EP3046912A1 - Trifluorométhylpyrimidones disubstituées et leur utilisation comme antagonistes du ccr2 - Google Patents

Trifluorométhylpyrimidones disubstituées et leur utilisation comme antagonistes du ccr2

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Publication number
EP3046912A1
EP3046912A1 EP14766967.5A EP14766967A EP3046912A1 EP 3046912 A1 EP3046912 A1 EP 3046912A1 EP 14766967 A EP14766967 A EP 14766967A EP 3046912 A1 EP3046912 A1 EP 3046912A1
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EP
European Patent Office
Prior art keywords
compound
formula
acute
salts
trifluoromethyl
Prior art date
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Application number
EP14766967.5A
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German (de)
English (en)
Inventor
Alexander Straub
Marie-Pierre Collin
Michael Koch
Jutta Meyer
Karl-Heinz Schlemmer
Carl Friedrich Nising
Nicole BIBER
Sonja Anlauf
Matthias Beat WITTWER
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Bayer Pharma AG
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Bayer Pharma AG
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Priority to EP14766967.5A priority Critical patent/EP3046912A1/fr
Publication of EP3046912A1 publication Critical patent/EP3046912A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to novel 2,5-disubstituted 6- (trifluoromethyl) pyrimidin-4 (3H) -one 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 the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
  • Chemotactic cytokines or chemokines may be present in most tissues, such as the heart, kidney, and lung, as well as vessels, as part of the immune response to tissue injury or inflammatory stimuli, e.g. bacterial toxins. They are critically responsible for the recruitment of specific leukocyte subpopulations (such as neutrophils, monocytes, basophils, eosinophils, effector T cells, dendritic cells) to the site of inflammation [Mackay, Nature Immunol. 2 (2), 95-101 (2001)].
  • leukocyte subpopulations such as neutrophils, monocytes, basophils, eosinophils, effector T cells, dendritic cells
  • chemokines are also involved in the regulation of hematopoiesis, cell proliferation, angiogenesis or tumor growth.
  • chemokines are classified into four distinct subgroups (CXC, CC, C and CX3C) [Bacon et al., J. Interferon Cytokine Res. 22 (10), 1067-1068 (2002 )].
  • the largest family includes the CC chemokines, which also include the classic inflammatory chemokines, such as the MCPs (monocyte chemoattractant protein), whose expression in most tissues is associated with tissue damage or infection via pro-inflammatory cytokines, e.g.
  • IL-1 IL-1, TNF- ⁇ or IFN- ⁇ [Rollins, in: Cytokine Reference, Oppenheim et al., Ed., Academic Press, London, 1 145-1 160 (2000)].
  • the 48 chemokines identified in humans bind to specific chemokine receptors belonging to the family of G protein-coupled receptors.
  • the CC chemokine receptor CCR2 is found, inter alia, on the surface of macrophages, monocytes, B cells, activated T cells. dendritic cells, epithelial cells and activated Endothelial cells express and bind the inflammatory chemokines MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (CCL7), and MCP-4 (CCL13). MCP-1 appears to be the only ligand to selectively bind to CCR2 [Struthers and Pasternak, Current Topics in Medicinal Chemistry 10 (13), 1278-1298 (2010)].
  • MCP-1 is expressed by cardiomyocytes, mesangial cells, alveolar cells, T-lymphocytes, macrophages and monocytes [Deshmane et al., J. Interferon Cytokine Res. 29, 31 3-326 (2009)].
  • the CC chemokine receptor CCR2 is also the only characterized high affinity receptor for MCP-1 [Struthers and Pasternak, Current Topics in Medicinal Chemistry 10 (13), 1278-1298 (2010)]. In humans, CCR2 is expressed on the vast majority of blood monocytes [Tacke and Randolph. Immunobiology 211, 609-618 (2006)].
  • CCR2 CCR2 activation by MCP-1 plays a crucial role in the infiltration and activation of monocytes [Dobaczewski and Frangogiannis, Frontiers in Bioscience Sl, 391-405 (2009); Charo and Ransohoff, N. Engl. J. Med. 354 (6), 610-621 (2006)] in the context of the cellular immune response as well as in chronic inflammatory processes, eg in the heart and in the kidney.
  • This infiltration of monocytes and their differentiation into macrophages is also a second source of pro-inflammatory modulators, such as TNF- ⁇ , IL-8, II.-! 2 and matrix metalloproteases (MMPs).
  • MMPs matrix metalloproteases
  • CCR2 mediates the migration of monocytes from the bone marrow and their subsequent immigration into inflammatory areas
  • CCR2 + monocytes [Dobaczewski and Frangogiannis, Frontiers in Bioscience Sl, 391-405 (2009)], suggesting a role for CCR2 in fibrosis (eg the lung or liver).
  • CCR2-mediated monocyte migration is also one of the first steps in the development of atherosclerosis [Gu et al., Mol. Cell 2 (2), 275-281 (1998)].
  • CCR2 / MCP-1 can reduce an inflammatory response in various diseases and reduces monocyte infiltration into inflamed lesions (arthritis, asthma).
  • Cellular responses mediated by CCR2 / MCP-1 are involved in numerous diseases, such as cardiomyopathies, myocardial infarction, myocarditis, chronic heart failure, diabetic kidney disease, acute renal damage, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), asthma, atherosclerosis , inflammatory bowel disease (IBD), diabetes, neuropathic pain, macular degeneration, angiogenesis and cancer [Struthers and Pasternak, Current Topics in Medicinal Chemistry 10 (13), 1278-1298 (2010); Carter, Expert Opin. Ther. Fat. 23 (5), 549-568 (2013); Higgins et al., Chemokine Research, Basic Research and Clinical Application, Vol. Ii, Birkhäuser-Verlag
  • Neutrophils accumulate in the infarcted myocardium in the first hours after ischemia with a maximum accumulation after one day.
  • monocytes and macrophages dominate cell infiltrate in the first two weeks after infarction [Nahrendorf et al., Circulation 121, 2437-2445 (2010)]. This goes hand in hand with an upregulation of MCP! [Hayasaki et al., Circ. J. 70 (3), 342-351 (2006)].
  • Neutrophils as well as monocytes and macrophages produce locally proteolytic enzymes as well as reactive oxygen species (ROS) and thereby damage cardiomyocytes that have survived the ischemic period.
  • ROS reactive oxygen species
  • CCR2-deficient mice show a reduction in infarct size and reduced remodeling after myocardial infarction [Hayasaki et al., Circ. J. 70 (3), 342-35! (2006)].
  • MCP-1-deficient mice show attenuated remodeling after myocardial infarction [Dewald et al., Circ. Res. 96 (8), 881-889 (2005)].
  • the object of the present invention was thus to identify and provide new substances which act as potent antagonists of the CCR2 receptor and are suitable as such for the treatment and / or prevention, in particular of cardiovascular, renal, inflammatory and fibrotic diseases.
  • WO 201 1/1 14148-A1 and WO 2012/041817-A1 have recently disclosed bicyclic pyrimidine
  • A is C-H, C-F or N,
  • R 4A , R 4B and R 5 independently of one another denote hydrogen or (Ci-C4) -Aikyi, and their salts, solvates and solvates of the salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, of the compounds of the formula (I) mentioned below
  • 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 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.
  • 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 sols sort at Atropi).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • 6- (trifluoromethyl) pyrimidin-4 (3i7) -one derivatives of the formula (I) according to the invention can also be prepared in the tautomeric pyrimidine-4 (1H) -one form ( ⁇ ) or 4-hydroxypyrimidine form (I. ") (see Scheme 1 below); these tautomeric forms are expressly encompassed by the present invention.
  • the present invention also includes all suitable isotopic variants of the compounds according to 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 ⁇ (deuterium), ⁇ (tritium), 13 C, 14 C, 1 N ,!
  • Certain isotopic variants of a compound of the invention 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 * 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;
  • modifications of the compounds according to the invention may therefore possibly 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 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. Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • (( ';-( - ⁇ ) - Alk vi is in the context of the invention a straight-chain or branched alkyl radical having 1 to 4 carbon atoms Preferred examples which may be mentioned are: methyl, ethyl, M-propyl, isopropyl, w-Butyl,..
  • radicals are substituted in the compounds according to the invention, the radicals can, if not otherwise Substitution with one or two identical or different substituents is preferred, Substitution with a substituent being particularly preferred
  • the present invention comprises compounds of the formula (I), in which one
  • A is C-H, C-F or N,
  • E is CH 2 , O or S
  • R ! and R independently of one another are hydrogen, fluorine, chlorine, methyl or trifluoromethyl, where at least one of the two radicals R 1 and R is fluorine, chlorine or trifluoromethyl, and
  • R 4A , R 4B and R 5 independently of one another denote hydrogen or (GC 4 ) -alkyl, and also their salts, derivatives and solvates of the salts.
  • Preferred in the context of the present invention are compounds of the formula (I) in which
  • A is CH or CF
  • E is CH -. O or S
  • R 1 is fluorine, chlorine or trifluoromethyl
  • R - is hydrogen, fluorine, chlorine, methyl or trifluoromethyl
  • R 4A and R 4 independently of one another denote hydrogen, methyl or ethyl, and their salts, solvates and derivatives of the salts.
  • A is CH
  • E is (TT or O, R? Stands for fluorine, chlorine or trifluoromethyl
  • R is fluorine or chlorine
  • a particular embodiment of the present invention comprises compounds of the formula (I) in which
  • A stands for CH, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of formula (I), in which
  • E is CH 2 , and their salts, solvates and solvates of the 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
  • R 1 and R 2 are each chlorine, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of formula (I), in which
  • R 1 is trifluoromethyl
  • R - represents chlorine, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the
  • R 3 is ethyl, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of formula (I), in which R 3 is cyclopropyl, and i re salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which R 3 is a group of the formula -NR 4A R 4 , in which
  • R 4A and R 4B are each hydrogen, and their salts, solvates and solvates of the salts.
  • Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that
  • E 1 is CH 2 or O and is methyl, ethyl, propyl or is-butyl, with a compound of the formula (III) in which R 'has the abovementioned meaning, or a salt thereof, to give a compound of the formula (IA) according to the invention
  • Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or ferric butanol, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ethers, hydrocarbons or chlorinated hydrocarbons such as benzene, toluene, xylene or chlorobenzoi, or dipolar aprotic solvents such as acetonitrile, butyronitrile, N, N-dimethylformamide (DMF), N-dimethylacetamide (DMA), dimethyl sulfide oxide (DM SO), NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents.
  • m
  • the compound of the formula (III) is preferably used in the form of a salt, for example as hydrochloride, the reaction taking place in such a case in the presence of a base.
  • a base for this purpose are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium carbonate.
  • potassium iert.-butoxide, or conventional tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine, pyridine or 4-N, N-dimethyl laminopyridine.
  • potassium carbonate, sodium methoxide or N-diisopropylethylamine is used as the base.
  • reaction (II) + (III) - »(I-A) is generally carried out in a temperature of from + 20 ° C to + 150 ° C, preferably at + 60 ° C to + 120 ° C.
  • the process step (IV) + (V) - »(IB) is generally carried out in a temperature range from + 80 ° C. to + 150 ° C. in a correspondingly high-boiling inert solvent, such as, for example, ethylene glycol, bis ( 2-methoxyethyl) ether, N, N-dimethylformamide (DMF), N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP).
  • ethylene glycol is used.
  • Suitable bases for this reaction are in particular alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium. Butylate, or alkali metal hydrides such as sodium or potassium. Preferably, cesium carbonate is used.
  • the compounds of the formula (II) in turn can be prepared by reacting a trifluoroacetoacetic acid ester of the formula (VI)
  • X is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate,
  • T 2 is methyl or ethyl
  • Inert solvents for process step (VI) + (VII) -> (II-A) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl ether butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimeth oxyethane or bis (2-methoxyethyl) ether, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-dimethylacetamide.
  • ethers such as diethyl ether, diisopropyl ether, methyl ether butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-d
  • Methylpyrrolidinone NMP
  • DMPU NN'-dimethylpropyl enharnsto ff
  • T etrahy dro is preferably used for.
  • Suitable bases for this reaction are in particular suitable alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropyl amide
  • tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine.
  • Preference is given to using NN-diisopropylethylamine as the base.
  • the reaction (VI) + (VII) - (II-A) is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 100 ° C.
  • an alkylation catalyst such as, for example, lithium chloride or bromide, sodium or potassium iodide, tetra-M-butylammonium bromide or benzyltriethylammonium chloride, is advantageous.
  • Suitable inert solvents for process step (VIII) + (IX) - »(II-B) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, r-butanol or ieri.-butanol, ethers such as diethyl ether, diisopropyl ether, Methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons or chlorinated hydrocarbons such as benzene, toluene, xylene or chlorobenzene, or dipolar aprotic solvents such as acetonitrile , Butyronitrile, A ⁇ N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N,
  • Alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate, or sodium or potassium tert-butylate
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as lithium or potassium
  • bis (trimethylsilyl) amide or lithium diisopropylamide used.
  • sodium hydride is used.
  • reaction (VIII) + (IX)> (II-B) is generally carried out in a temperature range from 0 ° C to
  • the subsequent bromination of (X) to compound (V) is preferably carried out with the aid of elemental bromine, N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin in an inert solvent, such as dicliloromethane, Chloroform, tetrahydrofuran, acetonitrile, N, N-dimethylformamide (DMF) or acetic acid, within a temperature range of -78 ° C to + 50 ° C.
  • NSS N-bromosuccinimide
  • 1,3-dibromo-5,5-dimethylhydantoin in an inert solvent, such as dicliloromethane, Chloroform, tetrahydrofuran, acetonitrile, N, N-dimethylformamide (DMF) or acetic acid, within a temperature range of -78 ° C to + 50 ° C.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention are potent antagonists of the CCR2 receptor and are therefore particularly suitable for the treatment and / or prevention of diseases, in particular of cardiovascular, renal, inflammatory, allergic and / or fibrotic disorders.
  • cardiovascular diseases are understood as meaning, for example, the following diseases: acute and chronic heart failure, arterial hypertension, coronary heart disease, acute coronary syndrome, myocardial infarction (STEMI, NSTEMI), acute myocardial infarction, stable and unstable angina pectoris, myocardial ischemia, autoimmune Heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock, Atherosclerosis, Hcr / hypertrophy.
  • diseases acute and chronic heart failure, arterial hypertension, coronary heart disease, acute coronary syndrome, myocardial infarction (STEMI, NSTEMI), acute myocardial infarction, stable and unstable angina pectoris, myocardial ischemia, autoimmune Heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock, Atherosclerosis, Hcr / hypertrophy.
  • PTA percutaneous transluminal angioplasties
  • PTCA transluminal coronary angio
  • heart failure encompasses both acute and chronic manifestations of heart failure as well as more specific or related forms of the disease, such as acute decompensated heart failure, right heart failure, left ventricular failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac insufficiency in valvular heart failure, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid valve insufficiency, pulmonary valve enstenos, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, dia
  • the compounds according to the invention are suitable for the treatment and / or prevention of kidney diseases, in particular of acute and chronic renal insufficiency as well as of acute and chronic renal failure.
  • the term acute renal insufficiency includes acute manifestations of renal disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, ischemic kidney disease (AKI), intradialytic hypotension, volume depletion (eg due to dehydration or blood loss), shock, acute glomerulonephritis, hemolytic uremic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence-Jones kidney in plasmocytoma, acute supra- or subvesical drainage obstructions, immunological kidney diseases such as renal trans- implantation rejection and immune complex-induced kidney disease, tubular dilatation, hyperphosphatemia, acute renal disease characterized by the need for dialysis, kidney partial resection, forced diuresis dehydration, uncontrolled hypertension with malignant hypertension, urinary tract obstruction, urinary tract obstruction also include systemic diseases associated with glomerular involvement such
  • diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which are diagnostically characterized, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, altered renal enzyme activity such as glutamylsynthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis, as well as chronic kidney disease in renal cell carcinoma after partial kidney resection , in dehydration by forced diuresis, uncontrolled increase in blood pressure with malignant hypertension, urinary tract obstruction, urinary tract infections and amyloidosis, also systemic diseases with glomerular involvement such as rheumatologic-immunological
  • 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 For example, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hypcralcemia, hyponatraemia) and disorders in bone and carbohydrate metabolism.
  • renal insufficiency such as For example, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hypcralcemia, hyponatraemia) and disorders in bone and carbohydrate metabolism.
  • the compounds of the invention are also useful for the treatment and / or prevention of polycystic kidney disease (PCKD) and the syndrome of inappropriate ADH secretion (SIADI I).
  • PCKD polycystic kidney disease
  • SIADI I syndrome of inappropriate ADH secretion
  • the compounds according to the invention are also suitable for the treatment and / or prevention of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (A DS), acute lung injury (ALI), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke induced pulmonary emphysema), cystic fibrosis (CF), cardiogenic shock, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic enteritis ( IBD, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory eye diseases.
  • PAH pulmonary arterial hypertension
  • COPD chronic obstructive pulmonary disease
  • a DS acute respiratory syndrome
  • ALI acute lung injury
  • pulmonary fibrosis pulmonary emphysema (e
  • the compounds of this invention may also be used to treat and / or prevent 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
  • bronchitis chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiolitis obliterans, bronchiectasis, pneumonia, idiopathic interstitial 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 season-dependent allergic rhinitis, eg hay fever) and of polyps.
  • 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, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibroid diseases of the eye .
  • the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial flare, cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders.
  • the compounds of the invention may also be used for the treatment and / or prevention of metabolic diseases, such as obesity and type 2 diabetes, which are also associated with chronic inflammation, further for the treatment and / or prevention of neurodegenerative diseases including Alzheimer's disease, multiple Slaskosis and ischemic brain damage, as well as pain, especially neuropathic pain.
  • metabolic diseases such as obesity and type 2 diabetes, which are also associated with chronic inflammation
  • neurodegenerative diseases including Alzheimer's disease, multiple Slaskosis and ischemic brain damage, as well as pain, especially neuropathic pain.
  • the compounds according to the invention can also be used for the treatment and / or prevention of cancers (skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, carcinomas of the gastrointestinal tract, liver, abdominal salivary gland, 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), gastrointestinal and abdominal diseases (glossitis, gingivitis, periodontitis, esophagus, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, Proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, pancreatitis and cholecystitis), skin diseases (allergic skin diseases, psoriasis, p
  • the compounds of the invention are further useful in the treatment and / or prevention of ophthalmic diseases such as glaucoma, age-related macular degeneration (AMD), dry (non-exudative) AMD, wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), diabetic Retinopathy, atrophic changes in retinal pigment epithelium (RPE), hypertrophic retinal epithelial changes, macular edema, diabetic macular edema, retinal vein occlusions, choroidal retinal veins, macular edema due to retinal vein occlusion, angiogenesis at the front of the eye such as corneal angiogenesis, for example Keratitis, corneal transplantation or keratoplasty, corneal angiogenesis due to hypoxia (by extensive wearing of contact lenses), pterygium conjunctivae, subretinal edema and intraretinal edema.
  • the compounds of the invention are particularly useful for the treatment and / or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic renal failure and acute lung injury.
  • 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.
  • a further subject of the present invention are therefore medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the abovementioned disorders.
  • suitable combination active ingredients are exemplified and preferably mentioned:
  • 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
  • MMPs matrix metalloproteases
  • stromelysin in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (in this case in particular MMP-1, MMP-3, MMP) 8, MMP-9, MMP-10, MMP-11 and MMP-13) and Metailo-Elastase (MMP-12);
  • Organic nitrates and NO donors such as sodium nitroprusside, nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular riociguat as well as those described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549 described compounds; NO and heme-independent activators of soluble guanlate cyclase, such as, in particular, the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adeno sinmonopho sphat
  • Phosphodiesterases 1, 2, 3, 4 and / or 5, in particular PDF, 5-inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil;
  • Prostacyclin analogs and IP receptor agonists such as, by way of example and by way of preference, iloprost, beraprost, treprostinil, epoprostenol or NS-304;
  • Bronchodilator agents by way of example and preferably from the group of beta-adrenergic receptor agonists, in particular albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, salbutamol or salmeterol, and the group of anticholinergics, in particular ipratropium bromide, tiotropium bromide or oxitropium bromide;
  • Anti-inflammatory agents by way of example and with preference from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flu
  • the energy metabolism of the heart affecting compounds such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;
  • Vasopressin receptor antagonists such as, by way of example and by way of preference, Conivaptan, Tolvaptan, Lixivaptan, Mozavaptan, Satavaptan, SR-121463, RWJ-676070 or BAY 86-8050; ⁇ Hypoglycemic agents (antidiabetics), by way of example and preferably from the group of biguanides, such as metformin, sulfonylureas, such as glibenclamide or glimerase, glinides, such as repaglinide or nateglinide, DPP IV inhibitors, such as sitagliptin, vildagliptin or saxagliptin, the glucosidase inhibitors such as acarbose or miglitol, and the amylin analogs such as pramlintide; Hypertensive agents, by way of example and by way of preference from the group of calcium antagonists, angiotens
  • Antithrombotic agents by way of example and preferably from the group of antiplatelet agents, anticoagulants and pro-fibrino-lytic substances; and or
  • 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 alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
  • 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 alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents,
  • the compounds according to the invention are used in combination with a kinase inhibitor, such as, by way of example and by way of preference, ninetanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib , Pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, lonafarnib, pelitinib, semaxanib, tandutinib or tipifarnib.
  • a kinase inhibitor such as, by way of example and by way of preference, ninetanib, dasatinib, nilotinib, bosutinib, regorafenib, soraf
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Tor antagonists, Rho kinase inhibitors 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 an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, melanol pranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebi
  • 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 used in combination with an ACE inhibitor, such as by way of example and preferably enalapril.
  • an ACE inhibitor such as by way of example and preferably enalapril.
  • 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 according to 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 of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI- 23095, SB-772077, GSK-269962A or BA-1049.
  • the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, B endro flumethiazi, chlorothiazide, hydro chlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide , Metolazone, quinethazone, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and per fibrinolytic 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, by way of example and by way of preference, 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.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, apixaban.
  • 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.
  • the 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 alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reab tion inhibitors, lipase inhibitors and the lipoprotein (a) understood antagonists.
  • 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 according to 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) ,
  • 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, for example and preferably, Lovas tatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavas tatin.
  • statins such as, for example and preferably, Lovas tatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavas tatin.
  • 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.
  • an ACAT inhibitor as exemplified and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797 administered.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of 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.
  • the compounds according to the invention are administered in combination with a PPAR delta 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, coiestipol, colesolvam, cholesta gel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • 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.
  • 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 amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound according to the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft) rapidly disintegrating in the oral cavity gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • absorption step e.g., intravenous, intraarterial, intracardiac, 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 powdered inhalants, 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, Shaking mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (for example patches)
  • transdermal therapeutic systems for example patches
  • milk pastes, foams, scattering powders, implants or stents.
  • Preference is given to oral and intravenous 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.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dode
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 50 mg / kg and most preferably 0.1 to 30 mg / kg body weight.
  • the amount is generally about 0.1 to 50 mg per inhalation.
  • Purity specifications usually refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined using the ⁇ -NMR spectrum. If no purity is specified, it is usually 100% o purity according to automatic peak integration in the LC / M S chromate program or purity was not explicitly determined.
  • the compounds of the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, provided the compounds of the invention have a sufficiently basic or acidic functionality.
  • a salt can be dene methods known in the art are converted into the corresponding free base or acid.
  • the reaction was then diluted with ethyl acetate, washed with water and the aqueous phase back extracted with ethyl acetate.
  • the combined organic phases were washed with water and dried over sodium sulfate. After being filtered off from the desiccant, it was evaporated in vacuo. After drying in a high vacuum, 38.3 g of the target compound were obtained (96% of theory, purity 90%). The product could be further reacted without further purification.
  • the combined organic phases were washed with a 1: 1 mixture of saturated aqueous ammonium chloride solution and 25% aqueous ammonia until no more blue discoloration of the aqueous phase was detected and the organic phase was colorless.
  • the organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtering off the drying agent, it was concentrated in vacuo. After drying the residue in a high vacuum, 178 mg (85% of theory, purity 85%) of the title compound were obtained. The product could be used without further purification in subsequent reactions.
  • the precipitated solid was filtered off, washed with water, taken up in a little ethyl acetate and the resulting solution was added dropwise with stirring in 1 liter of petroleum ether.
  • the resulting precipitate was filtered off with suction, taken up in 100 ml of 0.5 N sulfuric acid and 100 ml of acetonitrile, stirred for 30 minutes and then added to 1 liter of water. After 15 minutes of stirring, sucked off again and the precipitate washed with water.
  • the product was taken up in ethyl acetate and re-evaporated together with silica gel in vacuo.
  • Example 8 In analogy to Example 1, the example compounds listed in Table 8 were prepared by reacting guanidine hydrochloride with the corresponding benzyl- or phenoxy-substituted trifluoromethylketoesters: Tabelie 8
  • reaction time 18 h
  • Example 25A 175 mg (0.43 mmol) of methyl [5- (3,4-dichlorobenzyi) -6-oxo-4- (trifluoromethyl) -l, 6-dihydropyrimidiri- 2-yl] acetate (Example 25A) were dissolved in 1.7 ml of THF , treated with 1.72 ml of 1 N aqueous lithium hydroxide solution and stirred at 23 ° C for 18 h.
  • Example 19 or Example 25A Analogously to Example 19 or Example 25A, the example compounds listed in Table 10 were prepared by reacting the relevant amidines (imidamides) or their salts with the corresponding benzyl- or phenoxy-substituted trifluoromethylketoesters:
  • Example 35 the example compounds listed in Table 1 1 were prepared by reacting 3,3-diaminoprop-2-enamide hydrochloride with the corresponding benzyl- or phenoxy-substituted Trifluormethyiketoestem:
  • Example 35 Analogously to Example 35, the example compounds listed in Table 12 were prepared by reacting 2-hydroxyethanimidamide with the corresponding phenoxy-substituted trifluoromethylketoesters:
  • Example 17 In analogy to Example 2 or Example 25 A, the example compounds listed in Table 17 were prepared by reacting the respective guanidines or amidines (carboximidamides) or their salts with the corresponding substituted trifluoromethylketoesters:
  • the antagonistic effect of test substances on CCR2 was determined in a functional Ca 2+ release test.
  • the binding of CCL2 / MCP-1 to CCR2 leads to a conformational change of the receptor, which results in Gi / Gq protein activation and intracellular signaling cascade. Among other things, this leads to an intracellular Ca 2+ release.
  • the test cell used was a human CCR2-transfected Chem-1 cell line (ChemiSCREEN TM CCR2B Calcium-Optimized FLIPR Cell Line, Merck Millipore).
  • the test substances were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM and serially diluted in DMSO for a 10-point dose-response analysis in 1: 3.16 increments.
  • DMSO dimethyl sulfoxide
  • the substances were prediluted in Tyrode with 2 mM CaCl 2 and 0.05% BSA.
  • Those in DM EM high glucose [supplemented with 10% FCS, 1 mM pyruvate, 15 mM H EPES. 500 ⁇ g / ml of geniticin and non-essential amino acids (NEAA)] were cultured at 5,000 cells / 25 ⁇ in 384 well, Seeded Greiner cell culture plates (# 781092) and incubated at 37 ° C for 24 h.
  • the seeding medium consisted of EM high glucose [supplemented with 5% FCS. 1 mM pyruvate. 15 mM H EPES.
  • MCP-1 was used at the ECso equivalent concentration determined in a pre-test (usually about 5 nM). The Ca 2+ release was monitored over a period of 120 sec in 1 sec increments in a proprietary fluorescence imaging instrument. The molar concentration of the test substance which caused a 50% inhibition of the MC P-1 effect (IC 5 o value) was determined by means of a 4-parameter logistics function (Hill function).
  • Example No. IC50 [nM] Example No. IC50
  • the antagonistic effect of test substances on CCR2 was determined in a ⁇ -arrestin test.
  • the PathHunter ⁇ -arrestin GPCR assay system (DiscoveRx Corporation, Ltd.) is a cell-based functional method for detecting the binding of ⁇ -arrestin to an activated receptor.
  • the molecular basis is ⁇ -galactosidase complementation, which is measured by the enzymatic turnover of a chemiluminescent substrate.
  • the test cell used was a murine CCR2 transfected U20S- ⁇ -arrestin cell line (93-0543C3, DiscoveRx Corporation, Ltd.).
  • test substances were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM and serially diluted in DMSO for 10-point dose-response analysis in 1: 3.16 increments. According to the desired test concentrations, the substances were prediluted in Tyrode with 2 mM CaCl 2 and 0.05% BSA.
  • DMSO dimethyl sulfoxide
  • the cells cultured in MEM Hagle (supplemented with 10% PCS, 50 U / ml penicillin, 50 ⁇ g / ml streptomycin, 250 ⁇ g / ml hygromycin and 500 ⁇ g / ml geniticin) were incubated with 2000 cells / 25 ⁇ in 384 well, ⁇ 0 ' Seeded black Greiner cell culture plates (# 781092) and incubated at 37 ° C for 24 h.
  • the seeding medium consisted of Opti-MEM (supplemented with 1%> FCS, 50 U / ml penicillin and 50 ⁇ g / ml streptomycin).
  • the cells were preincubated with 10 ⁇ of the test substances diluted in buffer for 10 min before adding 10 ⁇ agonist solution [human MCP-1 (PeproTech, # 300-04) in Tyrode with 0.05% BSA].
  • 10 ⁇ agonist solution human MCP-1 (PeproTech, # 300-04) in Tyrode with 0.05% BSA].
  • the human MCP-1 was used with the Et "so-value, appropriate concentration, which was determined in a preliminary test (typically about 3 nM).
  • the assay was performed in an identical manner as described above under B-2a, but using murine MCP-1 (PeproTech, # 250-10) as the agonist.
  • murine MCP-1 PeproTech, # 250-10
  • Table 2b the IC50 values thus determined from this assay are listed for individual exemplary embodiments (in some cases as mean values from a plurality of independent one-time determinations):
  • the antagonistic effect of test substances on human CC receptors was determined in functional Ca 2+ release tests using Ca 2+ -sensitive fluorescent dyes.
  • SCREN TM CCR Caicium Optimized FLIPR Cell Lines, Merck Millipore, CCR1: HTS005C, CCR3: HTS008C, CCR4: HTS009C, CCR5 Rhesus Monkey: HTSO1 OC; CCR6: HTSOL IC; CCR7: HTS012C; CCR8: HTS013C; CCR9: HTS036C; CCR10: HTS014C).
  • the substance test was performed with a FLIPR tetra instrument (Molecular Devices).
  • the respective agonist was added at a concentration corresponding to the ECso value.
  • the Ca 2+ release was measured over a period of 180 seconds.
  • the substance test was carried out with an EnVision microplate reader (Perkin Elmer) with which the chemiluminescent conversion of the ⁇ -galactosidase substrate is detected.
  • the respective agonist was added at a concentration corresponding to the ECso value.
  • test cells used were CHO-Kl cell lines transfected with the respective receptor and aequorin (Euroscreen SA, rCCR2: FAST-0616A, rCCR5: FAST-0617A).
  • Luminescent detection of Ca 2+ release was performed using a Functional Drug Screening System 6000 (FDSS 6000) luminometer (Hamamatsu). The respective agonist was added at a concentration corresponding to the ECso value.
  • FDSS 6000 Functional Drug Screening System 6000
  • B-sixth THP-1 migration assay The migration of TH-1 cells is analyzed by means of a CytoSelect 96-cell migration assay (5 ⁇ m membrane pores), Fiuormetric (BioCat GmbH) or a comparable assay, and the effect of test substances on the migration behavior is investigated. Alternatively, macrophages are isolated from whole blood (from dog, pig or human) and used to perform a migration assay.
  • THP-1 cells are incubated with 9-cis retinoic acid for 7-24 h to initiate differentiation of the cells. During the incubation, the medium test substance is added, and then RNA was isolated (TRIzol ®, In vi trogen). After reprocessing of the RNA and reverse transcription (ImProm-IITM Reverse Transcription System, Promega A3800), a gene expression analysis is performed on MCP-1 using TaqMan.
  • PBMC assay B-eighth Human whole blood assay (PBMC assay) / MCP-1-induced gene expression
  • the blood is drawn in heparin-monovettes (Sarstedt), then the blood is collected and pipetted 2.5 ml each into the wells of a 12-well plate. 2.5 ⁇ of solvent or test substance solution are added by pipette to each well, mixed on a plate shaker for about 5 minutes and then incubated for 20 min at 37 ° C. in an incubator. Thereafter, the addition of hMCP-1 (100 ng / ml), about 4 minutes of mixing on a plate shaker and then incubation for 4 h at 37 ° C in the incubator.
  • hMCP-1 100 ng / ml
  • RNA and reverse transcription Improm-IITM Reverse Transcription System, Promega A3800 is performed gene expression analysis by Taqman.
  • AMI Acute myocardial infarction
  • Male Wistar rats (280-300 g, Harlan Nederland) are intubated with 160 mg / kg ketamine, 8 mg / kg xylazine, intubated to a respiratory pump (ugo basile 7025 rodent, 0.4-0.5 liter / min, 60 x / min ) and ventilated with 60% compressed air / 40% O2.
  • the body temperature is maintained at 37-38 ° C by a heat mat.
  • analgesics 00:03 mg / kg sc Temgesic ® can optionally be added.
  • the surgical area is disinfected (eg with Cutasept ® ), the thorax of the animal is opened between the 3rd and 4th rib and fixed using a rib spreader.
  • the heart of the animal is dissected free under the heart ear and undercut about 2 mm below the auricular end with a 5-0 Prolene thread. Both ends of the thread are pushed through a PE50-Stempei and the thread ends wound around a needle holder. Due to the resulting tension, the coronary artery of the left ventricle (LAD) is disconnected. A bulldog clamp is placed on the PE50 stem and thus occludes the LAD (occlusion time 30 minutes). After this time, release the Bulldog clamp and remove the PE50 punch; the thread remains. The thorax is closed again and the muscle layers and the epidermis are sewn up with coated Vicryl L 5-0 (V990H).
  • Antisedan ® im is injected to abolish anesthesia.
  • the animals are anaesthetized again (2% isoflurane / compressed air / O), and a pressure catheter (Miliar SPR-320 2F) is transferred to the left via the carotid artery after measuring the systemic blood pressure Introduced ventricle.
  • Heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) are recorded and evaluated using the Powerlab system (AD Instruments) and the LabChart software.
  • a blood sample is taken to determine the substance plasma levels and plasma biomarkers and the animals are killed.
  • the area at risk and infarct size are determined by perfusion with Evans Blue (0.2%) followed by TTC staining.
  • Male Wistar rats (280-300 g, Harlan Nederland) are anesthetized with 5% isoflurane in anesthesia cage, intubated, connected to a ventilation pump (ugo basile 7025 rodent, 0.4-0.5 liter / min, 60 x / min) and treated with 5% Enflurane / compressed air / O 2 ventilated.
  • the body temperature is maintained at 37-38 ° C by a heat mat.
  • a painkiller may optionally 12:03 mg kg sc Temgesic ® are given.
  • the thorax is opened laterally between the third and fourth ribs and the heart is exposed.
  • the coronary artery of the left ventricle is punctured with a occlusion thread (Prolene Ethicon 5-0, EH7401 H) just below its origin (below the left atrium) and permanently tied.
  • a occlusion thread Prolene Ethicon 5-0, EH7401 H
  • the thorax is closed again and the muscle layers as well as the epidermis are sewn with coated Vicryl I. 5-0 (V990H).
  • the surgical suture is wetted with Spmhpflaster (eg Nebacetin ® N spray dressing, active ingredient neomycin sulfate) and then terminated the anesthetic.
  • the occlusion thread can be placed around the LAD without closing it.
  • the LAD occlusion is then performed by tightening the outward occlusion suture.
  • the animals are randomized by Troponin determination and divided into individual treatment groups and a control group without substance treatment.
  • a "sham" group in which only the surgical procedure, but not the LAD occlusion was performed, carried along. Treatment with the test substance takes place over 8 weeks by gavage or by addition of the test substance in the feed or drinking water.
  • a pressure catheter (Miliar SPR-320 2F) is introduced via the carotid artery into the left ventricle.
  • heart rate left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt) and relaxation rate (tau) are determined with the aid of lab-Systems (AD Instruments) and the LabChart software were recorded and evaluated.
  • a blood sample is taken to determine the substance plasma levels and plasma biomarkers and the animals are killed.
  • Heart ventricles, left ventricle plus septum, right ventricle), liver, lung and kidney are removed and weighed.
  • mice Male Sprague Dawley rats (200-250 g, Charles River) are anesthetized with 5% isoflurane in anesthesia cage. In the tolerance stage, the animals are intubated with the help of a guide wire with a Braunüle (16G) and administered the Noxe (3 mg / kg LPS in 100 ⁇ physiological saline solution) via the tube. Control animals receive 100 ⁇ saline solution. 24 hours after application of the Noxe lungs are lungs. Before lavage, the animals are weighed again to determine the lung index (lung weight / body weight). For the lavage, the animals are anesthetized with isoflurane. The trachea is prepared and a Braunüle (16G) is integrated.
  • the lung is rinsed with 1.5 ml of physiological saline solution three times.
  • the lavage is kept on ice, pooled per animal and measured on the CellDyn 3700 for the determination of inflammatory cells (white blood cells, neutrophils, monocytes).
  • mice Male mice (Balb / cAnN, about 20 g, Charles River) are anesthetized with compressed air / oxygen / 5% isoflurane. 100 ⁇ of a solution of the noxa to be administered (3 mg / kg LPS or 10 ng LPS MCP-1, see Maus et al., Am. J. Resp. Grit. Care Med. 2001, 164 (3), 406 -41 1) deep into the mouth above the larynx. The animal breathes in the liquid completely. 24 to 48 hours after administration of the noxa lung lavage takes place. To do this, the mice are anaesthetized again as described above. The thorax is opened and the trachea is dissected free.
  • an indwelling cannula is inserted (20G) and fixed with a thread.
  • 0.5 ml of physiological saline solution is added to the lungs via the cannula.
  • the lavage obtained in this way is transferred to a vessel.
  • the lung is rinsed with a total of 1 .5 ml of saline solution.
  • the lavage is stored on ice and the inflammatory cells (white blood cells, neutrophils and monocytes) are quantified on the CellDyn 3700.
  • Leptin receptor-deficient db / db mice serve as a murine model of type 2 diabetes.
  • these animals have contractile defects of the heart, on the other hand they also have a malfunctioning disorder [Belke et al., In: Animal Models in Diabetes Research, Methods in Molecular Biology, Vol. 933 (2012); Sayyed et al, Kidney Int. 201 1, 80, 68-78; Li et al., Acta Pharmacol. Sin. 2010, 31, 560-569].
  • Male db / db mice with or without unilateral nephrectomy are treated with test substances and the effect on cardiac and renal function is investigated.
  • test substances can also be shown in the Alport mouse model of kidney damage [Clauss et al. , Pathol. 2009, 218 (1), 40-47].
  • MCP-1-induced monocyte recruitment in the rat Male Sprague Dawley rats (200-250 g, Charles River) are anesthetized with 5% isoflurane in the anesthesia cage. In the tolerance stage, MCP-1 (10 ⁇ g in 200 ⁇ NaCl solution) is administered via the tail vein, thus inducing the recruitment of monocytes from the bone marrow. Sixty minutes after administration of MCP-1, the rats are anaesthetized again, painlessly killed and the blood picture (neutrophils, monocytes) determined (Advia 21201, Siemens). The effect of test substances on the MCP-1 -induced increase in monocytes measured in the blood is examined.
  • 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 as a guideline for the compression.
  • composition Composition:
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension. production:
  • the rhodigel is suspended in ethanol, the compound 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 according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • I.v. solution The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and bottled in sterile and pyrogen-free injection containers.

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Abstract

La présente invention concerne des nouveaux dérivés de la 6-(trifluorométhyl)-pyrimidine-4(3H) -one 2,5-disubstituée, des procédés pour leur préparation, leur utilisation seul ou en combinaison pour le traitement et/ou la prévention de maladies et leur utilisation pour la production de médicaments pour le traitement et/ou la prévention de maladies, en particulier pour le traitement et/ou la prévention de maladies cardiovasculaires, rénales, inflammatoires et fibrotiques.
EP14766967.5A 2013-09-16 2014-09-12 Trifluorométhylpyrimidones disubstituées et leur utilisation comme antagonistes du ccr2 Withdrawn EP3046912A1 (fr)

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US10385028B2 (en) 2017-12-14 2019-08-20 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
US11730714B2 (en) 2017-12-14 2023-08-22 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
US11147788B2 (en) 2017-12-14 2021-10-19 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
US11591284B2 (en) 2017-12-14 2023-02-28 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
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