DE102010030187A1 - New 4-cyano-2-sulfonylphenyl-pyrazolyl-substituted pyridinones and pyrazinones compounds are human neutrophil elastase inhibitors, useful to treat and prevent e.g. pulmonary arterial hypertension and chronic obstructive pulmonary disease - Google Patents

Abstract

4-Cyano-2-sulfonylphenyl-pyrazolyl-substituted pyridinone and pyrazinone compounds (I) are new. 4-Cyano-2-sulfonylphenyl-pyrazolyl-substituted pyridinone and pyrazinone compounds of formula (I) and their salts, solvates or solvates of the salts, are new. A : CH or N; R1 : CH 3or ethyl; R2, R3 : (1-4C)-alkyl or H; R4 : H, F or Cl; and R5 : (1-6C)-alkyl (optionally substituted with (1-4C)-alkoxy, di(1-4C)-alkylamino, (3-6C)-cycloalkyl, phenyl or 6-membered heteroaryl or up to five times with F). Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with one or more inert, non-toxic excipients. [Image] ACTIVITY : Hypotensive; Respiratory-Gen.; CNS-Gen.; Antiasthmatic; Antiinflammatory; Antitussive; Virucide; Antiallergic; Cardiant; Vasotropic; Antibacterial; Immunosuppressive; Antiarteriosclerotic; Uropathic; Antiarthritic; Antirheumatic; Dermatological; Ophthalmological; Anticoagulant; Thrombolytic; Nephrotropic; Antiarrhythmic; Cerebroprotective; Antilipemic; Hemostatic; Analgesic; Antianginal; Antidiabetic; Metabolic; Anorectic; Cytostatic; Gastrointestinal-Gen.; Antidiarrheic; Hepatotropic; Neuroprotective; Nootropic; Antiparkinsonian; Anticonvulsant; Antidepressant; Immunomodulator; Antithyroid; Antipsoriatic; Antiseborrheic; Osteopathic. MECHANISM OF ACTION : Human neutrophil elastase inhibitor; Cytochrome P450 inhibitor. The human neutrophil elastase inhibiting activity of (I) was tested in vitro. The results showed that 5-{1-[4-cyano-2-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-carboxamide exhibited an IC 50value of 0.5 nM.

Description

The present application relates to novel thioaryl-containing pyrazinone and pyridone 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 diseases of the lungs and the cardiovascular system.

Human leukocyte elastase (HLE, EC 3.4.21.37), also called human neutrophil elastase (HNE, hNE), belongs to the family of serine proteases. The proteolytic enzyme is found in the azurophilic granules of polymorphonuclear leukocytes (polymorphonuclear leukocytes, PMN leukocytes). Intracellular elastase plays an important role in the defense against pathogens by breaking down foreign particles taken up via phagocytosis. Activated neutrophils release the HNE from the granules into the extracellular space (extracellular HNE), leaving some of the released HNE on the outside of the neutrophil cell membrane (membrane-bound HNE). The highly active enzyme is capable of degrading a variety of connective tissue proteins, e.g. As the proteins elastin, collagen and fibronectin. Elastin occurs in high concentrations in all tissue types that show high elasticity, e.g. In the lungs and arteries. In a variety of pathological processes (eg, tissue injury), HNE plays a role in tissue remodeling. In addition, HNE is an important modulator in inflammatory processes. For example, HNE induces increased gene expression of interleukin-8 (IL-8).

Thus, it is believed that HNE plays an important role in many diseases, injuries and pathological changes whose genesis and / or progression is associated with inflammatory events and / or proliferative and hypertrophic tissue and vascular remodeling. These may be, in particular, diseases and / or damage to the lung or the cardiovascular system, or these may be sepsis, cancers or other inflammatory diseases.

In particular, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and cystic fibrosis (cystic fibrosis CF, also called cystic fibrosis), pulmonary emphysema (emphysema) and acute lung injury (ALI). Diseases and damages of the cardiovascular system in which the HNE is involved are, for example, tissue changes in heart failure and reperfusion damage after myocardial infarction (AMI), cardiogenic shock, acute coronary syndrome (acute acute coronary syndrome) coronary syndrome, ACS) as well as aneurysms. Diseases associated with sepsis include, for example, a systemic inflammatory response syndrome (SIRS), severe sepsis, septic shock, and multi-organ failure (MOF) ) as well as 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 HNE plays a role are rheumatoid diseases, for example rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (ulcerative colitis) , UC) and arteriosclerosis.

In general, it is believed that elastase-mediated pathological processes underlie a shifted balance between free elastase and the body's elastase inhibitor protein (mainly alpha-1-antitrypsin, AAT) [ Neutrophils and protease / antiprotease imbalance, Stockley, Am. J. Respir. Crit. Care Med. 160, 49-52 (1999) ]. AAT is present in plasma in high excess and thus very quickly neutralizes free HNE. In various pathological processes, the concentration of free elastase is increased, so that locally the balance between protease and protease inhibitor is shifted in favor of the protease. In addition, the membrane-bound elastase of the activated PMN cells is largely protected from inhibition by AAT. The same applies to the free elastase, which is located in a difficult-to-access microcompartment between the neutrophil cell and the adjacent tissue cell (eg endothelial cell). In addition, strongly oxidizing conditions prevail in the environment of activated leukocytes (English: oxidative burst), whereby AAT is oxidized and loses several orders of magnitude in the inhibitory effect.

Accordingly, new elastase-inhibiting agents (exogenously administered inhibitors of HNE) should have a low molecular weight in order to be able to reach and inhibit also the membrane-bound HNE and the HNE (see above) in the protected microcompartment. For this purpose, a good stability of the substances in vivo is necessary (low in vivo clearance). In addition, these compounds should be stable under oxidative conditions so as not to lose their inhibitory potency in disease.

Pulmonary arterial hypertension (PAH) is a progressive lung disease that, if untreated, leads to an average death within 2.8 years of diagnosis. An increasing constriction of the pulmonary circulation leads to an increase in the burden on the right heart, which can lead to right heart failure. By definition, chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value <20 mmHg). The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PAH, neomuscularization of primarily non-muscularized pulmonary vessels occurs, and the vascular musculature of the already muscularized vessels increases in size. This increasing obliteration of the pulmonary circulation causes a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in a right heart failure ( M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S ). With a prevalence of 1-2 per million, PAH is an extremely rare disease. The median age of the patients was estimated at 36 years, only 10% of the patents were over 60 years old. Significantly more women than men are affected ( GE D'Alonzo et al., Ann. Intern. Med. 1991, 115, 343-349 ).

Despite all advances in the treatment of pulmonary arterial hypertension, there is no prospect of curing this serious disease. Standard therapies on the market (eg, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, exercise tolerance, and prognosis of patients. These are primarily hemodynamic therapy principles that affect vascular tone but have no direct impact on the pathogenic remodeling processes. In addition, the applicability of these drugs by the z. T. serious side effects and / or complicated application forms limited. The period of time during which the clinical situation of patients can be improved or stabilized under specific monotherapy is limited (eg due to tolerance development). Finally, there is a therapy escalation and thus a combination therapy in which several drugs have to be given at the same time.

New combination therapies are one of the most promising future treatment options for the treatment of pulmonary arterial hypertension. In this context, the exploration of new pharmacological mechanisms for the treatment of PAH is of particular interest ( Ghofrani et al., Herz 2005, 30, 296-302 ; EB Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619 ; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733 ). Above all, such treatment options that directly intervene in the remodeling process (anti-remodeling mechanisms, reverse-remodeling mechanisms), could be the basis of a more causal treatment and thus bring a great advantage for the patients. New therapies should be combinable with the known ones. To minimize the risk of interfering drug interactions in such combination therapy, these new agents should not or only to a limited extent inhibit metabolising P450 CYP enzymes.

Today it is believed that elastase plays a central role in pathological remodeling. In animal models and in patients with increased pulmonary arterial pressure (pulmonary arterial hypertension), connective tissue fragmentation (internal elastic lamina) has been observed [ Rabinovitch et al., Lab. Invest. 55, 632-653 (1986) ], and in animal models of pulmonary arterial hypertension (hypoxic rat and mouse model, monocrotaline rat model), increased elastase activity associated with fragmentation of the connective tissue was demonstrated [ Todorovich-Hunter et al., Am. Rev. Respir. Dis. 146, 213-223 (1992) ]. It is believed that the tissue remodeling to be observed is induced in the course of disease progression of pulmonary arterial hypertension by elastase-mediated release of connective tissue growth factors, e.g. B. basic fibroblast growth factor (bFGF) [ Rabinovitch, Am. J. Physiol. 277, L5-L12 (1999) ]. In the hypoxic mouse model for pulmonary arterial hypertension, a positive effect with an overexpressed elastase inhibitor protein could be shown [ Zaidi et al., Circulation 105, 516-521 (2002) ]. In the monocrotaline rat model for pulmonary arterial hypertension, a positive effect could be demonstrated with synthetic, low molecular weight elastase inhibitors; this also had a favorable effect on tissue remodeling [ Cowan et al., Nature Med. 6, 698-702 (2000) ]. All previously known However, low molecular weight elastase inhibitors are less selective, chemically reactive, and / or orally available only to a limited extent, thus hindering the clinical development of an oral elastase inhibitor in these indications.

The term "pulmonary arterial hypertension" includes certain forms of pulmonary hypertension, such as. B. established by the World Health Organization (WHO) ( Clinical Classification of Pulmonary Hypertension, Venice 2003 ; G. Simonneau et al., J. Am. Coll. Cardiol. 2004, 43, 5S-12S ).

According to this classification, pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, also referred to as primary pulmonary hypertension, PPH), familial pulmonary arterial hypertension (FPAH), persistent pulmonary hypertension of the newborn and associated pulmonary arterial Hypertension (APAH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, the use of certain drugs and medications (for example, appetite suppressants), with diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage disorders, Gaucher's disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy.

Other forms of pulmonary hypertension include, for example, pulmonary hypertension associated with left ventricular disease, e.g. As in ventricular or valvular diseases associated with respiratory and / or pulmonary diseases associated pulmonary hypertension, z. In chronic obstructive pulmonary disease, interstitial lung disease or pulmonary fibrosis, pulmonary hypertension due to chronic thrombotic and / or embolic diseases, e.g. As in thromboembolic obstruction of pulmonary arteries, as well as by general inflammatory disease processes or caused by special causes pulmonary hypertension (eg, in schistosomiasis, sarcoidosis and tumor diseases).

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 past two to three decades, include the use of bronchodilators to open blocked airways and, in certain situations, corticosteroids to control the inflammation of the lungs [ 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. 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 result to an excessive degradation of the elastin of the alveolar bodies [ JE Gadek et al., J. Clin. Invest. 68, 889-898 (1981) ; Z. Werb et al., J. Invest. Dermatol. 79, 154-159 (1982) ; A. Janoff, Am. Rev. Respir. Dis. 132, 417-433 (1985) ; PJ Barnes, N. Engl. J. Med. 343, 269-280 (2000) ]. This tissue breakdown causes a collapse of the bronchi. This is accompanied by a decreased elasticity of the lung, which leads to a hindrance of the respiratory flow and impaired breathing. In addition, frequent and prolonged inflammation of the lungs may lead to bronchial remodeling and, as a consequence, to the formation of lesions. Such lesions contribute to the onset of chronic cough that marks chronic bronchitis.

Alpha-1-antitrypsin (AAT) is a small endogenous protein and, as mentioned above, is the most important endogenous elastase inhibitor. In patients with a genetic deficiency of this protein (AATD), the protease / antiprotease balance is shifted. The effective radius and the duration of action of the HNE are correspondingly increased by a factor of 2.5 and 6.5 in AATD patients [ TG Liou and EJ Campbell, Biochemistry 1995, 16171-16177 ]. AATD patients are at an increased risk of developing emphysema or COPD, and in many AATD patients, lung transplantation is indicated.

Acute lung injury (ALI) and its more pronounced form, acute respiratory distress syndrome (ARDS), are serious illnesses associated with mortality of 50-60%. According to the definition of the North American-European Consensus Conference (NAECC) of 1994, ALI and ARDS are defined by an acute causative disorder, bilateral radiologically visible infiltrates, a PaO ₂ / FiO ₂ index of ≤ 300 mmHg (ALI) and ≤ 200, respectively mmHg (ARDS), a pulmonary capillary occlusion pressure of <18 mmHg or missing clinical evidence of left atrial hypertension.

The development of acute lung injury may be preceded by both pulmonary and extrapulmonary diseases. Pulmonary-specific predisposing factors include aspiration of gastric contents, pneumonia, smoke poisoning, pulmonary contusion, and near-drowning. Gastric aspiration and pneumonia in particular are often seen as the initial disease for ALI / ARDS pulmonary origin. Indirect events are mainly polytrauma, sepsis, multiple blood transfusions, acute pancreatitis and burns. The incidence is 17.9 cases for ALI and 13.5 cases for ARDS per 100 000 inhabitants and year [ Luhr et al., Am. J. Respir. Crit. Care Med. 159, 1849-1861 (1999) ].

A central role in the development of these diseases is the massive inflammatory changes in the lungs, which are triggered by a widespread system of mediators. An important role in the development of lung damage also plays the neutrophil granulocytes, the number of which increases constantly with the duration of the inflammatory process [ Chollet-Martin et al., Am. J. Respir. Crit. Care Med. 594-601 (1996) ]. The effect of the mediators causes damage to the alveolar capillary membranes, resulting in a permeability increase of the alveolar capillary barrier. By increasing the permeability, protein-rich fluid can penetrate into the alveoli and also into the interstitium; it forms a pulmonary low-pressure edema. Characteristic of ALI / ARDS is that it is a non-cardiogenic induced edema. The edema fluid mainly contains fibrin, erythrocytes, leukocytes, hyaline membranes and other proteins. The protein-rich exudate together with the products of activated neutrophils leads to a dysfunction of the surfactant. The inflammatory processes lead to the damage and loss of type II pneumocytes that form surfactant, resulting in a decrease in surfactant production. Due to the surfactant deficiency, the surface tension in the alveoli increases; Alveoli collapse, atelectases are formed. Continuing perfusion thus results in a ventilation-perfusion disorder, which results in an increase in the pulmonary right-left shunt. In addition, compliance decreases, alveolar dead space increases, as there are areas that are ventilated, but are not adequately perfused due to pulmonary hypertension.

In the bronchoalveolar lavage fluid of ARDS patients (HALF) increased elastase activity was measured, which is associated with the severity of lung injury. In animal models where the lungs are damaged (eg by administration of LPS), this effect can be re-adjusted. Treatment with elastase inhibitors (eg, sivelestat or Elafin, see below) significantly reduces the elastase activity in the RALF and improves lung function.

For the treatment of acute lung injury associated with SIRS, an elastase inhibitor is approved in Japan and South Korea (Sivelestat, Elaspol ^® ). The reversible but reactive compound has only a relatively weak activity against the HNE (K, 200 nM) and also acts against the elastase of the pancreas (IC ₅₀ 5.6 μM). The drug is administered intravenously, oral administration is not possible.

Elafin and structural analogues are also being studied as therapeutically useful elastase inhibitors. Elafin is an endogenous small protein that inhibits both elastase and proteinase 3. Due to the proteinogenic nature, however, oral administration of Elafin is not possible.

In WO 2004/024700 . WO 2004/024701 . WO 2005/082863 and WO 2005/082864 Various 1,4-diaryl-dihydropyrimidin-2-one derivatives are disclosed as HNE inhibitors for the treatment of chronic obstructive pulmonary disease, acute coronary syndrome, myocardial infarction and heart failure. Di- and multimers of such compounds for the treatment of respiratory diseases are described in WO 2006/082412 . WO 2006/136857 and WO 2007/042815 claimed. 4-aryl-dihydropyrimidin-2-one derivatives as inhibitors of calcium channel function for the treatment of hypertension are described in WO 2005/009392 described. In WO 2007/129060 become tetrahydropyrrolopyrimidinediones and multimers thereof as HNE inhibitors disclosed. Meanwhile, in WO 2008/003412 the use of 1,4-diaryl-dihydropyrimidin-2-one derivatives for the treatment of pulmonary arterial hypertension has been described.

WO 2007/129962 discloses 2-pyridone derivatives as elastase inhibitors WO 2007/129963 discloses pyrazinone derivatives as elastase inhibitors whose potency (IC 50) and metabolic stability are still in need of improvement in order to open up a better therapeutic window.

WO 2009/061271 discloses specific dihydropyrazine derivatives, namely 6-heteroaryl-5-methyl-3-oxo-4- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrazine-2-carboxamide derivatives as elastase inhibitors.

WO 2009/080199 discloses providing 4-cyanophenyl / pyridyl dihydropyrimidinones which also have a trifluorophenyl and a sulfonyl substitution. The provision of further structural classes with the highest possible potency (IC 50) and high metabolic stability is a general need, for example, a desired dosage (eg once daily) or to achieve a smaller tablet shape.

It has now been found that certain pyridone and pyrazinone derivatives are particularly suitable for the treatment and / or prevention of diseases. These compounds described below are low molecular weight, non-reactive and selective inhibitors of human neutrophil elastase (HNE), which surprisingly have a markedly greater inhibition (IC 50) and higher metabolic stability compared to the compounds known from the prior art thus represent promising starting points for new drugs for the treatment and / or prevention, in particular of diseases of the lung and the cardiovascular system.

The pyrazinones and pyridones of the present invention are structurally structurally characterized by a sulfonyl substituent in the ortho position to the 5-membered heterocycle, which surprisingly results in the improved properties of the compounds described above.

in welcher
A für CH oder N steht,
R¹ steht für Methyl oder Ethyl,
R² und R³ stehen unabhängig voneinander für (C₁-C₄)-Alkyl oder Wasserstoff,
R⁴ steht für H, F oder Cl welches in meta oder para Position zum 6-Ringheterocyclus den Phenylring substituiert,
R⁵ steht für (C₁-C₆)-Alkyl, das mit (C₁-C₄)-Alkoxy, Di-(C₁-C₄)-Alkylamino, (C₃-C₆)-Cycloalkyl, Phenyl oder 6-gliedrigem Heteroaryl oder bis zu fünffach Fluor substituiert sein kann.
sowie ihre Salze, Solvate und Solvate der Salze.In detail, the present invention relates to compounds of the general formula (I)

in which
A is CH or N,
R ¹ is methyl or ethyl,
R ² and R ³ independently of one another are (C ₁ -C ₄ ) -alkyl or hydrogen,
R ⁴ is H, F or Cl which in meta or para position to the 6-ring heterocycle substitutes the phenyl ring,
R ⁵ is (C ₁ -C ₆ ) -alkyl which is substituted by (C ₁ -C ₄ ) -alkoxy, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl, phenyl or 6-membered heteroaryl or up to five times fluorine may be substituted.
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 listed below and their salts, solvates and solvates of the salts and those 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.

Depending on their structure, the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

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

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 themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
(C ₁ -C ₆ ) -Alkyl are in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, neopentyl and n-hexyl
(C ₁ -C ₄ ) -Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
Di (C ₁ -C ₄ ) -alkylamino in the context of the invention is an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 4 carbon atoms. Examples which may be mentioned by way of example and with preference: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-methylamino, N-isopropyl-Nn-propylamino, N, N-diisopropylamino, Nn-butyl-N-methylamino and N-tert-butyl-N-methylamino.
(C ₃ -C ₆ ) -cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. By way of example and preferably mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
6-membered heteroaryl is in the context of the invention an aromatic heterocycle (heteroaromatic) with a total of 6 ring atoms containing one or two ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally a ring Nitrogen atom is linked. Preference is given to pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

R¹, R², R³, R⁴ und R⁵ jeweils die oben angegebenen Bedeutungen haben,
und ihre Salze, Solvate und Solvate der Salze.Of particular importance are compounds according to formula (Ia),

R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the meanings given above,
and their salts, solvates and solvates of salts.

More preferably, R ^{1 is} methyl.

With particular preference, R ^{4 is} hydrogen.

In a likewise preferred embodiment, R ² and R ^{3 are} methyl or hydrogen, more preferably R ^{2 is} methyl and R ^{3 is} H.

In a preferred embodiment, R ⁵ is (C ₁ -C ₆ ) -alkyl, which may be substituted by up to 5-fold fluorine.

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.

A further preferred embodiment relates to compounds of the formula (I) in which
A is CH or N,
R ^{1 is} methyl or ethyl,
R ² and R ³ independently of one another are methyl or H,
R ⁴ is H, F or Cl which in meta or para position to the 6-ring heterocycle is substituted by the phenyl ring,
R ^{5 is} (C ₁ -C ₆ ) -alkyl which may be substituted by up to 5-fold fluorine,
and their salts, solvates and solvates of the salts.

Particular preference is given to compounds of the formula (I) in which R ² and R ^3, independently of one another, are methyl or H.

In a particularly preferred embodiment, the present invention relates to compounds of formula (I) in the
A is N or CH,
R ¹ , R ² and R ^{5 are} methyl and
R ³ and R ⁴ stand for H.

A likewise preferred embodiment relates to compounds of the formula (I) in which
A is CH or N,
R ¹ is methyl
R ² and R ³ independently of one another are (C ₁ -C ₄ ) -alkyl or hydrogen,
R ⁴ is H,
R ⁵ is (C ₁ -C ₆ ) -alkyl which is substituted by (C ₁ -C ₄ ) -alkoxy, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl, phenyl or 6-membered heteroaryl or up to five times fluorine may be substituted.
and their salts, solvates and solvates of the salts.

In a further preferred embodiment, R ² and R ³ independently of one another are methyl or H.

R ^{5 is} particularly preferably (C ₁ -C ₆ ) -alkyl which may be substituted by up to 5-fold fluorine.

in welcher
R¹ für Methyl oder Ethyl,
R² und R³ unabhängig voneinander für (C₁-C₄)-Alkyl oder Wasserstoff und
R⁴ für H, F oder Cl welches in meta oder para Position zum 6-Ringheterocyclus den Phenylring substituiert,
R⁶ unabhängig voneinander für (C₁-C₄)-Alkyl
stehen,
in Gegenwart eines Katalysators und gegebenenfalls in Gegenwart einer Base umsetzt mit einer Verbindung der Formel III

in welcher R⁵ für (C₁-C₆)-Alkyl, das mit (C₁-C₄)-Alkoxy, Di-(C₁-C₄)-alkylamino, (C₃-C₆)-Cycloalkyl, Phenyl oder 6-gliedrigem Heteroaryl oder bis zu fünffach Fluor substituiert sein kann, steht.The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)

in which
R ^{1 is} methyl or ethyl,
R ² and R ^{3 are} independently (C ₁ -C ₄ ) -alkyl or hydrogen and
R ^{4 represents} H, F or Cl which in meta or para position to the 6-ring heterocycle substitutes the phenyl ring,
R ^{6 are} independently (C ₁ -C ₄ ) -alkyl
stand,
in the presence of a catalyst and optionally in the presence of a base with a compound of formula III

in which R ^{5 is} (C ₁ -C ₆ ) -alkyl which is substituted by (C ₁ -C ₄ ) -alkoxy, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl, phenyl or 6-membered heteroaryl or up to five times fluorine.

in welcher R¹, R², R³ und R⁴ die oben angegebene Bedeutung haben,
durch Umsetzung mit geeigneten Zinnverbindungen hergestellt werden, wobei X Brom oder Iod sein kann. Die Herstellung von Verbindungen der Formel IV ist in WO 2007/129962 und WO 2007/129963 offenbart.Compounds of the formula (II) can be palladium-catalyzed from the corresponding halides of the formula IV

in which R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning,
by reaction with suitable tin compounds, where X can be bromine or iodine. The preparation of compounds of formula IV is in WO 2007/129962 and WO 2007/129963 disclosed.

Compounds of formula III are prepared by oxidation with suitable oxidizing agents of the corresponding thio-substituted precursors V

mit Thiolen oder Thiolaten der Formel R⁵-SH oder R⁵-S^– in Gegenwart einer Base hergestellt werden können.In which R ^{5 has} the abovementioned meaning,
won
which in turn by reaction of the corresponding fluorine-containing compounds VI

with thiols or thiolates of the formula R ⁵ -SH or R ⁵ -S ^- can be prepared in the presence of a base.

durch eine Sandmeier Reaktion. VII wird hergestellt aus dem Hydrazin VIII

durch säurevermittelte Reaktion mit 3,3-Dimethoxypropionitril. Das Hydrazin VIII wird gewonnen durch Umsetzung von käuflichem 3,4-Difluorbenzonitril mit Hydrazin.
und gegebenenfalls die so erhaltenen Verbindungen der Formel (I) nach dem Fachmann bekannten Methoden in ihre Enantiomere und/oder Diastereomere trennt und/oder mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren in ihre Solvate, Salze und/oder Solvate der Salze überführt.Compound VI is obtained from Compound VII

through a Sandmeier reaction. VII is prepared from hydrazine VIII

by acid-mediated reaction with 3,3-dimethoxypropionitrile. The hydrazine VIII is obtained by reacting commercially available 3,4-difluorobenzonitrile with hydrazine.
and if appropriate, the compounds of the formula (I) thus obtained are separated into their enantiomers and / or diastereomers by methods known to those skilled in the art and / or with the appropriate (i) solvents and / or (ii) bases or acids in their solvates, salts and / or or solvates of the salts.

Suitable solvents for process step (II) + (III) → (I) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1, 2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as ethyl acetate, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, 1,4-dioxane is used.

Suitable bases for process step (II) + (III) → (I) are customary inorganic bases such as, for example, sodium carbonate, cesium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate. The bases can be used as aqueous solution. Preferably, sodium carbonate is used. The base is generally used in an amount of 0.25 mol to 100 mol, based on 1 mol of the compound (III).

Suitable catalysts for process step (II) + (III) → (I) are palladium-containing reagents such as, for example, palladium-triphenylphosphane (1: 4). In addition, combinations of palladium-containing reagents and copper (I) iodide such as palladium-triphenylphosphane (1: 4) and copper (I) iodide can be used. Preference is given to using palladium-triphenylphosphane (1: 4). The catalyst is generally used in an amount of 0.01 mol to 10 mol, based on 1 mol of the compound (III).

The process step (II) + (III) → (I) is generally carried out in a temperature range from + 20 ° C to + 200 ° C, preferably at + 60 ° C to + 120 ° C, more preferably at + 120 ° C. , The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 20 bar). In general, one works at elevated pressure (solvent pressure) in a closed vessel in a microwave apparatus.

Suitable solvents for process step (IV) → (II) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1, 2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ketone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP ). It is likewise possible to use mixtures of the solvents mentioned. Preferably, 1,4-dioxane is used.

Suitable tin reagents for process step (IV) → (II) are customary distannanes and organic tin halides, for example hexamethyldistannane, hexabutyldistannan and tri-n-butyltin chloride. Hexamethyl distannane is preferably used. The tin reagent is generally used in an amount of 0.25 mol to 10 mol, based on 1 mol of the compound (IV).

Suitable catalysts for process step (IV) → (II) are palladium-containing reagents such as, for example, palladium-triphenylphosphane (1: 4). In addition, additives such as lithium chloride and 2,6-di-tert-butyl-4-methylphenol may be added. Preference is given to using palladium-triphenylphosphane (1: 4). The catalyst is generally used in an amount of 0.01 mol to 10 mol, based on 1 mol of the compound (IV).

The process step (IV) → (II) is generally carried out in a temperature range from + 20 ° C to + 200 ° C, preferably at + 60 ° C to + 120 ° C, more preferably at + 120 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Suitable solvents for process step (V) → (III) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, Hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as ethyl acetate, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, dichloromethane is used.

As the oxidizing agent for process step (V) → (III) is hydrogen peroxide, sodium metaperiodate, oxones, and customary peracids and hydroperoxides such as 3-chlorobenzenecarboperoxoic acid and tert-butyl hydroperoxide. Preferably, 3-chlorobenzenecarboperoxoic acid is used. The oxidizing agent is generally used in an amount of 0.25 mol to 10 mol, based on 1 mol of the compound (V).

The process step (V) → (III) is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at -20 ° C to + 25 ° C, particularly preferably at 0 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Suitable solvents for process step (VI) → (V) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1, 2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using N, N-dimethylformamide.

Suitable sulfur-containing reactants for process step (VI) → (V) are both thiols and inorganic salts of thiols, for example lithium, sodium, potassium or cesium methanethiolate. The thiol component is generally used in an amount of 0.25 mol to 10 mol, based on 1 mol of the compound (VI).

Suitable bases for process step (VI) → (V) are customary inorganic bases such as, for example, sodium carbonate, cesium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate. Preferably, potassium carbonate is used. The base is generally used in an amount of 0.25 mol to 100 mol, based on 1 mol of the compound (VI).

The process step (VI) → (V) is generally carried out in a temperature range from -20 ° C to + 120 ° C, preferably at 0 ° C to + 80 ° C, more preferably at + 25 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Suitable solvents for process step (VII) → (VI) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1, 2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ketone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP ). It is likewise possible to use mixtures of the solvents mentioned. Preferably, acetonitrile is used.

Suitable diazotizing agents for process step (VII) → (VI) are customary organic and inorganic nitrites, such as, for example, 1,1-dimethylethyl nitrite, sodium nitrite, tert-butyl nitrite, isoamyl nitrite, n-butyl nitrite or n-pentyl nitrite. Preference is given to using n-pentyl nitrite. The diazotizing agent is generally in an amount of 0.25 mol to 10 mol, based on 1 mol of the compound (VII) used.

For the introduction of the bromine in process step (VII) → (VI), reagents which are commonly used in a Sandmeier reaction are, for example, mixtures of copper (I) and copper (II) bromide, hydrobromic acid and copper, hydrobromic acid and acetic acid, tribromomethane and bromine. Preference is given to using mixtures of copper (I) and copper (II) bromide. The bromine-containing reagent is generally used in an amount of 0.25 mol to 100 mol, based on 1 mol of the compound (VII). Copper (II) bromide is added in catalytic amounts.

The process step (VII) → (VI) is generally carried out in a temperature range from -20 ° C to + 120 ° C, preferably at 0 ° C to + 80 ° C, more preferably at + 25 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Suitable solvents for process step (VIII) → (VII) are customary organic solvents which do not change under the reaction conditions. These include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloromethane or Chlorobenzene, or other solvents such as N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, ethanol is used.

Suitable acids for process step (VIII) → (VII) are customary organic and inorganic acids, such as, for example, concentrated hydrochloric acid, dilute hydrochloric acid, or sulfuric acid. Preferably, concentrated hydrochloric acid is used. The acid is generally used in an amount of 0.25 mol to 100 mol, based on 1 mol of the compound (VIII).

The process step (VIII) → (VII) is generally carried out in a temperature range from 0 ° C to + 180 ° C, preferably at + 80 ° C to + 120 ° C, more preferably at + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Suitable solvents for process step 3,4-difluorobenzonitrile + hydrazine → (VIII) are customary organic solvents which do not change under the reaction conditions. These include, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1, 2-dichloroethane, trichloromethane or chlorobenzene, or other solvents such as acetonitrile, N, N-dimethylformamide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, acetonitrile is used.

Schema 2:

The process step 3,4-difluorobenzonitrile + hydrazine → (VIII) is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 50 ° C to + 100 ° C, more preferably at + 80 ° C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure. Scheme 1:

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 according to the invention are low molecular weight, non-reactive and selective inhibitors of human neutrophilic elastase, which surprisingly show markedly greater inhibition of this protease compared to the compounds known from the prior art. In addition, the compounds of the invention unexpectedly have a lower in vitro clearance to hepatocytes and thus have improved metabolic stability.

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 neutrophilic elastase (HNE) is involved in the course of an inflammatory event and / or a tissue or vascular remodeling.

For the purposes of the present invention, these include in particular diseases such as pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha -1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema, cystic fibrosis (CF), acute coronary syndrome (ACS), heart muscle inflammation (myocarditis) and other autoimmune heart diseases (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), myocardial infarction, cardiogenic shock , Heart failure, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF), atherosclerosis, inflammatory kidney disease, chronic enteritis (IBD, CD, UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.

The compounds of the present invention may further be used for the treatment and / or prevention of asthmatic diseases of varying degrees of severity with intermittent or persistent history (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medication or dust-induced asthma) to shape bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiolitis obliterans, bronchiectasis, pneumonia, farmer's lung and related diseases, cough and cold sores (chronic inflammatory cough, iatrogenic cough), nasal mucosal inflammation (including medicinal rhinitis, vasomotor rhinitis and seasonal, allergic rhinitis, eg hay fever) and polyps.

In addition, the compounds according to the invention can also be used for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thrombosis, diabetic and non-diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome hypertensive nephrosclerosis, microalbuminuria, acute and chronic renal insufficiency, acute and chronic renal failure, cystitis, urethritis, prostatitis, epidymitis, oophoritis, salpingitis, vulvovaginitis, erectile dysfunction, Hunner's ulcer, Peyronie's disease, arterial hypertension, shock, atrial and ventricular arrhythmias, transient and ischemic attacks, myocardial insufficiency, stroke, endothelial dysfunction, peripheral and cardiac vascular diseases, peripheral circulatory disorders, edema such as pulmonary edema, cerebral edema, renal edema and Cardiac insufficiency-related edema, restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, at elevated levels of fibrinogen and low density LDL and at elevated levels of plasminogen activator inhibitor 1 (FIG. PAI-1), dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidaemias) and metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, Insulin resistance, glucose intolerance, obesity and diabetic sequelae such as retinopathy, nephropathy and neuropathy), cancers (skin cancer, brain tumors, breast cancer, bone marrow tumors, leukemia, liposarcoma, carcinomas of the gastrointestinal tract, Le pancreas, lung, kidney, ureter, prostate and genital tract, as well as malignant tumors of the lymphoproliferative system, such as Diseases of the gastrointestinal tract and the abdomen (glossitis, gingivitis, periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiac disease, hepatitis, liver fibrosis, liver cirrhosis , Pancreatitis and cholecystitis), diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), immune diseases, thyroid disorders (hyperthyroidism), skin diseases (psoriasis, acne, Eczema, atopic dermatitis, multiple forms of dermatitis such as abacribus dermatitis, dermatitis actinica, dermatitis allergica, ammoniacal dermatitis, dermatitis artefacta, autogenous dermatitis, dermatitis atrophicans, dermatitis calorica, dermatitis combustionis, dermatitis congelationis, dermatitis cosmetica, escharotica dermatitis, dermatitis exfoliate iva, dermatitis gangraenose, dermatitis haemostatica, dermatitis herpetiformis, dermatitis lichenoides, dermatitis linearis, malignant dermatitis, medimencatosa dermatitis, palmaris et plantaris dermatitis, dermatitis parasitaria, dermatitis photoallergica, dermatitis phototoxica, dermatitis pustularis, dermatitis seborrhoica, dermatitis solaris, dermatitis toxica, dermatitis ulcerative colitis, dermatitis veneata, infectious dermatitis, pyogenic dermatitis and Rosszea-type dermatitis, as well as keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematosus, erythema, lymphoma, skin cancer, sweet syndrome, Weber-Christian syndrome, scarring, wart formation, Chilblains), inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis, iritis, uveitis, choroiditis, ophthalmitis), viral diseases (by influenza, adeno and coronaviruses such. HPV, HCMV, HIV, SARS), skeletal bone and joint and skeletal muscle disorders (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, haemophilic arthritis, juvenile chronic arthritis, rheumatoid arthritis and metastatic arthritis, in addition to the still syndrome, Felty syndrome, Sjörgen syndrome, Clutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome, multiple forms of arthropathies such as arthropathy deformans, arthropathy neuropathica, ovaripriva arthropathy, arthropathy psoriatica and arthropathy tabica, systemic sclerosis , various forms of inflammatory myopathies such as Myo epidemica, myopathy fibrosa, myopathy myoglobinurica, 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), of inflammatory Arterial changes (various forms of arteritis such. B. endarteritis, mesarteritis, periarteritis, panarteritis, rheumatoid arthritis, arthritis deformans, temporal arteritis, cranial arteritis, gigantocellular arteritis and granulomatous arteritis, as well as the Horton syndrome, Churg-Strauss syndrome and Takayasu's arteritis), the Muckle Well Syndrome, Kikuchi's disease, polychondritis, scleroderma and other diseases an inflammatory or immunological component, such as cataract, cachexia, osteoporosis, gout, incontinence, leprosy, Sezary syndrome and paraneoplastic syndrome, organ rejection rejection reactions, and wound healing and angiogenesis especially in chronic wounds.

Because of their property profile, the compounds of the invention are particularly useful for the treatment and / or prevention of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory syndrome (ARDS ), Pulmonary emphysema, alpha-1-antitrypsin deficiency (AATD), cystic fibrosis (CF), sepsis and systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF, MODS), inflammatory bowel disease (IBD, Crohn's disease, colitis ), chronic bronchitis, bronchiolitis, asthma, rhinitis, rheumatoid arthritis, inflammatory skin and eye diseases, arteriosclerosis and cancers.

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 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.

• • die Signaltransduktionskaskade inhibierende Verbindungen, beispielhaft und vorzugsweise aus der Gruppe der Kinase-Inhibitoren, insbesondere aus der Gruppe der Tyrosinkinase- und/oder Serin/Threoninkinase-Inhibitoren;
• • Verbindungen, die den Ab- und Umbau der Extrazellulärmatrix inhibieren, beispielhaft und vorzugsweise Inhibitoren der Matrix-Metalloproteasen (MMPs), insbesondere Inhibitoren von Stromelysin, Kollagenasen, Gelatinasen und Aggrecanasen (hierbei vor allem von MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 und MMP-13) sowie der Metallo-Elastase (MMP-12);
• • organische Nitrate und NO-Donatoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO;
• • NO-unabhängige, jedoch Häm-abhängige Stimulatoren der löslichen Guanylatcyclase, wie insbesondere die in WO 00/06568 , WO 00/06569 , WO 02/42301 und WO 03/095451 beschriebenen Verbindungen;
• • NO- und Häm-unabhängige Aktivatoren der löslichen Guanylatcyclase, wie insbesondere die in WO 01/19355 , WO 01/19776 , WO 01/19778 , WO 01/19780 , WO 02/070462 und WO 02/070510 beschriebenen Verbindungen;
• • Prostacyclin-Analoga, wie beispielhaft und vorzugsweise Iloprost, Beraprost, Treprostinil oder Epoprostenol;
• • Verbindungen, die die lösliche Epoxidhydrolase (sEH) inhibieren, wie beispielsweise N,N'-Dicyclohexylharnstoff, 12-(3-Adamantan-1-yl-ureido)-dodecansäure oder 1-Adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-harnstoff;
• • den Energiestoffwechsel des Herzens beeinflussende Verbindungen, wie beispielhaft und vorzugsweise Etomoxir, Dichloracetat, Ranolazine oder Trimetazidine;
• • Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) und/oder cyclischem Adenosinmonophosphat (CAMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2, 3, 4 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil;
• • antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen;
• • den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Inhibitoren, Vasopeptidase-Inhibitoren, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker, Mineralocorticoid-Rezeptor-Antagonisten, Rho-Kinase-Inhibitoren sowie der Diuretika;
• • bronchodilatorisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der beta-adrenergen Rezeptor-Agonisten, wie insbesondere Albuterol, Isoproterenol, Metaproterenol, Terbutalin, Formoterol oder Salmeterol, oder aus der Gruppe der Anticholinergika, wie insbesondere Ipratropiumbromid;
• • anti-inflammatorisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Glucocorticoide, wie insbesondere Prednison, Prednisolon, Methylprednisolon, Triamcinolon, Dexamethason, Beclomethason, Betamethason, Flunisolid, Budesonid oder Fluticason; und/oder
• • den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie beispielhaft und vorzugsweise HMG-CoA-Reduktase- oder Squalensynthese-Inhibitoren, der ACAT-Inhibitoren, CETP-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer und Lipoprotein(a)-Antagonisten.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• 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;
• Compounds which inhibit the degradation and remodeling of the extracellular matrix, by way of example and preferably inhibitors of matrix metalloproteases (MMPs), in particular inhibitors of stromelysin, collagenases, gelatinases and aggrecanases (in this case in particular MMP-1, MMP-3, MMP) 8, MMP-9, MMP-10, MMP-11 and MMP-13) and metallo-elastase (MMP-12);
• • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• NO-independent, but heme-dependent stimulators of soluble guanylate cyclase, such as those in WO 00/06568 . WO 00/06569 . WO 02/42301 and WO 03/095451 described compounds;
• • NO- and heme-independent activators of soluble guanylate cyclase, especially those in WO 01/19355 . WO 01/19776 . WO 01/19778 . WO 01/19780 . WO 02/070462 and WO 02/070510 described compounds;
• Prostacyclin analogs, such as by way of example and preferably iloprost, beraprost, treprostinil or epoprostenol;
• Compounds which inhibit the soluble epoxide hydrolase (sEH), such as N, N'-dicyclohexylurea, 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, ranolazines or trimetazidines;
• Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (CAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil and tadalafil;
• Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
• Antihypertensive agents, by way of example and by way of preference from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Mineralocorticoid receptor antagonists, Rho kinase inhibitors and diuretics;
• Bronchodilator agents, by way of example and preferably from the group of beta-adrenergic receptor agonists, in particular albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or from the group of anticholinergics, in particular ipratropium bromide;
• Anti-inflammatory agents, by way of example and preferably from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone; and or
• Lipid metabolism-modifying agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, peltinib, semaxanib, sorafenib, sunitinib, tandutinib, Tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or 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, bivalirudin or Clexane.

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

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 rivaroxaban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD No. 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 blockers, beta-receptor blockers, mineralocorticoid receptor antagonists , Rho kinase inhibitors 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, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

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 preferably 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 or eplerenone.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.

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.

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 ECHT 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 by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

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, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

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 can be applied in a suitable manner, such as. As oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or 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 working, 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 that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out 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 are suitable as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are z. As inhalation medicines (including powder inhalers, nebulizers, aerosols), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures ), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, scattering powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral, intravenous and inhalative 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 u. a. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (For example, 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 of 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 of body weight.

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.

The percentages in the following tests and examples 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, unless stated otherwise.

A. Examples

Abbreviations:

• aq.

  aqueous, aqueous solution

  c

  concentration

  cat.

  catalytic

  DC

  TLC

  DCI

  direct chemical ionization (in MS)

  least.

  distilled

  DIEA

  N, N-diisopropylethylamine

  DMAP

  4-N, N-dimethylaminopyridine

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  ee

  enantiomeric excess

  ent

  enantiomerically pure, enantiomer

  eq.

  Equivalent (s)

  IT I

  Electrospray ionization (in MS)

  et

  ethyl

  GC-MS

  Gas chromatography-coupled mass spectrometry

  H

  Hour (s)

  HPLC

  High pressure, high performance liquid chromatography

  conc.

  concentrated

  LC-MS

  Liquid chromatography-coupled mass spectrometry

  mCPBA

  meta-chloroperbenzoic

  me

  methyl

  minute

  Minute (n)

  MPLC

  medium pressure

  MS

  Mass spectrometry

  MTBE

  Methyl tert-butyl ether

  NMR

  nuclear magnetic resonance spectrometry

  nPentONO

  n-pentyl

  Ph

  phenyl

  quant.

  quantitative (at yield)

  rac

  racemic, racemate

  RT

  room temperature

  R _t

  Retention time (by HPLC)

  Mp.

  melting point

  Bu

  tert-butyl

  TFA

  trifluoroacetic

  TFAA

  trifluoroacetic

  THF

  tetrahydrofuran

  UV

  Ultraviolet spectrometry

  v / v

  Volume to volume ratio (of a solution)

HPLC, LC-MS and GC-MS methods:

Method 1

• Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 μ 20 mm × 4 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 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% flow: 2.5 ml / min, oven: 55 ° C; Flow 2 / ml; UV detection: 210 nm.

Method 2

• Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 × 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 Furnace: 50 ° C; Flow: 0.40 ml / min; UV detection: 210-400 nm.

Method 3

• Device Type MS: Waters (Micromass) Quattro Micro; Device type HPLC: Agilent 1100 series; Column: Thermo Hypersil GOLD 3 μ 20 × 4 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 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow 2.5 ml) → 5.00 min 100% A; Oven: 50 ° C; Flow: 2 ml / min; UV detection: 210 nm

Method 4

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

Starting compounds and intermediates:

Example 1A, 5-iodo-N, 6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2-dihydropyridine-3-carboxamide

The production took place as in WO 2007/129962 described. Example 2A, 3-fluoro-4-hydrazinobenzonitrile

20 g (0.141 mol) of 3,4-difluorobenzonitrile were initially charged in 250 ml of acetonitrile and treated dropwise with 35.6 ml (0.719 mol) of hydrazine hydrate (1: 1). The mixture was then stirred at 70 ° C. overnight. The reaction mixture was concentrated, the residue was first stirred with water and then with diethyl ether and filtered with suction. The solid was washed with diethyl ether and dried under high vacuum. 20.17 g (95 d.th.) of the target compound were obtained.
LC-MS (method 1): R _t = 0.82 min; MS (ESpos): m / z = 153 [M + H] ⁺ . Example 3A, 4- (5-amino-1H-pyrazol-1-yl) -3-fluorobenzonitrile

42 μ 1 (0.340 mmol) of 3,3-dimethoxypropanonitrile and 62 mg (0.408 mmol) of 3-fluoro-4-hydrazinobenzonitrile were introduced into 900 .mu.l of ethanol and treated with 180 .mu.l of conc. Hydrochloric acid added. The mixture was then stirred at 100 ° C for 1 h. The product was isolated directly by preparative HPLC (methanol / water gradient). 55 mg (80% of theory) of the target compound were obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.10 (dd, 1H), 7.83 (d, 1H), 7.70 (t, 1H), 7.41 (d, 1H), 5.45 (d, 1H) ,
LC-MS (Method 4): R _t = 0.58 min; MS (ESpos): m / z = 203 [M + H] ⁺ . Example 4A, 4- (5-bromo-1H-pyrazol-1-yl) -3-fluorobenzonitrile

153 mg (0.757 mmol) of 4- (5-amino-1H-pyrazol-1-yl) -3-fluorobenzonitrile were dissolved in 3 ml of acetonitrile and added to a solution of 151 μl (1,135 mmol) of pentyl nitrite and 130 mg (0.908 mmol). Copper (I) bromide in 3 ml of acetonitrile was added dropwise. Subsequently, 2 mg (0.009 mol) of copper (II) dibromide were added and the reaction mixture was stirred at room temperature for 1.5 h. The product was isolated by preparative HPLC (acetonitrile / water gradient). 101 mg (50% of theory) of the target compound were obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.25 (dd, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.86 (t, 1H), 6.79 (d, 1H) ,
LC-MS (Method 4): R _t = 0.58 min; MS (ESpos): m / z = 203 [M + H] ⁺ . Example 5A, 4- (5-bromo-1H-pyrazol-1-yl) -3- (methylsulfanyl) benzonitrile

290 mg (1.090 mmol) of 4- (5-bromo-1H-pyrazol-1-yl) -3-fluorobenzonitrile were initially charged in 3 ml of DMF, and 76 mg (1090 mmol) of sodium methanethiolate and 376 mg (2.725 mmol) of potassium carbonate were added successively , It was stirred overnight at room temperature before the reaction mixture was poured onto water and extracted with ethyl acetate. The organic phase was separated, washed with water and sat. NaCl solution. washed, dried over sodium sulfate, filtered off and concentrated. The residue was purified on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). 257 mg (77% of theory) of the target compound were obtained in 95% purity.
LC-MS (Method 4): R _t = 1.12 min; MS (ESpos): m / z = 294 [M + H] ⁺ . Example 6A, 4- (5-bromo-1H-pyrazol-1-yl) -3- (methylsulfonyl) benzonitrile

257 mg (0.830 mmol) of 4- (5-bromo-1H-pyrazol-1-yl) -3- (methylsulfanyl) benzonitrile were introduced into 7 ml of dichloromethane and at 0 ° C with 494 mg (2.075 mmol) of 72.5% 3rd -Chlorbenzolcarboperoxoic acid added. The mixture was then stirred for 30 min at 0 ° C before the reaction mixture was allowed to come to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane and washed twice with 1 N sodium hydroxide solution. The organic phase was dried over sodium sulfate and concentrated. 282 mg (98% of theory) of the target compound were obtained in 95% purity.
LC-MS (Method 2): R _t = 0.83 min; MS (ESpos): m / z = 326 [M + H] ⁺ . Example 7A N, 6-Dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -5- (trimethylstannyl) -1,2-dihydropyridine-3-carboxamide

1 g (2.293 mmol) of 5-iodo-N, 6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2-dihydropyridine-3-carboxamide was initially charged in 20 ml of 1,4-dioxane and 570 .mu.l (2.751 mmol) hexamethyldistannane, 301 mg (7.107 mmol) of lithium chloride, 25 mg (0.0115 mmol) of 2,6-di-tert-butyl-4-methylphenol and 265 mg (0.229 mmol) of palladium-triphenylphosphane (1 : 4). The mixture was then stirred at 120 ° C under reflux for 2.5 h. The reaction mixture was concentrated and the residue was purified on silica gel (eluent: cyclohexane / ethyl acetate 1: 1). 610 mg (56% of theory) of the target compound were obtained.
LC-MS (method 2): R _t = 1.20 min; MS (ESpos): m / z = 475 [M + H] ⁺ .

EXAMPLES

example 1

5- {1- [4-cyano-2- (methylsulfonyl) phenyl] -1H-pyrazol-5-yl} -N, 6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1, 2-dihydropyridine-3-carboxamide

69 mg (0.211 mmol) of 4- (5-bromo-1H-pyrazol-1-yl) -3- (methylsulfonyl) benzonitrile were initially charged in 2 ml of 1,4-dioxane and treated successively with 100 mg (0.211 mmol) of N, 6 -Dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -5- (trimethylstannyl) -1,2-dihydropyridine-3-carboxamide, 12 mg (0.011 mmol) of palladium triphenylphosphane (1: 4) and 211 1 ml (0.423 mmol) of sodium carbonate solution (2 M in water) before the reaction mixture was stirred for 1 h at 120 ° C and 300 W in the microwave (CEM). The product was isolated by preparative HPLC (acetonitrile / water gradient). 30 mg (25% of theory) of the target compound were obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.08 (q, 1H), 8.53 (d, 1H), 8.26 (dd, 1H), 8.11 (d, 1H), 7.95-7.89 (m, 2H), 7.83 (t, 2H), 7.66 (d, 1H), 7.56 (d, 1H), 6.71 (d, 1H), 3.63 (s, 3H), 2.71 (d, 3H), 1.95 (s, 3H ).
LC-MS (Method 3): R _t = 2.19 min; MS (ESpos): m / z = 556 [M + H] ⁺ .

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds of the invention can be demonstrated in the assays described below:

Abbreviations:

• AMC

  7-amido-4-methylcoumarin

  BSA

  bovine serum albumin

  HEPES

  N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid

  HNE

  human neutrophil elastase

  IC

  inhibitory Concentration

  MeOSuc

  methoxysuccinyl

  v / v

  Volume to volume ratio (of a solution)

  w / v

  Weight to volume ratio (of a solution)

B-1. In vitro HNE inhibition test

The potency of the compounds of the invention is determined in an in vitro inhibition test. The HNE-mediated amidolytic cleavage of a suitable peptide substrate in this case leads 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 an IC ₅₀ value.

Execution:

In a 384-well microtiter plate, a total of 50 μl assay buffer (0.1 M HEPES pH 7.4, 0.5 M NaCl, 0.1% w / v BSA, 1% v / v DMSO), enzyme (80 pM HNE, Serva , Heidelberg) and substrate (20 μM MeOSuc-Ala-Ala-Pro-Val-AMC, from Bachem, Weil am Rhein) in the presence and absence of the test substance for two hours at 37 ° C incubated. The fluorescent light intensity of the test mixtures is measured (ex. 380 nm, em. 460 nm). The IC ₅₀ values are determined by plotting the fluorescent light intensity versus the drug concentration.

IC ₅₀ values representative of the compounds of the invention (at a HNE concentration of 80 pM) are set forth in Table A below: TABLE A Inhibition of human neutrophil elastase (HNE) Exemplary embodiment no. IC ₅₀ [nM] 1 0.5

For 5- [1- (4-cyanophenyl) -1H-pyrazol-5-yl] -N, 6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2-dihydropyridine-3- carboxamide WO 2007/129962 In this test, an IC ₅₀ of 1.1 nM was measured.

B-2. CYP Inhibition Assay

The ability of substances to inhibit CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in humans is investigated using pooled human liver microsomes as the enzyme source in the presence of standard substrates (see below) that form CYP-specific metabolites. The inhibition effects are investigated at six different concentrations of the test compounds [2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μM], 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 results comparable between different series.

Execution:

Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan or midazolam with human liver microsomes in the presence of six different concentrations each of a test compound (as a potential inhibitor) is performed on a workstation (Tecan, Genesis, Crailsheim, Germany). Standard incubation mixtures contain 1.3 mM NADP, 3.3 mM MgCl ₂ × 6 H ₂ O, 3.3 mM glucose-6-phosphate, glucose-6-phosphate dehydrogenase (0.4 U / ml) and 100 mM phosphate buffer (pH 7.4) in a total volume of 200 μl. 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 adding 100 μl of acetonitrile, which is a suitable internal standard. Precipitated proteins are separated by centrifugation, the supernatants are pooled and analyzed by LC-MS / MS.

B-3. 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 μM) and at low cell counts (preferably at 1 x 10 ⁶ cells / ml) to ensure as linear as possible 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 "F _max " values are calculated (see below).

The CL and F _max values are a measure of the phase I and phase 2 metabolism of the compounds in the hepatocytes. In order to minimize the influence of the organic solvent on the enzymes in the incubation approaches, its concentration generally becomes 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 based on half-lives much longer than the incubation period (typically 90 minutes) can only be considered as rough guidelines.

The calculated parameters and their meaning are: Fmax well-stirred [%] maximum possible bioavailability after oral administration Calculation: (1-CLblood well-stirred / QH) · 100 CLblood well-stirred [L / (h · kg)] calculated blood clearance (well-stirred model) Calculation: (QH · CL'intrinsic) / (QH + CL'intrinsic) CL'intrinsic [ml / (min.kg)] maximum ability of the liver (the hepatocytes) to metabolize a compound (assuming that the Liver blood flow is not rate-limiting) Calculation: CL'intrinsic, apparent · species-specific hepatocyte count [1.1 · 108 / g liver] · species-specific liver weight [g / kg] CL'intrinsic, apparent normalizes the elimination constant by passing it through the [Ml / (min * mg)] divided hepatocyte cell number x (x x 106 / ml) is divided Calculation: kel [1 / min] / (cell count [x x 106] / incubation volume [ml]) (QH = species-specific liver blood flow).

For the compounds of the invention, representative values from this assay after incubation of the compounds with rat hepatocytes are given in Table B below: TABLE B Calculated blood clearance and bioavailability after incubation with rat hepatocytes Exemplary embodiment no. CL _blood [L / (h · kg)] F _max [%] 1 2.7 35

For 5- [1- (4-cyanophenyl) -1H-pyrazol-5-yl] -N, 6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2-dihydropyridine-3- carboxamide WO 2007/129962 In this test, a CL _blood of 3.6 L / (h.kg) and a F _max of 15% were measured.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

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Claims (10)

Compound of the formula (I)

in which A is CH or N, R ¹ is methyl or ethyl, R ² and R ³ are independently (C ₁ -C ₄ ) -alkyl or hydrogen, R ⁴ is H, F or Cl which is in meta or para to the 6-membered heterocycle, the phenyl ring is substituted, R ⁵ is (C ₁ -C ₆ ) -alkyl which is reacted with (C ₁ -C ₄ ) -alkoxy, di (C ₁ -C ₄ ) -alkylamino, ( C ₃ -C ₆ ) cycloalkyl, phenyl or 6-membered heteroaryl or may be substituted up to five times fluorine. and their salts, solvates and solvates of the salts. A compound of the formula (I) according to claim 1, in which A is CH and its salts, solvates and solvates of the salts. A compound of the formula (I) according to claim 1 or 2, in which R ^{2 is} methyl and R ^{3 is} H, and their salts, solvates and solvates of the salts. A compound of the formula (I) according to any one of claims 1 to 3, in which R ^{5 is} (C ₁ -C ₆ ) -alkyl which may be substituted by up to 5-fold fluorine, and also their salts, solvates and solvates of the salts. Process for the preparation of the compounds of the formula (I) according to the invention, characterized in that a compound of the formula (II)

in which R ^{1 is} methyl or ethyl, R ² and R ^{3 are} independently (C ₁ -C ₄ ) -alkyl or hydrogen and R ^{4 is} H, F or Cl which in meta or para position to the 6-ring heterocycle substitutes the phenyl ring , R ^{6 are} independently (C ₁ -C ₄ ) -alkyl. in the presence of a catalyst and optionally in the presence of a base with a compound of formula III

in which R ^{5 is} (C ₁ -C ₆ ) -alkyl which is substituted by (C ₁ -C ₄ ) -alkoxy, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl, phenyl or 6-membered heteroaryl or up to five times fluorine A compound as defined in any one of claims 1 to 4 for the treatment and / or prevention of diseases. A compound as defined in any one of claims 1 to 4 for use in a method for the treatment and / or prevention of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), the acute lung injury (ALI), acute respiratory syndrome (ARDS), pulmonary emphysema, alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF). Use of a compound as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory syndrome (ARDS), pulmonary emphysema, alpha-1-antitrypsin deficiency (AATD) and cystic fibrosis (CF). A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4 in combination with one or more inert non-toxic pharmaceutically acceptable excipients. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4, in combination with one or more further active ingredients selected from the group consisting of kinase inhibitors, matrix metalloprotease inhibitors, stimulators and activators of soluble guanylate cyclase, prostacyclin analogues, endothelin receptor Antagonists, phosphodiesterase inhibitors, beta-adrenergic receptor agonists, anticholinergics and glucocorticoids.