NEUROBIOL DISEASE, vol. 48, 2012, pages 58 - 65
KITANAKA ET AL., PROSTAGLANDINS, vol. 48, 1994, pages 31 - 41
LAZO ET AL., CANCER CHEMOTHER. BIOL. RESPONSE MODIF., vol. 15, 1994, pages 44 - 50
LETTIERI ET AL., CHEST, vol. 129, 2006, pages 746 - 752
LEY ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 183, 2011, pages 431 - 440
M. HIRATA ET AL., NATURE, vol. 349, 1991, pages 617 - 620
M. HUMBERT ET AL., J. AM. COLL. CARDIOL., vol. 43, 2004, pages 13S - 24S
M. KOTANI ET AL., GENOMICS, vol. 40, 1997, pages 425 - 434
M. KOTANI ET AL., MOL. PHARMACOL., vol. 48, 1995, pages 869 - 879
M. NGUYEN ET AL., NATURE, vol. 390, 1997, pages 78 - 81
N. YANG ET AL., J. CLIN. INVEST., vol. 111, 2003, pages 727 - 735
OGA ET AL., NAT. MED., vol. 15, 2009, pages 1426 - 1430
OLMAN, NAT. MED., vol. 15, 2009, pages 1360 - 1361
O'REILLY ET AL., AM. J. PHYSIOL. LUNG CELL. MOL. PHYSIOL., vol. 288, 2005, pages L1010 - L1016
P. J. BARNES, N. ENGL. J. MED., vol. 343, 2000, pages 269 - 280
S. ALI ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 17397 - 17403
S. L. BUCHWALD ET AL., CHEM. SCI., vol. 4, 2013, pages 916
S. NARUMIYA ET AL., PHYSIOL. REV., vol. 79, 1999, pages 1193 - 1226
S. NARUMIYA; G. A. FITZGERALD, J. CLIN. INVEST., vol. 108, 2001, pages 25 - 30
SALES ET AL., AM J PATHOL, vol. 176, 2010, pages 431
SALES ET AL., ENDOCRINOLOGY, vol. 148, 2007, pages 3635 - 44
SAUSSY JR. ET AL., J. BIOL. CHEM., vol. 261, 1986, pages 3025
SCHMIDT ET AL., EUR. J. BIOCHEM., vol. 228, no. 1, 1995, pages 23
SHARIF ET AL., BR. J. PHARMACOL., vol. 131, no. 6, 2000, pages 1025
SHIMBORI ET AL., EXP. LUNG RES., vol. 36, 2010, pages 292 - 301
SINAIKO ET AL., CIRCULATION, vol. 111, 2005, pages 1985 - 1991
STRIETER ET AL., CHEST, vol. 136, 2009, pages 1364 - 1370
SUGIMOTO ET AL., J. BIOL. CHEM., vol. 269, 1994, pages 1356 - 1360
SUGIMOTO ET AL., J. PHARMACOL. EXP. THER., vol. 305, no. 1, 2003, pages 347
T. ITO ET AL., CURR. MED. CHEM., vol. 14, 2007, pages 719 - 733
T. KUNIKATA ET AL., NAT. IMMUNOL., vol. 6, 2005, pages 524 - 531
T. MATSUOKA ET AL., SCIENCE, vol. 287, 2000, pages 2013 - 2017
T. MURATA ET AL., NATURE, vol. 388, 1997, pages 678 - 682
TETRAHEDRON LETTERS, vol. 53, no. 1, 2012, pages 59 - 63
VON DER BECK ET AL., DER PNEUMOLOGE, vol. 10, no. 2, 2013, pages 105 - 111
WATANABE ET AL., J. BIOL. CHEM., vol. 260, 1985, pages 7035 - 7041
WOODWARD ET AL., PHARMACOL. REV., vol. 63, 2011, pages 471 - 538
WRIGHT ET AL., BR. J. PHARMACOL., vol. 123, no. 7, 1998, pages 1317
XIAO ET AL., ARTERIOSCLER THROMB VASC BIOL., vol. 35, 2015, pages 1687 - 1695
Y. CHENG ET AL., SCIENCE, vol. 296, 2002, pages 539 - 541
Y. MATSUOKA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 102, 2005, pages 16066 - 16071
YANG ET AL., J RECEPT SIGNAL TRANSDUCT, vol. 33, no. 1, 2013, pages 14 - 27
ZHANG ET AL., FRONTIERS IN PHARMACO/, vol. 1, 2010, pages 1 - 7
ZHANG ET AL., FRONTIERS IN PHARMACOL., vol. 1, 2010, pages 1 - 7

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