JP2009541384A - Use of 1,4-diaryl-dihydropyrimidin-2-one derivatives for the treatment of pulmonary arterial hypertension - Google Patents

Abstract

  The present invention relates to 1,4-diaryl-dihydropyrimidin-2-one derivatives of formula (I) for the treatment and / or prevention of pulmonary arterial hypertension and other forms of pulmonary hypertension, and pulmonary arterial hypertension and other forms of It relates to their use for the manufacture of a medicament for the treatment and / or prevention of pulmonary hypertension.

Description

  The present application relates to the use of 1,4-diaryldihydropyrimidin-2-one derivatives of formula (I) for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension, and pulmonary arterial hypertension and other types of It relates to their use for the manufacture of a medicament for the treatment and / or prevention of pulmonary hypertension.

  Pulmonary arterial hypertension (PAH) is a progressive pulmonary disorder that, if untreated, leads to death on average 2.8 years after diagnosis. Increasing pulmonary circulation contraction leads to increased stress on the right heart, which can develop into right heart failure. By definition, the mean pulmonary artery pressure (mPAP) for chronic pulmonary hypertension is> 25 mmHg at rest or> 30 mmHg (normal value <20 mmHg) during exertion. The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and reconstruction of pulmonary blood vessels. In chronic PAH, there is initially muscularization of pulmonary blood vessels that is not muscularized, and the circumference of vascular muscles of already muscularized blood vessels increases. This increased blockage of the pulmonary circulation results in progressive stress in the right heart, which leads to a decrease in stroke from the right heart and ultimately results in right heart failure (M. Humbert et al., J. Am Coll. Cardiol. 2004, 43, 13S-24S). PAH is a very rare disorder with a prevalence of 1-2 per million. The average age of patients is estimated at 36 years and only 10% of patients are over 60 years. Clearly, women are more affected than men (G.E.D'Alonzo et al., Ann. Intern. Med. 1991, 115, 343-349).

  Despite any progress in the treatment of pulmonary arterial hypertension, there is still no prospect of cure for this serious disorder. Standard therapeutics available on the market (eg, prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) can improve quality of life, exercise tolerance and patient prognosis. These therapeutic principles are primarily hemodynamic and affect vascular tone, but have no direct effect on the pathological remodeling process. In addition, the possibility of using these drugs may be limited by serious side effects and / or complex dosage forms. The period during which a patient's clinical situation can be improved or stabilized by certain monotherapy is limited. Eventually, treatment expands, thus applying a combination therapy where multiple drugs must be given simultaneously.

  New combination therapy is one of the most promising therapeutic options for the treatment of pulmonary arterial hypertension. In this regard, the discovery of new pharmacological mechanisms for the treatment of PAH is of particular interest (Ghofrani et al., Herz 2005, 30, 296-302; EB Rosenzweig, Expert Opin. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733). Treatment options that directly intervene in the remodeling event (anti-remodeling mechanism) may form the basis of a more causal treatment, and thus would be very advantageous for the patient. In this regard, it should be possible to combine known and new therapies. In order to minimize the risk of interfering drug-drug interactions in such combination therapy, these novel active ingredients should inhibit the metabolic P450 CYP enzyme only to a very low extent or not at all. is there.

  The term “pulmonary arterial hypertension” includes certain types of pulmonary hypertension, for example as specified by the World Health Organization (WHO) (Clinical Classification of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am. Coll. Cardiol. 2004, 43, 5S-12S).

  According to this classification, pulmonary arterial hypertension includes idiopathic pulmonary hypertension (IPAH, formerly called primary pulmonary hypertension), familial pulmonary arterial hypertension (FPA), and collagen fibrosis, congenital systemic-pulmonary shunt ( congenital systemic-pulmonary shunts), portal hypertension, HIV infection, intake of certain drugs and medicines, other disorders (thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary peripheral vasodilatation, abnormal hemoglobinopathy Concomitant pulmonary arteries associated with significant venous / capillary involvement, such as pulmonary vein occlusion and pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension in newborns Hypertension (APAH) is included.

  Other types of pulmonary hypertension include, for example, left heart disorders, such as pulmonary hypertension associated with ventricular or heart valve disorders, airway and / or lung disorders, such as chronic obstructive pulmonary disease, interstitial Pulmonary hypertension associated with pulmonary fibrosis, pulmonary hypertension associated with pulmonary fibrosis, chronic thrombotic and / or embolic disorders, eg pulmonary hypertension associated with thromboembolic occlusion of pulmonary arteries, and common inflammatory diseases Pulmonary hypertension (eg, associated with schistosomiasis, sarcoidosis, neoplastic disease) caused by a specific process or specific cause.

  Human leukocyte elastase (HLE, EC 3.4.21.37), also called human neutrophil elastase (HNE, hNE), belongs to the family of serine proteases. This proteolytic enzyme is found in azurophilic granules of polymorphonuclear leukocytes (PMN leukocytes). Intracellular elastase plays an important role in defense against pathogens by degrading foreign particles taken up by phagocytosis. Activated neutrophil cells release HNE from the granules into the extracellular space (extracellular HNE), and some of the released HNE remains outside the neutrophil cell membrane (membrane-bound HNE). This highly active enzyme can degrade many connective tissue proteins such as the proteins elastin, collagen and fibronectin. Elastin is present in high concentrations in all tissue types that exhibit high elasticity, for example in the lungs and arteries. HNE is involved in tissue degradation and deformation (tissue remodeling) associated with a number of pathological processes (eg, tissue damage). HNE is also a modulator of important inflammatory processes. HNE induces, for example, increased interleukin-8 (IL-8) gene expression. Thus, HNE is present in many lung disorders (eg, chronic obstructive pulmonary disease, COPD; acute respiratory distress syndrome, ARDS; cystic fibrosis, CF; emphysema) and also cardiovascular disorders (eg, after myocardial infarction) It is assumed that it plays an important role in tissue changes (related to heart failure).

In animal models and patients with elevated pulmonary arterial pressure (pulmonary arterial hypertension), connective tissue (inner elastic lamina) fragmentation could be found [Rabinovitch et al., Lab. Invest. 55 , 632-653 (1986) ]. In an animal model of pulmonary arterial hypertension (hypoxic and monocrotaline rat model), elastase activity could be shown to be associated with connective tissue fragmentation [Todorovich-Hunter et al., Am. Rev. Respir Dis. 146 , 213-223 (1992)]. The tissue remodeling observed during the disease process of pulmonary arterial hypertension is suspected to be induced by the release of connective tissue-related growth factor mediated by elastase, eg, basic fibroblast growth factor bFGF [Rabinovitch, Am. J. Physiol. 277 , L5-L12 (1999)]. In a hypoxic mouse model of pulmonary arterial hypertension, a positive effect by overexpressed elastase inhibitor protein could be shown [Zaidi et al., Circulation 105 , 516-521 (2002)]. In a monocrotaline rat model of pulmonary arterial hypertension, a positive effect of a synthetic low molecular weight elastase inhibitor could be shown [Cowan et al., Nature Med. 6 , 698-702 (2000)]. However, all previously disclosed low molecular weight elastase inhibitors are poorly selective, chemically reactive and / or have limited oral availability, and thus to date these indications Development of oral elastase inhibitors for the disease.

In general, elastase-mediated pathological processes are assumed to be based on the imbalance of free elastase and endogenous 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 a large excess in plasma and therefore neutralizes free HNE very quickly. The concentration of free elastase rises in various pathological processes so that there is a local shift in favor of the protease in the balance between protease and protease inhibitor. In addition, membrane-bound elastase of activated PMN cells is very substantially protected from inhibition by AAT. The same applies to free elastase located in inaccessible microcompartments between neutrophil cells and adjacent tissue cells (eg, endothelial cells). In addition, strong oxidative conditions prevail in the vicinity of activated leukocytes (oxidative burst), so AAT is oxidized and loses its inhibitory effect by orders of magnitude.

  A novel elastase inhibitory active ingredient (an exogenously administered inhibitor of HNE) can thus reach and inhibit membrane-bound HNE and HNE present in protected microcompartments (see above). Should be. What is also needed for this purpose is good in vivo substance stability (low in vivo clearance). In addition, these compounds should be stable under oxidizing conditions so that they do not lose their inhibitory power in pathological processes. Indications for which combination therapy is performed or foreseen in the future, such as PAH, in particular, may have only a small interaction with an enzyme (P450 CYP enzyme) that can transform and degrade the active pharmaceutical ingredient. It is advantageous.

  WO 2004/024700, WO 2004/024701, WO 2005/082863 and WO 2005/082864 treat various 1,4-diaryldihydropyrimidin-2-one derivatives for the treatment of chronic obstructive pulmonary disease, acute coronary syndrome, myocardial infarction and heart failure. As an HNE inhibitor for

  It has now surprisingly been found that certain 1,4-diaryldihydropyrimidin-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 are sufficiently high in bioavailability after oral administration and / or parenteral administration. Has good solubility for, exhibits low in vitro clearance with respect to hepatocytes, and only little inhibition of the CYP enzyme from microsomes. They are therefore a very promising starting point for new medicaments for the treatment of pulmonary arterial hypertension, as monotherapy or in combination with other active ingredients.

［式中、
Ｘは、ＣＨまたはＮであり、
Ｒ^１は、水素、式−（ＣＨ_２）_ｎ−Ｃ（＝Ｏ）−Ｏ−Ｒ^１Ａまたは−（ＣＨ_２）_ｎ−Ｃ（＝Ｏ）−ＮＲ^１ＢＲ^１Ｃの基、または、式

の基であり
｛式中、＊は、Ｎ原子への結合点を意味し、
ｎは、１または２の数であり、
Ｒ^１Ａは、水素または（Ｃ_１−Ｃ_４）−アルキルであり、
そして、Ｒ^１ＢおよびＲ^１Ｃは、相互に独立して、水素または（Ｃ_１−Ｃ_４）−アルキルである｝、
Ｒ^２は、シアノ、または、式−Ｃ（＝Ｏ）−Ｒ^２Ａまたは−Ｃ（＝Ｏ）−Ｏ−Ｒ^２Ａの基であり
｛式中、Ｒ^２Ａは、（Ｃ_１−Ｃ_６）−アルキルまたは（Ｃ_３−Ｃ_６）−シクロアルキルであり、これらの各々は、２個までの同一かまたは異なるヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、ヒドロキシカルボニル、アミノ、モノ−および／またはジ−（Ｃ_１−Ｃ_４）−アルキルアミノにより置換されていてもよく、各場合で、化学的に安定な化合物が得られる限り、ＣＨ_２基は、Ｏ原子により置き換えられていてもよい｝、
そして、
Ｒ^３は、水素であり、かつ、Ｒ^４は、水素、フッ素または塩素であるか、
または、
Ｒ^３は、フッ素または塩素であり、かつ、Ｒ^４は水素である］
の化合物、並びに、それらの塩、溶媒和物および塩の溶媒和物の、肺動脈高血圧および他のタイプの肺高血圧の処置および／または予防用の医薬を製造するための使用に関する。 The present invention relates to general formula (I)

[Where:
X is CH or N;
R ¹ is hydrogen, a group of formula — (CH ₂ ) _n —C (═O) —O—R ^1A or — (CH ₂ ) _n —C (═O) —NR ^1B R ^1C , or a formula

{Wherein * represents the point of attachment to the N atom,
n is a number of 1 or 2,
R ^1A is hydrogen or (C ₁ -C ₄ ) -alkyl;
And R ^1B and R ^1C , independently of one another, are hydrogen or (C ₁ -C ₄ ) -alkyl},
R ² is cyano or a group of formula —C (═O) —R ^2A or —C (═O) —O—R ^2A {wherein R ^2A is (C ₁ -C ₆ ) — Alkyl or (C ₃ -C ₆ ) -cycloalkyl, each of which is up to 2 identical or different hydroxy, (C ₁ -C ₄ ) -alkoxy, hydroxycarbonyl, amino, mono- and / or May be substituted by di- (C ₁ -C ₄ ) -alkylamino, and in each case the CH ₂ group may be replaced by an O atom as long as a chemically stable compound is obtained} ,
And
R ³ is 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 salt solvates for the manufacture of a medicament for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension.

の基であり
｛式中、＊は、Ｎ原子への結合点を意味する｝、
Ｒ^２が、シアノ、アセチル、シクロブチルカルボニル、メトキシカルボニル、エトキシカルボニルまたは２−ヒドロキシエトキシカルボニルであり、
Ｒ^３が、水素であり、
そして、
Ｒ^４が、水素またはフッ素である、
式（Ｉ）の化合物、並びに、それらの塩、溶媒和物および塩の溶媒和物の使用である。 In this regard, preference is given to:
X is CH or N;
R ¹ is hydrogen, a group of formula —CH ₂ —C (═O) —OH or —CH ₂ —C (═O) —NH ₂ , or a formula

{Wherein * represents the point of attachment to the N atom},
R ² is cyano, acetyl, cyclobutylcarbonyl, methoxycarbonyl, ethoxycarbonyl or 2-hydroxyethoxycarbonyl,
R ³ is hydrogen;
And
R ⁴ is hydrogen or fluorine,
The use of compounds of formula (I) and their salts, solvates and solvates of salts.

を有する式（Ｉ）の化合物、並びに、それらの塩、溶媒和物および塩の溶媒和物の使用である。 Particularly preferred is the following structure:

And the use of salts, solvates and solvates of the salts thereof.

を有する式（Ｉ）の化合物、並びに、それらの塩、溶媒和物および塩の溶媒和物の使用である。 Particularly preferred is the following structure:

And the use of salts, solvates and solvates of the salts thereof.

を有する式（Ｉ）の化合物、並びに、それらの塩、溶媒和物および塩の溶媒和物に、そして、疾患の処置および／または予防のためのそれらの使用に関する。 Some of the 1,4-diaryldihydropyrimidin-2-one derivatives of formula (I) are novel per se. Accordingly, the present invention further comprises the following structure:

And to their salts, solvates and solvates of salts thereof and to their use for the treatment and / or prevention of diseases.

  The compounds of the present invention or compounds that can be used according to the present invention (also referred to generically as compounds of the present invention) are the compounds of formula (I) and their salts, solvates and solvates of salts. And the compounds of the above and below described formulas encompassed by formula (I) and their salts, solvates and solvates of the salts, and the compounds described below as exemplary embodiments encompassed by formula (I) and These salts, solvates and salt solvates (when the compounds described below which are encompassed by formula (I) are not yet salts, solvates and salt solvates).

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From a mixture of such enantiomers and / or diastereomers, a stereomerically pure component can be isolated by known methods.
Where the compounds of the invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

For the purposes of the present invention, preferred salts are physiologically acceptable salts of the compounds of the present invention. Also included are salts that are not themselves suitable for pharmaceutical use, but can be used, for example, for the isolation or purification of the compounds of the invention.

  Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Examples include 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 salts.

  Physiologically acceptable salts of the compounds of the present invention include conventional base salts such as, and preferably, alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium and magnesium salts). ) And ammonia or an organic amine having 1 to 16 C atoms (eg and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol) , Procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine).

For the purposes of the present invention, a solvate represents a form of the compound according to the invention which forms a complex by coordination with solvent molecules in the solid or liquid state. Hydrates are a special form of solvates where coordination occurs with water. Hydrates are the preferred solvates for the present invention.

  In addition, the present invention includes prodrugs of the compounds of the present invention. The term “prodrug”, which itself may be biologically active or inactive, is converted to a compound of the invention during its remaining time (eg, by metabolism or hydrolysis). The compound is included.

In the context of the present invention, substituents have the following meanings unless otherwise indicated:
(C ₁ -C ₆ ) -alkyl and (C ₁ -C ₄ ) -alkyl are, for the purposes of the present invention, straight or branched chain having 1 to 6 and 1 to 4 carbon atoms, respectively. Represents an alkyl radical. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples which may be preferably mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

(C ₃ -C ₆ ) -cycloalkyl represents a monocyclic saturated cycloalkyl group having 3 to 6 carbon atoms for the purposes of the present invention. Examples which may be preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(C ₁ -C ₄ ) -Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms for the purposes of the present invention. Examples which may be preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

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

Di- (C ₁ -C ₄ ) -alkylamino represents, for the purposes of the present invention, two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. Represents an amino group having Examples which may be preferably mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-methylamino, N -Isopropyl-Nn-propylamino, N, N-diisopropylamino, Nn-butyl-N-methylamino and N-tert-butyl-N-methylamino.

（式中、Ｘは上記の意味を有する）
の化合物を、酸または酸無水物の存在下、３成分のワンポット反応で、または連続的に、式（ＩＩＩ）

（式中、Ｒ^２は上記の意味を有する）
の化合物、および式（ＩＶ）

（式中、Ｒ^３およびＲ^４は上記の意味を有する）
の化合物と反応させ、式（Ｉ−Ａ）

（式中、Ｒ^２、Ｒ^３、Ｒ^４およびＸは、各々上記の意味を有する）
の化合物を得、Ｒ^１が水素ではない場合、後者を、塩基の存在下で、式（Ｖ）
Ｒ^１＊−Ｚ （Ｖ）
（式中、Ｒ^１＊は、上記Ｒ^１の意味を有するが、水素ではなく、
そして、Ｚは、ハロゲン、メシレート、トシレートまたはトリフレートなどの脱離基である）
の化合物と反応させ、かくして得られる式（Ｉ−Ａ）または（Ｉ）の化合物を、当業者に知られている方法によりそれらのエナンチオマーおよび／またはジアステレオマーに分離し、必要に応じて、適当な（ｉ）溶媒および／または（ｉｉ）塩基もしくは酸で、それらの溶媒和物、塩および／または塩の溶媒和物に変換することにより製造する。 The compounds of formula (I) according to the invention are for the most part disclosed in WO 2004/024700, WO 2005/082863 and WO 2005/082864. They can be produced as detailed therein or in a similar manner. In general, the compound of formula (I) has the formula (II)

(Wherein X has the above meaning)
In the presence of an acid or anhydride in a three-component one-pot reaction or continuously,

(Wherein R ² has the above meaning)
And a compound of formula (IV)

(Wherein R ³ and R ⁴ have the above meanings)
With a compound of formula (IA)

(Wherein R ² , R ³ , R ⁴ and X each have the above meaning)
If R ¹ is not hydrogen, the latter is obtained in the presence of a base in the formula (V)
R ¹ * -Z (V)
(Wherein R ^{1 *} has the meaning of R ¹ above, but is not hydrogen,
Z is a leaving group such as halogen, mesylate, tosylate or triflate)
And the compounds of formula (IA) or (I) thus obtained are separated into their enantiomers and / or diastereomers by methods known to those skilled in the art, and if necessary, Prepared by conversion to the solvates, salts and / or solvates of the salts with the appropriate (i) solvent and / or (ii) base or acid.

  Suitable solvents for step (II) + (III) + (IV) → (IA) are ordinary organic solvents that do not change under the reaction conditions. These include, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethers such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol. Alcohols, hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halohydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloromethane or chlorobenzene, or ethyl acetate, acetonitrile, dimethyl sulfoxide or Other solvents such as N, N-dimethylformamide are included. It is likewise possible to use mixtures of the abovementioned solvents. Preferably, tetrahydrofuran or dioxane is used.

  Suitable acids for step (II) + (III) + (IV) → (IA) are the usual inorganic or organic acids or acid anhydrides. These preferably include carboxylic acids such as acetic acid or trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, phosphonic acid or phosphoric acid or phosphonic acid. Acid anhydrides such as polyphosphoric acid, polyphosphoric acid ethyl ester or propanephosphonic acid anhydride are included. Preferably, polyphosphoric acid ethyl ester is used. In general, the acid is used in an amount of 0.25 mol to 100 mol, based on 1 mol of compound (III).

  Step (II) + (III) + (IV) → (IA) is generally carried out in the temperature range of + 20 ° C. to + 150 ° C., preferably + 60 ° C. to + 100 ° C. This reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). It is generally carried out at atmospheric pressure.

  Suitable solvents for step (IA) + (V) → (I) are the usual organic solvents which do not change under the reaction conditions. These include, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethers such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, dichloromethane Halohydrocarbons such as 1,2-dichloroethane, trichloromethane or chlorobenzene, or ethyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ketone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N, N′-dimethyl Other solvents such as propylene urea (DMPU) or N-methylpyrrolidone (NMP) are included. It is likewise possible to use mixtures of the abovementioned solvents. Preferably, tetrahydrofuran or dimethylformamide is used.

  Suitable as the base of the step (IA) + (V) → (I) are ordinary inorganic or organic bases. These preferably include alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium, potassium, calcium or cesium, alkali metal alcoholates such as sodium or potassium tert-butoxide, 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, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, Pyridine or 4-N, N-dimethylaminopyridine is included. Potassium carbonate, cesium carbonate or sodium hydride are preferably used. The base is generally used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of compound (IA).

  Step (IA) + (V) → (I) is generally carried out in the temperature range of 0 ° C. to + 150 ° C., preferably + 20 ° C. to + 80 ° C. This reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). It is generally carried out at atmospheric pressure.

  Compounds of formula (II), (III), (IV) and (V) are commercially available, known from the literature or can be prepared analogously to methods known from the literature.

The compounds of the formula (I) which can be used according to the invention are, where necessary and expedient, starting from the other compounds of the formula (I) obtained by the methods described above, with individual substituents, in particular R ¹ and R ² can also be produced by modification of the functional group. These variations are carried out in the usual way, for example esterification, ester cleavage or hydrolysis, reduction, catalytic hydrogenation, oxidation, hydroxylation, amination or alkylation, and the introduction of temporary protecting groups And reactions such as removal.

The above method can be illustrated by the following reaction scheme:
Scheme 1

Scheme 2

  The compounds of the present invention are low molecular weight, non-reactive, selective and potent neutrophil elastase inhibitors with favorable physicochemical and pharmacokinetic properties. In particular, their bioavailability after oral administration is sufficiently high and / or their solubility is satisfactory for parenteral administration, and they exhibit low in vitro clearance with respect to hepatocytes, and Inhibition of the CYP enzyme from microsomes is negligible.

  Accordingly, the compounds of the present invention are associated with pulmonary arterial hypertension, including subtypes such as idiopathic and familial pulmonary arterial hypertension, and, for example, portal hypertension, fibrotic disorders, HIV infection or inappropriate drugs or toxicants Particularly suitable for the treatment and / or prevention of pulmonary arterial hypertension.

  The compounds of the invention can also be used for the treatment and / or prevention of other types of pulmonary hypertension. Thus, for example, they can be used for the treatment and / or prevention of left atrial or left ventricular disorders and pulmonary hypertension associated with left heart valve disorders. In addition, the compounds of the present invention may be used in lungs associated with chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, disorders with alveolar hypoventilation, altitude sickness and lung development disorders. Suitable for the treatment and / or prevention of hypertension.

  The compounds according to the invention are furthermore suitable for the treatment and / or prevention of chronic thrombotic and / or embolic disorders, for example pulmonary hypertension based on thromboembolism of the proximal pulmonary artery, occlusion of the distal pulmonary artery and pulmonary embolism . The compounds of the present invention may further comprise pulmonary hypertension associated with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and pulmonary hypertension with external compression of the blood vessels (lymph node, tumor, fibrosing mediastinitis) Can be used to treat and / or prevent pulmonary hypertension when caused by

  The compounds of the present invention result from pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive and / or fibrotic pulmonary disorders and chronic thrombotic and / or embolic disorders because of their pharmacological action profiles. Particularly suitable for the treatment and / or prevention of possible pulmonary hypertension.

The compounds of the present invention can be used alone or in combination with other active ingredients. The invention further relates to a medicament comprising at least one compound according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the disorders mentioned above. Suitable active ingredients for the combination are for example and preferably the following:
Compounds which inhibit the signaling cascade, for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinases and / or serine / threonine kinase inhibitors;
Organic nitrates and NO sources such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 and inhaled NO;
NO-dependent but heme-dependent soluble guanylate cyclase stimulators, such as in particular the compounds described in WO 00/06568, WO 00/0669, WO 02/42301 and WO 03/095451;
NO and heme-independent activators of soluble guanylate cyclase, such as, in particular, the compounds described in WO01 / 19355, WO01 / 19776, WO01 / 19778, WO01 / 19780, WO02 / 070462 and WO02 / 070510;
A prostacyclin analog, such as, and preferably, iloprost, beraprost, treprostinil or epoprostenol;
Compounds that inhibit soluble epoxide hydrolase (sEH), such as N, N′-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) dodecanoic acid or 1-adamantan-1-yl-3- {5 -[2- (2-ethoxyethoxy) ethoxy] pentyl} urea;
Compounds that affect the energy metabolism of the heart, eg and preferably etomoxyl, dichloroacetic acid, ranolazine or trimetazidine;
Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE5 Inhibitors such as sildenafil, vardenafil and tadalafil;
A substance having an antithrombotic action, for example and preferably from the group of platelet aggregation inhibitors, anticoagulants or fibrinolysis-promoting substances;
For example and preferably calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, Rho-kinase Active ingredients that lower blood pressure from the group of inhibitors and diuretics; and / or
-For example and preferably thyroid receptor agonists, cholesterol synthesis inhibitors, eg and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha Modify lipid metabolism from the group of PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists Active ingredients.

  In a preferred embodiment of the invention, a compound of the invention is added to a kinase inhibitor such as, for example and preferably, bortezomib, caneltinib, erlotinib, gefitinib, imatinib, lapatinib, restaurinib, ronafanib, pegaptanib, peritinib, cemanifib, solatinib, , Sunitinib, tandutinib, tipifanib, batalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

  A substance having an antithrombotic action preferably means a compound from the group of platelet aggregation inhibitors, anticoagulants or substances that promote fibrinolysis.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, bivalirudin or clexane.

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

  In a preferred embodiment of the invention, the compounds of the invention are converted into a factor Xa inhibitor, for example and preferably rivaroxaban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD. -3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV803, SSR-126512 or SSR-128428.

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

  Substances that lower blood pressure are preferably calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, Rho Means a compound from the group of kinase inhibitors and diuretics.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.

  In a preferred embodiment of the invention, the compounds of 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 of the invention are added to beta-receptor blockers, such as, for example and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, methyliprano. Administered in combination with roll, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, seriprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol .

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

  In a preferred embodiment of the invention, the compounds of the invention are combined with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril To administer.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist such as by way of example and preferably 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 of 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 of the invention are used as Rho kinase inhibitors, 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 of the invention are administered in combination with a diuretic such as by way of example and preferably furosemide.

  Substances that modify lipid metabolism are preferably CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, It means compounds from the group of PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529414), JJT-705 or CETP vaccine (Avant).

  In a preferred embodiment of the invention, the compounds according to the invention are converted to thyroid receptor agonists such as, for example and preferably, D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS23425 or axitirome. Administration in combination with (CGS26214).

  In a preferred embodiment of the invention, the compound of the invention is an HMG-CoA reductase inhibitor from the class of statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin. Administer in combination.

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

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

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

  In a preferred embodiment of the invention, the compounds of 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 of the invention are administered in combination with a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamacueside.

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

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as by way of example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

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

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

  The present invention further provides a left atrial or left ventricular disorder, a left heart valve disorder, for the treatment and / or prevention of idiopathic or familial pulmonary arterial hypertension, or pulmonary arterial hypertension associated with drugs, toxicants or other disorders. Chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, disorders with alveolar hypoventilation, altitude sickness and lung development disorders, chronic thrombotic and / or embolic disorders, for example For the treatment and / or prevention of pulmonary hypertension associated with thromboembolism of the proximal pulmonary artery, occlusion of the distal pulmonary artery and pulmonary embolism, or with respect to sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and For the manufacture and manufacture of a medicament for the treatment and / or prevention of pulmonary hypertension due to external compression of blood vessels, alone or in combination with one or more of the above-mentioned active ingredients It relates to the use of the compound.

  The invention further provides for the treatment of pulmonary arterial hypertension and other types of pulmonary hypertension in humans and animals by administering an effective amount of at least one compound of the invention or a medicament comprising at least one compound of the invention. And / or preventive methods.

  The medicament manufactured according to the use according to the invention, or the medicament used according to the invention, contains at least one compound of the invention, usually one or more inert, non-toxic pharmaceutically. With suitable adjuvants.

  The present invention further provides for the treatment and / or prophylaxis of the above-mentioned disorders, comprising at least one compound of the invention in combination with one or more inert, non-toxic pharmaceutically suitable adjuvants. It relates to the medicine.

The compounds of the present invention may have systemic and / or local effects. For this purpose, they are suitable, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or It can be administered by the otic route or as an implant or stent.
The compounds of the present invention can be administered in dosage forms suitable for these administration routes.

  Suitable for oral administration functions according to the prior art, delivers the compounds of the invention rapidly and / or in a modified manner, and allows the compounds of the invention to be in crystalline and / or amorphous and / or Contained in dissolved form, for example tablets (uncoated and coated tablets, such as coatings that are resistant to gastric juice or insoluble or delayed dissolving to control the release of the compounds of the invention Tablets that disintegrate rapidly in the mouth, or films / oblates, film / lyophilizers, capsules (eg, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, Suspensions, aerosols or liquids.

  Parenteral administration avoids the absorption phase (eg, intravenous, intraarterial, intracardiac, spinal or lumbar) or includes absorption (eg, intramuscular, subcutaneous, intradermal, transdermal) Or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Suitable for other routes of administration are, for example, pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops, liquids or sprays; tablets, films / oblates or capsules for tongue, sublingual or buccal administration Suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, Foam, dusting powder, implant or stent.
Oral or parenteral administration is preferred, especially oral and intravenous administration.

  The compounds of the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These adjuvants include, among others, carriers (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg, sodium dodecyl sulfate, polyoxysorbitan oleate), Binders (eg polyvinylpyrrolidone), synthetic and natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg inorganic pigments such as iron oxide) and flavors and / or odors Concealing agents are included.

  In general, it is advantageous to administer an amount of about 0.001 to 1 mg / kg body weight parenterally, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results. It was revealed. For oral administration, the dosage is from about 0.01 to 100 mg / kg body weight, preferably from about 0.01 to 20 mg / kg body weight, particularly preferably from 0.1 to 10 mg / kg body weight.

  Nevertheless, it may be necessary to deviate from the above amounts as needed, in particular depending on body weight, route of administration, individual response to the active ingredient, formulation type and time or interval at which the administration is carried out. . Thus, it may be sufficient to make less than the above-mentioned minimum amount, while in other cases the upper limit mentioned must be exceeded. When administered in relatively large amounts, it may be desirable to distribute these into multiple individual doses over the day.

The following exemplary embodiments illustrate the invention. The present invention is not limited to these examples.
The percentage data in the following tests and examples are percentages by weight unless otherwise indicated; parts are parts by weight. Liquid / liquid solution solvent ratio, dilution ratio and concentration data are based on volume in each case unless otherwise noted.

A. Examples
Abbreviations:

HPLC and LC-MS methods:
Method 1 (analytical HPLC):
HPLC instrument type: HP 1100 series; UV DAD; column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 mm; eluent A: water 1 l + 50% formic acid 0.5 ml, eluent B: acetonitrile 1 l + 50% formic acid 0.5 ml Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 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 HPLC):
HPLC instrument type: HP 1050 series; UV DAD; column: Phenomenex Synergi 2 μ Max-RP Mercury 20 mm × 4 mm; eluent A: water 1 l + 0.05% trifluoroacetic acid, eluent B: acetonitrile 1 l; gradient: 0 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 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: HClO ₄ (70%) 5 ml / L, 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; 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: HClO ₄ (70%) 5 ml / L, 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 rate: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.

Method 5 (Analytical HPLC of chiral phase):
Selector poly (chiral silica gel phase based on N-methacryloyl-D-leucine tert-butylamide; column: 250 mm x 4.6 mm; eluent: ethyl acetate; flow rate: 2.0 ml / min; temperature: 24 ° C; UV detection : 260 nm.

Method 6 (LC-MS):
MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795 / HP 1100; Column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm x 4 mm; Acetonitrile 1 l + 50% formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow rate: 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):
MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: Water 1 l + 50% formic acid 0.5 ml; Formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow rate: 0.0 min 1 ml / min → 2 0.5 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: Water 1 l + 50% formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 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 HyPURITY Aquastar 3 μ 50 mm x 2.1 mm; Eluent A: Water 1 l + 50% formic acid 0.5 ml; Eluent B: Acetonitrile 1 l + 50% formic acid 0.5 ml; 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 rate: 0 0.8 ml / min; UV detection: 210 nm.

Method 10 (LC-MS):
MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 series; UV DAD; column: Phenomenex Gemini 3 μ30 mm x 3.0 mm; eluent A: water 1 l + 50% formic acid 0.5 ml, eluent B: acetonitrile 1 l + 50% formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow rate: 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):
Instrument: Gilson Abimed HPLC; Binary pump system; Column: Kromasil-100A C18, 5 μm, 250 mm x 21 mm; eluent A: water / 0.5% trifluoroacetic acid, eluent B: acetonitrile; 10 min 10% B, gradient 10.01-55 min 100% B; flow rate: 20 ml / min; UV detection: 210 nm.

Method 12 (preparative HPLC):
Instrument: Gilson Abimed HPLC; Binary pump system; Column: Kromasil-100A C18, 5 μm, 250 mm x 20 mm; eluent A: water / 0.05% trifluoroacetic acid, eluent B: acetonitrile; 1 min 10% B, gradient 1.01-30 min 95% B, 30.01-34 min 95% B, 34.01-35 min 10% B; flow rate: 25 ml / min; UV detection: 210 nm.

Method 13 (preparative HPLC):
Instrument: Gilson Abimed HPLC; Binary pump system; Column: Kromasil-100A C18, 5 μm, 250 mm x 20 mm; Eluent A: Water / 0.1% trifluoroacetic acid, Eluent B: Acetonitrile; 0- 1 min 10% B, gradient 1.01-40 min 90% B, 40-45 min 90% B; flow rate: 25 ml / min; UV detection: 210 nm.

Method 14 (preparative HPLC):
Instrument: 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, Gradient 3.01-27 min 98% B, 27.01-34 min 98% B, 34.01-38 min 10% B; flow rate: 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 rate: 50 ml / min; column temperature: RT; UV detection: 210 nm.

Method 16 (Preparative HPLC of chiral phase):
Enantiomeric separation in chiral silica gel phase based on selector poly (N-methacryloyl-L-leucine tert-butylamide); column: 125 mm x 20 mm; sample is dissolved in 1: 5 THF / ethyl acetate mixture; eluent: Ethyl acetate; flow rate: 20 ml / min; UV detection: 260 nm; temperature: 24 ° C.

Method 17 (Preparative HPLC of chiral phase):
Enantiomeric separation in chiral silica gel phase based on selector poly (N-methacryloyl-L-leucine D-menthylamide); column: 250 mm x 30 mm; eluent: step gradient 100% ethyl acetate → 100% methanol; Flow rate: 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 rate: 2 ml / min.

Method 18 (Preparative HPLC of chiral phase):
Enantiomeric separation in a chiral silica gel phase based on selector poly (N-methacryloyl-L-leucine 1-menthylamide); column: 680 mm x 40 mm; eluent: step gradient 100% ethyl acetate → 100% methanol; Flow rate: 50 ml / min; Temperature: 24 ° C .; UV detection: 260 nm. Analytical column: 250 mm x 4.6 mm; eluent: ethyl acetate; flow rate: 2 ml / min.

Method 19 (Preparative HPLC of chiral phase):
Enantiomeric separation in chiral silica gel phase based on selector poly (N-methacryloyl-L-leucine D-menthylamide); column: 250 mm x 30 mm; eluent: step gradient 100% ethyl acetate → 100% methanol; Flow rate: 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 rate: 2 ml / min.

Method 20 (Preparative HPLC of chiral phase):
Enantiomeric separation in chiral silica gel phase based on selector poly (N-methacryloyl-D-leucine 3-pentylamide); column: 500 mm x 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 rate: 100 ml / min; temperature: 24 ° C .; UV detection: 340 nm.

Method 21 (Preparative HPLC of chiral phase):
Enantiomeric separation in chiral silica gel phase based on selector poly (N-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 rate: 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 rate: 2 ml / min.

Method 22 (preparative HPLC):
Instrument: 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, gradient to 90% B in 45 minutes.

Method 23 (preparative HPLC):
Instrument: 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, gradient 3.01-34 min 95% B, 34.01-38 min 95% B, 38.01-40 min 10% B; flow rate: 50 ml / min; UV detection: 210 nm.

Method 24 (LC-MS):
MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; flow rate: 2 ml / min; oven: 40 ° C .; UV detection: 210 nm.

Method 25 (LC-MS):
Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Eluent A: Water 1 l + 50% formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; flow rate: 2 ml / min; oven: 40 ° C .; UV detection: 208-400 nm.

５−フルオロ−３−（トリフルオロメチル）アニリン３４ｇ（１８９.８１９ｍｍｏｌ）を、２−プロパノール２２７ｍｌに溶解し、５０℃で、トリメチルシリルイソシアネート３２.８０３ｇ（２８４.７２８ｍｍｏｌ）を１０分間かけて滴下して添加する。混合物を５０℃で終夜撹拌し、次いでロータリーエバポレーターで濃縮する。残渣をジクロロメタンで撹拌し、固体を吸引濾過し、高真空下で乾燥する。標的化合物２５.０ｇ（理論値の５９％）を得る。
LC-MS (方法 7): R_t = 1.69 分; MS (ESIpos): m/z (%) = 223.0 (100) [M+H]⁺
HPLC (方法 3): R_t = 3.88 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 6.12 (br. s, 2H), 7.12 (d, 1H), 7.53 (d, 1H), 7.61 (s, 1H), 9.12 (br. s, 1H). Starting compounds and intermediates:
Example 1A
N- [3-Fluoro-5- (trifluoromethyl) phenyl] urea

34 g (189.819 mmol) of 5-fluoro-3- (trifluoromethyl) aniline is dissolved in 227 ml of 2-propanol, and 32.803 g (284.728 mmol) of trimethylsilyl isocyanate is added dropwise at 50 ° C. over 10 minutes. Added. The mixture is stirred at 50 ° C. overnight and then concentrated on a rotary evaporator. The residue is stirred with dichloromethane and 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 _t = 3.88 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 6.12 (br.s, 2H), 7.12 (d, 1H), 7.53 (d, 1H), 7.61 (s, 1H), 9.12 (br. s, 1H).

４−フルオロ−３−（トリフルオロメチル）アニリン２５００ｍｇ（１３.９５７ｍｍｏｌ）を１Ｎ塩酸１５ｍｌに溶解し、シアン酸カリウム１１３２ｍｇ（１３.９５７ｍｍｏｌ）を添加する。懸濁液を室温で終夜撹拌し、次いで酢酸エチルで希釈し、透明な２相溶液を得る。有機相を分離し、水相を酢酸エチルで抽出する。合わせた有機相を乾燥し、溶媒をロータリーエバポレーターで除去し、粗生成物をシリカゲルでクロマトグラフィーする（溶離剤：ジクロロメタン／メタノール８０：１、次いで１０：１）。標的化合物２１８０ｍｇ（理論値の７０％）を得る。
LC-MS (方法 10): R_t = 1.82 分; MS (ESIpos): m/z (%) = 223.0 (100) [M+H]⁺. Example 2A
N- [4-Fluoro-3- (trifluoromethyl) phenyl] urea

Dissolve 2500 mg (13.957 mmol) of 4-fluoro-3- (trifluoromethyl) aniline in 15 ml of 1N hydrochloric acid and add 1132 mg (13.957 mmol) of potassium cyanate. The suspension is stirred at room temperature overnight and then diluted with ethyl acetate to give a clear two-phase solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried, the solvent is removed on a rotary evaporator and the crude product is chromatographed on silica gel (eluent: dichloromethane / methanol 80: 1, then 10: 1). 2180 mg (70% of theory) of the target compound are obtained.
LC-MS (Method 10): R _t = 1.82 min; MS (ESIpos): m / z (%) = 223.0 (100) [M + H] ⁺ .

アルゴン保護ガス雰囲気下、（４Ｒ）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１［３（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボン酸（２.０５ｇ、５ｍｍｏｌ；ＷＯ２００５／０８２８６３、実施例１０Ａに従い製造）を、乾燥ＤＭＦ（２１ｍｌ）に導入し、１,１'−カルボニルジイミダゾール（２.４３ｇ、１５ｍｍｏｌ）を添加する。混合物を室温で３０分間撹拌する。次いでそれを濃縮し、酢酸エチル（約１５０ｍｌ）に取り、飽和重炭酸ナトリウム水溶液（約５０ｍｌ）および飽和塩化ナトリウム水溶液（５０ｍｌ）で洗浄し、硫酸ナトリウムで乾燥し、濾過し、真空で濃縮する。表題化合物を粗生成物（２.８７ｇ、定量的収量、純度約８０％）として得、それをさらに精製せずに反応させる。
HPLC (方法 2): R_t = 2.3 分. Example 3A
4-{(4R) -5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro Pyrimidin-4-yl} benzonitrile

(4R) -4- (4-cyanophenyl) -6-methyl-2-oxo-1 [3 (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5 under argon protective gas atmosphere Carboxylic acid (2.05 g, 5 mmol; prepared according to WO 2005/082863, Example 10A) is introduced into dry DMF (21 ml) and 1,1′-carbonyldiimidazole (2.43 g, 15 mmol) is added. The mixture is stirred at room temperature for 30 minutes. It is then concentrated, taken up in ethyl acetate (ca. 150 ml), washed with saturated aqueous sodium bicarbonate solution (ca. 50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The title compound is obtained as a crude product (2.87 g, quantitative yield, purity about 80%), which is reacted without further purification.
HPLC (Method 2): R _t = 2.3 min.

この反応はアルゴン下で実施する。アリル（４Ｒ）−３−（２−ｔｅｒｔ−ブトキシ−２−オキソエチル）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボキシレート（２.５０ｇ、４.５ｍｍｏｌ；ラセミ化合物の製造には、ＷＯ２００５／０８２８６３、実施例２３Ａ参照）およびモルホリン（５８８ｍｇ、６.８ｍｍｏｌ）を、ＴＨＦ（２５ｍｌ）に導入する。混合物を注意深く排気し、次いでアルゴンを導入する。次いで、テトラキス（トリフェニルホスフィン）パラジウム（０）（２６０ｍｇ、０.２２５ｍｍｏｌ）を添加し、反応混合物をＲＴで６０分間撹拌する。その後、ＨＰＬＣチェックは完全な変換を示す。反応混合物を真空で濃縮し、残渣を酢酸エチル（２００ｍｌ）に取る。次いで、有機相を飽和塩化アンモニウム溶液（７５ｍｌ）、水（５０ｍｌ）および飽和塩化ナトリウム溶液で洗浄する。有機相を硫酸ナトリウムで乾燥し、濾過し、濃縮し、残渣を分取ＨＰＬＣ（カラム：Kromasil 5μm；溶離剤：アセトニトリル／水＋０.１％ＴＦＡ１０：９０→９０：１０）により精製する。かくして、表題化合物を固体（１.９ｇ、理論値の８２％）として得る。
LC-MS (方法 7): R_t = 2.4 分; MS (ESIpos): m/z (%) = 516 (5) [M+H]⁺; MS (ESIneg): m/z (%) = 514.2 (100) [M-H]. Example 4A
(4R) -3- (2-tert-butoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1, 2,3,4-tetrahydropyrimidine-5-carboxylic acid

This reaction is carried out under argon. Allyl (4R) -3- (2-tert-butoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1 , 2,3,4-Tetrahydropyrimidine-5-carboxylate (2.50 g, 4.5 mmol; for the preparation of the racemate, see WO 2005/082863, Example 23A) and morpholine (588 mg, 6.8 mmol) Introduce into THF (25 ml). The mixture is carefully evacuated and then argon is introduced. Tetrakis (triphenylphosphine) palladium (0) (260 mg, 0.225 mmol) is then added and the reaction mixture is stirred at RT for 60 minutes. The HPLC check then shows complete conversion. The reaction mixture is concentrated in vacuo and the residue is 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 and concentrated, 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 _t = 2.4 min; MS (ESIpos): m / z (%) = 516 (5) [M + H] ⁺ ; MS (ESIneg): m / z (%) = 514.2 (100) [MH].

ラセミのエチル４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボキシレート（６０ｇ；製造には、ＷＯ２００４／０２４７００、実施例１参照）を、酢酸エチル（３６０ｍｌ）に溶解し、クロマトグラフィー（方法２０）によりエナンチオマーに分画する。表題化合物（２９.９ｇ、理論値の９９％、９９.１％ｅｅ）および異性体のエチル（４Ｓ）−４−（４−シアノフェニル）−６−メチル−２オキソ−１［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボキシレートを得る。
HPLC (方法 5): R_t = 1.55 分.
さらなる分析データは、ラセミ化合物について報告されたものに相当する（ＷＯ２００４／０２４７００、実施例１参照）。 Exemplary embodiments:
Example 1
Ethyl (4R) -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 For production, WO 2004/024700, see Example 1) is dissolved in ethyl acetate (360 ml) and fractionated into enantiomers by chromatography (Method 20). The title compound (29.9 g, 99% of theory, 99.1% ee) and the isomeric ethyl (4S) -4- (4-cyanophenyl) -6-methyl-2oxo-1 [3- (tri Fluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate.
HPLC (Method 5): R _t = 1.55 min.
Further analytical data correspond to those reported for the racemate (see WO 2004/024700, Example 1).

５−メチルヘキサン−２,４−ジオン２０００ｍｇ（１５.６０４ｍｍｏｌ）、４−ホルミルベンゾニトリル２０４６ｍｇ（１５.６０４ｍｍｏｌ）および１−［３−（トリフルオロメチル）フェニル］ウレア３１８６ｍｇ（１５.６０４ｍｍｏｌ）を、ＴＨＦ６０ｍｌに溶解し、エチルポリホスフェート（ＰＰＥ）１０ｇを添加する。混合物を８０℃で終夜撹拌し、次いで水と酢酸エチルとに分配する。有機相を分離し、硫酸ナトリウムで乾燥し、濾過し、溶媒をロータリーエバポレーターで除去する。残渣を最初にシリカゲルのフラッシュクロマトグラフィー（溶離剤：シクロヘキサン／酢酸エチル１：１）により、次いでキラル相の分取ＨＰＬＣ（方法１８）により精製し、かくして、エナンチオマーを分離する（所望のエナンチオマー：Ｒ_ｔ＝４.７０分）。分取ＨＰＬＣ（方法１５）によるさらなる精製により、表題化合物５３０ｍｇ（理論値の８％）を得る。
MS (ESIpos): m/z (%) = 428 (100) [M+H]⁺
HPLC (方法 3): R_t = 8.33 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 0.80 (d, 3H), 0.95 (d, 3H), 1.86 (s, 3H), 2.95 (tt, 1H), 5.48 (d, 1H), 7.55 (d, 1H), 7.62 (d, 2H), 7.68 (t, 1H), 7.70 (s, 1H), 7.77 (d, 1H), 7.89 (d, 2H), 8.41 (d, 1H). Example 2
4-{(4R) -5-isobutyryl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidin-4-yl} benzonitrile

5-methylhexane-2,4-dione 2000 mg (15.604 mmol), 4-formylbenzonitrile 2046 mg (15.604 mmol) and 1- [3- (trifluoromethyl) phenyl] urea 3186 mg (15.604 mmol) Dissolve in 60 ml of THF and add 10 g of ethyl polyphosphate (PPE). The mixture is stirred at 80 ° C. overnight 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 first purified by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) and then by preparative HPLC of the chiral phase (method 18), thus separating the enantiomers (desired enantiomer: R _t = 4.70 minutes). Further purification by preparative HPLC (Method 15) gives 530 mg (8% of theory) of the title compound.
MS (ESIpos): m / z (%) = 428 (100) [M + H] ⁺
HPLC (Method 3): R _t = 8.33 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.80 (d, 3H), 0.95 (d, 3H), 1.86 (s, 3H), 2.95 (tt, 1H), 5.48 (d, 1H) , 7.55 (d, 1H), 7.62 (d, 2H), 7.68 (t, 1H), 7.70 (s, 1H), 7.77 (d, 1H), 7.89 (d, 2H), 8.41 (d, 1H).

ラセミ化合物をＷＯ２００５／０８２８６４（実施例２０）に記載の通りに製造する。ラセミ体をキラル相の分取ＨＰＬＣ（方法１９）によりエナンチオマーに分離する。
HPLC (方法 19): R_t = 2.68 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.67 (m, 1H), 1.82 (m, 2H), 1.94 (s, 3H), 1.96-2.19 (m, 3H), 3.49 (dt, 1H), 5.37 (d, 1H), 7.53 (d, 1H), 7.61 (d, 2H), 7.68 (m, 2H), 7.78 (d, 1H), 7.89 (d, 2H), 8.42 (d, 1H). Example 3
4-{(4R) -5- (cyclobutylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidin-4-yl } Benzonitrile

The racemate is prepared as described in WO2005 / 082864 (Example 20). The racemates are separated into enantiomers by preparative HPLC (chiral 19) of the chiral phase.
HPLC (Method 19): R _t = 2.68 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.67 (m, 1H), 1.82 (m, 2H), 1.94 (s, 3H), 1.96-2.19 (m, 3H), 3.49 (dt, 1H), 5.37 (d, 1H), 7.53 (d, 1H), 7.61 (d, 2H), 7.68 (m, 2H), 7.78 (d, 1H), 7.89 (d, 2H), 8.42 (d, 1H ).

４−｛（４Ｒ）−５−（シクロブチルカルボニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−４−イル｝ベンゾニトリル１７０ｍｇ（０.３８７ｍｍｏｌ）を、ＤＭＦ３ｍｌに溶解し、ｔｅｒｔ−ブチルブロモアセテート９１ｍｇ（０.４６４ｍｍｏｌ）および炭酸カリウム９６ｍｇ（０.６９６ｍｍｏｌ）を添加する。混合物を室温で終夜撹拌する。次いで、さらにｔｅｒｔ−ブチルブロモアセテート９１ｍｇ（０.４６４ｍｍｏｌ）および炭酸カリウム５０ｍｇ（０.３６２ｍｍｏｌ）を添加し、懸濁液を５０℃で６時間にわたり撹拌する。後処理に、混合物を水３０ｍｌに添加する。水相を数回酢酸エチルで抽出し、有機相を合わせ、溶媒をロータリーエバポレーターで除去する。残渣をメタノールに取り、分取ＨＰＬＣ（方法１４）により精製する。標的化合物１９６ｍｇ（理論値の９２％）を得る。
LC-MS (方法 10): R_t = 3.06 分; MS (ESIpos): m/z (%) = 554.2 (18) [M+H]⁺. Example 4
tert-Butyl [(6R) -6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6- Dihydropyrimidin-1 (2H) -yl] acetate

4-{(4R) -5- (cyclobutylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidin-4-yl } 170 mg (0.387 mmol) of benzonitrile are dissolved in 3 ml of DMF, and 91 mg (0.464 mmol) of tert-butyl bromoacetate and 96 mg (0.696 mmol) of potassium carbonate are added. The mixture is stirred overnight at room temperature. A further 91 mg (0.464 mmol) of tert-butyl bromoacetate and 50 mg (0.362 mmol) of potassium carbonate are then added and the suspension is stirred at 50 ° C. for 6 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 removed 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 _t = 3.06 min; MS (ESIpos): m / z (%) = 554.2 (18) [M + H] ⁺ .

アルゴン保護ガス雰囲気下、エチル（４Ｒ）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボキシレート（１０.７４ｇ、２５ｍｍｏｌ）および固体炭酸カリウム（５.５３ｇ、４０ｍｍｏｌ）をジメチルホルムアミド（１００ｍｌ）に導入する。撹拌しながら、ｔｅｒｔ−ブチルブロモアセテート（７.８ｇ、４０ｍｍｏｌ）を滴下して添加する。反応混合物を室温で２０時間撹拌し、次いで６０℃でさらに３時間反応させる。反応混合物を真空で濃縮し、残渣を酢酸エチル（２００ｍｌ）に取る。次いで、有機相を水（２ｘ各回５０ｍｌ）で、次いで飽和塩化ナトリウム水溶液（５０ｍｌ）で洗浄し、硫酸ナトリウムで乾燥し、濾過し、濃縮する。粗生成物をシリカゲルでフラッシュクロマトグラフィーする（溶離剤：シクロヘキサン→シクロヘキサン／酢酸エチル６：４のグラジエント）。表題化合物１２.５ｇ（理論値の９１％）を固体として得る。
LC-MS (方法 8): R_t = 2.94 分; MS (ESIpos): m/z (%) = 488.1 (100) [M+H-C₄H₈]⁺;
MS (ESIneg): m/z (%) = 542.2 (100) [M-H]
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.05 (t, 3H), 1.25 (s, 9H), 2.05 (s, 3H), 3.85 (d, 1H), 4.0 (m, 3H), 5.55 (s, 1H), 7.60-7.90 (m, 8H). Example 5
tert-Butyl [(6R) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro Pyrimidine-1 (2H) -yl] acetate

Ethyl (4R) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro under argon protective gas atmosphere Pyrimidine-5-carboxylate (10.74 g, 25 mmol) and solid potassium carbonate (5.53 g, 40 mmol) are introduced into dimethylformamide (100 ml). While stirring, tert-butyl bromoacetate (7.8 g, 40 mmol) is added dropwise. The reaction mixture is stirred at room temperature for 20 hours and then reacted at 60 ° C. for a further 3 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate (200 ml). The organic phase is then washed with water (2 × 50 ml each time) and then with a saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated. The crude product is flash chromatographed on silica gel (eluent: cyclohexane → cyclohexane / ethyl acetate 6: 4 gradient). 12.5 g (91% of theory) of the title compound are obtained as a solid.
LC-MS (Method 8): R _t = 2.94 min; MS (ESIpos): m / z (%) = 488.1 (100) [M + HC ₄ H ₈ ] ⁺ ;
MS (ESIneg): m / z (%) = 542.2 (100) [MH]
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.05 (t, 3H), 1.25 (s, 9H), 2.05 (s, 3H), 3.85 (d, 1H), 4.0 (m, 3H) , 5.55 (s, 1H), 7.60-7.90 (m, 8H).

アリル（４Ｒ）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボキシレート（ＷＯ２００５／０８２８６３、実施例６Ａに従い製造）２００ｍｇ（０.４５３ｍｍｏｌ）を、アセトン／水（３：１）２０ｍｌに溶解する。溶液を０℃に冷却し、アセトン／水（３：１）１０ｍｌ中の過マンガン酸カリウム７２ｍｇ（０.４５３ｍｍｏｌ）の溶液を添加する。室温で９０分間撹拌した後、飽和チオ硫酸ナトリウム溶液を添加し、混合物をさらに３０分間撹拌する。少量のメタノールで溶出する珪藻土カラムでの吸引濾過により、混合物を後処理する。有機相を分離した後、水相を酢酸エチルで２回逆抽出する。合わせた有機相を濃縮し、残渣を分取ＨＰＬＣ（方法１４）により精製する。表題化合物１１９ｍｇ（理論値の５４％）を得る。
LC-MS (方法 8): R_t = 2.06 分; MS (ESIpos): m/z (%) = 476.1 (100) [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ = 2.05 (s, 3H), 3.19-3.31 (m, 2H), 3.60 (m, 1H), 3.89 (ddd, 1H), 4.05 (ddd, 1H), 4.61 (q, 1H), 4.92 (dd, 1H), 5.44 (m, 1H), 7.57 (br. s, 1H), 7.63 (m, 2H), 7.70 (m, 2H), 7.79 (d, 1H), 7.87 (d, 2H), 8.41 (m, 1H). Example 6
2,3-dihydroxypropyl (4R) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine -5-carboxylate

Allyl (4R) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (Manufactured according to WO2005 / 082863, Example 6A) 200 mg (0.453 mmol) is dissolved in 20 ml of acetone / water (3: 1). The solution is cooled to 0 ° C. and a solution of 72 mg (0.453 mmol) potassium permanganate in 10 ml acetone / water (3: 1) is 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 mixture is worked up by suction filtration on a diatomaceous earth column eluting with a small amount of methanol. After separating 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 title compound are obtained.
LC-MS (Method 8): R _t = 2.06 min; MS (ESIpos): m / z (%) = 476.1 (100) [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.05 (s, 3H), 3.19-3.31 (m, 2H), 3.60 (m, 1H), 3.89 (ddd, 1H), 4.05 (ddd, 1H), 4.61 (q, 1H), 4.92 (dd, 1H), 5.44 (m, 1H), 7.57 (br.s, 1H), 7.63 (m, 2H), 7.70 (m, 2H), 7.79 (d , 1H), 7.87 (d, 2H), 8.41 (m, 1H).

２,４−ペンタンジオン４６５ｍｇ（４.６４６ｍｍｏｌ）、４−ホルミルベンゾニトリル６０９ｍｇ（４.６４６ｍｍｏｌ）およびＮ−［４−フルオロ−３−（トリフルオロメチル）フェニル］ウレア１２００ｍｇ（４.６４６ｍｍｏｌ）を、ＴＨＦ１２ｍｌに溶解し、エチルポリホスフェート（ＰＰＥ）３０００ｍｇを添加する。混合物を還流下で６時間撹拌し、次いでロータリーエバポレーターで濃縮する。残渣を最初にシリカゲルのフラッシュクロマトグラフィー（溶離剤：シクロヘキサン／酢酸エチル５：１→２：１→１：１）により、次いで分取ＨＰＬＣ（方法１４）により精製する。得られるラセミ体をキラル相の分取ＨＰＬＣ（方法１７）により分画する。かくして、表題化合物３０３ｍｇ（理論値の１６％）を得る。
HPLC (方法 17): R_t = 4.70 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 2.02 (s, 3H), 2.20 (s, 3H), 5.47 (d, 1H), 7.61 (m, 4H), 7.74 (br. s, 1H), 7.88 (d, 2H), 8.48 (d, 1H). Example 7
4-{(4R) -5-acetyl-1- [4-fluoro-3- (trifluoromethyl) phenyl] -6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl } Benzonitrile

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 were Dissolve in 12 ml of THF and add 3000 mg of ethyl polyphosphate (PPE). The mixture is stirred at reflux for 6 hours and then concentrated on a rotary evaporator. The residue is purified first 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 fractionated by chiral phase preparative HPLC (Method 17). This gives 303 mg (16% of theory) of the title compound.
HPLC (Method 17): R _t = 4.70 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.02 (s, 3H), 2.20 (s, 3H), 5.47 (d, 1H), 7.61 (m, 4H), 7.74 (br. S, 1H), 7.88 (d, 2H), 8.48 (d, 1H).

ｔｅｒｔ−ブチル［（６Ｒ）−６−（４−シアノフェニル）−５−（シクロブチルカルボニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］アセテート１９０ｍｇ（０.３４３ｍｍｏｌ）を、ジクロロメタン３ｍｌに溶解し、トリフルオロ酢酸３ｍｌを添加し、混合物を室温で２時間撹拌する。反応混合物を濃縮し、残渣を分取ＨＰＬＣ（方法１４）により精製する。表題化合物１６０ｍｇ（理論値の９４％）を得る。
LC-MS (方法 10): R_t = 2.62 分; MS (ESIpos): m/z (%) = 498.1 (100) [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ = 1.66 (m, 1H), 1.83 (m, 2H), 1.92 (s, 3H), 2.02 (m, 2H), 2.16 (m, 1H), 3.53 (dt, 1H), 3.84 (d, 1H), 4.18 (d, 1H), 5.60 (s, 1H), 7.59 (d, 1H), 7.65-7.74 (m, 4H), 7.81 (d, 1H), 7.88 (d, 2H), 12.70 (s, 1H). Example 8
[(6R) -6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine- 1 (2H) -yl] acetic acid

tert-Butyl [(6R) -6- (4-cyanophenyl) -5- (cyclobutylcarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6- 190 mg (0.343 mmol) of dihydropyrimidin-1 (2H) -yl] acetate are dissolved in 3 ml of dichloromethane, 3 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated and the residue is purified by preparative HPLC (Method 14). 160 mg (94% of theory) of the title compound are obtained.
LC-MS (Method 10): R _t = 2.62 min; MS (ESIpos): m / z (%) = 498.1 (100) [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.66 (m, 1H), 1.83 (m, 2H), 1.92 (s, 3H), 2.02 (m, 2H), 2.16 (m, 1H) , 3.53 (dt, 1H), 3.84 (d, 1H), 4.18 (d, 1H), 5.60 (s, 1H), 7.59 (d, 1H), 7.65-7.74 (m, 4H), 7.81 (d, 1H ), 7.88 (d, 2H), 12.70 (s, 1H).

ＷＯ２００４／０２４７００（実施例７４）に記載の通りに、表題化合物を製造する。 Example 9
5-{(4R) -5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidin-4-yl} pyridine-2 -Carbonitrile

The title compound is prepared as described in WO 2004/024700 (Example 74).

ＷＯ２００４／０２４７００（実施例７２）に記載の通りに、表題化合物を製造する。 Example 10
2-hydroxyethyl (4R) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5 -Carboxylate

The title compound is prepared as described in WO 2004/024700 (Example 72).

アルゴン保護ガス雰囲気下、４−｛（４Ｒ）−５−（１Ｈ−イミダゾール−１−イルカルボニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−４−イル｝ベンゾニトリル（実施例３Ａ；２.２６ｇ、５ｍｍｏｌ）を、Ｎ,Ｎ−ジメチルエタノールアミン（２０ｍｌ）に溶解し、次いで１００℃で３時間撹拌する。混合物を真空で濃縮し、残渣を酢酸エチル（１５０ｍｌ）に取り、次いで水（５０ｍｌ）および飽和塩化ナトリウム溶液（５０ｍｌ）で洗浄する。有機相を硫酸ナトリウムで乾燥し、濾過し、濃縮する。残渣を分取ＨＰＬＣ（方法２２）により精製する。表題化合物２.３８ｇ（理論値の７７％）を得る。
LC-MS (方法 10): R_t = 1.2 分; MS (ESIpos): m/z (%) = 473.5 (100) [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ = 2.05 (s, 3H), 2.10 (br. s, 6H), 2.40 (m, 2H), 4.10 (m, 2H), 5.40 (d, 1H), 7.55-7.70 (m, 5H), 7.80 (d, 1H), 7.90 (d, 2H), 8.40 (d, 1H). Example 11
2- (Dimethylamino) ethyl (4R) -4- (4-cyanophenyl) -6-methyl-2oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine -5-carboxylate trifluoroacetate

4-{(4R) -5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2 under argon protective gas atmosphere , 3,4-Tetrahydropyrimidin-4-yl} benzonitrile (Example 3A; 2.26 g, 5 mmol) is dissolved in N, N-dimethylethanolamine (20 ml) and then stirred at 100 ° C. for 3 hours. The mixture is concentrated in vacuo and the residue is 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-d ₆ ): δ = 2.05 (s, 3H), 2.10 (br.s, 6H), 2.40 (m, 2H), 4.10 (m, 2H), 5.40 (d, 1H), 7.55-7.70 (m, 5H), 7.80 (d, 1H), 7.90 (d, 2H), 8.40 (d, 1H).

アルゴン保護ガス雰囲気下、２,４−ペンタンジオン（９０.１ｍｇ、０.９ｍｍｏｌ）を、ＴＨＦ（１０ｍｌ）に導入する。４−シアノベンズアルデヒド（１１８ｍｇ、０.９ｍｍｏｌ）、Ｎ−［３−フルオロ−５−（トリフルオロメチル）フェニル］ウレア（２００ｍｇ、０.９ｍｍｏｌ）およびエチルポリホスフェート（５５１ｍｇ）を連続的に添加する。ＴＬＣチェックが完全な変換を示すまで（約４時間）、混合物を還流下で撹拌する。混合物を真空で濃縮し、残渣を直接クロマトグラフィーする（biotage 中圧システム、シリカゲルカラム、溶離剤：シクロヘキサン／酢酸エチル５：１→３：１→２：１→１：１）。ラセミの表題化合物１８８ｍｇ（理論値の５０％）を得る。続いて、ラセミ体をクロマトグラフィー（方法１６）によりエナンチオマーに分離する。エナンチオマーピュアな表題化合物（＞９９.５％ｅｅ）２８ｍｇを、ラセミ体６５ｍｇから得る。
HPLC (方法 16): R_t = 23.27 分
LC-MS (方法 7): R_t = 2.2 分; MS (ESIpos): m/z (%) = 418.1 (100) [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ = 2.00 (s, 3H), 2.20 (s, 3H), 5.44 (d, 1H), 7.55 (m, 4H), 7.75 (br. s, 1H), 7.85 (d, 2H), 8.45 (d, 1H). Example 12
4-{(4R) -5-acetyl-1- [3-fluoro-5- (trifluoromethyl) phenyl] -6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl } Benzonitrile

Under an argon protective gas atmosphere, 2,4-pentanedione (90.1 mg, 0.9 mmol) is introduced into THF (10 ml). 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 added sequentially. The mixture is stirred at reflux until TLC check shows complete conversion (about 4 hours). The mixture is concentrated in vacuo and the residue is directly chromatographed (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. Subsequently, the racemate is separated into the enantiomers by chromatography (Method 16). 28 mg of enantiomerically pure title compound (> 99.5% ee) is obtained from 65 mg of racemate.
HPLC (Method 16): R _t = 23.27 min
LC-MS (Method 7): R _t = 2.2 min; MS (ESIpos): m / z (%) = 418.1 (100) [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.00 (s, 3H), 2.20 (s, 3H), 5.44 (d, 1H), 7.55 (m, 4H), 7.75 (br. S, 1H), 7.85 (d, 2H), 8.45 (d, 1H).

ｔｅｒｔ−ブチル［（６Ｒ）−６−（４−シアノフェニル）−５−（エトキシカルボニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］アセテート（１６５ｍｇ、０.３０ｍｍｏｌ）を、アルゴン保護ガス雰囲気下、ジクロロメタン（１.５ｍｌ）に導入し、トリフルオロ酢酸（１.５ｍｌ）を添加し、混合物を室温で４時間撹拌する。反応混合物を真空で濃縮し、残渣を分取ＨＰＬＣ（方法１３）により精製する。表題化合物１３２ｍｇ（理論値の８９％）を得る。
HPLC (方法 2): R_t = 3.0 分
LC-MS (方法 7): R_t = 2.3 分; MS (ESIpos): m/z (%) = 488.1 (100) [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ = 1.10 (t, 3H), 2.05 (s, 3H), 3.75 (d, 1H), 4.05 (q, 2H), 4.10 (d, 1H), 5.60 (s, 1H), 7.60-7.75 (m, 5H), 7.80 (d, 1H), 7.90 (d, 2H), 12.70 (s, 1H). Example 13
[(6R) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetic acid

tert-Butyl [(6R) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro Pyrimidin-1 (2H) -yl] acetate (165 mg, 0.30 mmol) was introduced into dichloromethane (1.5 ml) under an argon protective gas atmosphere, trifluoroacetic acid (1.5 ml) was added and the mixture was allowed to cool to room temperature. For 4 hours. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC (Method 13). 132 mg (89% of theory) of the title compound are obtained.
HPLC (Method 2): R _t = 3.0 min
LC-MS (Method 7): R _t = 2.3 min; MS (ESIpos): m / z (%) = 488.1 (100) [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.10 (t, 3H), 2.05 (s, 3H), 3.75 (d, 1H), 4.05 (q, 2H), 4.10 (d, 1H) , 5.60 (s, 1H), 7.60-7.75 (m, 5H), 7.80 (d, 1H), 7.90 (d, 2H), 12.70 (s, 1H).

表題化合物を、ＷＯ２００５／０８２８６４（実施例５）に記載の通りに製造する。 Example 14
[(6R) -5-{[2- (carboxymethoxy) ethoxy] carbonyl} -6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 3,6-dihydropyrimidin-1 (2H) -yl] acetic acid

The title compound is prepared as described in WO2005 / 082864 (Example 5).

アルゴン保護ガス雰囲気下、水素化ナトリウム（１.１７ｇ、２９.２ｍｍｏｌ）を、ＴＨＦ（５０ｍｌ）に導入する。ＴＨＦ（１５０ｍｌ）中の実施例２の化合物（５.０ｇ、１１.７ｍｍｏｌ）の溶液を、ゆっくりと添加し、反応混合物を室温で発泡させながら１時間撹拌する。次いで、ｔｅｒｔ−ブチルブロモアセテート（３.４ｇ、１７.５ｍｍｏｌ）をゆっくりと添加する。２時間後、薄層クロマトグラムは、完全な変換を示す。水（３００ｍｌ）を注意深く混合物に添加する。水相を固体塩化ナトリウムで飽和させ、酢酸エチルで３回抽出する。合わせた有機相を硫酸ナトリウムで乾燥し、濾過し、真空で濃縮する。残渣をシリカゲルに吸収させ、ＭＰＬＣ（シリカゲル２００ｇ、溶離剤：シクロヘキサン／酢酸エチル４：１）により精製する。純度７９％で５ｇ、純度７０％で４.４ｇの表題化合物を得、さらに分取ＨＰＬＣにより精製できる。
LC-MS (方法 7): R_t = 2.8 分; MS (ESIpos): m/z (%) = 486 (100) [M-C₄H₈+H]⁺;
MS (ESIneg): m/z (%) = 540 (100) [M-H].
さらなる分析データについて、ラセミ化合物（ＷＯ２００５／０８２８６３、実施例３４Ａ）について報告されたものを参照せよ。 Example 15
tert-Butyl [(6R) -6- (4-cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetate

Sodium hydride (1.17 g, 29.2 mmol) is introduced into THF (50 ml) under an argon protective gas atmosphere. A solution of the compound of Example 2 (5.0 g, 11.7 mmol) in THF (150 ml) is slowly added and the reaction mixture is stirred for 1 hour while bubbling at room temperature. Then tert-butyl bromoacetate (3.4 g, 17.5 mmol) is added slowly. After 2 hours, the thin layer chromatogram shows complete conversion. Water (300 ml) is carefully added to the mixture. 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 of silica gel, eluent: cyclohexane / ethyl acetate 4: 1). The title compound is obtained in 5 g at 79% purity and 4.4 g in 70% purity and can be further purified by preparative HPLC.
LC-MS (Method 7): R _t = 2.8 min; MS (ESIpos): m / z (%) = 486 (100) [MC ₄ H ₈ + H] ⁺ ;
MS (ESIneg): m / z (%) = 540 (100) [MH].
For further analytical data, see what has been reported for the racemate (WO2005 / 082863, Example 34A).

ｔｅｒｔ−ブチル［（６Ｒ）−６−（４−シアノフェニル）−５−イソブチリル−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６ジヒドロピリミジン−１（２Ｈ）−イル］アセテート（４.４３ｇ、８.２ｍｍｏｌ）を、アルゴン保護ガス雰囲気下、ジクロロメタン（５０ｍｌ）に導入し、トリフルオロ酢酸（１８.７ｇ、１６４ｍｍｏｌ）を添加し、混合物を室温で約４時間（ＴＬＣチェックが完全な変換を示すまで）撹拌する。反応混合物を真空で濃縮し、残渣をクロマトグラフィー（Biotage クロマトグラフィーシステム、シリカゲル、溶離剤：ジクロロメタン→ジクロロメタン／メタノール１００：１→５０：１）により精製する。表題化合物１.４４ｇ（理論値の３４％）を得る。
LC-MS (方法 7): R_t = 2.3 分; MS (ESIpos): m/z (%) = 486.1 (100) [M+H]⁺;
MS (ESIneg): m/z (%) = 484.2 (80) [M-H], 969.5 (100)
¹H-NMR (400 MHz, DMSO-d₆): δ = 0.60 (d, 3H), 0.70 (d, 3H), 1.60 (s, 3H), 2.70 (m, 1H), 3.60 (d, 1H), 4.00 (d, 1H), 5.50 (s, 1H), 7.35-7.50 (m, 5H), 7.60 (d, 1H), 7.65 (d, 2H), 12.50 (br. s, 1H). Example 16
[(6R) -6- (4-Cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -Yl] acetic acid

tert-Butyl [(6R) -6- (4-cyanophenyl) -5-isobutyryl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6 dihydropyrimidine-1 ( 2H) -yl] acetate (4.43 g, 8.2 mmol) was introduced into dichloromethane (50 ml) under an argon protective gas atmosphere, trifluoroacetic acid (18.7 g, 164 mmol) was added, and the mixture was stirred at room temperature. Stir for 4 hours (until TLC check shows complete conversion). The reaction mixture is concentrated in vacuo and the residue is purified by chromatography (Biotage chromatography system, 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 _t = 2.3 min; MS (ESIpos): m / z (%) = 486.1 (100) [M + H] ⁺ ;
MS (ESIneg): m / z (%) = 484.2 (80) [MH], 969.5 (100)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.60 (d, 3H), 0.70 (d, 3H), 1.60 (s, 3H), 2.70 (m, 1H), 3.60 (d, 1H) , 4.00 (d, 1H), 5.50 (s, 1H), 7.35-7.50 (m, 5H), 7.60 (d, 1H), 7.65 (d, 2H), 12.50 (br.s, 1H).

表題化合物を、ＷＯ２００５／０８２８６３（実施例２１）に記載の通りに製造する。 Example 17
3-{[(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] methyl} benzoic acid

The title compound is prepared as described in WO2005 / 082863 (Example 21).

表題化合物を、ＷＯ２００５／０８２８６３（実施例２２）に記載の通りに製造する。 Example 18
4-{[(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] methyl} benzoic acid

The title compound is prepared as described in WO2005 / 082863 (Example 22).

この反応は、アルゴン下で実施する。固体水素化ナトリウム（３.７６ｇ、９３.９ｍｍｏｌ）を、ＴＨＦ（４５０ｍｌ）中の｛４Ｒ｝−４−｛５−アセチル−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロ−４−ピリミジニル｝ベンゾニトリル（１５.０ｇ、３７.６ｍｍｏｌ；ＷＯ２００５／０８２８６４、実施例１８Ａ）の溶液に、数回に分けて添加する。混合物をＲＴで１時間撹拌し、次いでｔｅｒｔ−ブチルブロモアセテート（１１ｇ、５６.３ｍｍｏｌ）をゆっくりと添加し、混合物を再度ＲＴで１時間撹拌する。ＴＬＣチェックは、完全な変換を示す。水（５００ｍｌ）を混合物に注意深く添加する。飽和塩化ナトリウム水溶液を添加し、次いで、混合物を酢酸エチルで３回抽出する。合わせた有機相を硫酸ナトリウムで乾燥し、濾過し、真空で濃縮する。粗生成物をＭＰＬＣによりシリカゲル（溶離剤：シクロヘキサン／塩化メチレン１：１）で精製する。無色固体を生成物として得（９.９４ｇ、理論値の５１％）、さらなる精製段階を経ずに、次の反応で用いることができる。
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.25 (s, 9H), 2.00 (s, 3H), 2.20 (s, 3H), 3.95 (d, 1H), 4.15 (d, 1H), 5.70 (s, 1H), 7.60-7.90 (m, 8H). Example 19
tert-Butyl [(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetate

This reaction is carried out under argon. Solid sodium hydride (3.76 g, 93.9 mmol) was added to {4R} -4- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) in THF (450 ml). Phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile (15.0 g, 37.6 mmol; WO 2005/082864, Example 18A) is added in several portions. The mixture is stirred at RT for 1 h, then tert-butyl bromoacetate (11 g, 56.3 mmol) is slowly added and the mixture is again stirred at RT for 1 h. A TLC check indicates complete conversion. Water (500 ml) is carefully added to the mixture. Saturated aqueous sodium chloride solution is added and the mixture is 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). A colorless solid is obtained as product (9.94 g, 51% of theory) and can be used in the next reaction without further purification steps.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.25 (s, 9H), 2.00 (s, 3H), 2.20 (s, 3H), 3.95 (d, 1H), 4.15 (d, 1H) , 5.70 (s, 1H), 7.60-7.90 (m, 8H).

この反応は、アルゴン下で実施する。トリフルオロ酢酸（３６.５ｍｌ、４７３.２ｍｍｏｌ）を、ジクロロメタン（１６０ｍｌ）中の実施例１９の化合物（１２.２ｇ、２３.７ｍｍｏｌ）の溶液に添加する。反応混合物をＲＴで終夜撹拌する。次いで、ＴＬＣチェックは、完全な変換を示す。続いて、混合物を真空で濃縮し、残渣をシリカゲルのフラッシュクロマトグラフィー（溶離剤：塩化メチレン→塩化メチレン／メタノール１００：１→塩化メチレン／メタノール５０：１）により精製する。生成物として固体を得る（７.５５ｇ、理論値の７０％）。
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.95 (s, 3H), 2.25 (s, 3H), 2.95 (d, 1H), 4.15 (d, 1H), 5.80 (s, 1H), 7.55-7.90 (m, 8H). Example 20
[(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -Yl] acetic acid

This reaction is carried out under argon. Trifluoroacetic acid (36.5 ml, 473.2 mmol) is added to a solution of the compound of Example 19 (12.2 g, 23.7 mmol) in dichloromethane (160 ml). The reaction mixture is stirred at RT overnight. The TLC check then indicates complete conversion. The mixture is subsequently 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). A solid is obtained as product (7.55 g, 70% of theory).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.95 (s, 3H), 2.25 (s, 3H), 2.95 (d, 1H), 4.15 (d, 1H), 5.80 (s, 1H) , 7.55-7.90 (m, 8H).

この反応は、アルゴン下で実施する。実施例２０の［（６Ｒ）−５−アセチル−６−（４−シアノフェニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］酢酸（１２.０ｇ、２６.２ｍｍｏｌ）を、ＤＭＦ（１５０ｍｌ）に導入し、０℃で、ＨＡＴＵ（１９.９５ｇ、５２.５ｍｍｏｌ）を添加し、混合物を２０分間撹拌する。次いで、塩化アンモニウム（７.０ｇ、１３１.２ｍｍｏｌ）およびＮ,Ｎ−ジイソプロピルエチルアミン（２３.７ｇ、１８３.６ｍｍｏｌ）を添加し、混合物をＲＴで９０分間撹拌する。次いで、ＨＰＬＣまたはＴＬＣチェックは、完全な変換を示す。反応混合物を真空で濃縮する。次いで、残渣を酢酸エチル（４００ｍｌ）に取り、重炭酸ナトリウム水溶液（７０ｍｌ）、１０％強度クエン酸溶液（３ｘ各回７０ｍｌ）、重炭酸ナトリウム溶液（７０ｍｌ）および飽和塩化ナトリウム溶液（７０ｍｌ）で連続的に洗浄する。有機相を硫酸ナトリウムで乾燥し、濾過し、真空で濃縮し、残渣を高真空下で乾燥する。得られる粗生成物を分取ＨＰＬＣにより精製する。この目的で、粗生成物をアセトニトリル（８０ｍｌ）、メタノール（６０ｍｌ）、水（２０ｍｌ）およびトリフルオロ酢酸（１ｍｌ）の混合物に溶解する。Kromasil 100 C18 5 μm を固定相（カラム寸法：２５０ｍｍｘ２０ｍｍ）として使用する。０.２％強度ＴＦＡ／アセトニトリル１：１で、均一溶媒の溶出を実施する。かくして、無色固体を生成物として得る（９.１ｇ、理論値の７６％）。
LC-MS (方法 8): R_t = 2.2 分; MS (ESIpos): m/z (%) = 457.0 (100) [M+H]⁺, 439.9 (60);
MS (ESIneg): m/z (%) = 455.0 (100) [M-H]
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.95 (s, 3H), 2.25 (s, 3H), 3.40 (d, 1H), 4.15 (d, 1H), 5.65 (s, 1H), 7.15 (br. s, 1H), 7.45 (br. s, 1H), 7.60-7.90 (m, 8H). Example 21
2-[(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 ( 2H) -yl] acetamide

This reaction is carried out under argon. [(6R) -5-acetyl-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine of Example 20 1 (2H) -yl] acetic acid (12.0 g, 26.2 mmol) is introduced into DMF (150 ml), at 0 ° C. HATU (19.95 g, 52.5 mmol) is added and the mixture is stirred for 20 minutes. To do. Ammonium chloride (7.0 g, 131.2 mmol) and N, N-diisopropylethylamine (23.7 g, 183.6 mmol) are then added and the mixture is stirred at RT for 90 minutes. HPLC or TLC check then indicates 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% strength citric acid solution (3 × 70 ml each time), sodium bicarbonate solution (70 ml) and saturated sodium chloride solution (70 ml). To wash. The organic phase is dried over sodium sulfate, filtered, concentrated in vacuo and the residue is dried under high vacuum. The resulting crude product is purified by preparative HPLC. For this purpose, the crude product is dissolved in a mixture of acetonitrile (80 ml), methanol (60 ml), water (20 ml) and trifluoroacetic acid (1 ml). Kromasil 100 C18 5 μm is used as stationary phase (column dimensions: 250 mm × 20 mm). Elution of homogeneous solvent is performed with 0.2% strength TFA / acetonitrile 1: 1. A colorless solid is thus obtained 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-d ₆ ): δ = 1.95 (s, 3H), 2.25 (s, 3H), 3.40 (d, 1H), 4.15 (d, 1H), 5.65 (s, 1H) , 7.15 (br.s, 1H), 7.45 (br.s, 1H), 7.60-7.90 (m, 8H).

実施例１３の［（６Ｒ）−６−（４−シアノフェニル）−５−（エトキシカルボニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］酢酸１００ｍｇ（０.２０５ｍｍｏｌ）を、ＴＨＦ７.５ｍｌに溶解し、−２０℃に冷却する。Ｎ−メチルモルホリン５２ｍｇ（０.５１３ｍｍｏｌ）およびエチルクロロホルメート５６ｍｇ（０.５１３ｍｍｏｌ）をこの溶液に添加する。混合物を−２０℃で３０分間撹拌し、次いで、ＴＨＦ１.５ｍｌ中の３５％強度アンモニア水溶液０.２ｍｌの混合物を添加する。次いで、反応混合物をゆっくりと室温に到達させ、次いで、フラスコの内容物を３Ｎ塩酸に入れる。水相を酢酸エチルで抽出し、分離する。有機相を硫酸ナトリウムで乾燥し、濾過し、濃縮する。残渣を分取ＨＰＬＣ（方法２３）により精製する。かくして、表題化合物７８ｍｇ（理論値の７８％）を得る。
MS (ESIpos): m/z (%) = 487 (100) [M+H]⁺
HPLC (方法 4): R_t = 4.31 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.12 (t, 3H), 2.03 (s, 3H), 3.31 (d, 1H), 4.05 (dq, 2H), 4.12 (d, 1H), 5.51 (s, 1H), 7.16 (s, 1H), 7.44 (s, 1H), 7.63-7.66 (m, 3H), 7.73 (t, 1H), 7.78 (s, 1H), 7.82 (d, 1H), 7.89 (d, 2H). Example 22
Ethyl (4R) -3- (2-amino-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2 , 3,4-Tetrahydropyrimidine-5-carboxylate

[(6R) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6- of Example 13 100 mg (0.205 mmol) of dihydropyrimidin-1 (2H) -yl] acetic acid is dissolved in 7.5 ml of THF and cooled to -20 ° C. 52 mg (0.513 mmol) of N-methylmorpholine and 56 mg (0.513 mmol) of ethyl chloroformate are added to this solution. The mixture is stirred at −20 ° C. for 30 minutes and then a mixture of 0.2 ml of 35% strength aqueous ammonia solution in 1.5 ml of THF is added. The reaction mixture is then allowed to slowly reach room temperature and then the contents of the flask are placed in 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 78 mg (78% of theory) of the title compound.
MS (ESIpos): m / z (%) = 487 (100) [M + H] ⁺
HPLC (Method 4): R _t = 4.31 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.12 (t, 3H), 2.03 (s, 3H), 3.31 (d, 1H), 4.05 (dq, 2H), 4.12 (d, 1H) , 5.51 (s, 1H), 7.16 (s, 1H), 7.44 (s, 1H), 7.63-7.66 (m, 3H), 7.73 (t, 1H), 7.78 (s, 1H), 7.82 (d, 1H ), 7.89 (d, 2H).

表題化合物を、ＷＯ２００５／０８２８６３（実施例１５Ａ）に記載の通りに製造する。 Example 23
(4R) -4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The title compound is prepared as described in WO2005 / 082863 (Example 15A).

（４Ｒ）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボニトリル５９００ｍｇ（１５.４３１ｍｍｏｌ）を、ＤＭＦ１５０ｍｌに溶解し、炭酸カリウム７６７７ｍｇ（５５.５５１ｍｍｏｌ）およびｔｅｒｔ−ブチルブロモアセテート７２２４ｍｇ（３７.０３４ｍｍｏｌ）を添加する。次いで、反応混合物を６０℃で終夜撹拌する。続いて、溶媒をロータリーエバポレーターで除去し、残渣を酢酸エチルおよび水の混合物に取る。有機相を分離し、硫酸ナトリウムで乾燥し、濾過し、濃縮する。残渣をシリカゲルに吸収させ、シリカゲルのＭＰＬＣにより精製する（溶離剤：シクロヘキサン／酢酸エチル１：２）。かくして、表題化合物５５７０ｍｇ（理論値の７３％）を得る。
LC-MS (方法 6): R_t = 2.65 分; MS (ESIneg): m/z (%) = 495.2 (100) [M-H]^-
1H-NMR (400 MHz, DMSO-d₆): δ = 1.29 (s, 9H), 1.86 (s, 3H), 3.71 (d, 1H), 3.96 (d, 1H), 5.49 (s, 1H), 7.70-7.75 (m, 2H), 7.78 (d, 2H), 7.84 (d, 1H), 7.87 (s, 1H), 7.96 (d, 2H). Example 24
tert-Butyl [(6R) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetate

(4R) -4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carbonitrile 5900 mg (15.431 mmol) is dissolved in 150 ml of DMF and 7777 mg (55.551 mmol) of potassium carbonate and 7224 mg (37.034 mmol) of tert-butyl bromoacetate are added. The reaction mixture is then stirred at 60 ° C. overnight. Subsequently, the solvent is removed on a rotary evaporator and the residue is 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 absorbed onto 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 _t = 2.65 min; MS (ESIneg): m / z (%) = 495.2 (100) [MH] ^-
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.29 (s, 9H), 1.86 (s, 3H), 3.71 (d, 1H), 3.96 (d, 1H), 5.49 (s, 1H) , 7.70-7.75 (m, 2H), 7.78 (d, 2H), 7.84 (d, 1H), 7.87 (s, 1H), 7.96 (d, 2H).

ｔｅｒｔ−ブチル［（６Ｒ）−５−シアノ−６−（４−シアノフェニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］アセテート５８４０ｍｇ（１１.７６２ｍｍｏｌ）をジクロロメタン４０ｍｌに溶解し、トリフルオロ酢酸１３４１２ｍｇ（１１７.６２５ｍｍｏｌ）を添加する。混合物を５０℃で５時間撹拌する。次いで、揮発性成分をロータリーエバポレーターで除去する。残渣をシリカゲルのＭＰＬＣにより精製する（溶離剤：ジクロロメタン／メタノール１０：１）。かくして、表題化合物３１２０ｍｇ（理論値の５８％）を得る。
LC-MS (方法 10): R_t = 2.47 分; MS (ESIpos): m/z (%) = 441.1 (100) [M+H]⁺. Example 25
[(6R) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -Yl] acetic acid

tert-Butyl [(6R) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetate 5840 mg (11.762 mmol) is dissolved in dichloromethane 40 ml and trifluoroacetic acid 13412 mg (117.625 mmol) is added. The mixture is stirred at 50 ° C. for 5 hours. The volatile components are then removed with 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 _t = 2.47 min; MS (ESIpos): m / z (%) = 441.1 (100) [M + H] ⁺ .

［（６Ｒ）−５−シアノ−６−（４−シアノフェニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］酢酸１００ｍｇ（０.２２７ｍｍｏｌ）を、ＴＨＦ５ｍｌに溶解し、−２０℃に冷却する。Ｎ−メチルモルホリン５７ｍｇ（０.５６８ｍｍｏｌ）およびエチルクロロホルメート６２ｍｇ（０.５６８ｍｍｏｌ）をこの溶液に添加する。混合物を−２０℃で３０分間撹拌し、次いで、ＴＨＦ１.５ｍｌ中の３５％強度アンモニア水溶液０.１５ｍｌの混合物を添加する。次いで、反応混合物をゆっくりと室温に到達させ、次いで、フラスコの内容物を３Ｎ塩酸に入れる。水相を酢酸エチルで抽出し、分離する。有機相を硫酸ナトリウムで乾燥し、濾過し、濃縮する。残渣を分取ＨＰＬＣ（方法２３）により精製する。かくして、表題化合物４４ｍｇ（理論値の４４％）を得る。
MS (DCI): m/z (%) = 457 (100) [M+NH₄]⁺, 440 (6) [M+H]⁺
HPLC (方法 3): R_t = 4.19 分
¹H-NMR (400 MHz, DMSO-d₆): δ = 1.82 (s, 3H), 3.20 (d, 1H), 4.10 (d, 1H), 5.45 (s, 1H), 7.12 (s, 1H), 7.39 (s, 1H), 7.72-7.76 (m, 4H), 7.83 (d, 1H), 7.87 (s, 1H), 7.89 (d, 2H). Example 26
2-[(6R) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 ( 2H) -yl] acetamide

[(6R) -5-cyano-6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -Yl] Acetic acid 100 mg (0.227 mmol) is dissolved in 5 ml THF and cooled to -20 <0> C. 57 mg (0.568 mmol) of N-methylmorpholine and 62 mg (0.568 mmol) of ethyl chloroformate are added to this solution. The mixture is stirred at −20 ° C. for 30 minutes and then a mixture of 0.15 ml of 35% strength aqueous ammonia solution in 1.5 ml of THF is added. The reaction mixture is then allowed to slowly reach room temperature and then the contents of the flask are placed in 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 + NH ₄ ] ⁺ , 440 (6) [M + H] ⁺
HPLC (Method 3): R _t = 4.19 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.82 (s, 3H), 3.20 (d, 1H), 4.10 (d, 1H), 5.45 (s, 1H), 7.12 (s, 1H) , 7.39 (s, 1H), 7.72-7.76 (m, 4H), 7.83 (d, 1H), 7.87 (s, 1H), 7.89 (d, 2H).

（４Ｒ）−３−（２−ｔｅｒｔ−ブトキシ−２−オキソエチル）−４−（４−シアノフェニル）−６−メチル−２−オキソ−１−［３−（トリフルオロメチル）フェニル］−１,２,３,４−テトラヒドロピリミジン−５−カルボン酸（実施例４Ａ；５１５ｍｇ、１ｍｍｏｌ）、２−ブロモエタノール（５２１ｍｇ、４ｍｍｏｌ）およびＮ,Ｎ−ジイソプロピルエチルアミン（２５８ｍｇ、２ｍｍｏｌ）を、ＤＭＦ（１５ｍｌ）中、７０℃で２４時間撹拌する。次いで、反応混合物を真空で濃縮し、残渣を酢酸エチルに取る。有機相を水で、次いで濃塩化ナトリウム水溶液で洗浄する。次いで、それを硫酸ナトリウムで乾燥し、濾過し、濃縮する。粗生成物をシリカゲルのフラッシュクロマトグラフィーにより精製する（溶離剤：シクロヘキサン→シクロヘキサン／酢酸エチル１：２）。無色固体を生成物として得る（４７２ｍｇ、理論値の８４％）。
LC-MS (方法 8): R_t = 2.6 分; MS (ESIpos): m/z (%) = 504.1 (100), 560 (20) [M+H]⁺;
MS (ESIneg): m/z (%) = 558.4 (100) [M-H]. Example 27
tert-Butyl [(6R) -6- (4-cyanophenyl) -5-[(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 3,6-dihydropyrimidin-1 (2H) -yl] acetate

(4R) -3- (2-tert-butoxy-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1, 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) were added to DMF (15 ml). The mixture is stirred at 70 ° C. for 24 hours. The reaction mixture is then concentrated in vacuo and the residue is taken up in ethyl acetate. The organic phase is washed with water and then with a 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 (eluent: cyclohexane → cyclohexane / ethyl acetate 1: 2). A colorless solid is obtained as product (472 mg, 84% of theory).
LC-MS (Method 8): R _t = 2.6 min; MS (ESIpos): m / z (%) = 504.1 (100), 560 (20) [M + H] ⁺ ;
MS (ESIneg): m / z (%) = 558.4 (100) [MH].

ｔｅｒｔ−ブチル［（６Ｒ）−６−（４−シアノフェニル）−５−［（２−ヒドロキシエトキシ）カルボニル］−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］アセテート（実施例２７；２３５ｍｇ、０.４２ｍｍｏｌ）を、ジクロロメタン（２ｍｌ）に導入する。次いで、トリフルオロ酢酸（２ｍｌ）を添加し、混合物をＲＴで２４時間撹拌する。次いで、反応混合物を真空で濃縮し、粗生成物を分取ＨＰＬＣ（カラム：Kromasil 5 μm；溶離剤：アセトニトリル／水＋０.１％ＴＦＡ１０：９０→９０：１０）により精製する。表題化合物を固体として得る（１１５ｍｇ、理論値の５４％）。
LC-MS (方法 7): R_t = 1.9 分; MS (ESIpos): m/z (%) = 504.1 (100) [M+H]⁺; MS (ESIneg): m/z (%) = 502.1 (70) [M-H]. Example 28
[(6R) -6- (4-Cyanophenyl) -5-[(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6 -Dihydropyrimidin-1 (2H) -yl] acetic acid

tert-Butyl [(6R) -6- (4-cyanophenyl) -5-[(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 3,6-Dihydropyrimidin-1 (2H) -yl] acetate (Example 27; 235 mg, 0.42 mmol) is introduced into dichloromethane (2 ml). Trifluoroacetic acid (2 ml) is then added and the mixture is stirred at RT for 24 hours. The reaction mixture is then concentrated in vacuo 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 _t = 1.9 min; MS (ESIpos): m / z (%) = 504.1 (100) [M + H] ⁺ ; MS (ESIneg): m / z (%) = 502.1 (70) [MH].

この反応は、アルゴン下で実施する。［（６Ｒ）−６−（４−シアノフェニル）−５−［（２−ヒドロキシエトキシ）カルボニル］−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］酢酸（実施例２８；４０ｍｇ、７９μｍｏｌ）をＤＭＦ（２ｍｌ）に導入し、０℃で、ＨＡＴＵ（１５１ｍｇ、０.４ｍｍｏｌ）を添加し、混合物を２０分間撹拌する。次いで、塩化アンモニウム（２１ｍｇ、０.４ｍｍｏｌ）およびＮ,Ｎ−ジイソプロピルエチルアミン（１０３ｍｇ、０.８ｍｍｏｌ）を添加し、反応混合物をＲＴで１６時間撹拌する。得られる粗混合物を分取ＨＰＬＣにより直接精製する（カラム：Gromsil C18 10 μm；溶離剤：アセトニトリル／水＋０.１％ＴＦＡ１０：９０→９０：１０）。表題化合物を無色固体として得る（１６ｍｇ、理論値の４０％）。
LC-MS (方法 24): R_t = 2.9 分; MS (ESIpos): m/z (%) = 503.2 (60) [M+H]⁺, 441.2 (100);
MS (ESIneg): m/z (%) = 501.2 (100) [M-H]
¹H-NMR (400 MHz, DMSO-d₆): δ = 2.00 (s, 3H), 3.30 (d, 1H), 3.50 (t, 2H), 4.05 (m, 2H), 4.15 (d, 1H), 5.55 (s, 1H), 7.15 (br. s, 1H), 7.50 (br. s, 1H), 7.60-7.90 (m, 8H). Example 29
2-Hydroxyethyl (4R) -3- (2-amino-2-oxoethyl) -4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl]- 1,2,3,4-tetrahydropyrimidine-5-carboxylate

This reaction is carried out under argon. [(6R) -6- (4-cyanophenyl) -5-[(2-hydroxyethoxy) carbonyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6 -Dihydropyrimidin-1 (2H) -yl] acetic acid (Example 28; 40 mg, 79 μmol) was introduced into DMF (2 ml), at 0 ° C. HATU (151 mg, 0.4 mmol) was added and the mixture was allowed to reach for 20 min. Stir. Ammonium chloride (21 mg, 0.4 mmol) and N, N-diisopropylethylamine (103 mg, 0.8 mmol) are then added and the reaction mixture is stirred at RT for 16 h. The resulting crude mixture is purified directly by preparative HPLC (column: Gromsil C18 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 _t = 2.9 min; MS (ESIpos): m / z (%) = 503.2 (60) [M + H] ⁺ , 441.2 (100);
MS (ESIneg): m / z (%) = 501.2 (100) [MH]
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.00 (s, 3H), 3.30 (d, 1H), 3.50 (t, 2H), 4.05 (m, 2H), 4.15 (d, 1H) , 5.55 (s, 1H), 7.15 (br.s, 1H), 7.50 (br.s, 1H), 7.60-7.90 (m, 8H).

［（６Ｒ）−６−（４−シアノフェニル）−５−（エトキシカルボニル）−４−メチル−２−オキソ−３−［３−（トリフルオロメチル）フェニル］−３,６−ジヒドロピリミジン−１（２Ｈ）−イル］酢酸（実施例１３）９７５ｍｇ（２.００ｍｍｏｌ）を、ＤＭＦ４ｍｌに溶解し、２ＭジメチルアミンのＴＨＦ溶液２.２ｍｌ（４.４０１ｍｍｏｌ）を添加する。次いで、４−Ｎ,Ｎ−ジメチルアミノピリジン４４９ｍｇ（４.００ｍｍｏｌ）、１−ヒドロキシ−１Ｈ−ベンゾトリアゾール水和物５９５ｍｇ（４.４０１ｍｍｏｌ）および１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩８４４ｍｇ（４.４０１ｍｍｏｌ）を添加する。混合物をＲＴで終夜撹拌する。混合物をロータリーエバポレーターで濃縮した後、粗生成物を分取ＨＰＬＣ（方法２３）により精製する。かくして、表題化合物７９５ｍｇ（理論値の７７％）を得る。
LC-MS (方法 25): R_t = 3.67 分; MS (ESIpos): m/z (%) = 515.4 (100) [M+H]⁺. Example 30
Ethyl (4R) -4- (4-cyanophenyl) -3- [2- (dimethylamino) -2-oxoethyl] -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl]- 1,2,3,4-tetrahydropyrimidine-5-carboxylate

[(6R) -6- (4-cyanophenyl) -5- (ethoxycarbonyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydropyrimidine-1 (2H) -yl] acetic acid (Example 13) 975 mg (2.00 mmol) is dissolved in 4 ml of DMF and 2.2 ml (4.401 mmol) of 2M dimethylamine in THF is added. Then, 449 mg (4.00 mmol) of 4-N, N-dimethylaminopyridine, 595 mg (4.401 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 844 mg (4.401 mmol) of hydrochloride are added. The mixture is stirred overnight at RT. After the mixture is concentrated 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 _t = 3.67 min; MS (ESIpos): m / z (%) = 515.4 (100) [M + H] ⁺ .

B. Evaluation of Pharmacological Activity The pharmacological effects of the compounds of the present invention can be demonstrated in the following assays:
Abbreviations:

B-1. In Vitro HNE Inhibition Assay The efficacy of the compounds of the present invention is confirmed by an in vitro inhibition assay. In this regard, amidolytic cleavage of the appropriate peptide substrate mediated by HNE leads to an increase in fluorescence. The fluorescence signal intensity is directly proportional to the enzyme activity. The effective concentration of test compound at which half of the enzyme is inhibited (fluorescence signal intensity 50%) is shown as IC ₅₀ .

Method:
Enzyme (80 pM HNE; from Serva, Heidelberg) and substrate (20 μM MeOSuc-Ala-Ala-Pro-Val-AMC; from Bachem, Weil am Rhein) in a total of 50 μl assay buffer (0.1 M HEPES pH 7.4, 0.5M NaCl, 0.1% w / v BSA, 1% v / v DMSO) in an 384 well microtiter plate in the presence and absence of test substance at 37 ° C. Incubate for hours. The intensity of fluorescence from the assay mixture is measured (Ex. 380 nm, Em. 460 nm). IC ₅₀ values are determined by plotting the intensity of fluorescence against the concentration of active substance.

Representative IC ₅₀ values for the compounds of the present invention are shown in the table below:
TABLE : Inhibition of human neutrophil elastase (HNE)

B-2. Animal model of pulmonary arterial hypertension Pulmonary hypertension induced by monocrotaline in rats is a widely used animal model of pulmonary arterial hypertension. Monocrotaline, a pyrrolizidine alocaloid, is metabolized to toxic monocrotaline pyrrole in the liver after subcutaneous injection, causing endothelial damage to the pulmonary circulation within a few days, followed by remodeling of small pulmonary arteries (media hypertrophy) ), De novo muscularization). A single subcutaneous injection is sufficient to induce overt pulmonary hypertension in rats within 4 weeks [Cowan et al., Nature Med. 6 , 698-702 (2000)].

Male Sprague-Dawley rats are used for this model. On day 0, animals receive a monocrotaline 60 mg / kg subcutaneous injection. Animal treatment does not begin earlier than 14 days after monocrotaline injection and continues for at least 14 days. At the end of the study, the animals are subjected to hemodynamic studies and arterial and central venous oxygen saturation is measured. For hemodynamic measurements, rats are first anesthetized with pentobarbital (60 mg / kg). The animal is then tracheotomized and ventilated (rate: expiratory rate 60 / min; expiratory / inspiratory ratio: 50:50; positive end expiratory pressure: 1 cmH ₂ O; tidal volume: 10 ml / kg body weight; FIO _2: 0.5). Anesthesia is maintained by isoflurane inhalation anesthesia. Systemic blood pressure is measured in the left carotid artery using a Millar microchip catheter. A polyethylene catheter is advanced through the right jugular vein into the right ventricle and the right ventricular pressure is measured. Measure cardiac output by temperature dilution. Following hemodynamic measurements, the heart is removed and the ratio of the right ventricle to the left ventricle including the septum is determined. In addition, plasma samples are obtained and biomarkers (eg, proBNP) and plasma substance levels are measured.

B-3. CYP Inhibition Assay Standards for the formation of CYP-specific metabolites using pooled human liver microsomes as the source of enzymes that could inhibit human CYP1A2, CYP2C9, CYP2D6 and CYP3A4 In the presence of the target substrate (described below). Six different concentrations of test compound (2.8, 5.6, 8.3, 16.7, 25 and 50 μM) were used to form a CYP-specific metabolite of a standard substrate in the absence of the test compound. The inhibitory effect is examined and the corresponding IC ₅₀ value calculated. In order to be able to compare results between different series, a standard inhibitor that specifically inhibits a single CYP isoform is always included in the incubation.

Method:
Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan or midazolam with human liver microsomes in each case in the presence of 6 different concentrations of test compound (as a potential inhibitor) workstation (Tecan, Genesis , Crailsheim, Germany). The standard incubation mixture was 1.3 mM NADP, 3.3 mM MgCl ₂ x6H 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. The test compound is preferably dissolved in acetonitrile. 96-well plates are incubated with pooled human liver microsomes at 37 ° C. for a defined time. The reaction is stopped by the addition of 100 μl of acetonitrile, in which there is always a suitable internal standard. Precipitated protein is removed by centrifugation and the supernatants are combined and analyzed by LC-MS / MS.

B-4. Hepatocyte assay to measure metabolic stability To ensure as linear kinetic conditions as possible during the experiment, the compound was used at a low concentration (preferably less than 1 μM) and a low cell number ( The metabolic stability of the test compound in the presence of hepatocytes is determined by incubation at preferably 1 * 10 ⁶ cells / ml). To measure the compound half-life (ie degradation), seven samples of the incubation solution are taken in a fixed time pattern for LD-MS analysis. Various clearance parameters (CL) and F _max values are calculated from this half-life (see below).

Cl and F _max values represent measurements of the first and second phase metabolism of the compound in hepatocytes. This concentration is generally limited to 1% (acetonitrile) or 0.1% (DMSO) to minimize the effect of organic solvents on the enzyme in the incubation mixture.

The number of hepatocytes in the liver 1.1 * 10 ⁸ cells / g liver is used for calculations for all species and breeds. CL parameters calculated based on half-life extending beyond the incubation time (usually 90 minutes) can only be considered a rough guideline.

The calculated parameters and their meanings are as follows:
F _max well stirred [%] Maximum possible bioavailability calculation after oral administration: (1-CL _blood well stirred / QH) * 100
CL _blood well stirred [L / (h * kg)] Calculated blood clearance (fully stirred model)
Calculation: (QH * CL ′ _intrinsic ) / (QH + CL ′ _intrinsic )
CL ′ _Endogenous [ml / (min * kg)] Maximum capacity of liver (hepatocytes) to metabolize compound (assuming liver blood flow is not rate limiting)
Calculation: CL ' _{endogenous, apparent} * species-specific hepatocyte count [1.1 * 10 ⁸ / g liver] * species-specific liver weight [g / kg]
CL ′ _{endogenous, apparent} [ml / (min * mg)] Calculation to normalize it by dividing the elimination constant by the number of hepatocyte cells used x (x * 10 ⁶ / ml): k _el [1 / min] / (cell number [x * 10 ⁶ ] / incubation volume [ml])
(QH = species-specific liver blood flow)

C. Exemplary Embodiments of Pharmaceutical Compositions The compounds of the present invention can be converted into pharmaceutical formulations in the following manner:
tablet:
composition:
100 mg of a compound of the invention, 50 mg lactose (monohydrate), 50 mg corn starch (natural), 10 mg polyvinylpyrrolidone (PVP25) (BASF Co., Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablet weight 212mg, diameter 8mm, curvature radius 12mm.
Manufacturing:
A mixture of the compound of the invention, lactose and starch is granulated with 5% strength aqueous PVP solution (m / m). After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is compressed with a normal tableting machine (see above for tablet shape). The tableting force of the guideline for tableting is 15 kN.

Suspensions that can be administered orally:
composition:
Compound 1000mg of the present invention, ethanol ^(96%) 1000mg, Rhodigel ^(R) (FMC xanthan gum, Pennsylvania, USA) 400 mg and water 99 g.
10 ml of oral suspension corresponds to a single dose of 100 mg of the compound of the invention.
Manufacturing:
Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water with stirring. The mixture is stirred for about 6 hours until the Rhodigel swelling is complete.

Solution that can be administered orally:
composition:
500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100 mg of the compound according to the invention.
Manufacturing:
The compound of the invention is suspended in a mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention is completely dissolved.

iv solution:
The compounds of the present invention are dissolved in physiologically tolerated solvents (eg, isotonic saline, 5% glucose solution and / or 30% PEG400 solution) at a concentration below saturation solubility. The solution is sterilized by filtration and used to fill sterile pyrogen-free injection containers.

Claims (13)

Formula (I)

[Where:
X is CH or N;
R ¹ is hydrogen, a group of formula — (CH ₂ ) _n —C (═O) —O—R ^1A or — (CH ₂ ) _n —C (═O) —NR ^1B R ^1C , or a formula

{Wherein * represents the point of attachment to the N atom,
n is a number of 1 or 2,
R ^1A is hydrogen or (C ₁ -C ₄ ) -alkyl;
And R ^1B and R ^1C , independently of one another, are hydrogen or (C ₁ -C ₄ ) -alkyl},
R ² is cyano or a group of formula —C (═O) —R ^2A or —C (═O) —O—R ^2A {wherein R ^2A is (C ₁ -C ₆ ) — Alkyl or (C ₃ -C ₆ ) -cycloalkyl, each of which is up to 2 identical or different hydroxy, (C ₁ -C ₄ ) -alkoxy, hydroxycarbonyl, amino, mono- and / or Optionally substituted by di- (C ₁ -C ₄ ) -alkylamino, in each case the CH ₂ group may be replaced by an O atom},
And
R ³ is hydrogen and R ⁴ is hydrogen, fluorine or chlorine,
Or
R ³ is fluorine or chlorine, and R ⁴ is hydrogen]
Or a salt, solvate and one of the salts thereof for the manufacture of a medicament for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension. Where
X is CH or N;
R ¹ is hydrogen, a group of formula —CH ₂ —C (═O) —OH or —CH ₂ —C (═O) —NH ₂ , or a formula

{Wherein * represents the point of attachment to the N atom},
R ² is cyano, acetyl, cyclobutylcarbonyl, methoxycarbonyl, ethoxycarbonyl or 2-hydroxyethoxycarbonyl,
R ³ is hydrogen;
And
R ⁴ is hydrogen or fluorine,
Use according to claim 1 of the compound of formula (I) according to claim 1 or one of its salts, solvates and solvates of salts.

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

4. A compound of formula (I) according to claim 1, 2 or 3 and its salts, solvates and solvates of salts selected from the group of compounds consisting of Use as described in. The following structure:

A compound of formula (I) according to claim 1 having one of the following: and salts, solvates and solvates of the salts thereof.   6. A compound according to claim 5 for the treatment and / or prevention of disease.   6. At least one compound of formula (I) according to any one of claims 1 to 5, as well as kinase inhibitors, stimulators and activators of soluble guanylate cyclase, prostacyclin analogues, endothelin receptors A combination comprising one or more additional active ingredients selected from the group consisting of antagonists and phosphodiesterase inhibitors.   Use of the combination according to claim 7 for the manufacture of a medicament for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension.   Left atrial or left ventricular disorder, left heart valve disorder, chronic obstructive pulmonary disease for the treatment and / or prevention of idiopathic or familial pulmonary arterial hypertension or pulmonary arterial hypertension associated with medicine, toxicants or other disorders , Interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, disorders with alveolar hypoventilation, altitude sickness, impaired lung development, chronic thrombotic and / or embolic disorders, or sarcoidosis, histiocytosis Claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of pulmonary hypertension due to external compression of blood vessels, for the treatment and / or prevention of X or lymphangioleiomyomatosis Use of a compound of formula (I) according to any of the above or a combination according to claim 7.   6. A medicament comprising a compound according to claim 5 optionally in combination with one or more inert, non-toxic pharmaceutically suitable auxiliaries.   8. A medicament comprising a combination according to claim 7 optionally in combination with one or more inert, non-toxic pharmaceutically suitable adjuvants.   12. A medicament according to claim 10 or claim 11 for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension.   An effective amount of at least one compound of formula (I) according to any of claims 1 to 5, a combination according to claim 7, or at least one of claims 1 to 5. A method for the treatment and / or prevention of pulmonary arterial hypertension and other types of pulmonary hypertension in humans and animals by administering a medicament comprising a compound of formula (I) as defined above.