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WO2015150366A1 - Dérivés d'éthers phénoliques à substitutions cycliques et leur utilisation - Google Patents

Dérivés d'éthers phénoliques à substitutions cycliques et leur utilisation Download PDF

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Publication number
WO2015150366A1
WO2015150366A1 PCT/EP2015/056990 EP2015056990W WO2015150366A1 WO 2015150366 A1 WO2015150366 A1 WO 2015150366A1 EP 2015056990 W EP2015056990 W EP 2015056990W WO 2015150366 A1 WO2015150366 A1 WO 2015150366A1
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compound
mmol
added
formula
mixture
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Inventor
Volkhart Min-Jian Li
Hartmut Beck
Yolanda Cancho Grande
Hannah JÖRIßEN
Martina Delbeck
Heinrich Meier
Andreas Timmermann
Mario Jeske
Dirk Brohm
Michael Gerisch
Dieter Lang
Elisabeth Woltering
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to novel, cyclically substituted phenol ether 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 respiratory, pulmonary and cardiovascular diseases.
  • Human macrophage elastase belongs to the family of matrix metallo-peptidases (MMPs) and is also called human matrix metallo-peptidase 12 (hMMP-12).
  • MMPs matrix metallo-peptidases
  • hMMP-12 human matrix metallo-peptidase 12
  • the protein is increased i.a. formed by macrophages after contact with "irritating" substances or particles, activated and released.
  • Such substances and particles may, for example, be contained as impurities in suspended particles, as may be mentioned, inter alia. in cigarette smoke or industrial dusts.
  • endogenous and foreign body cell constituents and cellular debris are counted among these irritant particles, as they may be present in some cases in high concentrations in inflammatory processes.
  • the highly active enzyme is capable of degrading a variety of connective tissue proteins, e.g. primarily the protein elastin (hence the name), as well as other proteins and proteoglycans such as collagen, fibronectin, laminin, chondroitin sulfate, heparan sulfate and others.
  • This proteolytic activity of the enzyme enables macrophages to penetrate the basal membrane.
  • Elastin for example, occurs in high concentrations in all tissue types that exhibit high elasticity, e.g. in the lungs and arteries.
  • the HME plays an important role in tissue degradation (tissue remodeling).
  • the HME is an important modulator in inflammatory processes.
  • TGF-ß tumor necrosis factor-alpha
  • TGF-ß transforming growth factor -beta
  • MMP-12 also plays a role in host defense, particularly in the regulation of antiviral immunity, presumably through intervention in the interferon-alpha (IFN- ⁇ ) -mediated signaling pathway [A new transcriptional role-matrix matrix metalloproteinase -12 in antiviral immunity, Marchant et al., Nature Med. 20, 493-502 (2014)].
  • IFN- ⁇ interferon-alpha
  • HME plays an important role in many diseases, injuries and pathological changes, their emergence and / or progression with an infectious or non-infectious inflammatory event and / or a proliferative and hypertrophic tissue and vascular remodeling.
  • diseases and / or damage to the lung, the kidney or the cardiovascular system or these may be cancerous diseases or other inflammatory diseases [Macrophage metalloelasta.se (MMP-12) as a target for inflammatory respiratory diseases, Lagente et al., Expert Opin. Ther.
  • diseases and injuries of the lung are in particular the chronic obstructive pulmonary illness (COPD), the lung emphysema (lung emphysema), interstitial pulmonary diseases (interstitial lung diseases, ILD) such as the pulmonary fibrosis (ideopathic pulmonary fibrosis, IPF) and pulmonary sarcoidosis (pulmonary sareoidosis), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), also called cystic fibrosis).
  • ILD interstitial lung diseases
  • ILD interstitial lung diseases
  • pulmonary fibrosis ideopathic pulmonary fibrosis, IPF
  • pulmonary sarcoidosis pulmonary sarcoidosis
  • CF cystic fibrosis
  • liver fibrosis and systemic sclerosis are mentioned as examples.
  • Atherosclerosis here in particular carotid arteriosclerosis
  • infective endocarditis in particular viral myocarditis
  • cardiomyopathy Cardiac insufficiency in particular viral myocarditis
  • cardiomyopathy Cardiac insufficiency in particular viral myocarditis
  • cardiomyopathy Cardiac insufficiency in particular viral myocarditis
  • cardiomyopathy Cardiac insufficiency CAD
  • cardiogenic shock acute coronary syndrome (ACS)
  • aneurysms myocardial infarct
  • AMDI myocardial infarct
  • CKD chronic kidney disease
  • Alport syndrome also mentioned here are the metabolic syndrome and obesity.
  • SIRS systemic inflammatory response syndrome
  • MODF multi-organ dysfunction
  • intravascular Coagulation dissminated intravascular coagulation, DIC
  • rheumatoid diseases for example rheumatoid arthritis, as well as chronic bowel inflammation (IBD; Crohn's disease, CD, ulcerative colitis, ulcerative colitis , UC).
  • elastase-mediated pathological processes underlie a shifted balance between free elastase (HME) and the body's own elastase inhibitor protein (tissue inhibitor of metalloproteinase, ⁇ ).
  • HME free elastase
  • ⁇ tissue inhibitor of metalloproteinase
  • MMP-2 oxidative stress, protease-antiprotease imbalance, and inflammation
  • MMP-7 Matrilysins
  • MMP-12 HME (MMP-12) is so far the only representative of metallo-elastase.
  • MMPs are assembled into the group of so-called MT-MMPs (membrane-type MMPs), since they have a characteristic domain that anchors the protein in the membrane (MMP-14, MMP-15, MMP-16, MMP-17 , MMP-24, MMP-25).
  • MMP-14, MMP-15, MMP-16, MMP-17 , MMP-24, MMP-25 common to all MMPs is a conserved zinc-binding region in the active site of the enzyme, which is important for catalytic activity and is also found in other metalloproteins (eg a disintegrin and metalloproteinase, ADAM).
  • ADAM disintegrin and metalloproteinase
  • the complexed zinc is masked by a sulfhydryl group in the N-terminal pro-peptide domain of the protein, resulting in an enzymatically inactive pro-form of the enzyme. Only after cleavage of this pro-peptide domain is the zinc in the active center of the enzyme freed from this coordination and the enzyme thereby activated (so-called activation by cysteine switch) [matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases, Hu et al ., Nature Rev. Drug Discov. 6, 480-498 (2007)].
  • MMPs MMPs and other similar molecules
  • ADAMs eg ADAMs
  • Numerous in vitro and preclinical in vz 'vo experiments have contributed much to a better understanding of MMPs in different disease models (eg transgenic animals, knock-out animals and genetic data from human studies).
  • the validation of a target with regard to a possible drug therapy can ultimately only be carried out in clinical trials on humans or patients.
  • the first generation of MMP inhibitors has been clinically studied in cancer studies.
  • the desired effect on one or more MMP targets has been masked by an undesired effect on one or more MMP anti-targets or by an undesired effect on another target site (off-target) [Validating matrix metalloproteinases as drug targets and anti-targets for Cancer Therapy, Coverall & Kleifeld, Nature Rev. Cancer 6, 227-239 (2006)].
  • MMP-12 inhibitors Newer MMP inhibitors, which are characterized by increased selectivity, have now also been clinically tested, including compounds explicitly referred to as MMP-12 inhibitors, but so far also without any conclusive clinical success. At a closer Look here, too, the previously described as selective inhibitors have been found to be not so selective.
  • test compound MMP408 shows a significantly decreased affinity for the mouse orthologous MMP-12 target: IC 50 2 nM (human MMP-12), IC 50 160 nM (murine MMP-12), IC 50 320 nm (MMP-12 of the Rat) [see above Li et al., 2009; Mukhopadhyay et al., 2010].
  • the potency at the target MMP-12 itself is very important.
  • a highly potent compound will result in a lower therapeutic dose than a less potent compound, and generally a lower dose should be associated with a reduced likelihood of side effects.
  • the free fraction is defined as the available amount of one A compound that is not bound to components of the blood plasma, which are mainly blood protein components such as eg albumin).
  • the specificity is therefore of paramount importance.
  • novel macrophage elastase inhibiting agents should have high selectivity and specificity in order to be able to specifically inhibit HME.
  • a good metabolic stability of the substances is necessary (low clearance).
  • these compounds should be stable under oxidative conditions so as not to lose their inhibitory potency in disease.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the first symptoms of the disease usually appear from the fourth to fifth decade of life. In the following years, the shortness of breath is often aggravated and it manifests cough, associated with an extensive and sometimes purulent sputum and a stenosis breathing to a dyspnea.
  • COPD is primarily a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a major medical problem and is the sixth most common cause of death worldwide. About 4-6% of over 45's are affected.
  • the underlying mechanism involves immune cells that release various chemokines during the inflammatory response of the lungs.
  • neutrophilic cells and subsequently alveolar macrophages are lured to the lung connective tissue and lumen.
  • Neutrophils secrete a protease cocktail containing mainly HNE and proteinase 3.
  • Activated macrophages release the HME.
  • the protease / antiprotease balance is shifted locally in favor of the proteases, which leads inter alia to an uncontrolled elastase activity and, as a consequence thereof, to an excessive degradation of the elastin of the alveolar bodies. This tissue breakdown causes a collapse of the bronchi.
  • HME protein is associated with smoking or COPD status: detectable HME levels are lowest in non-smokers, slightly higher in former smokers and smokers, and in COPD - Patients significantly increased [Elevated MMP-12 protein levels in induced sputum from patients with COPD, Demedts et al., Thorax 61, 196-201 (2006)]. Similar data were collected with human sputum samples and bronchial alveolar washing fluid (BALF).
  • BALF bronchial alveolar washing fluid
  • HME could be detected and quantified on activated macrophages: HME amount COPD patient / smoker> COPD patient / former smoker> former smoker> Non-smoker [Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD, Babusyte et al., Respir. Res. 8, 81-90 (2007)].
  • IPD interstitial lung disease
  • IPF idiopathic pulmonary fibrosis
  • MMP-12 expression is also known in ischemic kidney injuries, as is the involvement of MMP-12 in further inflammatory kidney disease [JNK signaling in human and experimental renal ischemia / reperfusion injury, Kanellis et al., Nephrol. Dial. Transplant. 25, 2898-2908 (2010); Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis, Kaneko et al., J. Immun. 170, 3377-3385 (2003); Role for macrophage metallo elastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome, Rao et al., Am. J. Pathol.
  • the object of the present invention was therefore to identify and provide new substances which act as potent, selective and specific inhibitors of human macrophage elastase (HME / MMP-12) and as such for the treatment and / or prevention of, in particular, respiratory diseases, the Lungs and the cardiovascular system are suitable.
  • HME / MMP-12 human macrophage elastase
  • WO 96/15096-A1 is 4-aryl- and 4-biaryl-substituted 4-oxobutanoic acid derivatives with inhibitory activity towards MMP-2, MMP-3, MMP-9 and, to a lesser extent, MMP-1; Because of this profile of action, the compounds have been found to be particularly suitable for the treatment of osteoarthritis, rheumatoid arthritis and tumor diseases.
  • WO 98/09940 A1 and WO 99/18079 A1 other biarylbutanoic acid derivatives have been disclosed as inhibitors of MMP-2, MMP-3 and / or MMP-13, which are suitable for the treatment of various diseases.
  • WO 00/40539 A1 claims the use of 4-biaryl-4-oxobutanoic acids for the treatment of pulmonary and respiratory diseases, based on a different degree of inhibition of MMP-2, MMP-3, MMP-8, MMP-9, MMP-12 and MMP-13 through these compounds.
  • WO 2012/014114-A1 describes 3-hydroxypropionic acid derivatives and WO 2012/038942-A1 describes oxy- or sulfonylacetic acid derivatives as dual MMP-9/12 inhibitors.
  • PTP-1B protein tyrosine phosphatase 1B
  • the compounds of the invention are characterized by a significant inhibitory activity and selectivity towards the rodent orthologous MMP-12 peptidases, such as mouse MMP-12 (also referred to as murine macrophage elastase, MME) and rat MMP-12.
  • mouse MMP-12 also referred to as murine macrophage elastase, MME
  • rat MMP-12 This allows a more comprehensive preclinical evaluation of the substances in various established animal models of the diseases described above.
  • the present invention relates to compounds of the general formula (I)
  • A is -O- or -S-
  • L is -CH 2 - or -CH 2 CH 2 -
  • Cy is a cyclic group of the formula
  • R 1 is a substituent selected from the group fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, (trifluoromethyl) sulfanyl, methoxycarbonylamino and 2-oxo-l, 3-oxazolidin-3-yl, where such a substituent may be bonded in the designated position 2, 3 and / or 4, m is the number 1 or 2, wherein in the event that the substituent R 1 occurs twice, its individual meanings may be the same or different, and
  • R 2 is hydrogen or fluorine, represents CH or N, is a substituent selected from the group fluorine, chlorine, methyl, fluoromethyl, difluoromethyl and trifluoromethyl, where such a substituent, if present, in the designated position 6, 7 and / or n is 0, 1 or 2, wherein, in the event that the substituent R 3 occurs twice, its individual meanings may be the same or different, and their salts, solvates and solvates of the salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include, in particular, the salts derived from customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, / V, / V-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, dimethylaminoethanol, diethylaminoethanol, choline, procaine, dicyclohexylamine, dibenzylamine, / V-methylmor - pholine, / V-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.
  • customary bases such
  • solvates 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, 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 includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • enantiomerically pure in the context of the present invention is understood to mean that the compound concerned with respect to the absolute configuration of the chiral center is present in an enantiomeric excess of more than 95%, preferably more than 98%.
  • the enantiomeric excess (ene, ee value) is calculated here by evaluating the chromatogram of a HPLC analysis on a chiral phase according to the following formula:
  • Enantiomer 1 (area%) + enantiomer 2 (area%)
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ⁇ (deuterium), ⁇ (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I
  • Certain 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.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • modifications of the compounds 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 of the invention.
  • the present invention comprises, as prodrugs, hydrolyzable ester derivatives of the carboxylic acids of the formula (I) according to the invention.
  • esters which can be hydrolyzed in physiological media, under the conditions of the biological assays described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the main biologically active compounds.
  • esters preference is given to (C 1 -C -alkyl esters in which the alkyl group may be straight-chain or branched.) Particular preference is given to methyl, ethyl or ethyl-butyl esters.
  • 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 particular embodiment of the present invention comprises 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 comprises compounds of the formula (I) in which
  • L is -CH 2 -, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Cy is a cyclic group of the formula
  • R 1A is chlorine, methyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl
  • R 1B is hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Cy is a cyclic group of the formula
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Y is CH, and their salts, solvates and solvates of the salts.
  • L is -CH 2 - or -CH 2 CH 2 -
  • Cy is a cyclic group of the formula
  • R 1B is hydrogen, chlorine, methyl, trifluoromethyl or trifluoromethoxy
  • Y is CH
  • R 3 is a substituent selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, such substituent, when present, being attached in the designated position 6, 7 or 8 and n being 0 or 1, and theirs Salts, solvates and solvates of salts.
  • A is -O- or -S-
  • L is -CH 2 - or -CH 2 CH 2 -
  • Cy is a cyclic group of the formula
  • R 3 is a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.
  • R 3 is a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.
  • A is -O-
  • L is -CH 2 -
  • Cy is a cyclic group of the formula
  • R 1B is hydrogen or chlorine
  • R 3 is a substituent selected from the group of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and n is the number 1, and their salts, solvates and solvates of the salts.
  • the invention further provides a process for the preparation of the compounds according to the invention, which comprises reacting di-ieri-butyl (2-hydroxyethyl) malonate of the formula (II)
  • Z 1 represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (VI)
  • A has the abovementioned meaning, is a temporary protective group such as, for example, acetyl or benzoyl and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, in the presence of a base to give a compound of the formula (VIII)
  • L and Cy have the abovementioned meanings and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to the compound of the formula (VI)
  • the compounds of the formula (I) are separated into their enantiomers and / or diastereoisomers and / or if appropriate reacted with the appropriate (i) solvents and / or (ii) bases to give their solvates, salts and / or solvates of the salts ,
  • reaction (II) + (III) - (IV) is carried out under the usual conditions of a "Mitsunobu reaction" in the presence of a phosphine and an azodicarboxylate [see, e.g. D.L. Hughes, Org. Reactions 42, 335 (1992); D.L. Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)].
  • Suitable phosphine components are triphenylphosphine, tri-n-butylphosphine, 1,2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine, (4-dimethylaminophenyl) diphenylphosphine or tris (4-dimethylaminophenyl ) phosphine.
  • DPPE 1,2-bis (diphenylphosphino) ethane
  • diphenyl (2-pyridyl) phosphine diphenyl (2-pyridyl) phosphine
  • (4-dimethylaminophenyl) diphenylphosphine or tris (4-dimethylaminophenyl ) phosphine.
  • azodicarboxylate for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), Oi tert-butylazodicarboxylat, / V, / V, / VW tetramethylazodicarboxamide (TMAD), l, l '- (azodicarbonyl) di-piperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD) can be used.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • TMAD Oi tert-butylazodicarboxylat, / V, / V, / VW tetramethylazodicarboxamide
  • ADDP 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,
  • Inert solvents for reaction (II) + (III) - (IV) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl ferric butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ethers, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, or polar aprotic solvents such as acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N-dimethylformamide (DMF), N-dimethylacetamide (DMA), ⁇ , ⁇ '-dimethylpropyleneurea (DMPU) or / V-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preference is given to using t
  • reaction (II) + ( ⁇ ) - (IV) is usually carried out in a temperature range from -20 ° C to + 60 ° C, preferably at 0 ° C to + 40 ° C.
  • the use of a microwave apparatus in this reaction may be advantageous.
  • Suitable bases for the alkylation reactions (IV) + (V) -> (VI) and (IV) + (Vit) -> (VIII) are particularly suitable alkali metal alcoholates such as sodium or potassium methoxide, sodium or Potassium ethoxide or sodium or potassium feri.-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium diisopropylamide or lithium, sodium or potassium bis (trimethylsilyl) amide, or conventional organometallic bases such as phenyllithium or n-, sec- or ieri-butyllithium.
  • sodium hydride or potassium ieri.-butoxide is used.
  • Suitable inert solvents for process steps (IV) + (V) -> (VI) and (IV) + (VII) -> (VIII) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl ieri-butyl ether, tetrahydrofuran, 1 , 4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane or cyclohexane, or dipolar aprotic solvents such as acetonitrile, butyronitrile, A 1 -dimethylformamide (DMF) , Dimethylacetamide (DMA), ⁇ , ⁇ '-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO). It is also possible to
  • the reactions (IV) + (V) - (VI) and (IV) + (VII) - (VIII) are generally in a temperature range from -70 ° C to + 100 ° C, preferably at 0 ° C to +60 ° C performed.
  • the cleavage of an acetyl or benzoyl protective group PG in process step (VIII) - (IX) is preferably carried out with the aid of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, or an alkali metal alkoxide, such as sodium or potassium methoxide or sodium or potassium.
  • Suitable solvents for this reaction are, in particular, water, alcohols, such as methanol, ethanol, n-propanol or isopropanol, ethers, such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or mixtures of these solvents.
  • ethers such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or mixtures of these solvents.
  • Sodium methoxide in a solvent mixture of methanol and tetrahydrofuran is preferably used for the cleavage.
  • the reaction is generally carried out in a temperature range from 0 ° C to + 60 ° C.
  • a silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, feri.-butyldimethylsilyl or ieri.-butyldiphenylsilyl can be used as the temporary protective group PG in (VII).
  • Their cleavage in process step (VIII) - (IX) is carried out in the usual way with the aid of a fluoride such as tetrabutylammonium fluoride (TBAF).
  • TBAF tetrabutylammonium fluoride
  • Another possibility is the use of benzyl as protecting group PG; this can be removed by hydrogenolysis in a known way [see also T.W. Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].
  • Suitable bases for the alkylation reaction (IX) + (X) - (VI) are in particular 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 ieri.-butoxide, or alkali metal hydrides such as sodium or potassium hydride.
  • 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 ieri.-butoxide
  • alkali metal hydrides such as sodium or potassium hydride.
  • potassium carbonate is used.
  • Inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl isl-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, Toluene, xylene, pentane, hexane or cyclohexane, or polar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N , N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use mixture
  • the ester cleavage and decarboxylation to the monocarboxylic acid in process step (VI) - (I) is achieved by treatment of the diester with a strong acid such as trifluoroacetic acid or hydrogen chloride and subsequent heating of the intermediately formed dicarboxylic acid.
  • the reaction can be carried out in a one-pot process, without isolation of the intermediate, or in two stages.
  • the ester cleavage is usually carried out in a temperature range from 0 ° C to + 30 ° C.
  • the subsequent decarboxylation is usually carried out in a temperature range from + 100 ° C. to + 150 ° C. in a correspondingly high-boiling inert solvent; Preferably, 1,4-dioxane is used for this purpose.
  • the process steps described above can be carried out at normal, at elevated or at reduced pressure (for example in the range from 0.5 to 5 bar); In general, one works at normal pressure.
  • the separation of stereoisomers (enantiomers and / or diastereomers) of the compounds of the formula (I) according to the invention can be achieved by customary methods known to the person skilled in the art. Preferably, chromatographic methods for achiral or chiral separation phases are used for this purpose. Alternatively, it is also possible to carry out a separation via diastereomeric salts of the carboxylic acids of the formula (I) with chiral amine bases.
  • the 1,2,3-triazine-4 (3i7) -one derivatives of the formula (II) can be prepared in a simple manner by treatment of ori / amino aminocarboxamides of the formula (XI) in which R 3 , n and Y have the meanings given above, accessible with sodium nitrite in aqueous hydrochloric acid [see, eg, D. Fernandez-Forner et al., Tetrahedron 47 (42), 8917-8930 (1991)].
  • the compounds of the formula (V) can be prepared starting from compounds of the formula (II) or (II)
  • 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 of the invention are potent, non-reactive and selective inhibitors of human macrophage elastase (HME / hMMP-12), which have a significantly improved profile of potency and selectivity compared to the compounds known in the art.
  • many of the compounds of the invention have one low in vziro clearance and good metabolic stability. Overall, this property profile makes it possible for the compounds according to the invention to have low dosability and, as a result of the more targeted mode of action, a reduced risk of the occurrence of undesired side effects in the therapy.
  • the compounds according to the invention are therefore particularly suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which, in the course of an infectious or non-infectious inflammatory event and / or a tissue or vascular remodeling, the macrophage elastase (HME / hMMP-12).
  • these include, in particular, diseases of the respiratory tract and the lungs, such as chronic obstructive pulmonary disease (COPD), asthma and the group of interstitial lung diseases (ILD), and diseases of the cardiovascular system, such as arteriosclerosis and aneurysms ,
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung diseases
  • arteriosclerosis and aneurysms diseases of the cardiovascular system, such as arteriosclerosis and aneurysms
  • COPD chronic obstructive pulmonary disease
  • pulmonary emphysema e.g. Cigarette smoke-induced pulmonary emphysema, chronic bronchitis (CB), pulmonary hypertension in COPD (PH-COPD), bronchiectasis (BE) and combinations thereof, especially in acute exacerbating stages of the disease (AE-COPD).
  • CB chronic bronchitis
  • PH-COPD pulmonary hypertension in COPD
  • BE bronchiectasis
  • AE-COPD acute exacerbating stages of the disease
  • Types of asthma include asthmatic diseases of varying degrees of severity with intermittent or persistent history, such as refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and medication-induced or dust-induced asthma.
  • interstitial lung diseases includes idiopathic pulmonary fibrosis (IPF), pulmonary sarcoidosis and acute interstitial pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, cryptogenic organizing pneumonia, desquamative interstitial pneumonia and unclassifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause, and other interstitial lung diseases of unknown cause.
  • IPF idiopathic pulmonary fibrosis
  • pulmonary sarcoidosis and acute interstitial pneumonia
  • non-specific interstitial pneumonia non-specific interstitial pneumonia
  • lymphoid interstitial pneumonia lymphoid interstitial pneumonia
  • respiratory bronchiolitis with interstitial lung disease cryptogenic organizing pneumonia
  • desquamative interstitial pneumonia and unclassifiable idiopathic interstitial pneumonia granulomatous interstitial lung disease
  • interstitial lung disease of known cause
  • the compounds of the invention may also be used for the treatment and / or prevention of other respiratory and pulmonary diseases, such as pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS ), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, infectious and non-infectious cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including drug rhinitis , vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever) and of polyps.
  • PAH pulmonary arterial hypertension
  • PH bronchiolitis
  • the group of diseases of the cardiovascular system includes, in particular, arteriosclerosis and its secondary diseases, such as, for example, Stroke in arteriosclerosis of the cervical arteries (carotid arteriosclerosis), myocardial infarction in arteriosclerosis of the coronary arteries, peripheral arterial occlusive disease (PAOD) as a result of arteriosclerosis of the leg arteries, as well as aneurysms, in particular aneurysms of the aorta, e.g.
  • arteriosclerosis and its secondary diseases such as, for example, Stroke in arteriosclerosis of the cervical arteries (carotid arteriosclerosis), myocardial infarction in arteriosclerosis of the coronary arteries, peripheral arterial occlusive disease (PAOD) as a result of arteriosclerosis of the leg arteries, as well as aneurysms, in particular aneurysms of the aorta, e.g.
  • Atherosclerosis hypertension, injuries and inflammations, infections (eg rheumatic fever, syphilis, Lyme disease), congenital connective tissue weaknesses (eg in Marfan syndrome and Ehlers-Danlos syndrome) or as a result of a volume burden of the aorta in congenital heart defects with right-left shunt or shunt-dependent perfusion of the lungs, as well as aneurysms of the coronary arteries in the course of a disease in Kawasaki syndrome and in brain areas in patients with a congenital malformation of the aortic valve.
  • infections eg rheumatic fever, syphilis, Lyme disease
  • congenital connective tissue weaknesses eg in Marfan syndrome and Ehlers-Danlos syndrome
  • the compounds of the invention may also be used for the treatment and / or prevention of other cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina pectoris, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, arrhythmias Atria and ventricles as well as conduction disorders such as atrio-ventricular blockades of grade I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, extrasystoles of the atrium and ventricle, AV junctional Extrasystoles, sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy
  • cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as 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 insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxicity Cardiomyopathy, cardiac storage disorders and diastolic and systolic
  • kidney diseases in particular renal insufficiency and kidney failure.
  • renal insufficiency and renal failure include both acute and chronic manifestations thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection and Alport syndrome, immune complex-induced kidney disease, toxic-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive Nephrosclerosis and nephrotic syndrome, which are abnormally elevated diagnostic
  • the present invention also encompasses the use of the compounds according to the invention for the treatment and / or prevention of secondary effects of renal insufficiency, such as, for example, tonia, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • renal insufficiency such as, for example, tonia, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorders (BOO), lower urinary tract syndromes (LUTS) , neurogenic overactive bladder (OAB), incontinence such as mixed, urgency, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostatic hyperplasia
  • BOO bladder emptying disorders
  • LUTS lower urinary tract syndromes
  • OAB neurogenic overactive bladder
  • incontinence such as mixed, urgency, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile dysfunction and female sexual dysfunction.
  • the compounds of the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, ulcerative colitis ), Pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases, and inflammatory ocular diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • MOF multiple organ failure
  • IBD chronic intestinal inflammation
  • IBD chronic intestinal inflammation
  • Crohn's disease chronic intestinal inflammation
  • ulcerative colitis ulcerative colitis
  • Pancreatitis peritonitis
  • cystitis cystitis
  • urethritis prostatitis
  • the compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrous diseases of the internal organs, such as, for example, the lung, 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, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, Morphaea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue diseases (eg sarcoidosis).
  • the compounds of the invention may also be used to promote wound healing, to
  • the compounds of the present invention can be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.
  • anemias such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias.
  • the compounds according to the invention are also suitable for the treatment of cancers, such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, cancers, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, and malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.
  • cancers such as, for example, skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, cancers, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, and malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma.
  • the compounds according to the invention can be used for the treatment and / or prevention of lipid metabolism disorders and dyshpidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolaemia), xanthomatosis, Tangier's disease, obesity (obesity), obesity , metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), diseases of the gastrointestinal tract and the abdomen (Glositis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibro
  • the compounds according to the invention are particularly suitable for the treatment and / or prevention of respiratory and pulmonary diseases, especially chronic obstructive pulmonary disease (COPD), in particular pulmonary emphysema, chronic bronchitis (CB), pulmonary Hypertension in COPD (PH-COPD) and bronchiectasis (BE) as well as combinations of these diseases, especially in acute exacerbating stages of COPD (AE-COPD), asthma and interstitial lung diseases, in particular idiopathic pulmonary fibrosis ( IPF) and pulmonary sarcoidosis, diseases of the cardiovascular system, in particular atherosclerosis, especially carotid arteriosclerosis, as well as viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral arterial occlusive disease (PAOD), as well as of chronic kidney diseases and the Alport syndrome.
  • COPD chronic obstructive pulmonary disease
  • CB chronic bronchit
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a health disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or 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 the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • a further subject of the present invention are therefore medicaments comprising at least one of the compounds according to the invention and one or more further active ingredients, in particular for the purpose of treatment and / or prevention of the aforementioned diseases.
  • Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:
  • Anti-obstructive / bronchodilatory agents e.g. for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics), the inhaled anti-muscarinic substances and the PDE 4 inhibitors;
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma by way of example and preferably from the group of inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics), the inhaled anti-muscarinic substances and the PDE 4 inhibitors;
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • 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 4 inhibitors such as roflumi last and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil;
  • PDE phosphodiesterases
  • roflumi last and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil,
  • sGC soluble guanylate cyclase
  • HNE human neutrophil elastase
  • Sivelastat Sivelastat
  • DX-890 Reltran
  • Prostacyclin analogs and IP receptor agonists such as by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol or NS-304;
  • Endothelin receptor antagonists such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan;
  • Antiinflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN- ⁇ , pirfenidone or etanercept;
  • Anti-fibrotic agents such as, by way of example and by way of preference, lysophosphatidic acid receptor 1 (LPA-1) antagonists, lysyl oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, vasoactive intestinal peptide (VIP), VIP analogs, ⁇ v ⁇ 6 Integrin antagonists, cholchicine, I
  • Lipid metabolizing 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 reabsorption inhibitors, and lipoprotein (a) antagonists;
  • the hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Mineralocorticoid receptor antagonists and diuretics;
  • the signal transduction cascade inhibiting compounds by way of example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or
  • Serine / threonine kinase inhibitors such as, by way of example and by way of illustration, nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, Pelitinib, semaxanib or tandutinib; Compounds that block the binding of serotonin to its receptor, by way of example and preferably antagonists of the 5-HT2B receptor, such as PRX-08066;
  • Antagonists of growth factors, cytokines and chemokines by way of example and preferably antagonists of TGF- ⁇ , CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;
  • Rho kinase inhibiting compounds such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; Compounds which inhibit the soluble epoxide hydrolase (sEH), such as N, N'-cycloalkyloxyurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3 ⁇ 5- [2- (2-ethoxyethoxy) ethoxy] pentyl ⁇ urea;
  • SEH soluble epoxide hydrolase
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances;
  • chemotherapeutic agents as e.g. used for the treatment of neoplasms of the lungs or other organs; and / or antibiotics, in particular from the group of fluoroquinolonecarboxylic acids, such as by way of example and preferably ciprofloxacin or moxifloxacin.
  • the compounds according to the invention are administered in combination with a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.
  • a beta-adrenergic receptor agonist such as, for example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, repro sterol, salbutamol or salmeterol.
  • the compounds according to the invention are administered in combination with an anti-muscarinergic substance, such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • an anti-muscarinergic substance such as by way of example and preferably ipratropium bromide, tiotropium bromide or oxitropium bromide.
  • the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.
  • a corticosteroid such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • 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 GPITb / nia antagonist, by way of example and preferably tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with 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 or embursatan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone, eplerenone or finerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone, eplerenone or finerenone.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth- azon, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trich
  • the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as 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, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions according to the invention with one or more further active compounds selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarcinogenic substances, PDE 4 inhibitors, PDE 5 inhibitors, sGC activators, sGC Stimulants, HNE inhibitors, prostacyclin analogs, endothelin antagonists, statins, antifibrotic agents, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.
  • further active compounds selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarcinogenic substances, PDE 4 inhibitors, PDE 5 inhibitors, sGC activators, sGC Stimulants, HNE inhibitors, prostacyclin analogs, endothelin antagonists, statins, antifibrotic agents, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic, or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the 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 as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention
  • Parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • a resorption step eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly
  • absorption for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers, metered dose aerosols
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (for example patches)
  • milk pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl
  • the dosage is about 0.01 to 100 mg kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight.
  • the amount is generally about 0.1 to 50 mg per inhalation.
  • Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. Purity specifications usually refer to corresponding peak integrations in the LC / MS chromatogram, but may additionally have been determined with the help of the--NMR spectrum. If no purity is specified, it is usually a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined. Data on yields in% d. Th. Are purity-corrected as a rule, provided that a purity of ⁇ 100% is specified. For solvent-containing or contaminated batches, the yield may be formally "> 100%"; in these cases, the yield is not solvent or purity corrected.
  • Example 22A di-tert-butyl [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] ⁇ 2-oxo-2- [4- (tetrahydro-2-yl) pyran-4-ylmethoxy) phenyl] ethyl ⁇ malonate
  • the aqueous phase was extracted with 100 ml Efhyl- acetate, and the combined organic phases were washed once with 300 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to a volume of about 70 ml. After cooling to 0 ° C. for 30 min, the solid formed was filtered off and washed twice with 5 ml of ethyl acetate each time. After drying in vacuo, 4.65 g (74% of theory) of a first batch of the title compound were obtained.
  • Example 49A di-tert-butyl- (2- ⁇ 4- [(3-chlorobenzyl) oxy] phenyl ⁇ -2-oxoethyl) ⁇ 2- [4-oxo-7- (trifluoromethyl) -1,3,3- benzotriazine-3 (AH) -yl] ethyl ⁇ malonate
  • (+/-) - 4- (4- ⁇ [3-chloro-4- (trifluoromethoxy) benzyl] oxy ⁇ phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine - 3 (4 //) - yl) ethyl] butanoic acid
  • (+) - 4- (4- ⁇ [3-chloro-4- (trifluoromethoxy) benzyl] oxy ⁇ phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 /) - yl) ethyl] butanoic acid (enantiomer 2)
  • (+) - 4- (4- ⁇ [4-Chloro-3- (trifluoromethoxy) benzyl] oxy ⁇ phenyl) -4-oxo-2- [2- (4-oxo-1,2,3-benzotriazine-3 (4 //) - yl) ethyl] butanoic acid (enantiomer 2)
  • Example 21A To the 275 mg (0.40 mmol, not purity-corrected) compound of Example 21A was added 4 mL of a 1: 1 mixture of dichloromethane and trifluoroacetic acid cooled to 0 ° C. The mixture was stirred at RT for 1 h. After concentration, the residue was added twice in succession with toluene and concentrated again. The residue was then taken up in 4 ml of dioxane and heated to reflux with stirring for 3 h. After concentration, the residue was taken up in a little acetonitrile and purified by preparative HPLC (Method 8). 125 mg (59% of theory) of the title compound were obtained.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente demande concerne de nouveaux dérivés d'éthers phénoliques à substitutions cycliques, des procédés pour leur préparation, leur utilisation seuls ou en combinaison pour le traitement et/ou la prévention de maladies ainsi que leur utilisation dans la préparation de médicaments destinés au traitement et/ou à la prévention de maladies, en particulier pour le traitement et/ou la prévention de maladies des voies respiratoires, des poumons et du système cardiovasculaire.
PCT/EP2015/056990 2014-04-03 2015-03-31 Dérivés d'éthers phénoliques à substitutions cycliques et leur utilisation Ceased WO2015150366A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5863915A (en) * 1996-05-15 1999-01-26 Bayer Corporation Substituted 4-arylbutyric acid derivatives as matrix metalloprotease
WO2000040539A1 (fr) * 1998-12-30 2000-07-13 Bayer Aktiengesellschaft Utilisation de derives d'acides 4-biarylbutyrique et 5-biarylpentanoique substitues, en tant qu'inhibiteurs de la metalloprotease matricielle, pour le traitement des maladies respiratoires
WO2012014114A1 (fr) * 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase de matrice
WO2012038942A1 (fr) * 2010-09-24 2012-03-29 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase matricielle

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5863915A (en) * 1996-05-15 1999-01-26 Bayer Corporation Substituted 4-arylbutyric acid derivatives as matrix metalloprotease
WO2000040539A1 (fr) * 1998-12-30 2000-07-13 Bayer Aktiengesellschaft Utilisation de derives d'acides 4-biarylbutyrique et 5-biarylpentanoique substitues, en tant qu'inhibiteurs de la metalloprotease matricielle, pour le traitement des maladies respiratoires
WO2012014114A1 (fr) * 2010-07-30 2012-02-02 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase de matrice
WO2012038942A1 (fr) * 2010-09-24 2012-03-29 Ranbaxy Laboratories Limited Inhibiteurs de métalloprotéinase matricielle

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales

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