WO2016113205A1 - Pentafluoréthylpyrimidinones substituées et leur utilisation - Google Patents

Pentafluoréthylpyrimidinones substituées et leur utilisation Download PDF

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WO2016113205A1
WO2016113205A1 PCT/EP2016/050338 EP2016050338W WO2016113205A1 WO 2016113205 A1 WO2016113205 A1 WO 2016113205A1 EP 2016050338 W EP2016050338 W EP 2016050338W WO 2016113205 A1 WO2016113205 A1 WO 2016113205A1
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compound
formula
salts
acute
solvates
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Carl Friedrich Nising
Nicole BIBER
Michael Koch
Jutta Meyer
Matthias Beat WITTWER
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Bayer Pharma AG
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to new 2,5-disubstituted 6- (pentafluoroethyl) 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 thus play a central role in the development and course of numerous inflammatory diseases by the recruitment of inflammatory cells [Schall, Cytokine 3, 165-183 (1991); Schall et al., Curr. Opin. Immunol. 6, 865-873 (1994)]. In addition to the chemotactic effect, 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.
  • chemokines identified in humans bind to specific chemokine receptors belonging to the family of G protein-coupled receptors.
  • the CC chemokine receptor CCR2 is activated, among others, on the surface of macrophages, monocytes, B cells, activated T cells, dendritic cells, and epithelial cells 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, 313-326 (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 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 proinflammatory modulators such as TNF-OC, IL-8, IL-12 and matrix metalloproteases (MMPs).
  • MMPs matrix metalloproteases
  • CCR2 mediates the migration of monocytes from the bone marrow and their subsequent immigration into inflammatory areas [Carter, Expert Opin. Ther. Patents 23 (5), 549-568 (2013)].
  • fibrocytes appear to be formed from the population of 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 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, chronic 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. Pat. 23 (5), 549-568 (2013); Higgins et al., Chemokine Research, Basic Research and Clinical Application, Vol. II, Birkhäuser-Verlag, 115-123 (2007)].
  • 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 is accompanied by an upregulation of MCP-1 [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), 342-351 (2006)].
  • MCP-1-deficient mice show attenuated remodeling after myocardial infarction [Dewald et al., Circ. Res. 96 (8), 881-889 (2005)].
  • ApoE_ ⁇ mice a markedly improved infarct healing in blockade of the CCR2 receptor shows [Majmudar et al., Circulation 127 ', 2038-2046 (2013)].
  • the CC chemokine receptor CCR1 is expressed on the surface of many immune cells and non-immune cells, such as macrophages, monocytes, B cells, CD4 + T cells, CD8 + T cells, NK cells, basophils, eosinophils, mast cells, neutrophil granulocytes , dendritic cells, Kupffer cells, astrocytes, neurons, mesenchymal stem cells, osteoblasts and osteoclasts [Karash et al. , Curr. Top. Med. Chem. 14 (13), 1553-1573 (2014)].
  • non-immune cells such as macrophages, monocytes, B cells, CD4 + T cells, CD8 + T cells, NK cells, basophils, eosinophils, mast cells, neutrophil granulocytes , dendritic cells, Kupffer cells, astrocytes, neurons, mesenchymal stem cells, osteoblasts and osteoclasts [Karash et al. ,
  • CCRl binds at least 7 different ligands: CCL3 (MIP-1c), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL14, CCL15 and CCL23.
  • CCRl plays an important role in the migration of monocytes into inflamed tissue. It seems to be particularly important here that in addition to migration CCRl mediated also integrins such as Mac-1 (CDl lb) are up-regulated, whereby a firm adhesion of the leukocytes is mediated to the endothelium.
  • CDl lb Mac-1
  • the chemokine receptor CCR1 thus has a non-redundant significance for leukocyte adhesion to activated endothelium, an important step in transendothelial migration [Anders et al., Kidney Int. 69, 29-32 (2006)]. Furthermore, activated monocytes themselves can secrete the CCRI ligand CCL3 and thus initiate the migration of further monocytes into inflamed tissue. This suggests that CCR1 and its ligands play an important role in the maintenance of chronic inflammation. CCRl-mediated signal transduction also contributes to the inflammatory process through increased T-cell activation and Tnl / Tiü polarization. Accordingly, the chemokine receptor CCR1 is associated with a variety of diseases such as multiple sclerosis, rheumatoid arthritis, COPD, Alzheimer's disease, atherosclerosis, and inflammatory kidney disease.
  • diseases such as multiple sclerosis, rheumatoid arthritis, COPD, Alzheimer's disease, atherosclerosis, and
  • the CC chemokine receptor CCR5 is also expressed on numerous immune cells and non-immune cells, such as monocytes, macrophages, CD4 + T cells, CD8 + T cells, NK cells, basophils, mast cells, dendritic cells, astrocytes, microglial cells. Cells, neurons, osteo- blasts, Kupffer cells, hepatic stellate cells, vascular endothelial cells, and vascular smooth muscle cells [Karash et al, Curr. Top. Med. Chem. 14 (13), 1553-1573 (2014)].
  • Known ligands of CCR5 are CCL3 (MIP-1 oc), CCL4 (MIP-1 ⁇ ) and CCL5 (RANTES).
  • chemokines CCL8, CCL13 and CCL11 can also activate CCR5, albeit at a lower potency [White et al, Pharmacol. Rev. 65, 47-89 (2013)].
  • the chemokine CCL5 which can be produced by T cells, but also by platelets, macrophages, fibroblasts and endothelial cells, induces the migration / recruitment of T cells, NK cells, mast cells and basophils.
  • the incidence of CCR5-positive cells is observed in numerous inflammatory diseases such as atherosclerosis, graft rejection, colitis, arthritis, multiple sclerosis and liver fibrosis.
  • CCR5 / CCL5 is believed to play a role in enhancing inflammation in various "sterile", ie pathogen-free, inflammatory responses.
  • CCR5 also plays an important role as a co-receptor / entry factor for CCR5-tope HIV strains.
  • Individuals with a homozygous deletion in the CCR5 coding region (CCR5 ⁇ 32) are resistant to HIV infections [Pease and Horuk, Expert Opin. Ther. Patents 19 (2), 199-221 (2009); Marques et al, Expert Opinion. Ther. Targets 17 (12), 1439-1460 (2013)].
  • the object of the present invention was thus to identify and provide new substances which act as potent antagonists of the CCR2 receptor and moreover have a significant CCR1 and CCR5 antagonistic active component.
  • Such compounds should be particularly suitable for the treatment and / or prevention of cardiovascular, renal, inflammatory and fibrotic disorders.
  • WO 2004/018435-A1 describes substituted pyrimidine derivatives as modulators of the activity of chemokine receptors, in particular CXCR2.
  • WO 2011/114148-A1 and WO 2012/041817-A1 disclose bicyclic pyrimidine derivatives as antagonists of the CCR2 receptor.
  • WO 95/11235-A1 WO 03/051906-A2
  • WO 03/072107-A1 WO 2004 / 111014-A1
  • WO 2005/026148-A1 WO 2005/095381-A1
  • WO 2009/019656-A1 WO 2010/144345-A1
  • WO 2011/022440-A2 substituted aryl and heteroaryl compounds which appear suitable as modulators of the PI3K-AKT-mTOR signaling pathway, in particular for the treatment of neurodegenerative disorders.
  • WO 2007/048734-A1 discloses 2-pyrazolylpyrimidines for controlling phytopathogenic harmful fungi.
  • JP 07-196628-A [Chem. Abstr. 123: 340181] describes a process for the preparation of perfluoroalkylpyrimidines.
  • WO 93/08169-A1 discloses various 6- (perfluoroalkyl) pyrimidine-4 (3H) -one derivatives as synthesis intermediates for the preparation of substituted 4-aminopyrimidines which act as angiotensin II antagonists.
  • the present invention relates to compounds of the general formula (I)
  • R 1 and R 2 are independently hydrogen, fluorine, chlorine, methyl, difluoromethyl or trifluoromethyl, wherein at least one of the two radicals R 1 and R 2 is different from hydrogen, and
  • (Iii) one or two times, same or different, with a radical selected from the group fluorine, chlorine, bromine, difluoromethyl, trifluoromethyl, (Ci-C alkyl, cyclopropyl, phenyl, hydroxy, difluoromethoxy, trifluoromethoxy, (Ci-C Alkoxy, (C 1 -C 4 -alkoxymethyl, (Trifluoromethyl) sulfanyl, (Ci-C 4 ) -alkylsulfanyl, (Ci-C 4 ) -alkylsulfinyl, (Ci-C 4 ) -alkylsulfonyl, amino, mono- (Ci-C4) -alkylamino, di (Ci -C4) -alkylamino and (Ci-C4) -alkylcarbonyl- amino and (iv) can be fused with a phenyl or pyridyl ring, which
  • 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), mentioned below, are not already salts, solvates and solvates of the salts.
  • Compounds of the invention are also N-oxides of the compounds of formula (I) and their salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, Fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and embonic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, succinic, Fumar
  • Physiologically acceptable salts of the compounds according to the invention also include 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 16C - As exemplified and preferably ethylamine, diethylamine, triethylamine, Af, Af-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, dimethylaminoethanol, diethylaminoethanol, choline, procaine, dicyclohexylamine, dibenzylamine, Af-methylmorpholine, Af-methylpiperidine, arginine , Lysine and 1,2-ethylenediamine.
  • customary bases such as, by way of example and by way of preference, alkali metal salt
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds 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 atropisomers).
  • the present invention therefore encompasses the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • 6- (pentafluoroethyl) pyrimidin-4 (3H) -one derivatives of the formula (I) according to the invention can also be obtained in the tautomeric pyrimidine-4 (1H) -one form ( ⁇ ) or 4-hydroxypyrimidine form (I). (See Scheme 1 below), both tautomeric forms being expressly encompassed by the present invention
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • an isotopic variant of a compound of the invention in this case, a compound is understood in which at least one atom is exchanged within the inventive compound for another atom of the same atomic number, but with a different atomic mass than the usual or predominantly occurring in nature atomic mass.
  • 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), ⁇ (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution 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.
  • incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging body half-life or reducing the required dose of the active ingredient; 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 reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds according to the invention.
  • (C 1 -C 4) -Alkyl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • alkyl radical having 1 to 4 carbon atoms.
  • (C 1 -C 4) -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, -propoxy, isopropoxy, -butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • (C 1 -C 4) -alkoxymethyl in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms which is linked to the rest of the molecule via a methylene group [-CH 2 -] bound to the O atom.
  • methoxymethyl, ethoxymethyl, "-propoxymethyl, isopropoxymethyl butoxymethyl and tert-butoxymethyl.
  • (C 1 -C 4) -alkylsulfanyl [also referred to as (C 1 -C 4) -alkylthio] is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is linked via an S atom to the rest of the molecule.
  • Examples which may be mentioned are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • Mono- (C 1 -C 4) -alkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, propylamino, isopropylamino, butylbutylamino and tert-butylamino.
  • Di- (C 1 -C 4) -alkylamino in the context of the invention represents an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 4 carbon atoms.
  • (C 1 -C 4) -Alkylcarbonylamino in the context of the invention is an amino group having a straight-chain or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl radical and is linked via the carbonyl group to the N-atom.
  • alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl radical and is linked via the carbonyl group to the N-atom.
  • 5- or 6-membered aza-heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, which contains a ring nitrogen atom and moreover one or two further, identical or different ring heteroatoms may contain from the series N, O and S and which is linked via a ring carbon atom or alternatively, if it allows the valence, via a ring nitrogen atom.
  • Examples which may be mentioned are pyrrolyl, pyrazolyl, imidazolyl, 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, 1, 2,4-thiadiazolyl, 1, 3,4-thiadiazolyl, pyridyl, Pyrimidinyl, pyrazinyl, pyridazinyl, 1, 2,4-triazinyl and 1, 3,5-triazinyl.
  • 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.
  • A is CH 2 or O
  • R 1 is chlorine, methyl, difluoromethyl or trifluoromethyl
  • a particular embodiment of the present invention relates to compounds of the formula (I) in which
  • A is O, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 1 is chlorine, methyl, difluoromethyl or trifluoromethyl and R 2 is chlorine, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 3 is pyrazolyl, 1, 2-oxazolyl, 1, 3-oxazolyl, 1, 2-thiazolyl, 1, 3-thiazolyl, imidazolyl, 1, 2,3-triazolyl or 1, 2,4-triazolyl, which is a - or doubly, identically or differently, may be substituted by a radical selected from the group chlorine, trifluoromethyl, methyl, hydroxy, methoxy, methylsulfanyl and amino, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 3 is pyrazolyl, 1, 2-oxazolyl, 1, 2-thiazolyl, imidazolyl or 1, 2,3-triazolyl, which are mono- or disubstituted, identical or different, with a radical selected from the series Chloro, trifluoromethyl, methyl, hydroxy, methoxy, methylsulfanyl and amino may be substituted, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 3 is pyrazolyl, 1, 2-oxazolyl, 1, 2-thiazolyl or imidazolyl, which may be fused with a phenyl or pyridyl ring, which in turn may be substituted by fluoro, chloro, methyl, trifluoromethyl or methoxy, and their salts, solvates and solvates of salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 3 is pyridyl, pyrimidinyl or pyridazinyl, which may be monosubstituted or disubstituted by identical or different substituents selected from the group consisting of chlorine, trifluoromethyl, methyl, hydroxy, methoxy, methylsulfanyl and amino, and their salts, solvates and Solvates of salts.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 3 is amino, and their salts, solvates and solvates of the salts.
  • Particularly preferred in the context of the present invention are compounds of the formula (I) in which
  • A stands for O
  • R 1 is chloro, methyl, difluoromethyl or trifluoromethyl
  • R 2 is chloro and R 3 is pyrazolyl, 1, 2-oxazolyl, 1,3-oxazolyl, 1, 2-thiazolyl, 1,3-thiazolyl, imidazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, pyridyl or pyrimidinyl which may each be substituted by methyl, hydroxy, methoxy, methylsulfanyl or amino, or represents amino, and their salts, solvates and solvates of the salts.
  • the present invention comprises compounds of the formula (I) in which
  • A stands for O
  • R 1 is chlorine, methyl, difluoromethyl or trifluoromethyl
  • R 2 is chlorine
  • R 3 is pyrazolyl, 1, 2-thiazolyl, pyridyl or pyrimidinyl, which may each be substituted by hydroxy, methoxy, methylsulfanyl or amino, or is amino, 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
  • a 1 is CH 2 or O.
  • T 1 is methyl, ethyl, propyl or is-butyl
  • a 2 is O or S, in the form of an alkali metal salt or in the presence of a base with a compound mel (V)
  • Suitable inert solvents for process step (II) + (III) -> (IA) are, for example, alcohols such as methanol, ethanol, -P -propanol, isopropanol, -B-butanol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, methyl tert-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 acetone.
  • alcohols such as methanol, ethanol, -P -propanol, isopropanol, -B-butanol or tert-butanol
  • ethers such as
  • DMF N-dimethylformamide
  • DMA N, N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • DMPU dimethyl sulfoxide
  • ⁇ N-methylpyrrolidinone
  • methanol, ethanol, 1, 4-dioxane or N, N-dimethylformamide is used.
  • the compound of the formula (III) is preferably used in
  • suitable bases are in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal bicarbonates 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, sodium or potassium or sodium or Potassium tert-butoxide, or conventional tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal bicarbonates 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, sodium or potassium or sodium or Potassium tert-butoxide
  • conventional tertiary amine bases such as tri
  • reaction (II) + (III) -> (IA) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 70 ° C to + 120 ° C, with the aid of a microwave apparatus of Advantage can be.
  • the process step (IV) + (V) -> (IB) is generally carried out in a temperature range of + 80 ° C to + 150 ° C in a correspondingly high-boiling inert solvent, such as ethylene glycol, bis (2-methoxyethyl) ethers, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (II).
  • ethylene glycol is used.
  • Suitable bases for this reaction are, in particular, alkali metal hydroxides, such as lithium, sodium or potassium hydroxide, alkali metal carbonates, such as lithium, sodium, potassium or cesium carbonate, alkali metal alcoholates, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert. Butylate, or alkali metal hydrides such as sodium or potassium. Cesium carbonate is preferably used.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
  • alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert.
  • Butylate, or alkali metal hydrides such as sodium or potassium.
  • Cesium carbonate is preferably used.
  • a peroxide or a peracid such as hydrogen peroxide, potassium permanganate, potassium monopersulfate, peracetic acid or meta-chloroperbenzoic acid.
  • a variant of the preparation method [A] described above consists in that, instead of the ⁇ -ketoester (II), a corresponding methylenol ether derivative of the formula (XIV) (as E / Z isomer mixture)
  • methylenol ethers can be prepared in a known manner by treating the ⁇ -ketoester (II) with trimethyloxonium tetrafluoroborate in the presence of a base such as, for example, potassium tert-butoxide or 1,8-bis (N, N-dimethylamino) naphthalene ("proton sponge"). ).
  • a base such as, for example, potassium tert-butoxide or 1,8-bis (N, N-dimethylamino) naphthalene ("proton sponge").
  • the methylation reaction is generally carried out in a temperature range from -20 ° C to + 20 ° C in an inert solvent such as tetrahydrofuran or dichloromethane.
  • the compounds of the formula (II) in turn can be prepared by reacting [Al] with a ⁇ -keto ester of the formula (VI) in which T 1 has the abovementioned meaning, in the presence of a base with a compound of the formula (VII)
  • R and R have the abovementioned meanings and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, a compound of the formula (II-A)
  • T, R and R have the meanings given above, alkylated or
  • T 1 , R 1 and R 2 have the meanings given above, acylated.
  • Inert solvents for process step (VI) + (VII) -> ( ⁇ - ⁇ ) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or Bis (2-methoxyethyl) ether, 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 -Methylpyrrolidinone ( ⁇ ) or NN'-dimethylpropyleneurea (DMPU).
  • ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl
  • Suitable bases for this reaction are in particular 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-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine. Preference is given to using N, N-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-n-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, propanol, isopropanol, butanol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, Methyl tert-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, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneure
  • Alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, or amides such as lithium or potassium bis (trimethyl silyl) amide or lithium diisopropylamide.
  • sodium hydride is used.
  • reaction (VIII) + (IX) -> (II-B) is usually carried out in a temperature range of + 120 ° C.
  • the compounds of the formula (V) can be prepared by reacting a ⁇ -keto ester of the formula (VI) analogously to process [A] in which T 1 has the abovementioned meaning, with a compound of the formula (III) in which R 3 has the abovementioned meaning, or a salt thereof, to give a compound of the formula (X)
  • 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 dichloromethane, Chloroform, tetrahydrofuran, acetonitrile, N, N-dimethylformamide (DMF) or acetic acid, within a temperature range of -78 ° C to + 50 ° C.
  • NBS N-bromosuccinimide
  • DMF N-dimethylformamide
  • Aza-heteroaryl ring can alternatively be prepared by reacting a compound of formula (II)
  • Het * is within the scope of R 3 above for an optionally substituted or fused 5-membered aza-heteroaryl ring as shown, containing an NH-group, implements.
  • the reaction (XII) + (XIII) -> (IC) is usually in a temperature range of + 100 ° C to + 200 ° C in a high-boiling inert solvent such as toluene, N, N-dimethylformamide (DMF ), NN-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone ( ⁇ ).
  • a non-nucleophilic base For example, potassium carbonate, sodium or potassium tert-butoxide or sodium hydride are suitable for this purpose.
  • 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, which additionally have a significant CCR1 and CCR5-antagonistic active component.
  • the compounds are therefore particularly suitable for the treatment and / or prevention of diseases, in particular of cardiovascular, renal, inflammatory, allergic and / or fibrotic diseases.
  • 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 Cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transitory and ischemic attacks, stroke, preeclampsia, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial Pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, arterial and venous thrombosis, thromboembolic disorders, edema such as pulmonary edema, brain edema, renal edema or heart failure bedi edema
  • cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as more specific or related forms thereof, such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects
  • Heart valve failure heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac memory diseases, diastolic heart failure, systolic heart failure and
  • 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 kidney failure.
  • the term acute renal insufficiency includes acute manifestations of kidney 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 obstruction, immunological kidney diseases such as renal transplant rejection and immune complex-induced kidney disease, tubular dilatation, hyperphosphatemia, acute renal diseases that may be characterized by the need for dialysis, and partial resections of the kidney, dehydrata tion by forced diuresis, uncontrolled hypertension with malignant hypertension, urinary tract obstruction, urinary tract infections and amyloidosis
  • renal hypoperfusion
  • chronic renal insufficiency encompasses chronic manifestations of kidney disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomeruli pathologies, glomerular and tubular proteinuria, renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport's syndrome, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, renal immunological diseases such as kidney transplant Rejection and immune complex-induced kidney disease, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive n
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hypercalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hypercalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prevention of polycystic kidney disease (PCKD) and the syndrome of inadequate ADH secretion (SIADH).
  • PCKD polycystic kidney disease
  • SIADH syndrome of inadequate 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 (ARDS), of acute Lung injury (ALI), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke induced 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
  • ARDS acute respiratory syndrome
  • ALI acute Lung injury
  • pulmonary fibrosis pulmonary emphysema (e
  • the compounds of the invention may also 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), bronchiolitis obliterans, bronchiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lung and related diseases, cough and Colds (chronic inflammatory cough, iatrogenic cough), nasal irritation (including rhinitis, vasomotor rhinitis and seasonal, 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,
  • 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 fibrosis, cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic diseases, scleroderma, amyotrophic lateral sclerosis (ALS), morphea, keloids, hypertrophic scarring (also after surgery), diabetic retinopathy and proliferative vitroretinopathy.
  • ALS amyotrophic lateral sclerosis
  • 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 Sclerosis 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 Sclerosis 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, 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), gastrointestinal and abdominal disorders (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,
  • the compounds according to the invention are furthermore suitable for the treatment and / or prevention of ophthalmological diseases such as, for example, glaucoma, age-related macular degeneration (AMD), dry (non-exudative) AMD, moist (exudative, neovascular) AMD, choroidal neovascularization (CNV ), diabetic retinopathy, atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium, macular edema, diabetic macular edema, retinal vein occlusion, choroidal retinal vein occlusion, macular edema due to retinal vein occlusion, angiogenesis in the anterior surface of the eye such as corneal angiogenesis for example after keratitis, corneal transplantation or Keratoplasty, corneal angiogenesis due to hypoxia (by extensive wearing of contact lenses), pterygium conjunctivae, subretinal edema and
  • the compounds according to the invention are suitable for the treatment and / or prevention of elevated and high intraocular pressure as a result of traumatic hyphaema, periorbital edema, postoperative viscoelastic retention or intraocular inflammation.
  • the compounds according to the invention can also be used for the treatment and / or prevention of uveitis.
  • 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 To develop, to experience, to suffer or to have symptoms of such conditions and / or 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 Erkran- kungen, 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.
  • the present invention therefore further relates to 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 aforementioned diseases.
  • Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:
  • the signal transduction cascade inhibiting compounds for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors;
  • MMPs matrix metalloproteases
  • MMP-12 metallo-elastase
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, 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;
  • soluble guanylate cyclase • NO and heme-independent activators of soluble guanylate cyclase, 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;
  • Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP) for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil;
  • Prostacyclin analogs and IP receptor agonists such as by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol or NS-304;
  • Bronchodilatory 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 preferably from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone; Compounds which inhibit the soluble epoxide hydrolase (sEH), such as N, N'-di-cyclohexylurea, 12- (3-adam
  • Vasopressin receptor antagonists such as, by way of example and by way of illustration, Conivaptan, Tolvaptan, Lixivaptan, Mozavaptan, Satavaptan, SR-121463, RWJ-676070 or BAY 86-8050;
  • Hypoglycemic agents by way of example and preferably from the group of biguanides, such as metformin, sulfonylureas, such as glibenclamide or glimeramide, 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;
  • biguanides such as metformin, sulfonylureas, such as glibenclamide or glimeramide
  • glinides such as repaglinide or nateglinide
  • DPP IV inhibitors such as sitagliptin, vildagliptin or saxagliptin
  • the glucosidase inhibitors such as acar
  • Hypertensive agents by way of example and by way of preference from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptors
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic 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 adsorbers, bile acid rejection 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 adsorbers, bile acid rejection inhibitors,
  • the compounds according to the invention are used in combination with a kinase inhibitor, such as, by way of example and by way of illustration, ninabediban, 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 illustration, ninabediban, dasatinib, nilotinib, bosutinib, regorafeni
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, 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.
  • 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 preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • 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, irbesartan, olmesartan, eprosartan or azilsartan.
  • angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • 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 or eplerenone.
  • the compounds according to the invention are administered 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.
  • 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, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethia
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, 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.
  • 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, edoxaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, apixaban, edoxaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • 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.
  • 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
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers polymeric bile
  • 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).
  • 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.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds of 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 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 lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • 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, as well as 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, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically 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 application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers, dosing aerosols
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye 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.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers eg, albumin
  • stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odor remedies 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, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin), stabilizers
  • 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.
  • Device type MS Thermo Scientific FT-MS; Device type UHPLC: Thermo Scientific UltiMate 3000; Column: Waters HSST3 C18, 1.8 ⁇ , 2.1 x 75 mm; Eluent A: 1: 1 water + 0.01% formic acid, eluent B: 1: 1 acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B -> 2.5 min 95% B -> 3.5 min 95% B; Oven: 50 ° C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm.
  • 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.
  • N-dimethylformamide was dropwise added 81 g (526 mmol) of phosphoryl chloride at -5 ° C to 0 ° C under a nitrogen atmosphere. After stirring for 20 min at 0 ° C, 30 g (173 mmol) of ethyl 2- (carbamoylhydrazono) propanoate was added portionwise at 0 ° C to 5 ° C over 20 min. The reaction mixture was stirred at 60 ° C. for 1 h and then at 80 ° C. for 3 h. stir. After cooling to room temperature, the mixture was carefully hydrolyzed by adding 600 ml of ice water and then adjusted to pH 10 by addition of sodium hydroxide.
  • the product contained about 18% of the corresponding methyl ester (methyl (2E / Z) -2- [4-chloro-3- (difluoromethyl) phenoxy] -4,4,5,5,5-pentafluoro-3 - Methoxypent-2-enoate) as a minor component.
  • Example 1 Exemplary embodiments: Example 1
  • Example 7A 195 mg (1.33 mmol) of 1H-pyrazole-3-carboximidamide hydrochloride (Example 7A) were initially charged in 4 ml of 1,4-dioxane and treated with 245 mg (1.77 mmol) of potassium carbonate. The mixture was stirred for 10 min at room temperature and then with 200 mg (0.44 mmol) of ethyl 2- [4-chloro-3- (trifluoromethyl) phenoxy] -4,4,5,5,5-pentafluoro-3-oxopentanoate ( Example 4A). The reaction mixture was then stirred for 1.5 hours in a microwave apparatus at 120 ° C.
  • Example 10A 4-methoxy-1H-pyrazole-3-carboximidamide hydrochloride
  • Example 10A 4-methoxy-1H-pyrazole-3-carboximidamide hydrochloride
  • Example 17A 100 mg (0.24 mmol) of ethyl 2- [4-chloro-3- (difluoromethyl) phenoxy] -4,4,5,5,5-pentafluoro-3-methoxy-pent-2-enoate (Example 17A) were dissolved in 2 ml of 1,4-dioxane and treated with 130 mg (0.94 mmol) of potassium carbonate and 69 mg (0.47 mmol) of 1H-pyrazole-3-carboximidamide hydrochloride (Example 7A). The reaction mixture was stirred at 100 ° C for 48 h.
  • Example 10 In analogy to Example 53, the example compounds listed in Table 10 were prepared by reacting the relevant amidines (carboximidamides) or their salts with the corresponding phenoxy-substituted 4,4,5,5,5-pentafluoro-3-methoxypent-2-enoates were:
  • Example 19A 115 mg (0.23 mmol) of ethyl 2- [3-chloro-4- (trifluoromethyl) phenoxy] -4,4,5,5,5-pentanucoro-3-methoxy-pent-2-enoate (Example 19A) were dissolved in 2 ml of 1,4-dioxane and with 129 mg (0.94 mmol) of potassium carbonate and 125 mg (0.47 mmol) of 1- (4-methoxybenzyl) -1H-l, 2,4-triazole-3-carboximid- amide (Example 13A ). The reaction mixture was stirred for 18 h at 100 ° C and then held in a microwave apparatus for 1 h at 120 ° C.
  • Example 73 35 mg (0.09 mmol) of 2-amino-5 - [(3,4-dichlorophenyl) sulfanyl] -6- (pentafluoroethyl) pyrimidin-4 (3H) -one (Example 73) were dissolved at room temperature in 3 ml of acetic acid and washed with 5 ⁇ hydrogen peroxide solution (30 wt .-% in water). The reaction mixture was stirred for 4 h at 45 ° C. Subsequently, another 5 ⁇ hydrogen peroxide solution (30 wt .-% in water) was added and the mixture stirred for 18 h at 50 ° C on.
  • 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 / G q 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 used for a 10-point dose-response analysis in steps of 1: 3.16 serially in DMSO. thinned. 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 DMEM high glucose [supplemented with 10% FCS, 1 mM pyruvate, 15 mM HEPES, 500 g / ml geniticin and non-essential amino acids (NEAA)] were cultured at 5000 cells / 25 ⁇ in 384 well, ⁇ CLEAR / black Seeded culture plates (Greiner, # 781092) and incubated at 37 ° C for 24 h.
  • the seeding medium consisted of DMEM high glucose [supplemented with 5% FCS, 1 mM pyruvate, 15 mM HEPES, 50 U / ml penicillin, 50 ⁇ g / ml streptomycin and nonessential amino acids (NEAA)].
  • the medium was then removed and the cells loaded with the dye Fluo-4 for 60 min at 37 ° C [25 ⁇ Tyrode with 3 ⁇ Fluo-4 AM (1 mM DMSO stock solution), 0.4 mg / ml Brilliant Black, 2.5 mM Probenicid, 0.03% Pluronic F-127].
  • the cells were pre-incubated with 10 ⁇ M of the test substances diluted in buffer for 10 min before adding 20 ⁇ M agonist solution (MCP-1 in Tyrode with 0.05% BSA). 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 MCP-1 effect was determined by means of a 4-parameter logistics function (Hill function).
  • the antagonistic effect of test substances on CCR1 was also determined in a functional Ca 2+ release test.
  • the binding of CCL3 / MIP-10C to CCR1 leads to a conformational change of the receptor that has a Gi / Gq protein activation and intracellular signaling cascade result. Among other things, this leads to intracellular Ca 2+ release.
  • the test cell used was a human CCR1-transfected Chem-1 cell line (Chemical SCREEN TM CCR1 Calcium-Optimized FLIPR Cell Line, Merck Millipore, HTS005C).
  • test substances were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM and diluted serially in DMSO for a 10-point dose-response analysis in 1: 3.16 increments. According to the desired test concentrations, the substances were in Tyrode with
  • the cells cultured in DMEM high glucose [supplemented with 10% FCS, 1 mM pyruvate, 15 mM HEPES, 500 g / ml geniticin and non-essential amino acids (NEAA)] were cultured at 2000 cells / 30 ⁇ in 384 well, ⁇ CLEAR / black Seeded culture plates (Greiner, # 781092) and incubated at 37 ° C for 24 h.
  • the seeding medium consisted of DMEM without glucose [supplemented with 5% FCS, 400 ⁇ M glucose, 1 mM pyruvate, 15 mM HEPES, 50 U / ml penicillin, 50 ⁇ M streptomycin and non-essential amino acids (NEAA)]. Subsequently, the medium was removed and the cells loaded for 30 min at 37 ° C with the dye fluo-8 [25 ⁇ Tyrode with
  • MIP-1 oc PeproTech, # 300-08
  • MIP-loc was used at the ECso equivalent concentration determined in a pre-test (usually about 1 nM). The Ca 2+ release was monitored over a period of 180 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 MIP-loc effect (IC 50 value) was determined by means of a 4-parameter logistics function (Hill function).
  • the antagonistic effect of test substances on CCR5 was also determined in a functional Ca 2+ release test.
  • the binding of CCL3 / MIP-10C to CCR5 leads to a conformational change of the receptor, which results in Gi / G q protein activation and intracellular signaling cascade. Among other things, this leads to intracellular Ca 2+ release.
  • the test cell used was a human CCR5-transfected CHO-Kl cell line with aequorin (Euroscreen FAST-062A).
  • 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 DMEM / F 12 medium [supplemented with 10% FCS, 50 U / ml penicillin, 50 ⁇ ⁇ ⁇ streptomycin, 400 g / ml geniticin and 250 ⁇ g / ml zeocin] were transfected at 2,000 cells / 25 ⁇ into 384 seeded, ⁇ CLEAR / black cell culture plates (Greiner, # 781092) and incubated at 30 ° C for 24 h.
  • the seeding medium consisted of Opti-MEM [supplemented with 1% FCS, 50 U / ml penicillin, 50 ⁇ g / ml streptomycin and 5 ⁇ g / ml coelenterazine].
  • the cells were preincubated with 10 ⁇ of the test substances diluted in buffer for 10 min before adding 20 ⁇ agonist solution [ ⁇ -loc (PeproTech, # 300-08) in Tyrode with 0.05% BSA].
  • MIP-1a was used at the ECso equivalent concentration determined in a pre-test (usually about 3 nM). Ca 2+ release was monitored over a 90 second period in 1 sec increments in a proprietary fluorescence imaging instrument.
  • the molar concentration of the test substance which caused a 50% inhibition of the MIP-loc effect was determined by means of a 4-parameter logistics function (Hill function).
  • Hill function 4-parameter logistics function
  • the antagonistic effect of test substances on CCR2 was also 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. Molecular basis is a ⁇ -galactosidase complementation, which is measured by the enzymatic conversion 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 Eagle (supplemented with 10% FCS, 50 U / ml penicillin, 50 g / ml streptomycin, 250 g / ml hygromycin, and 500 g / ml geniticin) were incubated with 2,000 cells / 25 ⁇ in 384 well, ⁇ CLEAR / 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 [murine MCP-1 (PeproTech, # 250-10) in Tyrode with 0.05% BSA].
  • the murine MCP-1 was used at the EC5o equivalent concentration determined in a preliminary test (usually about 3 nM). After incubation for 90 min at 37 ° C, the solution was removed, and with the aid of the PathHunter Detection Reagent (93-001, DiscoveRx Corporation, Ltd.), recruitment of ⁇ -arrestin to CCR2 was detected according to the manufacturer's instructions.
  • Luminescence was measured after 60 min of incubation in a proprietary luminescence imaging system. Meter.
  • the molar concentration of the test substance which caused a 50% inhibition of the MCP-1 effect was determined by means of a 4-parameter logistics function (Hill function).
  • Example No. IC50 MCP-1 [nM] Example No. IC50 MCP-1 [nM]
  • Test cells used were Chem-1 or Chem-5 cell lines transfected with the respective receptor (ChemiSCREEN TM CCR Calcium-Optimized FLIPR Cell Lines, Merck Millipore, CCR3: HTS008C, CCR4: HTS009C, CCR6: HTS011C, CCR7: HTS012C, CCR8: HTS013C; CCR9: HTS036C; CCR10: HTS014C).
  • Chem-1 or Chem-5 cell lines transfected with the respective receptor (ChemiSCREEN TM CCR Calcium-Optimized FLIPR Cell Lines, Merck Millipore, CCR3: HTS008C, CCR4: HTS009C, CCR6: HTS011C, 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.
  • test cells used were U20S or CHO-Kl- ⁇ arrestin cell lines transfected with the respective murine receptor (DiscoveRx Corporation, Ltd .; mCCR1: 93-0561C3; mCCR3: 93-0522C2; mCCR4: 93-0515C2; mCCR5: 93-0470C2; mCCR6: 93-0694C2; mCCR7: 93-0528C2; mCCR8: 93-0556C2; mCCR9: 93-0734C2).
  • the antagonistic effect of test substances on CCR2 (rat) and CCR5 (rat) was determined in functional Ca 2+ release tests using the Ca 2+ -sensitive photoprotein aequorin [Vakili et al., J. Immunol. 167, 3406 (2001); Fichna et al., J. Pharmacol. Exp. Ther. 317, 1150 (2006); Silvano et al., Mol. Pharmacol. 78, 925 (2010)].
  • the 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
  • THP-1 cells The migration of THP-1 cells is analyzed by means of a CytoSelect 96-well cell migration assay (5 ⁇ m membrane pores), Fluormetric (BioCat GmbH) or a comparable assay, and the effect of test substances on the migration behavior is investigated.
  • 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 subsequently RNA was isolated (TRIzol ®, Invitrogen). After work-up of the RNA and reverse transcription (ImProm-II TM Reverse Transcription System, Promega A3800), a gene expression analysis on MCP-1 by means of TaqMan.
  • 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
  • mice Male Sprague Dawley rats (200-250 g, Charles River) are anesthetized with 5% isoflurane in the narcotic cage.
  • MCP-1 (10 ⁇ g in 200 ⁇ NaCl solution) is administered via the tail vein, thus inducing the recruitment of monocytes from the bone marrow.
  • the rats 60 minutes after administration of MCP-1, the rats are anaesthetized again, killed without pain and the blood picture (neutrophils, monocytes) determined (Advia 2120i, Siemens).
  • the effect of test substances on the MCP-1-induced increase in monocytes measured in the blood is investigated.
  • 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 supported about 2 mm below the end of the ear with a 5-0 Prolene thread. Both ends of the thread are pushed through a PE50 punch and the thread ends are 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 punch and thus occluded 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). Subsequently, Antisedan ® im is injected to abolish anesthesia.
  • LAD coronary artery of the left ventricle
  • the animals are anaesthetized again (2% isoflurane / compressed air / 02), 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 , Subsequently, a blood sample for determining the substance plasma levels and plasma biomarkers is taken and the Killed animals. 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 the anesthesia cage, intubated, connected to a respiratory pump (ugo basile 7025 rodent, 0.4-0.5 liter / min, 60 x / min) and with 5% enflurane / compressed air / C respirator.
  • the body temperature is maintained at 37-38 ° C by a heat mat.
  • 0.03 mg / kg sc Temgesic ® may be given as analgesic.
  • the thorax is opened laterally between the third and fourth ribs and the heart is exposed.
  • the left ventricular coronary artery is punctured with an occlusion suture (Prolene Ethicon 5-0, EH7401H) just below its origin (below the left atrium) and permanently ligated.
  • the thorax is closed again and the muscle layers and the epidermis are sewn up with coated Vicryl L 5-0 (V990H).
  • the surgical suture is wetted with spray plaster (eg Nebacetin ® N spray dressing, active substance neomycin sulfate) and then the anesthesia is stopped.
  • spray plaster eg Nebacetin ® N spray dressing, active substance neomycin sulfate
  • the occlusion thread can be placed around the LAD without closing it. After closing the thorax and a healing phase (up to 1 week later), 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 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.
  • 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 noxae to be administered (3 mg / kg LPS or 10 ng LPS / MCP-1, see Maus et al., Am. J. Resp. Crit. Care Med. 2001, 164 (3), are used with a pipette. 406-411) 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.
  • This lavage s the lungs three times.
  • the lavage obtained in this way is transferred to a vessel.
  • the lungs are 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 on the one hand contractile defects of the heart, on the other hand also a renal dysfunction [Belke et al, in: Animal Models in Diabetes Research, Methods in Molecular Biology, Vol. 933 (2012); Sayyed et al., Kidney Int. 2011, 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. B-17th Analysis in renal ischemia-reperfusion model (mouse and rat)
  • test substances can also be demonstrated in the Alport mouse model of kidney damage [Clauss et al., J. Pathol. 2009, 218 (1), 40-47].
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • 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.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • i.v. 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%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution 30%.

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Abstract

La présente invention porte sur de nouveaux dérivés de 6-pentafluoréthyl)pyrimidin-4(3H) disubstitués en 2 et 5, sur des procédés pour les préparer, sur leur utilisation seuls ou en associations pour le traitement et/ou la prévention de maladies, ainsi que sur leur utilisation pour préparer des médicaments destinés au traitement et/ou à la prévention de maladies, en particulier au traitement et/ou à la prévention de maladies cardiovasculaires, rénales, inflammatoires et fibrotiques.
PCT/EP2016/050338 2015-01-13 2016-01-11 Pentafluoréthylpyrimidinones substituées et leur utilisation Ceased WO2016113205A1 (fr)

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Cited By (8)

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WO2019189731A1 (fr) * 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2020116296A1 (fr) 2018-12-07 2020-06-11 ユニマテック株式会社 Composé de pyrimidine fluoré et procédé de production associé
CN113474336A (zh) * 2019-02-28 2021-10-01 先正达农作物保护股份公司 具有含硫取代基的杀有害生物活性的杂环衍生物
WO2021222972A1 (fr) * 2020-05-06 2021-11-11 Dimerix Bioscience Ltd Traitement du syndrome de détresse respiratoire aiguë
WO2021222971A1 (fr) * 2020-05-06 2021-11-11 Dimerix Bioscience Ltd Traitement du syndrome de détresse respiratoire aiguë induite par un virus
WO2024252006A1 (fr) 2023-06-07 2024-12-12 Syngenta Crop Protection Ag Synthèse d'acyl sulfoximines cycliques
US12448362B2 (en) 2020-05-19 2025-10-21 Unimatec Co., Ltd. Fluorine-containing pyrimidine compound and fluorine-containing pyrimidinone compound
US12569481B2 (en) 2020-06-12 2026-03-10 Vanderbilt University Methods of treatment for gastrointestinal motility disorders

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CN111918865A (zh) * 2018-03-30 2020-11-10 住友化学株式会社 杂环化合物和含有该杂环化合物的有害节肢动物防除组合物
JPWO2019189731A1 (ja) * 2018-03-30 2021-04-22 住友化学株式会社 複素環化合物及びそれを含有する有害節足動物防除組成物
JP7301042B2 (ja) 2018-03-30 2023-06-30 住友化学株式会社 複素環化合物及びそれを含有する有害節足動物防除組成物
US11779018B2 (en) 2018-03-30 2023-10-10 Sumitomo Chemical Company, Limited Heterocyclic compound and arthropod pest control composition containing same
WO2019189731A1 (fr) * 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2020116296A1 (fr) 2018-12-07 2020-06-11 ユニマテック株式会社 Composé de pyrimidine fluoré et procédé de production associé
US12043615B2 (en) 2018-12-07 2024-07-23 Unimatec Co., Ltd. Fluorine-containing pyrimidine compound and method for manufacturing the same
CN113474336A (zh) * 2019-02-28 2021-10-01 先正达农作物保护股份公司 具有含硫取代基的杀有害生物活性的杂环衍生物
WO2021222972A1 (fr) * 2020-05-06 2021-11-11 Dimerix Bioscience Ltd Traitement du syndrome de détresse respiratoire aiguë
WO2021222971A1 (fr) * 2020-05-06 2021-11-11 Dimerix Bioscience Ltd Traitement du syndrome de détresse respiratoire aiguë induite par un virus
US12448362B2 (en) 2020-05-19 2025-10-21 Unimatec Co., Ltd. Fluorine-containing pyrimidine compound and fluorine-containing pyrimidinone compound
US12569481B2 (en) 2020-06-12 2026-03-10 Vanderbilt University Methods of treatment for gastrointestinal motility disorders
WO2024252006A1 (fr) 2023-06-07 2024-12-12 Syngenta Crop Protection Ag Synthèse d'acyl sulfoximines cycliques

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