ES2414865T3 - Pyrimidinone derivatives as therapeutic agents against acute and chronic, ischemic and remodeling inflammatory processes - Google Patents

Abstract

Compounds of the general formula (I) ** Formula ** in which A represents a phenyl or pyridyl ring, R1, R2 and R3 independently represent hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy o-C1-C6 alkoxy, in which C1-C6 alkyl and C1-C6 alkoxy can also be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy, R4 represents trifluoromethylcarbonyl, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, alkenoxycarbonyl-C1-C6, hydroxycarbonyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, arylaminocarbonyl-C6-C10, arylcarbonyl, heteroarylcarbonyl heterocyclylcarbonyl heterocyclylcarbonyl heterocyclylcarbonyl heterocyclylcarbonyl heterocyl carbonyl or cyano, in which the C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, mono- and di-alkylaminocarbonyl-C1-C4 can also be substituted with one to three identical or different radicals selected from the group consisting of C3-cycloalkyl -C8, hydroxy, C1-alkoxy -C4, C1-C4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, alkylcarbonylamino-C1-C4, (alkylcarbonyl-C1-C4) alkylamino-C1-C4, cyano, amino, mono- and di-alkylamino-C1-C4, heteroaryl, heterocyclyl and tri- (C1-C6-alkyl) -silyl and in which the heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl can also be substituted with C1-C4 alkyl, R5 represents alkyl -C1-C4, which may be substituted with one to three identical or different radicals, selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkenoxy, C1-C6 alkylthio, amino, mono- and dialkylamino-C1-C6, arylamino, hydroxycarbonyl, alkoxycarbonyl-C1-C6 and the radical -O-alkyl-C1-C4-O-alkyl-C1-C4.

Description

Pyrimidinone derivatives as therapeutic agents against acute and chronic, ischemic and remodeling inflammatory processes

The present invention relates to novel heterocyclic derivatives, methods for their preparation and use5 in medicaments, especially for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and development of heart failure.

The fibrous elastin protein, which comprises an appreciable percentage of the total protein content in some tissues, such as arteries, some ligaments, the lungs and the heart, can be hydrolyzed or destroyed in other ways by a selected group of enzymes classified as elastases. Human leukocytic elastase (ELH, 10 EC 3.4.21.37), also known as human neutrophil elastase (ENH), is a strongly basic, glycosylated serine protease and is found in the azurophilic granules of human polymorphonuclear leukocytes (PMN). ENH is released by activated PMNs and has been implicated as a cause in the pathogenesis of acute and chronic inflammatory diseases. ENH is capable of degrading a wide range of matrix proteins including elastin and collagen and in addition to these actions on connective tissue, ENH has a wide range of

15 range of inflammatory actions including upward regulation of the expression of the IL-8 gene, edema formation, hyperplasia of the mucous glands and mucus hypersecretion. It also acts as a mediator in tissue lesions by hydrolyzing collagen structures, for example in the heart after an acute heart attack or during the development of heart failure, thus damaging endothelial cells, inducing extravasation of neutrophils that adhere to the endothelium and influencing The same adhesion procedure.

20 Pulmonary diseases where ENH is thought to play an active role include pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, including smoking-induced emphysema, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis . Cardiovascular diseases, ENH is involved in the potentiated generation of ischemic tissue injury followed by myocardial dysfunction after acute myocardial infarction and in the procedures of

25 remodeling that occurs during the development of heart failure. ENH has also been implicated as a cause in diseases such as rheumatoid arthritis, atherosclerosis, brain trauma, cancer and related conditions in which the involvement of neutrophils is involved.

Therefore, inhibitors of ELH activity may be potentially useful in the treatment of a number of inflammatory diseases, especially in chronic obstructive pulmonary diseases [R.A. 30 Stockley, Neutrophils and protease / antiprotease imbalance, Am. J. Respir. Crit. Care 160, S49-S52 (1999)]. ELH activity inhibitors may also be potentially useful in the treatment of acute myocardial syndrome, unstable angina pectoris, acute myocardial infarction and graft aortocoronary bypass (CABG) [C.P. Tiefenbacher et al., Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, S563-570 (1997); Dinerman et al., 35 Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction, J. Am. Coll. Cardiol 15, 1559-1563 (1990)], of the development of heart failure [S.J. Gilbert et al. Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34, S377-S383 (1997)] and in atherosclerosis [Dollery et al., Neutrophil elastase in human atherosclerotic plaque, Circulation 107, 2829-2836 (2003)]. EP 0 528 633 A and US 5 532 366 disclose ENH inhibitors. The document

WO 01 378 37 A refers to IL-8 that inhibits quinazolin-2-one derivatives.

The synthesis of 5-ethoxycarbonyl-1-phenyl-6-methyl-4- (3-nitrophenyl) -3,4-dihydropyrimidin-2 (1H) -one is described in J. Heterocyclic Chem. 38, 1051 (2001) . No pharmacological activity of this compound is mentioned.

The present invention relates to compounds that respond to the general formula (I)

45 in which A represents a phenyl or pyridyl ring,

R1, R2. and R3 independently represent among them hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl and C1-C6 alkoxy can also be substituted. with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy,

R4 represents trifluoromethylcarbonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkenoxycarbonyl,

5-hydroxycarbonyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, arylaminocarbonyl-C6-C10, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano alkyl, in which the alkylcarbonyl-C1-C6-C6-alkoxycarbonyl , the mono- and di-alkylaminocarbonyl-C1-C4 may also be substituted with one to three identical or different radicals selected from the group consisting of cycloalkyl-C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, alkylcarbonylamino-C1-C4, (alkylcarbonyl-C1-C4) alkylamino-C1-C4, cyano, amino, mono- and di-alkylamino-C1-C4, heteroaryl , heterocyclyl and tri- (C1-C6-alkyl) -silyl and in which the heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl can also be substituted with C1-C4 alkyl,

R5 represents C1-C4 alkyl, which may be substituted with one to three identical or different radicals, selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkenoxy, C1-C6 alkylthio, amino ,

Mono- and di-C1-C6 alkylamino, arylamino, hydroxycarbonyl, C1-C6 alkoxycarbonyl and the radical -O-C1-C4 alkyl-O-C1-C4 alkyl,

or

R5 represents amino,

R6 represents hydrogen, C1-C6 alkyl, formyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, cycloalkylcarbonyl-C3-C8, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, N- (alkylsulfonyl-C1- C4) -aminocarbonyl, N (alkylsulfonyl-C1-C4) -N- (alkyl-C1-C4) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C1-C6 alkyl, mono- and di- C1-C4 alkylaminocarbonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, heteroaryl and heterocyclyl may be substituted with one to three odifferent identical radicals selected from the group consisting of aryl, heteroaryl, hydroxy, alkoxy C1-C4, hydroxycarbonyl,

C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino-C1-C4, alkylcarbonylamino-C1-C4, tri- (C1-C6-alkyl) -silyl , cyano, N- (mono- and di-alkylamino-C1-C4-alkyl-C1-C4) aminocarbonyl, N- (alkoxy-C1-C4-alkyl-C1-C4) -aminocarbonyl and halogen,

or

R6 represents a remainder of the formula

in which

R6A

is selected from the group consisting of hydrogen and C1-C6 alkyl and

n represents an integer 1 or 2,

R7 represents halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl and the

C1-C6 alkoxy may be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy,

and

Y1, Y2, Y3, Y4 and Y5 independently represent each other CH or N, containing the ring well 0, 1

or 2 nitrogen atoms.

The compounds according to this invention may also be present in the form of their salts, hydrates and / or solvates.

In the context of the present invention physiologically acceptable salts are preferred.

Physiologically acceptable salts according to the invention are non-toxic salts that are generally accessible by reacting the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose. Non-limiting examples of pharmaceutically acceptable salts of the compounds (I) include the

45 alkali metal salts, for example lithium, potassium and sodium salts, alkaline earth metal salts such as magnesium and calcium salts, quaternary ammonium salts such as, for example, detriethylammonium salts, acetates, benzenesulfonates, benzoates, dicarbonates, disulfates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, smokers, gluconates, glutamates, hexyl resorcinates, hydrobromides, hydrochlorides, hydroxynaphtates, iodides, isothionates, lactates, laurates, malate, maleates, maleate mesylates, methyl bromides, methylnitrates, methyl sulfates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, polygalacturonates, salicylates, stearates, succinate sulfates, tartrates, tosylates, valerates and other salts for medicinal purposes.

Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as, for example, hemi-, mono- or dihydrates.

Solvates of the compounds of the invention or their salts are stoichiometric compositions of the solvent compounds.

The present invention includes both the individual enantiomers or diastereomers and the corresponding diastereomeric mixtures or mixtures of the compounds according to the invention and their respective salts. In addition, all possible tautomeric forms of the compounds described above according to the present invention are included. The diastereomeric mixtures can be separated into the individual isomers by chromatographic procedures. The racemates can be divided into the respective enantiomers either by chromatographic procedures in chiral phases or by resolution.

In the context of the present invention, substituents, if not otherwise specified, generally have the following meanings:

Alkyl generally represents a straight or branched chain hydrocarbon radical with 1 to 6, preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino.

Illustrative alkoxy and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylcarbonyl in general represents a straight or branched chain hydrocarbon radical having 1 to 6, preferably 1 to 4, carbon atoms, which has a carbonyl function in the bonding position. Examples that do not involve any limit include formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, nhexanoyl.

Illustrative alkoxycarbonyl and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, n-hexoxycarbonyl.

Alkylamino represents an alkylamino radical with one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N -dietylamino, N-ethyl-N-methylamino, N-methyl-Npropylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino .

Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl , N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-npentylaminocarbonyl and Nn -hexyl-N-methylaminocarbonyl.

Alkylsulfonyl in general represents a straight or branched chain hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms having a sulfonyl function in the bonding position. Non-limiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl.

Cycloalkyl in general represents a cyclic hydrocarbon radical saturated with 3 to 8, preferably 3 to 6, carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl by itself and in arylcarbonyl represents an aromatic carbocyclic radical of mono- to tricyclic having generally 6 to 14 carbon atoms, illustratively and preferably representing phenyl, naphthyl and phenanthrenyl.

Arylcarbonyl represents illustrative and preferably benzoyl and naphthoyl.

Heteroaryl by itself and in heteroarylcarbonyl represents a mono- or bicyclic aromatic radical that generally has 5 to 10 and preferably 5 or 6 ring atoms and up to 5 and preferably up to 4 heteroatoms selected from the group consisting of S, O and N, representing illustrative and preferably thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, oxodiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl.

Heteroarylcarbonyl illustratively and preferably represents thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pirimidilcarbonilo, pyridazinylcarbonyl, indolylcarbonyl, indazolilcarbonilo, benzofuranilcarbonilo, benzotiofenilcarbonilo, quinolilicarbonilo, isoquinolilcarbonilo.

Heterocyclyl by itself or in heterocyclylcarbonyl represents a non-aromatic, mono-opicyclic, preferably mono- or bicyclic heterocyclic radical generally having 4 to 10 and preferably 5 to 8 ring atoms and up to 3 and preferably up to 2 heteroatoms and / or hetero groups selected from the group consisting of N, O, S, SO and SO2. Heterocyclic radicals can be saturated or partially unsaturated. Preference is given to 5 to 8-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms selected from the group consisting of O, N and S, such as illustrative and preferably tetrahydrofuran-2-yl, pyrrolidine-1-yl, pyrrolidine-2- yl, pyrrolidine-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.

Heterocyclylcarbonyl represents illustrative and preferably tetrahydrofuran-2-carbonyl, pyrrolidine-1-carbonyl, pyrrolidine-2-carbonyl, pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl, morpholinecarbonyl perhydroazepinecarbonyl.

Halogen represents fluorine, chlorine, bromine and iodine.

When it is indicated that Y1, Y2, Y3, Y4 and Y5 represent CH or N, CH refers to a ring carbon atom that is substituted with a substituent R3 or R7.

A * symbol next to a link indicates the point of attachment in the molecule.

In another embodiment, the present invention relates to compounds of the general formula (I) in which

A represents a phenyl or pyridyl ring,

R1, R2. and R3 independently represent each other hydrogen, halogen, nitro, cyano, C1-C6 alkyl,

Hydroxy or C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-alkoxy -C4,

R4

represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkenoxycarbonyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, arylaminocarbonyl-C6-C10, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl or heteroaryl in which the C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, the

Mono- and di-alkylaminocarbonyl-C1-C4 may also be substituted with one to three radicals, identical or different, selected from the group consisting of cycloalkyl-C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, alkylcarbonylamino-C1-C4, amino, mono- and di-alkylamino-C1-C4, heteroaryl, heterocyclyl and tri- (C1-C6-alkyl) -silyl.

R5

represents C1-C4 alkyl, which may be substituted with one to three identical or different radicals,

20 selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkenoxy, C1-C6 alkylthio, amino, mono- and di-C1-C6 alkylamino, arylamino, hydroxycarbonyl, C1-C6 alkoxycarbonyl and the radical -O-C1-C4 alkyl-O-C1-C4 alkyl,

or R5

represents amino, R6

25 represents hydrogen, C1-C6 alkyl, formyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, cycloalkylcarbonyl-C3-C8, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, N- (alkylsulfonyl-C1- C4) -aminocarbonyl, N (alkylsulfonyl-C1-C4) -N- (alkyl-C1-C4) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C1-C6 alkyl, mono- or di -C1-C4 alkylaminocarbonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, heteroaryl and heterocyclyl may be substituted with one to three identical radicals or

30 different selected from the group consisting of aryl, heteroaryl, hydroxy, C1-C4 alkoxy, hydroxycarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino -C1-C4, alkylcarbonylamino-C1-C4, tri- (C1-C6-alkyl) -silyl, cyano, N- (mono- and di-alkylamino-C1-C4-alkyl-C1-C4) aminocarbonyl, N- ( C1-C4 alkoxy-C1-C4 alkyl) -aminocarbonyl and halogen,

or

35 R6 represents a remainder of the formula

in which R6A

is selected from the group consisting of hydrogen and C1-C6 alkyl and n represents an integer 1 or 2.40 R7 represents halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which alkyl- C1-C6 and C1-Alkoxy

C6 may also be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy and Y1, Y2, Y3, Y4 and Y5 independently of each other represent CH or N, containing the ring well 0,

either 1 or 2 nitrogen atoms.

In another embodiment, the present invention relates to compounds of the general formula (I) in which A represents a phenyl or pyridyl ring, R1, R2 and R3 independently represent each other, hydrogen, fluorine, chlorine , bromine, nitro, cyano,

methyl, ethyl, trifluoromethyl or trifluoromethoxy,

R4

represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, C1-C4 monoalkylaminocarbonyl or cyano, in which C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl and C1-C4 monoalkylaminocarbonyl substituted with one to three identical or different radicals selected from the group consisting of cycloalkyl-C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, amino, mono- or di

5-C1-C4 alkylamino, heteroaryl and heterocyclyl,

R5

represents methyl or ethyl, R6

represents hydrogen, C1-C6 alkyl, mono- or di-alkylaminocarbonyl-C1-C4, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6 or heterocyclylcarbonyl, wherein C1-C6 alkyl and alkoxycarbonyl-C1-C6 they may be substituted with one to three identical or different radicals selected from the group consisting of

10 heteroaryl, hydroxy, C1-C4 alkoxy, hydroxycarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and dialkylaminocarbonyl-C1-C4, cyano, amino, mono- and di-alkylamino-C1-C4,

or

R6 represents a remainder of the formula

15 in which R6A

is selected from the group consisting of hydrogen and C1-C4 alkyl and n represents an integer 1 or 2, R7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, and

20 Y1, Y2, Y3, Y4 and Y5, each represent CH.

In another embodiment, the present invention relates to compounds of the general formula (I), in which A represents a phenyl or pyridyl ring, R1 and R3 each represent hydrogen,

R2 represents fluorine, chlorine, bromine nitro or cyano, R4

represents cyano, C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl, in which the C1-C4 alkoxycarbonyl may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, mono - and di-alkylamino-C1-C4, heteroaryl and heterocyclyl,

R5

 represents methyl,

R6 represents hydrogen, C1-C4 alkyl, mono- or di-alkylaminocarbonyl-C1-C4, C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl, wherein C1-C4 alkyl and C1-C4 alkoxycarbonyl they may be substituted with a radical selected from the group consisting of heteroaryl, hydroxy, C1-C4 alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino-C1-C4,

or

R6

35 represents a remainder of the formula

in which R6A

is selected from the group consisting of hydrogen and methyl, R7 represents trifluoromethyl or nitro,

and

Y1, Y2, Y3, Y4 and Y5, each represent CH.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R 1 is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R2 is cyano, especially in which A is phenyl or pyridyl and R2 is a cyano positioned in relation to the central ring of dihydropyrimidinone.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R3 is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R4 is alkoxycarbonyl-C1-C4 optionally substituted with hydroxy, especially 2-hydroxyethoxycarbonyl, or in which R4 is C1-alkylcarbonyl -C4, especially methylcarbonyl.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R5 is methyl.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R 6 is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formula (I) in which R 7 is trifluoromethyl or nitro, especially in which R 7 is trifluoromethyl located in the meta position relative to the dihydropyrimidinone center ring.

In another embodiment, the present invention relates to compounds of the general formula (IA),

in which

Z represents CH or N and

R1, R3, R4 and R6 have the meaning indicated above.

The compounds of the present invention in which R 6 is hydrogen can undergo an enolization to the corresponding hydroxyamidines:

The compounds of the general formula (I) can be synthesized by condensing compounds of the general formula (II)

in which A, R1 and R2 have the meaning indicated above, with compounds of the general formula (III)

in which

R4 and R5 have the meaning indicated above, 10 and compounds of the general formula (IV)

wherein R3, R7 and Y1 to Y5 have the meaning indicated above, in the presence of an acid in a three component reaction / one step or sequentially to give compounds

15 of the general formula (IB)

in which

A, R1 to R5, R7 and Y1 to Y5 have the meaning indicated above,

optionally followed by the reaction of the compounds of the general formula (IB) with compounds of the general formula (V)

R6 * -X (V)

in which

R6 * has the meaning of R6 as indicated above, but does not represent hydrogen and

X represents a leaving group, such as halogen, tosylate, mesylate or sulfate,

in the presence of a base.

The compounds of the general formula (I) in which R4 represents cyano, R5 represents amino and R6 represents hydrogen, can on the other hand be prepared by condensing compounds of the general formula (II) with compounds of the general formula (IV) and a compound of the formula (VI)

NC-CH2-CN (VI)

in the presence of an acid, either in a three component reaction / one stage or sequentially.

Generally the solvents suitable for the procedure (II) + (III) / (VI) + (IV) - (IB) are common organic solvents that do not change in the reaction conditions. These include ethers such as diethyl ether, ether diisopropyl, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. Tetrahydrofuran is preferred for the process.

Generally suitable acids for process (II) + (III) / (VI) + (IV) - (IB) are inorganic inorganic acids. These preferably include carboxylic acids, such as, for example, acetic acid or acidotrifluoroacetic acid, sulfonic acids, such as, for example, methanesulfonic acid or p-toluenesulfonic acid, hydrochloric acid or phosphoric acids such as polyphosphoric acids. Preference is given to the polyphosphoric acid ethyl ester. The acid is used in an amount of 0.25 moles to 100 moles, relative to 1 mole of the compound of the general formula (III).

In general, the process is carried out in a temperature range from +20 ° C to +150 ° C, preferably from +60 ° C to +100 ° C.

Generally the procedure is carried out at normal pressure. However, it is also possible to carry it out at elevated or reduced pressure (for example, in a range from 50,000 to 500,000 pascals (from 0.5 to 5 bar)).

Generally suitable solvents for process (IB) + (V) - (I) are usual organic solvents that do not change under the conditions of the reaction. These include ethers, such as diethyl ether, ether diisopropyl, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene , or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. For the procedure it is preferred

40 tetrahydrofuran.

Generally suitable bases for the process (IB) + (V) - (I) are organic or inorganic bases. These

preferably they include cyclic amines, such as, for example, piperidine or 4-N, N-dimethylaminopyridine, or trialkylamines (C1-C4) such as, for example, triethylamine or diisopropylethylamine, or hydrides such as sodium hydride. Preference is given to sodium hydride. The base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (IV).

5 In general, the process is carried out at a temperature range of 0 ° C to +150 ° C, preferably from +20 ° C to +80 ° C, especially at room temperature.

Generally the procedure is carried out at normal pressure. However, it can also be carried out at elevated pressure or at reduced pressure (for example, in a range from 50,000 to 500,000 pascals (from 0.5 to 5bar)).

The compounds of the general formulas (II), (III), (IV), (V) and (VI) are known per se or can be prepared by usual procedures.

The procedure mentioned above can be illustrated by the following scheme:

The compounds according to the invention show an unpredictable, useful spectrum of pharmacological activity and pharmacokinetics. Therefore they are suitable for use as medicines for the treatment and / or prophylaxis of diseases in humans and animals.

Surprisingly, the compounds of the present invention show a human elastasaneutrophil (ENH) inhibitory activity and are therefore suitable for the preparation of medicaments for the treatment of diseases associated with ENH activity. Thus, they can provide effective treatment for acute and chronic inflammatory disorders20, such as rheumatoid arthritis, atherosclerosis and especially acute and chronic lung diseases, such as pulmonary fibrosis, cystic fibrosis, pneumonia, acute dyspnoea syndrome (ARDS), in particular pulmonary emphysema, including induced emphysema portabaquismo and chronic obstructive pulmonary diseases (COPD), chronic bronchitis and bronchiectasis. The compounds of the present invention can additionally provide an effective treatment for ischemic cardiovascular diseases25 such as acute coronary syndrome, acute myocardial infarction, stable and unstable angina pectoris, aortocoronary bypass (CABG) and development of heart failure, paraatherosclerosis, mitral valve disease. atrial septum defects, transluminal percutaneous coronary angioplasty (PTCA), inflammation after open heart surgery and to treat pulmonary hypertension. They can also prove useful for effective treatment of rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis30, ulcerative colitis, periodontal disease, Chury-Strauss syndrome, acute and chronic atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous pemphigus, sepsis, alcoholic hepatitis, liver fibrosis, Behcet disease, allergic fungal sinusitis, allergic sinusitis, Crohn's disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal diseases, chronic suppurative otitis media, venous and chronic ulcers of the extremities, inflammatory bowel disease, viral infections and bacterial, trauma

35 craniocerebral, stroke and other disorders in which neutrophil involvement is involved.

The present invention additionally provides medicaments containing at least one compound according to the invention, preferably together with one or more pharmacologically safe excipients or vehicle substances, in addition to its use for the aforementioned purposes.

The active component can act systemically and / or locally. For this purpose, it can be applied in a suitable way, for example orally, parenterally, lungly, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctively, otically or as an implant.

For these routes of application, the active component can be administered in suitable application forms.

Useful oral application forms include application forms that rapidly release the active component and / or in modified form, such as for example tablets (uncoated or coated tablets, for example with an enteric coating), capsules, sugar-coated tablets, granules, pills, powders, emulsions, suspensions, solutions and aerosols.

Parenteral application can be carried out with the avoidance of an absorption stage (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Useful forms of parenteral application include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

Suitable forms for other routes of application include for example inhalation pharmaceutical forms (including inhalation powders, nebulizers), nasal drops / solutions, aerosols; tablets or capsules to be administered lingually, sublingually or orally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, stirring mixtures), lipophilic suspensions, ointments, creams, milks, pastes, dusts or implants.

The active components can be converted into the aforementioned application forms in a manner known per se. This is accomplished using pharmaceutically suitable, non-toxic inert excipients. These include other vehicles (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulfate), dispersing agents (for example polyvinyl pyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (for eg antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxides) or taste and / or odor correctors.

For human use, in the case of oral administration, it is advisable to administer doses of 0.001 mg / kg to 50 mg / kg, preferably 0.01 mg / kg to 20 mg / kg. In case of parenteral administration, such as, for example, intravenously or through the mucous membranes nasally, buccally or inhalatively, it is advisable to use doses of 0.001 mg / kg to 0.5 mg / kg.

Despite this, in certain circumstances it may be necessary to deviate from the amounts mentioned, namely as a function of body weight, route of application, individual behavior against the active component, the way of preparation and the time or interval at which you have Place the application. For example, in some cases it may be sufficient to use less than the minimum amount mentioned above, while in other cases, the upper limit mentioned will have to be exceeded. In the case of the application of larger amounts, it may be advisable to divide them into a plurality of individual doses disseminated throughout the day.

The percentages in the tests and examples that follow are, unless otherwise specified, by weight; The parts are by weight. Solvent ratios, dilution ratios and reported concentrations for liquid / liquid solutions are all based on volume.

A. Evaluation of physiological activity

The ability of the compounds of the invention to inhibit the activity of neutrophil elastase can be demonstrated, for example, using the following tests:

I. In vitro enzymatic assays of human neutrophil elastase (ENH)

Contents of the essay

Assay buffer; 0.1 M HEPES-NaOH buffer, pH 7.4, 0.5 M NaCl, 0.1% bovine serum albumin (w / v):

adequate concentration (see below) of ENH (18 U / mg liof., No. 20927.01, SERVA Electroforesis GmbH, Heidelberg, Germany) in assay buffer;

adequate concentration (see below) of substrate in assay buffer;

adequate concentration of the test compounds diluted with test buffer of a solution stored 10 mM in DMSO.

Example A

In vitro inhibition of ENH using a fluorogenic peptide substrate (continuous signal reading, 384 MTP assay format):

In this protocol, the MeOSuc-Ala-Ala-Pro-Val-AMC elastase substrate (No. 324740, Calbiochem-Novabiochem Corporation, Merck Kga, Darmstadt, Germany) is used. The test solution is prepared by mixing 10 µl of the dilution of the test compound, 20 µl of the dilution of the ENH enzyme (final concentration 8-0.4! U / ml, routinely deforms 2.1! U / ml ) and 20 µl of the substrate dilution (final concentration 1 mM-1 µM, routinely 20 µM), respectively. The solution is incubated for 0-2 hours at 37 ° C (routinely one hour). The fluorescence of the released AMC due to the enzymatic reaction is measured at 37 ° C (TECAN spectra fluor plus platereader). The rate at which the fluorescence increases (ex. 395 nm, em. 460 nm) is proportional to elastase activity. The IC50 values are determined by RFU graphs versus [I]. The Km and Km (app) values are determined by Lineweaver-Burk graphs and converted into Ki values by Dixon graphs.

The preparation examples had IC50 values within the range of 5 nM-5 µM in this assay. Representative data are collected in Table 1:

Table 1

Example No.

IC50 (nM)

one

8

9

40

14

 5

fifteen

 8

16

 10

twenty

 700

24

 13

26

 10

28

 fifty

58

 1100

60

 5

72

 6

73

 60

74

 twenty

103

 60

109

 fifteen

110

 fifty

Example B

In vitro inhibition of ENH using an insoluble, fluorogenic elastin substrate (discontinuous signal reading5, 96 MTP test format):

In this protocol, the elastin-fluorescein elastase substrate (No. 100620, ICN Biomedicals GmbH, Eschwege, Germany) is used. The test solution is prepared by mixing 3 µl of the dilution of the test compound, 77 µl of the dilution of the ENH enzyme (final concentration 0.22 U / ml-2.2 mU / ml, usually 21.7! U / ml) and 80 µl of the substrate suspension (final concentration 2 mg / ml). The suspension is incubated for 0-16 hours at 37 ° C10 (usually for four hours) under conditions of moderate agitation. By stopping the enzymatic reaction, 160 µl of 0.1 M acetic acid (50 mM final concentration) is added to the test solution. The elastinafluorescein polymer is separated by centrifugation (Eppendorf 5804 centrifuge, 3,000 rpm, 10 minutes). The supernatant is transferred to a new MTP and the fluorescence of the fluorescein peptide released due to the enzymatic reaction (BMG Fluostar plate reader) is measured. The fluorescence rate (ex. 490 nm, em. 520 nm) is proportional to the

15 elastase activity. The IC50 values are determined by RFU graphs versus [I].

II. In vitro human neutrophil assays

Example A

In vitro test of PMN elastolysis:

This assay is used to determine the elastolytic capacity of human polymorphonuclear cells (PMN) and to determine the proportion of degradation due to neutrophil elastase. [cf. Z.W. She et al., Am. J. Respir. Cell Mol. Biol. 9, 386-392 (1993)].

Tritiated elastin is coated, in suspension, on a 96-well plate at 10 µg per well. Test and reference compounds [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), WO 95/21855) and the protease C1 inhibitor (C1 PI)] are added to the wells in the appropriate concentrations. Human PMN cells are separated from the peripheral venous blood of healthy donors and resuspended in culture media. Neutrophils are added to the coated wells in concentrations ranging from 1 x 106 to 1 x 105 cells per well. Swine pancreatic elastase (1.3 µM) is used as a positive test control and C1PI (1.2 µM) is used as the positive neutrophil elastase inhibitor. Cellular control is PMN without compound at each appropriate cell density. Cells plus compounds are incubated in a humidified incubation oven at 37 ° C for 430 hours. The plates are centrifuged allowing the collection of a supernatant only from cells. The supernatant is transferred at 75 µl volumes to the corresponding wells of a 96-well LumaplateTM plate (plates

containing scintillation solids). The plates are dried until there is no visible liquid in the wells and read on a beta counter for three minutes per well.

Elastolysis of elastin-3H results in an increase in the supernatant counts. An inhibition of this elastolysis shows a decrease, from the cellular control, of tritium in the supernatant. C1PI resulted in 83.46% ± 3.97% (mean ± standard mean error) of inhibition at 1.2 µM (n = 3 different donors at 3.6 x 105 cells per well). IC50 values were obtained for the reference compound ZD-0892, with a value of 45.50 ± 7.75 nM (mean ± standard mean error) (n = 2 different donors at 3.6 x 105 cells per well).

Since ZD-0892 is a selective PMN elastase inhibitor along with C1PI inhibition data, these results indicate that most of the degradation of elastin by PMN is due to neutrophil elastase and not to another elastolytic enzyme, such as matrix metalloproteases (MMP). The compounds of this invention are evaluated for their inhibitory activity in this ENH-dependent model of neutrophil elastolysis.

Example B

In vitro inhibition of membrane-bound elastase:

Measurement of elastase inhibition bound to neutrophil membranes is performed using a human neutrophil assay. Neutrophils are stimulated with LPS at 37 ° C for 35 minutes and then 1,600 rpm is centrifuged. Subsequently, the membrane-bound elastase is fixed to the neutrophils with 3% paraformaldehyde and 0.25% glutaraldehyde for 3 minutes at 4 ° C. The neutrophils are then centrifuged and the vehicle and compound under evaluation are added, followed by the addition of the MeOSuc-Ala-Ala-Pro-Val-AMC substrate (No. 324740, Calbiochem-Novabiochem Corporation, Merck KgaA, Darmstadt, Germany ) to 200 µM. After an incubation period of 25 minutes at 37 ° C, the reaction is stopped with PMSF (phenylmethanesulfonyl fluoride) and the fluorescence is read at ex: 400 nm and em: 505 nm. IC50 values are determined by interpolation from the graphs of relative fluorescence versus inhibitor concentration.

III. In vivo models

Example A

In vivo model of acute lung injury in the rat:

The instillation of human neutrophil elastase (ENH) inside the rat lung causes a lung lung injury. The extent of this injury can be determined by measuring pulmonary hemorrhage.

The rats are anesthetized with Hypnorm / Hypnovel / water and ENH or salinomediating serum is instilled in the lungs by means of a micropulverizer. The test compounds are administered by venous injection, orally by inhalation at certain times, before ENH administration. Sixty minutes after the administration of elastase, the animals are sacrificed by an overdose of anesthesia (sodium pentobarbitone) and the lungs are washed with 2 ml of heparinized phosphate buffered saline (PBS). The volume of bronchoalveolar lavage (LBA) is recorded and the samples are stored on ice. Each LBA sample is centrifuged 900 rpm for 10 minutes at 4 ° C-10 ° C. The supernatant is discarded and the cell precipitate is resuspended in PBS and the sample is centrifuged again. Again the supernatant is discarded and the cell precipitate is suspended in 1 ml of 0.1% cetyltrimethylammonium bromide (CTAB) / PBS lysing the cells. The samples are frozen until the blood content is tested. Before bleeding analysis, samples are thawed and mixed. 100 µl of each sample are introduced into wells apart from a flat-bottom 96-well plate. All samples are tested in duplicate. The blank includes 100 µl of 0.1% CTABS / PBS. The absorbance of the contents of the wells is measured at 415 nm using a spectrophotometer. A standard curve is constructed by measuring the OD at 415 nm of the different blood concentrations in 0.1% CTABS / PBS. Blood content values are calculated by comparison with the standard curve (including each plate) and are normalized for the volume of LBA fluid recovered.

The compounds of this invention of this invention are evaluated intravenously, orally or by inhalation by determining their inhibitory activity in this model of ENH-induced bleeding in rats.

Example B

In vivo model of acute myocardial infarction in the rat:

Elastase inhibitors are tested in a rat model in which a heart attack is induced by a thread. Male Wistar rats (weighing more than 300 g) receive 10 mg / kg of aspirin 30 minutes before surgery. They are anesthetized by isoflurane and given ventilation throughout the procedure (120-130 beats / minute, 200-250 µl of systolic volume; MiniVent Type 845, Hugo Sachs Elektronic, Germany). After performing a left thoracotomy at the level of the fourth intercostal space, the pericardium is opened and the heart is briefly exposed. A thread is passed around the left coronary artery (ICA) without occluding the artery. The thread is passed under the skin towards the neck of the animal. The chest is closed and recovery of the animal is allowed for 4 days. On the fifth day, the rats are anesthetized with ether for 3 minutes and the thread is tied and the ICA occluded with ECG control. Test compounds are administered before or after occlusion of the ICA orally, intraperitoneally or intravenously (in the form of bowling or by permanent infusion). After 1 hour of occlusion, the thread reopens allowing reperfusion. The hearts of the excised and the sizes of the infarcts are determined 48 hours later by staining the hearts reoccluded with blue Evans, followed by staining with TTC (triphenyltetrazolium chloride) of 2 mm sections of the heart. The non-toxic areas (non-occluded tissue) are stained blue, the ischemic areas (occluded but living tissue) are stained red and the necrotic areas (dead occluded tissue) remain white. Each section of tissue is scanned and infarction sizes are determined by computerized planimetry.

B. Examples

Abbreviations:

ac.

aqueous

conc.

concentrated

DMF

N, N-dimethylformamide

DMSO

dimethylsulfoxide

EI

electron impact ionization (for MS)

ESI

electrospray ionization (for MS)

HPLC

high pressure liquid chromatography

CL-MS

liquid chromatography coupled to mass spectroscopy

Pf

melting point

EM

mass spectroscopy

NMR

nuclear magnetic resonance

from tr.

of the theoretical (performance)

Tr

retention time (for HPLC)

THF

tetrahydrofuran.

General Procedures:

All reactions are carried out under argon atmosphere conditions unless otherwise specified. Solvents are used as supplied by Aldrich without further purification. "Silica gel" or "silica" refers to silica gel 60 (0.040 mm-0.063 mm) from Merck KgaA company. Melting points were obtained with a Buchi512 or similar melting point determination device and are uncorrected.

Compounds purified by preparative HPLC are purified on an RP18 column with acetonitrile and water as the eluent, using a gradient 1: 9 to 9: 1.

LC-EM / HPLC procedures:

LC-MS procedure 1:

Instrument: Micromass Quattro LCZ, HP1100; column: Uptisphere HDO, 50 mm x 2.0 mm, 3 µm; eluent A: water

+ 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; gradient; 0.0 minutes 100% A - 0.2 minutes 100% A - 2.9 minutes 30% A - 3.1 minutes 10% A - 4.5 minutes 10% A; oven: 55 ° C; flow: 0.8 ml / minute; UV detection: 208-400 nm.

CL-EM 2 procedure:

Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 µm; eluent A: water + 0.1% acidid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0 minutes 5% B - 5.0 minutes 10% B - 6.0 minutes 10% B; temperature: 50 ° C; flow: 1.0 ml / minute; UV detection: 210 nm.

CL-EM procedure 3:

Instrument: Micromass Platform LCZ, HP1100; column: Aquasil C-18, 50 mm x 2.0 mm, 3 µm; eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; gradient: 0.0 minutes 100% A -0.2 minutes 100% A - 2.9 minutes 30% A - 3.1 minutes 10% A - 4.5 minutes 10% A; oven: 55 ° C; flow: 0.8 ml / minute; UV detection: 208-400 nm.

HPLC procedure 4

Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 µm; eluent A = 5 ml of HClO4 / l H2O, B = acetonitrile; gradient: 0 minutes B 2%, 0.5 minutes B 2%, 4.5 minutes B 90%; 6.5 minutes B at 90%; flow: 0.75 ml / minute; temperature: 30 ° C; UV detection: 210 nm.

CL-EM procedure 5

Instrument: Micromass TOF-MUX-Quad-parallel parallel injection interface, with HPLC Waters 600; column: Uptisphere HDO, 50 mm x 2.0 mm, 3.0 µm; eluent A: 11 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml 50% formic acid; gradient: 0.0 minutes 100% A - 0.2 minutes 100% A -2.9 minutes 30% A - 3.1 minutes 10% A -4.5 minutes 10% A - 100% A % -6.5 minutes A 100%; oven: room temperature: flow: 0.8 ml / minutes; UV detection: 210 nm.

LC-MS procedure 6

Instrument: Micromass Platform LCZ with HPLC Agilent Serie1100; column: Grom-SIL I20 ODS-4 HE, 50mm x 2.0mm, 3 µm; eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% acididoform; gradient: 0.0 minutes 100% A - 0.2 minutes 100% A - 2.9 minutes 30% A -3.1

5 minutes 10% A - 4.5 minutes 10% A; oven: 55 ° C; flow: 0.8 ml / minute; UV detection: 208-400 nm.

CL-EM procedure 7

Instrument: Micromass Quattro LCZ with HPLC Agilent 1100 Series; column: Uptisphere HDO, 50 mm x 2.0 mm, 3 µm; eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 minutes 100% A - 0.2 minutes 100% A - 2.9 minutes 30% A - 3.1 minutes A at

10 10% - 4.5 minutes A at 10%; oven: 55 ° C; flow: 0.8 ml / minute; UV detection: 208-400 nm.

Starting Materials:

Reference Example 1A

2-Bromo-5- (1,3-dioxolan-2-yl) pyridine

The compounds 6-bromo-3-pyridinecarbaldehyde (500 mg, 2.7 mmol) and 1,2-ethanediol (200 mg, 3.2 mmol) are dissolved in toluene (50 ml) together with Amberlyst 15 (100 mg) in a round bottom flask equipped with a reflux condenser and a Dean-Stark manifold. The reaction is stirred at reflux overnight, then cooled to room temperature, filtered and concentrated in vacuo. The crude product is subjected to silica gel chromatography with cyclohexane and ethyl acetate as eluent giving rise to the title compound.

20 in the form of a colorless oil. Yield: 0.489 g (79% of tr.). HPLC (procedure 4): 3.46 min. MS (IEpos): m / z = 231 (M + H) +. 1H NMR (300 MHz, CDCl3): 8 = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H ) ppm.

Reference Example 2A 5- (1,3-dioxolan-2-yl) -2-pyridinecarbonitrile

Compounds 1A (2.8 g, 12.5 mmol), zinc cyanide (1.6 g, 13.8 mmol) and tetrakis- (triphenylphosphine) palladium (0) (1.4 g, 1.3 mmol) Dissolve in dimethylformamide (100 ml) and stir overnight (18 h) at 80 ° C. An additional 30 tetrakis (triphenylphosphine) palladium (0.1 g) (0.1 g) is added and the reaction is stirred again overnight (18 h) at 80 ° C, then left at room temperature for 2 days (48 hours) . The solvent is removed in vacuo, water (100 ml) is given to the residue and the product is extracted with ethyl acetate (1 L). The organic phase is washed with brine (200 ml), dried with magnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is subjected to silica gel chromatography with cyclohexane and ethyl acetate as eluent, giving rise to the title compound.

35 in the form of a white amorphous solid.

Yield: 0.94 g (42% of tr.).

HPLC (procedure 4): 3.21 min.

MS (IEpos): m / z = 177 (M + H) +.

1H NMR (400 MHz, DMSO-d6): 8 = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4.13-3.94 (m , 4H) ppm.

Reference Example 3A

5-formyl-2-pyridinecarbonitrile

5 Procedure a):

Prepared analogously to the procedure of Dodd, D et al. [J. Org. Chem. 1992, 57, 7226-7234]: to a stirred solution of 5- (1,3-dioxolan-2-yl) -2-pyridinecarbonitrile (Example 2A; 850 mg, 4.8 mmol) in acetone / water 85 : 15 (59.5 ml) p-toluenesulfonic acid (102 mg, 0.59 mmol) is added. The reaction is stirred at reflux for a whole night (18 h) and then more p-toluenesulfonic acid (50 mg) and water (5 ml) are added. The reaction is stirred at reflux.

10 for another 48 hours. The solution is cooled to room temperature and deactivated with a saturated sodium bicarbonate solution. The product is extracted with ethyl acetate (3 x 100 ml), dried over demagnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC resulting in a pale yellow solid.

Yield: 0.66 g (93% of tr.).

15 Mp .: 80 ° C-82 ° C.

HPLC (procedure 4): 2.13 min.

MS (IEpos): m / z = 133 (M + H) +.

1H NMR (400 MHz, DMSO-d6): 8 = 10.18 (s, 1H), 9.21 (m, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm .

Procedure b):

1.04 g (8.2 mmol) of oxalyl chloride are dissolved in 8 ml of dichloromethane. 1.28 g (16.4 mmol) of dimethylsulfoxide are added dropwise at a temperature of 78 ° C. The solution is stirred at -78 ° C for 20 minutes, then add 1 g (7.46 mmol) of the compound of Example 5A, dissolved in 7 ml of dichloromethane and stirring at -78 ° C is continued for another 2 hours. Then 3.4 g (33.6 mmol) of triethylamine are added dropwise and then decanted to room temperature, the mixture is purified by column chromatography (silica, eluent

Cyclohexane to cyclohexane / ethyl acetate 2: 1).

Yield: 0.76 g (77% of tr.).

Analytical data: see above.

Reference Example 4A

5-methyl-2-pyridinecarbonitrile

30 36 g (209 mmol) of 2-bromo-5-methylpyridine and 37.5 g (418 mmol) of copper cyanide are refluxed for two hours in 500 ml of dimethylformamide. After cooling to 50 ° C, 10% solution of ammonium aqueous (500 ml) is added with stirring. Make the product extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The product is purified by column chromatography (silica,

Eluent cyclohexane / ethyl acetate 9: 1).

Yield: 18 g (73% of tr.).

1H NMR (300 MHz, CDCl3): 8 = 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm.

Reference Example 5A

5- (hydroxymethyl) -2-pyridinecarbonitrile

The compound of Example 4A (13 g, 110 mmol) is dissolved in 400 ml of tetrachloromethane and 29.4 g (165 are added.

5 mmol) of N-bromosuccinimide and 0.4 g (1.6 mmol) of dibenzoyl peroxide. The reaction mixture is refluxed for three hours, cooled to room temperature and filtered. The solution is washed with aqueous thiosulfate sodium, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is dissolved in 200 ml of dioxane and 200 ml of water, calcium carbonate (44 g, 440 mmol) is added and the mixture is stirred at reflux for 2 hours. After cooling to room temperature, the mixture is filtered and dichloromethane is added. After the

After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent cyclohexane / ethyl acetate 2: 1).

Yield: 5.2 g (35% of tr.).

1H NMR (300 MHz, DMSO-d6): 8 = 4.7 (d, 2H), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 (s, 1H) ppm .

Preparation Examples:

15 Example 1

Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

7.0 g (34.29 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 8.89 g (68.58 mmol) of 4-cyanobenzaldehyde, 8.92 g (68.58 mmol) are suspended of ethyl 3-oxobutanoate and 20 g of the polyphosphoric acid ethyl ester in 250 ml of THF. The

The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 13.4 g (91%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H), 2.0 (s, 3H), 4.0 (c, 2H), 5.4 (d, 1H); 7.6 (m, 3 H); 7.7 (m, 3H); 7.9 (m, 25 2H); 8.4 (d, 1 H) ppm.

Example 2

4- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile 265 mg (1.3 mmol ) of N- [3- (trifluoromethyl) phenyl] urea, 131 mg (1.0 mmol) of 4-cyanobenzaldehyde and 100 mg (1.0 mmol) of 2,4-pentanedione in 2 ml of THF and amounts are added catalytic concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the

The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 29 mg (7%).

1H NMR (200 MHz, DMSO-d6): 8 = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1 H); 7.5 (m, 1 H); 7.6 (m, 3 H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 2H); 8.5 (d, 1 H) ppm.

10 Example 3

Ethyl 4- (4-bromophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

204 mg (1.0 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 142 mg (0.77 mmol) of 4-bromobenzaldehyde and 100 mg (0.77 mmol) of ethyl-3-oxobutanoate are suspended in 2 ml of THF and acid catalyst amounts are added

15 concentrated hydrochloric. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 23 mg (6%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (c, 2H); 5.3 (d, 1 H); 7.4 (m, 2H); 7.6 (m, 3 H); 7.7 (m, 20 3H); 8.3 (d, 1 H) ppm.

Example 4

Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [4-fluorophenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 154 mg (1.0 mmol) are suspended N- [4-fluorophenyl] urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of ethyl-3-oxobutanoate in 2 ml of THF and catalyst amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the

The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 40 mg (14%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (c, 2H); 5.3 (d, 1 H); 7.3 (m, 4H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1 H) ppm.

10 Example 5

Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3-chlorophenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

170 mg (1.0 mmol) of N- [3-chlorophenyl] urea, 100 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of ethyl 3-oxobutanoate are suspended in 2 ml of THF and catalytic amounts of hydrochloric acid are added

15 concentrated. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 13 mg (4%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (c, 2H); 5.3 (d, 1 H); 7.2 (m, 1 H); 7.4 (m, 3 H); 7.5 (m, 20 2H); 7.9 (m, 2H); 8.3 (d, 1 H) ppm.

Example 6

4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (1S) -2-methoxy-1-methyl -2-oxoethyl

200 mg (0.98 mmol) of N- [3- (trifluoromethyl) phenylurea, 129 mg (0.98 mmol) of 4-cyanobenzaldehyde, 92 mg (0.49 mmol) of (1 S) -2-methoxy- are suspended 1-methyl-2-oxoethyl-3-oxobutanoate and 295 mg of the polyphosphoric acid ethyl ester in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the

The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent. A mixture of diastereomers is obtained.

Yield: 96 mg (40%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.3 (d, 3H); 1.4 (d, 3H); 2.0 (s, 3H + 3H); 3.6 (s, 3H); 3.6 (s, 3H); 5.0 (m, 1H + 1H); 5.4 (m, 1H + 1H); 7.6-7.9 (m, 8H + 8H); 8.4 (m, 1H + 1H) ppm.

10 Example 7

4- {6-methyl-5- (4-morpholinylcarbonyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile

150 mg (0.73 mmol) of N- [3- (trifluoromethyl) phenylurea, 96 mg (0.73 mmol) of 4-cyanobenzaldehyde, 63 mg (0.37 mmol) of 4- (4-morpholinyl) - are suspended - 4-oxo-2-butanone and 220 mg of the polyphosphoric acid ethyl ester in 3 ml of THF.

The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane / methanol as eluent.

Yield: 28 mg (16%).

1H NMR (300 MHz, DMSO-d6): 8 = 1.5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H); 5.3 (s at 1H); 7.6 (m, 2H); 7.7 (m, 1 H); 7.8 (m, 20 2H); 7.9 (m, 2H); 8.0 (s at 1H) ppm.

Example 8

4- (4-Cyanophenyl) -N, N-diethyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide 200 mg are suspended (0.98 mmol) of N- [3- (trifluoromethyl) phenylurea, 128 mg (0.98 mmol) of 4-cyanobenzaldehyde, 77 mg (0.49 mmol) of 4- (4-diethylamino) -4-oxo- 2-butanone and 295 mg of the polyphosphoric acid ethyl ester in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is

5 removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane / methanol as eluent.

Yield: 106 mg (47%).

1H NMR (300 MHz, DMSO-d6): 8 = 0.9 (m, 6H); 3.1 (m, 4H); 5.2 (s at 1H); 7.6 (m, 2H); 7.7 (m, 1 H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (sa, 1 H) ppm.

10 Example 9

6-amino-4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarbonitrile

400 mg (1.97 mmol) of N- [3- (trifluoromethyl) phenylurea, 199 mg (1.51 mmol) of 4-cyanobenzaldehyde and 100 mg (1.51 mmol) of malononitrile are suspended in 2 ml of THF and Catalytic amounts of hydrochloric acid are added

15 concentrated. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane / methanol as eluent.

Yield: 4 mg (1%).

1H NMR (400 MHz, DMSO-d6): 8 = 5.2 (d, 1H); 6.0 (s, 2H); 7.6 (m, 3 H); 7.7 (m, 2H); 7.8 (m, 1 H); 7.9 (m, 2H); 8.4 (d, 20 1H) ppm.

Example 10

Ethyl (4-cyanophenyl) -3-formyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 100 mg (0 , 23 mmol) of Example 1 in 1 ml of dimethylformamide and 35.7 (0.23 mmol) phosphorylchloride are added. The reaction mixture is stirred at 70 ° C for two hours. After cooling to room temperature, the product is isolated by preparative HPLC.

Yield: 43 mg (41%).

1H NMR (300 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.1 (s, 3H); 4.1 (c, 2H); 6.4 (s, 1 H); 7.6 (m, 2H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 4H); 9.2 (s, 1 H) ppm.

Example 11

4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

3 g (7 mmol) of Example 1 are dissolved in a mixture of 50 ml of water and 100 ml of 5% KOH in ethanol. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane / methanol as eluent.

Yield: 1.27 g (45%).

15 NMR-1H (300 MHz, DMSO-d6): 8 = 2.0 (s, 3H); 5.4 (d, 1 H); 7.6 (m, 1 H); 7.6 (m, 2H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 3 H); 8.3 (d, 1 H); 12.5 (s, 1 H) ppm.

Example 12

4- (4-Cyanophenyl) -6-methyl-2-oxo-N-propyl-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide 40 mg (0 , 1 mmol) of Example 11 in 2 ml of dimethylformamide, 7 mg (0.11 mmol) of npropylamine, 15 mg (0.11 mmol) of 1-hydroxy-1H-benzotriazolhydrate and 12 mg (0.1 mmol) are added ) of 4- dimethylaminopyridine.The reaction mixture is stirred at 0 ° C, then 21 mg (0.11 mmol) of 1- (3-dimethylaminopropyl) -3 is added

5 ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 18 hours, after which water and ethyl acetate are added. The organic phase is washed with saturated aqueous KHSO4, water and brine, dried over sodium sulfate and evaporated in vacuo to dryness. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

Yield: 29 mg (66%).

10 NMR-1H (300 MHz, DMSO-d6): 8 = 0.7 (t, 3H); 1.3 (sext, 2H); 1.7 (s, 3H); 3.0 (c, 2H); 5.4 (d, 1 H); 7.6 (m, 3 H); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1 H); 8.1 (d, 1 H) ppm.

Example 13

4- (4-cyanophenyl) -N- (2-methoxyethyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

48 mg (0.12 mmol) of Example 11 are dissolved in 2 ml of dimethylformamide, 10 mg (0.13 mmol) of 2-methoxyethylamine, 18 mg (0.13 mmol) of 1-hydroxy-1 H -benzotriazolhydrate are added and 15 mg (0.12 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred at 0 ° C, then 25 mg (0.13 mmol) of 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is washed with saturated aqueous KHSO4, water and

Brine, dried over sodium sulfate and evaporated in vacuo to dryness. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

Yield: 22 mg (40%).

1H NMR (300 MHz, DMSO-d6): 8 = 1.7 (s, 3H); 3.2 (s, 3H); 3.3 (m, 4H); 5.4 (d, 1 H); 7.6 (m, 3 H); 7.7 (m, 3H); 7.9 (m, 2H); 8.1 (m, 1 H) ppm.

25 Example 14

Ethyl 4- (4-cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 89 mg (0 , 21 mmol) of Example 1 to a suspension of 12.4 mg (0.31 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 26 mg (0.21 mmol) of dimethyl sulfate are added and the mixture is stirred at room temperature for another two

5 hours. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to dryness. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

Yield: 85 mg (93%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (c, 2H); 5.5 (s, 1 H); 7.6 (m, 3 H); 7.7 (m, 10 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.

Example 15

Ethyl 3-acetyl-4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

100 mg (0.23 mmol) of Example 1 are added to a 12 mg (0.28 mmol) suspension of 60% sodium hydride

15 (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 91 mg (1.16 mmol) of acetyl hydrochloride are added and the mixture is stirred at room temperature for another two hours. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to dryness. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

20 Yield: 93 mg (85%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H); 4.2 (m, 2H); 6.7 (s, 1 H); 7.4 (m, 1 H); 7.5 (m, 2H); 7.6 (m, 1 H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 2H) ppm.

Example 16

Diethyl 6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-1,5 (2H) -pyrimidinecarboxylate 100 mg (0, 23 mmol) of Example 1 to a suspension of 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then 126 mg (1.16 mmol) of ethyl chlorocarbonate are added and the mixture is stirred at room temperature for other

5 two hours. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to dryness. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

Yield: 92 mg (79%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.2 (t, 3H; t, 3H); 2.1 (s, 3H); 4.2 (m, 2H); 4.3 (c, 2H); 6.4 (s, 1 H); 7.4 (m, 1 H); 7.5 10 (m, 3 H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 2H) ppm.

Example 17

Ethyl 4- (4-cyanophenyl) -6-methyl-1- (3-methylphenyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

150 mg (1.0 mmol) of N- [3-methylphenyl] urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg are suspended

15 (0.77 mmol) of ethyl 3-oxobutanoate in 2 ml of THF and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 8 mg (3%).

20 NMR-1H (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.0 (c, 2H); 5.3 (d, 1 H); 7.0 (m, 2H); 7.2 (m, 1 H); 7.3 (m, 1 H); 7.6 (m, 2H); 7.9 (m, 2H); 8.2 (d, 1 H) ppm.

Example 18

Ethyl 4- (4-chlorophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 204 mg (1.0 mmol) of N- [3-trifluoromethyl) phenyl] urea, 108 mg (0.77 mmol) of 4-chlorobenzaldehyde and 100 mg (0.77 mmol) of ethyl 3-oxobutanoate in 2 ml of THF and amounts are added catalytic concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the

The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 29 mg (9%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (c, 2H); 5.3 (d, 1 H); 7.5 (m, 5H); 7.6 (m, 1 H); 7.7 (m, 2H); 8.3 (d, 1 H) ppm.

10 Example 19

Ethyl 6- (bromomethyl) -4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

3 g (7 mmol) of Example 1 are dissolved in 100 ml of chloroform. At 0 ° C, 558 mg (3.48 mmol) of bromine are added dropwise. The mixture is stirred at room temperature for two hours, then the solvent is removed in vacuo. The residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 3.2 g (90%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 4.0 (c, 2H, d, 1H); 4.6 (da, 1H); 5.4 (d, 1 H); 7.6 (m, 3 H); 7.7 (m, 2H); 7.8 (m, 1 H); 7.9 (m, 2H); 8.6 (d, 1 H) ppm.

Example 20

Ethyl 4- (4-cyanophenyl) -6 - [(diethylamino) methyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

20 mg (0.04 mmol) of Example 19 are dissolved in 2 ml of acetone and 8 mg (0.10 mmol) of diethylamine are added.The mixture is stirred at room temperature for 18 hours, then the solvent is removed in vacuo . The residue is purified by preparative HPLC.

Yield: 15 mg (75%).

1H NMR (300 MHz, DMSO-d6): 8 = 0.6 (t, 6H); 1.1 (t, 3H); 2.0 (m, 2H); 2.2 (m, 2H); 3.1 (da, 1H); 3.9 (da, 1H); 4.1 (c, 2H); 5.4 (d, 1 H); 7.5 (m, 1 H); 7.6 (m, 4H); 7.7 (m, 1 H); 7.9 (m, 2H) ppm.

Example 21

Ethyl 6- (anilinomethyl) -4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

50 mg (0.10 mmol) of Example 19 are dissolved in 2 ml of acetone and 18 mg (0.20 mmol) of aniline are added. The mixture is stirred at room temperature for 18 hours, then the solvent is removed in vacuo. The residue is purified by preparative HPLC.

Yield: 28 mg (55%).

15 NMR-1H (300 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 3.6 (d / d, 1H); 4.1 (c, 2H); 4.4 (d / d, 1H); 5.4 (m, 2H); 6.2 (m, 2H); 6.5 (m, 1 H); 6.9 (m, 2H); 7.6 (m, 6H); 7.9 (m, 2H); 8.4 (d, 1 H) ppm.

Example 22

(+) - Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate The enantiomers of Example 1 separated by preparative HPLC in a chiral phase: 100 mg of compound dissolved in 1.5 ml of ethyl acetate, KBD column 8361 (chiral silica gel selector, based on the N-methacryloyl-L-leucine-1- monomer Methylamide, see EP-A-379917), 250 mm x 20 mm, ethyl acetate as

5 eluent, flow of 25 ml / min, temperature of 23 ° C, injection volume 2,500 µl, detection at 254 nm.

1H NMR (300 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (c, 2H); 5.4 (d, 1 H); 7.6 (m, 3 H); 7.7 (m, 2H); 7.8 (m, 1 H); 7.9 (m, 2H); 8.4 (d, 1 H) ppm.

[C] 20 = + 3.3 ° (A = 589 nm, dichloromethane, c = 535.0 mg / 100 ml).

Example 23

(-) - Ethyl 4- (4-cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

100 mg (0.23 mmol) of Example 22 are added to a suspension of 14 mg (0.35 mmol) of 60% sodium hydride (mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for two hours. Then add 29 mg (0.23 mmol) of dimethyl sulfate and the mixture is stirred at room temperature for another two

15 hours. After water and ethyl acetate are added, the organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo to dryness. The product is purified by silica column chromatography with cyclohexane / ethyl acetate as eluent.

Yield: 76 mg (74%).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (c, 2H); 5.5 (s, 1 H); 7.6 (m, 3 H); 7.7 (m, 20 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.

[C] 20 = -18.1 ° (A = 589 nm, dichloromethane, c = 530.0 mg / 100 ml).

Example 24

Ethyl 4- (6-cyano-3-pyridinyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate To a stirred solution from Example 3A (76 mg, 0.58 mmol) in tetrahydrofuran (5 ml), ethyl 3-oxobutanoate (75 mg, 0.58 mmol), N- [3- (trifluoromethyl) phenyl] urea (118 mg, 0 , 58 mmol) and polyphosphoric acid ethyl ester (200 mg; freshly prepared according to the procedure of Cava et al., J. Org. Chem. 1969, 34, 2665). The mixture of

The reaction is refluxed for two days (48 hours), after which the solution is diluted with DMSO (2 ml) and purified by preparative HPLC. The product fractions are concentrated in vacuo and subjected to a new chromatography. on silica with cyclohexane and ethyl acetate as eluent.

Yield: 92 mg (35% of tr.).

MS (ESIpos): m / z = 431 (M + H) +.

10 HPLC (procedure 4) = 4.63 minutes.

1 H NMR (300 MHz, DMSO-d6): 8 = 8.76 (s, 1 H); 8.36 (d, 1 H); 8.16-8.00 (m, 2H); 7.83-7.74 (m, 2H); 7.75-7.58 (m, 2H); 5.47 (d, 1 H); 4.03 (quartet, 2H); 2.06 (s, 3 H); 1.08 (t, 3H) ppm.

Example 25

4- {5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinyl} benzonitrile

To a solution of 501 mg (1.25 mmol) of the compound of Example 11 in 5 ml of dry dimethylformamide are added 567 mg (3.5 mmol) of N, N-carbonylimidazole. After leaving the reaction mixture at rest for a whole night, the solvent is evaporated under vacuum. The residue is fixed in ethyl acetate and washed with water and brine. After drying with magnesium sulfate, the solvent is evaporated in vacuo.

20 Yield: 500 mg (88.6% of tr.).

MS (EI): m / z = 452 (M + H) +.

1H NMR (200 MHz, DMSO-d6): 8 = 1.40 (d, 3H); 5.5 (d, 1 H); 7.0 (s, 1 H); 7.55-8.0 (m, 9H); 8.4 (s, 1 H); 8.45 (d, 1 H) ppm.

Example 26

2- 2-Hydroxyethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of ethylene glycol. The reaction mixture is seated at approximately 100 ° C for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent

5 B: water + conc. Ammonia 0.1%; gradient: 0 minutes A 10%, 2 minutes A 10%, 6 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 minutes A 10%; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 22 mg (49.4% of tr.).

10 MS (EI): m / z = 446 (M + H) +.

1H NMR (300 MHz, DMSO-d6): 8 = 2.05 (d, 3H); 3.5 (quartet, 2H); 3.95-4.15 (m, 2H); 4.75 (tr, 1 H); 5.45 (d, 1 H); 7.55-7.75 (m, 5H); 7.75 (d, 1 H); 7.85 (d, 2H); 8.35 (d, 1 H) ppm.

Example 27

4- (Dimethylamino) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 2- (dimethylamino) ethanol. The reaction mixture is stirred at approximately 100 ° C for one hour. After cooling the reaction mixture, it is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes A at 10%, 2 minutes A at 10%, 6

20 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 minutes A 10%; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 24 mg (50.8% of tr.).

MS (EI): m / z = 473 (M + H) +.

NMR-1H (300 MHz, DMSO-d6): 8 = 2.05 (d, 3H), 2.1 (s, 6H), 2.4 (m, 2H), 4.1 (m, 2H) , 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (m, 2H), 7.8 (d, 1H), 7.85 ( d, 2H), 8.35 (d, 1H) ppm.

Example 28

4- (4-Pyridinyl) ethyl 4- (4-pyridinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 2- (4-pyridinyl) ethanol. The reaction mixture is stirred at approximately 100 ° C for one hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 µm; solvent A: acetonitrile,

5 solvent B: 0.1% concentrated ammonia water +; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield: 17 mg (33.5% of tr.).

MS (EI): m / z = 507 (M + H) +.

10 NMR-1H (300 MHz, DMSO-d6): 8 = 2.0 (d, 3H), 2.9 (tr, 2H), 4.3 (tr, 2H), 5.25 (d, 1H) , 7.15 (d, 2H), 7.45 (d, 2H), 7.5 (d, 1H), 7.65 (tr, 2H), 7.8 (m, 3H), 8.35 ( d, 1H), 8.4 (d, 2H) ppm.

Example 29

2- (2-Pyridinyl) ethyl-4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 2- (2-pyridinyl) ethanol. The reaction mixture is stirred at approximately 100 ° C for one hour. After cooling the reaction mixture, it is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes A 10%, 2 minutes A 10%, 6 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 minutes A 10%, wavelength: 220 nm;

20 injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 22 mg (43.4% of tr.).

MS (EI): m / z = 507 (M + H) +.

1H NMR (300 MHz, DMSO-d6): 8 = 2.0 (d, 3H), 3.0 (tr, 2H), 4.4 (tr, 2H), 5.25 (d, 1H), 7.15-7.25 (m, 2H), 7.4 (d, 2H), 7.5 (d, 1H), 7.6-7.75 (m, 3H), 7.8 (m , 3H), 8.3 (d, 1H), 8.45 (d, 1H) ppm.

Example 30

4- (2-Oxo-1-pyrrolidinyl) 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ethyl

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 1- (2-hydroxyethyl) -2-pyrrolidone. The reaction mixture is stirred at approximately 100 ° C for one hour. After cooling the reaction mixture is buried by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm x 50 mm, 5 µm; solvent A:

5 acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes A 10%, 2 minutes A 10%, 6 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 minutes A 10%; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 25 mg (48.8% of tr.).

10 MS (EI): m / z = 513 (M + H) +.

1H NMR (300 MHz, DMSO-d6): 8 = 1.8 (quintuple, 2H), 2.0 (d, 3H), 2.1 (tr, 2H), 3.2 (tr, 2H), 3.4 (tr, 2H), 4.0-4.2 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7 , 7 (tr, 2H), 7.8 (d, 1H); 7.9 (d, 2H); 8.4 (d, 1 H) ppm.

The following compounds are prepared analogously to the procedures for Examples 14-16:

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

31

Example 1: ethyl bromoacetate 85  4.01 (1) 516

32

Example 1; Decyclopropanecarbonyl Chloride 79  4.09 (1) 498

33

Example 1; bromoethane fifteen  4.28 (2) 458

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

3. 4

Example 1; 4morpholinecarbonyl chloride 97  3.97 (2) 543

35

Example 1; dimethylcarbamic chloride 98  4.00 (2) 523 [M + Na]

36

Example 1; methyl chlorocarbonate 96  4.10 (2) 488

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

37

Example 1; benzyl bromide 58  4.59 (2) 520

38

Example 1; propanoyl chloride 43  4.42 (2) 486

39

Example 1; 2- methoxyethyl chlorocarbonate 95  4.12 (2) 532

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

40

Example 1; Isopropyl Chloridocarbonate 67  4.55 (2) 500

41

Example 1; diethylcarbamic chloride 18  4.25 (2) 529

42

Example 1; methyl (methylsulfonyl) -chlorocarbamic 40  4.10 (2) 565

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

43

Example 1; 2-bromoacetamide; 2.5 equiv. Nah 54  3.7 (3) 487

44

Example 1; 2-bromoacetic acid; 2.5 equiv. Nah 67  3.8 (3) 488

Four. Five

Example 1; 2-Bromoethanamine hydrobromide; 2.5 equiv. Nah 28  2.9 (2) 473

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

46

Example 1; 2 (chloromethyl) pyridine hydrochloride; 2.5 equiv. Nah 37  4.0 (3) 521

47

Example 1; N (2-Bromoethyl) -N hydrobromide, N-diethylamine; 2.5equiv. Nah 82  2.98 (2) 529

48

Example 1; 2-Bromo-N-methylacetamide; 2.5equiv. Nah 65  3.70 (2) 501

(continuation)

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

49

Example 1; 3 (chloromethyl) pyridine hydrochloride; 2.5 equiv. Nah fifteen  3.68 (2) 521

fifty

Example 1; 4 (chloromethyl) pyridine hydrochloride; 2.5 equiv. Nah twenty-one  3.47 (2) 521

51

Example 1; 2 (bromomethyl) -1Himidazole hydrobromide; 2.5 equiv. Nah 6 2.97 (2) 510

(continued) The following compounds are prepared analogously to the procedures of Examples 6 to 8:

Example No.

Structure Departure Materials Performance[%] Tr [min] Mass [M + H] +

52

Example 1; 3 (chloromethyl) -1,2,4oxodiazole 37  4.0 (3) 469

53

Example 1; 2-Bromo-N- (2methoxyethyl) acetamide 91  3.77 (2) 545

Example No.

Structure Starting materials Performance[%] Tr [min] Mass [M + H] +

54

N- [3 (trifluoromethyl) phenyl] urea; 4-cyano-benzaldehyde; Methyl 3-oxobutanoate 79  3.68 (2) 416

55

N- [3 (trifluoromethyl) phenyl] urea; 4-cyano-benzaldehyde; Cyclopropyl methyl 3-oxobutanoate 58  4.09 (2) 456

(continuation)

Example No.

Structure Starting materials Performance[%] Tr [min] Mass [M + H] +

56

N- [3 (trifluoromethyl) phenyl] urea; 4-cyano-benzaldehyde; Isopropyl 3-Oxobutanoate 85  4.03 (2) 444

57

N- [3 (trifluoromethyl) phenyl] urea; 4-cyano-benzaldehyde; (1R) -2-Methoxy-1-methyl2-oxo-ethyl 3-oxobutanoate 73  3.82 (2) 488

(continuation)

Example No.

Structure Starting materials Performance[%] Tr [min] Mass [M + H] +

58

N- [3 (trifluoromethyl) phenyl] urea; 4-cyano-benzaldehyde; N, N-dimethyl-3oxobutanamide 9 3.22 (2) 429

Example 59

4- (4-cyanophenyl) -6-methyl-3- [2- (4-morphonylyl) -2-oxoethyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4 -ethylhydro-5-pyrimidinecarboxylate

5 80 mg (0.16 mmol) of Example 44 are dissolved in 2 ml of dimethylformamide, 16 mg (0.18 mmol) of morpholine, 24 mg (0.18 mmol) of 1-hydroxy-1 H hydrate are added benzotriazole and 20 mg (0.16 mmol) of 4- dimethylaminopyridine.The reaction mixture is stirred at 0 ° C, then 35 mg (0.18 mmol) of 1- (3dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride are added . The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated in vacuo

10 until dry. If necessary, the product is subsequently purified by column chromatography or preparative HPLC.

Yield: 78 mg (85%).

1H NMR (300 MHz, DMSO-d6): 8 = 1.1 (t, 3H), 2.0 (s, 3H), 3.4 (m, 4H), 3.6 (m, 4H), 3.7 (d, 1H), 4.1 (m, 2H), 4.5 (d, 1H), 5.5 (s, 1H), 7.6 (m, 5H), 7.8 (m , 1H), 7.9 (m, 2H) ppm.

The following compounds are prepared analogously to the procedure for Example 59:

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

60

Example 44; Nmethylpiperazine 90  2.93 (2) 570

61

Example 44; N (2-aminoethyl) -N, N-dimethylamine 87  2.93 (2) 558

62

Example 44; dimethylamine (2M in THF) 83  3.84 (2) 515

The following compounds are prepared analogously to the procedure for Examples 6-8:

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H] +

63

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1- (3methyl-1,2,4-oxodiazol5-yl) acetone 2. 3  3.80 (3) 440

64

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1- (1,3benzothiazol-2-yl) acetone 2. 3  4.42 (2) 491

65

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 5-methyl-2,4-hexanedione 33  4.3 (1) 428

66

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1methoxy-2,4pentanedione 3 3.47 (2) 430

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H] +

67

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1 (2.furil) -1,3butanedione 13  3.70 (2) 452

68

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1-phenyl 1,3-butanedione 14  4.03 (2) 462

69

N- [3 (trifluoromethyl) phenyl] urea; 4-cyanobenzaldehyde; 1,1,1-trifluoro-2,4-pentanedione 5 3.9 (3) 454

Example 70

4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

200 mg (0.5 mmol) of Example 11 are dissolved in 5 ml of tetrahydrofuran and 6 mg (0.05 mmol) of 4-N, N is added

5 dimethylaminopyridine, 77 mg (0.6 mmol) of N, N-diisopropylethylamine and 115 mg (0.6 mmol) of benzotriazol-1-yloxy-tris (pyrrolidine) phosphonium hexafluorophosphate. The reaction mixture is stirred at room temperature for 15 minutes, then 5 ml (2.5 mmol) of ammonia (as 0.5 M solution in dioxane) is added. The reaction mixture is stirred at room temperature for 1 hour, then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated in vacuo to dryness. The product is subsequently purified by

10 preparative HPLC.

Yield: 55 mg (28% of tr.).

1H NMR (200 MHz, DMSO-d6): 8 = 1.8 (s, 3H); 5.4 (d, 1 H); 7.2 (sa, 1 H); 7.4 (sa, 1 H); 7.6 (m, 5H); 7.7 (m, 1 H); 7.9 (m, 2H); 8.1 (d, 1 H) ppm.

Example 71

15 (+) - 4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

The enantiomers of Example 11 are separated by preparative HPLC in a chiral phase [KBD column 8361 (chiral selector on silica gel based on N-methacryloyl-L-leucine-1-methylamide monomer, cf. EP-A379917), 250 mm x 20 mm, eluent: ethyl acetate-methanol-ethyl acetate, flow 25 ml / minute, temperature 23

20 ° C, detection at 254 nm].

1H NMR (300 MHz, DMSO-d6): 8 = 2.0 (s, 3H); 5.4 (d, 1 H); 7.6 (m, 1 H); 7.6 (m, 2H); 7.7 (m, 1 H); 7.8 (m, 1 H); 7.9 (m, 3 H); 8.3 (d, 1 H); 12.5 (s, 1 H) ppm.

[C] 20 = + 2.5 ° (A = 589 nm, methanol, c = 505 mg / 100 ml).

Example 72

(+) - 2-Hydroxyethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate Argon atmosphere, 1,560 mg (3.89 mmol) of the compound of Example 71 are added to 19.6 ml of DMF. After

of adding 1,095 ml (7.86 mmol) of triethylamine and 1.11 ml (15.7 mmol) of 2-bromoethanol, the reaction mixture is

Stir at approximately 70 ° C for 8 hours. After cooling, the reaction mixture is concentrated in vacuo. He

The residue is fixed in ethyl acetate and washed with water. After drying with magnesium sulfate, the organic phase is

evaporates under vacuum The residue is fixed in 8 ml of methanol and purified by preparative HPLC (column: Nucleosil

100-5C 18 Nautilus, 20 x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.3% formic acid;

gradient: A 10% for 0 minutes, A 10% for 2 minutes, A 90% for 6 minutes, A 90%

for 7 minutes, 10% A for 7.1 minutes, 10% A for 8 minutes; wavelength: 220 nm; injection volume10: approximately 500 µl; number of injections: 18). The fractions that contain the product are

combine and lyophilize.

Yield: 1290 mg (74.5% of tr.).

MS (EI): m / z = 446 (M + H) +.

1H NMR (300 MHz, DMSO-d6): 8 = 2.05 (d, 3H); 3.5 (quartet, 2H); 3.95-4.15 (m, 2H); 4.75 (tr, 1 H); 5.45 (d, 1 H); 7.55-7.75 (m, 5H); 7.75 (d, 1 H); 7.85 (d, 2H); 8.35 (d, 1 H) ppm.

[C] 20 = + 14.3 ° (A = 589 nm, methanol, c = 455 mg / 100 ml).

Example 73

5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinyl} -2-pyridinecarbonitrile

To a stirred solution of Example 3A (75 mg, 0.57 mmol) in tetrahydrofuran (5 ml) is given 2,4-pentadione (57 mg, 0.57 mmol), N- [3- (trifluoromethyl) phenyl] urea (116 mg, 0.57 mmol) and polyphosphoric acid ethyl ester (200 mg) [freshly prepared according to the procedure of Cava et al., Org. Chem. 34, 2665 (1969)]. The reaction mixture is subjected to flow for 24 hours, after which the solution is diluted with DMSO (2 ml) and purified by HPLC.

Yield: 101 mg (44% of tr.).

NMR-1H (200 MHz, DMSO-d6): 8 = 2.02 (s, 3H), 2.24 (s, 3H), 5.54 (d, 1H), 7.52-7.90 ( m, 4H); 8.08 (d, 2H); 8.50 (d, 1 H); 8.81 (s, 1 H) ppm.

Example 74

(+) 5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinyl} -2-pyridinecarbonitrile The enantiomers of Example 73 is separated by chiral phase preparative HPLC [KBD column 8361 (chiral selector on silica gel, based on the N-methacryloyl-L-leucine-1-methylamide monomer, cf. EP-A379917), 250 mm x 20 mm, eluent: ethyl acetate-methanol-ethyl acetate, 25 ml / minute flow, 23 ° C of

5 temperature, 254 nm detection].

1H NMR (300 MHz, CDCl3): 8 = 2.06 (s, 3H); 2.35 (s, 3 H); 5.69 (d, 1 H); 6.02 (d, 1 H); 7.29-7.50 (m, 2H); 7.57-7.75 (m, 3H); 7.83 (dd, 1 H); 8.74 (d, 1 H) ppm. MS (ESIpos): m / z = 401 (m + H) +. [C] 20 = + 25.1 ° (A = 589 nm, methanol, c = 505 mg / 100 ml).

Example 75 4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) -phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate 2- (2-pyridinyl) methyl

To a solution of 40.1 mg (0.1 mmol) of the compound of Example 11 in 0.4 ml of dry dimethylformamide are added 48.6 mg (0.3 mmol) of N, N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with dichloromethane. After drying with magnesium sulfate, the solvent was evaporated in vacuo. To the residue 0.5 ml of (2-pyridinyl) methanol are added. The reaction mixture is stirred at approximately 100 ° C for 1 hour. After cooling, the reaction mixture is purified by preparative HPLC (Nucleosil 100-5C 18 Nautilus 20 mm x 50 mm column, 5 µm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 minutes A 10%, 2 minutes A 10%, 6 minutes A 90%, 7

20 minutes A at 90%, 7.1 minutes A at 10%, 8 minutes A at 10%; flow rate: 25 ml / min; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 17 mg (34.5% of tr.).

MS (EI): m / z = 493 (m + H) +.

NMR-1H (300 MHz, DMSO-d6): 8 = 2.1 (d, 3H); 5.15 (dd, 2H); 5.45 (d, 1 H); 7.05 (d, 1 H); 7.3 (dd, 1 H); 7.5-7.85 (m, 9H); 8.35 (d, 1 H); 8.5 (d, 2H) ppm.

Example 76

4- (3-Pyridinyl) ethyl 4- (3-pyridinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) -phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

To a solution of 60.2 mg (0.15 mmol) of the compound of Example 11 in 0.57 ml of dry dimethylformamide is

add 72.9 mg (0.45 mmol) of N, N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour,

The reaction mixture is diluted with water and extracted with ethyl acetate. After drying with sulfate

5 mg, the solvent is evaporated in vacuo. To the residue 185 mg (1.5 mmol) of 2- (3-pyridyl) ethanol and 20 µl are added

(0.27 mmol) of triethylamine. The reaction mixture is stirred at 100 ° C for 1 hour. Then the reaction mixture

diluted with 0.4 ml of methanol, filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18

Nautilus 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0

minutes A 10%, 2 minutes A 10%, 6 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 10 minutes A 10%; flow rate: 25 ml / min; wavelength: 220 nm; injection volume: approximately 500 µl;

number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 44 mg (57.9% of tr.).

LC-MS (EI, procedure 5): m / z = 507 (m + H) +, Tr = 3.19 minutes.

Example 77

4- (4-Cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) -phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

4.1 g (9.25 mmol) of Example 14 are dissolved in 100 ml of ethanol. To this solution is added 6.2 ml (27.6 mmol) of a solution of potassium hydroxide in water (25% by weight). The reaction mixture is allowed to stand at room temperature for 18 hours. Then an additional 12.4 ml (55.2 mmol) of a solution of

20 potassium hydroxide in water (25% by weight) and the reaction mixture is stirred for 2 hours. The reaction mixture is diluted with water and extracted three times with ethyl acetate. The aqueous phase is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. This last extract is dried over magnesium sulfate and evaporated in vacuo. Purification of the residue is carried out by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

25 Yield: 1.5 mg (39% of tr.).

MS (EI): m / z = 416 (M + H) +.

1H NMR (300 MHz, DMSO-d6): 8 = 2.0 (s, 3H); 2.8 (s, 3H); 5.5 (d, 1 H); 7.6-7.8 (m, 6H); 7.9 (d, 2H); 12.6 (s, 1 H) ppm.

The following examples are prepared analogously to the procedure for example 76:

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

78

Example 11; 3 pyridinyl methanol 56.9  3.45 (5) 493

79

Example 11; 2 hydroxyacetamide 1) 61.1  3.38 (5) 459

80

Example 11; 2-hydroxyethyl (methyl) formamide 80.9  3.5 (5) 487

81

Example 11; 2-hydroxyethylacetamide 56.2  3.44 (5) 487

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

82

Example 11; (1methyl-1H-imidazol5-yl) methanol1) 45.8  2.87 (5) 496

83

Example 11; 2 (1H-pyrazol-1il) ethanol 60.6  3.7 (5) 496

84

Example 11; 2 (1H-1,2,4-triazol1-yl) -ethanol1) 67.1  3.48 (5) 497

85

Example 11; 2-hydroxyethyl acetate 56.1  3.98 (5) 488

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

86

Example 11; 2 (dimethylamino) -2methyl-1-propanol 34.6  2.9 (5) 502

87

Example 11; 3 (dimethylamino) propanol 54.8  2.86 (5) 487

88

Example 11; 2- (1 pyrrolidinyl) -ethanol 56.2  2.86 (5) 500

89

Example 77; 2- (3pyridinyl) -ethanol 58.9  3.36 (5) 522

90

Example 77; (3pyridinyl) -methanol 61.9  3.64 (5) 507

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

91

Example 77; 2 hydroxyacetamide 1) 53.6  3.54 (5) 473

92

Example 77; 2-hydroxyethyl (methyl) formamide 54.6  3.68 (5) 501

93

Example 77; 2-hydroxyethylacetamide 66.6  3.59 (5) 501

94

Example 77; (1methyl-1H-imidazol5-yl) -methanol1) 34.0  3.02 (5) 510

95

Example 77; 2 (1H-pyrazol-1-yl) ethanol 61.5  3.91 (5) 510

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

96

Example 77; 2 (1H-1,2,4-triazol1-yl) -ethanol1) 71.8  3.64 (5) 511

97

Example 77; 2-hydroxyethyl acetate 53.2  4.12 (5) 502

98

Example 77; 2 (dimethylamino) -2methyl-1-propanol 25.9  3.02 (5) 516

99

Example 77; 3 (dimethylamino) propanol 54.6  2.98 (5) 502

100

Example 77; 2- (1 pyrrolidinyl) -ethanol 55.9  2.98 (5) 514

(continuation)

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H]

101

Example 77; (2pyridinyl) -methanol 67.1  3.91 (5) 507

1) In this case, the alcohol used is a solid and the reaction is carried out in the presence of 0.4 ml DMF.

Example 102

4- (4-Cyanophenyl) -1- (3,5-dichlorophenyl) -6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ethyl

5 Under argon, 30.8 mg (0.15 mmol) of N- (3,5-dichlorophenyl) urea are stirred together with 39.3 mg (0.3 mmol) of 4formylbenzonitrile, 39 mg (0.3 mmol) of ethyl 3-oxo-butanoate and 90 mg of trimethylsilyl polyphosphate in 0.5 ml of deioxane at 80 ° C for 4 hours. After adding a small amount of DMSO, the reaction mixture is filtered and purified by preparative HPLC (column: Agilent Zorbax Extend C 18 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + ac ammonia concentrated; gradient: 0 minutes 10% A, 2 minutes 10% A,

10 6 minutes A 90%, 7 minutes A 90%, 7.1 minutes A 10%, 8 minutes A 10%; flow rate: 25 ml / min; wavelength: 220 nm; injection volume: approximately 500 µl; number of injections: 1). Fractions containing the product are combined and concentrated in vacuo.

Yield: 38.1 mg (59% of tr.).

LC-MS (EI, procedure 7): m / z = 431 (M + H) +; Tr = 4.14 minutes.

15 Example 103

Ethyl 6-methyl-4- (3-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

30.6 mg (0.15 mmol) of N- [3- (trifluoromethyl) phenyl] urea are stirred together with 45.3 mg (0.3 mmol) of 3-nitrobenzaldehyde, 39 mg (0.3 mmol) of Ethyl 3-oxobutanoate and 90 mg of polyphosphoric acid ethyl ester [freshly prepared according to the procedure of Cava et al., J. Org. Chem. 34, 2665 (1969)] in 0.5 ml of dioxane and 0.1 ml of DMF at 805 ° C for 18 hours. After adding 200 µl of DMF, the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5C 18 Nautilus 20 mm x 50 mm, 5 µm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes A at 10%; flow rate: 25 ml / min; wavelength: 220 nm; injection volume: approximately 800 µl; number of injections: 1). The fractions that contain the

10 product are combined and concentrated in vacuo.

Yield: 34 mg (50.4% of tr.).

LC-MS (EI, procedure 6): m / z = 450 (M + H) +, Tr = 3.94 minutes.

The following compounds are prepared analogously to the procedure of Example 102:

Exemplon

Structure Starting materials Performance [%] Tr [min] (procedure) Mass [M + H] +

104

N- (3-nitrophenyl) urea; 4-chlorobenzaldehyde; Ethyl 3-oxobutanoate 70.5  3.65 (6) 417

105

N- (3-nitrophenyl) urea; 3 nitrobenzaldehyde; Ethyl 3-oxobutanoate 81.3  3.61 (6) 427

106

N- (3-nitrophenyl) urea; 4fluorobenzaldehyde; Ethyl 3-oxobutanoate 56.8  3.63 (6) 400

107

N- (3-nitrophenyl) urea; 4-bromobenzaldehyde; Ethyl 3oxobutanoate 69.5  4.02 (5) 461

Example 108

4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidine-5-carboxylic acid ester

5 9.87 g (48.3 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 12.68 g (96.68 mmol) of 4-cyanobenzaldehyde, 15 g (96.68 mmol) of are suspended 2-Cyanoethyl 3-oxobutanoate and 37.5 g of polyphosphoric acid ethyl ester in 250 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

10 Yield: 25 g (100% of tr.).

1H NMR (200 MHz, DMSO-d6): 8 = 2.1 (s, 3H); 2.8 (m, 2H); 4.2 (m, 2H); 5.4 (d, 1 H); 7.6 (m, 4H); 7.7 (m, 2H); 7.9 (m, 2H); 8.5 (d, 1 H) ppm.

Example 109

4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidin-5-carbonitrile

0.609 g (1.52 mmol) of Example 70 are dissolved in 60 ml of THF and 1.24 g (12.93 mmol) of (methoxycarbonylsulfamoyl) -triethylammonium-N-betaine are added. The reaction mixture is stirred at room temperature for 1 hour, the solvent is removed in vacuo and the residue is purified by silica column chromatography with dichloromethane / methanol mixtures as eluent.

20 Yield: 249 mg (43% of tr.).

1H NMR (300 MHz, DMSO-d6): 8 = 1.8 (s, 3H); 5.4 (d, 1 H); 7.7 (m, 4H); 7.8 (m, 2H); 8.0 (m, 2H); 8.4 (d, 1 H) ppm.

Example 110

Ethyl 6-methyl-4- (4-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidin-5-carboxylate Suspension 7.84 g (38 , 4 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 5.81 g (38.4 mmol) of 4-cyanobenzaldehyde, 5.0 g (38.4 mmol) of ethyl 3-oxobutanoate and 15 g of polyphosphoric acid ethyl ester in 100 ml of THF. The mixture is refluxed for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the

The residue is purified by column chromatography on silica with toluene / ethyl acetate as eluent.

Yield: 8.75 g (51% of tr.).

1H NMR (200 MHz, DMSO-d6): 8 = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (m, 2H); 5.4 (d, 1 H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (m, 2H); 8.5 (d, 1 H) ppm.

Example 111

10-5-acetyl-6-methyl-4- (4-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine

0.407 g (2.0 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 0.302 g (2.0 mmol) of 4-nitrobenzaldehyde, 0.2 g (2.0 mmol) of 2.4 are suspended -pentanedione and 0.4 g of polyphosphoric acid ethyl ester in 20 ml of THF. The mixture is stirred under flow for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue

15 is purified by column chromatography on silica with cyclohexane / ethyl acetate as eluent.

Yield: 0.302 g (36% of tr.).

1H NMR (200 MHz, DMSO-d6): 8 = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1 H); 7.5-7.8 (m, 6H); 8.3 (m, 2H); 8.5 (d, 1 H) ppm.

C. Operational examples related to pharmaceutical compositions

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

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of depoilivinyl pyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate. Tablet weight, 212 mg; diameter, 8 mm; radius of curvature, 12 mm. 25

Preparation

The mixture of the active component, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is molded using a usual tablet press (tablet format, see above). Molding force

5 that is usually applied is 15 kN.

Suspension for oral administration Composition

1,000 mg of the compound of Example 1, 1,000 mg of ethanol (96%), 400 mg of Rhodigel (FMC xanthan gum, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.

Preparation

Rhodigel is suspended in ethanol and the active component is added to the suspension. Water is added with congestion. Stirring continues for approximately 6 hours until Rhodigel swells completely.

Claims (14)

1. Compounds of the general formula (I) in which 5 A represents a phenyl or pyridyl ring, R1, R2 and R3 independently represent among them hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl and C1-C6 alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy, R4 represents trifluoromethylcarbonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkenoxycarbonyl, Hydroxycarbonyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, arylaminocarbonyl-C6-C10, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano alkyl, in which the alkylcarbonyl-C1-C6-C6-alkoxycarbonyl , the mono- and di-alkylaminocarbonyl-C1-C4 may also be substituted with one to three identical or different radicals selected from the group consisting of cycloalkyl-C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, alkylcarbonylamino C1-C4, (alkylcarbonyl-C1-C4) alkylamino-C1-C4, cyano, amino, mono- and di-alkylamino-C1-C4, heteroaryl, heterocyclyl and tri- (alkyl-C1-C6) -silyl and en which heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl can also be substituted with C1-C4 alkyl, R5 represents C1-C4 alkyl, which may be substituted with one to three identical or different radicals, selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkenoxy, C1-C6 alkylthio, amino , monkey-and say 20-C1-C6 alkylamino, arylamino, hydroxycarbonyl, C1-C6 alkoxycarbonyl and the radical -O-C1-C4-O-C1-C4 alkyl, or R5 represents amino, R6 represents hydrogen, C1-C6 alkyl, formyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, cycloalkylcarbonyl-C3-C8, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, N- (alkylsulfonyl-C1- C4) -aminocarbonyl, N25 (alkylsulfonyl-C1-C4) -N- (alkyl-C1-C4) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, in which C1-C6 alkyl, mono- and di- C1-C4 alkylaminocarbonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, heteroaryl and heterocyclyl may be substituted with one to three odifferent identical radicals selected from the group consisting of aryl, heteroaryl, hydroxy, alkoxy C1-C4, hydroxycarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino-C1-C4, C1-C4-alkylcarbonylamino, tri- (C1-C6-alkyl) -silyl, cyano, mono- and di-C1-C4-alkylamino-C1-C4 alkylaminocarbonyl-C1-C4-alkoxy-aminocarbonyl-C1 -C4 and halogen, or R6 represents a remainder of the formula Wherein R6A is selected from the group consisting of hydrogen and C1-C6 alkyl and n represents an integer 1 or 2, R7 represents halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl and C1-C6 alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy, 5 e Y1, Y2, Y3, Y4 and Y5 independently represent each other CH or N, the ring containing either 0, 1 or 2 nitrogen atoms and when it is indicated that Y1, Y2, Y3, Y4 or Y5 = CH, CH will represent also a ring carbon atom, which is substituted with a substituent R3 and R7, and its salts, hydrates and / or solvates and its tautomeric forms. Compounds of the general formula (I) according to claim 1, wherein A represents a phenyl or pyridyl ring, R1, R2 and R3 independently represent each other hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl and C1-C6 alkoxy they may be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy, R4 represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, arylaminocarbonyl-C6-C10, heteroarylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonyl cyano, in which the alkylcarbonyl-C1-C6, the alkoxycarbonyl-C1-C6, the mono- and di-alkylaminocarbonyl-C1-C4 can also be substituted with one to three radicals, identical odistintos selected from the group consisting of cycloalkyl- C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, Hydroxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, alkylcarbonylamino-C1-C4, amino, mono- and di-alkylamino-C1-C4, heteroaryl, heterocyclyl and tri- (C1-C6-alkyl) -silyl . R5 represents C1-C4 alkyl, which may be substituted with one to three identical or different radicals, selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkenoxy, C1-C6 alkylthio, amino, mono- and dialkylamino-C1-C6, arylamino, hydroxycarbonyl, alkoxycarbonyl-C1-C6 and the radical -O-C1-C4-alkyl-O-C1-C4 alkyl, 25th R5 represents amino, R6 represents hydrogen, C1-C6 alkyl, formyl, aminocarbonyl, mono- or di-alkylaminocarbonyl-C1-C4, cycloalkylcarbonyl-C3-C8, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, N- (alkylsulfonyl-C1- C4) -aminocarbonyl, N (alkylsulfonyl-C1-C4) -N- (alkyl-C1-C4) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C1-C6 alkyl, mono- or di-alkylaminocarbonyl-C1-C4, alkylcarbonyl-C1-C6, alkoxycarbonyl-C1-C6, heteroaryl and heterocyclyl may be substituted with one to three identical or distinct radicals selected from the group consisting of aryl, heteroaryl, hydroxy , C1-C4 alkoxy, hydroxycarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino-C1-C4, alkylcarbonylamino-C1-C4, tri- ( C1-C6-alkyl-silyl, cyano, N- (mono- and di-C1-C4-alkylamino-C1-aminocarbonyl C4, C1-C4 alkoxy-C1-C4 alkylaminocarbonyl and halogen, or R6 represents a remainder of the formula in which R6A is selected from the group consisting of hydrogen and C1-C6 alkyl and n represents an integer 1 or 2, R7 represents halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which alkyl -C1-C6 and C1-C6 alkoxy they may also be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy, 45 and Y1, Y2, Y3, Y4 and Y5 independently of each other represent CH or N, the ring containing either 0 or 1 or 2 nitrogen atoms. 3. Compounds of the general formula (I) according to claim 1 or 2, wherein A represents a phenyl ring, or pyridyl, R1, R2 and R3 independently represent each other, hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy, R4 represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, 5-C1-C4 monoalkylaminocarbonyl or cyano, in which the C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl and C1-C4 monoalkylaminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of cycloalkyl- C3-C8, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, amino, mono- or C1-C4 dialkylamino, heteroaryl and heterocyclyl, R5 represents methyl or ethyl, R6 represents hydrogen, C1-C6 alkyl, mono- or di-alkylaminocarbonyl-C1-C4, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl or heterocyclylcarbonyl, wherein C1-C6 alkyl and C1-alkoxycarbonyl -C6 may be substituted with one to three identical or different radicals selected from the group consisting of heteroaryl, hydroxy, C1-C4 alkoxy, hydroxycarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, mono- and C1-C4 dialkylaminocarbonyl, cyano , amino, mono- and di-alkylamino-C1-C4, 15 o R6 represents a remainder of the formula in which R6A is selected from the group consisting of hydrogen and C1-C4 alkyl and 20 n represents an integer 1 or 2, R7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, and Y1, Y2, Y3, Y4 and Y5 each represent CH. 4. Compounds of the general formula (I) according to claims 1, 2 or 3, wherein A represents a phenyl or pyridyl ring, R1 and R3 each represent hydrogen, R2 represents fluorine, chlorine, bromine nitro or cyano, R4 represents cyano, C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl, in which the alkoxycarbonyl- C1-C4 may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, mono- and Di-alkylamino-C1-C4, heteroaryl and heterocyclyl, R5 represents methyl, R6 represents hydrogen, C1-C4 alkyl, mono- or di-alkylaminocarbonyl-C1-C4, alkylcarbonyl-C1-C4 or alkoxycarbonyl-C1-C4, in which C1-C4 alkyl and alkoxycarbonyl- C1-C4 may be substituted with a radical selected from the group consisting of heteroaryl, hydroxy, C1-C4 alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and Di-alkylaminocarbonyl-C1-C4, amino, mono- and di-alkylamino-C1-C4, or R6 represents a moiety of the formula in which R6A is selected from the group consisting of hydrogen and methyl, R7 represents trifluoromethyl or nitro, and Y1, Y2, Y3, Y4 and Y5 each represent CH. 5. Compounds of the general formula (I) according to at least one of claims 1 to 5, wherein R1 is hydrogen. 6. Compounds of the general formula (I) according to at least one of claims 1 to 6, wherein R2 is cyano. 7. Compounds of the general formula (I) according to at least one of claims 1 to 7, wherein R3 is hydrogen.

8.

Compounds of the general formula (I) according to at least one of claims 1 to 8, wherein R4 is C1-C4 alkoxycarbonyl optionally substituted with hydroxy or wherein R4 is C1-C4 alkylcarbonyl.

9.

Compounds of the general formula (I) according to at least one of claims 1 to 9, wherein R5 is methyl.

Compounds of the general formula (I) according to at least one of claims 1 to 10, wherein R6 is hydrogen.

eleven.

Compounds of the general formula (I) according to at least one of claims 1 to 11, wherein R 7 is trifluoromethyl or nitro.

12.

Compounds of the general formula (AI)

Wherein Z represents CH or N and R1, R3, R4 and R6 have the meaning indicated in claims 1 to 12. 13. Method for synthesizing the compounds of the general formula (I) or (IA), respectively, as defined in claims 1 to 13, condensing compounds of the general formula (II) in which A, R1 and R2 have the meaning indicated in claims 1 to 12, with compounds of the general formula (III) in which R4 and R5 have the meaning indicated in claims 1 to 12, and compounds of the general formula (IV) wherein R3, R7 and Y1 to Y5 have the meaning indicated in claims 1 to 12, in the presence of an acid either in a three component reaction / one step or sequentially to give compounds of the general formula (IB). Wherein A, R1 to R5, R7 and Y1 to Y5 have the meaning indicated in claims 1 to 12, optionally followed by the reaction of the compounds of the general formula (IB) with compounds of the general formula (V) R6 * -X (V) wherein R6 * has the meaning of R6 as indicated in claims 1 to 12, but does not represent hydrogen and X represents a leaving group, such as halogen, tosylate, mesylate or sulfate, in the presence of one base. 14. The composition containing at least one compound of the general formula (I) or (IA) as defined in claims 1 to 12 and a pharmacologically acceptable diluent.

fifteen.

A composition for use according to claim 14 for the treatment of acute and chronic, ischemic and / or restructuring inflammatory processes.

16.

Compounds of the general formula (I) or (IA) as defined in claims 1 to 12 for use for the preparation of medicaments.

17.

Compounds for use according to claim 16 for the preparation of medicaments for the treatment of acute and chronic, ischemic and / or restructuring inflammatory processes.

18.

Compounds for use according to claim 17, wherein the process is chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or development of heart failure.