ES2352711T3 - HETEROCYCLIC DERIVATIVES - Google Patents

Abstract

Compounds of the general formulas (IA) and (IB) ** (See formula) ** R1, R2 and R3 independently of each other, represent hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, wherein C1-C6 alkyl and C1-C6 alkoxy may be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C1C4 alkoxy, R4 represents C1-C6 alkyl, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono or C1-C4 dialkyl aminocarbonyl, C6-C10 aminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, in which C1-C6 alkyl, C1-C6 alkyl , C1-C6 alkoxy carbonyl, mono and C1-C4 dialkyl aminocarbonyl may also be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono and dia C1-C4 alkyl aminocarbonyl, C1-C4 alkyl carbonylamino, amino, mono and C1-C4 dialkyl amino, heteroaryl, heterocyclyl, tri- (C1-C6 alkyl) -silyl and cyano, 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, C2-C6 alkenoxy, C1-C6 alkyl thio, amino, mono and C1-C6 dialkyl amino, arylamino, hydroxycarbonyl, C1 alkoxy -C6 carbonyl and the radical -O-C1-C4 alkyl-C1-C4 alkyl, R6A represents hydrogen, C1-C6 alkylcarbonyl, C3-C8 cycloalkyl carbonyl, C1-C6 alkoxy carbonyl, mono or C1-C4 dialkyl aminocarbonyl, in which C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, mono and C1-C4 dialkyl aminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, R6B represents C1-C6 alkyl, which may be substituted with one to three r same or different additives selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, C1-C4 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono and C1-C4 dialkyl aminocarbonyl, C1-C4 alkylcarbonyloxy , aminocarbonyloxy, cyano, aryl, heteroaryl and heterocyclyl, in which the heteroaryl and heterocyclyl can be further substituted with one to two identical or different radicals selected from the group consisting of C1-C4 alkyl, hydroxy and oxo, R7 represents 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-C4 alkoxy, and Y1, Y2, Y3 and Y4 independently of each other, represent CH or N, in which the ring contains 0, 1 or 2 nitrogen atoms.

Description

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

Fibrous elastin protein, which comprises a considerable percentage of all protein content in some tissues, such as arteries, some ligaments, lungs and heart, can be hydrolyzed or otherwise destroyed by a select group of enzymes classified as elastases. Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human neutrophil elastase (HNE), is a strongly basic glycosylated serine protease and is found in the azurophilic granules of human polymorphonuclear leukocytes (PMN). HNE is released from activated PMNs and has been causally implicated in the pathogenesis of acute and chronic inflammatory diseases. HNE is capable of degrading a wide variety of matrix proteins, including elastin and collagen, and in addition to these actions on connective tissue, HNE has a wide variety of inflammatory actions that include positive regulation of gene expression. IL-8, the formation of edemas, hyperplasia of the mucous glands and mucosal hypersecretion. It also acts as a mediator of tissue lesions by hydrolyzing collagen structures, for example in the heart after an acute myocardial infarction or during the development of heart failure, thus damaging endothelial cells, promoting extravasation of adherent neutrophils to the endothelium and influencing the adhesion process itself.

Lung diseases in which HNE is thought to play a role include pulmonary fibrosis, pneumonia, acute respiratory failure syndrome (SIRA), pulmonary emphysema, including smoking-induced emphysema, chronic obstructive pulmonary diseases ( COPD) and cystic fibrosis. In cardiovascular diseases, HNE is involved in the increased generation of ischemic tissue lesions followed by myocardial dysfunction after acute myocardial infarction and in the remodeling processes that take place during the development of heart failure. HNE has also been causally implicated in rheumatoid arthritis, atherosclerosis, brain trauma, cancer and in the

related conditions in which the participation of neutrophils is involved.

Therefore, HLE activity inhibitors can be potentially useful in the treatment of numerous inflammatory diseases, especially 5 chronic obstructive pulmonary diseases [R. A. Stockley, Neutrophils and protease / antiprotease imbalance, Am. J. Respir. Crit. Care 160, S49-S52 (1999)]. HLE activity inhibitors may also be potentially useful in the treatment of acute myocardial syndrome, unstable angina pectoris, acute myocardial infarction and coronary artery bypass grafts (IDAC) [C. P. 10 Tiefenbacher et al., Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, S563-S570 (1997); Dinerman et al., 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

15 metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34, S377-S383 (1997)] and atherosclerosis [Dollery et al., Neutrophil elastase in human atherosclerotic plaque, Circulation 107, 2829-2836 (2003)].

In J. Comb. Chem. 3, 624-630 (2001), J Fluorine Chem. 90, 17-21 (1998) and Khim.

20 Geterotsikl. Soedin 9, 1223-1227 (1986) [Chem. Abstr. 107, 39737 (1987)], the synthesis of certain derivatives of 6-methyl-1,4-diphenyl-3,4-dihydro-2 (1 H) -pyrimidinethione is described. These documents do not mention a specific pharmacological activity of these compounds.

The present invention relates to compounds of the general formulas (I-A) and (I-B)

image 1

in which

TO

represents an aryl or heteroaryl ring,

R1, R2 and R3

independently of each other, they represent 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 equal radicals or different selected from the group consisting of halogen, hydroxy and C1-C4 alkoxy,

R4

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

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, C2-C6 alkenoxy, C1-C6 alkyl thio, amino, mono and C1-alkyl -C6 amino, arylamino, hydroxycarbonyl, C1-C6 alkoxy carbonyl and the radical -O-C1-C4 alkyl-O-C1-C4 alkyl,

R6A

represents hydrogen, C1-C6 alkylcarbonyl, C3-C8 cycloalkyl carbonyl, C1-C6 alkoxycarbonyl, mono or C1-C4 dialkyl aminocarbonyl, wherein C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, mono and C1-C4 dialkyl aminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 amino dialkyl,

R6B

represents C1-C6 alkyl, which may be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, C1-C4 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl , mono and dialkyl C1-C4 aminocarbonyl, C1-C4 alkyl carbonyloxy, aminocarbonyloxy, cyano, aryl, heteroaryl and heterocyclyl, in which the heteroaryl and heterocyclyl can be further substituted with one to three equal or different radicals selected from the group consisting in C1-C4 alkyl, hydroxy and oxo,

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 which It consists of halogen, hydroxy and C1-C4 alkoxy,

and

Y1, Y2, Y3 and Y4 independently of each other, represent CH or N, in which the ring contains 0, 1 or 2 nitrogen atoms.

The compounds according to the present invention may also be present in their salt, hydrate and / or solvate forms.

Physiologically acceptable salts are preferably in the context of the present invention.

The physiologically acceptable salts according to the invention are non-toxic salts which, in general, can be accessed by reacting the compounds (I) with a base or an inorganic or organic acid conventionally used for this purpose. Non-limiting examples of pharmaceutically acceptable salts of compounds (I) include alkali metal salts, for example lithium, potassium and sodium salts, alkaline earth metal salts such as magnesium and calcium salts, ammonium salts. quaternary such as, for example, triethylammonium salts, acetates, benzene sulphonates, benzoates, dicarbonates, disulfates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dichlorohydrates, fumarates, gluconates, glutamates, hexyl resorcinates, hydrochlorides, hydrochlorides, hydroxynates , iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylnitrates, methylsulphates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, polygalacturonates, salicylates, stearates, sulphates, succinates, tartrates, tosylates , valerates and other salts used for medicinal purposes.

The 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 compounds with solvents.

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

In the context of the present invention, the substituents, if not indicated otherwise, generally have the following meaning:

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

Alkoxy illustrates illustratively and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkenoxy illustrates illustratively and preferably allyloxy, but-2-en-1-oxy, pent-3-en-1-oxy and hex-2-en-1-oxy.

Alkylthio illustrates illustratively and preferably methylthio, ethylthio, n-propylthio, isoptropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkylcarbonyl generally represents a straight or branched chain hydrocarbon radical having from 1 to 6, preferably from 1 to 4 carbon atoms, which is linked by means of a carbonyl group. Non-limiting examples include acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, n-hexanoyl.

Alkylcarbonylamino represents, in general, a straight or branched chain hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms having a carbonylamino (-CO-NH) function in the binding position and which is attached to the carbonyl group. Non-limiting examples include acetylamino, n-propionylamino, nbutyrylamino, isobutyrylamino, pivaloylamino, n-hexanoylamino.

Alkylcarbonyloxy represents, in general, a straight or branched chain hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms having a carbonyloxy (-CO-O) function at the junction position and which is attached to the carbonyl group. Non-limiting examples include acetyloxy, n-propionyloxy, n-butyryloxy, isobutyryloxy, pivaloyloxy, n-hexanoyloxy.

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

Cycloalkylcarbonyl represents a cycloalkyl radical having from 3 to 8, preferably from 3 to 6 carbon atoms that is attached by means of a carbonyl group, which illustrates illustratively and preferably cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, tert-butoxycarbonyl, npentoxycarbonyl and n-hexoxycarbonyl.

Alkylamino represents an alkylamino radical having one or two alkyl substituents (independently selected), illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, npentylamino, n-hexylamino, N, N-dimethylamino , N, N-diethylamino, N-ethyl-N-methylamino, Nmethyl-Nn-propylamino, 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 alkyl substituents (independently selected), illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, npropylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, npentylaminocarbonyl, n-hexylaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-aminolaminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-amino-aminocarbonyl, N-aminolaminocarbonyl, 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.

Aryl represents a monocyclic to tricyclic aromatic carbocyclic radical, generally having from 6 to 14 carbon atoms, which illustrates illustratively and preferably phenyl, naphthyl and phenanthrenyl. The same applies to radicals such as arylamino.

Heteroaryl per se 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, which illustrates illustratively and preferably thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl.

Heteroarylcarbonyl illustratively and preferably represents thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl,

pyridylcarbonyl,

pyrimidylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl,

indazolylcarbonyl,

benzofuranylcarbonyl, benzothienylcarbonyl, quinolinylcarbonyl,

isoquinolinylcarbonyl.

Heterocyclyl per se and in heterocyclylcarbonyl represents a non-heterocyclic radical mono or polycyclic aromatic, preferably mono or bicyclic, which generally has from 4 to 10 and, preferably, from 5 to 8 atoms in the ring 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 may be saturated or partially unsaturated. Preference is given to 5 to 8 membered monocyclic saturated heterocyclic radicals having up to two heteroatoms selected from the group consisting of O, N and S, such as, illustratively and preferably tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, perhydroazepinyl.

Heterocyclylcarbonyl

It represents from way illustrative Y from preference

tetrahydrofurancarbonyl,

pyrrolidinecarbonyl, piperidinecarbonyl, morpholincarbonyl,

thiomorpholincarbonyl, piperazinecarbonyl, perhydroazepincarbonyl.

Halogen represents fluorine, chlorine, bromine and iodine.

When it is indicated that Y1, Y2, Y3 and Y4 represent CH or N, CH will also represent a carbon atom of the ring, which is substituted with an R3 substituent.

In another embodiment, the present invention relates to compounds of the general formulas (I-A) and (I-B), in which

A represents an aryl or heteroaryl ring,

R1, R2 and R3 independently of each other, represent 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,

R 4 represents C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono or C 1 -C 4 alkylaminocarbonyl, C 6 -C 10 aryl aminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, in which C 1 -C 6 alkyl , C1-C6 alkoxy carbonyl, mono and C1-C4 dialkyl aminocarbonyl may be further substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono and C1-C4 dialkyl aminocarbonyl, C1-C4 alkyl carbonylamino, amino, mono and C1-C4 dialkyl amino, heteroaryl, heterocyclyl, 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, C2-C6 alkenoxy, C1-C6 alkylthio, amino, mono and C1-alkyl -C6 amino, arylamino, hydroxycarbonyl, C1-C6 alkoxy carbonyl and the radical -O-C1-C4 alkyl-O-C1-C4 alkyl,

R6A

represents hydrogen, C1-C6 alkylcarbonyl, C3-C8 cycloalkyl carbonyl, C1-C6 alkoxycarbonyl, mono or C1-C4 dialkyl aminocarbonyl, wherein C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, mono and C1-C4 dialkyl aminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 amino dialkyl,

R6B

represents C1-C6 alkyl, which may be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, aryl, heteroaryl and heterocyclyl,

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 which It consists of halogen, hydroxy and C1-C4 alkoxy,

and

Y1, Y2, Y3 and Y4 independently of each other, represent CH or N, in which the ring contains 0, 1 or 2 nitrogen atoms.

In another embodiment, the present invention relates to compounds of the general formulas (I-A) and (I-B), in which

A represents a phenyl or pyridyl ring,

R1, R2 and R3 independently of each other, represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,

R 4 represents C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono or C 1 -C 4 alkylcarbonyl or cyano, wherein C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy carbonyl and C 1 -C 4 alkylaminocarbonyl which can be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, amino, mono and C1-C4 dialkyl amino, heteroaryl and heterocyclyl,

R5 represents methyl or ethyl,

R6A

represents hydrogen, C1-C6 alkylcarbonyl or C3-C6 cycloalkyl carbonyl, wherein C1-C6 alkylcarbonyl may be substituted with a radical selected from the group consisting of C3-C6 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and dialkyl C1-C4 amino,

R6B

represents C1-C6 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, phenyl, heteroaryl and heterocyclyl,

R7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl,

and

Y1, Y2, Y3 and Y4 each represent CH.

In another embodiment, the present invention relates to compounds of the general formulas (I-A) and (I-B), 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 C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl, wherein C1-C4 alkoxycarbonyl may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, amino, mono and dialkyl C1-C4 amino, heteroaryl and heterocyclyl,

10 R5 represents methyl,

R6A

represents hydrogen, C1-C6 alkyl carbonyl or C3-C6 cycloalkyl carbonyl,

R6B

represents C1-C4 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, C1-C4 dialkyl amino, phenyl, pyridyl; imidazolyl, pyrrolidino and morpholino,

R7 represents trifluoromethyl or nitro,

20 e

Y1, Y2, Y3 and Y4 each represent CH.

In another embodiment, the present invention relates to compounds according to the general formulas (I-A) and (I-B), in which A is phenyl or pyridyl.

In another embodiment, the present invention relates to compounds according to the general formulas (I-A) and (I-B), in which R1 is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formulas (I-A) and (I-B), in which R2 is cyano, especially in which A is phenyl

or pyridyl and R2 is cyano located in position for relative to the central ring of dihydropyrimidinthiona.

In another embodiment, the present invention relates to compounds according to

general formulas (I-A) and (I-B), in which R3 is hydrogen.

In another embodiment, the present invention relates to compounds according to the general formulas (IA) and (IB), in which R4 is C1-C4 alkoxycarbonyl, which may be substituted with dimethylamino, diethylamino, N-ethylmethylamino, pyrrolidino or piperidino or in which R4 is C1-C4 alkylcarbonyl and especially methylcarbonyl.

In another embodiment, the present invention relates to compounds according to the general formulas (I-A) and (I-B), in which R5 is methyl.

In another embodiment, the present invention relates to compounds according to the general formula (I-A), wherein R6A is hydrogen.

In another embodiment, the present invention relates to compounds according to R6B

general formula (I-B), in which it is methyl, (1 H -imidazol-2-yl) methyl, 2 (dimethylamino) ethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2- (1-pyrrolidinyl) ethyl.

In another embodiment, the present invention relates to compounds according to the general formulas (I-A) and (I-B), in which R 7 is trifluoromethyl or nitro.

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

in which

image2

Z represents CH or N, and R1, R3 and R4 have the meaning indicated above.

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

5

10

wherein 15 Z represents CH or N, R1, R3 and R4 have the meaning indicated above, and R6B

image2

represents C1-C4 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 dialkyl amino, phenyl, pyridyl, imidazolyl, pyrrolidino and morpholino.

The compounds of the present invention, wherein R6A in the general formula (I-A) is

image3

The compounds of the general formulas (I-A), (I-B), (I-C) and (I-E), respectively, can be synthesized by condensation of the compounds of the general formula (II)

image2

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

image2

in which R4 and R5 have the meaning indicated above,

image4

wherein R3, R7 and Y1 to Y4 have the meaning indicated above, in the presence of an acid in a three-component / one-stage reaction or consecutively for

25

30

35

image5

in which

A, R1 to R5, R7 and Y1 to Y4 have the meaning indicated above, optionally followed by the reaction of the compounds of general formula (I-D) in the presence of a base

[A] with compounds of the general formula (V)

R6A * -XA

(V),

in which R6A * has the meaning of R6A as indicated above, but not represents hydrogen, and XA represents a leaving group, such as halogen, to give compounds of the general formula (I-A) or (I-C), respectively, or

[B] with compounds of the general formula (VI)

R6B-XB (VI),

in which R6B has the meaning indicated above and XB represents a group outgoing, such as halogen, tosylate, mesylate or sulfate, to give compounds of the general formula (I-B) or (I-E), respectively.

Suitable solvents for the process (II) + (III) + (IV) → (I-D) are usually common organic solvents that do not change in the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or alcohols such as methanol, ethanol, n-propanol, isopropanol, nbutanol or t -butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogen-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.

Acids suitable for procedure (II) + (III) + (IV) → (I-D) are generally

inorganic or organic acids. These preferably include carboxylic acids, such as, for example, acetic acid or trifluoroacetic 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 ethyl ester of the polyphosphoric acid or to the trimethylsilyl ester of the polyphosphoric acid. The acid is used in an amount of 0.25 mol to 100 mol, in relation to 1 mol of the compounds of the general formula (III).

The process is generally carried out in a temperature range of +20 ° C to +150 ° C, preferably from +60 ° C to +100 ° C.

The procedure is generally 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 0.5 to 5 bar).

Suitable solvents for the process (I-D) + (V) → (I-A) / (I-C) are usually common organic solvents that do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide or halogen 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.

Suitable bases for the procedure (I-D) + (V) → (I-A) / (I-C) are generally inorganic or organic bases. These preferably include cyclic amines, such as, for example, piperidine, pyridine or 4-N, N-dimethylaminopyridine, or trialkyl (C1-C4) amines such as, for example, triethylamine or diisopropylethylamine. Preference is given to piperidine. The base is used in an amount from 0.1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (I-D).

The process is generally carried out in a temperature range of -20 ° C to +120 ° C, preferably from +0 ° C to +80 ° C, especially at room temperature.

The procedure is usually 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 0.5 to 5 bar).

Suitable solvents for the process (I-D) + (VI) → (I-B) / (I-E) are usually common organic solvents that do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or halogen hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. Acetone is preferred for the process.

Suitable bases for the procedure (I-D) + (VI) → (I-B) / (I-E) are generally inorganic or organic bases. These preferably include alkali metal hydroxides, such as lithium, sodium or potassium hydroxide, alkali or alkaline earth metal carbonates, such as sodium, potassium, calcium or cesium carbonate, alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine or 4-N, N-dimethylaminopyridine, or trialkyl (C1- C4) amines such as, for example, triethylamine or diisopropylethylamine, or hydrides such as sodium hydride. Preference is given to potassium carbonate. The base is used in an amount from 0.1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (I-D).

To improve the reactivity of the compounds of the general formula (VI) in cases where XB is chloride or bromide, the process (ID) + (VI) → (IB) / (IE) is preferably carried out in the presence of amounts catalysts of iodide sources, such as potassium iodide or tretrabutylammonium iodide

The process is generally carried out in a temperature range of 0 ° C to +150 ° C, preferably from +0 ° C to +80 ° C and especially at room temperature.

The procedure is usually 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 0.5 to 5 bar).

The compounds of the general formulas (II), (III), (IV), (V) and (VI) are known per se,

or they can be prepared by usual procedures.

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

image2

The compounds according to the invention have an unpredictable useful pharmacological and pharmacokinetic activity spectrum. Therefore, they are suitable for use as medications for the treatment and / or prophylaxis of disorders in humans and animals.

Surprisingly, the compounds of the present invention show activity

inhibitor of human neutrophil elastase (HNE) and, therefore, are suitable for the preparation of medicaments for the treatment of diseases associated with the activity of HNE. In this way, they can provide effective treatment for acute and chronic inflammatory processes, such as rheumatoid arthritis, atherosclerosis and, especially, acute and chronic lung diseases, such as pulmonary fibrosis, cystic fibrosis, pneumonia, acute respiratory failure syndrome (SIRA ), particularly pulmonary emphysema, including smoking-induced emphysema, and chronic obstructive pulmonary diseases (COPD), chronic bronchitis and bronchiectasis. The compounds of the present invention can also provide an effective treatment for ischemic cardiovascular diseases such as acute coronary syndrome, acute myocardial infarction, stable and unstable angina pectoris, coronary artery bypass grafts (IDAC) and development. of heart failure, for example atherosclerosis, mitral valve disease, atrial septum defects, transluminal percutaneous coronary angioplasty (ACPT), inflammation after open heart surgery and for pulmonary hypertension. They may also be useful for effective treatment of rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, Chury-Strauss syndrome, acute and chronic atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous pemphigus, sepsis , alcoholic hepatitis, liver fibrosis, Behcet's disease, allergic fungal sinusitis, allergic sinusitis, Crohn's disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal diseases, chronic suppurative otitis media, chronic leg vein ulcers, inflammatory disease of the intestine, bacterial and viral infections, brain trauma, stroke and other conditions in which the participation of neutrophils is involved.

The present invention further provides medicaments containing at least one compound according to the invention, preferably together with one or more pharmacologically safe vehicles or excipients, and also their use for the purposes mentioned above.

The active component can act systemically and / or locally. For this purpose, it can be applied in a suitable manner, for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic 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 release the active component rapidly and / or in modified form, such as, for example, tablets (coated and uncoated tablets, for example with an enteric coating), capsules, tablets. coated with sugar, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral application can be carried out by avoiding an absorption stage (intravenously, intraarterially, intracardiacly, intraspinally or intralumbarly) or including an absorption stage (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Useful parenteral application forms include injection and infusion preparations 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 powder inhalers, nebulizers), nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or orally, suppositories, preparations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, stirring mixtures), lipophilic suspensions, ointments, creams, milks, pastes, fine powders or implants.

The active components can become the application forms cited in a manner known per se. This is accomplished using non-toxic, pharmaceutically suitable inert excipients. These include, but are not limited to, vehicles (for example, microcrystalline cellulose), solvents (for example, liquid polyethylene glycols), emulsifiers (for example, sodium dodecyl sulfate), dispersing agents (for example, polyvinylpyrrolidone), synthetic biopolymers and natural (for example, albumin), stabilizers (for example, antioxidants such as ascorbic acid), colorants (for example, inorganic pigments such as iron oxides) or taste and / or odor correctors.

For use in humans, in the case of oral administration, it is advisable to administer doses from 0.001 to 50 mg / kg, preferably from 0.01 mg / kg to 20 mg / kg. In the case of parenteral administration, such as, for example, intravenously or through the mucous membranes by nasal, oral or inhalation route, it is advisable to use doses from 0.001 mg / kg to 0.5 mg / kg.

Despite this, it may be necessary in certain circumstances to move away from the mentioned amounts, in particular depending on the body weight, the route of application, the individual behavior towards the active component, the way of preparation and the time or interval in The application takes place. For example, it may be sufficient in some cases to use less than the minimum amount mentioned above, while in other cases the upper limit mentioned must be exceeded. In the case of the application of larger amounts, it may be advisable to divide them into a plurality of individual doses distributed throughout the day.

The percentages in the following tests and examples are, unless otherwise indicated, by weight; The parts are by weight. Each of the proportions of solvents, dilution ratios and concentrations presented for the liquid / liquid solutions are based on volume.

A. Evaluation of physiological activity

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

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

Content of the essay

Assay buffer: 0.1 M HEPES-NaOH buffer pH 7.4, 0.5 M NaCl, serum albumin 0.1% bovine (w / v); adequate concentration (see below) of HNE (18 U / mg lyophil., No. 20927.01, SERVA Electrophoresis GmbH, Heidelberg, Germany) in assay buffer; adequate concentration (see below) of substrate in assay buffer; adequate concentration of test compounds diluted with assay buffer

a 10 mM stock solution in DMSO.

Example A In vitro inhibition of HNE using a fluorogenic peptide substrate (continuous reading signal, 384 MTP assay format)

In this protocol, the MeOSuc-Ala-Ala-Pro-Val-AMC elastase substrate (No. 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) was used. The test solution was prepared by mixing 10 µl of dilution of the test compound, 10 20 µl of HNE enzyme dilution (final concentration 8 -0.4 µU / ml, routinely 2.1 µU / ml) and 20 µl of dilution of substrate (final concentration 1 mM -1 µM, routinely 20 µM), respectively. The solution was incubated for 0 to 2 hours at 37 ° C (routinely one hour). The fluorescence of the AMC released due to the enzymatic reaction was measured at 37 ° C (fluorine spectrum plus TECAN plate reader). The rate of

The increase in fluorescence (ex. 395 nm, em. 460 nm) is proportional to elastase activity. IC50 values were determined by representations of RFU versus [I]. The values of Km and Km (ap.) Were determined by means of Lineweaver-Burk representations and converted into Ki values by means of Dixon representations.

20 The examples of preparations had IC50 values within the range of 5 nM to 5 µM in this assay. Table 1 shows representative data: Table 1

Example No.

IC50 [nM]

one

13

3

9

4

2. 3

6

70

7

10

9

40

12

100

14

10

fifteen

5

19

30

29

10

31

80

(continuation)

Example No.

IC50 [nM]

33

twenty

58

12

Example B

In vitro inhibition of HNE using a fluorogenic substrate, insoluble in elastin 5 (discontinuous reading signal, 96 MTP test format):

In this protocol the elastin-fluorescein elastase substrate (No. 100620, ICN Biomedicals GmbH, Eschwege, Germany) was used. The test solution was prepared by mixing 3 µl of test compound dilution, 77 µl of HNE 10 enzyme dilution (final concentration 0.22 U / ml-2.2 mU / ml, routinely 21.7 µU / ml) and 80 µl of substrate suspension (final concentration 2 mg / ml). The suspension was incubated for 0 to 16 hours at 37 ° C (routinely four hours) under conditions of light agitation. To stop the enzymatic reaction, 160 µl of 0.1 M acetic acid was added to the test solution (final concentration 50 mM). The polymeric elastin-fluorescein was separated by

15 centrifugation (Eppendorf 5804 centrifuge, 3,000 rpm, 10 minutes). The supernatant was transferred to a new MTP and the fluorescence of the peptide fluorescein released due to the enzymatic reaction (BMG Fluostar plate reader) was measured. The fluorescence rate (ex. 490 nm, em. 520 nm) is proportional to the activity of the elastase. IC50 values were determined by representations of RFU versus [I].

twenty

II. In vitro assays with human neutrophils

Example A

25 In vitro test of PMN elastolysis:

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

30 (1993)].

A 96-well plate was coated with tritiated elastin in suspension at a rate of 10 µg per well. Test and reference compound [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), WO 95/21855) and α1 protease inhibitor (α1PI)] were added to the wells at the appropriate concentrations. Human PMNs were separated from the peripheral venous blood of healthy donors and resuspended in the culture medium. Neutrophils were added to the coated wells at concentrations ranging from 1 x 106 to 1 x 105 cells per well. Swine pancreatic elastase (1.3 µM) was used as a positive control for the assay, and α1PI (1.2 µM) was used as a positive neutrophil elastase inhibitor. The cell control were PMN without compound at each appropriate cell density. Cells plus compounds were incubated in a humidified incubator at 37 ° C for 4 hours. The plates were centrifuged to allow only the supernatant to be collected. The supernatant was transferred in 75 µl volumes to the corresponding wells of a LumaplateTM 96-well plate (solid scintillation counting plates). The plates were dried until there was no visible liquid in the wells and read on a beta counter for 3 minutes per well.

Elastolysis of 3H-elastin results in an increase in supernatant counts. An inhibition of this elastolysis shows a decrease, from the cellular control, of tritium in the supernatant. α1PI gave 83.46 ± 3.97% (mean ± eem) 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 and were 45.50 ± 7.75 nM (mean ± eem) (n = 2 different donors at 3.6 x 105 cells per well).

Since ZD-0892 is a selective inhibitor of PMN elastase along with the α1PI inhibition data, these results indicate that most of the degradation of elastin by PMN is due to the release of neutrophil elastase, and not to another elastolytic enzyme such as matrix metalloproteses (MMP). The compounds of this invention were evaluated for their inhibitory activity in this HNE-dependent model of neutrophil elastolysis.

Example B

In vitro inhibition of membrane-bound elastase:

The measurement of elastase inhibition bound to neutrophil membranes was carried out using a human neutrophil assay. Neutrophils were stimulated with LPS at 37 ° C for 35 minutes and then centrifuged at 1600 rpm. Subsequently, the membrane-bound elastase was fixed to neutrophils with 3% paraformaldehyde and 0.25% glutaraldehyde for 3 minutes at 4 ° C. The neutrophils and the vehicle were then centrifuged and the compounds to be evaluated were added, followed by the addition of the MeOSuc-Ala-Ala-Pro-Val-AMC substrate (No. 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) at a concentration of 200 µM. After a 25 minute incubation at 37 ° C, the reaction was terminated with PMSF (phenylmethanesulfonyl fluoride) and the fluorescence was read at ex: 400 nm and em: 505 nm. IC50 values were determined by interpolation from representations of relative fluorescence versus inhibitor concentration.

III. In vivo models

Example A

In vivo model of acute lung injury in rats:

The instillation of human neutrophil elastase (HNE) in rat lung causes acute lung injury. The extent of this lesion can be evaluated by measuring lung hemorrhage.

The rats were anesthetized with Hypnorm / Hypnovel / water and instilled with HNE or saline solution administered by a micropulverizer to the lungs. The test compounds were administered by intravenous injection, by oral probe or by inhalation at the times established before the administration of the HNE. Sixty minutes after elastase administration, the animals were sacrificed by an anesthetic overdose (sodium pentobarbitone) and the lungs were washed with 2 ml of heparinized phosphate buffered saline (PBS). The volume of bronchoalveolar lavage (BAL) was recorded and the samples were kept on ice. Each BAL sample was centrifuged at 900 r.p.m. for 10 minutes at 4-10 ° C. The supernatant was discarded, the cell pellet was resuspended in PBS and the sample was centrifuged again. The supernatant was discarded again and the cell pellet was resuspended in 1 ml of 0.1% cetyltrimethylammonium bromide (CTAB) / PBS to lyse the cells. The samples were frozen until the blood content was tested. Before the bleeding test the samples were thawed and mixed. 100 µl of each sample was placed in a different well of a flat-bottom 96-well plate. All samples were tested in duplicate. 100 µl of CTAB / 0.1% PBS was included as blank. The absorbance of the well contents at 415 nm was measured using a spectrophotometer. A standard curve was constructed by measuring the OD at 415 nm of different blood concentrations in 0.1% CTAB / PBS. Blood content values were calculated by comparison with the standard curve (included in each plate) and normalized for the volume of recovered BAL fluid.

The compounds of this invention were evaluated intravenously, orally or by inhalation for their inhibitory activity in this model of HNE-induced hemorrhage in rats.

Example B

In vivo model of acute myocardial infarction in rats:

Elastase inhibitors were tested in a rat infarction model in rats. Male Wistar rats (weighing> 300 g) received 10 mg / kg of aspirin 30 minutes before surgery. They were anesthetized with isoflurane and ventilated (120-130 touches / min, 200-250 µl volume per touch; MiniVent Type 845, Hugo Sachs Elektronik, Germany) throughout the surgery. After a left thoracotomy in the fourth intercostal space, the pericardium was opened and the heart was slightly exteriorized. A thread was wrapped around the left coronary artery (LAD) without occluding the artery. The thread was passed under the skin to the neck of the animal. The chest was closed and the animal was allowed to recover for 4 days. On the fifth day, the rats were anesthetized with ether for 3 minutes, the thread was tied and the LAD was occluded under ECG control. Test compounds were administered before or after occlusion of the LAD per os, intraperitoneally or intravenously (bolus or permanent infusion). After 1 hour of occlusion, the thread was reopened to allow reperfusion. The hearts were removed and, 48 hours later, the infarction sizes were determined by staining the hearts reoccluded with Evans blue, followed by staining with TTC (triphenyltetrazolium chloride) of 2 mm heart sections. The normoxic areas (non-occluded tissue) were stained blue, the ischemic areas (occluded but surviving tissue) were stained red and the necrotic areas (dead occluded tissue) remained white. Each tissue section was scanned and infarction sizes were determined by computerized planimetry.

B. Examples Abbreviations:

DMF

N, N-dimethylformamide

DMSO

dimethylsulfoxide

IE

electron impact ionization (for MS)

IEV

Electrovaporization ionization (for MS)

h

hours)

HPLC

high performance liquid chromatography

CL-MS

liquid chromatography coupled with mass spectroscopy

EM

mass spectroscopy

NMR

nuclear magnetic resonance

from theorist

of the theoretical (for performance)

FI

reverse phase (for HPLC)

Tr

retention time (for HPLC)

THF

tetrahydrofuran

General Procedures:

All reactions were carried out under an argon atmosphere unless otherwise indicated. The solvents were used as purchased from commercial sources without further purification. "Silica gel" or "Silica" refers to silica gel 60 (0.040 mm -0.063 mm) from Merck KGaA company, Germany. The compounds purified on preparative HPLC were purified on an RP18 column with acetonitrile and water as eluent, using a gradient from 1: 9 to 9: 1.

CL-EM and HPLC procedures:

Procedure 1:

Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 µm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 minutes A at 90% → 4.0 minutes A at 10% → 6.0 minutes A at 10%; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.

Procedure 2:

MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2790; Column: Uptisphere HDO, 50 mm x 2.0 mm, 3.0 µm; Eluent A: water + 0.05% formic acid, Eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 minutes B at 5%

→ 2.0 minutes B at 40% → 4.5 minutes B at 90% → 5.5 minutes B at 90%; Temperature: 45 ° C; Flow: 0.75 ml / min; UV detection: 210 nm.

Procedure 3:

10 Instrument: Micromass Platform LCZ, HP1100; Column: Grom-Sil 120 ODS-4 HE, 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; Temperature:

15 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Procedure 4:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column:

20 Uptisphere HDO, 50 mm x 2.0 mm, 3 µm; Eluent A: 1 1 water + 1 ml of 50% formic acid, Eluent B: 1 1 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 10% A → 4.5 minutes 10% A; Temperature: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

25 Procedure 5:

MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, Eluent A: water + 0.05% formic acid; Gradient: 0.0

30 minutes B at 5% → 2.0 minutes B at 40% → 4.5 minutes B at 90% → 5.5 minutes B at 90%; Temperature: 45 ° C; Flow: 0.0 minutes 0.75 ml / min → 4.5 minutes 0.75 ml / min → 5.5 minutes 1.25 ml / min; UV detection: 210 nm.

Procedure 6:

MS instrument: Micromass ZQ; HPLC instrument: HP 1100 Series; UV DAD; Column: Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3.0 µm; Eluent A: water + 500 µl of

5 50% formic acid / 1, Eluent B: acetonitrile + 500 µl 50% formic acid / 1; Gradient: 0.0 minutes 0% B → 2.9 minutes 70% B → 3.1 minutes 90% B → 4.5 minutes 90% B; Temperature: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Procedure 7:

10 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 µm; Eluent A: 1 1 water + 1 ml of formic acid (50%), Eluent B: 1 1 acetonitrile + 1 ml of formic acid (50%); Gradient: 0.0 minutes 100% A → 0.2 minutes 100% A → 2.9 minutes 30% A → 3.1 minutes 10% A →

15 4.5 minutes at 10%; Temperature: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Procedure 8:

Instrument: Micromass quad injection in parallel TOF-MUX interface with HPLC

20 Waters 600; Column: Uptisphere HDO, 50 mm x 2.0 mm, 3.0 µm; Eluent A: 1 1 water + 1 ml of formic acid (50%), Eluent B: 1 1 acetonitrile + 1 ml of formic acid (50%); 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 → 4.6 100% A minutes → 6.5% A minutes; Temperature: room temperature; Flow: 0.8 ml / min; UV detection: 210 nm.

25

Preparation Examples:

Example 1

30 4- {5-Acetyl-6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile

image2

3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde were dissolved (238.2 mg, 1.82 mmol) and 2,4-pentanedione (181.9 mg, 1.82 mmol) in 5 ml of THF. Be ethyl polyphosphate (0.30 g) was added and the reaction mixture was stirred at room temperature reflux overnight. After cooling to room temperature, the reaction was quenched with 10 ml of water and extracted with 10 ml of ethyl acetate (2 x). Organic phases The combined were dried with sodium sulfate and the solvent was removed in vacuo. He product was purified by preparative HPLC (column RP18; eluent: water acetonitrile, gradient 10:90 to 90:10).

Yield: 53 mg (14% of theory) LC-MS (procedure 1): Tr = 4.48 min. MS (IEVpos): m / z = 416 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 10.32 (d, 1H); 7.93 (d, 2H); 7.43-7.84 (m, 6H); 5.48 (d, 1 H); 2.26 (s, 3 H); 1.99 (s, 3H) ppm.

Example 2

Methyl 4- (4-Cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

image2

3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde were dissolved (238.2 mg, 1.82 mmol) and methyl acetoacetate (211 mg, 1.82 mmol) in 5 ml of THF. Be ethyl polyphosphate (0.30 g) was added and the reaction mixture was stirred at room temperature reflux overnight. After cooling to room temperature, the reaction was quenched with 10 ml of water and extracted with 10 ml of ethyl acetate (2 x). Organic phases The combined were dried with sodium sulfate and the solvent was removed in vacuo. Be purified the product by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 315 mg (80% of theory) LC-MS (procedure 1): Tr = 4.70 min. MS (IEVpos): m / z = 432 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 10.24 (d, 1H); 7.92 (d, 2H); 7.54-7.83 (m, 6H); 5.40 (d, 1 H); 3.63 (s, 3 H); 2.06 (s, 3H) ppm.

Example 3

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

image2

3-Trifluoromethylphenyl thiourea (3.00 g, 13.6 mmol), 4-cyanobenzaldehyde (3.57 were dissolved g, 27.3 mmol) and ethyl acetoacetate (3.55 g, 27.3 mmol) in 50 ml of THF. Was added ethyl polyphosphate (4.50 g) and the reaction mixture was stirred at reflux temperature overnight. After cooling to room temperature, the reaction was quenched with 50 ml. of water and extracted with 100 ml of ethyl acetate (2 x). Organic phases The combined were dried with sodium sulfate and the solvent was removed in vacuo. Be purified the product by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 3.15 g (52% of theory) LC-MS (procedure 2): Tr = 4.10 min. MS (IEVpos): m / z = 446 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 10.18 (d, 1H); 7.92 (d, 2H); 7.45-7.82 (m, 6H); 5.40 (d, 1 H); 4.08 (q, 2H); 2.05 (s, 3H); 1.12 (t, 3H) ppm.

Example 4

4- (4-Cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetra-hydro-5pyrimidinecarboxamide

image2

3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde were dissolved (238.2 mg, 1.82 mmol) and 3-oxobutanamide (183 mg, 1.82 mmol) in 5 ml of THF. Be ethyl polyphosphate (0.30 g) was added and the reaction mixture was stirred at room temperature reflux overnight. After cooling to room temperature, the reaction was quenched with 10 ml of water and extracted with 10 ml of ethyl acetate (2 x). Organic phases The combined were dried with sodium sulfate and the solvent was removed in vacuo. Be purified the product by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 29 mg (8% of theory) LC-MS (procedure 1): Tr = 4.35 min. MS (IEVpos): m / z = 417 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 9.86 (d, 1H); 7.93 (d, 2H); 7.76 (d, 1 H); 7.67 (t, 1 H); 7.24-7.62 (m, 4H); 7.59 (d, 2H); 5.40 (d, 1 H); 1.74 (s, 3H) ppm.

Example 5

4- (4-Cyanophenyl) -N, 6-dimethyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5pyrimidinecarboxamide

image2

3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde were dissolved (238.2 mg, 1.82 mmol) and N-methyl-3-oxobutanamide (299 mg, 1.82 mmol) in 5 ml of THF. Ethyl polyphosphate (0.30 g) was added and the reaction mixture was stirred at room temperature. reflux overnight. After cooling to room temperature, the reaction was quenched with 10 ml of water and extracted with 10 ml of ethyl acetate (2 x). Organic phases The combined were dried with sodium sulfate and the solvent was removed in vacuo. Be purified the product by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 104 mg (27% of theory) LC-MS (procedure 1): Tr = 4.10 min. MS (IEVpos): m / z = 431 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 9.89 (d, 1H); 7.93 (d, 2H); 7.54 (d, 2H); 7.38-8.12 (m, 5H); 5.36 (d, 1 H); 2.59 (d, 3 H); 1.66 (s, 3 H) ppm.

Example 6

4- (4-Cyanophenyl) -N, N, 6-trimethyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5pyrimidinecarboxamide

image2

3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde were dissolved (238.2 mg, 1.82 mmol) and N, N-dimethyl-3-oxobutanamide (235 mg, 1.82 mmol) in 5 ml of THF. Ethyl polyphosphate (0.30 g) was added and the reaction mixture was stirred at reflux temperature overnight. After cooling to room temperature, it quenched the reaction with 10 ml of water and extracted with 10 ml of ethyl acetate (2 x). The combined organic phases were dried with sodium sulfate and the solvent was Vacuum removed. The product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 270 mg (67% of theory) LC-MS (procedure 1): Tr = 4.20 min. MS (IEVpos): m / z = 445 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 9.77 (d, 1H); 7.92 (d, 2H); 7.54 (d, 2H); 7.49-7.83 (m, 4H); 5.19 (s a, 1 H); 3.33 (s, 3 H); 2.78 (s, 3 H); 1.43 (s, 3H) ppm.

Example 7

Ethyl 4- (4-Cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 1000 mg, 2 , 24 mmol), iodomethane (350.5 mg, 2.47 mmol) and potassium carbonate (341 mg, 1.82 mmol) in 20 ml of acetone. Mix The reaction was stirred at room temperature overnight and the solvent was removed empty The product was purified by column chromatography (silica gel; eluent: cyclohexane-ethyl acetate, gradient 90:10 to 50:50).

Yield: 998 mg (97% of theory) LC-MS (procedure 3): Tr = 4.20 min. MS (IEVpos): m / z = 460 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 7.85 (d, 2H); 7.69-7.94 (m, 4H); 7.60 (d, 2H); 5.76 (s, 1 H); 4.04 (q, 2H); 2.14 (s, 3 H); 2.01 (s, 3H); 1.11 (t, 3H) ppm.

Example 8

4- (4-Cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) -phenyl] -1,4-dihydro-5-pyrimidinecarboxylate methyl 4- (4-cyanophenyl) -6 -methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro5-pyrimidinecarboxylate (Example 7; 100 mg, 0.22 mmol) and sodium methoxide (117.6 mg , 2.18 mmol) in 5 ml of methanol and stirred at reflux temperature for 3 hours. The reaction was quenched with 10 ml of water and the aqueous phase was extracted with 10 ml of methylene chloride (2 x). After drying with sodium sulfate, the solvent was removed in vacuo and the product was purified by column chromatography (silica gel; eluent: cyclohexane-ethyl acetate, gradient 90:10 to 50:50).

image2

Yield: 60 mg (62% of theory) LC-MS (procedure 2): Tr = 4.27 min. MS (IEVpos): m / z = 446 (M + H) +.

Example 9

Ethyl 4- (4-Cyanophenyl) -6-methyl-2- (ethylfulphanil) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0 , 22 mmol), iodoethane (38.5 mg, 0.25 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the product by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 62 mg (58% of theory) LC-MS (procedure 2): Tr = 4.67 min. MS (IEVpos): m / z = 474 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 7.85 (d, 2H); 7.68-7.94 (m, 4H); 7.60 (d, 2H); 5.75 (s, 1 H); 4.03 (q, 2H); 2.74 (m, 2 H); 2.01 (s, 3H); 1.11 (t, 3 H); 1.01 (t, 3H) ppm.

Example 10

4- (4-Cyanophenyl) -6-methyl-2- (propylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate Ethyl 4- (4-cyanophenyl) -6- ethyl methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 1-iodopropane (42.0 mg, 0.25 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

image2

Yield: 45 mg (41% of theory) LC-MS (procedure 3): Tr = 4.45 min. MS (IEVpos): m / z = 488 (M + H) +.

Example 11

Ethyl 4- (4-Cyanophenyl) -6-methyl-2- (butylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate Dissolved 4- (4-cyanophenyl) -6- ethyl methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 1-iodobutane (45.0 mg, 0.25 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

image2

Yield: 53 mg (47% of theory) LC-MS (procedure 3): Tr = 4.58 min. MS (IEVpos): m / z = 402 (M + H) +.

Example 12

Ethyl 4- (4-Cyanophenyl) -6-methyl-2 - [(4-pyridinylmethyl) sulfanyl] -1- [3- (trifluoro-methyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0 , 22 mmol), 4- (bromomethyl) pyridine hydrobromide (62.5 mg, 0.25 mmol), N, N, N-tributyl-1-butane-aminium iodide (7 mg, 0.03 mmol) and Potassium carbonate (65.2 mg, 0.47 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 34 mg (28% of theory) LC-MS (procedure 3): Tr = 3.92 min. MS (IEVpos): m / z = 537 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 8.34 (m, 2H); 7.89 (m, 2H); 7.82 (d, 2H); 7.72 (m, 2H); 7.57 (d, 2H); 7.53 (m, 1 H); 7.13 (dd, 1 H); 5.78 (s, 1 H); 3.94-4.14 (m, 4H); 2.00 (s, 3H); 1.10 (t, 3H) ppm.

Example 13

Ethyl 4- (4-Cyanophenyl) -6-methyl-2 - [(3-pyridinylmethyl) sulfanyl] -1- [3- (trifluoro-methyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0 , 22 mmol), 3 (chloromethyl) pyridine hydrochloride (40.5 mg, 0.25 mmol), N, N, N-tributyl-1-butane-aminium iodide (7 mg, 0.03 mmol) and carbonate of potassium (65.2 mg, 0.47 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 25 mg (21% of theory) LC-MS (procedure 2): Tr = 3.93 min. MS (IEVpos): m / z = 537 (M + H) +.

image6

Example 14

4- (4-Cyanophenyl) -2 - {[2- (diethylamino) ethyl] sulfanyl} -6-methyl-1- [3- (tri-fluoromethyl) phenyl] -1,4-dihydro

Ethyl 5-pyrimidinecarboxylate

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1-, 2,3,4-tetrahydro5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), N- (2-bromo-ethyl) -N, N-diethylamine (64.5 mg, 0.25 mmol) hydrobromide, N, N, N-tributyl-1-butaminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) in 3 ml of acetone and

20 stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 15 mg (12% of theory)

LC-MS (procedure 2): Tr = 3.17 min. MS (IEVpos): m / z = 545 (M + H) +.

Example 15

Ethyl 4- (4-Cyanophenyl) -2 - [(1 H -imidazol-2-ylmethyl) sulfanyl] -6-methyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0 , 22 mmol), 2- (bromomethyl) -1H-imidazole hydrobromide (64.5 mg, 0.25 mmol), N, N, N-tributyl-1-butaminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) in 3 ml of acetone and stirred at room temperature overnight. The solvent was removed by vacuum distillation and the product was purified by preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 13 mg (11% of theory) LC-MS (procedure 3): Tr = 3.74 min. MS (IEVpos): m / z = 526 (M + H) +.

Example 16

Trimethylsilyl 4- (4-Cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate Under argon, trimethylsilyl polyphosphate was dissolved (10.6 g) in 75.7 ml of absolute dioxane. To this solution was added 4-cyanobenzaldehyde (5.95 g, 45.4 mmol), 3trifluoromethylphenyl thiourea (5 g, 22.7 mmol) and ethyl 2-cyanoacetoacetate (6.4 g, 45.4 mmol). The reaction mixture was stirred at 80 ° C for 3 hours. After evaporating the dioxane solvent, the residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution, 38% sodium bisulfite solution and saturated sodium chloride solution. After drying with magnesium sulfate and evaporating off the solvent, the residue was dissolved in 15 ml of methanol and purified by means of preparative HPLC (column: Kromasil 100 C 18 5 µm, 30 mm x 150 mm; pre-column: Gromsil ODS 4 HE 15 µm, 10 mm x 20 mm; flow rate: 66 ml / min; solvent A: acetonitrile, solvent B: water; gradient: 0 min A 10%, 3 min A 10%, 11 min A 90% , 13 min A 90%, 13.2 min A 10%, 15 min A 10%; wavelength: 220 nm; injection volume: approx. 2000 µl; number of injections: 12). Fractions containing the product were combined and concentrated in vacuo.

image2

Yield: 7.73 g (72.3% of theory) MS (IEVpos): m / z = 471 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 10.3 (d, 1H); 7.9 (d, 2H); 7.4-7.8 (m, 6H); 5.4 (d, 1 HOUR); 4.25 (m, 2H); 2.9 (tr, 2H); 2.1 (s, 3H) ppm.

The following compounds were prepared analogously to that described for Example 16:

Ex. Nº

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

17

4-cyano-benzaldehyde; 3-chlorophenyl thiourea; ethyl acetoacetate 71 412

18

image2 3-nitro-benzaldehyde; 3trifluoromethylphenyl thiourea; ethyl acetoacetate 74 466

Example 19

4- (4-Cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-55 carboxylic acid

10

image2

2-Cyanoethyl 4- (4-cyanophenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 16; 47 mg) , 0.1 mmol) in 0.5 ml of dioxane. After adding 1,8-diazabicyclo [5.4.0] undec-7-ene (15 µl, 15 mg, 0.1 mmol), the mixture of The reaction was stirred at room temperature for 3 hours. The reaction mixture is diluted with 1N hydrochloric acid and extracted with ethyl acetate. After drying with sulfate magnesium and remove the solvent by evaporation, the residue was purified by means of 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; flow rate: 25 ml / min; gradient: 0 min A 10%, 2 min A 10%, 6 min A 90%, 7 min A 90, 7.1 min A at 10%, 8 min A at 10%; wavelength: 220 nm; injection volume: approx. 550 µI; number of injections: 1). The fractions containing the product were combined and concentrated in vacuo.

Yield: 7.73 g (72.3% of theory) MS (IE): m / z = 417 (M + H) + LC-MS (procedure 1): Tr = 4.2 min. 1H NMR (200 MHz, DMSO-d6): δ = 12.8 (wide s, 1H); 10.15 (d, 1 H); 7.9 (d, 2H); 7.47.8 (m, 6H); 5.4 (d, 1 H); 2.1 (s, 3H) ppm.

Example 20

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

5

10

fifteen

image2

4- {5-Acetyl-6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile was dissolved (Example 1; 100 mg, 0, 24 mmol) in 3 ml of methanol and sodium borohydride (10 mg, 0.26 mmol) was added. After stirring at room temperature for 1

20 hours, the crude mixture was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10) to give the product as a 1.6: 1 mixture of the two diastereomers.

Yield: 86 mg (86% of theory) 25 LC-MS (procedure 4): Tr = 4.10 min. MS (IEVpos): m / z = 418 (M + H) +.

Example 21

Ethyl 4- (4-Cyano-2-methylphenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

image2

4-Cyano-2-methylbenzaldehyde (200 mg, 1.38 mmol), 3-trifluoromethylphenyl thiourea were stirred (276 mg, 1.25 mmol), ethyl 3-oxobutanoate (179 mg, 1.38 mmol) and polyphosphate Trimethylsilyl (225 mg) in 5 ml of THF overnight at reflux temperature. The reaction mixture was cooled to room temperature and, after adding 20 ml of acid 0.5 M hydrochloric, the aqueous phase was extracted with ethyl acetate (2 x 20 ml). They washed organic phases with aqueous sodium carbonate solution and dried with sulfate sodium. The solvent was removed in vacuo and the crude product was purified by means of HPLC preparative (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 320 mg (56% of theory) LC-MS (procedure 5): Tr = 4.32 min. MS (IEVpos): m / z = 460 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 10.09 (d, 1H); 7.63-7.86 (m, 7H); 5.61 (d, 1 H); 3.97 (q, 2H); 2.56 (s, 3 H); 2.08 (s, 3 H); 1.00 (t, 3H) ppm.

Example 22

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

image2

4- {5-Acetyl-6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile was dissolved (Example 1; 100 mg, 0, 24 mmol) in 3 ml of THF. After adding pyridine (21 mg, 0.26 mmol) and propanoyl chloride (22 mg, 0.24 mmol), the mixture of reaction was stirred at room temperature overnight and then quenched with 10 ml of water. After extraction with ethyl acetate (2 x 10 ml), the phase was dried organic with sodium sulfate and the crude product was purified by chromatography Fast resolution silica gel using a gradient of cyclohexane / ethyl acetate.

Yield: 78 mg (69% of theory) LC-MS (procedure 6): Tr = 4.23 min. MS (IEVpos): m / z = 472 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 7.44-7.97 (m, 8H); 6.66 (s, 1 H); 3.28 (m, 1 H); 2.87 (m, 1 H); 2.45 (s, 3 H); 2.09 (s, 3 H); 1.17 (t, 3H) ppm.

The following compounds were prepared analogously to that described for Example 22:

Ex. Nº

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

2. 3

image2 Example 1; cyclopropyl carbonyl chloride 74 4.22 (6) 484

24

Example 1; cyclopentyl acetyl chloride 74 4.73 (6) 526

25

image2 Example 1; cyclobutyl carbonyl chloride 42 4.44 (6) 498

(continued) (continued)

Ex. Nº

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

26

image2 Example 3; propanoyl chloride 68 4.30 (7) 502

27

image2 Example 3; cyclopropyl carbonyl chloride 70 4.30 (7) 514

28

image2 Example 3; cyclopentyl acetyl chloride 61 4.60 (7) 556

Ex. Nº

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

29

Example 3; cyclobutyl carbonyl chloride 59 4.40 (7) 528

Example 30

5 4- {5-Acetyl-6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-4pyrimidinyl} benzonitrile

10

fifteen

image2

4- {5-Acetyl-6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4 was dissolved

20 pyrimidinyl} benzonitrile (Example 1; 100 mg, 0.24 mmol), 1-iodomethane (38.0 mg, 0.27 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) in 3 ml of Acetone and stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by means of preparative HPLC (column RP18; eluent: acetonitriloagua, gradient 10:90 to 90:10).

Yield: 67 mg (65% of theory) LC-MS (procedure 4): Tr = 4.30 min. MS (IEVpos): m / z = 430 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 7.55-7.96 (m, 8H); 5.85 (s, 1 H); 2.19 (s, 3 H); 2.16 (s, 3H); 1.98 (s, 3H) ppm.

Example 31

Ethyl 4- (4-Cyano-2-methylphenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoro-methyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

Ethyl 4- (4-cyano-2-methylphenyl) -6-methyl-2-thioxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 21; 100 mg, 0.22 mmol), 1-iodomethane (34.0 mg, 0.24 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) in 3 ml of acetone and stirred at room temperature for the night. The solvent was removed in vacuo and the crude product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 78 mg (76% of theory) LC-MS (procedure 3): Tr = 4.70 min.

MS (IEVpos): m / z = 474 (M + H) +.

Example 32

Acetic acid 2- [5-Acetyl-4- (4-cyanophenyl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -1,4-dihydropyrimidin-2-ylsulfanyl] ethyl ester

image2

To a solution of ethyl 2-bromoacetate (37.6 mg, 0.23 mmol) in 500 µl of DMF was added potassium carbonate (82.9 mg, 0.6 mmol) and 4- {5-acetyl- 6-methyl-2-thioxo-1- [3 (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile (Example 1; 62.3 mg, 0.15 mmol). The reaction mixture was stirred for 15 hours, filtered and purified by means of 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; flow rate: 25 ml / min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min A 10%, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 µl; number of injections: 1). The fractions containing the product were combined and concentrated in vacuo.

Yield: 0.6 mg (0.8% of theory) LC-MS (procedure 3): Tr = 4.38 min. MS (IEVpos): m / z = 502 (M + H) +.

The following compounds were prepared analogously to that described for Example 32:

Ex. Nº

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

33

Example 17; 3bromoprop carbamic acid ester 20.3 3.95 (7) 513

3. 4

image2 Example 3; 1- (2-Chloro-ethyl) pyrrolidine hydrochloride 3.3 3.19 (7) 543

35

image2 Example 17; 1- (2-Chloro-ethyl) pyrrolidine hydrochloride 3.8 3.16 (7) 509

(continued) (continued) (continued) (continued) (continued) (continued) (continued)

Ex. Nº

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

36

Example 17; 4- (2-Chloro-ethyl) morpholine hydrochloride 3.8 3.14 (7) 525

37

Example 17; 3bromopropan-1ol 34.5 4.02 (8) 470

38

image2 Example 3; 2-Bromoethanol 25.9 4.3 (7) 474

Ex. Nº

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

39

Example 3; 3-bromopropan-1ol 18.5 4.29 (3) 504

40

image2 Example 1; 2-BromoN, N-diethylacetamide 37.8 4.24 (3) 529

41

image2 Example 17; 2-Chloromethyl-1-1Himidazole Hydrochloride 54.1 3.59 (3) 506

Ex. Nº

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

42

Example 3; 2-bromoethyl acetate 16.3 4.49 (3) 532

43

image2 Example 3; Bromoacetic acid 26.5 3.94 (7) 504

44

image2 Example 17; iodomethane or 37.6 4.44 (3) 426

Ex. Nº

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

Four. Five

image2 Example 3; Bromoacetonitrile 49.5 3.71 (3) 485

46

image2 Example 3; 2-Chloromethyl-1-methyl-1Himidazole Hydrochloride 40.8 3.13 (7) 540

47

Example 3; 3-bromopropyl ester of carbamic acid 14.6 3.94 (7) 547

Ex. Nº

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

48

image2 Example 17; 2-Bromoethanol 33.6 4.21 (3) 456

49

image2 Example 3; 6-chloromethyl-1H-pyrimidin2,4-dione 53.8 3.75 (7) 570

fifty

image2 Example 1; iodoethane 24.0 4.05 (7) 444

Ex. Nº

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

51

Example 3; 2-bromopropionitril or 13.3 3.75 (3) 499

52

image2 Example 3; 2-BromoN, N-diethylacetamide 51.3 4.45 (3) 559

53

image2 Example 3; 2-BromoN-methylacetamide 59.4 3.9 (7) 517

Ex. Nº

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

54

image2 Example 3; 4-Chloromethyl-3,5-dimethylisoxazole 60.1 4.22 (7) 555

55

image2 Example 1; 4-Chloromethyl-2-methyl-thiazole hydrochloride 5.4 3.96 (7) 527

56

image2 Example 1; 4-Chloromethyl-3,5-dimethylisoxazole 21.6 4.02 (7) 525

Example 57

4- (4-Cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5 acid

pyrimidinecarboxylic

5

10

image2

4- (4-Cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) -phenyl] -1,4-dihydro-5 was dissolved

Methyl pyrimidinecarboxylate (Example 8; 9.51 g, 21.4 mmol) in 175 ml THF / ethanol / water (10: 5: 1). Potassium hydroxide (3.59 g, 64.1 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with 100 ml of water and the aqueous phase was washed with diethyl ether. The resulting aqueous phase was acidified to pH 1 with hydrochloric acid and the resulting precipitate was removed by filtration, dissolved in acetate.

20 ethyl and washed with water. After drying with sodium sulfate, the solvent was removed in vacuo to give the product.

Yield: 655 mg (7% of theory)

LC-MS (procedure 5): Tr = 3.77 min.

25 MS (IEVpos): m / z = 432 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 12.32 (wide s, 1H); 7.52-7.98 (m, 8H); 5.75 (s, 1 H); 2.15 (s, 3 H); 2.02 (s, 3H) ppm.

Example 58

30

2- (Diethylamino) ethyl 4- (4-diethylamino) ethyl 4- (4-cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylate

image2

4- (4-Cyanophenyl) -6-methyl-2- (methylsulfanyl) -1- [3- (trifluoromethyl) phenyl] -1,4-dihydro-5-pyrimidinecarboxylic acid (Example 57; 100 mg, 0.23 mmol) ) in 3 ml of acetone. Be added potassium carbonate (67 mg, 0.49 mmol), N- (2-bromoethyl) -N hydrobromide, N-diethylamine (67 mg, 0.25 mmol) and N, N, N-tributyl-1-butan iodide -aminio (approximately 5 mg), and the reaction mixture was stirred at room temperature During 4 hours. The solvent was removed in vacuo, ethyl acetate was added and after extraction with 1 N sodium hydroxide solution, the organic phase was dried and evaporated the solvent. The crude product was purified by means of preparative HPLC (column RP18; eluent: acetonitrile-water, gradient 10:90 to 90:10).

Yield: 90 mg (73% of theory) LC-MS (procedure 5): Tr = 3.00 min. MS (IEVpos): m / z = 531 (M + H) + 1H NMR (200 MHz, DMSO-d6): δ = 7.55-7.98 (m, 8H); 5.78 (s, 1 H); 4.07 (t, 2H); 2.62 (t, 2H); 2.41-2.58 (m, 4H); 2.15 (s, 3 H); 2.03 (s, 3H); 0.91 (t, 6H) ppm.

The following compounds were prepared analogously to that described for Example 58:

Ex. Nº

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

59

image2 Example 57; 1- (2-Chloro-ethyl) pyrrolidine hydrochloride 43 3.80 (4) 513

60

image2 Example 57; bromoacetat or ethyl 42 4,50 (4) 518

61

image2 Example 57; 2-Chloro-N-ethyl-N-Methylethanamine Hydrochloride 48 3.70 (4) 517

(continuation)

Ex. Nº

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

62

image2 Example 57; 1- (2-Chloro-ethyl) piperidine hydrochloride 46 3.80 (4) 543

63

image2 Example 57; methyl chloroacetate 71 4.10 (7) 504

C. Operational examples related to pharmaceutical compositions

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

Compressed:

10 Composition:

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

15 mm, radius of curvature 12 mm.

preparation:

The mixture of active component, lactose and starch was granulated with a 5% solution (m / m) of PVP in water. After drying, the granules were mixed with stearate

5 mg for 5 min. This mixture was molded using a usual tablet press (tablet format, see below). The applied molding force is typically 15 kN.

Suspension for oral administration

10

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, 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:

The Rhodigel was suspended in ethanol and the active component was added to the suspension. Water was added with stirring. Stirring was continued for approximately 6 hours until Rhodigel swelling was complete.

Claims (26)

1. Compounds of the general formulas (I-A) and (I-B) image 1 R1, R2 and R3 independently of each other, represent 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 C1C4 alkoxy, R4 represents C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono or C1-C4 dialkyl aminocarbonyl, C6-C10 aminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, in which C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy carbonyl, mono and C1-C4 dialkyl aminocarbonyl 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 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono and C1-C4 dialkyl aminocarbonyl, C1-C4 alkyl carbonylamino, amino, mono and C1-C4 dialkyl amino, heteroaryl, heterocyclyl, tri - (C1-C6 alkyl) -silyl and cyano, 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, C2-C6 alkenoxy, C1-C6 alkyl thio, amino, mono and dialkyl C1-C6 amino, arylamino, hydroxycarbonyl, C1-C6 alkoxycarbonyl and the radical -O-C1-C4 alkyl-C1-C4 alkyl; R 6A represents hydrogen, C 1 -C 6 alkylcarbonyl, C 3 -C 8 cycloalkyl carbonyl, C 1 -C 6 alkoxycarbonyl, mono or C 1 -C 4 alkylaminocarbonyl, in which C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy carbonyl, mono and C 1- dialkyl C4 aminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 amino dialkyl, R6B represents C1-C6 alkyl, which may be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, C1-C4 alkoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono and C1-C4 dialkyl aminocarbonyl, C1-C4 alkylcarbonyloxy, aminocarbonyloxy, cyano, aryl, heteroaryl and heterocyclyl, wherein the heteroaryl and heterocyclyl can also be substituted with one to two equal or different radicals selected from the group that consists of C1-C4 alkyl, hydroxy and oxo, 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 which It consists of halogen, hydroxy and C1-C4 alkoxy, and Y1, Y2, Y3 and Y4 independently of each other, represent CH or N, in which the ring contains 0, 1 or 2 nitrogen atoms. 2. Compounds of general formulas (I-A) and (I-B) according to Claim 1, wherein A represents an aryl or heteroaryl ring, R1, R2 and R3 independently of each other, represent hydrogen, halogen, nitro, cyano, C1-C6 alkyl, hydroxy or C1-C6 alkoxy, in which C1-C6 alkyl 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 C1C4 alkoxy, R4 represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono or C1-C4alkylcarbonyl, C6-C10 aminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C1-C6 alkyl , C1-C6 alkoxy carbonyl, mono and C1-C4 dialkyl aminocarbonyl may also be substituted with one to three equal radicals or different selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono and C1-C4 dialkyl aminocarbonyl, C1-C4 alkyl carbonylamino, amino, mono and dialkyl C1 -C4 amino, 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, C2-C4 alkenoxy, C1-C6 alkylthio, amino, mono and C1-alkyl -C6 amino, arylamino, hydroxycarbonyl, C1-C6 alkoxy carbonyl and the radical -O-C1-C4-alkyl-C1-C4 alkyl, R 6A represents hydrogen, C 1 -C 6 alkylcarbonyl, C 3 -C 8 cycloalkyl carbonyl, C 1 -C 6 alkoxycarbonyl, mono or C 1 -C 4 alkylaminocarbonyl, in which C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy carbonyl, mono and C 1- dialkyl C4 aminocarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 amino dialkyl, R6B represents C1-C6 alkyl, which may be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and C1-C4 dialkyl amino, aryl, heteroaryl and heterocyclyl, 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 which It consists of halogen, hydroxy and C1-C4 alkoxy, and Y1, Y2, Y3 and Y4 independently of each other, represent CH or N, in which the ring contains 0, 1 or 2 nitrogen atoms. 3. Compounds of general formulas (I-A) and (I-B) according to Claim 1 or 2, wherein A represents a phenyl or pyridyl ring, R1, R2 and R3 independently of each other, represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy, R4 represents C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono or C1-C4alkylcarbonyl or cyano, wherein C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl and C1-C4alkylcarbonyl may be substituted with one to three identical or different radicals selected from the group consisting of C3-C8 cycloalkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, amino, mono and C1-C4 dialkyl amino, heteroaryl and heterocyclyl, R5 represents methyl or ethyl, R 6A represents hydrogen, C 1 -C 6 alkylcarbonyl or C 3 -C 6 cycloalkyl carbonyl, wherein C 1 -C 6 alkylcarbonyl may be substituted with a radical selected from the group consisting of C 3 -C 6 cycloalkyl, hydroxy, C 1 -C 4 alkoxy, amino, mono and dialkyl C1-C4 amino, R6B represents C1-C6 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, mono and dialkyl C1-C4 amino, phenyl, heteroaryl and heterocyclyl, R7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, and Y1, Y2, Y3 and Y4 each represent CH. 4. Compounds of general formulas (I-A) and (I-B) according to claim 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 C1-C4 alkylcarbonyl or C1-C4 alkoxycarbonyl, wherein C1C4 alkoxycarbonyl may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy , C1-C4 alkoxy carbonyl, mono and C1-C4 dialkyl amino, heteroaryl and heterocyclyl, R5 represents methyl, R6A represents hydrogen, C1-C6 alkylcarbonyl or C3-C6 cycloalkyl carbonyl, R6B represents C1-C4 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 alkoxy, amino, C1-C4 dialkyl amino, phenyl, pyridyl, imidazolyl, pyrrolidino and morpholino, R7 represents trifluoromethyl or nitro, and Y1, Y2, Y3 and Y4 each represent CH.

5.

Compounds of general formulas (I-A) and (I-B) according to at least one of Claims 1 to 4, wherein A is phenyl or pyridyl.

6.

Compounds of general formulas (I-A) and (I-B) according to at least one of Claims 1 to 5, wherein R1 is hydrogen.

7. Compounds of general formulas (I-A) and (I-B) according to at least one of the 5 Claims 1 to 6, wherein R2 is cyano. 8. Compounds of general formulas (I-A) and (I-B) according to at least one of Claims 1 to 7, wherein R3 is hydrogen. Compounds of general formulas (IA) and (IB) according to at least one of Claims 1 to 8, wherein R4 is C1-C4 alkoxycarbonyl, which may be substituted with dimethylamino, diethylamino, N-ethylmethylamino, pyrrolidino or piperidino, or in which R4 is C1-C4 alkylcarbonyl. 10. Compounds of general formulas (I-A) and (I-B) according to at least one of Claims 1 to 9, wherein R5 is methyl. 11. Compounds of general formulas (I-A) and (I-B) according to at least one of Claims 1 to 10, wherein R7 is trifluoromethyl or nitro. twenty

12.

Compounds of general formula (I-A) according to at least one of Claims 1 to 11, wherein R6A is hydrogen.

13.

Compounds of general formula (I-B) according to at least one of Claims 1 to

11, wherein R6B is methyl, (1 H -imidazol-2-yl) methyl, 2- (dimethylamino) ethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2- (1-pyrrolidinyl) ethyl. 14. Compounds of general formula (I-C) 30 35 image2 Z represents CH or N, and R1, R3 and R4 have the meaning indicated in Claims 1 to 12. 15. Compounds of general formula (I-E) image2 Z represents CH or N, R1, R3 and R4 have the meaning indicated above, and R6B represents C1-C4 alkyl, which may be substituted with a radical selected from the group consisting of hydroxy, C1-C4 dialkyl amino, phenyl, pyridyl, imidazolyl, pyrrolidino and morpholino. 16. Procedure for synthesizing the compounds of the general formulas (I-A), (I-B), (IC) or (I-E); respectively, as defined in claims 1 to 15, by means of the condensation of compounds of general formula (II) image3 wherein A, R1 and R2 have the meaning indicated in Claims 1 to 15, with compounds of general formula (III) image3 wherein R4 and R5 have the meaning indicated in Claims 1 to 15, and compounds of general formula (IV) image3 wherein R3, R7 and Y1 to Y4 have the meaning indicated in Claims 1 to 15, in the presence of an acid in a three-component / one-stage reaction or consecutively to give compounds of the general formula (I-D) image3 in which A, R1 to R5, R7 and Y1 to Y4 have the meaning indicated in Claims 1 to 15, optionally followed by reacting the compounds of general formula (I-D) in the presence of a base [A] with compounds of the general formula (V) R6A * -XA (V), wherein R6A * has the meaning of R6A as set forth in claims 1 to 15, but does not represent hydrogen, and XA represents a leaving group, such as halogen, to give compounds of the general formula (IA) or (IC) , respectively, or [B] with compounds of the general formula (VI) R6B-XB (VI), wherein R6B has the meaning indicated in Claims 1 to 15, and XB represents a leaving group, such as halogen, tosylate, mesylate or sulfate, to give compounds of the general formula (I-B) or (I-E), respectively.

17.

The composition containing at least one compound of general formula (I-A) or (I-C), as defined in Claims 1 to 12 and 14, and a pharmacologically acceptable diluent.

18.

A composition according to Claim 17 for the treatment of inflammatory, ischemic and / or remodeling processes, acute or chronic.

19.

The process for the preparation of compositions according to Claim 17 and 18 characterized in that the compounds of general formula (IA) or (IC), as defined in Claims 1 to 12 and 14, together with usual auxiliary products are taken into a form of proper application.

twenty.

Use of the compounds of general formula (I-A) or (I-C), as defined in Claims 1 to 12 and 14, for the preparation of medicaments.

twenty-one.

Use according to Claim 20 for the preparation of medicaments for the

treatment of inflammatory, ischemic and / or remodeling processes, acute or chronic.

22

Use according to Claim 21, wherein the process is chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or the development of heart failure.

2. 3.

The composition containing at least one compound of general formula (I-B) or (I-E), as defined in Claims 1 to 11, 13 and 15, and a pharmacologically acceptable diluent.

24.

A composition according to Claim 23 for the treatment of inflammatory, ischemic and / or remodeling processes, acute or chronic.

25.

The process for the preparation of compositions according to Claim 23 and 24, characterized in that the compounds of general formula (IB) or (IE), as defined in Claims 1 to 11, 13 and 15, together with usual auxiliary products are placed according to a suitable application form.

26.

Use of the compounds of general formula (I-B) or (I-E), as defined in Claims 1 to 11, 13 and 15, for the preparation of medicaments.

27.

Use according to Claim 26 for the preparation of medicaments for the treatment of inflammatory, ischemic and / or remodeling processes, acute or chronic.

28.

Use according to Claim 27, wherein the process is chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or the development of heart failure.