EP3271334A1 - N-bicyclo-2-arylchinolino-4-carboxamides substitués et leur utilisation - Google Patents

N-bicyclo-2-arylchinolino-4-carboxamides substitués et leur utilisation

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Publication number
EP3271334A1
EP3271334A1 EP16709919.1A EP16709919A EP3271334A1 EP 3271334 A1 EP3271334 A1 EP 3271334A1 EP 16709919 A EP16709919 A EP 16709919A EP 3271334 A1 EP3271334 A1 EP 3271334A1
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EP
European Patent Office
Prior art keywords
mmol
methyl
mixture
compound
formula
Prior art date
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EP16709919.1A
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German (de)
English (en)
Inventor
Hartmut Beck
Tobias THALER
Raimund Kast
Mark Meininghaus
Carsten TERJUNG
Uwe Muenster
Britta Olenik
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Bayer Pharma AG
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Bayer Pharma AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to novel substituted V-bicyclo-2-arylquinoline-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. Upon 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 PGF2oc can also be formed enzymatically from other prostaglandins such as PGE2 or PGD2 [Watanabe et al, J. Biol. Chem. 1985, 260, 7035-7041].
  • PGF2oc is not stored, but released immediately after synthesis, causing its effects locally.
  • PGF2oc is an unstable molecule ( ⁇ 1 minute) rapidly enzymatically rearranged into the lung, liver and kidney to an inactive metabolite, 15-ketodihydro-PGF2oc [Basu et al., Acta Chem. Scand. 1992, 46, 108-110].
  • 15-Ketodihydro-PGF2 is detectable in larger amounts in plasma and later also in urine both under physiological and pathophysiological conditions.
  • the biological effects of PGF2oc come about through the binding and activation of a membrane-bound receptor, the PGF2oc 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].
  • the FP receptor In humans, there are two isoforms of the FP receptor, FPA and FPB. Of the prostanoid receptors, the FP receptor is the least selective, as PGD2oc and PGE2 bind to it with nanomolar affinities in addition to PGF2oc [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 increased intracellular calcium level leads to calmodulin-mediated stimulation of myosin light chain kinase (MLCK).
  • MLCK myosin light 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, 65, 471-538].
  • PGF2oc is involved in the regulation of numerous physiological functions, such as ovarian functions, embryonic development, changes in the endometrium, uterine contraction, Luteolysis and in the induction of labor and delivery. PGF2oc is also synthesized in the endometrium in epithelial cells where it stimulates cellular proliferation [Woodward et al, Pharmacol. Rev. 2011, 63, 471-538]. In addition, PGF2oc 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]. In kidney PGF2oc is involved in water absorption, natriuresis and diuresis.
  • PGF2oc regulates the intraocular pressure.
  • PGF2oc 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;
  • VEGF vascular endothelial growth factor
  • PGF2oc is a potent mitogen and survival factor for osteoblasts [Agas et al., J. Cell Physiol. 2013, 228, 25-29].
  • PGF2-FP receptor activation has been shown to be involved in various cardiovascular dysfunctions such as myocardial fibrosis, myocardial infarction and hypertension [Zhang et al, Frontiers in Pharmacol.
  • PGF2a receptor FP
  • BMP bone morphogenetic protein
  • More stable analogues of PGF2oc 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].
  • 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.
  • PGF2oc stimulates the Proliferation and collagen production via the FP receptor. Since this occurs independently of the pro- fibrotic 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 diseases and disorders of the lung 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 remodeling and remodeling in cancer processes are the invasion of cancer cells into the healthy tissue (metastasis) and the rebuilding of supplying blood vessels (neoangiogenesis).
  • 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. The onset of the disease is gradual and characterized by an increased shortness of breath and dry, irritating 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 has due to their frequency and the of an aggressive nature [Ley et al, Am. J. Respir. Crit. Care Med. 2011, 183, 431-440].
  • IPF can be either sporadic or familial. The causes are currently not clear.
  • 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].
  • fibrosis a decrease in the elasticity of the lung tissue, a reduction in the diffusion capacity and the development of severe hypoxia. Pulmonary functionally, a worsening of the forced vital capacity (FVC) and the diffusion capacity (DLCO) can be detected.
  • FVC forced vital capacity
  • DLCO diffusion capacity
  • Significant and prognostically significant comorbidities of IPF are acute exacerbation and pulmonary hypertension [Beck et al., The Pneumologist 2013, 10 (2), 105-111].
  • the prevalence of pulmonary hypertension in interstitial lung disease is 10-40% [Lettieri et al, Chest 2006, 129, ⁇ 6- ⁇ 52; Behr et al, Eur. Respir. J. 2008, 31, 1357-1367].
  • 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 there is a neomuscularization of primarily non-muscularized pulmonary vessels, and the vascular musculature of the 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.
  • PH-COPD failed these therapeutic principles (eg sildenafil, bosentan) in clinical trials, as they led to a decrease (desaturation) of the arterial oxygen content in patients as a result of unselective vasodilation.
  • the reason for this is probably an unfavorable influence on the ventilation-perfusion adaptation within the lungs in heterogeneous lung diseases due to the systemic administration of unselective vasodilatators [I. Blanco et al., Am. J. Respir. Crit. Care Med. 2010, 181, 270-278; D. Stolz et al., Eur. Respir. J. 2008, 32, 619-628].
  • 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., 2011, 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 a significant venous / capillary such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disease, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy.
  • APAH pulmonary arterial hypertension
  • diseases with a significant venous / capillary such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
  • other diseases such as thyroid disease, glycogen storage diseases, 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).
  • COPD chronic obstructive pulmonary disease
  • IDF 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 embolizations (eg due to tumors, parasites, foreign bodies).
  • CTEPH proximal and distal pulmonary arteries
  • non-thrombotic embolizations eg due to tumors, 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 (BOS) 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.
  • BOS is the most important long-term complication of lung transplantation 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. The damage and inflammatory changes of the epithelial cells as well as the subepithelial structures of the smaller airways lead to an excessive fibroproliferation due to an inadequate regeneration of the epithelium and an aberrant tissue repair.
  • 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 the over-45s are affected. Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, to alleviate the symptoms, to prevent acute deterioration and to slow down progressively impaired lung function.
  • the object of the present invention is the identification and provision of new 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 fibro- and inflammatory diseases ,
  • WO 95/32948-A1, WO 96/02509-A1, WO 97/19926-A1 and WO 2000/031038-AI disclose 2-arylquinoline-4-carboxamides as K3 or dual NK2 / NK3 antagonists, which are suitable for the treatment of diseases of the lung and the central nervous system.
  • WO 2000/064877 claims quinoline-4-carboxamide derivatives which can be used as NK3 antagonists for the treatment of various diseases, including the lungs and the central nervous system.
  • WO 2006/094237-A2 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 V, 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)
  • # l represents the point of attachment to the carbonyl group
  • # 2 represents the point of attachment to the nitrogen atom
  • R 6 is hydrogen, methyl or up to three times fluorine-substituted ethyl
  • R 7 is up to three times fluorine-substituted (C 1 -C 2) -alkyl
  • 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,
  • 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,
  • cyclopropyl and cyclobutyl may be substituted up to fourfold with 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 monosubstituted may be substituted by chlorine or bromine, or represents thiazolyl or pyridyl,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Compounds of the invention are also TV 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-TVTV, TV-trimethylethanamine), procaine, dicyclohexylamine, Di- benzylamine, TV-methylmorpholine, TV-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.
  • customary bases such as,
  • physiologically acceptable salts of the compounds according to the invention also include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example 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 embonic acid.
  • mineral acids for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedis
  • 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 co-ordinates with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. 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 components can be isolated in a known manner.
  • chromatographic methods are used for this purpose, in particular HPLC chromatography on achiral or chiral separation phases.
  • separation may also be effected via diastereomeric salts with the aid of 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, O, Is O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 82 Br, 123 I, 124 I, 129 I, and 131 I.
  • Certain isotopic variants of a compound of the invention may be useful, for example for the study of the mechanism of action or distribution of the drug in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • the incorporation of isotopes such as For example, of deuterium, lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as to prolong the half-life in the body or to a reduction of the required effective dose;
  • Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate 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 in vivo enzymatically or chemically to the free carboxylic acids, as the biologically mainly active compounds.
  • preference is given to (C 1 -C -alkyl esters in which the alkyl group may be straight-chain or branched.)
  • Particularly preferred are methyl, ethyl or fer-butyl esters.
  • (C 1 -C 4 -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, by way of example and preferably: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and ferric. butyl.
  • 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.
  • # l represents the point of attachment to the carbonyl group
  • # 2 represents the point of attachment to the nitrogen atom
  • Z is -OH or a group of the formula -NH-R 6 , or -NH-SO 2 -R 7 , in which
  • R 6 is hydrogen, methyl or up to three times fluorine-substituted ethyl
  • R 7 is up to three times fluorine-substituted (C 1 -C 2) -alkyl
  • 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, cyclopophenyl 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 (Ci-C- alkyl, up to three times fluorine-substituted methoxy, hydroxy, methylsulfanyl, cyclopropyl or cyclobutyl, wherein cyclopropyl and cyclobutyl may be up to four times substituted with fluorine, and
  • Ar is phenyl which may be substituted up to three times, identically or differently, by fluorine, chlorine, up to three times fluorine-substituted methyl and up to three times fluorine-substituted methoxy, or is thienyl, thiazolyl or pyridyl,
  • # l represents the point of attachment to the carbonyl group
  • # 2 represents the point of attachment to the nitrogen atom
  • Y is a group of the formula -C (H) (OH) - or -CHF-
  • R 1 is chlorine, bromine, iodine, methyl, isopropyl, ferric butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl
  • R 2 is hydrogen
  • R 3 and 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, and
  • 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 a group of the formula
  • # 3 represents the point of attachment to the quinoline ring
  • R 8 is chlorine or methyl
  • R 9 is chlorine or methoxy
  • R 1 is chlorine, bromine, iodine, methyl, isopropyl, tert. Butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, cyclopropyl or cyclobutyl,
  • R 2 is hydrogen
  • R 3 and 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, and Ar is phenyl which may be mono- or disubstituted by fluorine, for thienyl,
  • # 3 represents the point of attachment to the quinoline ring
  • R 8 is chlorine or methyl
  • R 9 is chlorine or methoxy
  • R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl, wherein at least one of R 3 and R 4 is in each case hydrogen,
  • R 5 is fluoro, chloro, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl, and
  • Ar represents phenyl, which may simply be substituted by fluorine,
  • R 1 is chlorine, bromine, iodine, methyl, feri. Butyl, difluoromethyl, trifluoromethyl, trimethylsilyl or
  • 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 fluoro, chloro, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl, and
  • Ar represents phenyl, which may simply be substituted by fluorine,
  • Z is a group of the formula -OH
  • R 1 is ethynyl, bromine or iodine
  • R 2 , R 3 and R 4 are each hydrogen
  • R 5 is chloro, methyl, methylsulfanyl or cyclopropyl
  • Ar is phenyl, and their salts, solvates and solvates of the salts.
  • R 1 is bromine or iodine
  • R 2 , R 3 and R 4 are each hydrogen
  • R 5 is chloro, methyl, methylsulfanyl or cyclopropyl
  • Ar is phenyl
  • a particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Z is a group of the formula -OH
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Z is a group of the formula -NH 2
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which the ring Q is a group of the formula
  • Y is a group of the formula -C (H) (OH) - or -CHF-,
  • Another particular embodiment of the present invention comprises compounds of the form which the ring Q is a group of the formula
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 1 is chlorine, bromine, iodine, methyl, isopropyl, feri. Butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, cyclopropyl or cyclobutyl, R 2 is hydrogen, and
  • R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl
  • R 3 and R 4 are in each case hydrogen
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 1 is chlorine, bromine, iodine, methyl, isopropyl, feri. Butyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl) sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl, R 2 is hydrogen, and
  • R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl
  • R 3 and R 4 are in each case hydrogen
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 1 is ethynyl
  • R 2 , R 3 and R 4 are each hydrogen
  • 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
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 1 is iodine
  • R 2 , R 3 and R 4 are each hydrogen
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R 5 is fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compound formula (I) in which
  • # 3 represents the point of attachment to the quinoline ring
  • R 8 is fluorine, chlorine or methyl
  • R 9 is fluorine, chlorine or methoxy
  • R 10 is fluorine or chlorine
  • R 11A , R 11B , R 12A , R 12B are each independently fluorine, or
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Ar is thienyl which may be mono- or disubstituted by methyl or simply by chlorine or bromine,
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Ar is phenyl which may be mono- or di-substituted by fluorine, thienyl,
  • # 3 represents the point of attachment to the quinoline ring
  • R 8 is chlorine or methyl
  • R 9 is chlorine or methoxy
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Ar is phenyl which may be monosubstituted or disubstituted by identical or different substituents, fluorine and chlorine, or is thienyl,
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Ar is phenyl
  • 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.
  • the invention further provides a process for preparing compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)
  • T represents an ester protective group, in particular (C 1 -C 4 -alkyl, benzyl or 4-methylphenylsulfonylethyl, to a compound of the formula (IV)
  • the coupling reaction (II) + (III) - »( ⁇ ) [amide formation] can be carried out either directly by means of a condensation or activating agent or via the intermediate of a carboxylic acid chloride or carboxylic imidazolide obtainable from (II).
  • Suitable condensation or activating agents are, for example, carbodiimides, such as N, N-diethyl, NN-dipropyl, N, N-diisopropyl, N, N-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -V'-ethylcarbodiimide hydrochloride (EDC).
  • Phosgene derivatives such as NN'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-fer-butyl-5 methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, chloroenamines such as 1-chloro-NN, 2-trimethyl-prop-1-en-1-amine, 1, 3, 5-triazine derivatives such as 4- (4,6-dimethoxy-l, 3,5-triazin-2-yl) -4-methylmorpholinium chloride, phosphorus compounds such as -Propanphosphonklad (PPA), cyanophosphonate, Diphenylphosphorylazid (DPPA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, PDA
  • condensation or activating agent is 0- (7-azabenzotriazol-1-yl) -A, V, V ', V'-tetramethyluronium hexafluoropliosplate (HATU) in combination with DIPEA.
  • the coupling with the amine component (III) is carried out in the presence of a customary base, such as, for example, sodium or potassium carbonate, triethylamine, DIPEA, A-methylmorpholine (NMM).
  • a customary base such as, for example, sodium or potassium carbonate, triethylamine, DIPEA, A-methylmorpholine (NMM).
  • NMP TV-methylpiperidine
  • pyridine 2,6-dimethylpyridine
  • 4-N N-methylaminopyridine
  • DMAP 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBU 1, 5-diazabicyclo [4.3.0] - ⁇ -5-ene
  • sodium or potassium methoxide sodium or potassium ethanolate
  • sodium or potassium fer-butylate sodium or potassium hydride
  • Preferred coupling method is the direct reaction of (II) with the amine compound (III) by means of a condensation or activating agent.
  • Inert solvents for the mentioned coupling reactions are - depending on the process used - for example, ethers such as diethyl ether, diisopropyl ether, methyl-feri.-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, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine , Dimethyl sul
  • V V-dimethylformamide
  • the couplings are generally carried out in a temperature range from 0 ° C to + 130 ° C, preferably at + 20 ° C to + 80 ° C.
  • the carboxylic acid imidazolides themselves are prepared by reaction of (II) with V, V'-carbonyldiimidazole (CDI) at elevated temperature (+ 60 ° C. to + 150 ° C.) in a correspondingly higher-boiling solvent such as V, V-dimethylformamide (DMF). available.
  • the preparation of the carboxylic acid chlorides is carried out in a conventional manner by treating (II) with thionyl chloride or oxalyl chloride in an inert solvent such as dichloromethane.
  • Suitable ester protecting groups T are generally all protective groups known to those skilled in the art, for example 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, suitably substituted Benzyl, such as diphenylmethyl (DPM), bis (or?
  • MTM methylthiomethyl
  • TTP tetrahydropyranyl
  • SEM 2- (trimethylsilyl) ethoxymethyl
  • BOM benzyloxymethyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • DTBMS di-tert-butylmethylsilyl
  • the cleavage of the ester protective group T in process step (IV) - »(IA) is carried out by customary methods by treating the ester in an inert solvent with an acid or base, the latter being the initially formed salt of the carboxylic acid is converted by subsequent treatment with acid in the free carboxylic acid.
  • an acid or base the latter being the initially formed salt of the carboxylic acid is converted by subsequent treatment with acid in the free carboxylic acid.
  • tert-butyl ester ester cleavage is preferably carried out with an acid.
  • Methyl and ethyl esters are preferably cleaved by means of a base.
  • Benzyl esters can alternatively also be removed by hydrogenation (hydrogenolysis) in the presence of a suitable catalyst, for example palladium on activated carbon.
  • Silyl esters may be obtained by treatment with acids or fluorides, e.g. Tetrabutylammoni- fluoride are split.
  • 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, N-dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of these solvents.
  • 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
  • Suitable bases are the inorganic bases customary for a hydrolysis reaction. These include in particular alkali or alkaline earth hydroxides such as lithium, sodium, potassium or barium hydroxide, or alkali 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, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluene sulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, if appropriate with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferably used.
  • the ester cleavage is usually carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 80 ° C.
  • the preparation of the acid chloride (V) in the usual manner by treatment of the carboxylic acid (IA) with oxalyl chloride or thionyl chloride in an inert solvent such as dichloromethane, trichloromethane or 1, 2-dichloroethane, optionally using a small amount ofV, V-dimethylformamide Catalyst.
  • the reaction is generally carried out at a temperature of 0 ° C to + 30 ° C.
  • a conventional tertiary amine base can also be used as auxiliary base, for example triethylamine, DIPEA, N-methylmorpholine (NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine or 4-N, N-dimethylaminopyridine (DMAP).
  • DIPEA N-methylmorpholine
  • NMP N-methylpiperidine
  • pyridine 2,6-dimethylpyridine or 4-N, N-dimethylaminopyridine (DMAP).
  • Inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl-fer-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, carbon tetrachloride, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO), V , V-di
  • mixtures of such solvents can be used.
  • water or a mixture of water with tetrahydrofuran, 1, 4-dioxane, 1,2-dimethoxyethane or acetone is used.
  • the reaction is usually carried out at a temperature of 0 ° C to + 40 ° C.
  • reaction is preferably carried out using sodium hydride as a base in tetrahydrofuran or N, N-dimethylformamide as an inert solvent at a temperature of from 0 ° C to + 80 ° C.
  • the compounds of the formula (II) can be prepared by reacting either analogously to processes known from the literature
  • the condensation of the isatin derivative (VII) with the ketomethylene compound (VIII) to the quinoline-4-carboxylic acid (II) in variant [A] can be carried out by heating the reactants in the presence of an aqueous acid such as sulfuric acid or concentrated hydrochloric acid, or Presence of an aqueous base, such as sodium or potassium hydroxide, can be achieved.
  • an aqueous acid such as sulfuric acid or concentrated hydrochloric acid
  • Presence of an aqueous base such as sodium or potassium hydroxide
  • the condensation reaction according to variant [B] to quinoline-4-carboxylic acid (II-A) is carried out in an analogous manner by heating the ori / zo-Aminophenylessigklareesters (IX) and the diketone (X) with aqueous acid, in particular concentrated hydrochloric acid.
  • aqueous acid in particular concentrated hydrochloric acid.
  • acetic acid is also preferably used here.
  • ori ⁇ o-Aminophenylessigklander ( ⁇ ) in turn, based on a method described in the literature by base-mediated reaction of the ⁇ -chloroacetic acid ester (XI)
  • the amine functionality of the compounds of formula (III) can be represented by known Curtius rearrangement from the corresponding carboxylic acid azide.
  • the carboxylic acid is first converted to the acid azide after activation of the acid functionality, for example as the carboxylic acid chloride or anhydride and then reacted directly with sodium azide.
  • the carboxylic acid may 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 ferric butanol or benzyl alcohol at elevated temperatures (see J. Am. Chem. 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 for the Curtius rearrangement is typically in the range + 40 ° C to + 120 ° C. 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.
  • 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, and lymphoid interstitial pneumonia Pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other unknown cause of interstitial lung disease, pulmonary arterial hypertension (PAH) and others 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 deficiency (AATD) , Pulmonary emphysema (eg, emphysem
  • the compounds according to the invention can furthermore be used for the treatment and / or prevention of asthmatic disorders of varying degrees of severity with intermittent or persistent course (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma ), of various 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 inflammations (including medicinal rhinitis, vasomotor Rhinitis and season-dependent allergic rhinitis, eg hay fever) and polyps.
  • intermittent or persistent course refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma
  • bronchitis chronic bronchitis, infectious bronchitis, eo
  • the compounds of the invention can also be used for the treatment and / or prevention of cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, arrhythmias Atria and ventricles as well as conduction disorders such as degree I-III atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysms, Sch
  • heart failure includes both acute and chronic manifestations of heart failure as well as specific or related forms thereof, such as acute congestive heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy, congenital heart disease, valvular heart failure, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis , diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders as well as diastolic and s
  • kidney diseases in particular renal insufficiency and kidney failure.
  • renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as these underlying or related renal diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis , tubulo-interstitial diseases, nephropathic diseases such as primary and congenital kidney disease, renal inflammation, immunological kidney diseases such as renal transplant rejection and immunocomplex-induced renal diseases, toxicity-induced nephropathy, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, Pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, which are diagnostically enhanced by,
  • the present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of secondary effects of renal insufficiency, such as hypertension, for example.
  • the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (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 prostatic hyperplasia
  • BPE benign prostatic hyperplasia
  • 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 according to the invention can also be used to treat disorders of the female reproductive system, such as uterine fibroids, endometriosis, dysmenorrhea and premature labor pains. Furthermore, they are suitable for the prophylaxis or treatment of hirsutism and hypertrichosis.
  • 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 fibrous diseases of the internal organs, such as, for example, the lung, heart, kidney, bone marrow and especially 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 consequence of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic Diseases, scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy 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 according to the invention can also be used for the treatment and / or prevention of anemias, such as haemolytic anemias, in particular hemoglobinopathies such as chelenzemia and thalassemia, megaloblastic anemia, iron deficiency anemia, acute blood loss anemia, displacement anemia, and aplastic anemia.
  • anemias such as haemolytic anemias, in particular hemoglobinopathies such as chelenzemia and thalassemia, megaloblastic anemia, iron deficiency anemia, acute blood loss anemia, displacement anemia, and aplastic anemia.
  • the compounds according to the invention are also suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, lipocarcinomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and Genital tract as well as malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.
  • cancers such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, lipocarcinomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and Genital tract as well as 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 dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, obesity (Adi - positas), obesity, metabolic disorders (metabolic syndrome, hyperglycaemia, insulin-dependent diabetes, non-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,
  • 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 fibrotic Skin and eye diseases and fibrotic disorders of the internal organs.
  • interstitial lung diseases especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), inflammatory and fibrotic Skin and eye diseases and fibrotic disorders of the internal organs.
  • IPF idiopathic pulmonary fibrosis
  • PH pulmonary hypertension
  • BOS bronchiolitis obliterans syndrome
  • inflammatory and fibrotic Skin and eye diseases and fibrotic disorders of the internal organs especially idiopathic pulmonary fibrosis (IPF), as well as pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, suppressing or curing a disease, a disease, a disease, an injury or a disease health disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means prevention, prophylaxis or “prevention” are used synonymously in the context of the present invention and designate the avoidance or reduction of the risk To get, to experience, to suffer or to have a disease, a disease, a disease, an injury or a health disorder, a development or progression of such conditions and / or the symptoms of such conditions.
  • the treatment or prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • 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 phosphorous inhibitors diesterases
  • sildenafil sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil
  • PDE phosphorous inhibitors diesterases
  • sGC soluble guanylate cyclase
  • sGC soluble guanylate cyclase
  • Prostacyclin analogs and IP receptor agonists such as, by way of example and preferably, iloprost, beraprost, treprostinil, epoprostenol or selexipag;
  • Endothelin receptor antagonists such as, by way of example and by way of preference, 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 by way of preference, nintedanib, dasatinib, nilotinib, bosutinib, regorafenib , Sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,
  • MMPs matrix metalloproteases
  • stromelysin collagenases, gelatinases and aggrecanases
  • MMP-9 MMP-10, MMP-11 and MMP-13
  • 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-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • 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 ß-adrenergic receptor agonists (ß-mimetics) and the inhaled anti-muscarinergen substances;
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma by way of example and preferably from the group of inhaled or systemically applied ß-adrenergic receptor agonists (ß-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 preferably adenosine A2b receptor antagonists, sphingosine 1-phosphate receptor 3 (SlP3) antagonists, autotaxine inhibitors, lysophosphatidic acid receptor 1 (LPA-1) and Lysophosphatidic acid receptor 2 (LPA-2) antagonists, lysyl oxidase (LOX) inhibitors, lysyl oxidase like-2 inhibitors, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, v ⁇ 6 integrin Antagonists, TGF- ⁇ antagonists, Wnt signaling inhibitors or CCR2 antagonists;
  • adenosine A2b receptor antagonists such as by way of example and preferably adenosine A2b receptor antagonists, sphingosine 1-phosphate receptor 3 (SlP3) antagonists, autotaxine inhibitors, lysophosphatidic acid receptor 1 (LPA-1) and Lysophosphatidic acid receptor 2 (LP
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII 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 inhibitors oc, PPAR- ⁇ and / or PPAR-5 agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; and or
  • chemotherapeutic agents as 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, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol.
  • a ⁇ -adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, 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.
  • 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, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, 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, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, for example and preferably, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, for 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-3112, 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-3112, 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, for example and preferably, coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, receptor blockers, ⁇ -receptor blockers, mineralocorticoid receptor antagonists and of diuretics.
  • 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.
  • the compounds according to the invention are administered in combination with an oci-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, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, betainol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a ⁇ -receptor blocker such as by way of example and preferably propranolol, atenolol, timolo
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • 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 used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methycothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetoazamide, 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, methycothiazide, polythiazide, trichloromethia
  • 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-, PPAR- gamma and / or PPAR-5 agonists, cholesterol absorption inhibitors, polymeric bile acid sorbents, bile acid reab tion inhibitors, lipase inhibitors and the lipoproteins 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 sorbents
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • 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.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-.gamma.-agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-.gamma.-agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-5 agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • a PPAR-5 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.
  • 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 of 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.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, 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. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating the application forms, which Compounds according to the invention in crystalline and / or amo lyzed and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing an ⁇ ⁇ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • ⁇ ⁇ e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally
  • absorption e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • suitable as application forms i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers, metered dose 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.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxy-sorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • taste and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxy-sorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers for example, antioxidant
  • 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 in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain sufficiently basic or acidic 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 'H-NMR spectrum. If no purity is specified, it is usually a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined.
  • the aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The aqueous phase was also concentrated and the two residues were combined. Subsequently, the combined residue was purified by column chromatography (silica gel, eluent ethyl acetate / methanol 5: 1). The product-containing fractions were combined and concentrated, and the residue was stirred in a pentane / ferric. Butyl methyl ether / methanol mixture. The solid was filtered off and dried in vacuo. There were obtained 0.60 g (27% of theory, purity 82%) of the title compound.
  • the combined organic phases were dried over sodium sulfate, filtered and concentrated.
  • the aqueous phase was also concentrated and the two residues were combined and pre-purified by column chromatography (silica gel, ethyl acetate / methanol gradient).
  • the prepurified product was dissolved in a mixture of acetonitrile, methanol, water and TFA and purified by preparative HPLC (column: Kinetix Cl 8, 5 ⁇ m, 100 mm ⁇ 21.5 mm, flow: 25 ml / min, detection: 210 nm, gradient of water / Acetonitrile / (water + 1% formic acid) 60: 35: 5-> 25: 70: 5; Running time 6 min). 56 mg (2% of theory, purity 100%) of the title compound were obtained.
  • the filtrate was concentrated in vacuo and the residue obtained by concentration of the filtrate was dissolved in a mixture of 38 ml of DMSO and water and purified by preparative HPLC [column: Chromatorex C18; 125 mm x 30 mm; Flow: 100 ml / min; Detection: 210 nm; Injection 1 ml; Gradient acetonitrile / water / (water + 0.1% TFA) 10: 85: 5 ⁇ 60: 35: 5; Running time 6.5 min)]. 173 mg (45% of theory, purity 100%) of the title compound were obtained.

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Abstract

L'invention concerne de nouveaux dérivés N-bicyclo-2-arylchinolino-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.
EP16709919.1A 2015-03-18 2016-03-15 N-bicyclo-2-arylchinolino-4-carboxamides substitués et leur utilisation Withdrawn EP3271334A1 (fr)

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WO2017153235A1 (fr) * 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-3-aryl-1-naphthamides substitués et leur utilisation
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JP7107963B2 (ja) 2017-04-10 2022-07-27 バイエル・アクチエンゲゼルシヤフト 置換されたｎ－アリールエチル－２－アリールキノリン－４－カルボキサミド類及びそれの使用
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EP0940391B1 (fr) 1994-05-27 2004-08-18 GlaxoSmithKline S.p.A. Dérivés de quinoléine en tant qu'antagonistes du récepteur de tachykinine NK3
IT1270615B (it) 1994-07-14 1997-05-07 Smithkline Beecham Farma Uso di derivati di chinolina
AR004735A1 (es) 1995-11-24 1999-03-10 Smithkline Beecham Spa Quinoleina 4-amido sustituida, un procedimiento para su preparacion, una composicion farmaceutica que los contiene y el uso de los mismos para lapreparacion de un medicamento.
GB9825554D0 (en) * 1998-11-20 1999-01-13 Smithkline Beecham Spa Novel Compounds
AU4802500A (en) 1999-04-26 2000-11-10 Neurogen Corporation 2-aminoquinolinecarboxamides: neurokinin receptor ligands
US20090069301A1 (en) 2005-03-03 2009-03-12 Sirtris Pharmaceuticals, Inc. Acridine and Quinoline Derivatives as Sirtuin Modulators
WO2011153553A2 (fr) 2010-06-04 2011-12-08 The Regents Of The University Of California Méthodes et compositions pour l'inhibition de kinases
EP2635280A4 (fr) 2010-11-05 2014-05-28 Univ Minnesota Modulateurs de la cytosine désaminase pour l'amélioration de la transfection d'adn
EP2684167B1 (fr) 2011-03-08 2020-09-09 Eutropics Pharmaceuticals, Inc. Compositions et méthodes utiles dans le traitement de maladies
EP2844638A1 (fr) 2012-05-03 2015-03-11 Takeda GmbH Nouveaux agonistes du récepteur ep2
EP2948450A4 (fr) 2013-01-28 2016-11-09 Viamet Pharmaceuticals Inc Composés inhibiteurs de métalloenzyme

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US10117864B2 (en) 2018-11-06
CA2979926A1 (fr) 2016-09-22
US20180036300A1 (en) 2018-02-08

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