WO2015150364A1 - Substituted benzotriazinone butane acids and use thereof - Google Patents

Abstract

The present application relates to novel substituted 4-(1,2,3-benzotriazine-4-on-3-yl)butane acid derivatives, to methods for the preparation thereof, to the use thereof alone or in combination for the treatment and/or prevention of disorders, and to the use thereof for producing medicaments for the treatment and/or prevention of disorders, especially for treatment and/or prevention of diseases of the respiratory tract, lung and of the cardiovascular system.

Description

 Substituted Benzotriazinonbutansäuren and their use

The present application relates to novel substituted 4- (l, 2,3-benzotriazin-4-on-3-yl) butanoic acid derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their Use for the manufacture 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 (HME, EC 3.4.24.65) belongs to the family of matrix metallo-peptidases (MMPs) and is also called human matrix metallo-peptidase 12 (hMMP-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. In a broader sense, endogenous and foreign body cell constituents and cellular debris are counted among these irritant particles, as they can 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. In a variety of pathological processes, such as tissue injury, the HME plays an important role in tissue degradation (tissue remodeling). In addition, the HME is an important modulator in inflammatory processes. It is a key molecule in the recruitment of inflammatory cells, for example by releasing the central inflammatory mediator tumor necrosis factor-alpha (TNF-α) and interfering with the transforming growth factor -beta (TGF-β) mediated signaling pathway [Hydrolysis ofa Broad Spectrum of Extracellular Matrix Proteins by Human Macrophage Elastase, Gronski et al., J. Biol. Chem. 272, 12189-12194 (1997)]. MMP-12 also plays a role in host defense, particularly in the regulation of antiviral immunity, presumably through intervention in the interferon-alpha (IFN-α) -mediated signaling pathway [A new transcriptional role-matrix matrix metalloproteinase -12 in antiviral immunity, Marchant et al., Nature Med. 20, 493-502 (2014)].

It is therefore assumed that the HME plays an important role in many diseases, injuries and pathological changes, their development and / or progression an infectious or non-infectious inflammatory event and / or a proliferative and hypertrophic tissue and vascular remodeling. These may be, in particular, 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 Opinion. Ther. Targets 13, 287-295 (2009); Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis, Kaneko et al., J. Immunol. 170, 3377-3385 (2003); A Selective Matrix Metalloelastase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E Knock-out Mice, Johnson et al., Arterioscler. Thromb. Vase. Biol. 31, 528-535 (2011); Impaired Coronary Collateral Growth in the Metabolic Syndrome is Mediated by Matrix Metalloelastase 12-dependent Production of Endodontin and Angiostatin, Dodd et al., Arterioscler. Thromb. Vase. Biol. 33, 1339-1349 (2013); Carcinoma, Chetty et al., Pharmacogenomics 12, 535-546 (2011)]. Matrix metalloproteinase pharmacogenomics in non-small-cell lung carcinoma. In this context to be named 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). , Asthma and infectious, especially viral respiratory diseases. As other fibrotic diseases, liver fibrosis and systemic sclerosis are mentioned as examples. Diseases and injuries of the cardiovascular system in which the HME is involved are, for example, tissue and vascular changes in arteriosclerosis, here in particular carotid arteriosclerosis, infective endocarditis, in particular viral myocarditis, cardiomyopathy Cardiac insufficiency, cardiogenic shock, acute coronary syndrome (ACS), aneurysms, myocardial infarct (AMI) reperfusion injury, ischemic damage to the kidney or retina, and chronic disease such as chronic kidney disease. chronic kidney disease, CKD) and Alport syndrome. Also mentioned here are the metabolic syndrome and obesity. Diseases associated with sepsis include systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock and multi-organ dysfunction (MODF), as well as intravascular Coagulation (disseminated intravascular coagulation, DIC). Examples of tissue degradation and remodeling in cancerous processes are the invasion of cancer cells into healthy tissue (metastases). stasis formation) and the re-education of supplying blood vessels (neo-angiogenesis). Other inflammatory diseases in which the HME plays a role are rheumatoid diseases, for example rheumatoid arthritis, as well as chronic bowel inflammation (IBD; Crohn's disease, CD, ulcerative colitis, English, ulcerative Colitis, UC).

In general, elastase-mediated pathological processes are thought to be based on a shift in the balance between free elastase (HME) and the body's own tissue inhibitor of metalloproteinase (TEVIP). In various pathological, especially inflammatory processes, the concentration of free elastase (HME) is increased, so that locally the balance between protease and anti-protease is shifted in favor of the protease. A similar (in) equilibrium exists between the elastase of the neutrophil cells (human neutrophil elastase, HNE, a member of the serine protease family) and the endogenous anti-protease AAT (alpha-1 anti-trypsin, a member of the serine protease family). Inhibitors, SERPINs). Both equilibria are coupled with each other since HME cleaves and inactivates the inhibitor of HNE, and conversely, HNE cleaves and inactivates the HME inhibitor, thereby additionally shifting the respective protease / anti-protease imbalances. In addition, oxidative bursi are prevalent in the environment of localized inflammation, further increasing protease / anti-protease imbalance [Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation, Fischer et al. , Int. J. COPD 6, 413-421 (2011)].

There are currently more than 20 known MMPs that are historically roughly classified into different classes in terms of their most prominent substrates, eg gelatinases (MMP-2, MMP-9), collagenases (MMP-1, MMP-8, MMP-13), stromelysins (MMP-3, MMP-10, MMP-11) and Matrilysins (MMP-7, MMP-26). HME (MMP-12) is so far the only representative of metallo-elastase. In addition, further 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). 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). 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 by 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)].

Most known synthetic MMP inhibitors have a zinc-complexing functional group, very often for example a hydroxamate, a carboxylate or a thiol [Recent Developments in the Design of Specific Matrix Metalloproteinase Inhibitors aided by Structural and Computational Studies, B.G. Rao, Curr. Pharm. Des. 1J, 295-322 (2005)]. The scaffold of these inhibitors is often similar to peptides, one speaks of so-called peptidomimetics (usually with a poor oral bioavailability), or it has no similarity to peptides, one speaks more generally of small molecules (small molecules, SMOLs ). The physicochemical and pharmacokinetic properties of these inhibitors have, in general, a great influence on which targets and which unwanted molecules (anti-targets, off-targets) are "hit" in which tissue and for what period to what extent ,

It is a major challenge to determine the specific role of a particular MMP in a disease process. This is compounded in particular by the fact that there are a large number of MMPs and other similar molecules (eg ADAMs), associated with a large number of physiological substrates that are possible in each case and thus possibly also associated inhibitory or activatory effects in a variety of signal transduction pathways. 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 take place in clinical trials on humans or patients. The first generation of MMP inhibitors has been clinically studied in cancer studies. At that time, only a few representatives of the MMP protein family were known. None of the tested inhibitors could clinically convince, since at effective dosages, the side effects were not tolerated. As it became clear in the course of the knowledge of further MMPs, the representatives of the first inhibitor generation were non-selective inhibitors, ie a large number of different MMPs were equally inhibited (pan-MMP inhibitors, pan-MMPIs). Presumably, 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)]. 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. On closer examination, the inhibitors previously described as selective have also proved to be less selective.

Thus, for the clinical test compound "MMP408" as a ΜΜΡ-12 inhibitor, a certain to marked selectivity in vitro over MMP-13, MMP-3, MMP-14, MMP-9, Agg-1, MMP-1, Agg-2 , MMP-7 and TACE [A Selective Matrix Metalloprotease 12 Inhibitor for Potential Treatment of Chronic Obstructive Pulmonary Disease (COPD): Discovery of (S) -2- (8- (methoxycarbonylamino) dibenzo [b, d] furan- 3-sulfonamido) -3-methylbutanoic acid (MMP408), Li et al., J. Med. Chem. 52, 1799-1802 (2009)]. In vitro micrographs of MMP-2 and MMP-8 indicate less favorable selectivity towards these two MMPs [matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults, Mukhopadhyay et al., J. Biol. Allergy Clin. Immunol. 126, 70-76 (2010)]. The same is true for the clinical test substance AZD1236 for the treatment of COPD, which is described as a dual MMP-9/12 inhibitor. [Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate / severe COPD: A randomized controlled trial, Dahl et al., Pulm. Pharmacol. Therap. 25, 169-177 (2012)]. The development of this compound was discontinued in 2012; here, too, marked inhibition of MMP-2 and MMP-13 is reported [http://www.wipo.int/research/en/details.jsp? id = 2301].

When assessing MMP selectivity, a cautious assessment of the predictive power of animal models is also indicated. For example, the test compound MMP408 shows a significantly reduced affinity for the mouse orthologous MMP-12 target: IC ₅₀ 2 nM (human MMP-12), IC50 160 nM (murine MMP-12), IC50 320 nm (rat MMP-12). [see above, Li et al., 2009; Mukhopadhyay et al., 2010]. Information on the potency against other mouse MMPs has not been published. It seems similar with the test substance AZD1236 [see http: //www.wipo. int / research / en / details.jsp? id = 2301 for cross-reactivity in different animal species].

In addition to the selectivity profile across species boundaries, the potency at the target MMP-12 itself is very important. With a comparatively similar pharmacokinetic profile, 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. This applies in particular to the inclusion of the so-called "free fraction" (fraction unbound, f _u ) of a compound which coincides with the the desired target or unwanted anti- and off-targets (the "free fraction" is defined as the available amount of a compound that is not bound to constituents of the blood plasma, which are primarily blood protein components such as albumin) , In addition to MMP selectivity, specificity is therefore of paramount importance.

Accordingly, novel macrophage elastase inhibiting agents should have high selectivity and specificity in order to be able to specifically inhibit HME. For this purpose, a good metabolic stability of the substances is necessary (low clearance). In addition, these compounds should be stable under oxidative conditions so as not to lose their inhibitory potency in disease.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease characterized by obstruction of respiratory flow, which is caused by pulmonary emphysema and / or chronic bronchitis. 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 those over 45 years old are affected.

Although the obstruction of the respiratory flow can be only partially and temporally limited, COPD is not curable. The aim of the treatment is thus to improve the quality of life, alleviate the symptoms, prevent acute worsening and slow down the progressive impairment of lung function. Existing pharmacotherapies, which have barely changed over the last two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control lung inflammation [Chronic Obstructive Pulmonary Disease, PJ. Barnes, N. Engl. J. Med. 343, 269-280 (2000)]. The chronic inflammation of the lungs, caused by cigarette smoke or other irritants, is the driving force of disease development. The underlying mechanism involves immune cells that release various chemokines during the inflammatory response of the lungs. As a result, 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. As a result, the protease / antipro shifted tease balance in favor of the proteases, resulting inter alia in an uncontrolled elastase activity and as a result, to an excessive degradation of the elastin of the alveolar. This tissue breakdown causes a collapse of the bronchi. This is accompanied by a decreased elasticity of the lung, which leads to a hindrance of the respiratory flow and impaired breathing. In addition, frequent and prolonged inflammation of the lungs may lead to bronchial remodeling and, as a consequence, to the formation of lesions. Such lesions contribute to the onset of chronic cough that marks chronic bronchitis.

Studies with human sputum samples have shown that the amount of 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). Here, 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)].

One of the COPD-related inflammatory lung diseases is interstitial lung disease (ILD), in particular idiopathic pulmonary fibrosis (IPF) and sarcoidosis [Commonalities between the pro-fibrotic mechanisms in COPD and IPF, LA Murray, Pulm , Pharmacol. Therap. 25, 276-280 (2012); The pathogenesis of COPD and IPF: distinct horns of the same devil ?, Chilosi et al., Respir. Res. 13: 3 (2012)]. Again, the homeostasis of the extracellular matrix is disturbed. Data from genome-wide association studies suggest a special role of HME in the disease process of such fibro- genetic diseases [Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis, Crouser et al., Am. J. Respir. Crit. Care Med. 179, 929-938 (2009); Association of a Functional Polymorphism in the Matrix Metalloproteinase-12 Promoter Region with Systemic Sclerosis in an Italian Population, Manetti et al., J. Rheumatol. 37, 1852-1857 (2010); Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage, Manetti et al., Ann. Rheum. Dis. 7J, 1064-1070 (2012)].

In addition, there is further preclinical evidence for a significant role of HME in ischemic-inflammatory disease processes [Macrophage Metalloelastase (MMP-12) deficiency]. ency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy, Li et al., PLoS ONE 7 (12), e52699 (2012)]. Significantly higher MMP-12 expression is also known in ischemic kidney injuries, as is the involvement of MMP-12 in other inflammatory kidney diseases [JNK signaling in human and experimental renal ischemia / reperfusion injury, Kanellis et al., Nephral. 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 Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome, Rao et al., Am. J. Pathol. 169, 32-46 (2006); Differential regulation of metabolites in experimental chronic renal allograft rejection: potential markers and novel therapeutic targets, Berthier et al., Kidney Int. 69, 358-368 (2006); Macrophage infiltration and renal damage are independent of matrix metalloproteinase 12 (MMP-12) in the obstructed kidney, Abraham et al., Nephrology 17, 322-329 (2012)].

The object of the present invention was therefore the identification and provision of novel 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, in particular of respiratory diseases , the lungs and the cardiovascular system are suitable.

From the patent applications WO 96/15096-A1, WO 97/43237-A1, WO 97/43238-A1, WO 97/43239-A1, WO 97/43240-A1, WO 97/43245-A1 and WO 97/43247 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. In 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. Furthermore, 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.

In view of the above-described object, however, it has been found that these prior art MMP inhibitors often have disadvantages such as inadequate MMP-12 inhibitory potency, insufficient MMP-12 selectivity compared to other MMPs, and others / or limited metabolic stability. Further arylalkanecarboxylic acid derivatives are described in WO 2004/092146-A2, WO 2004/099168-A2, WO 2004/099170-A2, WO 2004/099171-A2, WO 2006/050097-A1 and WO 2006/055625-A2 as inhibitors of Protein tyrosine phosphatase 1B (PTP-1B) for the treatment of diabetes, cancers and neurodegenerative diseases. It has now surprisingly been found that certain 4- (l, 2,3-benzotriazin-4-on-3-yl) butanoic acid derivatives have a significantly improved profile in terms of their potency and selectivity towards the human macrophage elastase (HME / hMMP -12) in comparison to the compounds known from the prior art. In addition, many of the compounds of the present invention have low in vivo 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.

In addition, 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. This allows a more complete 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)

in welcher

in which

R ^{1 represents} straight-chain (C 3 -C 5) -alkyl in which a CE group may be replaced by O, straight-chain hydroxy (C 1 -C 4) -alkyl or (C 3 -C 6) -cycloalkyl which may be substituted by hydroxyl can, stands and either (a) Y stands for CH and R ^{2 is} a substituent selected from the group fluorine, chlorine, methyl, fluoromethyl, di-fluoromethyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, or (b) Y is N and

R ^{2 is} hydrogen or a substituent selected from methyl and trifluoromethyl bound in the designated 6- or 7-position, as well as 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.

In the context of the invention, 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 in which the co- Ordination with water takes place. 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, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of 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.

The term "enantiomerically pure" in the context of the present invention is understood to mean that the relevant compound is present in an absolute configuration of the chiral center 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%)

 ee = x 100%

 Enantiomer 1 (area%) + enantiomer 2 (area%)

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as Ή (deuterium), Ή (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 Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ L 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 the distribution of active ingredient 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. In addition, the incorporation of isotopes, such as from Deuterium, lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as to prolong the half-life in the body or to a reduction of the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds. In addition, the present invention also includes prodrugs of the compounds of the invention. The term "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.

In particular, the present invention comprises, as prodrugs, hydrolyzable ester derivatives of the carboxylic acids of the formula (I) according to the invention. These are understood to mean 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. As such 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.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C 1 -C 5) -alkyl in the context of the invention is a straight-chain saturated alkyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: n-propyl, n-butyl and n-pentyl.

Hydroxy-C 1 -C 4 -alkyl in the context of the invention is a straight-chain saturated alkyl radical having 1 to 4 carbon atoms which terminally carries a hydroxy group as substituent. By way of example and by way of preference: hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl.

In the context of the invention, (C 3 -C 6) -cycloalkyl is a monocyclic saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. If 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

R ^{1 is} (C 3 -C ₆ ) -cycloalkyl, and their salts, solvates and solvates of the salts. Another particular embodiment of the present invention comprises compounds of the formula (I) in which

Y stands for CH and

R ^{2 is} a substituent selected from the group consisting of chlorine, methyl and trifluoromethyl, which is bonded in the designated 6- or 7-position, and their salts, solvates and solvates of the salts.

Another particular embodiment of the present invention comprises compounds of the formula (I) in which

Y stands for N and

R ^{2 is} hydrogen, and their salts, solvates and solvates of the salts.

Preferred in the context of the present invention are compounds of the formula (I) in which R ^{1 is} n-butyl, hydroxymethyl, methoxymethyl, cyclopropyl or cyclopentyl and either (a)

Y stands for CH and

R ^{2 is} a substituent selected from methyl and trifluoromethyl bound in the designated 6- or 7-position, or (b)

Y stands for N and

R ^{2 is} hydrogen, 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

R ^{1 is} n-butyl or cyclopentyl,

Y stands for CH and

R ^{2 is} a substituent selected from methyl and trifluoromethyl bound in the designated 6- or 7-position, as well as their salts, solvates and solvates of the salts.

Of particular importance in the context of the present invention are compounds of the formula (I-A)

in welcher R¹, R² und Y die oben angegebenen Bedeutungen haben und das mit * gekennzeichnete chirale C-Atom in enantiomerenreiner Form die abgebildete S- Konfiguration aufweist, sowie ihre Salze, Solvate und Solvate der Salze. Die in den jeweiligen Kombinationen bzw. bevorzugten Kombinationen von Resten im einzelnen angegebenen Reste-Definitionen werden unabhängig von den jeweiligen angegebenen Kombinationen der Reste beliebig auch durch Reste-Definitionen anderer Kombinationen ersetzt.

in which R ¹ , R ² and Y have the abovementioned meanings and the chiral carbon atom marked with * in enantiomerically pure form has the depicted S configuration, and also its salts, solvates and solvates of the salts. The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

Another object of the invention is a process for the preparation of the compounds of the invention, characterized in that di-ieri.-butyl- (2-hydroxyethyl) malonate of the formula

(Π)

in Gegenwart eines Phenylphosphins und eines Azodicarboxylats mit einem Triazin-4(3 /)- Derivat der Formel (ΙΠ)

in the presence of a phenylphosphine and an azodicarboxylate with a triazine-4 (3 /) derivative of the formula (II)

in which R ² and Y have the abovementioned meanings, to give a compound of the formula (IV)

(IV), in welcher R² und Y die oben angegebenen Bedeutungen haben, umsetzt und die Verbindung der Formel (IV) dann entweder

(IV), in which R ² and Y have the meanings given above, and then reacting the compound of formula (IV) either

[A] in the presence of a base with a compound of the formula (V)

in which R ^{1 has} the abovementioned meaning and represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, a compound of the formula (VI)

in welcher R¹, R² und Y die oben angegebenen Bedeutungen haben, alkyliert oder zunächst mit einer Verbindung der Formel (VII)

in which R ¹ , R ² and Y have the meanings given above, alkylated or first reacted with a compound of the formula (VII)

(VII), in welcher

(VII) in which

PG is a temporary protecting group such as acetyl or benzoyl and a leaving group such as chlorine, bromine, iodine, mesylate, triflate or

Tosylate, in the presence of a base, to give a compound of formula (VIII)

in welcher PG, R² und Y die oben angegebenen Bedeutungen haben, alkyliert, anschließend die Schutzgruppe PG abspaltet und die resultierende Verbindung der Formel (IX)

in which PG, R ² and Y have the meanings given above, followed by deprotection of the protective group PG and the resulting compound of the formula (IX)

in welcher R² und Y die oben angegebenen Bedeutungen haben, dann in Gegenwart einer Base mit einer Verbindung der Formel (X)

in which R ² and Y have the meanings given above, then in the presence of a base with a compound of the formula (X)

R ^{1 /} Z ³ (X), in which R ^{1 has} the meaning given above and is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, to the compound of formula (VI)

in welcher R¹, R² und Y die oben angegebenen Bedeutungen haben, alkyliert und die so nach Methode [A] oder [B] erhaltene Verbindung der Formel (VI) schließlich durch Behandlung mit einer Säure und nachfolgendes Erhitzen in die Carbonsäure der Formel (I)

in which R ¹ , R ² and Y have the meanings given above, alkylating and the compound of the formula (VI) thus obtained by method [A] or [B] finally by treatment with an acid and subsequent heating in the carboxylic acid of formula ( I)

in which R ¹ , R ² and Y have the meanings given above, and if appropriate the compounds of the formula (I) are separated into their enantiomers and / or diastereoisomers and / or optionally with the appropriate (i) solvents and / or ( ii) reacting bases to their solvates, salts and / or solvates of the salts. The 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, eg, DL Hughes, Org. Reactions 42, 335 (1992). ; DL Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)]. Examples of 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. As azodicarboxylate can for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), ΌΊ-tert-butyl azodicarboxylate, / V, / V, / VW-tetramethyl azodicarboxamide (TMAD), 1,1'-azodicarbonyl di-piperidine (ADDP) or 4,7- Dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD) can be used. Preference is given to using triphenylphosphine in combination with diisopropyl azodicarboxylate (DIAD).

Inert solvents for the reaction (Π) + (III) - (IV) 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 polar aprotic solvents such as acetonitrile, butyronitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) , JV, JV'-dimethylpropyleneurea (DMPU) or / V-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preference is given to using tetrahydrofuran.

The reaction (II) + (ΠΙ) - (IV) is usually carried out in a temperature range from -20 ° C to + 60 ° C, preferably at 0 ° C to + 40 ° C. Optionally, the use of a microwave oven may be advantageous in this reaction.

Suitable bases for the alkylation reactions (IV) + (V) -> (VI) and (IV) + (VII) -> (VIII) are particularly suitable 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, 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 , Preferably, 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), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) or dimethyl sulfoxide (DMSO). It is also possible to use mixtures of such solvents. Preferably, A 1 -dimethylformamide (DMF) is used. 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. Particularly suitable solvents for this reaction are 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. 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. Alternatively, a silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, ieri-butyldimethylsilyl or tert-butyldiphenylsilyl may be used as the temporary hydroxy-protecting 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). Another possibility is the use of benzyl as protecting group PG; this can be removed by hydrogenolysis in a known way [see also TW Greene and PGM 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 -iati-butoxide, or alkali hydrides such as sodium or potassium hydride. Preferably, potassium carbonate is used.

Inert solvents for this reaction are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert. -b tyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-meth- oxyethyl) 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'-dimethylpropylurea (DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use mixtures of such solvents. Preferably, acetonitrile is used.

The reaction (IX) + (X) - (VI) is generally carried out in a temperature range from 0 ° C to + 100 ° C. 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 be performed. For the ester cleavage, in the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of reaction with hydrogen chloride, preferably 1,4-dioxane, in each case under anhydrous conditions, as solvent. 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 may be carried out at normal, elevated or 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 welcher R² und Y die oben angegebenen Bedeutungen haben, mit Natriumnitrit in wässriger Salzsäure zugänglich [siehe z.B. D. Fernandez-Forner et ah , Tetra- hedron 47 (42), 8917-8930 (1991)] .

in which R ² 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)

(XII) (ΧΠΙ), in which R ^{1 has} the meaning given above, obtained by literature methods for α-halogenation of methyl ketones, the transformation of alcohols into halides or the formation of sulfonic acid esters from alcohols. The compounds of the formulas (XII) and (ΧΠΙ) in turn can be prepared analogously to the process step (IX) + (X) - (VI) described above by base-catalyzed alkylation of the phenol of the formula (XIV) or (XV)

in welcher R¹ und Z³ die oben angegebenen Bedeutungen haben, hergestellt werden.

in which R ¹ and Z ^{3 have} the meanings given above, are prepared.

The compounds of formulas (II), (VII), (X), (XI), (XIV) and (XV) are either commercially available or described as such in the literature or, starting from other commercially available compounds, be prepared by the skilled person, known from the literature. Numerous detailed regulations and further references are also contained in the Experimental Section in the section on the Preparation of Starting Compounds and Intermediates.

The preparation of the compounds of the invention can be exemplified by the following reaction scheme:

scheme

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. Moreover, many of the compounds of the invention to a low in vz ^'iro clearance and a good metabolic stability. This property profile Overall, a low dosability and, as a result of the more targeted mode of action, a reduced risk of the occurrence of undesirable side effects in the therapy can be expected for the compounds according to the invention.

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).

For the purposes of the present invention, 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 ,

The manifestations of chronic obstructive pulmonary disease (COPD) include, in particular, 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).

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.

The group of interstitial lung diseases (ILD) 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 interstitialile Pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous interstitial lung disease, interstitial lung disease of known cause and other interstitial lung diseases of unknown 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), of acute respiratory syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF), various types of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchiectasis, pneumonia, farmer's lung and related diseases, infectious and non-infectious cough and cold diseases (chronic inflammatory cough, iatrogenic cough), inflammations of the nose (including rhinitis, vasomotor rhinitis and season-dependent allergic rhinitis, eg hay fever). fen) and polyps.

For the purposes of the present invention, 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) due to arteriosclerosis of the leg arteries, as well as aneurysms, in particular aneurysms of the aorta, e.g. as a result of 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 a shunt-dependent perfusion of the lungs, as well as aneurysms on coronary vessels in the course of a disease in Kawasaki syndrome and in brain areas in patients with a congenital aortic valve malformation.

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, atrial arrhythmias and of the 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, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), boxer cardiomyopathy, shock like cardiogenic shock, septic shock, and anaphylactic shock, and for the treatment and / or prevention of thromboembolic disorders and ischaemias, such as myocardial ischemia, cardiac hypertrophy, transitory and ischemic attacks, pre-eclampsia, inflammatory cardiovascular diseases, coronary artery spasms, and peripheral arteries; Edema such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, microvascular and macrovascular lesions (vasodilatation) for example, after thrombosis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.

For the purposes of the present invention, the term 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 valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy cardiac storage disorders as well as diastolic and systolic heart failure. The compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure. For the purposes of the present invention, the terms 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 diagnostically by, for example, abnormally decreased creatinine and / or water excretion Increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered renal enzyme activity such as glutamylsynthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphatemia, and / or the need for dialysis can be characterized. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism. Moreover, 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.

In addition, 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.

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 , For the purposes of the present invention, the term fibrotic disorders encompasses 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, morphea, Keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis). The compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, e.g. after glaucoma surgery, and for cosmetic purposes on aging or keratinizing skin.

Also, the compounds of the invention may be used for the treatment and / or prevention of anemias, such as hemolytic anemias, especially hemoglobinopathies such as sickle cell anemia and thalassemias, megaloblastic anemias, iron deficiency anemias, acute blood loss anemia, crowding anaemias and aplastic anemias. The compounds of the invention are also useful in the treatment of cancers such as skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinomas of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract, and of malignant tumors of the lymphoproliferative system, such as Hodgkin's and Non-Hodgkin's Lymphoma. In addition, the compounds according to the invention can be used for the treatment and / or prevention of lipid metabolism disorders and dyslipidemias (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemias, hypercholesterolemia, abetalipoproteinemia, sitosterolemia), xanthomatosis, Tangier's disease, 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 fibrosis, liver cirrhosis, pancreatitis and cholecystitis), from E diseases of the central nervous system and of neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid diseases (hyperthyroidism), skin diseases (psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis such as dermatitis abacribus, dermatitis actinica, dermatitis allergica, ammoniacal dermatitis, dermatitis artefacta, autogenica dermatitis, dermatitis atrophicans, dermatitis calorica, dermatitis, dermatitis congelationis, dermatitis cosmetica, dermatitis escharotica, exfoliative dermatitis, gangrenous dermatitis, dermatitis haemostatica , Dermatitis herpetiformis, dermatitis lichenoides, dermatitis linearis, malignant dermatitis, median catosis, dermatitis palmaris et plantaris, dermatitis parasitaria, dermatitis photoallergica, dermatitis phototoxica, dermatitis pustularis, dermatitis seborrhoica, dermatitis sola Risks, dermatitis toxica, ulcerative colitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and rosacea-like dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, sweet syndrome, Weber-Christian Syndrome, scarring, wart formation, chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (influenza, adeno- and coronaviruses such as HPV, HCMV, HIV, SARS), diseases of the skeletal bone and joints and skeletal muscle (various forms of arthritis such as arthritis alcaptonurica, arthritis ankylosans, arthritis dysenterica, arthritis exsudativa, arthritis fungosa, arthritis gonorrhoica, arthritis mutilans, psoriatic arthritis, arthritis purulenta, arthritis rheumatica, Arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica, arthritis villonodu laris pigmentosa, atypical arthritis, haemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, in addition to the Still syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome. drom, various forms of arthropathies such as arthropathy deformans, arthropathy neuropathic, ovarian arthropathy, arthropathy psoriatica and arthropathy tabica, systemic Sclerosis, multiple forms of inflammatory myopathies such as myopathy epidemica, myopathy fibrosa, myopathy myoglobinurica, myopathy ossificans, myopathy ossificans neurotica, myopathy ossificans progressiva multiplex, myopathy purulenta, myopathy rheumatica, myopathy trichinosa, myopathy tropica and myopathy typhosa, as well as the gtther syndrome and Münchmeyer syndrome), inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, arteritis deformus, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, and horton Syndrome, Kikuchi's disease, polychondritis, scleroderma, and other diseases with an inflammatory or immunological component, such as cataracts, cachexia, chondrocyte syndrome, and Takayasu's arteritis. Osteoporosis, gout, inco ntinenz, leprosy, Sezary syndrome and paraneoplastic syndrome, in rejection reactions after organ transplantation and for wound healing and angiogenesis, especially in chronic wounds.

Because of their property profile, 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 disease (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 artery disease (PAOD), as well as chronic kidneys - diseases and the Alport syndrome.

The aforementioned well-characterized human diseases of similar etiology may also be present in other mammals and also be treated there with the compounds of the present invention.

For the purposes of the present invention, the term "treatment" or "treating" 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. The term "therapy" is understood to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.

The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. Suitable combination active substances for this purpose are by way of example and preferably mentioned: · anti-obstructive / bronchodilatory agents, as used, for example, for the treatment of chronic obstructive pulmonary disease (COPD) or of bronchial asthma. by way of example and preferably from the group of inhaled or systemically applied 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 roflumilast and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil;

NO and heme-independent activators of soluble guanylate cyclase (sGC), 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;

NO-independent, but heme-dependent stimulators of soluble guanylate cyclase (sGC), 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;

Compounds which inhibit human neutrophil elastase (HNE), in particular Sivelastat, DX-890 (Reltran) and those described in WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005 / 080372, WO 2005/082863, WO 2005/082864, WO 2009/080199, WO 2009/135599, WO 2010/078953 and WO 2010/115548 compounds;

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 preferably bosentan, darusentan, ambrisentan or sitaxsentan; anti-inflammatory, immunomodulatory, immunosuppressant and / or cytotoxic agents, by way of example and preferably from the group of systemic or inhaled corticosteroids, and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxycarbamide, azithromycin, IFN-γ, pirfenidone or etanercept; Antifibrotic 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, α _v β6 Integrin antagonists, cholchicine, IFN-β, D-penicillamine, inhibitors of the WNT signaling pathway or CCR2 antagonists; · Fat 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, PPARs alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists;

Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, 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 preferably nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib , Cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib or tandutinib;

Compounds which 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-β, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins; The Rho kinase inhibiting compounds, such as exemplified and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

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; · The energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine; 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a corticosteroid, such as by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / nia antagonist, such as, by way of example and by way of preference, tirofiban or abciximab. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. Among 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.

In a preferred embodiment of the invention, 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).

In a preferred embodiment of the invention, 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) , In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid absorption inhibitor, by way of example and by way of example. preferably ASBT (= IB AT) inhibitors such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, 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.

Particularly preferred are combinations of the compounds 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.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic, or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning, 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 the release of the compound according to the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) which break quickly in the oral cavity, dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or solutions. 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). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example 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.

Preferred are oral, intrapulmonary (inhalative) and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, 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) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg kg, preferably about 0.01 to 0.5 mg kg body weight, in order to achieve effective results. When administered orally, 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. For intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases, it may be sufficient to make do with less than the aforementioned minimum amount, while in other cases, the said upper limit is exceeded got to. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

A. Examples

 Abbreviations and acronyms: abs. absolutely

 Ac acetyl

aq. aqueous, aqueous solution

br. wide (at NMR signal)

 Example. Example

 Bu Butyl

c concentration

about circa, about

cat. catalytic

 CI chemical ionization (in MS)

d doublet (by NMR)

d day (s)

 TLC thin layer chromatography

 DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DIAD diisopropyl azodicarboxylate

 DMF N, -dimethylamine

 DMSO dimethyl sulfoxide

dt doublet of triplet (by NMR)

d. Th. Of theory (in chemical yield)

ee enantiomeric excess

 EI electron impact ionization (in MS)

ent enantiomerically pure, enantiomer

eq. Equivalent (s)

 ESI electrospray ionization (in MS)

Et ethyl GC gas chromatography

 GC / MS gas chromatography-coupled mass spectrometry h hour (s)

 HPLC high pressure, high performance liquid chromatography

iPr isopropyl

concentrate concentrated (at solution)

 LC liquid chromatography

 LC / MS liquid chromatography-coupled mass spectrometry

Literature (position)

m multiplet (by NMR)

 Me methyl

min minute (s)

 MPLC medium pressure liquid chromatography (over silica gel; also "flash"

Called chromatography ")

 Ms methanesulfonyl (mesyl)

 MS mass spectrometry

 NMR nuclear magnetic resonance spectrometry

 Pd / C palladium on charcoal

 Ph phenyl

 Pr Propyl

q (or quart) quartet (by NMR)

qd Quartet by Dublett (by NMR)

quant. quantitative (at chemical yield)

quint quintet (by NMR)

rac racemic, racemate

R _f retention index (at DC)

 RP reverse phase (reversed phase, for HPLC)

 RT room temperature

 Retention time (for HPLC, LC / MS)

s singlet (by NMR)

 SCF supercritical liquid chromatography

sept septet (by NMR)

t triplet (by NMR)

tBu teri-butyl

td triplet of doublet (by NMR)

Tf trifluoromethylsulfonyl (triflyl) TFA trifluoroacetic acid

 THF tetrahydrofuran

 Ts £> ara-tolylsulfonyl (tosyl)

 UV ultraviolet spectrometry

v / v volume to volume ratio (of a solution)

together

HPLC and LC / MS methods:

Method 1 (LC / MS):

 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ, 30 x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.

Method 2 (LC / MS):

 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 208-400 nm.

Method 3 (LC / MS):

 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A-> 0.5 min 97% A-> 3.2 min 5% A -> 4.0 min 5% A; Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm.

Method 4 (LC / MS):

 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ, 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A-> 0.1 min 90% A-> 1.5 min 10% A -> 2.2 min 10% A; Oven: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.

Method 5 (LC / MS):

Instrument MS: Waters Micromass QM; Instrument HPLC: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.5 μ, 3.0 x 50 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, Eluent B: 1 liter acetonitrile; Gradient: 0.0 min 98% A -> 0.2 min 98% A -> 3.0 min 5% A -> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.

Method 6 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 40 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-6.00 min 10:90, sample injection at 3.00 min; 6.00-27.00 min to 95: 5; 27.00-38.00 min 95: 5; 38.00-39.00 min to 10:90; 39.00-40.20 min 10:90.

Method 7 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-5.00 min 10:90, sample injection at 3.00 min; 5.00-23.00 min to 95: 5; 23.00-30.00 min 95: 5; 30.00-30.50 min to 10:90; 30.50-31.20 min 10:90.

Method 8 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 40 mm; Eluent A: water with 0.1% formic acid, eluent B: acetonitrile; Gradient: 0 min 10% B, 6 min 10% B, 27 min 95% B, 38 min 95% B, 40 min 10% B; Flow: 50 ml / min; Running time per separation: 40 min; Detection: 210 nm. Method 9 (preparative HPLC):

 Column: Reprosil C18, 10 μm, 250 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-5.00 min 10:90, sample injection at 3.00 min; 5.00-20.00 min to 95: 5; 20.00-30.00 min 95: 5; 30.00-30.50 min to 10:90; 30.50-31.20 min 10:90.

Method 10 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / acetonitrile; Gradient: 0-6 min 70:30, 6-22 min to 20:80, 22-46 min 20:80, 46-58 min to 70:30.

More information:

 The percentages in the following example and test descriptions are by weight unless otherwise indicated; Parts are parts by weight. 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 one 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.

The following descriptions of the coupling patterns of ^ -NMR signals were partly taken directly from the suggestions of the ACD SpecManager (ACD / Labs Release 12.00, Product version 12.5) and not necessarily rigorously questioned. In part, the suggestions of the SpecManager were adapted manually. Manually customized descriptions are usually based on the visual appearance of the signals in question and do not necessarily correspond to a rigorous, physically correct interpretation. As a rule, the indication of the chemical shift refers to the center of the relevant signal. For wide multiplets, an interval is specified. Solvent or water concealed signals were either tentatively assigned or are not listed.

Melting points and melting ranges, where indicated, are not corrected.

For all reactants or reagents, the preparation of which is not explicitly described below, it is true that they were obtained commercially from generally available sources. For all other reactants or reagents, the preparation of which is also not described below and which were not commercially available or obtained from sources that are not generally available, reference is made to the published literature describing their preparation.

Starting compounds and intermediates:

Example 1A

6- (trifluoromethyl) -1,3,3-benzotriazine-4 (3 /) -one

Zu einer Suspension von 24.4 g (119.51 mmol) 2-Amino-5-(trifluormethyl)benzamid in 174 ml eines 2: 1-Gemisches von Wasser und konz. Salzsäure bei 0°C wurde eine Lösung von 9.08 g (131.47 mmol) Natriumnitrit in 74 ml Wasser langsam hinzugegeben, wobei die Innentemperatur unter 5°C gehalten wurde. Nach 30 min Rühren bei 0°C Badtemperatur wurden unter weiterer Eisbad-Kühlung langsam 74 ml (0.74 mol) 10 M Natronlauge hinzugegeben, wobei die Innentempera- tur auf ca. 20°C anstieg. Es bildete sich zunächst eine Lösung, aus welcher dann eine Suspension entstand, die zur besseren Rührbarkeit mit 100 ml Wasser verdünnt wurde. Nach 1.5 h Rühren bei RT wurde das Gemisch vorsichtig mit konz. Salzsäure sauer gestellt (pH = 2). Der gebildete Niederschlag wurde abfiltriert und dreimal mit Wasser nachgewaschen. Nach Trocknen an der Luft und danach im Vakuum wurden 24.74 g (96% d. Th.) der Titelverbindung erhalten. Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 15.31 (br. s, 1H), 8.46 (s, 1H), 8.40 (d, 2H).

To a suspension of 24.4 g (119.51 mmol) of 2-amino-5- (trifluoromethyl) benzamide in 174 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 9.08 g (131.47 mmol) of sodium nitrite in 74 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 minutes at a bath temperature of 0 ° C., 74 ml (0.74 mol) of 10 M sodium hydroxide solution were slowly added with further ice-bath cooling, the internal temperature rising to about 20 ° C. It first formed a solution from which then a suspension was formed, which was diluted for better stirrability with 100 ml of water. After stirring at RT for 1.5 h, the mixture was carefully poured with conc. Hydrochloric acid acidified (pH = 2). The precipitate formed was filtered off and washed three times with water. After drying in air and then in vacuo, 24.74 g (96% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-de): δ [ppm] = 15.31 (br.s, 1H), 8.46 (s, 1H), 8.40 (d, 2H).

LC / MS (Method 2, ESIpos): R _t = 0.78 min, m / z = 216 [M + H] ⁺ .

Example 2A

7-methyl-1,2,3-benzotriazine-4 (3 /) -one

To a suspension of 7.64 g (50.87 mmol) of 2-amino-4-methylbenzamide in 80 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 3.86 g (55.96 mmol) of sodium nitrite in 32 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 40 minutes at 0 ° C. bath temperature, 32 ml (0.32 mol) of 10 M sodium hydroxide solution were slowly added with further cooling with ice bath, the internal temperature being reduced to ca. 20 ° C rise and existing solid went into solution. After the internal temperature had dropped back to about 5-10 ° C, the mixture was carefully added with conc. Hydrochloric acid acidified (pH = 2). The precipitate formed was filtered off and washed three times with water. After drying in air and then in vacuo, 8.19 g (99% of theory) of the title compound were obtained.

Ή NMR (400 MHz, CDCL): δ [ppm] = 11.87 (br.s, 1H), 8.25 (d, 1H), 7.99 (s, 1H), 7.65 (d, 1H), 2.62 (s, 3H ).

LC / MS (Method 2, ESIpos): R _t = 0.57 min, m / z = 162 [M + H] ⁺ . Example 3A 7- (trifluoromethyl) -1,3,3-benzotriazine-4 (3 //) -one

To a suspension of 5.60 g (27.43 mmol) of 2-amino-4- (trifluoromethyl) benzamide in 40 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 2.08 g (30.17 mmol) of sodium nitrite in 17 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 40 minutes at 0 ° C. bath temperature, 17 ml (0.17 mol) of 10 M sodium hydroxide solution were slowly added with further ice-bath cooling, the internal temperature rising to about 30 ° C. After the internal temperature had dropped back to about 5-10 ° C, the suspension was carefully added with conc. Hydrochloric acid acidified (pH = 2). The solid was filtered off and washed three times with water. After drying in air and then in vacuo, 5.64 g (93% of theory, purity 97%) of the title compound were obtained.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 12.57 (br.s, 1H), 8.64-8.37 (m, 2H), 8.05 (d, 1H). LC / MS (Method 2, ES Ineg): R _t = 0.73 min, m / z = 214 [MH] ^" .

Example 4A

Pyrido [3,2-d] [1,2,3] triazine-4 (3 /) -one

To a suspension of 3.20 g (23.33 mmol) of 3-aminopyridine-2-carboxamide in 25 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 1.78 g (25.67 mmol) of sodium nitrite in 11 ml of water was slowly added, the internal temperature was kept below 5 ° C. From the suspension, a solution was obtained, which was stirred for a further 40 min at 0 ° C bath temperature. Then, with further ice-bath cooling, 11 ml (0.11 mol) of 10 M sodium hydroxide solution were added slowly, the internal temperature rising somewhat. After the internal temperature had dropped back to about 5-10 ° C, the resulting suspension was carefully mixed with conc. Hydrochloric acid acidified (pH = 2). The solid was filtered off, washed three times with water and stirred with diethyl ether. After drying in air and then in vacuo, 2.80 g (81% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 15.24 (br.s, 1H), 9.11 (dd, 1H), 8.61 (dd, 1H), 8.07 (dd, 1H).

LC / MS (Method 3, ESIpos): R _t = 0.38 min, m / z = 149 [M + H] ⁺ . Example 5A

Di-ieri-butyl {2- [4- (cyclopropylmethoxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

Schritt 1:

Step 1:

 Di-ieri-butyl {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 //) -yl] ethyl} malonate

A solution of 18.78 g (71.58 mmol) of triphenylphosphine in 210 ml of THF was added under argon at RT with 14.8 ml (71.58 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and briefly stirred. The internal temperature rose to 40 ° C and it formed a precipitate. Then, 14.0 g (65.08 mmol) of the compound from Example 1A were added and the mixture was stirred for a further few minutes. Subsequently, 18.64 g (71.58 mmol) of di-ieri-butyl- (2-hydroxyethyl) malonate [for the preparation see US 6,900,194, intermediate 5E] were added, the internal temperature rising to 60 ° C. The solution was further stirred for 1 h. Thereafter, the solvent was removed and the residue was taken up in 200 ml of ethyl-butyl-methyl ether. The resulting solid was filtered off, with 30 ml of tert. -Butyl methyl ether washed and discarded. The filtrate was concentrated and the residue was purified by column chromatography (1 kg silica gel, eluent cyclohexane / ethyl acetate 9: 1). There were obtained 26.44 g (89% of theory) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.65 (s, 1H), 8.28 (d, 1H), 8.15 (dd, 1H), 4.60 (t, 2H), 3.29 (t, 1H), 2.43 (q, 2H), 1.45 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.37 min, m / z = 457 [M + H] ⁺ .

Step 2:

Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) - yl] ethyl} malonate

To a solution of 24.44 g (53.43 mmol) of the compound from Example 5A / step 1 in 400 ml of DMF under argon was slowly added portionwise at RT 2.78 g (69.45 mmol, 60% dispersion in mineral oil) of sodium hydride. After stirring for 10 min at rt, the mixture was cooled to 0 ° C and a solution of 18.76 g (58.77 mmol) of 4- (bromoacetyl) phenylbenzoate in 100 ml of DMF was added. The mixture was stirred for 2 h at RT. After removing the solvent, the residue was added with 500 ml of water and 500 ml of ethyl acetate, and the phases were separated. The aqueous phase was extracted once with 500 ml of ethyl acetate, and the combined organic phases were washed once with 1 liter of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was mixed with about 200 ml ieri.-butyl methyl ether and stirred over the weekend. The solid which was present was filtered off and washed twice with 100 ml each of ethyl-butyl methyl ether. After drying in vacuo, 21.31 g (52% of theory, purity 91%) of a first batch of the title compound were obtained. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by flash chromatography (400 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). This gave 840 mg (2% of theory, purity 99%) of a second batch of the title compound. Two further, partially purified fractions from column chromatography were combined, dissolved in 120 ml of THF and purified by preparative HPLC (column: Chromatorex C18, 10 μm, spring column 250 × 20 mm, flow: 250 ml / min, detection: 210 nm, injection volume 20 ml, temperature: 22 ° C, eluent: methanol / water gradient). There were obtained in this way 6.65 g (17% of theory, purity 97%) of a third batch of the title compound.

Ή-NMR (400 MHz, CDCh): δ [ppm] = 8.60 (s, 1H), 8.25-8.19 (m, 3H), 8.11 (dd, 1H), 8.07 (d, 2H), 7.70-7.63 (m , 1H), 7.58-7.51 (m, 2H), 7.32 (d, 2H), 4.61-4.54 (m, 2H), 3.78 (s, 2H), 2.74-2.67 (m, 2H), 1.49 (s, 18H ). LC / MS (Method 2, ESIpos): R _t = 1.54 min, m / z = 696 [M + H] Step 3:

 Diieri. -bu ty 1- [2 - (4 -hy droxypheny

3 (4H) -y 1] ethyl} malonate

Zu einer Lösung von 7.42 g (10.67 mmol) der Verbindung aus Beispiel 5A / Schritt 2 in einem Gemisch aus 150 ml THF und 50 ml Methanol unter Argon wurden 0.61 ml (0.58 mmol) einer 30%-igen Natriummethylat-Lösung in Methanol bei RT hinzugegeben. Das Gemisch wurde 2 h bei 60°C Badtemperatur gerührt. Nach Abkühlen auf RT wurde das Gemisch mit 200 ml Ethylacetat und 200 ml Wasser versetzt und die Phasen getrennt. Die wässrige Phase wurde mit 100 ml Efhyl- acetat extrahiert, und die vereinigten organischen Phasen wurden einmal mit 300 ml gesättigter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet, filtriert und auf ein Volumen von ca. 70 ml eingeengt. Nach 30 min Kühlen auf 0°C wurde der gebildete Feststoff abfiltriert und zweimal mit jeweils 5 ml Ethylacetat gewaschen. Nach Trocknen im Vakuum wurden 4.65 g (74% d. Th.) einer ersten Charge der Titelverbindung erhalten. Das Filtrat wurde eingeengt, und der Rückstand wurde in wenig Dichlormethan aufgenommen und dann mittels Säulenchromatographie gereinigt (Kieselgel, Laufmittel Cyclohexan/Ethylacetat 7:3, Biotage -Anlage). Es wurden so 0.89 g (14% d. Th.) einer zweiten Charge der Titelverbindung erhalten.

To a solution of 7.42 g (10.67 mmol) of the compound of Example 5A / Step 2 in a mixture of 150 ml of THF and 50 ml of methanol under argon was added 0.61 ml (0.58 mmol) of a 30% sodium methylate solution in methanol at RT added. The mixture was stirred for 2 h at 60 ° C bath temperature. After cooling to RT, 200 ml of ethyl acetate and 200 ml of water were added to the mixture, and the phases were separated. 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. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by column chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 7: 3, Biotage system). This gave 0.89 g (14% of theory) of a second batch of the title compound.

Ή-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.58 (s, 1H), 8.22 (dd, 1H), 8.10 (dd, 1H), 7.86 (d, 2H), 6.86-6.83 (br. s, 1H), 6.83 (d, 2H), 4.59-4.53 (m, 2H), 3.70 (s, 2H), 2.72-2.66 (m, 2H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.31 min, m / z = 592 [M + H] ⁺ .

Step 4:

Di-ieri-butyl {2- [4- (cyclopropylmethoxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 5A / step 3 in 3 ml of acetonitrile were added 68 mg (0.51 mmol) (bromomethyl) cyclopropane and 70 mg (0.51 mmol) of potassium carbonate. The mixture was stirred for 16 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added. After shaking and phase separation, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 96 mg (80% of theory, purity 91%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 1.50 min, m / z = 646 [M + H] ⁺ . Example 6A

Di-tert-butyl {2- [4- (2-methoxyethoxy) phenyl] -2-oxoethyl} {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 5A / Step 3 in 3 ml of acetonitrile was added 70 mg (0.51 mmol) of 2-bromoethyl methyl ether and 70 mg (0.51 mmol) of potassium carbonate. The mixture was stirred for 16 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added. After shaking and phase separation, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. There were obtained 99 mg (82% of theory, purity 91%) of the title compound.

LC / MS (Method 2, ESIpos): R _t = 1.42 min, m / z = 650 [M + H] ⁺ .

Example 7A (+/-) - di-tert-butyl- (2-oxo-2- {4- [2- (tetrahydro-2-pyran-2-yloxy) -ethoxy] -phenyl} -ethyl) {2- [4 oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

To a solution of 100 mg (0.17 mmol) of the compound from Example 5A / Step 3 in 3 ml of acetonitrile was added 106 mg (0.51 mmol) of (+/-) -2- (2-bromo-hexoxy) -tetrahydro-2i-7-pyran and 70 mg (0.51 mmol) of potassium carbonate. The mixture was stirred for 16 h at 80 ° C bath temperature. After cooling to RT, ethyl acetate and water were added. After shaking and phase separation, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 120 mg (96% of theory, purity 97%) of the title compound were obtained.

LC / MS (Method 3, ESIpos): R _t = 3.16 min, m / z = 720 [M + H] ⁺ . Example 8A

Di-ieri-butyl {2-oxo-2- [4- (pentyloxy) phenyl] ethyl} {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 ( 4 /) - yl] ethyl} malonate

To a suspension of 500 mg (0.71 mmol, purity 85%) of the compound from Example 5A / Step 3 in 8 ml of acetonitrile were added 200 mg (1.44 mmol) of potassium carbonate and 0.11 ml (0.86 mmol) of 1-bromopentane. The mixture was stirred at reflux for 4 h. After cooling to RT, 5 ml of water were added. After stirring for a few minutes, the solid was filtered off, washed twice with water and dried in vacuo. The solid was then stirred in diethyl ether, filtered off and dried again in vacuo. There were obtained 446 mg (94% of theory, purity 96%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.40 (s, 1H), 8.35 (d, 2H), 7.84 (d, 2H), 6.94 (d, 2H), 4.48-4.41 ( m, 2H), 4.02 (t, 2H), 3.63 (s, 2H), 2.57-2.47 (obscured, 2H), 1.78-1.68 (m, 2H), 1.40 (s, 18H), 1.39-1.31 (obscured, 4H), 0.93-0.87 (m, 3H).

LC / MS (Method 3, ESIpos): R _t = 3.39 min, m / z = 662 [M + H] ⁺ .

Example 9A

Di-ieri-butyl {2- [4- (cyclopentylmethoxy) phenyl] -2-oxoethyl} [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) yl) ethyl] malonate

Schritt 1:

Step 1:

 Di-ieri-butyl- [2- (7-methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) ethyl] malonate

A solution of 12.46 g (47.50 mmol) of triphenylphosphine in 100 ml of THF under argon was added at RT with 9.85 ml (47.50 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. For dilution, another 10 ml of THF was added. Subsequently, 6.96 g (43.19 mmol) of the compound from Example 2A were added and the suspension was stirred for a further 5 min. Then a solution of 11.81 g (45.35 mmol) of di-ieri-butyl- (2-hydroxyethyl) malonate [for the preparation see US Pat. No. 6,900,194, intermediate 5E] in 30 ml of THF was added slowly and the mixture was added for 1 h RT stirred. Thereafter, the mixture was concentrated, and the residue was stirred in 50 ml of a 10: 1 mixture of cyclohexane and ethyl acetate. After cooling to 0 ° C, the solid present was filtered off and discarded. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, mobile phase cyclohexane / ethyl acetate 95: 5-90: 10-85: 15). After concentration of the combined product-containing fractions, the residue was taken up in a little dichloromethane and treated with pentane, whereupon a solid precipitated. After stirring in the cold, the solid was filtered off and dried in vacuo. There were obtained 8.56 g (49% of theory) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.23 (d, 1H), 7.92 (s, 1H), 7.61 (d, 1H), 4.55 (t, 2H), 3.29 (td, 1H), 2.60 (s, 3H), 2.42 (q, 2H), 1.45 (s, 18H). LC / MS (Method 1, ESIpos): R _t = 1.33 min, m / z = 404 [M + H] ⁺ .

Step 2:

Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (7-methyl-4-oxo-1,2,3-benzotriazine] 3 (4 //) - yl) ethyl] malonate

To a mixture of 1.05 g (26.33 mmol, 60% dispersion in mineral oil) of sodium hydride in 80 ml of DMF under argon, a solution of 8.50 g (21.07 mmol) of the compound from Example 9A / step 1 in 80 ml of DMF slowly at RT added. It was then stirred until completion of the evolution of gas at RT and then at 50 ° C for about 10 min. After cooling to RT, a solution of 8.26 g (23.17 mmol, purity 90%) of 4- (bromoacetyl) phenylbenzoate in 80 ml of DMF was added rapidly, the temperature being kept at RT by further cooling. The mixture was then stirred for a further 15 min at RT. Thereafter, the mixture was taken up in ethyl acetate and water and adjusted to pH 4-5 with 10% citric acid solution. After phase separation, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 90: 10-85: 15-80: 20). 11.80 g (87% of theory) of the title compound were obtained. Ή NMR (400 MHz, CDCb): δ [ppm] = 8.23-8.16 (m, 3H), 8.07 (d, 2H), 7.87 (s, 1H), 7.69-7.64 (m, 1H), 7.59-7.51 (m, 3H), 7.32 (d, 2H), 4.55-4.48 (m, 2H), 3.79 (s, 2H), 2.72-2.66 (m, 2H), 2.57 (s, 3H), 1.48 (s, 18H ).

LC / MS (Method 2, ESIpos): R _t = 1.51 min, m / z = 642 [M + H] ⁺ .

Step 3:

Di-tert-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 / f) -yl) -] ethyl] malonate

To a solution of 3.10 g (4.44 mmol, purity 92%) of the compound of Example 9A / Step 2 in a mixture of 24 mL THF and 9 mL methanol was added 0.25 mL (1.33 mmol) of a 30% sodium methylate solution in methanol added at RT. The mixture was stirred for 4.5 h at 50 ° C bath temperature. Subsequently, a further 0.1 ml (0.52 mmol) of the 30% sodium methylate solution in methanol were added and the mixture was stirred for a further hour. After removal of the solvent, the residue was taken up in a mixture of 100 ml of ethyl acetate, 200 ml of water and 150 ml of saturated sodium chloride solution. After phase separation, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was stirred in pentane and the resulting solid was filtered off and dried in vacuo. There were obtained 1.95 g (76% of theory, purity 93%) of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.18 (d, 1H), 7.90-7.82 (m, 3H), 7.58 (d, 1H), 7.52 (s, 1H), 6.83 (d, 2H), 4.55-4.49 (m, 2H), 3.72 (s, 2H), 2.72-2.66 (m, 2H), 2.58 (s, 3H), 1.48 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.25 min, m / z = 538 [M + H] ⁺ .

Step 4:

Di-ieri-butyl {2- [4- (cyclopentylmethyl) phenyl] -2-oxoethyl} [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) yl) ethyl] malonate

To a solution of 200 mg (0.37 mmol) of the compound from Example 9A / Step 3 in 5 mL acetonitrile was added 121 mg (0.74 mmol) (bromomethyl) cyclopentane and 154 mg (1.12 mmol) potassium carbonate. The mixture was stirred at reflux for 16 h. After cooling to RT, the mixture was mixed with 30 ml of water and stirred for a few minutes. The solid present was filtered off, washed twice with water and once with pentane and dried in vacuo. 203 mg (87% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.17 (d, 1H), 7.93 (d, 2H), 7.85 (s, 1H), 7.55 (d, 1H), 6.89 (d, 2H) , 4.53-4.46 (m, 2H), 3.89 (d, 2H), 3.71 (s, 2H), 2.70-2.63 (m, 2H), 2.57 (s, 3H), 2.44-2.32 (m, 1H), 1.90 -1.80 (m, 2H), 1.71-1.58 (m, 4H), 1.47 (s, 18H), 1.37 (d, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.60 min, m / z = 620 [M + H] ⁺ .

Example 10A

Di-tert-butyl [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] {2-oxo-2- [4- (pentyloxy) - phenyl] ethyl} malonate

To a solution of 800 mg (1.19 mmol, purity 80%) of the compound from Example 9A / Step 3 in 7.5 ml of acetonitrile was added 329 mg (2.38 mmol) of potassium carbonate and 0.18 ml (1.43 mmol). 1 bromopentane added. The mixture was stirred first at RT for 19 h and then under reflux for about 8 h. After cooling to RT, 5 ml of water were added to the mixture. After stirring for a few minutes, the solid was filtered off, washed once with water and dried in vacuo. 465 mg (58% of theory, purity 90%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.08 (d, 1H), 7.94 (s, 1H), 7.87 (d, 2H), 7.72 (d, 1H), 6.97 (d, 2H), 4.42-4.36 (m, 2H), 4.04 (t, 2H), 3.64 (s, 2H), 2.59-2.42 (occluded, 5H), 1.78-1.68 (m, 2H), 1.38 (s, 18H) , 1.44-1.31 (obscured, 4H), 0.90 (t, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.69 min, m / z = 608 [M + H] ⁺ . Example IIA

Di-ieri-butyl {2- [4- (cyclopentylmethoxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (AH) - yl] ethyl} malonate

Step 1:

Di-ieri-butyl {2- [4-oxo-7- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] ethyl} malonate

Eine Lösung von 14.31 g (54.56 mmol) Triphenylphosphin in 165 ml THF unter Argon wurde bei RT mit 11.31 ml (54.57 mmol, Reinheit 95%) Diisopropylazodicarboxylat (DIAD) versetzt und kurz nachgerührt. Anschließend wurden 11.0 g (49.60 mmol, Reinheit 97%) der Verbindung aus Beispiel 3A hinzugegeben und die Suspension ca. 5 min weiter gerührt. Danach wurden 15.49 g (59.52 mmol) Di-teri.-butyl-(2-hydroxyethyl)malonat [zur Herstellung siehe US 6 900 194, Inter- mediat 5E] hinzugegeben und das Gemisch weiter 1 h bei RT gerührt. Anschließend wurde das Gemisch mit 500 ml Ethylacetat versetzt und jeweils einmal mit 500 ml Wasser und 500 ml gesättigter Natriumchlorid-Lösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wurde in 150 ml Ethylacetat aufgenommen und in der Wärme gelöst. Nach Abkühlen auf RT fiel ein Feststoff aus, welcher zweimal mit 70 ml feri.-Butyl-methylether gewaschen und anschließend verworfen wurde. Das Filtrat wurde eingeengt, und der Rückstand wurde in wenig Dichlormethan aufgenommen und dann mittels Flash-Chromatographie gereinigt (Kieselgel, Laufmittel Cyclohexan/Ethylacetat 9: 1). Es wurden 2.85 g (12% d. Th., Reinheit 95%) einer ersten Charge der Titelverbindung und 13.19 g (58% d. Th., Reinheit 100%) einer zweiten Charge erhal- ten.

A solution of 14.31 g (54.56 mmol) of triphenylphosphine in 165 ml of THF under argon was treated at RT with 11.31 ml (54.57 mmol, purity 95%) of diisopropyl azodicarboxylate (DIAD) and stirred briefly. Subsequently, 11.0 g (49.60 mmol, purity 97%) of the compound from Example 3A were added and the suspension was stirred for a further 5 min. Thereafter, 15.49 g (59.52 mmol) of di-tert-butyl- (2-hydroxyethyl) malonate [for the preparation see US Pat. No. 6,900,194, Intermediate 5E] were added and the mixture was stirred at RT for a further 1 h. Subsequently, the mixture was mixed with 500 ml of ethyl acetate and washed once each with 500 ml of water and 500 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was taken up in 150 ml of ethyl acetate and dissolved in the heat. After cooling to RT, a solid precipitated, which was washed twice with 70 ml of ferric butyl methyl ether and then discarded. The filtrate was concentrated and the residue was taken up in a little dichloromethane and then purified by flash chromatography (silica gel, eluent cyclohexane / ethyl acetate 9: 1). 2.85 g (12% of theory, purity 95%) of a first batch of the title compound and 13.19 g (58% of theory, purity 100%) of a second batch were obtained.

Ή NMR (400 MHz, CDCb): δ [ppm] = 8.49 (d, 1H), 8.43 (s, 1H), 8.00 (dd, 1H), 4.59 (t, 2H), 3.29 (t, 1H), 2.43 (q, 2H), 1.45 (s, 18H).

LC / MS (Method 3, ESIpos): R _t = 2.85 min, m / z = 458 [M + H] ⁺ .

Step 2:

Di-tert-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - yl] ethyl} malonate

To a mixture of 1.50 g (37.48 mmol, 60% dispersion in mineral oil) of sodium hydride in 90 ml of DMF under argon was added a solution of 13.19 g (28.83 mmol) of the compound from Example I IA / Step 1 in 90 ml of DMF slowly added at RT. It was then stirred at 50 ° C for about 30 min. After cooling to RT, a solution of 10.12 g (31.72 mmol) was added. 4- (bromoacetyl) phenylbenzoate in 90 ml of DMF and the mixture was stirred at RT overnight. Then, the mixture was added with 400 ml of ethyl acetate and 400 ml of water. After phase separation, the aqueous phase was extracted once with 200 ml of ethyl acetate. The combined organic phases were washed once with 300 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (1 kg silica gel, eluent cyclohexane / ethyl acetate 9: 1). 6.16 g (30% of theory, purity 97%) of a first batch of the title compound were obtained. In addition, partially purified product fractions were obtained, which were combined and subsequently purified by preparative HPLC (column: Daiso C18, 10 μm, Bio Dan 300 × 100 mm, flow: 250 ml / min, detection: 210 nm, injection volume 10 ml, temperature: 20 ° C, eluent: isocratic methanol / water 90:10). This gave 3.37 g (17% of theory) of a second batch of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.43 (d, 1H), 8.38 (s, 1H), 8.23-8.19 (m, 2H), 8.06 (d, 2H), 7.96 (dd, 1H), 7.70-7.64 (m, 1H), 7.54 (d, 2H), 7.31 (d, 2H), 4.60-4.54 (m, 2H), 3.78 (s, 2H), 2.74- 2.67 (m, 2H) , 1.49 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.60 min, m / z = 696 [M + H] ⁺ .

Step 3:

 Di-ieri-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4H) -y 1] ethyl} malonate

To a solution of 6.20 g (8.02 mmol, purity 90%) of the compound from Example I IA / step 2 in a mixture of 42 ml of THF and 16 ml of methanol was added 0.46 ml (2.41 mmol) of a 30% sodium methylate solution in Methanol added at RT. The mixture was stirred for 4 h at 50 ° C bath temperature. It was then diluted with ethyl acetate and the solution was then washed once with water. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed once with saturated sodium chloride solution. dried, dried over sodium sulfate, filtered and concentrated to a small residual volume. The resulting solid was filtered off, washed twice with pentane and dried in vacuo. This gave 3.92 g (83% of theory) of a first batch of the title compound. The filtrate was concentrated, the residue was combined with 520 mg of a partially purified fraction from a previous experiment, then dissolved in a little dichloromethane and purified by column chromatography (120 g silica gel, eluent cyclohexane / ethyl acetate 7: 3, Interchim). There was thus obtained 1.25 g of a second batch of the title compound.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.42 (d, 1H), 8.36 (s, 1H), 7.95 (dd, 1H), 7.85 (d, 2H), 6.85-6.79 (m, 3H), 4.59-4.53 (m, 2H), 3.70 (s, 2H), 2.73-2.66 (m, 2H), 1.48 (s, 18H). LC / MS (Method 3, ESIpos): R _t = 2.78 min, m / z = 592 [M + H] ⁺ .

Step 4:

 Di-ieri-butyl {2- [4- (cyclopentylmethoxy) phenyl] -2-oxoethyl} {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine-3 (AH) - yl] ethyl} malonate

Zu einer Lösung von 500 mg (0.85 mmol) der Verbindung aus Beispiel I IA / Schritt 3 in 9 ml Acetonitril wurden 234 mg (1.69 mmol) Kaliumcarbonat und 165 mg (1.01 mmol) (Brommethyl)- cyclopentan hinzugegeben. Das Gemisch wurde 16 h unter Rückfluss gerührt. Anschließend wurden weitere 90 mg (0.55 mmol) (Brommethyl)cyclopentan hinzugegeben und das Gemisch nochmals 20 h unter Rückfluss gerührt. Nach Abkühlen auf RT wurden dem Gemisch 10 ml Wasser zugesetzt. Nach einigen Minuten Rühren wurde der vorhandene Feststoff abfiltriert, zweimal mit Wasser nachgewaschen und im Vakuum getrocknet. Es wurden 490 mg (85% d. Th., Reinheit 98%) der Titelverbindung erhalten.

To a solution of 500 mg (0.85 mmol) of the compound of Example I IA / Step 3 in 9 mL of acetonitrile was added 234 mg (1.69 mmol) of potassium carbonate and 165 mg (1.01 mmol) of (bromomethyl) cyclopentane. The mixture was stirred at reflux for 16 h. Subsequently, a further 90 mg (0.55 mmol) of (bromomethyl) cyclopentane were added and the mixture was stirred for a further 20 h under reflux. After cooling to RT, 10 ml of water were added to the mixture. After stirring for a few minutes, the solid was filtered off, washed twice with water and dried in vacuo. 490 mg (85% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.41 (d, 1H), 8.35 (s, 1H), 7.96-7.87 (m, 3H), 6.88 (d, 2H), 4.59-4.52 ( m, 2H), 3.88 (d, 2H), 3.71 (s, 2H), 2.72-2.65 (m, 2H), 2.43-2.30 (m, 1H), 1.91-1.78 (m, 2H), 1.70-1.57 ( m, 4H), 1.47 (s, 18H), 1.42-1.27 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.64 min, m / z = 674 [M + H] ⁺ . Example 12A

Di-ieri-butyl {2- [4- (cyclopentylmethoxy) phenyl] -2-oxoethyl} [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4H) -yl) ethyl] malonate

Step 1:

 Di-tert-butyl [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl) -malonate

A mixture of 2.94 g (11.30 mmol) of di-ieri-butyl (2-hydroxyethyl) malonate [for preparation, see US 6,900,194, intermediate 5E], 4.45 g (16.95 mmol) of triphenyl phosphine and 2.51 (16.95 mmol) of the compound from Example 4A in 100 ml of THF under argon was stirred for 30 min at RT and then slowly added at RT with 3.36 ml (16.94 mmol) of diisopropyl azodicarboxylate (DIAD). After further stirring overnight, the solvent was removed, and the residue was added with 100 ml of cyclohexane and stirred for 30 minutes in the heat. The resulting solid was filtered off and the filtrate was concentrated. This residue was added again with 100 ml of cyclohexane and stirred again for 10 min in the heat. The solid was filtered off again and the filtrate was concentrated again. The resulting residue was then purified by means of MPLC purified (silica gel, eluent cyclohexane / ethyl acetate 20: 1). 4.40 g (99% of theory, still containing impurities) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.12 (dd, 1H), 8.62 (dd, 1H), 8.07 (dd, 1H), 4.46 (t, 2H), 3.44 (t, 1H), 2.26 (q, 2H), 1.39 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 391 [M + H] ⁺ .

Step 2:

 Di-ieri-butyl {2- [4- (benzoyloxy) phenyl] -2-oxoethyl} [2- (4-oxopyrido [3,2-d] [1,2,3] triazine 3 (4 / /) -yl) ethyl] malonate

Zu einem Gemisch von 133 mg (3.34 mmol, 60%-ige Dispersion in Mineralöl) Natriumhydrid in 10 ml DMF unter Argon wurde eine Lösung von 1.24 g (3.18 mmol) der Verbindung aus Beispiel 12A / Schritt 1 in 10 ml DMF langsam bei RT hinzugegeben (exotherme Reaktion). Es wurde anschließend ca. 30 min bei RT bis zum Abklingen der Gasentwicklung gerührt. Dann wurde eine Lösung von 1.22 g (3.81 mmol) 4-(Bromacetyl)phenylbenzoat in 10 ml DMF hinzugegeben, und das Gemisch wurde 1 h bei RT nachgerührt. Anschließend wurde das Gemisch in Wasser eingetragen und dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden einmal mit gesättigter Natriumchlorid-Lösung gewaschen, über Magnesiumsulfat getrocknet, filtriert und eingeengt. Der Rückstand wurde mittels Flash-Chromatographie gereinigt (Kieselgel, Laufmittel Dichlormethan/Methanol 100: 1). Nach Vereinigen der produkthaltigen Fraktionen und Entfernen des Lösungsmittels wurde der Rückstand in Diethylether verrührt. Der vorhandene Feststoff wurde abfiltriert und im Vakuum getrocknet. Es wurden 1.07 g (53% d. Th.) der Titelverbindung erhalten.

To a mixture of 133 mg (3.34 mmol, 60% dispersion in mineral oil) of sodium hydride in 10 ml of DMF under argon was added a solution of 1.24 g (3.18 mmol) of the compound from Example 12A / Step 1 in 10 ml of DMF slowly at RT added (exothermic reaction). It was then stirred for about 30 min at RT until the evolution of gas subsided. Then a solution of 1.22 g (3.81 mmol) of 4- (bromoacetyl) phenylbenzoate in 10 ml of DMF was added and the mixture was stirred at RT for 1 h. Then the mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluent dichloromethane / methanol 100: 1). After combining the product-containing fractions and removing the solvent, the residue was stirred in diethyl ether. The resulting solid was filtered off and dried in vacuo. 1.07 g (53% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.11 (dd, 1H), 8.59 (dd, 1H), 8.17 (d, 2H), 8.09 (d, 2H), 8.05 (dd, 1H), 7.81-7.75 (m, 1H), 7.67-7.61 (m, 2H), 7.47 (d, 2H), 4.52-4.45 (m, 2H), 3.77 (s, 2H), 2.74-2.67 (obscured, 2H), 1.42 (s, 18H). LC / MS (Method 2, ESIpos): R _t = 1.37 min, m / z = 629 [M + H] ⁺ .

Step 3:

 Di-tert-butyl- [2- (4-hydroxyphenyl) -2-oxoethyl] [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) -yl ) - ethyl] malonate

To a solution of 1.07 g (1.58 mmol, purity 93%) of the compound from Example 12A / Step 2 in a mixture of 20 ml of THF and 70 ml of methanol under argon was added 90 μΐ (0.48 mmol) of a 30% sodium methylate solution in methanol at RT. The mixture was stirred for 35 minutes at 50 ° C bath temperature. It was then diluted with ethyl acetate and the solution was washed once with water. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 905 mg (99% of theory, purity 92%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 10.40 (br.s, 1H), 9.09 (dd, 1H), 8.57 (dd, 1H), 8.04 (dd, 1H), 7.82 (i.e. , 2H), 6.82 (d, 2H), 4.46-4.40 (m, 2H), 3.61 (s, 2H), 2.56-2.45 (covert, 2H), 1.39 (s, 18H).

LC / MS (Method 2, ESIpos): R _t = 1.08 min, m / z = 525 [M + H] ⁺ .

Step 4:

Di-ieri-butyl {2- [4- (cyclopentylmethoxy) phenyl] -2-oxoethyl} [2- (4-oxopyrido [3,2-d] [1,2,3] triazine 3 (4 / /) - yl) efhyl] malonate

To a solution of 250 mg (0.48 mmol) of the compound of Example 12A / Step 3 in 35 mL of acetonitrile was added 132 mg (0.95 mmol) of potassium carbonate and 163 mg (1.00 mmol) of (bromomethyl) cyclopentane. The mixture was stirred at reflux overnight. After cooling to RT, ethyl acetate was added and the mixture was washed with water, saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dried in vacuo. 280 mg (70% of theory, purity 72%) of the title compound were obtained.

LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 607 [M + H] ⁺ .

Exemplary embodiments: Example 1

(+ / -) - 4- [4- (Cyclopropylmethoxy) phenyl] -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine 3 (4 /) -y 1] ethyl} butanoic acid

A solution of 96 mg (0.14 mmol) of the compound from Example 5A in 2 ml of a 4N solution of hydrogen chloride in dioxane and another 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 minutes. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 43 mg (64% of theory, purity 100%) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.49 (s, 1H), 8.46-8.37 (m, 2H), 7.93 (d, 2H), 7.01 (d, 2H), 4.62-4.42 (m, 2H), 3.91 (d, 2H), 3.47-3.38 (m, 1H), 3.27-3.16 (m, 1H), 2.99- 2.87 (m, 1H), 2.29-2.17 (m, 1H), 2.12-1.99 (m, 1H), 1.31-1.17 (m, 1H), 0.63-0.53 (m, 2H), 0.38-0.30 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.15 min, m / z = 490 [M + H] ⁺ .

Example 2

(+/-) - 4- [4- (2-Methoxyethoxy) phenyl] -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - y 1] ethyl} butanoic acid

Eine Lösung von 99 mg (0.14 mmol) der Verbindung aus Beispiel 6A in 2 ml einer 4 N Lösung von Chlorwasserstoff in Dioxan und weiteren 2 ml Dioxan wurde 10 min bei 150°C in der Mikrowelle erhitzt. Anschließend wurde das Gemisch eingeengt und der Rückstand mittels präparativer HLPC gereinigt (Reprosil C18, Eluent: Acetonitril/W asser + 0.2% Trifluoressigsäure). Es wurden 54 mg (75% d. Th., Reinheit 96%) der Titelverbindung erhalten. Ή-NMR (400 MHz, DMSO-d₆): δ [ppm] = 12.29 (br. s, 1H), 8.49 (s, 1H), 8.46-8.37 (m, 2H), 7.94 (d, 2H), 7.04 (d, 2H), 4.61-4.44 (m, 2H), 4.21-4.15 (m, 2H), 3.70-3.65 (m, 2H), 3.48-3.37 (m, 1H), 3.31 (s, 3H), 3.25 (s, 1H), 2.99-2.86 (m, 1H), 2.29-2.15 (m, 1H), 2.14-2.00 (m, 1H).

A solution of 99 mg (0.14 mmol) of the compound from Example 6A in 2 ml of a 4 N solution of hydrogen chloride in dioxane and a further 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). 54 mg (75% of theory, purity 96%) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.29 (br.s, 1H), 8.49 (s, 1H), 8.46-8.37 (m, 2H), 7.94 (d, 2H), 7.04 (d, 2H), 4.61-4.44 (m, 2H), 4.21-4.15 (m, 2H), 3.70-3.65 (m, 2H), 3.48-3.37 (m, 1H), 3.31 (s, 3H), 3.25 (s, 1H), 2.99-2.86 (m, 1H), 2.29-2.15 (m, 1H), 2.14-2.00 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 1.01 min, m / z = 494 [M + H] ⁺ .

Example 3 (+/-) - 4- [4- (2-Hydroxyethoxy) phenyl] -4-oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) - y 1] ethyl} butanoic acid

Eine Lösung von 120 mg (0.16 mmol, Reinheit 97%) der Verbindung aus Beispiel 7A in 2 ml einer 4 N Lösung von Chlorwasserstoff in Dioxan und weiteren 2 ml Dioxan wurde 10 min bei 150°C in der Mikrowelle erhitzt. Anschließend wurde das Gemisch eingeengt und der Rückstand mittels präparativer HLPC gereinigt (Reprosil C18, Eluent: Acetonitril/W asser + 0.2% Trifluoressig- säure). Es wurden 27 mg (35% d. Th., Reinheit 100%) der Titelverbindung erhalten.

A solution of 120 mg (0.16 mmol, purity 97%) of the compound from Example 7A in 2 ml of a 4 N solution of hydrogen chloride in dioxane and a further 2 ml of dioxane was heated in the microwave at 150 ° C. for 10 min. The mixture was then concentrated and the residue was purified by preparative HPLC (Reprosil C18, eluent: acetonitrile / water + 0.2% trifluoroacetic acid). There were obtained 27 mg (35% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.49 (s, 1H), 8.46-8.38 (m, 2H), 7.94 (d, 2H), 7.03 (d, 2H), 4.61- 4.44 (m, 2H), 4.10-4.04 (m, 2H), 3.74 (t, 2H), 3.47-3.37 (m, 1H), 3.27-3.19 (m, 1H), 2.98-2.88 (m, 1H), 2.29-2.17 (m, 1H), 2.13-2.01 (m, 1H).

LC / MS (Method 2, ESIpos): R _t = 0.89 min, m / z = 480 [M + H] ⁺ . Example 4

(+/-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- [4- (pentyloxy-phenyl) butanoic acid

A solution of 431 mg (0.65 mmol) of the compound from Example 8A in 7 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was heated to reflux with stirring for 3 h. After cooling to RT and concentration, 304 mg of a residue were obtained. Of these, 63 mg were taken and stirred with acetonitrile. The resulting solid was filtered off and dried. 25 mg (7% of theory, purity 98%) of a first batch of the title compound were obtained. The remaining residue gave 241 mg (73% of theory, not purity-corrected) of a second crop of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.49 (s, 1H), 8.44-8.39 (m, 2H), 7.93 (d, 2H), 7.01 ( d, 2H), 4.60-4.49 (m, 2H), 4.05 (t, 2H), 3.41 (dd, 1H), 3.22 (dd, 1H), 2.96-2.89 (m, 1H), 2.29-2.18 (m, 1H), 2.11-2.02 (m, 1H), 1.77-1.69 (m, 2H), 1.43-1.30 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.30 min, m / z = 506 [M + H] ⁺ .

Separation of the enantiomers:

241 mg of the compound from Example 4 were heat-dissolved in 14 ml of ethanol / acetonitrile and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 5) and 6) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 0.25 ml; Temperature: 40 ° C; Eluent: t = 0-7.5 min 70% acetonitrile / 30% ethanol + 0.2% acetic acid]:

Example 5 (+) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -yl] ethyl} -4- [4- (pentyloxy) - phenyl] butanoic acid

Yield: 77 mg; ee value = 100%

[from ²⁰ = + 7-4 °, 589 nm, c = 0.29 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, IH), 8.49 (s, IH), 8.44-8.39 (m, 2H), 7.93 (d, 2H), 7.01 ( d, 2H), 4.60-4.49 (m, 2H), 4.05 (t, 2H), 3.41 (dd, IH), 3.22 (dd, IH), 2.96-2.89 (m, IH), 2.29-2.18 (m, IH), 2.11-2.02 (m, IH), 1.77-1.69 (m, 2H), 1.43-1.30 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 506 [M + H] ⁺ .

Example 6

(-) - 4-Oxo-2- {2- [4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4/) -yl] ethyl} -4- [4- (pentyloxy) ) - phenyl] butanoic acid

Yield: 80 mg; ee value = 96%

[a] _D ²⁰ = -8.4 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, IH), 8.49 (s, IH), 8.44-8.39 (m, 2H), 7.93 (d, 2H), 7.01 ( d, 2H), 4.60-4.49 (m, 2H), 4.05 (t, 2H), 3.41 (dd, IH), 3.22 (dd, IH), 2.96-2.89 (m, IH), 2.29-2.18 (m, IH), 2.11-2.02 (m, IH), 1.77-1.69 (m, 2H), 1.43-1.30 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 1, ESIpos): R _t = 1.27 min, m / z = 506 [M + H] ⁺ .

Example 7

(+/-) - 4- [4- (cyclopentylmethoxy) phenyl] -2- [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] - 4-oxobutanoic acid

A solution of 179 mg (0.29 mmol) of the compound from Example 9A in 3 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (Method 7). The clean product fractions were combined and evaporated to a small residual volume of aqueous phase. The resulting solid was filtered off, washed three times with water and twice with pentane and dried in vacuo. 108 mg (80% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.14 (d, 1H), 8.01 (s, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.02 (d, 2H), 4.56-4.39 (m, 2H), 3.94 (d, 2H), 3.46-3.36 (m, 1H), 3.26-3.17 (m, 1H), 2.95-2.85 (m, 1H), 2.57 (s, 3H), 2.38-2.25 (m, 1H), 2.25-2.13 (m, 1H), 2.09-1.98 (m, 1H), 1.83-1.72 (m, 2H), 1.67-1.48 ( m, 4H), 1.39-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 464 [M + H] ⁺ .

Separation of the enantiomers:

88 mg of the compound from Example 7 were dissolved in 12 ml of isopropanol / isohexane / acetonitrile and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 8 and 9) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 20 ml / min; Detection: 210 nm; Injection volume: 1.75 ml; Temperature: 40 ° C; Eluent: t = 0-12.5 min 50% isohexane / 50% isopropanol + 0.2% trifluoroacetic acid]: Example 8

(-) - 4- [4- (Cyclopentylmethoxy) phenyl] -2- [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- oxobutanoic

Yield: 33 mg; ee value = 100%

[α] _D ²⁰ = -7.4 °, 589 nm, c = 0.31 g / 100 ml, DMSO Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.14 (i.e. , 1H), 8.01 (s, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.02 (d, 2H), 4.56-4.40 (m, 2H), 3.94 (d, 2H), 3.46- 3.37 (m, 1H), 3.22 (dd, 1H), 2.95- 2.85 (m, 1H), 2.57 (s, 3H), 2.39-2.26 (m, 1H), 2.25-2.13 (m, 1H), 2.09-1.96 (m, 1H), 1.83-1.71 (m, 2H), 1.67-1.48 (m, 4H), 1.40-1.27 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 464 [M + H] ⁺ .

Example 9 (+) - 4- [4- (Cyclopentylmethoxy) phenyl] -2- [2- (7-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4- oxobutanoic

Yield: 34 mg; ee value = 87%

[a] _D ²⁰ = + 5.6 °, 589 nm, c = 0.31 g / 100 ml, DMSO

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (s, 1H), 8.14 (d, 1H), 8.01 (s, 1H), 7.93 (d, 2H), 7.76 (dd, 1H), 7.02 (d, 2H), 4.56-4.40 (m, 2H), 3.94 (d, 2H), 3.46-3.37 (m, 1H), 3.22 (dd, 1H), 2.95-2.85 (m, 1H) , 2.57 (s, 3H), 2.38-2.26 (m, 1H), 2.26-2.13 (m, 1H), 2.09-1.98 (m, 1H), 1.83-1.72 (m, 2H), 1.68-1.47 (m, 4H), 1.39-1.28 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.26 min, m / z = 464 [M + H] ⁺ .

Example 10 (+/-) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (pentyloxy) phenyl] butanoic acid

A solution of 454 mg (0.75 mmol) of the compound of Example 10A in 8 ml of a 4N solution of hydrogen chloride in dioxane was stirred at RT overnight. The mixture was then stirred under reflux for 3.5 h. After cooling to RT, the mixture was concentrated and the residue was treated with dioxane. After re-concentration, 343 mg of a residue was obtained. Of these, 50 mg were removed and stirred with 1 ml of acetonitrile and a few drops of methanol. The resulting solid was filtered off and dried. 48 mg (14% of theory, purity 97%) of a first batch of the title compound were obtained. The remaining residue gave 293 mg (75% of theory, purity 86%) of a second crop of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.14 (d, IH), 8.01 (s, IH), 7.93 (d, 2H), 7.76 (s, IH), 7.02 (d, 2H), 4.55-4.42 (m, 2H), 4.05 (t, 2H), 3.41 (dd, IH), 3.21 (dd, IH), 2.94-2.87 (m, IH), 2.57 (s, 3H), 2.22 -2.15 (m, IH), 2.08-1.99 (m, IH), 1.77-1.70 (m, 2H), 1.44-1.32 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.20 min; m / z = 452 [M + H] ⁺ . Separation of the enantiomers:

 293 mg of the compound from Example 10 were dissolved in 50 ml of acetonitrile / methanol / dioxane and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 11 and 12) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 25 ml / min; Detection: 210 nm; Injection volume: 3 ml; Temperature: 40 ° C; Eluent: t = 0-9.3 min 70% acetonitrile / 30% methanol + 0.2% acetic acid]:

Example 11

(+) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (pentyloxy) phenyl ] - butanoic acid

Yield: 122 mg; ee value = 100% [a] _D ²⁰ = + 30.8 °, 589 nm, c = 0.41 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 8.14 (d, IH), 8.01 (s, IH), 7.93 (d, 2H), 7.76 (s, IH), 7.02 (d, 2H ), 4.55-4.42 (m, 2H), 4.05 (t, 2H), 3.41 (dd, IH), 3.21 (dd, IH), 2.94-2.87 (m, IH), 2.57 (s, 3H), 2.22- 2.15 (m, IH), 2.08-1.99 (m, IH), 1.77-1.70 (m, 2H), 1.44-1.32 (m, 4H), 0.90 (t, 3H).

LC / MS (Method 2, ESIpos): R _t = 1.20 min; m / z = 452 [M + H] ⁺ . Example 12

(-) - 2- [2- (7-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) ethyl] -4-oxo-4- [4- (pentyloxy) phenyl ] - butanoic acid

Yield: 117 mg; ee value = 99.6%

[a] _D ²⁰ = -30.4 °, 589 nm, c = 0.36 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.14 (d, IH), 8.01 (s , IH), 7.93 (d, 2H), 7.76 (s, IH), 7.02 (d, 2H), 4.55-4.42 (m, 2H), 4.05 (t, 2H), 3.41 (dd, IH), 3.21 ( dd, IH), 2.94-2.87 (m, IH), 2.57 (s, 3H), 2.22-2.15 (m, IH), 2.08-1.99 (m, IH), 1.77-1.70 (m, 2H), 1.44- 1.32 (m, 4H), 0.90 (t, 3H). LC / MS (Method 2, ESIpos): R _t = 1.23 min, m / z = 452 [M + H] ⁺ . Example 13

(+/-) - 4- [4- (Cyclopentylmethoxy) phenyl] -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -1,3,3-benzotriazine 3 (4 /) -y 1] ethyl} butanoic acid

A solution of 466 mg (0.69 mmol) of the compound from Example 11A in 7.5 ml of a 4 N solution of hydrogen chloride in dioxane was stirred at RT overnight. Subsequently, the mixture was stirred under reflux for 3 h. After cooling to RT and concentration, the residue was dried in vacuo. 370 mg (> 100% of theory, still containing solvent) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.49 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.91 (d, 2H), 6.91 (d, 2H) , 4.66 (t, 2H), 3.89 (d, 2H), 3.54-3.43 (m, 1H), 3.28-3.15 (m, 2H), 2.49-2.30 (m, 2H), 2.28-2.16 (m, 1H) , 1.90-1.78 (m, 2H), 1.69-1.53 (m, 4H), 1.42-1.29 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.32 min, m / z = 518 [M + H] ⁺ . Separation of the enantiomers:

 350 mg of the compound from Example 13 were dissolved in 30 ml of acetonitrile / methanol and separated by preparative HPLC on a chiral phase into the enantiomers (see Examples 14 and 15) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 230 nm; Injection volume: 0.08 ml; Temperature: 25 ° C; Eluent: t = 0-15 min 80% acetonitrile + 0.2% acetic acid / 20% methanol + 0.2% acetic acid]:

Example 14

(+) - 4- [4- (cyclopentylmethoxy) phenyl] -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -y 1] ethyl} butanoic acid

The product-containing batch obtained after separation of the enantiomers was purified by preparative HPLC (Method 9). 56 mg of the title compound were obtained (ee value = 100%). [a] _D ²⁰ = + 31.5 °, 589 nm, c = 0.34 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.91 (d, 2H), 6.90 (d, 2H) , 4.66 (t, 2H), 3.89 (d, 2H), 3.55-3.43 (m, 1H), 3.26-3.12 (m, 2H), 2.48-2.30 (m, 2H), 2.27- 2.15 (m, 1H) , 1.90-1.78 (m, 2H), 1.70-1.52 (m, 4H), 1.42-1.29 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.30 min, m / z = 518 [M + H] ⁺ .

Example 15

(-) - 4- [4- (Cyclopentylmethoxy) phenyl] -4-oxo-2- {2- [4-oxo-7- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) -y 1] ethyl} butanoic acid

The product-containing batch obtained after separation of the enantiomers was purified by preparative HPLC (Method 9). There was obtained 60 mg of the title compound (ee value = 91%).

[a] _D ²⁰ = -27.4 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.48 (d, 1H), 8.44 (s, 1H), 8.00 (d, 1H), 7.91 (d, 2H), 6.90 (d, 2H) , 4.66 (t, 2H), 3.89 (d, 2H), 3.55-3.43 (m, 1H), 3.26-3.14 (m, 2H), 2.48-2.30 (m, 2H), 2.27-2.15 (m, 1H) , 1.91-1.79 (m, 2H), 1.70-1.52 (m, 4H), 1.42-1.29 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.30 min, m / z = 518 [M + H] ⁺ .

Example 16

(+/-) - 4- [4- (Cyclopentylmethoxy) phenyl] -4-oxo-2- [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 / ) -yl) ethyl] butanoic acid

A solution of 696 mg (1.15 mmol) of the compound from Example 12A in 2 ml of dichloromethane was admixed with 2 ml of trifluoroacetic acid and stirred at RT for 5 h. The mixture was then concentrated, the residue was dissolved in 5 ml of dioxane and the solution was stirred under reflux for 4 h. After cooling to RT and concentration, the residue was purified by preparative HPLC (eluent: acetonitrile / water gradient). 311 mg (55% of theory, purity 100%) of the title received connection.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 12.30 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.94 (i.e. , 2H), 7.03 (d, 2H), 4.62-4.45 (m, 2H), 3.94 (d, 2H), 3.47-3.38 (m, IH), 3.27-3.19 (m, IH), 2.98-2.88 (m , IH), 2.38-2.27 (m, IH), 2.27-2.17 (m, IH), 2.12-2.00 (m, IH), 1.84-1.72 (m, 2H), 1.68-1.47 (m, 4H), 1.40 -1.28 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 451 [M + H] ⁺ .

Separation of the enantiomers:

 311 mg of the compound from Example 16 were dissolved in 20 ml of acetonitrile / methanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 17 and 18) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm ; Flow: 20 ml / min; Detection: 270 nm; Injection volume: 0.45 ml; Temperature: 25 ° C; Eluent: t = 0-5.88 min. 50% acetonitrile + 0.2% acetic acid / 50% methanol + 0.2% acetic acid]:

Example 17

(+) - 4- [4- (Cyclopentylmethoxy) phenyl] -4-oxo-2- [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) - yl) ethyl] butanoic acid

Yield: 112 mg; ee value = 100%

[from ²⁰ = + 59.0 °, 589 nm, c = 0.30 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.27 (br.s, IH), 9.13 (dd, IH), 8.63 (dd, IH), 8.08 (dd, IH), 7.94 ( d, 2H), 7.02 (d, 2H), 4.61-4.45 (m, 2H), 3.94 (d, 2H), 3.47-3.37 (m, IH), 3.27-3.18 (m, IH), 2.98-2.88 ( m, IH), 2.38-2.27 (m, IH), 2.27-2.16 (m, IH), 2.12-2.00 (m, IH), 1.84-1.70 (m, 2H), 1.67-1.49 (m, 4H), 1.38-1.28 (m, 2H).

LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 451 [M + H] ⁺ .

Example 18

(-) - 4- [4- (Cyclopentylmethoxy) phenyl] -4-oxo-2- [2- (4-oxopyrido [3,2-d] [1,2,3] triazine-3 (4 /) - yl) ethyl] butanoic acid

Yield: 118 mg; ee value = 100%

[a] _D ²⁰ = -21.0 °, 589 nm, c = 0.51 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.30 (br.s, 1H), 9.13 (dd, 1H), 8.63 (dd, 1H), 8.08 (dd, 1H), 7.94 ( d, 2H), 7.02 (d, 2H), 4.62-4.43 (m, 2H), 3.94 (d, 2H), 3.47-3.37 (m, 1H), 3.27-3.18 (m, 1H), 2.98-2.88 ( m, 1H), 2.38-2.27 (m, 1H), 2.27-2.17 (m, 1H), 2.12-2.00 (m, 1H), 1.83-1.72 (m, 2H), 1.67-1.48 (m, 4H), 1.39-1.28 (m, 2H). LC / MS (Method 2, ESIpos): R _t = 1.07 min, m / z = 451 [M + H] ⁺ .

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated by in vitro and in vivo studies, as are known to the person skilled in the art. The following application examples describe the biological activity of the compounds according to the invention without restricting the invention to these examples.

Abbreviations and acronyms:

APMA 4-aminophenyl mercuric acetate

Brij®- ³⁵ polyoxyethylene lauryl ether

 BSA bovine serum albumin

 CYP cytochrome P450

 Dap (or Dpa) L-2,3-diaminopropionic acid (β-amino-L-alanine)

 DMSO dimethyl sulfoxide

 Dnp 2,4-dinitrophenyl

 EDTA ethylenediaminetetraacetic acid

 HEPES 2- [4- (2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid

 HME human macrophage elastase

 IC inhibitory concentration

 Mca (7 -methoxycumarin-4-yl) acetyl

 MMP matrix metallopeptidase

 MTP microtiter plate

NADP ⁺ nicotinamide adenine dinucleotide phosphate (oxidized form)

 NADPH nicotinic acid amide adenine dinucleotide phosphate (reduced form)

Nval Norvaline

 PEG polyethylene glycol

 Tris tris (hydroxymethyl) aminomethane

v / v volume to volume ratio (of a solution)

w / w weight to weight ratio (of a solution)

B-l. In vitro HME inhibition test

The potency of the compounds of the invention compared to HME (MMP-12) is determined in a in vi tro-inhibited st. The HME-mediated amidolytic cleavage of a suitable peptide substrate results here in a fluorescence light increase. The signal intensity of the fluorescent light is directly proportional to the enzyme activity. The effective concentration of a test compound, at Half of the enzyme is inhibited (50% signal intensity of the fluorescent light) is given as IC ₅ o value.

Standard in vitro HME inhibition test:

In a 384 well microtiter plate are used in a test volume of 41 μΐ of test buffer (0.1 M HEPES pH 7.4, 0.15M NaCl, 0.03M CaCl, 0.004 mM ZnCk, 0.02M EDTA, 0.005% Brij ^®), the enzyme ( 0.5 nM HME, R & D Systems, 917-MP, autocatalytic activation according to the manufacturer's instructions) and the intramolecularly quenched substrate [5 μM Mca-Pro-Leu-Gly-Leu-Glu-Glu-Ala-Dap (Dnp) -NH ₂ ; Bachem, M-2670] in the presence and absence of the test substance (as a solution in DMSO) for two hours at 37 ° C incubated. The fluorescent light intensity of the test mixtures is measured (excitation 323 nm, emission 393 nm). The IC 50 values are determined by plotting the fluorescent light intensity versus the drug concentration.

Highly sensitive in vitro HME inhibition test:

 If subnanomolar IC values are obtained in the case of highly potent test substances in the standard HME inhibition test described above, a modified test is used for their more precise determination. In this case, a ten-fold lower enzyme concentration is used (final concentration, for example, 0.05 nM) in order to achieve an increased sensitivity of the test. The incubation time of the test is chosen to be longer (e.g., 16 hours).

In vitro HME inhibition test in the presence of serum albumin in the reaction buffer:

This test corresponds to the standard HME inhibition test described above, but using a modified reaction buffer. This reaction buffer additionally contains bovine serum albumin (BSA, fatty acid free, A6003, Sigma-Aldrich) of a final concentration of 2% (w / w), which corresponds approximately to half of the physiological serum albumin content. The enzyme concentration in this modified assay is slightly elevated (e.g., 0.75 nM), as is the incubation time (e.g., three hours).

Table 1 below shows for individual embodiments of the invention the IC 50 values from the standard or highly sensitive HME inhibition test (in part as averages of several independent individual determinations and rounded to two significant digits): Table 1: Inhibition of human macrophage elastase (HME / hMMP-12)

B-2. In vitro MMP inhibition tests

The potency of the compounds of the invention over other MMPs (and thus its selectivity) is also determined in vz ^'iro inhibition assays. The MMP-mediated amidolytic cleavage of a suitable peptide substrate also leads here to a fluorescence light increase. The signal intensity of the fluorescent light is directly proportional to the enzyme activity. The effective concentration of a test compound in which half of the enzyme is inhibited (50% signal intensity of the fluorescent light) is given as IC 50 value. a) Human MMPs:

In vitro MMP-1 inhibition test:

Recombinant MMP-1 (R & D Systems, 901-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-1 reaction tion is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-2 inhibition test:

Recombinant MMP-2 (R & D Systems, 902-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-3 inhibition test:

Recombinant MMP-3 (R & D Systems, 513-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by adding the intramolecularly quenched substrate McA-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-002 ) so that a total test volume of 50 μΐ results. The course of the MMP-3 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-7 inhibition test:

Recombinant MMP-7 (R & D Systems, 907-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-7 Reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-8 inhibition test:

Recombinant MMP-8 (R & D Systems, 908-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-9 inhibition test:

Recombinant MMP-9 (R & D Systems, 911-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-10 inhibition test:

Recombinant MMP-10 (R & D Systems, 910-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is achieved by addition of the intramolecularly quenched substrate McA. Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-002) is started, resulting in a total test volume of 50 μΐ. The course of the MMP-10 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over a period of 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-13 inhibition test:

Recombinant MMP-13 (R & D Systems, 511-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-13 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.).

In vitro ΜΜΡ-14 inhibition test:

Recombinant MMP-14 (R & D Systems, 918-MP) is enzymatically activated according to the manufacturer's instructions by using recombinant furin (R & D Systems, 1503-SE). To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010). so that a total test volume of 50 μΐ results. The course of the MMP-14 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro ΜΜΡ-16 inhibition test:

Recombinant MMP-16 (R & D Systems, 1785-MP) is enzymatically activated according to the manufacturer's instructions by using recombinant furin (R & D Systems, 1503-SE). To 24 μΐ activated enzyme (final concentration eg 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the test to be examined Compound (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-16 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In the following Tables 2A and 2B representative representative embodiments of the invention show the IC 50 values from these tests for the inhibition of human MMPs (in part as mean values from several independent individual determinations and rounded to two significant digits):

Table 2A: Inhibition of human MMPs

Example MMP-1 MMP-2 MMP-3 MMP-7 MMP-8

 Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

 1> 40000 4700 17000 5500 85

 2> 40000 1200 5300 20000 9

 3 13000 12000> 40000> 40000 100

 5> 40000 2700 3100 5700 120

 7> 30000 2100 3900> 30000 71

 9> 30000 1600 2200> 30000 53

 11> 30000 5200 4000> 30000 200

Table 2B: Inhibition of human MMPs

Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16

 Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

 1 2600 2200 5600 4500 8000

 2 700 810 1100 2400 3900

 3 2100 4000 8900 13000 13000

 5 750 2800 3600 9500 19000

7 280 650 330 3200 1600 Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16

 Nos. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

 9 280 310 200 2200 920

 11 480 300 1200> 30000 16000

Comparing the inhibition data presented in Tables 1 and 2A / 2B shows that the compounds according to the invention in general and their more active enantiomers in particular have a very high inhibitory potency (frequently in the sub-nanomolar range) over HME and at the same time a very high selectivity ( usually two to four orders of magnitude or more) relative to related human MMPs. b) MMPs of rodents:

In vitro MMP-2 inhibition test of the mouse:

Recombinant mouse MMP-2 (R & D Systems, 924-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) that a total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro MMP-3 inhibition test of the mouse:

Recombinant mouse MMP-3 (R & D Systems, 548-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by addition of the intramolecularly quenched substrate Mca-Arg-Pro-Lys-Pro-Val-Glu-Nval-Trp-Arg-Lys (Dnp) -NH2 (final concentration eg 5 μΜ; R & D Systems, ES-002) so that a total test volume of 50 μΐ results. The course of the MMP-3 reaction is determined by measuring the fluorescence intensity (excitation 320 nm, Emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C).

In vitro MMP-7 inhibition test of the mouse:

Recombinant mouse MMP-7 (R & D Systems, 2967-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.5 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-7 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro MMP-8 inhibition test of the mouse:

Recombinant mouse MMP-8 (R & D Systems, 2904-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

In vitro MMP-9 inhibition test of the mouse:

Recombinant mouse MMP-9 (R & D Systems, 909-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is carried out by addition of the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-001), resulting in a total test volume of 50 μΐ. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro ΜΜΡ-12 inhibition test of the mouse:

Recombinant mouse MMP-12 (R & D Systems, 3467-MP) is autocatalytically activated according to the manufacturer's instructions. To 24 μΐ activated enzyme (final concentration eg 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-010) that a total test volume of 50 μΐ results. The course of the MMP-12 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

Highly sensitive in vitro MMP-12 inhibition test of the mouse:

 If subnanomolar IC values are obtained in the case of highly potent test substances in the mouse MMP-12 inhibition test described above, a modified test is used for more precise determination. In this case, a tenfold lower enzyme concentration is used (final concentration, for example, 0.1 nM) in order to achieve an increased sensitivity of the test. The incubation time of the test is chosen to be longer (e.g., 16 hours).

Rat in vitro MMP-2 inhibition test:

Recombinant rat MMP-2 (R & D Systems, 924-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 10 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-2 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). Rat in vitro MMP-8 inhibition test:

Recombinant rat MMP-8 (R & D Systems, 3245-MP) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCh, 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO , suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecularly quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-010) a total test volume of 50 μΐ results. The course of the MMP-8 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

Rat in vitro MMP-9 inhibition test:

Recombinant mouse MMP-9 (R & D Systems, 5427-MM) is chemically activated according to the manufacturer's instructions by using APMA. To 24 μΐ activated enzyme (final concentration eg 0.1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (as a solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by adding the intramolecularly quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH ₂ (final concentration eg 5 μΜ; R & D Systems, ES-001) Total test volume of 50 μΐ results. The course of the MMP-9 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (eg over 120 minutes at a temperature of 32 ° C.). In vitro ΜΜΡ-12 inhibition test of the rat:

Rat MMP-12 (Uniprot NP_446415.1; construct L96-V277) is expressed with an additional N-terminal His tag and a TEV consecutive cleavage sequence using a pDEco7 vector in E. coli (BL21). The recombinantly expressed protein forms an intracellular insoluble protein complex (so-called inclusion body). This is solubilized after separation and intensive washing under denaturing conditions. For this purpose, the inclusion body pellet fraction from a 250 ml E. coli culture in a volume of 120 ml buffer A (50 mM Tris pH 7.4, 100 mM NaCl, 0.03 mM ZnCh, 10 mM CaCh, 8 M urea). The soluble protein is renatured by dialysing each 60 ml of the sample several times at 4-8 ° C against buffer B (50 mM Tris pH 7.4, 100 mM NaCl, 0.03 mM ZnCl ₂ , 10 mM CaCl ₂ ). After dialysis the sample is centrifuged (25,000 xg). The refolded protein is in the supernatant with a yield of 3.7 mg per 250 ml-E. coli culture. The protein thus obtained is enzymatically active without further purification operations or protease-mediated cleavage processes.

To 24 μΐ MMP-12 protein (final concentration, for example 1 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl _2, 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the examined test compound ( as solution in DMSO, suitable concentrations eg 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP) pipetted. The enzymatic reaction is started by addition of the intramolecular quenched substrate Mca-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ; R & D Systems, ES-001), giving a total assay volume of 50 μΐ results. The course of the MMP-12 reaction is measured by measuring the fluorescence intensity (excitation 320 nm, emission 410 nm) over a suitable period of time (for example over 120 minutes at a temperature of 32 ° C.).

Table 3 below shows representative IC ₅₀ values from mouse MMP inhibition assays (in part as averages of several independent determinations and rounded to two significant digits) for representative embodiments of the invention:

Table 3: Inhibition of mouse MMPs

The compounds according to the invention thus have a high inhibitory potency against mouse MMP-12 and at the same time a high selectivity (usually one to three orders of magnitude) over related murine MMPs.

B-3. Animal model of pulmonary emphysema

Elastase-induced pulmonary emphysema in mouse, rat or hamster is a widely used animal model of pulmonary emphysema [The Fas / Fas-ligand pathway does not mediate the apoptosis in elastase-induced emphysema in mice, Sawada et al., Exp. Lung Res. 33, 277-288 (2007)]. The animals receive orotracheal instillation of porcine pancreatic elastase. The treatment of the animals with the test substance begins on the day of instillation of the porcine pancreatic elastase and extends over a period of 3 weeks. At the end of the study, lung compliance is determined and alveolar morphometry performed.

B-4. Animal model of silica-induced lung inflammation Orotracheal administration of silica to mouse, rat or hamster causes lung inflammation [Involvement of leukotrienes in the pathogenesis of silica-induced pulmonary fibrosis in mice, Shimbori et al., Exp. Lung Res. 36, 292-301 (2010)]. The animals are treated with the test substance on the day of the instillation of the silica. After 24 hours bronchioalveolar lavage is performed to determine cell content and biomarkers. B-fifth Animal model of silica-induced pulmonary fibrosis

Mouse, rat, or hamster-induced lung induced fibrosis is a widely used animal model of pulmonary fibrosis in mice, Shimbori et al., Exp. Lung Res. 36, 292-301 (2010) )]. The animals receive an orotracheal instillation of silica. The treatment of the animals with the test substance starts on the day of the instillation of the silica or therapeutically one week later and extends over a period of 6 weeks. At the end of the study, a bronchioalveolar lavage is performed to determine cell content and biomarkers, and a histological assessment of pulmonary fibrosis is performed.

B-sixth Animal model of ATP-induced pulmonary inflammation Intratracheal administration of ATP (adenosine triphosphate) to the mouse leads to lung inflammation [ATP via the P2Y receptors: an experimental study, Matsuyama et al ., Respir. Res. 9:79 (2008)]. The animals are treated with the test substance for 24 h on the day of instillation of ATP (by gavage, by addition in feed or drinking water, by osmotic minipump, by subcutaneous or intraperitoneal injection or by inhalation). At the end of the experiment a bronchio-alveolar lavage is performed to determine the cell content and the pro-inflammatory markers.

B. 7 CYP Inhibition Assay

The ability of substances to inhibit the CYP enzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in humans is investigated using pooled human liver microsomes as the enzyme source in the presence of standard substrates (see below) that form CYP-specific metabolites. The inhibition effects are observed at six different concentrations of the test compounds. [2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μΜ], was compared with the extent of CYP-specific metabolite formation of the standard substrates in the absence of the test compounds and the corresponding IC 50 values were calculated. A standard inhibitor that specifically inhibits a single CYP isoform is always incubated to make results comparable between different series.

Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan or midazolam with human liver microsomes in the presence of six different concentrations of each test compound (as a potential inhibitor) is performed on a workstation (Tecan, Genesis, Crailsheim, Germany). Standard incubation mixtures contain 1.3 mM NADP ⁺ , 3.3 mM MgCl ₂ × 6 H ₂ O, 3.3 mM glucose-6-phosphate, glucose 6-phosphate dehydrogenase (0.4 U / ml) and 100 mM phosphate buffer (pH 7.4). in a total volume of 200 μΐ. Test compounds are preferably dissolved in acetonitrile. 96-well plates are incubated for a defined time at 37 ° C with pooled human liver microsomes. The reactions are stopped by addition of 100 μL acetonitrile, which is a suitable internal standard. Precipitated proteins are separated by centrifugation, the supernatants are pooled and analyzed by LC-MS / MS.

B-eighth Hepatocyte assay for determination of metabolic stability

The metabolic stability of test compounds to hepatocytes is determined by incubating the compounds at low concentrations (preferably below or around 1 μΜ) and at low cell counts (preferably at 1 × 10 ⁶ cells / ml) in order to obtain linear kinetic conditions in the Try to make sure. Seven samples from the incubation solution are taken at a fixed time interval for LC-MS analysis to determine the half-life (ie, degradation) of each compound. From this half-life different "clearance" parameters (CL) and "Fmax" values are calculated (see below). The CL and Fmax values are a measure of the phase I and phase 2 metabolism of the compounds in the hepatocytes. In order to minimize the influence of the organic solvent on the enzymes in the incubation approaches, its concentration generally becomes apparent 1% (acetonitrile) or 0.1% (DMSO) limited.

For all species and breeds, a hepatocyte cell count in the liver of 1.1 * 10 ⁸ cells / g liver is expected. CL parameters based on half-lives much longer than the incubation period (typically 90 minutes) can only be considered as rough guidelines.

The calculated parameters and their meaning are: I max well-stirred [] maximum bioavailability after oral administration

Calculation: (1-C iood well-stirred / QH) * 100

 CLbiood well-stirred [L / (h * kg)] calculated blood clearance (well-stirred model)

 Calculation: (QH * CL'intrinsic) / (QH + CL'intrinsic)

 CL'intrinsic [ml / (min * kg)] maximum ability of liver (hepatocytes) to metabolize a compound (assuming that liver blood flow is not rate limiting)

 Calculation: CL'intnnsic, apparent * species-specific hepatocyte count [1.1 * IC g liver] * species-specific liver weight [g / kg]

CL'intrinsic, apparent [ml / (min * mg)] normalizes the elimination constant by dividing it by the hepatocyte cell number x (x * 10 ⁶ / ml) used. Calculation: k _e i [1 / min] / (cell number [x * 10 ⁶ ] / incubation volume [ml])

(QH = species-specific liver blood flow).

Table 4 below shows, for representative embodiments of the invention, the CL and Fmax values from this assay after incubation of the compounds with rat hepatocytes (partly as averages of several independent individual determinations):

Table 4: Calculated blood clearance and bioavailability after incubation with rat hepatocytes

B. 9 Metabolism investigation

To determine the metabolism profile of the compounds according to the invention, they are incubated with liver microsomes or with primary fresh hepatocytes of various animal species (eg rat, dog) as well as of human origin in order to obtain information on the most complete hepatic phase I and phase II metabolism and on the Obtain and compare enzymes involved in metabolism. The compounds of the invention are incubated at a concentration of about 1-10 μΜ. For this purpose, stock solutions of the compounds are prepared at a concentration of 0.1-1 mM in acetonitrile and then pipetted with a 1: 100 dilution in the incubation mixture. The liver microsomes are incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP ⁺ , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C. Primary hepatocytes are also incubated in suspension in William's E medium at 37 ° C. After an incubation period of 0-4 h, the incubation mixtures are stopped with acetonitrile (final concentration about 30%) and the protein is centrifuged off at about 15,000 × g. The thus stopped samples are either analyzed directly or stored at -20 ° C until analysis.

The analysis is carried out by means of high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this, the supernatants of the incubation samples are chromatographed with suitable C18 reverse phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% aqueous formic acid. The UV chromatograms in combination with the mass spectrometric data serve to identify, structure elucidate and quantitatively estimate the metabolites and to quantitatively determine the metabolic decrease of the compounds according to the invention in the incubation mixtures.

B-tenth Pharmacokinetic studies in vivo The substance to be tested is administered intravenously to rats or mice as a solution (eg in appropriate plasma with a small amount of DMSO or in a PEG / ethanolAmerge mixture), the oral administration is carried out as a solution (eg in Solutol / EthanolAer - or PEG / ethanol / water mixtures) or as a suspension (eg in Tylose) each via a gavage. After substance administration, the animals are bled at fixed times. This is heparinized, then plasma is recovered therefrom by centrifugation. The test substance is analytically quantified in the plasma via LC-MS / MS. From the plasma concentration-time curves determined in this way, the pharmacokinetic parameters are calculated using an internal standard and with the aid of a validated computer program, such as AUC (area under the concentration-time curve), Cmax (maximum plasma concentration), tm (half-life), Vss (distribution volume) and CL (clearance) and the absolute and relative bioavailability F and F _re i (iv / po comparison or comparison of suspension to solution after po administration). C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

 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). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

 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 at 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.

Claims

claims Compound of the formula (I)

in which R ^{1 is} straight-chain (C ₃ -Cs) -alkyl in which a CE group may be replaced by O, for straight-chain hydroxy (C ₁ -C 4) -alkyl or for (C ₃ -C 6) -cycloalkyl which is substituted by hydroxyl may be substituted, and either (a) Y stands for CH and R ^{2 is} a substituent selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl and trifluoromethyl which is bonded in the designated 6- or 7-position, or (b) Y stands for N and R ^{2 is} hydrogen or a substituent selected from methyl and trifluoromethyl bound in the designated 6- or 7-position, as well as their salts, solvates and solvates of the salts. 2. A compound of formula (I) according to claim 1, in which R ^{1 is} n-butyl, hydroxymethyl, methoxymethyl, cyclopropyl or cyclopentyl and either (a) Y stands for CH and R ^{2 is} a substituent selected from methyl and trifluoromethyl which is bonded in the designated 6- or 7-position, or (b) Y is N and R ^{2 is} hydrogen, and their salts, solvates and solvates of the salts. 3. A compound of formula (I) according to claim 1 or 2, in which R ^{1 is} n-butyl or cyclopentyl, Y stands for CH and R ^{2 is} a substituent selected from methyl and trifluoromethyl bound in the designated 6- or 7-position, as well as their salts, solvates and solvates of the salts. 4. A compound according to claim 1, 2 or 3 having the formula (I-A)

in which R ¹ , R ² and Y have the meanings given in claim 1, 2 or 3 and the chiral carbon atom marked with * in enantiomerically pure form has the imaged π-configuration, and also its salts, solvates and solvates of the salts. Process for the preparation of a compound as defined in claims 1 to 4, characterized in that di-ieri-butyl- (2-hydroxyethyl) malonate of the formula (Π)

in the presence of a phenylphosphine and an azodicarboxylate with a triazine-4 (3 //) -one derivative of the formula (ΠΙ)

in which R ² and Y have the meanings given in claims 1 to 4, to give a compound of the formula (IV)

in which R ² and Y have the meanings given in claims 1 to 4, and then reacting the compound of formula (IV) either [A] in the presence of a base with a compound of the formula (V)

(V) in which R ^{1 has} the meaning given in claims 1 to 4 and 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)

in which R ¹ , R ² and Y have the meanings given in claims 1 to 4, alkylated or [B] first with a compound of the formula (VII)

in which PG is a temporary protecting group such as acetyl or benzoyl and is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, in the presence of a base to give a compound of the formula (VIII)

in which PG, R ² and Y have the meanings given above, followed by deprotection of the protective group PG and the resulting compound of the formula (IX)

in which R ² and Y have the meanings given in claims 1 to 4, then in the presence of a base with a compound of formula (X) R ¹ ^^ Z ³ (X), in which R ^{1 has} the meaning given in claims 1 to 4, and Z ^{3 is} a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, to the compound of formula (VI)

in which R ¹ , R ² and Y have the meanings given in claims 1 to 4, alkylated and the thus obtained by method [A] or [B] compound of formula (VI) finally by treatment with an acid and subsequent heating in the carboxylic acid of the formula (I)

in which R ¹ , R ² and Y have the meanings given in claims 1 to 4, and the compounds of the formula (I) are optionally separated into their enantiomers and / or diastereomers and / or optionally with the appropriate (i) solvents and / or (ii) reacting bases to their solvates, salts and / or solvates of the salts. 6. A compound as defined in any one of claims 1 to 4 for the treatment and / or prevention of diseases. A compound as defined in any one of claims 1 to 4 for use in a method for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), Bronchiectasis, asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral vascular disease, as well as chronic kidney disease and Alport syndrome. Use of a compound as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), bronchiectasis , Asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, atherosclerosis, carotid atherosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral vascular disease, as well as chronic renal disease and Alport syndrome. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4 in combination with one or more inert non-toxic pharmaceutically acceptable excipients. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4 in combination with one or more other active ingredients selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarinergic substances, PDE 4 inhibitors, PDE 5 Inhibitors, sGC activators, sGC stimulators, HNE inhibitors, prostacyclin analogs, endothelin antagonists, statins, antifibrotic agents, antiinflammatory agents, immunomodulating agents, immunosuppressive agents and cytotoxic agents. A pharmaceutical composition according to claim 9 or 10 for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), bronchiectasis, asthma, interstitial lung disease, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, atherosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral vascular disease, as well as chronic kidney disease and Alport syndrome. Method for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD), pulmonary emphysema, chronic bronchitis, pulmonary hypertension in COPD (PH-COPD), bronchiectasis, asthma, interstitial lung diseases, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, of arteriosclerosis, carotid Atherosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their sequelae such as stroke, myocardial infarction and peripheral arterial disease, as well as chronic kidney disease and Alport syndrome in humans and animals by administering an effective amount of at least one compound as in any of claims 1 to 4, or a pharmaceutical composition as defined in any one of claims 9 to 11.