EP3126358A1

EP3126358A1 - 2,5-disubstituted cyclopentane carboxylic acids for the treatment of respiratoy tract diseases

Info

Publication number: EP3126358A1
Application number: EP15712926.3A
Authority: EP
Inventors: Hartmut Beck; Volkhart Min-Jian Li; Yolanda Cancho Grande; Andreas Timmermann; Dirk Brohm; Hannah JÖRIßEN; Pamela BOGNER; Michael Gerisch; Dieter Lang
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2014-04-03
Filing date: 2015-03-31
Publication date: 2017-02-08
Also published as: CN106661008A; CA2944614A1; US20170114049A1; WO2015150350A1; JP2017509665A

Abstract

The invention relates to novel 2,5-disubstituted cyclopentane carboxylic 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

2,5-DISUBSTITUTED CYCLOPENTANCARBOXYLIC ACIDS FOR THE TREATMENT OF

RESPIRATORY DISEASES

The present application relates to novel 2,5-disubstituted cyclopentanecarboxylic 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 preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of respiratory, pulmonary and cardiovascular diseases.

Human macrophage elastase (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 may be present in some cases in high concentrations in inflammatory processes. The highly active enzyme is capable of degrading a variety of connective tissue proteins, e.g. primarily the protein elastin (hence the name), as well as other proteins and proteoglycans such as collagen, fibronectin, laminin, chondroitin sulfate, heparan sulfate and others. This proteolytic activity of the enzyme enables macrophages to penetrate the basal membrane. Elastin, for example, occurs in high concentrations in all tissue types that exhibit high elasticity, e.g. in the lungs and arteries. 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-ß) mediated signaling pathway [Hydrolysis of a 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 emergence and / or progression with 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 Opin. 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 atherosclerosis, 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 cancer processes are the invasion of cancer cells into the healthy tissue (metastasis) and the reformation 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, ulcerative colitis , UC). In general, it is believed that elastase-mediated pathological processes underlie a shifted balance between free elastase (HME) and the body's own elastase inhibitor protein (tissue inhibitor of metalloproteinase, ΤΓΜΡ). 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 HNE inhibitor and, conversely, HNE cleaves and inactivates the HME inhibitor, thereby additionally shifting the respective protease / anti-protease imbalances. In addition, in the environment of local inflammation, oxidative bursts prevail, further enhancing 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 after cleavage of this pro-peptide domain is the zinc in the active center of the enzyme freed from this coordination and the enzyme thereby activated (so-called activation by cysteine switch) [matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases, Hu et al ., Nature Rev. Drug Discov. 6, 480-498 (2007)]. 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, BG Rao , Curr. Pharm. Des. 11, 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 terms, a great influence on which targets and which undesired 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 be carried out 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. At a closer Look here, too, the previously described as selective inhibitors have been found to be not so 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, a marked inhibition of MMP-2 and MMP-13 is cited [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 decreased affinity for the mouse orthologous MMP-12 target: IC ₅₀ 2 nM (human MMP-12), IC ₅₀ 160 nM (murine MMP-12), IC ₅₀ 320 nm (MMP-12 of the Rat) [see above Li et al., 2009; Mukhopadhyay et al., 2010]. 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 various animal species].

In addition to the selectivity profile across species boundaries, the potency at the target MMP-12 itself is very important. With a comparably 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 is particularly true with the inclusion of the so-called "free fraction" (fraction unbound, f _u ) of a compound which can interact with the desired target or unwanted anti and off targets (the "free fraction" is defined as the available amount of one A compound that is not bound to components of the blood plasma, which are mainly blood protein components such as eg albumin). In addition to the MMP selectivity, the 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 over 45's 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 / antiprotease balance is shifted locally in favor of the proteases, which leads inter alia to an uncontrolled elastase activity and, as a consequence thereof, to an excessive degradation of the elastin of the alveolar bodies. This tissue breakdown causes a collapse of the bronchi. This goes hand in hand with a reduction in dermal elasticity of the lung, resulting in obstruction 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 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 further inflammatory kidney disease [JNK signaling in human and experimental renal ischemia / reperfusion injury, Kanellis et al., Nephrol. Dial. Transplant. 25, 2898-2908 (2010); Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis, Kaneko et al., J. Immun. 170, 3377-3385 (2003); Role for macrophage metallo elastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome, Rao et al., Am. J. Pathol. 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 to identify and provide new substances which act as potent, selective and specific inhibitors of human macrophage elastase (HME / MMP-12) and as such for the treatment and / or prevention of, in particular, respiratory diseases, the Lungs and the cardiovascular system are suitable. 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, in particular an inadequate inhibitory potency for MMP-12, an insufficient selectivity for MMP-12 compared to others MMPs and / 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 Inhibitors of protein tyrosine phosphatase 1B (PTP-1B) are described for the treatment of diabetes, cancers and neurodegenerative diseases.

It has now surprisingly been found that certain 2,5-disubstituted cyclopentanecarboxylic acid derivatives have a significantly improved profile with regard to their potency and selectivity with respect to the human macrophage elastase (HME / hMMP-12) in comparison to those of the prior art Technology known compounds. In addition, the compounds of the invention show good solubility in aqueous systems and low non-specific binding to blood plasma components such as albumin. The compounds of the invention also have low in vivo clearance and good metabolic stability. This property profile as a whole makes it possible for the compounds according to the invention to have low dosability and, as a consequence of the more targeted mode of action, a reduced risk of the occurrence of undesired side effects in the therapy.

The compounds of the present invention are also 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 which

A is -O- or -S-, n is the number 1 or 2 and

R ^{1 is} hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, and their salts, solvates and solvates of the salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include, in particular, the salts derived from customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, / V, / V-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, dimethylaminoethanol, diethylaminoethanol, choline, procaine, dicyclohexylamine, dibenzylamine, / V-methylmor - pholine, / V-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.

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 that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

The term "enantiomerically pure" in the context of the present invention is understood to mean that the compound in question in terms of the absolute configuration of the chiral centers 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%) As long as the compounds of this invention can exist in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 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 C1, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. In addition, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing 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.

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.

Preferred in the context of the present invention are compounds of the formula (I) in which

A is -O-, n is the number 1 or 2 and

R ^{1 is} hydrogen, methyl or trifluoromethyl, and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which

A is -O-, n is the number 2 and

Of particular importance in the context of the present invention are compounds of the formulas (IA) and (IB)

wherein A, n and R ^{1 have} the meanings defined above and the groups bound to the central cyclopentane ring have a relative irans arrangement to each other, and mixtures of these compounds, wherein A, n or R ¹ in such a mixture of (IA ) and (IB) are each identical, and the salts, solvates and solvates of the salts of these compounds and their mixtures. Preferred in the context of the present invention are the compounds of the formula (IA)

wherein A, n and R ^{1 have} the meanings defined above, in enantiomerically pure form with a, as designated, (lS, 2R, 5S) configuration on the central cyclopentane ring and the salts, solvates and solvates of the salts of these compounds.

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. The invention further provides a process for the preparation of the compounds according to the invention, which comprises reacting a compound of the formula (II)

in which A and R ^{1 have} the meanings given above,

Presence of a base with a compound of the formula (ΠΙ) in which n has the meaning given above and

X is a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IV)

in which n, A and R ^{1 have} the meanings given above, alkylated and then the 2- (trimethylsilyl) ethyl ester group with the aid of an acid or a fluoride reagent to the carboxylic acid of formula (I)

in which n, A and R ^{1 have} the abovementioned meanings, and if appropriate separates the compounds of the formula (I) thus obtained into their enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or (ii) Bases are converted into their solvates, salts and / or solvates of the salts.

Suitable bases for the alkylation reaction (II) + (ΠΙ) - (IV) are in particular suitable alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium ieri-butoxide, alkali metal hydrides such as sodium or potassium hydride, amide bases 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. Preference is given to using potassium carbonate or potassium ieri-butoxide. Suitable inert solvents for this reaction 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, N, N-dimethylformamide (DMF), Ν, Ν-Dimefhylacetamid (DMA), Ν, Ν'-Dimefhylpropylenharnstoff (DMPU), / V Methyl pyrrolidinone (NMP) or dimethyl sulfoxide (DMSO). It is also possible to use mixtures of such solvents. Preference is given to using acetonitrile or dimethylformamide (DMF).

The reaction (II) + (ΠΙ) - (IV) is generally carried out in a temperature range from 0 ° C to + 120 ° C, depending on the reactivity of the components involved. The cleavage of the 2- (trimethylsilyl) ethyl ester grouping in process step (IV) - (I) is carried out by customary methods with the aid of a strong acid, in particular trifluoroacetic acid, in an inert solvent such as dichloromethane or with the aid of a fluoride, in particular tetrabutylammonium fluoride ( TBAF), in an ethereal solvent such as tetrahydrofuran. The ester cleavage is usually carried out in a temperature range from -20 ° C to + 30 ° C.

The compounds of the formula (Π), in the case where A is -O-, can be prepared by reacting a compound of the formula (V)

in which

PG is a temporary protecting group such as benzyl, in the presence of an alkyl or aryl phosphine and an azodicarboxylate with a triazine-4 (3 //) -one derivative of the formula (VI)

in which R ^{1 has} the abovementioned meaning, to give a compound of the formula (VII)

(VII) in which PG and R ^{1 have} the abovementioned meanings, and then the protective group PG to give the compound of the formula (II-A)

in which R ^{1 has} the meaning given above, splits off.

The reaction (V) + (VI) - (VII) is carried out under the usual conditions of a "Mitsunobu reaction" in the presence of a phosphine and an azodicarboxylate [see, e.g. D.L. Hughes, Org. Reactions 42, 335 (1992); D.L. Hughes, Org. Prep. Proced. Int. 28 (2), 127 (1996)]. 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, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), Oi tert-butylazodicarboxylat, / V, / V, / VW tetramethylazodicarboxamide (TMAD), l, l '- (azodicarbonyl) di-piperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD) can be used. Preferably here tri-n-butylphosphine is used in conjunction with diethyl azodicarboxylate (DEAD).

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 acetonitrile , Butyronitrile, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N, N'-dimethylpropylurea (DMPU) or / V-methylpyrrolidinone (NMP). Also, mixtures of such solvents can be used. Preference is given to using tetrahydrofuran, toluene or a mixture of these two. The reaction (V) + (VI) -> (VII) is generally 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 apparatus in this reaction may be advantageous.

The removal of benzyl as a temporary protective group PG in process step (VII) - (II-A) is carried out in the usual manner by hydrogenation with gaseous hydrogen or, in the sense of a transfer hydrogenation, with the aid of a hydrogen donor such as ammonium formate, cyclohexene or cyclohexadiene, in each case in the presence of a suitable hydrogenation catalyst such as in particular palladium on activated carbon. The reaction is preferably carried out in an alcoholic solvent such as methanol or ethanol, in ethyl acetate or tetrahydrofuran or in a mixture of such solvents, optionally with the addition of water, in a temperature range from + 20 ° C to + 80 ° C [to possible alternative protecting groups and for introduction and removal of such protecting groups see also: TW Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].

Compounds of the formula (Π) in which A is -S- can be prepared by reacting the above-described compound of the formula (Π-Α) in the corresponding trifluoromethanesulfonate of the formula (VIII)

in which R ^{1 has} the abovementioned meaning, and then converting this in the presence of a suitable palladium catalyst with a trialkylsilanethiol, for example triisopropylsilanethiol, to give the compound of the formula (Π-Β) in which R ^{1 has} the meaning given above, converts.

The preparation of the trifluoromethanesulfonate (VIII) starting from the phenol (II-A) takes place in a conventional manner by reaction with trifluoromethanesulfonic anhydride in the presence of an amine base such as / V-diisopropylethylamine or pyridine. As the inert solvent, chlorinated hydrocarbons such as dichloromethane or chloroform are generally used, and the reaction is usually carried out in a temperature range of -20 ° C to + 25 ° C. Further conversion of the trifluoromethanesulfonate (VIII) into the thiophenol (Π-Β) takes place by palladium-catalyzed reaction with a trialkylsilanethiol, for example triisopropylsilanethiol. Suitable catalysts are, for example, palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, tetrakis (triphenylphosphine) palladium (O), Bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (O) or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride, each in combination with a phosphine ligand such as 2-dicyclohexylphosphino 2 ', 4', 6'-triisopropylbiphenyl (X-Phos), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-phos), 1,2,3,4,5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene (Q-phos), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos), 2,2'-bis (diphenylphosphino) -l, l- binaphthyl (BINAP), 2-dicyclohexylphosphino-2 '- (A', / V-dimethylamino) biphenyl or 2-di-ieri-butylphosphino-2 '- (/ V, / V-dimethylamino) biphenyl.

The reaction is usually carried out in the presence of a base. As such are alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal phosphates such as sodium or potassium phosphate, alkali fluorides such as potassium or cesium fluoride, alkali ieri.-butylates such as sodium or potassium ieri.-butoxide, tertiary amine bases such as triethylamine, -Mefhylmorpholin, / V-methylpiperidine, -Diisopropylefhylamin, pyridine or 4-A ^i, / V-dimethylaminopyridine, or Amide bases such as lithium, sodium or potassium bis (trimethylsilyl) amide. The reaction is carried out in an inert solvent such as toluene, xylene, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) or / V, / V Dimethylacetamide (DMA) or mixtures thereof in a temperature range of + 50 ° C to + 150 ° C, the use of a microwave apparatus may be advantageous.

Preferred for the transformation (VIII) - (II-B) is a catalyst / ligand / base system consisting of tris (dibenzylideneacetone) dipalladium (0), 4,5-bis (diphenylphosphino) -9,9-dimethyl-xanthene ( Xantphos) and -Diisopropylefhylamin used and 1,4-dioxane used as a solvent. The trialkylsilylsulfide initially formed in this reaction is split again under the conditions used here for aqueous reaction work-up and chromatographic product purification, so that the free thiophenol (Π-Β) is obtained directly [cf. also M. Kreis and S. Brase, Adv. Synth. Catal. 347 (2-3), 313-319 (2005); M.S. Chambers et al, Int. Pat. Appl. WO 2006/059149-A1, page 9; C.-K. Pei and M. Shi, Tetrahedron: Asymmetry 22 (11), 1239-1248 (2011)].

The individual process steps described above can be carried out at normal, at elevated or at reduced pressure (for example in the range from 0.5 to 5 bar); In general, one works at normal pressure.

The compounds of the formula (V), in turn, can be prepared in various ways, starting from compounds of the formula (IX) or (X), based on published synthesis processes.

(IX) (X),

wherein PG is as defined above and Hai is a halogen atom [see, e.g. the general preparative methods described in WO 96/15096-A1, pages 26-44, in particular the methods A, G, H and K].

In particular, compounds of formula (V) which have a relative trans arrangement of the groups attached to the central cyclopentane ring, i. Compounds of the formulas

(VA) and (VB)

(VA) (VB), in which PG has the abovementioned meaning, can be prepared in analogy to published synthesis methods, for example by reacting e o-2- (trimethylsilyl) efhyl 2-oxobicyclo [2.2.1] heptane-7 carboxylate of the formula (XI)

with a phenyl Grignard compound of the formula (XII)

in which PG and Hai have the meanings given above, to the adduct of the formula (XIII)

in which PG has the abovementioned meaning, then reacting the tertiary hydroxy group via the corresponding mesylate to give the olefin of the formula (XIV)

in which PG has the abovementioned meaning, it is then eliminated with methylmorpholine oxide together with osmium tetroxide as catalyst to give the 1,2-diol of the formula (XV)

pQ (XV), in which PG has the abovementioned meaning, then oxidizing this bicyclic diol with the aid of lead tetraacetate or sodium periodate to give the 2-formyl-5-keto-cyclopentanecarboxylic acid ester of the formula (XVI)

in which PG has the meaning given above, and finally with sodium borohydride to the hydroxymethyl compound of the formula (VA) in which PG has the meaning given above, reduced [cf. WO 96/15096-A1, preparative method K (pages 42-44)].

In the above-described synthetic sequence (XI) + (XII) -> (ΧΙΠ) -> (XIV) → (XV) → (XVI) - (VA), in order to simplify the relative configuration of the chiral centers, only the structural formula was used an enantiomer, even if the compounds in question were used or obtained in racemic form; The actual end product of such a racemic preparation process is the racemic mixture of compounds (V-A) and (V-B). The 1,2,3-triazine-4 (3 //) -one derivatives of the formula (VI) can be prepared in a simple manner by treatment of aminoaminobenzamides of the formula (XVII)

in which R ^{1 has} the abovementioned meaning, accessible with sodium nitrite in aqueous hydrochloric acid [see, eg, D. Fernandez-Forner et al., Tetrahedron 47 (42), 8917-8930 (1991)].

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. A separation of the compounds according to the invention into the corresponding enantiomers and / or diastereomers may, if appropriate, also be carried out at the stage of intermediates (II), (IV), (V), (VII), (II-A), (II) Π-Β) or (VA) / (VB), which are then further reacted in separated form according to the reaction sequence described above. For such a separation of the stereoisomers of intermediates, it is likewise preferred to use chromatographic methods on achiral or chiral separation phases.

The compounds of formulas (ΙΠ), (IX), (X), (XI), (ΧΠ) and (XVII) are either commercially available or described as such in the literature or, starting from other commercially available compounds, be prepared by the skilled worker, literature known methods. 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 schemes:

Scheme 1

(as a racemic mixture) Scheme 2

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. In addition, the compounds of the invention show good solubility in aqueous systems and low non-specific binding to blood plasma components such as albumin. The compounds of the invention also have low in vivo clearance and good metabolic stability. Overall, this property profile makes it possible to expect low dosability for the compounds according to the invention and, as a result of the more targeted mode of action, a reduced risk of the occurrence of undesired side effects in the therapy.

The compounds according to the invention are therefore particularly suitable for the treatment and / or prevention of diseases and pathological processes, in particular those in which, in the course of an infectious or non-infectious inflammatory event and / or a tissue or vascular remodeling, the macrophage elastase (HME / hMMP-12). 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 severity with intermittent or persistent events, 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 interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, granulomatous maternal 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, e.g. Pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), bronchiolitis obliterans syndrome (BOS), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD ) and cystic fibrosis (CF), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, infectious and non-infectious cough and cold diseases (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and seasonal, allergic rhinitis, eg hay fever) 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 arteriosclerosis, hypertension, injuries and inflammations, infections (eg rheumatic fever, syphilis, Lyme disease), congenital connective tissue weaknesses (eg in Marfan syndrome and Ehlers-Danlos syndrome) or as a result of a volume burden of the aorta in congenital heart defects with right-left shunt or shunt-dependent perfusion of the lungs, as well as aneurysms on coronary vessels in the course of a disease in Kawasaki syndrome and in brain areas in patients with a congenital malformation of the aortic valve.

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 such as cardiogenic shock, septic shock and anaphylactic shock, as well as for the treatment and / or prevention of thromboembolic disorders and ischemia, such as myocardial ischemia , Cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, coronary and peripheral arterial spasm, edema formation such as pulmonary edema, cerebral edema, renal edema or congestive heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria , Myocardial insufficiency, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as for the prevention of restenosis, for example after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal cor onarangioplasties (PTCA), heart transplants and bypass surgery.

For the purposes of the present invention, the term cardiac failure encompasses both acute and chronic manifestations of cardiac insufficiency as well as specific or related forms of disease 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 disease, heart valve defects, cardiac insufficiency in valvular heart failure, mitral 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 toxicity 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 diagnosed by, for example, abnormal decreased creatinine and / or water excretion, abnormally elevated blood levels of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamylsynthetase, altered urinosmolarity or urine levels, 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 includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, 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, eg, 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, warting, frostbite), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (by 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, purulenta arthritis, arthritis rheumatica, arthritis serosa, arthritis syphilitica, arthritis tuberculosa, arthritis urica, arthritis villonodularis pigmentosa, atypical arthritis, hemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis, and metastatic arthritis Still's syndrome, Felty's syndrome, Sjörgen's syndrome, Clutton's syndrome, Poncet's syndrome, Pott syndrome and Reiter's syndrome, multiple forms of arthropathies such as arthropathy deformans, neuropathic arthropathy, ovaripriva arthropathy, psoriatic arthropathy 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 Günther syndrome and the Münchmeyer syndrome ), inflammatory arterial changes (various forms of arteritis such as endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, arteritis deformans, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, and Horton syndrome, Churg-Strauss disease). Syndrome and Takayasu's arteritis), Mückle -Well's syndrome, Kikuchi's disease, polychondritis, sclerodermia and other diseases with an inflammatory or immunological component such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy , Sezary syndrome and par Anophilic syndrome, rejection after organ transplantation and 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. A further subject of the present invention are therefore medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned diseases. Suitable combination active ingredients for this purpose are by way of example and preferably mentioned:

Anti-obstructive / bronchodilatory agents, e.g. for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably from the group of inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics), the inhaled anti-muscarinic substances and the PDE 4 inhibitors;

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 4 inhibitors such as roflumi last and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil; · 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;

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;

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; lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; hypotensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics; the signal transduction cascade inhibiting compounds, for 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 by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

Compounds which inhibit the soluble epoxide hydrolase (sEH), such as N, N'-cycloalkyloxyurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3 { 5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea;

• 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, for 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 of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

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 of the invention are administered in combination with a bile acid reabsorption inhibitor such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as e.g. 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 of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. 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 manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. 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.

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)

(dba) ₃ Pd ₂ tris (dibenzylideneacetone) dipalladium (0)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet of doublet (by NMR)

DEAD Diethyl 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

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

NMO N-methylmorpholine N-oxide

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal

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

Rf Retention Index (at DC)

RP reverse phase (reversed phase, for HPLC)

RT room temperature

R _t retention time (for HPLC, LC / MS)

s singlet (by NMR)

sept septet (by NMR)

SFC supercritical liquid chromatography t triplet (by NMR)

tBu teri-butyl

td triplet of doublet (by NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry

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

Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

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, 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 2 (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 3 (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 l of 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 4 (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 5 (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 6 (preparative HPLC):

Column: Reprosil C18, 10 μm, 125 × 30 mm; Eluent: acetonitrile / water with 0.1% TFA; Gradient: 0-6.00 min 35:65, sample injection at 3.00 min; 6.00-27.00 min to 80:20; 27.00-30.00 min 95: 5; 30.00-33.00 min to 35:65.

Method 7 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 22 min), to 75 min 20:80.

Method 8 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 20 min), to 115 min 20:80. Method 9 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 21 min), to 75 min 20:80.

Method 10 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 25 min), to 75 min 20:80.

Method 11 (preparative HPLC):

Column: Reprosil-Pur C18, 10 μιη; Eluent: water / methanol; Gradient: 70:30 -> 50:50 (to 6 min) -> 20:80 (to 20 min), to 75 min 20:80.

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 a 100% purity according to automatic peak integration in the LC / MS chromatogram, or purity was not explicitly determined.

Data on yields in% d. Th. Are purity-corrected as a rule, provided that a purity of <100% is specified. For solvent-containing or contaminated batches, the yield may be formally "> 100%"; in these cases, the yield is not solvent or purity corrected. 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 ,

In the intermediates and exemplary embodiments described below, a designation "IRS, 2RS, 5SR" in the IUP AC name of the relevant example, in conjunction with the term "racemate", means that this is a racemic mixture of IR, 2R, 5S - Enantiomers (- each 1st letter after the position number in "IRS, 2RS, 5SR") with the appropriate lS, 2S, 5R-enantiomer (-> each 2nd letter after the position number) acts. The term "IRS, 2RS, 5SR" in connection with the statements "enantiomer 1" and "enantiomer 2" means that these are the two enantiomers in separated, isolated form, wherein an assignment of the absolute configuration (IR, 2R, 5S or IS, 2S, 5R) to these Enantiomers was not made. Similar terms such as "IRS, 2SR, 5RS", which result from the changed priority and / or order of parts of names due to the IUPAC nomenclature rules, shall be interpreted in an analogous manner according to this manual. In order to simplify the description of the relative stereochemical configuration of chiral centers, only the structural formula of one of the participating enantiomers is reproduced below in the structural formulas of racemic example compounds; As can be seen from the term "racemate" in the associated IUPAC name, in these cases the second enantiomer with the respectively opposite absolute configuration is always included.

Starting compounds and intermediates:

Example 1A

6- (trifluoromethyl) -l, 2,3-benzotriazin-4 (3 //) - one

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 1, ESIpos): R _t = 0.78 min, m / z = 216 [M + H] Example 2A

6-Mefhyl-l, 2,3-benzotriazin-4 (3 //) - one

To a suspension of 32.0 g (213.08 mmol) of 2-amino-5-methylbenzamide in 300 ml of a 2: 1 mixture of water and conc. Hydrochloric acid at 0 ° C, a solution of 16.17 g (234.38 mmol) of sodium nitrite in 120 ml of water was added slowly, keeping the internal temperature below 5 ° C. After stirring for 30 minutes at 0 ° C. bath temperature, 120 ml (1.2 mol) of 10 M sodium hydroxide solution were slowly added with further cooling of the ice bath, during which the internal temperature rose to about 20 ° C. and the solid present went into solution. After stirring for 1 h at RT, 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 in vacuo, 33.80 g (98% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 14.85 (br.s, 1H), 8.08 (d, 1H), 8.02 (s, 1H), 7.90 (d, 1H). LC / MS (Method 3, ESIpos): R _t = 1.40 min, m / z = 162 [M + H] ⁺ . Example 3A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(4-oxo-l, 2,3-benzotriazine - 3 (4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

Step 1:

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] -2-hydroxybicyclo [2.2.1] heptane-7-carboxylate

A solution of 24.30 g (95.52 mmol) of e o-2- (trimemylsilyl) ethyl 2-oxobicyclo [2.2.1] heptane-7-carboxylate [WO 96/15096, Example 360 / step 1] in 60 ml of THF was added at ca. .1 ° C internal temperature under argon slowly added to 114.62 ml (114.62 mmol) of a 1 M solution of 4- (benzyloxy) - phenylmagnesium bromide in THF, wherein the internal temperature rose to a maximum of 0 ° C. Subsequently, the cooling bath was removed and the mixture stirred for 1 h. The mixture was then treated with 200 ml of 5% citric acid solution and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on 1 kg of silica gel (mobile phase cyclohexane / ethyl acetate 9: 1). There were obtained 28.70 g (66% of theory, purity 97%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.49-7.27 (m, 7H), 6.95 (d, 2H), 5.09 (s, 2H), 5.05 (s IH), 4.10-4.00 (m, 2H), 2.44-2.37 (m, IH), 2.33-2.24 (m, IH), 2.23-2.11 (m, IH), 1.78-1.60 (m IH), 1.52-1.26 (m, 4H), 0.95-0.80 (m, 2H), 0.00 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 3.15 min, m / z = 421 [M + HH ₂ 0] ⁺ .

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] bicyclo [2.2.1] hept-2-ene-7-carboxylate

To a solution of 28.70 g (63.466 mmol) of the compound from Example 3A / step 1 in 150 ml of dichloromethane under argon was added at about 0 ° C, first 26.50 ml (190.40 mmol) of triethylamine and then slowly 9.82 ml (126.93 mmol) of methanesulfonyl chloride , wherein the internal temperature did not exceed 5 ° C. The mixture was then stirred at 0 ° C for 1.5 h. Thereafter, the mixture was diluted with dichloromethane and extracted with water. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by flash chromatography on 1 kg of silica gel (mobile phase cyclohexane / ethyl acetate 95: 5). 20.06 g (75% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de): δ [ppm] = 7.48-7.28 (m, 7H), 6.97 (d, 2H), 6.30 (d, 1H), 5.11 (s, 2H), 4.15-4.06 (m, 2H), 3.43 (brs s, 1H), 3.06 (brs s, 1H), 1.85-1.71 (m, 2H), 1.17-1.06 (m, 1H), 1.04-0.87 (m, 3H) , 0.04 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.61 min, m / z = 421 [M + H] ⁺ .

Step 3:

2- (trimethylsilyl) ethyl 2- [4- (benzyloxy) phenyl] -2,3-dihydroxybicyclo [2.2.1] heptane-7-carboxylate

To a degassed solution of 25.37 g (60.314 mmol, not purity-corrected) of the compound from Example 3A / step 2 in 150 ml of THF under argon at 0 ° C was a degassed solution of 15.90 g (135.71 mmol) / V-Methylmorpholin- / V oxide (NMO) in 42 ml of water under argon. 116 ml (9.05 mmol) of a 2.5% solution of osmium tetroxide in tert. Given -butanol. The mixture was then stirred at 0 ° C for 1 h. After a further 16 h stirring at RT, the mixture was diluted with 150 ml of ethyl acetate and extracted twice with 250 ml of 10% citric acid solution, twice with 300 ml of saturated sodium bicarbonate solution and twice with 300 ml of saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and concentrated. There were obtained 27.51 g (75% of theory, purity 75%) of the title compound. LC / MS (Method 1, ESIpos): R _t = 1.40 min, m / z = 437 [M + HH ₂ O] ⁺ . Step 4:

2- (trimethylsilyl) ethyl (1RS, 2RS, 5SR) -2- [4- (benzyloxy) benzoyl] -5-formylcyclopentanecarboxylate

(Racemate)

Method A:

To a solution of 27.42 g (60.31 mmol, not purity-corrected) of the compound from Example 3A / step 3 in 170 ml of methanol under argon was added slowly at -15 ° C bath temperature 30.96 g (66.34 mmol, purity 95%) of lead tetraacetate. The mixture was stirred at -15 ° C for 1 h. After warming to RT, the mixture was filtered through Celite and the filtration residue washed three times with 50 ml of methanol. The filtrate was concentrated and the residue was taken up in 500 ml of dichloromethane and 500 ml of water, without any phase separation. The mixture was then filtered through silica gel and the silica gel washed with dichloromethane. After phase separation, the aqueous phase was extracted once more with 150 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. There were obtained 27.1 g (86% of theory, purity 87%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.72 (d, 1H), 8.02 (d, 2H), 7.53-7.34 (m, 5H), 7.18 (d, 2H), 5.25 ( s, 2H), 4.17 (q, 1H), 4.09 (dd, 2H), 3.74 (t, 1H), 3.23-3.14 (m, 1H), 2.24-2.13 (m, 1H), 2.08-1.88 (m, 2H), 1.61-1.49 (m, 1H), 0.87-0.79 (m, 2H), 0.00 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.45 min, m / z = 425 [M + H-28]

Method B:

To a solution of 69.0 g (131 mmol, about 80% purity) of the compound from Example 3A / step 2 in a mixture of acetone / water / THF (3: 1: 1) were added at 0 ° C under argon first Add 76.87 g (656 mmol) of N-methylmorpholine N-oxide (NMO) and then 2.09 g (8.20 mmol) of a 4% solution of osmium tetroxide in water. The mixture was stirred at RT for 3 days. Subsequently, 105.26 g (492 mmol) of sodium periodate were added and the mixture was further stirred overnight at RT. After addition of ethyl acetate and 10% aqueous citric acid, the aqueous phase was separated and extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium bicarbonate solution and then stirred with magnesium silicate (Fluorisil). After filtration, the filter residue was washed with ethyl acetate. After concentration of the filtrate, the residue thus obtained was combined with the residues from two similar preliminary experiments [amounts used of the compound from Example 3A / step 2: 3.0 g (7.13 mmol) or 3.2 g (7.61 mmol)] and mixed together by flash chromatography. Purified by chromatography (silica gel, eluent petroleum ether / ethyl acetate 8: 2). This gave 53 g (58% of theory, taking into account preliminary tests, purity 89%) of the title compound.

Step 5:

2- (trimethylsilyl) ethyl (1RS, 2RS, 5SR) -2- [4- (benzyloxy) benzoyl] -5- (hydroxyethyl) cyclopentane carboxylate (racemate)

To a solution of 27.0 g (59.65 mmol, not purity-corrected) of the compound from Example 3A / step 4 in 135 ml of ethanol was added slowly at RT 677 mg (17.895 mmol) of sodium borohydride and the mixture was stirred at RT for 30 min. The mixture was then mixed with 400 ml of ammonium chloride solution and water and extracted twice with 300 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. This gave 21.90 g (70% of theory, purity 87%) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.95 (d, 2H), 7.48-7.31 (m, 5H), 7.12 (d, 2H), 5.20 (s, 2H), 4.64 ( t, 1H), 4.07-3.98 (m, 3H), 3.53-3.45 (m, 1H), 3.40-3.34 (m, 1H), 2.94 (t, 1H), 2.34-2.23 (m, 1H), 2.12- 2.01 (m, 1H), 1.90-1.78 (m, 1H), 1.67-1.47 (m, 2H), 0.82-0.75 (m, 2H), 0.00 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.34 min, m / z = 455 [M + H] ⁺ . Step 6:

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(4-oxo-l, 2,3-benzotriazine - 3 (4 //) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (1.10 mmol, not purity corrected) of the compound of Example 3A / Step 5 in 6 mL of THF under argon was added 243 mg (1.65 mmol) of l, 2,3-benzotriazine-4 (3 /) -one and Add 1.11 g (5.50 mmol) of tributylphosphine. Subsequently, 1.50 ml (3.30 mmol) of a 40% solution of diethyl azodicarboxylate (DEAD) in toluene were added dropwise at 0 ° C. The mixture was stirred at RT for about 1 h, then diluted with ethyl acetate and extracted twice with 5 ml each of water and twice with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 6). There were obtained 334 mg (52% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.44 (dd, 1H), 8.38 (d, 1H), 8.27 (td, 1H), 8.15-8.08 (m, 3H), 7.65- 7.48 (m, 5H), 7.29 (d, 2H), 5.37 (s, 2H), 4.74-4.62 (m, 2H), 4.26 (q, 1H), 3.40 (t, 1H), 3.13-3.01 (m, 1H), 2.36-2.25 (m, 1H), 2.21-2.10 (m, 1H), 1.96-1.84 (m, 1H), 1.77-1.65 (m, 1H), 0.53-0.46 (m, 2H), 0.17 ( s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 584 [M + H] ⁺ . Example 4A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-hydroxybenzoyl) -5 - [(4-oxo-l, 2,3-benzotriazin-3 ( 4 /) - yl) methyl] cyclopentanecarboxylate (racemate)

To a solution of 270 mg (0.46 mmol) of the compound of Example 3A in 12 mL of ethyl acetate under argon was added 25 mg (0.024 mmol) of palladium on charcoal (10% Pd). The mixture was then hydrogenated under normal pressure for 42 h. The mixture was then filtered through kieselguhr, the filter residue washed with ethyl acetate and the filtrate was concentrated. The residue thus obtained was taken up in a little dichloromethane and purified by column chromatography (25 g of silica gel, mobile phase cyclohexane / ethyl acetate 7: 3). 165 mg (72% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.37 (d, 1H), 8.16 (d, 1H), 7.98-7.88 (m, 3H), 7.84-7.77 (m, 1H), 6.89 ( d, 2H), 6.67 (br s, 1H), 4.77-4.70 (m, 1H), 4.68-4.60 (m, 1H), 4.20-4.10 (m, 1H), 3.88-3.81 (m, 2H), 3.46 (t, 1H), 3.08-2.94 (m, 1H), 2.19-2.04 (m, 1H), 2.01-1.86 (m, 2H), 1.72- 1.64 (m, partially occluded, 1H), 0.63-0.55 ( m, 2H), -0.09 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.23 min, m / z = 494 [M + H] ⁺ .

Example 5A

2- (trimethylsilyl) ethyl (1R5,25R, 5R5) -2 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (tetrahydro -2 / f-pyran-4-ylmefhoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 164 mg (0.33 mmol) of the compound from Example 4A in 3.7 ml of acetonitrile under argon was added 92 mg (0.66 mmol) of potassium carbonate and 71 mg (0.40 mmol) of 4- (bromomethyl) -tetrahydropyran and the mixture under 20 h under Reflux stirred. Subsequently, another 36 mg (0.20 mmol) of 4- (bromomethyl) tetrahydropyran were added and the mixture stirred again under reflux for 7 h. Then another 71 mg (0.40 mmol) of 4- (bromomethyl) tetrahydropyran and 46 mg (0.33 mmol) of potassium carbonate were added and the mixture was stirred under reflux for a further 17 h. After cooling to RT, the mixture was diluted with 30 ml of water and 30 ml of ethyl acetate, and after separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 4). The combined product-containing fractions were adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, then concentrated to a residual aqueous phase and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated and the residue was dried in vacuo. There were obtained 85 mg (42% of theory, purity 97%) of the title compound.

Ή NMR (400 MHz, CDCL): δ [ppm] = 8.37 (dd, 1H), 8.15 (d, 1H), 7.99-7.91 (m, 3H), 7.83-7.76 (m, 1H), 6.91 (i.e. , 2H), 4.77-4.68 (m, 1H), 4.67-4.59 (m, 1H), 4.23-4.13 (m, 1H), 4.03 (dd, 2H), 3.89-3.80 (m, 4H), 3.50-3.39 (m, partially occluded, 3H), 3.09-2.93 (m, 1H), 2.19-2.03 (m, 2H), 2.01-1.86 (m, 2H), 1.76 (dd, 2H), 1.71-1.62 (m, partial occluded, 1H), 1.47 (qd, 2H), 0.65-0.53 (m, 2H), -0.09 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 592 [M + H] ⁺ .

Example 6A

2- (trimethylsilyl) ethyl (1R5,25R, 5R5) -2 - [(4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- {4- [2- (2H) tetrahydro-2α-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylate (racemate)

To a solution of 3.88 g (7.47 mmol, purity 95%) of the compound from Example 4A in 41 ml of DMF under argon was added 1.01 g (8.96 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 1.73 g (8.96 mmol) of 4- (2-bromoethyl) tetrahydro-2i-7-pyran were added, and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, water and ethyl acetate were added to the mixture. After separating the phases, 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 column chromatography (300 g of silica gel, eluent cyclohexane / ethyl acetate 7: 3). There were obtained 2.91 g (64% of theory, purity 99%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.27 (d, 1H), 8.20 (d, 1H), 8.10 (t, 1H), 7.97-7.89 (m, 3H), 7.03 ( d, 2H), 4.57-4.44 (m, 2H), 4.14-4.03 (m, 3H), 3.82 (dd, 2H), 3.63-3.46 (m, 2H), 3.31- 3.17 (m, partially concealed, 3H) , 2.97-2.84 (m, 1H), 2.18-2.05 (m, 1H), 2.04-1.92 (m, 1H), 1.80- 1.48 (m, 6H), 1.29-1.13 (m, 3H), 0.37-0.26 ( m, 2H), -0.17 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 606 [M + H] ⁺ .

Example 7A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5- {[4-oxo-6- (trifluoromethyl) - l , 2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate (racemate)

To a solution of 13.88 g (30.53 mmol, not purity corrected) of the compound of Example 3A / Step 5 in 200 mL of toluene under argon was added 7.88 g (36.64 mmol) of the compound from Example 1A and 9.88 g (48.85 mmol) of tributylphosphine. Subsequently, 13.90 ml (30.53 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise at 0 ° C. The mixture was stirred at RT for 1 day and then concentrated. The residue was purified by flash chromatography (1 kg silica gel, eluent cyclohexane / ethyl acetate 9: 1). 9.06 g (44% of theory, purity 98%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.47-8.43 (m, 2H), 7.95 (d, 2H), 7.48-7.30 (m, 5H), 7.12 (d, 2H), 5.20 (s, 2H), 4.60-4.50 (m, 2H), 4.10 (q, 1H), 3.65-3.49 (m, 2H), 3.25 (t, 1H), 2.96-2.83 ( m, 1H), 2.19-2.07 (m, 1H), 2.07-1.95 (m, 1H), 1.80-1.68 (m, 1H), 1.63-1.50 (m, 1H), 0.39-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.57 min, m / z = 652 [M + H] ⁺ .

Example 8A 2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-hydroxybenzoyl) -5- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 /) - yl] methyl} cyclopentanecarboxylate (racemate)

1.05 g (16.66 mmol) of ammonium formate and 369 mg (0.35 mmol) of palladium on activated carbon (10 % Pd). The mixture was then stirred for 1 h at 75.degree. Thereafter, a further 105 mg (1.67 mmol) of ammonium formate were added and the mixture was stirred for a further 30 min at 75.degree. After cooling to RT, the mixture was filtered through kieselguhr, the filter residue washed with ethyl acetate and ethanol and the filtrate was concentrated. There were obtained 7.86 g (100% of theory) of the title compound. Ή NMR (400 MHz, DMSO-de): δ [ppm] = 10.40 (br.s, 1H), 8.52 (s, 1H), 8.47-8.42 (m, 2H), 7.85 (d, 2H), 6.84 (d, 2H), 4.60-4.51 (m, 2H), 4.05 (q, 1H), 3.64-3.48 (m, 2H), 3.23 (t, 1H), 2.96-2.82 (m, 1H), 2.17-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.49 (m, 1H), 0.38-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.31 min, m / z = 562 [M + H] ⁺ . Example 9A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- [4- (tetrahydro-2-pyran-4-ylmethoxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 1.07 g (1.90 mmol) of the compound from Example 8A in 20 ml of DMF under argon was added 256 mg (2.28 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 408 mg (2.28 mmol) of 4- (bromomethyl) tetrahydropyran were added, and the mixture was stirred for 2 h at a bath temperature of 100.degree. Subsequently, a further 136 mg (0.76 mmol) of 4- (bromomethyl) tetrahydropyran were added and the mixture was stirred for a further 2 hours at 100 ° C. bath temperature. After cooling to RT, the mixture was combined with the reaction mixtures of two similar preliminary experiments (batch size in each case 47 mg (0.08 mmol) of the compound from Example 8A). After removal of the DMF, 60 ml of water and 60 ml of ethyl acetate were added to this combined mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in a mixture of cyclohexane and ethyl acetate (9: 1) and purified by column chromatography (120 g silica gel, eluent cyclohexane / ethyl acetate 9: 1). 590 mg (47% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, CDC1 ₃ ): δ [ppm] = 8.66 (s, 1H), 8.28 (d, 1H), 8.14 (dd, 1H), 7.95 (d, 2H), 6.92 (d, 2H) , 4.78-4.62 (m, 2H), 4.21-4.13 (m, 1H), 4.03 (dd, 2H), 3.89-3.81 (m, 4H), 3.50-3.40 (m, 3H), 3.07-2.93 (m, 1H), 2.19-2.03 (m, 2H), 2.03-1.87 (m, 2H), 1.76 (dd, 2H), 1.72-1.61 (m, 1H), 1.47 (qd, 2H), 0.63-0.53 (m, 2H), -0.09 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.51 min, m / z = 560 [M + H] ⁺ .

Example 10A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- {4- [2- (tetrahydro-2ii-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylate (racemate)

To a solution of 250 mg (0.45 mmol) of the compound from Example 8A in 4.5 ml of DMF under argon was added 60 mg (0.53 mmol) of potassium feri-butoxide. After stirring at RT for 5 min, 103 mg (0.53 mmol) of 4- (2-bromoethyl) tetrahydro-2i-7-pyran were added, and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of tert-butyl methyl ether were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of ieri.-butyl-methyl ether and twice with 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (25 g silica gel, eluent cyclohexane / ethyl acetate 7: 3). There were obtained 138 mg (46% of theory, purity 100%) of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.45 (s, 2H), 7.93 (d, 2H), 7.04 (d, 2H), 4.60-4.50 ( m, 2H), 4.15-4.07 (m, 3H), 3.82 (dd, 2H), 3.64-3.47 (m, 2H), 3.31-3.18 (m, 3H), 2.97- 2.83 (m, 1H), 2.19- 2.06 (m, 1H), 2.06-1.94 (m, 1H), 1.81-1.49 (m, 6H), 1.29-1.14 (m, 3H), 0.36-0.22 (m, 2H), -0.18 (s, 9H) ,

LC / MS (Method 1, ESIpos): R _t = 1.53 min, m / z = 674 [M + H] ⁺ .

Example IIA

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- (4- {[(trifluoromethyl) sulfonyl] oxy} benzoyl) cyclopentanecarboxylate (racemate)

0.25 ml (3.12 mmol) of pyridine and then, slowly, 0.45 ml (2.67 mmol) of trifluoromethanesulfonic anhydride were added at 0 ° C. to a solution of 1.00 g (1.78 mmol) of the compound from Example 8A in 5.0 ml of dichloromethane under argon. The mixture was stirred for 1 h at 0 ° C, then treated with dichloromethane and washed once each with water and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. 1.21 g (98% of theory, purity 100%) of the title compound were obtained.

LC / MS (Method 2, ESIpos): R _t = 3.41 min, m / z = 694 [M + H] ⁺ . Example 12A

2- (trimethylsilyl) ethyl (IRS, 2SR ^^

methyl} -5- (4-sulfanylbenzoyl) cyclopentanecarboxylate (racemate)

To a solution of 800 mg (1.15 mmol) of the compound of Example IA in 10 ml of dioxane was successively 264 mg (1.38 mmol) of triisopropylsilanethiol, 298 mg (2.31 mmol) of N, N-diisopropylethylamine, 26 mg (0.03 mmol). Tris (dibenzylideneacetone) dipalladium and 33 mg (0.06 mmol) of 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (xanthphos). Subsequently, the degassed, purged with argon and stirred under reflux for 2.5 h. After cooling to RT, the mixture was treated with ethyl acetate and washed once with water. After a single extraction of the aqueous phase 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 preparative HPLC (Method 4). The product-containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution and concentrated to a small residual volume of water. After extracting this aqueous phase twice with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and the residue was dried in vacuo. 350 mg (35% of theory, purity 67%) of the title compound were obtained. According to LC / MS, it contained the corresponding disulfide (dimerized product, (+/-) - bis [2- (trimethylsilyl) ethyl] 2,2 '- [disulfandiylbis (benzene-4,1-diylcarbonyl)] bis ( 5- {[4-oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] methyl} cyclopentanecarboxylate) at 25%.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.52 (s, 1H), 8.44 (s, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 6.03 (br. s, 1H), 4.60-4.48 (m, 2H), 4.08 (q, 1H), 3.64-3.48 (m, 2H), 3.23 (t, 1H), 2.97-2.81 (m, 1H), 2.19-2.06 ( m, 1H), 2.06-1.94 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.48 (m, 1H), 0.37-0.22 (m, 2H), -0.18 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.44 min, m / z = 578 [M + H] ⁺ . Example 13A 2- (trimethylsilyl) ethyl (lR _l ^S, _l 2 ^S, R, ^5R.S,) -2- {[4-oxo-6- (trifluoromethyl) -l, 2,3-benzotriazin-3 ( 4 /) - yl] - methyl} -5- {4 - [(tetrahydro-2ii-pyran-4-ylmethyl) sulfanyl] benzoyl} cyclopentanecarboxylate

(Racemate)

To a solution of 200 mg of the compound from Example 12A (0.35 mmol, not purity-corrected, containing about 25% corresponding disulfide) in 14 ml of DMF, 96 mg (0.69 mmol) of potassium carbonate were added and the mixture was stirred for 2 min at RT. Subsequently, 136 mg (0.76 mmol) of 4- (bromomethyl) tetrahydropyran and 123 mg (1.04 mmol) of sodium hydroxy methanesulfinate were added and the mixture was stirred at RT for a further 30 min. The mixture was then concentrated, and the residue was added with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 248 mg (100% of theory, purity 95%) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.50 min, m / z = 676 [M + H] ⁺ .

Example 14A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- [4- (benzyloxy) benzoyl] -5 - [(6-methyl-4-oxo-l, 2 , 3-benzotriazine-3 (4 /) -yl) methyl] cyclopentanecarboxylate (racemate)

3.88 g (24.07 mmol) of the compound from Example 2A were added to a suspension of 9.60 g (20.06 mmol, purity 95%) of the compound from Example 3A / Step 5 in 110 ml of toluene under argon. Subsequently, 25.1 ml (100.30 mmol) of tributylphosphane and 27.4 ml (60.18 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise at 0 ° C. After stirring at RT for 2 h, the mixture was diluted with ethyl acetate and washed once with water. The aqueous phase was back-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 85:15 → 80:20). There were obtained 6.28 g (51% of theory, purity 98%) of the title compound. Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.12-8.05 (m, 2H), 7.97-7.88 (m, 3H), 7.48-7.27 (m, 5H), 7.12 (d, 2H ), 5.20 (s, 2H), 4.56-4.42 (m, 2H), 4.08 (q, 1H), 3.61-3.46 (m, 2H), 3.22 (t, 1H), 2.96-2.83 (m, 1H), 2.55 (s, 3H), 2.17-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.59- 1.47 (m, 1H), 0.38-0.23 (m, 2H ), -0.17 (s, 9H). LC / MS (Method 1, ESIpos): R _t = 1.49 min, m / z = 598 [M + H] ⁺ .

Example 15A

2- (trimethylsilyl) ethyl (lR _l ^S, 2R S _^l, ^5.S, R) -2- (4-hydroxybenzoyl) -5 - [(6-methyl-4-oxo-l, 2,3- benzotriazine-3 (4 //) - yl) -methyl] cyclopentanecarboxylate (racemate)

To a solution of 6.25 g (10.25 mmol, purity 98%) of the compound of Example 14A in a mixture of 50 ml of ethyl acetate and 50 ml of ethanol under argon was added 273 mg (0.26 mmol) of palladium on charcoal (10% Pd) and 969 mg (15.37 mmol) of ammonium formate. Subsequently, the mixture was stirred at 70 ° C for 2 h. After cooling to RT, the mixture was filtered through kieselguhr, the filter residue was washed with ethyl acetate, the filtrate was concentrated and the residue was dried in vacuo. There were obtained 5.20 g (97% of theory, purity 97%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 10.40 (br.s, 1H), 8.12-8.05 (m, 2H), 7.92 (dd, 1H), 7.84 (d, 2H), 6.84 (d, 2H), 4.57-4.42 (m, 2H), 4.03 (q, 1H), 3.62-3.46 (m, 2H), 3.21 (t, 1H), 2.96-2.83 (m, 1H), 2.55 ( s, 3H), 2.17-2.04 (m, 1H), 2.03-1.91 (m, 1H), 1.78-1.66 (m, 1H), 1.60-1.48 (m, 1H), 0.39-0.25 (m, 2H), -0.17 (s, 9H).

LC / MS (Method 1, ESIpos): R _t = 1.28 min, m / z = 508 [M + H] Example 16A

2- (trimethylsilyl) ethyl (IRS, 2SR, 5 ^

5- [4- (tetrahydro-2 / f-pyran-4-ylmefloxy) benzoyl] cyclopentanecarboxylate (racemate)

To a solution of 500 mg (0.96 mmol, purity 97%) of the compound from Example 15A in 5.3 ml of DMF under argon was added 129 mg (1.15 mmol) of potassium ieri-butoxide. After stirring at RT for 5 min, 205 mg (1.15 mmol) of 4- (bromomethyl) tetrahydro-2i-7-pyran were added and the mixture was stirred for 1 h at a bath temperature of 100.degree. After cooling and standing at RT overnight, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of 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 column chromatography (90 g silica gel, eluent cyclohexane / ethyl acetate 7: 3). 290 mg (41% of theory, purity 82%) of the title compound were obtained. LC / MS (Method 1, ESIpos): R _t = 1.43 min, m / z = 606 [M + H] ⁺ .

Example 17A

2- (trimethylsilyl) ethyl (IRS, 2SR, 5 ^

5- {4- [2- (tetrahydro-2-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylate (racemate)

To a solution of 200 mg (0.38 mmol, purity 97%) of the compound from Example 15A in 2.1 ml of DMF under argon, 51 mg (0.46 mmol) of potassium ieri. given butylate. After stirring at RT for 5 min, 89 mg (0.46 mmol) of 4- (2-bromoethyl) tetrahydro-2i-7-pyran were added and the mixture was stirred for 2 h at a bath temperature of 100.degree. After cooling to RT, 60 ml of water and 60 ml of ethyl acetate were added to the mixture. After separating the phases, the aqueous phase was extracted once with 30 ml of 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 column chromatography (40 g of silica gel, eluent cyclohexane / ethyl acetate 7: 3). There were obtained 142 mg (60% of theory, purity 100%) of the title compound.

LC / MS (Method 1, ESIpos): R _t = 1.46 min, m / z = 620 [M + H]

Embodiments:

example 1

(+/-) - (lRS, 2SR, 5RS) -2 - [(4-oxo-l, 2,3-benzotria ^^

ylmethoxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 83 mg (0.14 mmol) of the compound from Example 5A in 0.5 ml of dichloromethane was treated at 0 ° C. with 0.25 ml (3.24 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in acetonitrile and purified by preparative HPLC (Method 4). There were obtained 60 mg (85% of theory, purity 98%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (s, 1H), 8.26 (dd, 1H), 8.20 (d, 1H), 8.08 (td, 1H), 7.99-7.90 ( m, 3H), 7.04 (d, 2H), 4.59-4.46 (m, 2H), 4.14-4.05 (m, 1H), 3.93 (d, 2H), 3.87 (dd, 2H), 3.38-3.32 (partially obscured , 2H), 3.23 (t, 1H), 2.94-2.81 (m, 1H), 2.17-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.72-1.61 (m, 3H), 1.57-1.45 (m, 1H), 1.33 (qd, 2H). LC / MS (Method 1, ESIpos): R _t = 1.06 min, m / z = 492 [M + H] ⁺ .

Separation of the enantiomers:

30 mg of the racemic compound from Example 1 were dissolved in 12 ml of methanol / acetonitrile under heat and separated by means of preparative SFC on chiral phase into the enantiomers (see Examples 2 and 3) [column: Daicel Chiralpak AZ-H, 5 μιη, 250 mm x 20 mm; Flow: 80 ml / min; Detection: 210 nm; Injection volume: 1.0 ml; Temperature: 40 ° C; Eluent: 60% carbon dioxide / 40% ethanol].

Example 2

(+) - (1R5,25R, 5R5) -2 - [(4-Oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (tetrahydro-2ii-pyran 4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 14 mg; former purity = 100%; ee value = 99% [α] _D ²⁰ = + 66.9 °, 589 nm, c = 0.27 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.10 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.11-8.05 (m, 1H), 7.99 -7.89 (m, 3H), 7.04 (d, 2H), 4.59-4.46 (m, 2H), 4.14-4.05 (m, 1H), 3.93 (d, 2H), 3.87 (dd, 2H), 3.32-3.19 (m, partially occluded, 3H), 2.94-2.80 (m, 1H), 2.18-1.96 (m, 2H), 1.95-1.84 (m, 1H), 1.72-1.61 (m, 3H), 1.58-1.44 (m , 1H), 1.33 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 492 [M + H] ⁺ .

Example 3

(-) - (1R5,25R, 5R ^ -2 - [(4-Oxo-l, 2,3-benzotriazine-3 (4 /) - yl) methyl] -5- [4- (tetrahydro-2ii-pyran -4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 17 mg; former purity = 100%; ee value = 99%

[a] _D ²⁰ = -56.4 °, 589 nm, c = 0.28 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.07 (br.s, 1H), 8.26 (dd, 1H), 8.20 (d, 1H), 8.08 (td, 1H), 7.99- 7.89 (m, 3H), 7.04 (d, 2H), 4.53 (dd, 2H), 4.14-4.05 (m, 1H), 3.93 (d, 2H), 3.87 (dd, 2H), 3.34-3.28 (m, partially obscured, 2H), 3.24 (t, 1H), 2.98-2.81 (m, 1H), 2.17-1.96 (m, 2H), 1.95- 1.83 (m, 1H), 1.73-1.60 (m, 3H), 1.57 -1.45 (m, 1H), 1.33 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.04 min, m / z = 492 [M + H] ⁺ .

Example 4

(+/-) - (1R5,25R, 5R5) -2 - [(4-Oxo-1,2,3-benzotriazine-3 (4 /) - yl) methyl] -5- {4- [2- (2H) tetrahydro-2ii-pyran-4-yl) ethoxy] benzoyl} cyclopentane carboxylic acid (racemate)

A solution of 2.91 g (4.75 mmol, purity 99%) of the compound from Example 6A in 16 ml of dichloromethane was admixed at 0 ° C. with 8.0 ml (104 mmol) of trifluoroacetic acid and stirred at 0 ° C. for 2 h. The mixture was then concentrated and the residue was dried in vacuo. After adding a little ethyl acetate, a solid was obtained which was filtered off, rinsed once with a little ethyl acetate and pentane and dried in vacuo. This gave 2.11 g (88% of theory, purity 100%) of a first batch of the title compound. The remaining mother liquor was concentrated and the residue was purified by preparative HPLC [column: Kinetix C18, 5 μm, 100 mm × 21.2 mm; Flow: 25 ml / min; Detection: 210 nm; Injection volume: 0.5 ml; Temperature: 40 ° C; Eluent: 44% water / 45% acetonitrile / 11% formic acid in water, isocratic over 8 min]. 52 mg (2% of theory, purity 100%) of a second batch of the title compound were obtained in this way.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.14 (br.s, 1H), 8.26 (d, 1H), 8.20 (d, 1H), 8.11-8.05 (m, 1H), 7.99 -7.90 (m, 3H), 7.04 (d, 2H), 4.58-4.47 (m, 2H), 4.15-4.05 (m, 3H), 3.83 (dd, 2H), 3.34-3.19 (m, 3H), 2.94 -2.81 (m, 1H), 2.16-2.04 (m, 1H), 1.95-1.83 (m, 1H), 1.75-1.58 (m, 6H), 1.57-1.45 (m, 1H), 1.29-1.14 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 506 [M + H] ⁺ .

Separation of the enantiomers:

2.00 g of the racemic compound from Example 4 were dissolved in 20 ml of dioxane, mixed with 180 ml of a methanol / acetonitrile mixture, brought into solution in the heat and then separated by means of preparative SFC on a chiral phase into the enantiomers (see Examples 5 and 6 ) [Column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 80 ml / min; Detection: 210 nm; Injection volume: 1.2 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol, running time 16 min].

Example 5

(+) - (lR5,25R, 5R5) -2 - [(4-Oxo-l, 2,3-benzotriazine-3 (4 /) - yl) methyl] -5- {4- [2- (tetrahydrofuran) 2ii-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylic acid (enantiomer 1)

910 mg (former purity = 97%, ee value = 100%) of the title compound were obtained, which were taken up in 20 ml of acetonitrile and further purified by chromatography [column: Kinetix C18, 5 μm, 100 mm × 30 mm; Flow: 60 ml / min; Detection: 210 nm; Injection volume: 1.0 ml; Temperature: 30 ° C; Eluent: 45% water / 50% acetonitrile / 5% formic acid in water, isocratic over 4 min]. There were thus obtained 850 mg of the title compound in a former purity of 100%. [a] _D ²⁰ = + 71.0 °, 589 nm, c = 0.37 g / 100 ml, chloroform Ή-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, 1H), 8.26 (dd, 1H), 8.20 (d, 1H), 8.08 (td, 1H), 7.98- 7.90 (m, 3H), 7.04 (d, 2H), 4.58-4.47 (m, 2H), 4.14-4.05 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, partially obscured, 3H) , 2.88 (sext, 1H), 2.15-2.05 (m, 1H), 1.93-1.84 (m, 1H), 1.76-1.58 (m, 6H), 1.56-1.47 (m, 1H), 1.27-1.16 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.07 min, m / z = 506 [M + H] ⁺ .

Example 6

(-) - (1R5,25R, 5R ^ -2 - [(4-Oxo-l, 2,3-benzotriazine-3 (4 /) - yl) methyl] -5- {4- [2- (tetrahydro-) 2ii-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 903 mg; former purity = 100%; ee value = 100% [α] _D ²⁰ = -70.1 °, 589 nm, c = 0.35 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.26 (d, 1H), 8.20 (d, 1H), 8.11-8.05 (m, 1H), 7.99-7.90 (m, 3H), 7.04 (d, 2H), 4.59-4.47 (m, 2H), 4.14-4.06 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, 3H), 2.87 (sec, 1H), 2.17- 2.04 (m, 1H), 1.95-1.83 (m, 1H), 1.75-1.58 (m, 6H), 1.57-1.45 (m, 1H), 1.29-1.15 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.05 min, m / z = 506 [M + H] ⁺ .

Example 7

(+/-) - (lRS, 2SR, 5RS) -2- {[4-oxo-6- (trifl ^^

hydro-2-pyran-4-ylmethoxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 585 mg (0.89 mmol) of the compound from Example 9A in 3 ml of dichloromethane was admixed at 0 ° C. with 1.5 ml (19.47 mmol) of trifluoroacetic acid. The mixture was stirred for 5.5 h at 0 ° C and then concentrated. The residue was taken up in 5 ml of acetonitrile. This precipitated a solid, which was filtered off and dried in vacuo. There were obtained 468 mg (95% of theory, purity 100%) of the title compound. Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 ( d, 2H), 4.57 (d, 2H), 4.15-4.05 (m, IH), 3.93 (d, 2H), 3.87 (dd, 2H), 3.38-3.28 (covert, 2H), 3.24 (t, IH) , 2.94-2.79 (m, IH), 2.18-1.87 (m, 3H), 1.73-1.61 (m, 3H), 1.59-1.46 (m, IH), 1.33 (qd, 2H). LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 660 [M + H] ⁺ .

Separation of the enantiomers:

465 mg of the racemic compound from Example 7 were dissolved in 15 ml of DMSO and 30 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 8 and 9) [column: Daicel Chiralpak AY, 20 μm, 250 mm × 30 mm; Flow: 175 ml / min; Detection: 210 nm; Injection volume: 1.3 ml; Temperature: 38 ° C; Eluent: 75% carbon dioxide / 25% ethanol, running time 16.5 min].

Example 8

(+) - (IRS, 2SR, 5RS) -2- {[4-oxo-6- (trifluoro ^

hydro-2-pyran-4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1) Yield: 239 mg; former purity = 100%; ee value = 100% [from ²⁰ = + 80.2 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 (d, 2H), 4.57 (d, 2H), 4.15-4.05 (m, IH), 3.93 (d, 2H), 3.87 (dd, 2H), 3.37-3.28 (obscured, 2H), 3.24 (t, IH), 2.94-2.80 (m, IH), 2.17-1.88 (m, 3H), 1.72-1.61 (m, 3H), 1.58-1.46 (m, IH), 1.33 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 660 [M + H] ⁺ .

Example 9

(-) - (IRS, 2SR, 5R ^ -2- {[4-oxo-6- (trifluoromethylene)

hydro-2-pyran-4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 2) Yield: 228 mg; ee value = 100%

[a] _D ²⁰ = -88.9 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.96 (d, 2H), 7.04 (d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, IH), 3.93 (d, 2H), 3.87 (dd, 2H), 3.37-3.28 ( covers, 2H), 3.23 (t, 1H), 2.94-2.80 (m, 1H), 2.17-1.87 (m, 3H), 1.73-1.61 (m, 3H), 1.58-1.46 (m, 1H), 1.33 ( qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.17 min, m / z = 660 [M + H] ⁺ . Example 10 (+/-) - (IRS, 2SR, 5RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 //) - yl] methyl} - 5- {4- [2- (tetrahydro-2-i-pyran-4-yl) ethoxy] benzoyl} cyclopentane carboxylic acid (racemate)

A solution of 135 mg (0.20 mmol) of the compound from Example 10A in 0.7 ml of dichloromethane was treated at 0 ° C with 0.35 ml (4.54 mmol) of trifluoroacetic acid. The mixture was stirred for 2.5 h at 0 ° C and then concentrated. The residue was taken up in 2 ml of acetonitrile and purified by preparative HPLC (Method 5). 91 mg (80% of theory, purity 100%) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 ( d, 2H), 4.57 (d, 2H), 4.14-4.05 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, 3H), 2.93-2.81 (m, 1H), 2.17-2.03 ( m, 1H), 2.00-1.88 (m, 1H), 1.76-1.45 (m, 7H), 1.29-1.14 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 574 [M + H] ⁺ .

Separation of the enantiomers:

83 mg of the racemic compound from Example 10 were dissolved in 2 ml of ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 11 and 12) [column: Daicel Chiralpak AY-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 1 ml; Temperature: 45 ° C; Eluent: t = 0-15 min 25% isohexane / 75% ethanol + 0.2% acetic acid].

Example 11

(+) - (IRS, 2SR, 5RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 //) - yl] methyl} -5- {4 - [2- (tetrahydro-2-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylic acid (enantiomer 1) Yield: 38 mg; ee value = 100%

[a] _D ²⁰ = + 70.7 °, 589 nm, c = 0.10 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.13 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 (i.e. , 2H), 4.57 (d, 2H), 4.14-4.06 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, 3H), 2.91-2.83 (m, 1H), 2.16-2.04 (m , 1H), 1.99-1.88 (m, 1H), 1.75-1.58 (m, 6H), 1.57-1.47 (m, 1H), 1.29-1.15 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 574 [M + H] ⁺ . Example 12

(-) - (1R5,25R, 5R ^ -2- {[4-Oxo-6- (trifluoromethyl) -l, 2,3-benzotriazine-3 (4 ^ -yl] methyl} -5- {4- [ 2- (tetrahydro-2-i-pyran-4-yl) ethoxy] benzoyl} cyclopentane carboxylic acid (enantiomer 2)

Yield: 45 mg; ee value = 100%

[α] _D ²⁰ = -77.1 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.13 (s, 1H), 8.51 (s, 1H), 8.46-8.38 (m, 2H), 7.96 (d, 2H), 7.04 ( d, 2H), 4.57 (d, 2H), 4.15-4.05 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, 3H), 2.93-2.81 (m, 1H), 2.17-2.04 ( m, 1H), 1.99-1.87 (m, 1H), 1.74-1.58 (m, 6H), 1.58-1.47 (m, 1H), 1.29-1.15 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.22 min, m / z = 574 [M + H] ⁺ .

Example 13

(+/-) - (1R5,25R, 5R5) -2- {[4-oxo-6- (trifluoromethyl) -1,3,3-benzotriazine-3 (4 /) -yl] methyl} -5- { 4- [(tetrahydro-2-yl-pyran-4-ylmethyl) sulfanyl] benzoyl-1-cyclopentanecarboxylic acid (racemate)

A solution of 249 mg (0.35 mmol, purity 95%) of the compound from Example 13A in 3.5 ml of dichloromethane was treated at 0 ° C with 1.75 ml of trifluoroacetic acid. The mixture was added stirred for 15 min at 0 ° C and then for 1 h at RT and then concentrated. The residue was purified by preparative HPLC (Method 4). 163 mg (81% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.16 (br.s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.41 (d, 2H), 4.62-4.52 (m, 2H), 4.15-4.06 (m, 1H), 3.83 (dd, 2H), 3.30-3.19 (m, 3H), 3.02 (d, 2H), 2.94- 2.81 (m, 1H), 2.20-2.04 (m, 1H), 2.01-1.87 (m, 1H), 1.84-1.61 (m, 4H), 1.60-1.45 (m, 1H), 1.35-1.17 (m, 2H ).

LC / MS (Method 1, ESIpos): R _t = 1.20 min, m / z = 576 [M + H] ⁺ .

Separation of the enantiomers:

150 mg of the racemic compound from Example 13 were dissolved in 3 ml of acetonitrile / ethanol and separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 14 and 15) [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 4.6 mm; Flow: 20 ml / min; Detection: 230 nm; Injection volume: 0.06 ml; Temperature: 25 ° C; Eluent: t = 0-16 min 20% ethanol / 76% acetonitrile / 4% 5% acetic acid in acetonitrile]. Example 14

(-) - (IRS, 2SR, 5R ^ -2- {[4-oxo-6- (trifluoromethylene)

hydro-2-pyran-4-ylmethyl) sulfanyl] benzoyl} cyclopentanecarboxylic acid (enantiomer 1)

Yield: 59 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -85.6 °, 589 nm, c = 0.39 g / 100 ml, chloroform Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.15 (br. s, 1H), 8.51 (s, 1H), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.41 (d, 2H), 4.63-4.51 (m, 2H), 4.16-4.03 (m, 1H), 3.83 (dd , 2H), 3.29-3.19 (m, 3H), 3.02 (d, 2H), 2.94-2.81 (m, 1H), 2.18-2.05 (m, 1H), 2.02-1.86 (m, 1H), 1.83-1.61 (m, 3H), 1.59-1.44 (m, 1H), 1.36-1.19 (m, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 576 [M + H] ⁺ . Example 15

(+) - (IRS, 2SR, 5RS) -2- {[4-Oxo-6- (trifluoromethyl) -1,2,3-benzotriazine-3 (4 /) -yl] methyl} -5- {4- [(tetrahydro-2-pyran-4-ylmethyl) sulfanyl] benzoyl} cyclopentanecarboxylic acid (enantiomer 2)

Yield: 61 mg; former purity = 100%; ee [a] _D ²⁰ = + 53.1 °, 589 nm, c = 0.16 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.14 (br.s, IH), 8.51 (s, IH), 8.46-8.37 (m, 2H), 7.90 (d, 2H), 7.41 (d, 2H), 4.63-4.50 (m, 2H), 4.16-4.05 (m, IH), 3.83 (dd, 2H), 3.29-3.17 (m, 3H), 3.02 (d, 2H), 2.94- 2.77 (m, IH), 2.18-2.04 (m, IH), 2.02-1.86 (m, IH), 1.83-1.62 (m, 3H), 1.60-1.45 (m, IH), 1.35-1.20 (m, 2H ).

LC / MS (Method 1, ESIpos): R _t = 1.21 min, m / z = 576 [M + H] ⁺ .

Example 16

(+/-) - (1R5,25R, 5R5) -2 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [4- (tetrahydro-2-pyran-4-ylmethoxy) benzoyl] cyclopentane carboxylic acid (racemate)

A solution of 290 mg (0.39 mmol, purity 82%) of the compound from Example 16A in 1.3 ml of dichloromethane was treated at 0 ° C with 0.7 ml (8.65 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 4). 153 mg (77% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (dd, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.13-4.04 (m, IH), 3.93 (d, 2H), 3.88 (dd, 2H), 3.37-3.28 (m, 2H), 3.23 (t, IH), 2.93-2.80 (m, IH), 2.55 (s, 3H), 2.16-1.95 (m, 2H), 1.93-1.82 (m, IH), 1.71-1.61 (m, 3H), 1.50 (dd, IH), 1.33 (qd, 2H). LC / MS (Method 1, ESIpos): R _t = 1.06 min, m / z = 506 [M + H] ⁺ .

Separation of the enantiomers:

144 mg of the racemic compound from Example 16 were dissolved in 11 ml of ethanol and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 17 and 18) [column: Phenomenex amylose®, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; injections volume: 0.40 ml; Temperature: 40 ° C; Eluent: 65% carbon dioxide / 35% ethanol, running time 15 min].

Example 17

(+) - (IR 5,25 R, 5 R 5) -2 - [(6-Methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (tetrahydro 2-pyran-4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 1)

Yield: 63 mg; former purity = 94%; ee value = 100%

[from ²⁰ = + 68.4 °, 589 nm, c = 0.39 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.11-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (dd, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.14-4.04 (m, IH), 3.93 (d, 2H), 3.87 (dd, 2H), 3.37-3.28 (partially obscured, 2H), 3.23 (t, IH), 2.92-2.80 (m, IH), 2.55 (s, 3H), 2.16-1.94 (m, 2H), 1.93-1.82 (m, IH), 1.67 (d, 3H), 1.56-1.44 (m, IH), 1.33 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.07 min, m / z = 506 [M + H] ⁺ .

Example 18

(-) - (1R5,25R, 5R ^ -2 - [(6-Methyl-4-oxo-l, 2,3-benzotriazine-3 (4 /) -yl) methyl] -5- [4- (tetrahydro 2-pyran-4-ylmethoxy) benzoyl] cyclopentanecarboxylic acid (enantiomer 2)

Yield: 63 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = -63.7 °, 589 nm, c = 0.37 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, IH), 8.12-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (dd, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.14-4.04 (m, IH), 3.93 (d, 2H), 3.87 (dd, 2H), 3.37-3.28 (partially obscured, 2H), 3.22 (t, IH), 2.93-2.79 (m, IH), 2.55 (s, 3H), 2.16-1.96 (m, 2H), 1.94-1.81 (m, IH), 1.72-1.60 (m, 3H), 1.56 -1.43 (m, IH), 1.33 (qd, 2H).

LC / MS (Method 1, ESIpos): R _t = 1.07 min, m / z = 506 [M + H] ⁺ .

Example 19

(+/-) - (IR 5,25R, 5R 5) -2 - [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) -methyl] -5- [2- (tetrahydro-2i-pyran-4-yl) efhoxy] benzoyl} cyclopentane carboxylic acid (racemate)

A solution of 142 mg (0.23 mmol) of the compound from Example 17A in 0.8 ml of dichloromethane was treated at 0 ° C with 0.4 ml (5.03 mmol) of trifluoroacetic acid. The mixture was stirred at RT for 1 h and then concentrated. The residue was purified by preparative HPLC (Method 6). 84 mg (71% of theory, purity 100%) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.12 (br.s, 1H), 8.11-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (dd, 1H), 7.04 (d, 2H), 4.51 (d, 2H), 4.15-4.05 (m, 3H), 3.83 (dd, 2H), 3.32-3.20 (m, 3H), 2.93-2.80 (m, 1H), 2.55 ( s, 3H), 2.16-2.04 (m, 1H), 1.93-1.82 (m, 1H), 1.76-1.57 (m, 6H), 1.57-1.44 (m, 1H), 1.30-1.12 (m, 2H). LC / MS (Method 1, ESIpos): R _t = 1.14 min, m / z = 520 [M + H] ⁺ .

Separation of the enantiomers:

69 mg of the racemic compound from Example 19 were dissolved in 10 ml of ethanol / acetonitrile and separated into the enantiomers by means of preparative SFC on a chiral phase (see Examples 20 and 21) [column: Phenomenex amylose II, 5 μm, 250 mm × 20 mm; Flow: 100 ml / min; Detection: 210 nm; Injection volume: 0.40 ml; Temperature: 40 ° C; Eluent: 70% carbon dioxide / 30% ethanol, running time 18 min].

Example 20

(+) - (IRS, 2SR, 5RS) -2- [(6-methyl-4-oxo-1,2,3-benzotriazine-3 (4 /) -yl) methyl] -5- {4- [2 - (tetrahydro-2-i-pyran-4-yl) ethoxy] benzoyl} cyclopentanecarboxylic acid (enantiomer 1) Yield: 22 mg; former purity = 100%; ee value = 100%

[a] _D ²⁰ = + 50.6 °, 589 nm, c = 0.32 g / 100 ml, chloroform

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.10 (br.s, 1H), 8.12-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (d, 1H), 7.04 (d, 2H), 4.51 (d, 2H), 4.16-4.04 (m, 3H), 3.83 (dd, 2H), 3.32-3.19 (m, partially occluded, 3H), 2.93-2.79 (m, 1H), 2.55 (s, 3H), 2.17-2.04 (m, 1H), 1.94-1.82 (m, 1H), 1.76-1.58 (m, 6H), 1.56-1.44 (m, 1H), 1.29-1.11 (m, 2H ).

LC / MS (Method 1, ESIpos): R _t = 1.10 min, m / z = 520 [M + H] ⁺ . Example 21

(-) - (1R5,25R, 5R ^ -2 - [(6-Methyl-4-oxo-l, 23-benzotriazine-3 (4 /) -yl) methyl] -5- {4- [2- ( tetrahydro-2 / f-pyran-4-yl) ethoxy] berizoyl} cyclopentaricarboxylic acid (enantiomer 2)

Yield: 20 mg; former purity = 95%; ee value = 100% [a] _D ²⁰ = -50.6 °, 589 nm, c = 0.31 g / 100 ml, chloroform

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 12.10 (br.s, IH), 8.11-8.04 (m, 2H), 7.96 (d, 2H), 7.90 (dd, IH), 7.04 (d, 2H), 4.51 (d, 2H), 4.15-4.04 (m, 3H), 3.83 (dd, 2H), 3.32-3.19 (m, partially occluded, 3H), 2.93-2.79 (m, IH) , 2.55 (s, 3H), 2.16-2.04 (m, IH), 1.94-1.81 (m, IH), 1.74-1.57 (m, 6H), 1.56-1.44 (m, IH), 1.29-1.14 (m, 2H).

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be detected by in vitro and in vzvo studies, as are known to those 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

PBS phosphate buffered saline

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 fluorescence 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 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 assay buffer (0.1 M HEPES pH 7.4, 0.15M NaCl, 0.03M CaCl _2, 0.004 mM ZnCl _2, 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 batches 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).

In the following Table 1A, for individual embodiments of the invention, the IC 50 values from the standard or highly sensitive HME inhibition test are reproduced (partly as averages from several independent individual determinations and rounded to two significant digits): Table 1A: Inhibition of human macrophage elastase (HME / hMMP-12)

Representative embodiments of the invention are compared in the following Table 1B with the IC ₅₀ values from the HME inhibition test in the absence (see data in Table 1A) and presence of serum albumin (partly as averages from several independent determinations and rounded to two significant digits):

Table 1B: Inhibition of human macrophage elastase (HME / hMMP-12) in the absence (-) or presence (+) of serum albumin (BSA)

Example HME ICso [nM] HME ICso [nM]

No. (- BSA) (+ BSA)

1 0.040 6.45

2 0.071 6.71

4 0.37 37.3

5 0.085 4.06

8 0.016 2.45

11 0.19 39.2

15 0.026 16.0

19 0.12 32.0 Example HME ICso [nM] HME ICso [nM]

No. (- BSA) (+ BSA)

20 0.053 12.2

Comparison of the data presented in Table 1B shows that the compounds according to the invention still have a high inhibitory potency (frequently in the nanomolar range) compared to HME, even in the presence of serum albumin. This indicates a less pronounced nonspecific interaction of the compounds according to the invention with blood plasma components and thus allows an increased "free fraction" of these compounds in the blood, which should have a favorable effect on the vzVo activity.

B-2. In vitro MMP inhibition tests

The potency of the compounds of the invention over other MMPs (and thus their Selekivität) 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 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-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 concentra- tion, for example, 2 nM) in reaction buffer (50 mM Tris / HCl pH 7.5, 10 mM CaCl, 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the examined test compound (as a solution in DMSO, suitable concentrations, for example 1 nM to 30 μΜ) in a white 384-well microtiter plate (MTP). 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 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 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 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-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 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-10 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 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 CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) 1 μΐ of the test compound to be tested (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 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-14 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-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) 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 intramolecular quenched substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa (Dnp) -Ala-Arg-NH2 (final concentration eg 5 μΜ, R & D Systems, ES-010) is started so that 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, for representative embodiments of the invention, the IC 50 values from these assays for inhibiting human MMPs are reported (in part as averages of several independent determinations and rounded to two significant digits):

Table 2A: Inhibition of human MMPs

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]

1 450 120 110 160 1500

2 360 80 49 99 550

4 5000 170 460 2700 7100

5 460 13 67 250 940 Example MMP-9 MMP-10 MMP-13 MMP-14 MMP-16

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

7 120 11000 140 170 830

8 55 12 51 100 280

10 310 5100 230 600 1800

11 660 18 470 1200 3800

15 150 9 220 150 760

19 960 58 590 2700 2500

20 370 31 170 1000 3100

Comparing the inhibition data presented in Tables 1A and 2A / 2B shows that the compounds according to the invention in general and their more active stereoisomers in particular have a very high inhibitory potency (frequently in the sub-nanomolar range) compared to HME and at the same time a high to very high Have selectivity (usually one to three orders of magnitude or more) against 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) is 1 μΐ of the examined test compound (as a solution in DMSO, suitable concentrations pipetted example 1 nM to 30 μΜ) (in a white 384 well microtitre plate MTP). 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 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 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 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-7 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-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 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 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 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. Here, a tenfold lower enzyme concentration is used (final concentration, e.g., 0.1 nM) to achieve increased sensitivity of the assay. 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 CaCl ₂ , 150 mM NaCl, 0.05% Brij ^® -35) is 1 μΐ of the examined test compound (as a solution in DMSO, suitable concentrations pipetted example 1 nM to 30 μΜ) (in a white 384 well microtitre plate MTP). 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 (eg 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.). Rat in vitro MMP-12 inhibition test:

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 compo- sition (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 of buffer A (50 mM Tris pH 7.4, 100 mM NaCl, 0.03 mM ZnCl ₂ , 10 mM CaCl ₂ , 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 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-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

Example MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-12

No. IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM] IC50 [nM]

1 170 570 85 40 560 3.3

2 58 710 52 21 280 0.85

4 490 4000 1400 370 1500 7.7

5 45 270 130 54 210 0.67 Example MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-12 No. ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM] ICso [nM]

10 300 120 130 14 930 2.8

11 640 620 210 34 1900 9.4

19 840 3100 630 150 2200 7.6

20 340 670 200 46 800 1.7

Comparing the inhibition data presented in Table 3 shows that the compounds according to the invention in general and their more active stereoisomers in particular have a very high inhibitory potency (frequently in the nanomolar or even sub-nanomolar range) in relation to mouse MMP-12 and at the same time have high selectivity (usually one to two 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 starts on the day of the 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 leads to 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

Silica-induced lung fibrosis in mouse, rat or hamster is a widely used animal model of pulmonary fibrosis [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 receive oro-tracheal instillation of silica. The treatment of the animals with the test substance starts during the day the instillation of the silica or therapeutically a 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 causes 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 human CYP enzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in human is examined using pooled human liver microsomes as enzyme source in the presence of standard substrates (see above) which form CYP-specific metabolites. The inhibition effects are investigated at six different concentrations of the test compounds [2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μΜ], 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 calculated. A standard inhibitor that specifically inhibits a single CYP isoform is always incubated to make comparisons between different series comparable.

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 MgC x 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) to ensure the best possible linear kinetic conditions in the experiment , 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 represent a measure of the phase 1 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 mixtures, its concentration in the Generally limited to 1% (acetonitrile) and 0.1% (DMSO).

For all species and breeds, a hepatocyte cell count in the liver of 1.1 * 10 ⁸ cells / g liver is expected. CL parameters calculated using half-lives that are significantly longer than the incubation time (usually 90 minutes) can only be considered as rough guidelines.

The calculated parameters and their meaning are:

Fmax well-stirred [] maximum bioavailability after oral administration

Calculation: (l-CLbi ₀₀ d well-stirred / QH) * 100

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

Calculation: (QH * CL '; "trinsic) / (QH + CL';" trinsic)

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'mtrinsic, apparent * species-specific hepatocyte count [1.1 * 10 ⁸ / g liver] * species-specific liver weight [g / kg]

CL'mtrinsic, 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). In the following Table 4, for representative embodiments of the invention, the CL and Fmax values from this assay are shown 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 / ethanol / water mixture), the oral administration is carried out as a solution (eg in Solutol / Ethanol / water or PEG / ethanol / water mixtures) or as a suspension (eg in Tylose) in each case 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-MSMS. 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), t (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).

B-ll. Determination of solubility

Experimental procedure:

The test substance is dissolved in DMSO. An aliquot is taken from this solution and introduced into PBS buffer pH 6.5 (DMSO content: 1%). This solution / suspension is shaken for 24 h at room temperature. After ultra-centrifugation at 114,000 g for 30 min, the supernatant is removed, diluted with acetonitrile / water 8: 2 and analyzed by LC-MSMS. Quantification is via a five-point calibration curve of the test compound in DMSO.

Devices for LC-MSMS quantification:

AB Sciex TRIPLE QUAD 4500; Agilent 1260 with Primary Pump (G1312B Minity), Degasser (G4225A Minity), Column Thermostat (G1316C Minity); CTC Analytics PAL injection system THC-xt. HPLC method:

Eluent A: 0.5 ml of formic acid / liter of water, eluent B: 0.5 ml of formic acid / liter of acetonitrile; Gradient: 0 min 90% A -> 0.5 min 5% A -> 0.84 min 5% A -> 0.85 min 90% A ^ 1.22 min 90% A; Flow: 2.5 ml / min; Injection volume: 15 μΐ; Column: Waters OASIS HLB, 2.1 x 20 mm, 25 μ; Column temperature: 30 ° C; Splitter (before MS): 1:20.

MS methods:

Flow Injection Analysis (FIA) for optimization, Multiple Reaction Monitoring (MRM) for quantification; Eluent A: 0.5 ml of formic acid / liter of water, eluent B: 0.5 ml of formic acid / liter of acetonitrile; Flow: 0.25 ml / min; Injection volume: 15 μΐ; Column: stainless steel capillary; Capillary temperature: 25 ° C.

Table 5 below shows the solubility values of representative embodiments thus determined in PBS buffer pH 6.5:

TABLE 5 Solubility in PBS buffer pH 6.5

Example no. Solubility [mg / liter]

1 52.2

4 51.4

5 338.1

6 354.9

4.5

10 33.4

11 210

12 240

14 80

15 100

17 250

18,330

19 17

20 425.2 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

Patent claims

1. Compound of formula (I)

in which

A stands for -O- or -S-,

stands for the number 1 or 2

and

R ¹ represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl, or a salt, solvate or solvate of a salt of this compound.

2. A compound of formula (I) according to claim 1, in which

A stands for -O-,

stands for the number 1 or 2

and

represents hydrogen, methyl or trifluoromethyl,

or a salt, solvate or solvate of a salt of this compound.

3. A compound of formula (I) according to claim 1 or 2, in which

A stands for -O-,

stands for the number 2

and

R ¹ represents hydrogen, methyl or trifluoromethyl, or a salt, solvate or solvate of a salt of this compound.

4. A compound according to claim 1, 2 or 3 with the formula (I-A) or (I-B)

wherein A, n and R ¹ have the meanings defined in claim 1, 2 or 3 and the groups bonded to the central cyclopentane ring have a relative irans arrangement to one another, or a mixture of these compounds, where A, n and R ¹ , respectively in such a mixture of (IA) and (IB) are each identical, or a salt, solvate or solvate of a salt of these compounds or their mixture. 5. Compound according to claim 1, 2, 3 or 4 with the formula (IA)

wherein A, n and R ¹ have the meanings defined in claim 1, 2 or 3, in enantiomerically pure form with an, as designated, (IS,2R,5S) configuration on the central cyclopentane ring or a salt, solvate or Solvate of a salt of this compound.

Process for the preparation of a compound as defined in claims 1 to 5, characterized in that a compound of formula (Π)

in which A and R ¹ have the meanings given in claims 1 to 5, in the presence of a base with a compound of the formula (III) in which n has the meaning given in claims 1 to 5 and

X represents a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate to give a compound of the formula (IV)

in which n, A and R ¹ have the meanings given in claims 1 to 5, alkylated and then the 2-(trimethylsilyl)ethyl ester group using an acid or a fluoride reagent to give the carboxylic acid of the formula (I)

in which n, A and R ¹ have the meanings given in claims 1 to 5, splits off and optionally separates the compounds of formula (I) thus obtained into their enantiomers and/or diastereomers and/or with the corresponding (i) solvents and /or (ii) bases converted into their solvates, salts and/or solvates of the salts.

A compound as defined in any one of claims 1 to 5 for the treatment and/or prevention of diseases.

A compound as defined in any one of claims 1 to 5 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, arteriosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their complications such as stroke, myocardial infarction and peripheral arterial disease, as well as chronic kidney disease and Alport syndrome.

9. Use of a compound as defined in any one of claims 1 to 5 for the production 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 diseases, idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis, arteriosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their complications such as stroke, myocardial infarction and peripheral arterial disease, as well as chronic kidney disease and Alport syndrome . Medicaments containing a compound as defined in any one of claims 1 to 5, in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

Medicament containing a compound as defined in one of claims 1 to 5, in combination with one or more further active ingredients selected from the group consisting of corticosteroids, beta-adrenergic receptor agonists, anti-muscarinic substances, PDE 4 inhibitors, PDE 5 inhibitors, sGC activators, sGC stimulators, HNE inhibitors, prostacyclin analogues, endothelin antagonists, statins, antifibrotic agents, anti-inflammatory agents, immunomodulatory agents, immunosuppressive agents and cytotoxic agents.

Medicament according to claim 10 or 11 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, arteriosclerosis, carotid arteriosclerosis, viral myocarditis, cardiomyopathy and aneurysms, including their complications such as stroke, myocardial infarction and peripheral arterial disease, as well as chronic kidney disease and Alport syndrome.

Methods 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, arteriosclerosis, carotid arteriosclerosis, 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 one of claims 1 to 5, or a medicament as defined in one of claims 10 to 12.