EP2037930A1 - The use of 1,4-diaryl-dihydropyrimidine-2-on derivatives for treating pulmonary arterial hypertension - Google Patents

Abstract

The invention relates to the use of 1,4-diaryl-dihydropyrimidine-2-on derivatives of formula (I) to treat and/or prevent pulmonary arterial hypertension and other forms of pulmonary hypertension, as well as the use thereof for the production of drugs to treat and/or prevent pulmonary arterial hypertension and other forms of pulmonary hypertension.

Description

 Use of l, 4-diaryl-dihydropyrimidin-2-one derivatives for the treatment of pulmonary arterial hypertension

The present application relates to the use of l, 4-diaryl-dihydropyrimidin-2-one derivatives of the formula (I) for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension and their use for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

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 narrowing 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 path leads to a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in right-sided heart failure (Humbert, M. et al., J. Am.Coli., 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 (G.E. 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 capacity and prognosis of patients. These are primarily hemodynamic therapy principles that influence the vascular tone, but have no direct influence on the pathogenic remodeling processes. In addition, the applicability of these drugs is limited by the partly serious side effects and / or complex application forms. The period of time during which a patient's clinical situation can be improved or stabilized under specific monotherapy is limited. Finally, there is a therapy escalation and thus a combination therapy in which several medications must 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, those therapy options that directly intervene in the remodeling process (anti-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-drug interactions in such a combination therapy, these new drugs should not or only to a very limited extent inhibit metabolising P450 CYP enzymes.

The term "pulmonary arterial hypertension" includes certain forms of pulmonary hypertension, such as e.g. established by the World Health Organization (WHO) {Clinical Classification of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am. Coli. 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), familial pulmonary arterial hypertension (FPAH), and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medicines, with other diseases (thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with significant venous disease capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.

Other forms of pulmonary hypertension include, for example, pulmonary hypertension associated with left ventricular disease, for example ventricular or valvular disorders, pulmonary hypertension associated with respiratory and / or pulmonary diseases, eg chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis thrombotic and / or embolic diseases attributable to pulmonary hypertension, for example 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, tumor diseases). 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 able to break down a large number of connective tissue proteins, such as the proteins elastin, collagen and fibronectin. Elastin is found in high concentrations in all tissue types that show high elasticity, eg in the lungs and in arteries. In a large number of pathological processes (eg tissue injuries), HNE plays a role in tissue remodeling and reconstruction (English: tissue remodeling). In addition, HNE is an important modulator in inflammatory processes. For example, HNE induces increased gene expression of interleukin-8 (EL-8). It is therefore believed that the HNE is present in many lung diseases (eg, chronic obstructive pulmonary disease, COPD, acute respiratory distress syndrome, ARDS, cystic fibrosis, CF) Pulmonary emphysema, emphysema) and also in diseases of the cardiovascular system (eg tissue changes after a myocardial infarction and heart failure) plays an important role.

In animal models and in patients with increased pulmonary arterial pressure (pulmonary arterial hypotension), connective tissue fragmentation (internal elastic lamina) has been reported [Rabinovitch et al, Lab. luvest. 55, 632-653 (1986)]. In animal models of pulmonary arterial hypotension (hypoxic and monocrotaline rat model), increased elastase activity has been shown to be associated with connective tissue fragmentation [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, eg, basic fibroblast growth factor (bFGF [Rabinovitch, Am. Physiol., 277, L5-L12 (1999)]. In the hypoxic mouse model for pulmonary arterial hypotension, a positive effect with an overexpressed elastase inhibitor protein could be shown [Zaidi et al., Circulation JO5, 516-521 (2002 In the monocrotaline rat model for pulmonary arterial hypertension, a positive effect with synthetic, low-molecular-weight elastase inhibitors was shown to have a favorable effect on tissue remodeling [Cowan et al., Nature Med. 6, 698-702 (2000)]. However, all previously known low molecular weight elastase inhibitors are less selective, chemically reactive and / or limited orally available, which has hitherto thwarted clinical development of an oral elastase inhibitor in these indications.

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) [Stockley, Neutrophils and protease / antiprotease imbalance, 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 located in a difficult-to-access microcompartment between the neutrophil cell and the adjacent tissue cell (e.g., endothelial cell). In addition, strongly oxidizing conditions prevail around activated leukocytes (English, oxidative burst), whereby AAT is oxidized and loses several orders of magnitude in its 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) located in the protected microcompartment. For this purpose, a good stability of the substances in vivo is necessary (low in vjvo clearance). In addition, these compounds should be stable under oxidative conditions so as not to lose their inhibitory potency in disease. In indications where combination therapies are or are expected to occur in the future, such as PAH, particularly little interaction with enzymes that could rebuild and break down drugs (P450 CYP enzymes) is beneficial.

WO 2004/024700, WO 2004/024701, WO 2005/082863 and WO 2005/082864 disclose various 1,4-diaryl-dihydropyrimidin-2-one derivatives as HNE inhibitors for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, Myocardial infarction and heart failure revealed.

Surprisingly, it has now been found that certain 1, 4-diaryl-dihydropyrimidin-2-one derivatives are particularly suitable for the treatment of pulmonary arterial hypertension (PAH). These compounds described below are low molecular weight, non-reactive, selective and potent inhibitors of neutrophil elastase, which have a sufficiently high bioavailability after oral administration and / or a good solubility for parenteral administration and a low in vffro clearance against hepatocytes and a low level of inhibition tion of CYP enzymes from microsomes. Thus, they represent promising starting points for new drugs for the treatment of pulmonary arterial hypertension as a single therapy or in combination with other drugs.

The present invention relates to the use of compounds of the general formula (I)

in which

X is CH or N,

R ^{1 is} hydrogen, a group of the formula - (CH ₂ ) "- C (= O) -OR ^1A or - (CH ₂ ) _n -C (= O) -N _R IB _R IC _{or eme} G _{j -j} pp _g of p _orme i

stands in which

the point of attachment to the N atom means

the number 1 or 2 means

R ^IA is hydrogen or (C _r C ₄₎ -alkyl and

R ^1B and R ^1C are independently hydrogen or (C _r C ₄₎ -alkyl,

R ^{2 is} cyano or a group of the formula -C (= O) -R ^2A or -C (= O) -OR ^2A in which

R ^{2A is} (C _r C ₆ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, which in turn is up to twice, identically or differently, hydroxyl, (C ₁ -C ₄ ) -alkoxy, hydroxycarbonyl, amino,

Mono- and / or di- (C 1 -C ₄ ) -alkylamino may be substituted and in which in each case a CH ₂ group, as far as resulting in a chemically stable compound, may be exchanged for an O atom,

and

R ^{3 is} either hydrogen

and

R ^{4 is} hydrogen, fluorine or chlorine

or

R ^{3 is} fluorine or chlorine

and

R ^{4 is} hydrogen,

and their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

Preference is given here to the use of compounds of the formula (I) in which

X is CH or N,

R ^{1 is} hydrogen, a group of the formula -CH ₂ -C (= O) -OH or -CH ₂ -C (= O) -NH ₂ or a group of the formula

stands in which

* means the point of attachment to the N-atom,

R ^{Δ is} cyano, acetyl, cyclobutylcarbonyl, methoxycarbonyl, ethoxycarbonyl or 2-hydroxyethoxycarbonyl,

R ^{J is} hydrogen

and

R is hydrogen or fluorine,

and their salts, solvates and solvates of the salts.

Particularly preferred is the use of compounds of the formula (I) having the following structures:

and their salts, solvates and solvates of salts.

Very particular preference is given to the use of compounds of the formula (I) having the following structures:

and their salts, solvates and solvates of salts.

Some of the 1,4-diaryl-dihydropyrimidin-2-one derivatives of formula (I) are novel as such. Further subject of the present invention are therefore compounds according to formula (I) having the following structures their salts, solvates and solvates of the salts and their use for the treatment and / or prophylaxis of diseases.

Compounds according to the invention or compounds which can be used according to the invention, also referred to below as compounds according to the invention, are the compounds of the formula (I) and their salts, solvates and solvates of the salts encompassed by formula (I) Compounds of the formulas listed above or below, and their salts, solvates and solvates of the salts, and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as those of formula ( I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or 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 not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.

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

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 having from 1 to 16 carbon atoms. 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 in which the coordination with water takes place. 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:

In the context of the invention, (C 1 -C 4 -alkyl and (C 1 -C 4) -alkyl are a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, preference being given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms Methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

(CVCfi) -cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 6 carbon atoms. By way of example and preferably mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the context of the invention, (C ₁ -Cd) -alkoxy 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.

Mono (C ₁ -C 4) -alkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.

Di (C ₁ -C 4) -alkylamino in the context of the invention represents an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 4 carbon atoms. Preferred examples which may be mentioned are: / VN-dimethylamino, N ₁ N-Oi- ethylamino, JV-ethyl-N-methylamino, / V-methyl-ZV-n-propylamino, Ν-isopropyl-N-methylamino, N-isopropyl Nn-propylamino, N, N-diisopropylamino, / Vn-butyl / V-methylamino and /V- tert -butyl-N-methylamino.

The compounds of the formula (I) according to the invention are known, for the most part, from WO 2004/024700, WO 2005/082863 and WO 2005/082864. You can as described there in detail or by analogy thereto. In a general way, the compounds of the formula (I) can be prepared by reacting a compound of the formula (H)

in which X has the meaning given above,

in the presence of an acid or an acid anhydride in a 3-component one-pot reaction or sequentially with a compound of the formula (III)

in which R ^{2 has} the meaning given above,

and a compound of formula (IV)

in which R ³ and R ^{4 have} the meanings given above,

to a compound of the formula (I-A)

in which R, R, R and X each have the meanings given above,

and in the event that R ¹ does not represent hydrogen, in the presence of a base with a compound of formula (V)

R ' ^* -Z (V),

in which

R ^{1 * has} the abovementioned meaning of R ¹ , but does not stand for hydrogen,

and

Z is a leaving group such as, for example, halogen, mesylate, tosylate or triflate,

responds

and the compounds of the formula (IA) or (I) thus obtained are separated by methods known to those skilled in the art into their enantiomers and / or diastereomers and, if appropriate, with the appropriate (i) solvents and / or (ii) bases or acids in their solvates, Salts and / or solvates of the salts converted.

For the process step (II) + (Iü) + (IV) - »(IA) suitable solvents are common 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, dioxane or tetrahydrofuran, 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 ethyl acetate, acetonitrile, dimethyl sulfoxide or N ₁ N-dimethylformamide. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran or dioxane.

Suitable acids for process step (II) + (ED) + (IV) -> (I-A) are customary inorganic or organic acids or acid anhydrides. These include preferably carboxylic acids such as, for example, acetic acid or trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, phosphoric acids or phosphoric or phosphonic anhydrides such as polyphosphoric acid, ethyl polyphosphate or propanephosphonic anhydride. Preference is given to using polyphosphoric acid ethyl ester. The acid is generally used in an amount of 0.25 mol to 100 mol, based on 1 mol of the compound (HI).

The process step (H) + (HI) + (IV) - »(IA) is generally carried out in a temperature range of + 20 ° C to +150 ⁰ C, preferably at +60 ⁰ C to +100 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 (I-A) + (V) -> (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, dioxane or tetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, Trichloro- methane or chlorobenzene, or other solvents such as ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ketone, acetonitrile, dimethyl sulfoxide, Λf, N-dimethylformamide, ΛW-dimethyl propyleneurea (DMPU) or N-methylpyrrolidone (ΝMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran or dimethylformamide.

Suitable bases for process step (IA) + (V) → (I) are customary inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates, such as sodium or potassium maleate, alkali metal hydrides, such as sodium or potassium hydride, amides, such as lithium or potassium -bis- (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, W-methylmorpholine, Λf-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, / V-dimethylaminopyridine. Preference is given to using potassium carbonate, cesium carbonate or sodium hydride. The base is generally used in an amount of 0.1 mol to 10 mol, preferably from 1 mol to 3 mol, based on 1 mol of the compound (IA). The process step (IA) + (V) -> (I) is generally carried out in a temperature range from 0 ⁰ C to +150 ⁰ C, preferably at +20 ⁰ C to +80 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.

The compounds of the formulas (II), (HI), (IV) and (V) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

The compounds of the formula (I) which can be used according to the invention can, if appropriate, also be prepared by conversions of functional groups of individual substituents, in particular those listed under R ¹ and R ² , starting from other compounds of the formula (I) obtained by the above process , These conversions are carried out by conventional methods and include, for example, reactions such as esterification, ester cleavage or hydrolysis, reduction, catalytic hydrogenation, oxidation, hydroxylation, amination or alkylation, and the introduction and removal of temporary protecting groups.

The method described above can be illustrated by the following reaction schemes:

Scheme 1 Chiral HPLC

Scheme 2 The compounds of the invention are low molecular weight, non-reactive, selective and potent inhibitors of neutrophil elastase with appropriate physicochemical and pharmacokinetic properties. In particular, they have a sufficiently high bioavailability after oral administration and / or a good solubility for parenteral administration and show a low in vitro clearance to hepatocytes and only a slight inhibition of CYP enzymes from microsomes.

The compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension including their subforms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic disorders, HIV infection or improper medication or toxins associated pulmonary arterial hypertension.

The compounds of the invention may also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension. Thus, they can be used, for example, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases and in left-sided heart valve diseases. Moreover, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension in chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness and pulmonary developmental disorders.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension due to chronic thrombotic and / or embolic diseases, such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism. Furthermore, the compounds according to the invention can be used for the treatment and / or prophylaxis of pulmonary hypertension in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis as well as pulmonary hypertension caused by external vascular compression (lymph node, tumor, fibrosing mediastinitis).

Because of their pharmacological profile of action, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive and / or fibrotic lung diseases and pulmonary hypertension due to chronic thrombotic and / or embolic diseases. The compounds according to the invention can be used alone or in combination with other active substances. 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 for the treatment and / or prophylaxis 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;

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;

NO-independent, but heme-dependent, stimulators of soluble guanylate cyclase, in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

• NO and heme-independent activators of soluble guanylate cyclase, in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO

02/070510 compounds described;

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'-di-cyclohexylurea, 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;

Anti-thrombotic 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 preferably from the group of calcium antagonists, angiotensin A antagonists, ACE inhibitors, endothelialin antagonists, renin inhibitors, alpha receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists, Rho kinase inhibitors and diuretics; and or

Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, 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 GPuI / 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 rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

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

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, 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, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelialin 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 ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib (CP-529414), 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, mehnamide, pactimibe, eflucimibe or SMP-797.

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for 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 according to the invention are administered in combination with a polymeric bile acid adsorber, such as, for example and preferably, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of 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 e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

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

The present invention further provides for the use of the compounds according to the invention, alone or in combination with one or more of the abovementioned active compounds, for the production of a medicament for the treatment and / or prophylaxis of the idiopathic, familial or pulmonary arterial hypertension associated with drugs, toxins or other disorders, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases, left-sided heart valve diseases, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, pulmonary developmental disorders, chronic thrombotic and / or embolic diseases such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism, or in conjunction with sarcoidosis, histiocytosis X or Lymphangioleiomyomatose, as well as for the treatment and / or prophylaxis of Vascular compression of externally induced pulmonary hypertension.

Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administering an effective amount of at least one of the compounds of the invention or a drug containing at least one of the compounds of the invention.

The medicaments to be produced according to the invention or to be used according to the invention comprise at least one of the compounds according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients.

Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention in combination with one or more inert, non-toxic, pharmaceutically suitable excipients, for the treatment and / or prophylaxis of the aforementioned diseases.

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

For these applications, the compounds of the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-release or insoluble coatings that control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example, hard or soft gelatin capsules), dragees, granules, pellets, powders, Emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). 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 suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions , Ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg 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. For example, in some cases it may be sufficient to make do with less than the minimum amount mentioned above, while in other cases this 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 cat. catalytic

CDI N.ΛT-carbonyldiimidazole

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (in yield) ee enantiomeric excess eq. Equivalent (s)

ESI electrospray ionization (in MS) h hour (s)

HATU O- (7-azabenzotriazol-1-yl) -M / V, / V ', / V'-tetramethyluronium

hexafluorophosphate

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectrometry min minute (s)

MPLC medium pressure liquid chromatography

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

RT room temperature

R, retention time (by HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry v / v volume to volume ratio (of a solution)

HPLC and LC-MS methods:

Method 1 (analytical HPLC):

Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 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 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 2 (analytical HPLO:

Device type HPLC: HP 1050 Series; UV DAD; Column: Phenomenex Synergi 2 μ Max-RP Mercury 20 mm x 4 mm; Eluent A: 1: 1 water + 0.05% trifluoroacetic acid, eluent B: 1: 1 acetonitrile; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 3 (analytical HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.

Method 4 (analytical HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → 9.2 min 2% B → 10 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 5 (analytical HPLC on chiral phase):

Chiral silica gel phase based on the selector poly (N-methacryloyl-D-leucine-fer-butyl-amide; column: 250 mm x 4.6 mm; eluent: ethyl acetate; flow: 2.0 ml / min; temperature: 24 ° C; UV detection: 260 nm.

Method 6 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795 / HP 1100; Column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 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 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm. Method 7 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex synergic 2 μ Hydro-RP Mercury 20 mm x 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 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 8 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 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 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 9 (LC-MS):

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo HyPURTTY Aquastar 3 μ 50 mm x 2.1 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 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 10 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 μ 30 mm x 3.0 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 → 2.5 min 30% A → 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 11 (preparative HPLC):

Device: Gilson Abimed HPLC; binary pump system; Column: Kromasil-IOOA C 18, 5 μm, 250 mm x 21 mm; Eluent A: water / 0.5% trifluoroacetic acid, eluent B: acetonitrile; 0-10 min 10% B, ramp 10.01-55 min 100% B; Flow: 20 ml / min; UV detection: 210 nm. Method 12 (preparative HPLC):

Device: Gilson Abimed HPLC; binary pump system; Column: Kromasil-IOOA C18, 5 μm, 250 mm x 20 mm; Eluent A: water / 0.05% trifluoroacetic acid, eluent B: acetonitrile; 0-1 min 10% B, ramp 1.01-30 min 95% B, 30.01-34 min 95% B, 34.01-35 min 10% B; Flow: 25 ml / min; UV detection: 210 nm.

Method 13 (preparative HPLO:

Device: Gilson Abimed HPLC; binary pump system; Column: Kromasil-IOOA C18, 5 μm, 250 mm x 20 mm; Eluent A: water / 0.1% trifluoroacetic acid, eluent B: acetonitrile; 0-1 min 10% B, ramp 1.01-40 min 90% B, 40-45 min 90% B; Flow: 25 ml / min; UV detection: 210 nm.

Method 14 (preparative HPLC):

Device: Gilson Abimed HPLC; binary pump system; Column: GromSil 120 ODS-4HE, 250 mm x 40 mm, 10 μm; Eluent A: water, eluent B: acetonitrile; 0-3 min 10% B, ramp 3.01-27 min 98% B, 27.01-34 min 98% B, 34.01-38 min 10% B; Flow: 50 ml / min; UV detection: 214 nm.

Method 15 (preparative HPLC):

Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Column: GromSil 120 ODS-4HE, 10 μm, 250 mm x 30 mm; Eluent A: water, eluent B: acetonitrile; Gradient: 0.0 min 30% B → 3 min 30% B → 31 min 95% B → 44 min 95% B → 45 min 30% B; Flow: 50 ml / min; Column temperature: RT; UV detection: 210 nm.

Method 16 (preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-tert-butylamide); Column: 125 mm x 20 mm; the sample is dissolved in a mixture of THF / ethyl acetate 1: 5; Eluent: ethyl acetate; Flow: 20 ml / min; UV detection: 260 nm; Temperature: 24 ° C.

Method 17 (preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-d-menthylamide); Column: 250 mm x 30 mm; Eluent: Step gradient 100% ethyl acetate → 100% methanol; Flow: 50 ml / min; Temperature: 24 ° C; UV detection: 260 nm. Analytical column: 250 mm x 4.6 mm; Eluent: ethyl acetate / methanol 10: 1; Flow: 2 ml / min. Method 18 ( ^" preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-1-menthylamide); Column: 680 mm x 40 mm; Eluent: Step gradient 100% ethyl acetate → 100% methanol; Flow: 50 ml / min; Temperature: 24 ° C; UV detection: 260 nm. Analytical column: 250 mm x 4.6 mm; Eluent: ethyl acetate; Flow: 2 ml / min.

Method 19 (preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-D-menthylamide); Column: 250 mm x 30 mm; Eluent: Step gradient 100% ethyl acetate → 100% methanol; Flow: 30 ml / min; Temperature: 24 ° C; UV detection: 260 nm. Analytical column: 250 mm x 4.6 mm; Eluent: ethyl acetate / methanol 5: 1; Flow: 2 ml / min.

Method 20 (preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-D-leucine-3-pentylamide; column: 500 mm × 63 mm; eluent: step gradient 100% ethyl acetate (0-16.33 min) → 100% methanol (16.34-24.12 min) → 100% ethyl acetate (24.13-35.0 min), flow: 100 ml / min, temperature: 24 ° C, UV detection: 340 nm.

Method 21 (preparative HPLC on chiral phase):

Enantiomer separation on a chiral silica gel phase based on the selector poly (Λf-methacryloyl-L-leucine-dicyclopropylmethylamide); Column: 250 mm x 20 mm; Eluent: Step gradient isohexane / ethyl acetate (40:60) (0-8 min) → 100% ethyl acetate (8:01 -12 min) → isohexane / ethyl acetate (40:60) (12:01 -20 min); Flow: 25 ml / min; Temperature: 24 ^° C; UV detection: 280 nm. Analytical column: 250 mm x 4.6 mm; Eluent: ethyl acetate / isohexane 1: 1; Flow: 2 ml / min.

Method 22 (preparative HPLC):

Device: Gilson Abimed HPLC; binary pump system; Column: GromSil 120 ODS-4HE, 250 mm x 40 mm, 10 μm; Eluent A: water + 0.1% trifluoroacetic acid, eluent B: acetonitrile; 10% B, ramp to 90% B in 45 min.

Method 23 (preparative HPLC):

Device: Abimed Gilson Pump 305/306, Manometric Module 806; Column: GromSil C18, 250 mm x 30 mm, 10 μm; Eluent A: water + 0.1% trifluoroacetic acid, eluent B: acetonitrile; Gradient: 0- 3 min 10% B, ramp 3.01-34 min 95% B, 34.01-38 min 95% B, 38.01-40 min 10% B; Flow: 50 ml / min; UV detection: 210 nm.

Method 24 (LC-MS):

Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 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 → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 210 nm.

Method 25 (LC-MSV

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 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 → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 208-400 nm.

Starting compounds and intermediates:

Example IA

N- [3-fluoro-5- (trifluoromethyl) phenyl] urea

5-fluoro-3- (trifluoromethyl) aniline 34 g (189 819 mmol) are dissolved in 227 ml of 2-propanol and added dropwise over a period of 10 minutes with 32,803 g (284 728 mmol) trimethyl silyl isocyanate are added at 50 ⁰ C. The mixture is stirred overnight at 50 ° C and then concentrated on a rotary evaporator. The residue is stirred with dichloromethane, the solid is filtered off with suction and dried under high vacuum. 25.0 g (59% of theory) of the target compound are obtained.

LC-MS (Method 7): R _t = 1.69 min; MS (ESIpos): m / z (%) = 223.0 (100) [M + H] ⁺

HPLC (Method 3): R, = 3.88 min

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 6.12 (br.s, 2H), 7.12 (d, IH), 7.53 (d, IH), 7.61 (s, IH), 9.12 (br. s, IH).

Example 2A

N- [4-fluoro-3- (trifluorrnethyl) phenyl] urea

2500 mg (13.957 mmol) of 4-fluoro-3- (trifluoromethyl) aniline are dissolved in 15 ml of 1N hydrochloric acid and admixed with 1132 mg (13957 mmol) of potassium cyanate. The suspension is stirred overnight at room temperature and then diluted with ethyl acetate to give a clear biphasic Solution is formed The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. After drying the combined organic phases and stripping off the solvent on a rotary evaporator. Chromatography is carried out on silica gel (eluent dichloromethane / methanol 80 l, then 10 l). 70% d Th) of the target compound

LC-MS (method 10) R, = 1 82 min, MS (ESIpos) m / z (%) = 223 0 (100) [M + H] ⁺

Example 3A

4 - {(4 /?) - 5- (l // - imidazol-l-ylcarbonyl) -6-methyl-2-oxo-l- [3- (tπfluormethyl) phenyl] -l, 2,3,4- tetrahydropymidin-4-yl jbenzonitrile

Under an argon blanket gas atmosphere (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (tn-fluoromethyl) phenyl] -1,3,3,4- Tetrahydropyπmidin-5-carboxylic acid (2 05 g, 5 mmol, prepared according to WO 2005/082863, Example 10A) in dry DMF (21 ml) and admixed with l, l'-carbonyl-dinimidazole (2 43 g, 15 mmol) The mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated, taken up in ethyl acetate (about 150 ml), washed with saturated aqueous sodium bicarbonate solution (about 50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a crude product (2 87 g, quantitative yield, about 80% purity), which is reacted without further purification

HPLC (method 2) R ₁ = 2 3 mm

Example 4A

(4R) -3- (2-tert-Butoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1 - [3- (t -fluoromethyl) -phenyl] -1,2, 3,4-5-carboxylic acid tetrahydropyπmidin-

The reaction is carried out under argon. (4 /?) - 3- (2-heptabutoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] - l, 2,3,4-tetrahydropyrimidine-5-carboxylic acid allyl ester (2.50 g, 4.5 mmol, for the preparation of the racemic compound see WO 2005/082863, Example 23A) and morpholine (588 mg, 6.8 mmol) are dissolved in THF (25 ml) submitted. The batch is carefully evacuated and rinsed again with argon. Subsequently, tetrakis (triphenylphosphine) palladium (O) (260 mg, 0.225 mmol) is added and the reaction mixture is stirred at RT for 60 min. An HPLC control then indicates complete conversion. The reaction mixture is concentrated in vacuo and the residue taken up in ethyl acetate (200 ml). The organic phase is then washed with saturated ammonium chloride solution (75 ml), water (50 ml) and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered, concentrated by evaporation and the residue is purified by preparative HPLC (column: Kromasil 5 μm, eluent: acetonitrile / water + 0.1% TFA 10:90 → 90:10). The title compound is thus obtained as a solid (1.9 g, 82% of theory).

LC-MS (Method 7): R, = 2.4 min; MS (ESIpos): m / z (%) = 516 (5) [M + H] ⁺ ; MS (ES Ineg): m / z (%) = 514.2 (100) [M-Hf.

EXAMPLES

example 1

Ethyl (4Λ) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate

Racemic ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (60 g; WO 2004/024700, Example 1) is dissolved in ethyl acetate (360 ml) and separated by chromatography into the enantiomers (Method 20). The title compound (29.9 g, 99% of th., 99.1% ee) and the isomeric ethyl (4S) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl ) phenyl] -1,3,3,4-tetrahydropyrimidine-5-carboxylate.

HPLC (Method 5): R, = 1.55 min.

The further analytical data correspond to those reported for the racemic compound (see WO 2004/024700, Example 1).

Example 2

4 - {(4Λ) -5-isobutyryl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidin-4-yl} benzonitrile

2000 mg (15,604 mmol) of 5-methylhexane-2,4-dione, 2046 mg (15,604 mmol) of 4-formylbenzonitrile and 3186 mg (15,604 mmol) of 1- [3- (trifluoromethyl) phenyl] urea are dissolved in 60 ml of THF and with 10 g of ethyl polyphosphate (PPE). The mixture is stirred overnight at 80 ° C and then partitioned between water and ethyl acetate. The organic phase is separated, dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator. The residue is purified first by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) and then by preparative HPLC on a chiral phase (method 18), the enantiomers being separated (desired enantiomer: R, = 4.70 min). , After further purification by means of preparative HPLC (Method 15), 530 mg (8% of theory) of the title compound are obtained.

MS (ESIpos): m / z (%) = 428 (100) [M + H] ⁺

HPLC (Method 3): R, = 8.33 min

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 0.80 (d, 3H), 0.95 (d, 3H), 1.86 (s, 3H), 2.95 (tt, IH), 5.48 (d, IH) , 7.55 (d, IH), 7.62 (d, 2H), 7.68 (t, IH), 7.70 (s, IH), 7.77 (d, IH), 7.89 (d, 2H), 8.41 (d, IH).

Example 3

4 - {(4 /?) - 5- (cyclobutylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidin-4-yl } benzonitrile

The preparation of the racemic compound is carried out as described in WO 2005/082864 (Example 20). The racemate is separated into the enantiomers by preparative HPLC on a chiral phase (Method 19).

HPLC (Method 19): R, = 2.68 min

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.67 (m, IH), 1.82 (m, 2H), 1.94 (s, 3H), 1.96-2.19 (m, 3H), 3.49 (dt, IH) , 5.37 (d, IH), 7.53 (d, IH), 7.61 (d, 2H), 7.68 (m, 2H), 7.78 (d, IH), 7.89 (d, 2H), 8.42 (d, IH).

Example 4

tert. Butyl [(6 /?) - 6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 //) - yl] acetate

170 mg (0.387 mmol) of 4 - {(4 /?) - 5- (cyclobutylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) -phenyl] -1,3,3,4-tetrahydropyrimidine 4-yl} benzonitrile are dissolved in 3 ml of DMF and treated with 91 mg (0.464 mmol) of ferr-butyl bromoacetate and 96 mg (0.696 mmol) of potassium carbonate. The mixture is stirred overnight at room temperature. Subsequently, a further 91 mg (0.464 mmol) of ferric butyl bromoacetate and 50 mg (0.362 mmol) of potassium carbonate are added and the suspension is stirred at 50 ° C. for a period of six hours. For workup, the mixture is added to 30 ml of water. The aqueous phase is extracted several times with ethyl acetate, the organic phases are combined and the solvent is stripped off on a rotary evaporator. The residue is taken up in methanol and purified by preparative HPLC (Method 14). 196 mg (92% of theory) of the target compound are obtained.

LC-MS (Method 10): R, = 3.06 min; MS (ESIpos): m / z (%) = 554.2 (18) [M + H] ⁺ .

Example 5

[(6i?) - 6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / f ) -yl] acetic acid tert. butyl

Under an argon blanket gas atmosphere, ethyl (4Λ) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidine-5 carboxylate (10.74 g, 25 mmol) and solid potassium carbonate (5.53 g, 40 mmol) in dimethylformamide (100 ml). While stirring, bromoacetic acid ferf. butyl ester (7.8 g, 40 mmol) was added dropwise. The reaction mixture is stirred for 20 h at room temperature and then reacted at 60 ° C for a further 3 h. The reaction mixture is concentrated in vacuo and the residue taken up in ethyl acetate (200 ml). The organic phase is then washed with water (2 x 50 ml each) and then with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated. The Crude product is flash chromatographed on silica gel (eluent: gradient cyclohexane → cyclohexane / ethyl acetate 6: 4). There are obtained 12.5 g (91% of theory) of the title compound as a solid.

LC-MS (Method 8): R, = 2.94 min; MS (ESIpos): m / z (%) = 488.1 (100) [MH-HC ₄ H ₈ I ⁺ ; MS (ESIneg): m / z (%) = 542.2 (100) [MH] ^"

¹ H-NMR (400 MHz, DMSOd ₆ ): 6 = 1.05 (t, 3H), 1.25 (s, 9H), 2.05 (s, 3H), 3.85 (d, IH), 4.0 (m, 3H), 5.55 (s, IH), 7.60-7.90 (m, 8H).

Example 6

2,3-Dihydroxypropyl (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidine-5- carboxylate

200 mg (0.453 mmol) of AHyI (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine. 5-carboxylate (preparation according to WO 2005/082863, Example 6A) are dissolved in 20 ml of acetone / water (3: 1). The solution is cooled to 0 ⁰ C and a solution of 72 mg (0.453 mmol) of potassium permanganate in 10 ml of acetone / water (3: 1) was added. After stirring for 90 minutes at room temperature, saturated sodium thiosulfate solution is added and the mixture is stirred for a further 30 minutes. The workup is carried out by aspirating the batch through a kieselguhr column, which is eluted with a little methanol. After separation of the organic phase, the aqueous phase is back-extracted twice with ethyl acetate. The combined organic phases are concentrated and the residue is purified by preparative HPLC (Method 14). 119 mg (54% of theory) of the target compound are obtained.

LC-MS (Method 8): R, = 2.06 min; MS (ESIpos): m / z (%) = 476.1 (100) [M + H] ^{+ 1} H-NMR (400 MHz, DMSOd ₆ ): δ = 2.05 (s, 3H), 3.19-3.31 (m, 2H), 3.60 (m, IH), 3.89 (ddd, IH), 4.05 (ddd, IH) , 4.61 (q, IH), 4.92 (dd, IH), 5.44 (m, IH), 7.57 (br, s, IH), 7.63 (m, 2H), 7.70 (m, 2H), 7.79 (d, IH ), 7.87 (d, 2H), 8.41 (m, IH).

Example 7

4 - {(4 /?) - 5-acetyl-1- [4-fluoro-3- (trifluoromethyl) phenyl] -6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-4 yl jbenzonitrile

465 mg (4.646 mmol) of 2,4-pentanedione, 609 mg (4.646 mmol) of 4-formylbenzonitrile and 1200 mg (4.646 mmol) of N- [4-fluoro-3- (trifluoromethyl) phenyl] urea are dissolved in 12 ml of THF and with 3000 mg of ethyl polyphosphate (PPE). The mixture is stirred under reflux for six hours and then concentrated on a rotary evaporator. The residue is first purified by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1 → 2: 1 → 1: 1) and then by preparative HPLC (method 14). The resulting racemate is separated by preparative HPLC on a chiral phase (Method 17). This gives 303 mg (16% of theory) of the title compound.

HPLC (Method 17): R, = 4.70 min

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 2.02 (s, 3H), 2.20 (s, 3H), 5.47 (d, IH), 7.61 (m, 4H), 7.74 (br, s, IH) , 7.88 (d, 2H), 8.48 (d, IH).

Example 8

[(6 /?) - 6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / f) -yl] acetic acid

190 mg (0.343 mmol) tert. Butyl [(6 /?) - 6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 ( 2fl) -yl] acetate are dissolved in 3 ml of dichloromethane, treated with 3 ml of trifluoroacetic acid and stirred for two hours at room temperature. The reaction mixture is concentrated and the residue is purified by preparative HPLC (Method 14). 160 mg (94% of theory) of the target compound are obtained.

LC-MS (Method 10): R, = 2.62 min; MS (ESIpos): m / z (%) = 498.1 (100) [MIH] ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 1.66 (m, IH), 1.83 (m, 2H), 1.92 (s, 3H), 2.02 (m, 2H), 2.16 (m, IH) , 3.53 (dt, IH), 3.84 (d, IH), 4.18 (d, IH), 5.60 (s, IH), 7.59 (d, IH), 1.65-1 YES (m, 4H), 7.81 (d, IH), 7.88 (d, 2H), 12.70 (s, IH).

Example 9

5 - {(4A) -5-Acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidin-4-yl} pyridine-2-carbonitrile

The representation of the title compound is carried out as described in WO 2004/024700 (Example 74).

Example 10

2-hydroxyethyl (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidine-5- carboxylate

The representation of the title compound is carried out as described in WO 2004/024700 (Example 72).

Example 11

2- (dimethylamino) ethyl (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1 - [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydropyrimidine-5 carboxylate trifluoroacetate

Under an argon protective gas atmosphere is 4 - {(4 /?) - 5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1, 2, 3,4-tetrahydropyrimidin-4-yl} benzonitrile (Example 3A, 2.26 g, 5 mmol) in N, JV-dimethylethanolamine (20 ml) and then at 100 ^° C. for 3 h. stir. The reaction is concentrated in vacuo, the residue taken up in ethyl acetate (150 ml) and then washed with water (50 ml) and saturated sodium chloride solution (50 ml). The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (Method 22). 2.38 g (77% of theory) of the title compound are obtained.

LC-MS (Method 10): R _t = 1.2 min; MS (ESIpos): m / z (%) = 473.5 (100) [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 2.05 (s, 3H), 2.10 (br, s, 6H), 2.40 (m, 2H), 4.10 (m, 2H), 5.40 (d, IH), 7.55-7.70 (m, 5H), 7.80 (d, IH), 7.90 (d, 2H), 8.40 (d, IH).

Example 12

4 - {(4Λ) -5-Acetyl-1- [3-fluoro-5- (trifluoromethyl) phenyl] -6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl} benzonitrile

2,4-pentanedione (90.1 mg, 0.9 mmol) in THF (10 ml) is placed under an argon protective gas atmosphere. 4-Cyanobenzaldehyde (118 mg, 0.9 mmol), N- [3-fluoro-5- (trifluoromethyl) phenyl] urea (200 mg, 0.9 mmol) and ethyl polyphosphate (551 mg) are successively added. The reaction is stirred under reflux until the TLC control indicates complete conversion (approximately 4 h). The batch is concentrated in vacuo and the residue directly chromatographies (Biotage medium pressure system, silica gel column, eluent: cyclohexane / ethyl acetate 5: 1 → 3: 1 → 2: 1 → 1: 1). 188 mg (50% of theory) of the racemic title compound are obtained. The racemate is then separated into the enantiomers by chromatography (Method 16). From 65 mg of the racemate, 28 mg of the enantiomerically pure title compound (> 99.5% ee) are obtained.

HPLC (Method 16): R, = 23.27 min LC-MS (method 7): R, = 2.2 min; MS (ESIpos): m / z (%) = 418.1 (100) [M + H] ⁺

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 2.00 (s, 3H), 2.20 (s, 3H), 5.44 (d, IH), 7.55 (m, 4H), 7.75 (br, s, IH) , 7.85 (d, 2H), 8.45 (d, IH).

Example 13

[(6Λ) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / f) yl] acetic acid

[(6 /?) - 6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 ( 2 / f) -yl] -acet-butyl ester (165 mg, 0.30 mmol) is placed under an argon inert gas atmosphere in dichloromethane (1.5 ml), treated with trifluoroacetic acid (1.5 ml) and stirred for 4 h at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by preparative HPLC (Method 13). There are obtained 132 mg (89% of theory) of the title compound.

HPLC (Method 2): R, = 3.0 min

LC-MS (Method 7): R, = 2.3 min; MS (ESIpos): m / z (%) = 488.1 (100) [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 1.10 (t, 3H), 2.05 (s, 3H), 3.75 (d, IH), 4.05 (q, 2H), 4.10 (d, IH) , 5.60 (s, IH), 7.60-7.75 (m, 5H), 7.80 (d, IH), 7.90 (d, 2H), 12.70 (s, IH).

Example 14

[(6R) -5- {[2- (carboxymethoxy) ethoxy] carbonyl} -6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3, 6-dihydropyrimidine-1 (2W) -yl] acetic acid

The representation of the title compound is carried out as described in WO 2005/082864 (Example 5).

Example 15

[(6 /?) - 6- (4-cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidin-1 (2 / /)-yl]essigsäure-ter?.-butylester

Sodium hydride (1.17 g, 29.2 mmol) in THF (50 ml) is placed under an argon protective gas atmosphere. A solution of the compound from Example 2 (5.0 g, 11.7 mmol) in THF (150 ml) is added slowly and the reaction mixture is stirred under foaming for 1 h at RT. Subsequently, bromoacetic acid-tert-butyl ester (3.4 g, 17.5 mmol) is added slowly. After 2 h, the thin layer chromatogram shows complete conversion. The mixture is carefully mixed with water (300 ml). The aqueous phase is saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is absorbed on silica gel. and purified by MPLC (200 g silica gel, eluent: cyclohexane / ethyl acetate 4: 1). This gives 5 g of the title compound in 79% purity and 4.4 g in 70% purity, which can be finely purified by preparative HPLC.

LC-MS (Method 7): R, = 2.8 min; MS (ESIpos): m / z (%) = 486 (100) [MC ₄ H ₈ ^ -H] ⁺ ; MS (ES Ineg): m / z (%) = 540 (100) [MH] ^" .

For further analytical data, see the reports reported for the racemic compound (WO 2005/082863, Example 34A).

Example 16

[(6 /?) - 6- (4-cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidin-1 (2 / f) -yl] acetic acid

[(6 /?) - 6- (4-cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidin-1 (2 / f) -yl] -acetic acid tert-butyl ester (4.43 g, 8.2 mmol) is placed under argon protective gas atmosphere in dichloromethane (50 ml), treated with trifluoroacetic acid (18.7 g, 164 mmol) and stirred for about 4 h at room temperature ( until the TLC control indicates complete conversion). The reaction mixture is concentrated in vacuo and the residue is purified by chromatography (Biotage chromatography unit, silica gel, eluent: dichloromethane -> dichloromethane / methanol 100: 1 → 50: 1). 1.44 g (34% of theory) of the title compound are obtained.

LC-MS (Method 7): R, = 2.3 min; MS (ESIpos): m / z (%) = 486.1 (100) [M + H] ⁺ ; MS (ES Ineg): m / z (%) = 484.2 (80) [MH] ^" , 969.5 (100) ¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 0.60 (d, 3H), 0.70 (d, 3H), 1.60 (s, 3H), 2.70 (m, IH), 3.60 (d, IH), 4.00 (d, IH), 5.50 (s, IH), 7.35-7.50 (m, 5H), 7.60 (d, IH), 7.65 (d, 2H), 12.50 (br, s, IH).

Example 17

3- {[(6Λ) -5-Acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidin-1 (2 / f) -yl] methyl} benzoic acid

The representation of the title compound is as described in WO 2005/082863 (Example 21).

Example 18

4- {[(6 /?) - 5-Acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidine-1 (2 / f) -yl] methyl benzoic acid

The representation of the title compound is carried out as described in WO 2005/082863 (Example 22). Example 19

Tert-butyl [(6 /?) - 5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine l (2 / f) -yl] acetate

The reaction is carried out under argon. To a solution of {4Λ} -4- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,3,3,4-tetrahydro-4-pyrimidinyl} benzonitrile ( 15.0 g, 37.6 mmol, WO 2005/082864, Example 18A) in THF (450 ml) is added portionwise solid sodium hydride (3.76 g, 93.9 mmol). The mixture is stirred for 1 h at RT, then rerf.butyl bromoacetate (11 g, 56.3 mmol) is added slowly and stirred again for 1 h at RT. The DC control shows complete conversion. The mixture is carefully mixed with water (500 ml). Saturated aqueous sodium chloride solution is added and then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by MPLC on silica gel (eluent: cyclohexane / methylene chloride 1: 1). This gives a colorless solid as product (9.94 g, 51% of theory), which can be used in the subsequent reaction without further purification steps.

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 1.25 (s, 9H), 2.00 (s, 3H), 2.20 (s, 3H), 3.95 (d, IH), 4.15 (d, IH) , 5.70 (s, IH), 7.60-7.90 (m, 8H).

Example 20

[(6 /?) - 5-Acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / /) - yl] acetic acid

The reaction is carried out under argon. To a solution of the compound from Example 19 (12.2 g, 23.7 mmol) in dichloromethane (160 ml) is added trifluoroacetic acid (36.5 ml, 473.2 mmol). The reaction mixture is stirred overnight at RT. The DC control then shows complete sales. The mixture is then concentrated in vacuo and the residue is purified by flash chromatography on silica gel (eluent: methylene chloride → methylene chloride / methanol 100: 1 → methylene chloride / methanol 50: 1). The product obtained is a solid (7.55 g, 70% of theory).

¹ H-NMR (400 MHz, DMSO-dβ): δ = 1.95 (s, 3H), 2.25 (s, 3H), 2.95 (d, IH), 4.15 (d, IH), 5.80 (s, IH), 7.55-7.90 (m, 8H).

Example 21

2 - [(6 /?) - 5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 ( 2 //) - yl] acetamide

The reaction is carried out under argon. [(6 /?) - 5-Acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / f) -yl] acetic acid from Example 20 (12.0 g, 26.2 mmol) is initially charged in DMF (150 ml), at 0 ⁰ C with HATU (19.95 g, 52.5 mmol) and stirred for 20 min. Then ammonium chloride (7.0 g, 131.2 mmol) and N, 7V-diisopropylethylamine (23.7 g, 183.6 mmol) are added and the mixture is stirred at RT for 90 min. HPLC or TLC control then show complete conversion. The reaction mixture is concentrated in vacuo. The residue is then taken up in ethyl acetate (400 ml) and successively with aqueous sodium bicarbonate solution (70 ml), 10% citric acid solution (3 x 70 ml each), sodium bicarbonate solution (70 ml) and saturated sodium chloride solution (70 ml). The organic phase is dried over sodium sulfate, filtered, concentrated in vacuo and the residue dried under high vacuum. The resulting crude product is purified by preparative HPLC. To this is dissolved the crude product in a mixture of acetonitrile (80 ml), methanol (60 ml), water (20 ml) and trifluoroacetic acid (1 ml). The solid phase used is Kromasil 100 C18 5 μm (column size: 250 mm x 20 mm). It is eluted isocratically with 0.2% TFA / acetonitrile 1: 1. This gives a colorless solid as product (9.1 g, 76% of theory).

LC-MS (Method 8): R _t = 2.2 min; MS (ESIpos): m / z (%) = 457.0 (100) [M + H] ⁺ , 439.9 (60); MS (ESIneg): m / z (%) = 455.0 (100) [MH] ^"

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 1.95 (s, 3H), 2.25 (s, 3H), 3.40 (d, IH), 4.15 (d, IH), 5.65 (s, IH) , 7.15 (br s, IH), 7.45 (br s, IH), 7.60-7.90 (m, 8H).

Example 22

Ethyl (4 /?) - 3- (2-amino-2-oxo-ethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1 - [3- (trifluoromethyl) -phenyl] -l, 2 , 3,4-tetrahydropyrimidine-5-carboxylate

100 mg (0.205 mmol) of [(6 /?) - 6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3, 6-Dihydropyrimidin-l (2 //) - yl] acetic acid from Example 13 are dissolved in 7.5 ml of THF and cooled to -20 ° C. 52 mg (0.513 mmol) / V-methylmorpholine and 56 mg (0.513 mmol) of ethyl chloroformate are added to this solution. It is stirred for 30 min at -20 ⁰ C and then added to a mixture of 0.2 ml of 35% aqueous ammonia solution in 1.5 ml of THF. Subsequently, the reaction mixture is allowed to come slowly to room temperature and then gives the contents of the flask to 3 N hydrochloric acid. The aqueous phase is extracted with ethyl acetate and separated. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (Method 23). This gives 78 mg (78% of theory) of the title compound.

MS (ESIpos): m / z (%) = 487 (100) [M + H] ⁺

HPLC (Method 4): R, = 4.31 min

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.12 (t, 3H), 2.03 (s, 3H), 3.31 (d, IH), 4.05 (dq, 2H), 4.12 (d, IH), 5.51 (s, IH), 7.16 (s, IH), 7.44 (s, IH), 7.63-7.66 (m, 3H), 7.73 (t, IH), 7.78 (s, IH), 7.82 (d, IH), 7.89 (d, 2H).

Example 23

(4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The preparation of the title compound is carried out as described in WO 2005/082863 (Example 15A). Example 24

Tert-butyl [(6 /?) - 5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine 1 (2 //) - yl] acetate

5900 mg (15.431 mmol) of (4 /?) - 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5 Carbonitrile are dissolved in 150 ml of DMF and treated with 7677 mg (55,551 mmol) of potassium carbonate and 7224 mg (37,034 mmol) bromoacetic acid tert-butyl ester. The reaction mixture is then stirred overnight at 6O ⁰ C. Thereafter, the solvent is stripped off on a rotary evaporator and the residue taken up in a mixture of ethyl acetate and water. The organic phase is separated, dried over sodium sulfate, filtered and concentrated. The residue is applied to silica gel and purified by MPLC on silica gel (eluent: cyclohexane / ethyl acetate 1: 2). This gives 5570 mg (73% of theory) of the title compound.

LC-MS (Method 6): R, = 2.65 min; MS (ES Ineg): m / z (%) = 495.2 (100) [MH] ^"

¹ H-NMR (400 MHz, DMSOd ₆ ): 6 = 1.29 (s, 9H), 1.86 (s, 3H), 3.71 (d, IH), 3.96 (d, IH), 5.49 (s, IH), 7.70 -7.75 (m, 2H), 7.78 (d, 2H), 7.84 (d, IH), 7.87 (s, IH), 7.96 (d, 2H).

Example 25

[(6 /?) - 5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2 / f) -yl] acetic acid

5840 mg (11.762 mmol) of tert-butyl [(6/5) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] - 3,6-Dihydropyrimidin-l (2 / f) -yl] acetate are dissolved in 40 ml of dichloromethane and treated with 13412 mg (117,625 mmol) of trifluoroacetic acid. The batch is stirred at 50 ^° C. for 5 h. Thereafter, the volatiles are removed on a rotary evaporator. The residue is purified by MPLC on silica gel (eluent: dichloromethane / methanol 10: 1). This gives 3120 mg (58% of theory) of the title compound.

LC-MS (Method 10): R, = 2.47 min; MS (ESIpos): m / z (%) = 441.1 (100) [M + H] ⁺ .

Example 26

2 - [(6 /?) - 5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-pyrimidin-1 ( 2 //) - yl] acetamide

100 mg (0.227 mmol) of [(6 /?) - 5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine -l (2 //) - yl] acetic acid are dissolved in 5 ml of THF and to -20 ⁰ C overall cools. 57 mg (0.568 mmol) of Λf-methylmorpholine and 62 mg (0.568 mmol) of ethyl chloroformate are added to this solution. It is stirred for 30 min at -20 ⁰ C and then added to a mixture of 0.15 ml of 35% aqueous ammonia solution in 1.5 ml of THF. The reaction mixture is then allowed to come to room temperature slowly and then the contents of the flask are added to 3N hydrochloric acid. The aqueous phase is extracted with ethyl acetate and separated. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (Method 23). This gives 44 mg (44% of theory) of the title compound.

MS (DCI): m / z (%) = 457 (100) [M + NH4] ⁺ , 440 (6) [MH-H] ⁺

HPLC (Method 3): R, = 4.19 min

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 1.82 (s, 3H), 3.20 (d, IH), 4.10 (d, IH), 5.45 (s, IH), 7.12 (s, IH) , 7.39 (s, IH), 7.72-7.76 (m, 4H), 7.83 (d, IH), 7.87 (s, IH), 7.89 (d, 2H).

Example 27

[(6 /?) - 6- (4-cyanophenyl) -5 - [(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) -phenyl] -3,6- dihydropyrimidin-l (2 //) - yl] acetic acid butyl ester TEA .-?

(4 /?) - 3- (2-rerf.-butoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) -phenyl] -l , 2,3,4-tetrahydropyrimidine-5-carboxylic acid (Example 4A, 515 mg, 1 mmol), 2-bromoethanol (521 mg, 4 mmol) and N, N-diisopropylethylamine (258 mg, 2 mmol) are at 70 ⁰ C for 24 h in DMF (15 ml). The reaction mixture is then concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase is washed with water and then with concentrated aqueous sodium chloride solution. It is then dried over sodium sulfate, filtered and concentrated. The crude product is purified by flash chromatography on silica gel Purified (eluent: cyclohexane - »cyclohexane / ethyl acetate 1: 2). The product obtained is a colorless solid (472 mg, 84% of theory).

LC-MS (Method 8): R, = 2.6 min; MS (ESIpos): m / z (%) = 504.1 (100), 560 (20) [M + H] ⁺ ; MS (ES Ineg): m / z (%) = 558.4 (100) [MH] ^" .

Example 28

[(6 /?) - 6- (4-cyanophenyl) -5 - [(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) -phenyl] -3,6- dihydropyrimidin-l (2 / f) -yl] acetic acid

[(6 /?) - 6- (4-cyanophenyl) -5 - [(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) -phenyl] -3,6- tert-Butyl dihydropyrimidin-l (2 / f) -yl] acetate (Example 27; 235 mg, 0.42 mmol) is initially charged in dichloromethane (2 ml). Then trifluoroacetic acid (2 ml) is added and the mixture is stirred at RT for 24 h. The reaction mixture is then concentrated under reduced pressure and the crude product is purified by preparative HPLC (column: Kromasil 5 μm, eluent: acetonitrile / water + 0.1% TFA 10:90 → 90:10). The title compound is obtained as a solid (115 mg, 54% of theory).

LC-MS (method 7): R ₁ = 1.9 min; MS (ESIpos): m / z (%) = 504.1 (100) [M + H] ⁺ ; MS (ES Ineg): m / z (%) = 502.1 (70) [MH] ^" .

Example 29

2-Hydroxyethyl (4 /?) - 3- (2-amino-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1 - [3- (trifluoromethyl) phenyl] - l, 2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction is carried out under argon. [(6Λ) -6- (4-cyanophenyl) -5 - [(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine l (2 //) - yl] acetic acid (Example 28, 40 mg, 79 .mu.mol) is initially charged in DMF (2 ml), treated at 0 ^° C. with HATU (151 mg, 0.4 mmol) and stirred for 20 min. Then ammonium chloride (21 mg, 0.4 mmol) and Λf, Λf-diisopropylethylamine (103 mg, 0.8 mmol) are added and the reaction mixture is stirred for 16 h at RT. The crude mixture obtained is purified directly by preparative HPLC (column: Gromsil Cl 8 10 μm, eluent: acetonitrile / water + 0.1% TFA 10:90 → 90:10). The title compound is obtained as a colorless solid (16 mg, 40% of theory).

LC-MS (Method 24): R ₁ = 2.9 min; MS (ESIpos): m / z (%) = 503.2 (60) [M + H] ⁺ , 441.2 (100); MS (ES Ineg): m / z (%) = 501.2 (100) [M-HF

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 2.00 (s, 3H), 3.30 (d, IH), 3.50 (t, 2H), 4.05 (m, 2H), 4.15 (d, IH), 5.55 (s, IH), 7.15 (br s, IH), 7.50 (br s, IH), 7.60-7.90 (m, 8H).

Example 30

Ethyl (4 /?) - 4- (4-cyanophenyl) -3- [2- (dimethylamino) -2-oxoethyl] -6-methyl-2-oxo-1 - [3- (trifluoromethyl) phenyl] - l, 2,3,4-tetrahydropyrimidine-5-carboxylate

975 mg (2.00 mmol) of [(6A) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6- dihydropyrimidin-l (2 / f) -yl] acetic acid (Example 13) are dissolved in 4 ml of DMF and treated with 2.2 ml (4.401 mmol) of a 2 M solution of dimethylamine in THF. Subsequently, 449 mg (4.00 mmol) of 4-N, Λf-dimethylaminopyridine, 595 mg (4.401 mmol) of 1-hydroxy-1 // benzotriazole hydrate and 844 mg (4.401 mmol) of 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride added. It is stirred overnight at RT. After concentration of the batch on a rotary evaporator, the crude product is purified by preparative HPLC (Method 23). This gives 795 mg (77% of theory) of the title compound.

LC-MS (Method 25): R, = 3.67 min; MS (ESIpos): m / z (%) = 515.4 (100) [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

BNP brain natriuretic peptide

BSA bovine serum albumin

HEPES ΛH2-hydroxyethyl) piperazine-ΛT-2-ethanesulfonic acid

HNE human neutrophil elastase

IC inhibitory concentration

MeOSuc methoxysuccinyl

NADP nicotinamide adenine dinucleotide phosphate v / v volume to volume ratio (of a solution) w / v weight to volume ratio (of a solution)

B-I. 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, test 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, Fa. Bachern, 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.

Representative IC ₅₀ values representative of the compounds of this invention are shown in the following table: Table: Inhibition of human neutrophil elastase (HNE)

B-2. Animal model of pulmonary arterial hypertension

Rat monocrotaline-induced pulmonary hypertension is a widely used animal model of pulmonary arterial hypertension. The pyrrolizidine alkaloid monocrotaline is metabolized to the toxic monocrotaline pyrrole after subcutaneous injection in the liver and leads to endothelial damage in the pulmonary circulation within a few days, followed by remodeling of the small pulmonary arteries (medial hypertrophy, de novo muscularization). A single subcutaneous injection is sufficient to induce severe pulmonary hypertension in rats within 4 weeks [Cowan et al., Nature Med. 6, 698-702 (2000)]. The model uses male Sprague-Dawley rats. On day 0 the animals receive a subcutaneous injection of 60 mg / kg monocrotaline. The treatment of the animals begins at the earliest 14 days after the monocrotalin injection and extends over a period of at least 14 days. At the end of the study hemodynamic examinations of the animals as well as a determination of arterial and central venous oxygen saturation are carried out. For hemodynamic measurement, the rats are initially anesthetized with pentobarbital (60 mg / kg). The animals are then tracheotomized and artificially ventilated (frequency: 60 breaths / min, inspiration to expiration ratio: 50:50, positive end expiratory pressure: 1 cm H ₂ O, tidal volume: 10 ml / kg body weight, FIO ₂ : 0.5). The anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is determined in the left carotid artery using a Millar microtip catheter. A polyethylene catheter is advanced via the right jugular vein into the right ventricle to determine right ventricular pressure. Cardiac output is determined by thermodilution. Following hemodynamics, the heart is removed and the ratio of right to left ventricles, including the septum, is determined. Furthermore, plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained.

B-3. CYP Inhibition Assay

The ability of substances to inhibit CYPl A2, 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 examined at six different concentrations of the test compounds (2.8, 5.6, 8.3, 16.7, 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 of each test compound (as a potential inhibitor) is performed on a workstation (Tecan, Genesis, Crailsheim, Germany). Standard incubation mixtures contain 1.3 mM NADP, 3.3 mM MgCl ₂ × 6 H ₂ O, 3.3 mM glucose-6-phosphate, glucose-6-phosphate dehydrogenase (0.4 U / ml) and 100 mM phosphate buffer (pH 7.4) in a total volume of 200 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 by addition of 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-4. Hepatocyte assav to determine the metabolic stability

The metabolic stability of test compounds to hepatocytes is determined by incubating the compounds at low concentrations (preferably below 1 μM) and at low numbers of cells (preferably at 1 × 10 ⁶ cells / ml) in order to ensure the best possible linear kinetic conditions in the experiment. Seven samples from the incubation solution are taken at a fixed time interval for LC-MS analysis to determine the half life (ie degradation) of the compound. From this half-life, different "clearance" parameters (CL) and "F _m1x " values are calculated (see _below ).

The CL and F ^ sides are a measure of the phase I and phase 2 metabolism of the compound in the hepatocytes. In order to minimize the influence of the organic solvent on the enzymes in the incubation mixtures, 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 beyond the incubation period (typically 90 minutes) can only be considered as rough guidelines.

The calculated parameters and their meaning are:

F _max well-stirred [%] maximum bioavailability after oral administration

Calculation: (L-CL _b well-stirred / QH) * 100

CL _b i _ood well-stirred [L / (h * kg)] Calculated blood clearance (well stirred model) Calculation: (QH * CL ' _mttmsic ) / (QH + CL' _{mtn] lslc} )

CL ¹ _U1 ^ _111S1C [ml / (min * kg)] maximum ability of the liver (hepatocytes) to metabolize a compound (assuming that the hepatic blood flow is not velocity-imitating)

Calculation: CL ' _{mmnsic, apparent} * species-specific hepatocyte _count [1.1 * 10 ⁸ / g liver] * species-specific liver weight [g / kg]

CL'i _nt ri _ns i _c , _apparen i [ml / (min * mg)] normalizes the elimination _constant by dividing it by the hepatocyte cell number x (x * 10 ⁶ / ml) used

Calculation: k ^ [l / min] / (cell count [x * 10 ⁶ ] / incubation volume [ml])

(QH = species-specific liver blood flow).

C. Embodiments of Pharmaceutical Compositions

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

Tablet:

Composition:

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

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

production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

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

production:

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

Orally administrable solution:

Composition:

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

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

iv solution:

The compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Use of a compound of the formula (I)

in which

X is CH or N,

R ^{1 is} hydrogen, a group of the formula - (CH ₂ ) _n -C (= O) -OR ^1A or - (CH ₂ ) _n -C (= O) -NR ^1B R ^Ic or a group of the formula

stands in which

the point of attachment to the N atom means

the number 1 or 2 means

R ^{1A is} hydrogen or (C _r C ₄ ) alkyl

and

R ^1B and R ^1C are independently hydrogen or (C _r C ₄₎ -alkyl, R ^{2 is} cyano or a group of the formula -C (= O) -R ^2A or -C (= O) -OR ^2A in which

R ^2A (C _r C ₆ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, which in turn may be monosubstituted, identical or different, with hydroxy, (C ₁ -C ₄ ) -alkoxy, hydroxycarbonyl, amino, mono- and / or di- (C _r C ₄₎ alkylamino may be substituted and in which in each case one CH ₂ group can be replaced by an O atom,

and

R ^{3 is} either hydrogen

and

R ^{4 is} hydrogen, fluorine or chlorine

or

R ^{3 is} fluorine or chlorine

and

R ^{4 is} hydrogen,

or one of its salts, solvates or solvates of the salts

for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

2. Use according to claim 1, a compound of formula (I) according to claim 1, in which-

X is CH or N,

R ^{1 is} hydrogen, a group of the formula -CH ₂ -C (= O) -OH or -CH ₂ -C (^ O) -NH ₂ or a group of the formula

stands in which

* means the point of attachment to the N-atom,

R ^{1 is} cyano, acetyl, cyclobutylcarbonyl, methoxycarbonyl, ethoxycarbonyl or 2-hydroxyethoxycarbonyl,

R ^{3 is} hydrogen

and

R ^{4 is} hydrogen or fluorine,

or one of its salts, solvates or solvates of the salts.

Use according to claim 1 of a compound of formula (I) according to claim 1 or 2 selected from the group of compounds consisting of

and their salts, solvates and solvates of the salts.

4. Use according to claim 1 of a compound according to formula (I) according to claim 1, 2 or 3, selected from the group of compounds consisting of and their salts, solvates and solvates of the salts.

5. A compound according to formula (I) according to claim 1 having one of the following structures:

and their salts, solvates and solvates of the salts.

6. A compound according to claim 5 for the treatment and / or prophylaxis of diseases.

A combination comprising at least one compound of the formula (I) as defined in any one of claims 1 to 5 and one or more further active compounds selected from A group consisting of kinase inhibitors, simulants and activators of soluble guanylate cyclase, prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors.

8. Use of the combination according to claim 7 for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

Use of a compound of formula (I) as defined in any one of claims 1 to 5 or a combination as defined in claim 7 for the manufacture of a medicament for the treatment and / or prophylaxis of idiopathic, familial or medicated drugs, Pulmonary arterial hypertension associated with toxins or other diseases, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases, left-sided heart valve diseases, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, Pulmonary developmental disorders, chronic thrombotic and / or embolic diseases or in connection with sarcoidosis, histiocytosis X or Lymphangioleiomyomatose, as well as for the treatment and / or prophylaxis of external vascular compression caused by pulmonary hypertension.

10. A medicament containing a compound as defined in claim 5, optionally in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A medicament containing a combination as defined in claim 7, optionally in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

12. Medicament according to claim 10 or 11 for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

13. A method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administration of an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 5, a combination, as defined in claim 7 or a pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 5.