RU2376295C2 - Derivatives of pyrimidinone and pharmaceutical composition on their basis, which has properties of human neutrophil elastase inhibitor - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I)

, A means phenyl or pyridyl cycle, R¹ and R³ each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R⁴ means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO₂ possibly substituted with ketogroup, R⁵ means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y¹, Y², Y³, Y⁴ and Y⁵ each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

Description

The present invention relates to new heterocyclic derivatives, to methods for their preparation and to their use in medicines, in particular for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and progressive heart failure.

The fibrillar protein elastin, which in percentage terms makes up a significant proportion of all proteins in some tissues, for example, in arteries, in some connective tissues, in lung and heart tissues, can be hydrolyzed or otherwise destroyed by a special group of enzymes classified as elastases. Human leukocyte elastase (class 3.4.21.37), also known as human neutrophil elastase, is a glycosylated strongly basic serine protease, which is located in the azurophilic granules of human polymorphonuclear leukocytes. Human neutrophilic elastase is released from activated polymorphonuclear leukocytes, it can participate in the pathogenesis of acute and chronic inflammatory diseases. Human neutrophilic elastase causes degradation of a wide range of matrix proteins, including elastin and collagen, in addition to this effect on connective tissue, human neutrophilic elastase exhibits a wide range of inflammatory activity, including activation of IL-8 gene expression, edema formation, mucosal hyperplasia and mucus hypersecretion. It also acts as a mediator in damaged tissue as a result of hydrolysis of collagen structures, for example, in the heart after acute myocardial infarction or in the process of development of heart failure, thus damaging endothelial cells, promoting the transudation of neutrophils adjacent to the endothelium, and affecting the adhesion process itself.

Pulmonary diseases in which neutrophilic human elastase is thought to play a role include pulmonary fibrosis, pneumonia, acute respiratory disease syndrome, pulmonary emphysema, including smoking-induced emphysema, chronic obstructive pulmonary disease, and cystic fibrosis. In cardiovascular diseases, human neutrophilic elastase is involved in the development of ischemic tissue damage, followed by impaired functioning of the heart muscle after acute myocardial infarction and in the recovery processes that occur in progressive heart failure. Human neutrophilic elastase can also be involved in rheumatoid arthritis, atherosclerosis, brain injury, cancer, and similar conditions in which neutrophils are involved.

Accordingly, inhibitors of human neutrophilic elastase activity can be used to treat a large number of inflammatory diseases, in particular chronic obstructive pulmonary diseases [R. A. Stockley, Neutrophils and protease / antiprotease imbalance. Am. J. Respir. Crit. Care 160, S49-S52 (1999)]. Inhibitors of human neutrophilic elastase activity can also be used to treat acute myocardial syndrome, intermittent angina pectoris, acute myocardial infarction, and arterial-coronary artery bypass grafting [S. P. Tiefen-bacher 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)], with progressive heart failure [S.J. Gilbert et al., Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34. S377-S383 (1997)] and for atherosclerosis [Dollery et al., Neutrophil elastase in human atherosclerotic plaque. Circulation 107, 2829-2836 (2003)].

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

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

Where

A means an aryl or heteroaryl ring,

R ¹ , R ² and R ³ independently from each other mean a hydrogen atom, halogen, nitro group, cyano group, an alkyl group with the number of carbon atoms from one to six, a hydroxyl group or an alkoxy group with the number of carbon atoms from one to six, and the alkyl group with the number of carbon atoms from one to six and the alkoxy group with the number of carbon atoms from one to six can also be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group and an alkoxy group py with the number of carbon atoms from one to four,

R ⁴ means a trifluoromethylcarbonyl, alkylcarbonyl group with one to six carbon atoms in the alkyl residue, an alkoxycarbonyl group with one to six carbon atoms in the alkoxy group, an alkoxycarbonyl group with one to six carbon atoms in the alkyl radical, hydroxycarbonyl, aminocarbonyl a group, a mono- or dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an arylaminocarbonyl group with the number of carbon atoms yes, in the aryl residue from six to ten, an aryl carbonyl, heteroaryl carbonyl, heterocyclyl carbonyl, heteroaryl, heterocyclyl group or cyano group, the alkyl carbonyl group having from one to six carbon atoms in the alkyl radical, an alkoxycarbonyl group with one to six carbon atoms in the alkoxy radical , a mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl radicals from one to four may also be substituted one to three times by the same or different substituents selected from the group consisting of a cycloalkyl group with three to eight carbon atoms, a hydroxyl group, an alkoxy group with one to four carbon atoms, an alkoxycarbonyl group with one to four carbon atoms in the alkoxy radical, hydroxycarbonyl, aminocarbonyl groups, mono- and dialkylaminocarbonyl groups with the number of carbon atoms in each of the alkyl radicals from one to four, alkylcarbonylamino groups with the number of carbon atoms in the alkyl radical e from one to four, an alkylcarbonyl substituted alkylamino group with the number of carbon atoms in each of the alkyl residues from one to four, a cyano group, an amino group, a mono- and dialkylamino group with the number of carbon atoms in each of the alkyl residues from one to four, a heteroaryl, heterocyclyl group and trialkylsilyl groups with the number of carbon atoms in each of the alkyl residues from one to six, and where the heteroarylcarbonyl, heterocyclyl-carbonyl, heteroaryl and heterocyclyl groups may also be substituted alkyl groups with a carbon number from one to four,

R ⁵ means an alkyl group with one to four carbon atoms, which may be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group, an alkoxy group with one to six carbon atoms, alkenoxy groups with one to six carbon atoms, an alkylthiol group with one to six carbon atoms, an amino group, a mono and dialkylamino group with one to six carbon atoms in each of the alkyl residues, ar laminogruppy, hydroxycarbonyl groups, alkoxycarbonyl groups having carbon atoms in the alkoxy radical of one to six and an alkoxyalkoxy group having a carbon number in each of the alkoxy radicals of one to four,

or

R ⁵ means an amino group,

R ⁶ means a hydrogen atom, an alkyl group with one to six carbon atoms, a formyl, aminocarbonyl group, a mono- or dialkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, a cycloalkyl carbonyl group with the number of carbon atoms in the cycloalkyl radical from three to eight, an alkylcarbonyl group with one to six carbon atoms in the alkyl residue, an alkoxycarbonyl group with one to six carbon atoms in alkoxy residue, N-alkylsul an onyl-substituted aminocarbonyl group with one to four carbon atoms in the alkyl residue, an N-alkylsulfonyl substituted N-alkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, a heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclyl carbonyl group, carbon atoms from one to six, mono-and dialkyl-aminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, alkylcarbonyl a single group with one to six carbon atoms in the alkyl radical, one to six alkoxycarbonyl groups with one to six carbon atoms, one to three times heteroaryl and heterocyclyl groups are substituted with the same or different substituents selected from the group consisting of from an aryl, heteroaryl, hydroxyl group, an alkoxy group with one to four carbon atoms, a hydroxycarbonyl group, an alkoxycarbonyl group with the number of carbon atoms in the alkoxy radical from one to six, an aminocarbonyl, mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an amino group, a mono- and dialkylamino group with the number of carbon atoms in each of the alkyl residues from one to four, an alkylcarbonylamino group with the number carbon atoms in the alkyl residue from one to four, a trialkylsilyl group with the number of carbon atoms in each of the alkyl residues from one to six, a cyano group, an N-alkylaminoalkyl substituted aminocarbonyl group and N, N a dialkylaminoalkyl substituted amino carbonyl group with one to four carbon atoms in each of the alkyl radicals; an N-alkoxyalkyl substituted amino carbonyl group with one to four carbon atoms in each of the alkyl radicals and halogen atoms,

or

R ⁶ means a structural unit of the formula

,

или

,

or

Where

R ^{6A is} selected from the group consisting of a hydrogen atom and an alkyl group with one to six carbon atoms, and

n is an integer of 1 or 2,

R ⁷ means a halogen atom, a nitro group, a cyano group, an alkyl group with the number of carbon atoms from one to six, a hydroxyl group or an alkoxy group with the number of carbon atoms from one to six, and an alkyl group with the number of carbon atoms from one to six and an alkoxy group with the number of atoms carbon from one to six can also be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group and an alkoxy group with one to one carbon atoms tyreh,

and

Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another mean a CH group or a nitrogen atom, and the cycle may include 0, 1 or 2 nitrogen atoms.

Compounds corresponding to the present invention can also be presented in the form of their salts, hydrates and / or solvates.

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

In accordance with the invention, the concept of physiologically acceptable salts refers to non-toxic salts, which in General can be obtained by the reaction of compounds (I) with an inorganic or organic base or with an inorganic or organic acid, which are usually used for these purposes. Examples of pharmaceutically acceptable salts of compounds (I) that cannot be used to limit the scope of claims include alkali metal salts, for example lithium, potassium and sodium salts, alkaline earth metal salts such as magnesium and calcium salts, such as quaternary ammonium salts as, for example, triethylammonium salts, as well as acetates, benzenesulfonates, benzoates, dicarbonates, disulfates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexi resorcinates, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelic acid salts, mesylates, methyl bromides, methyl nitrates, methyl sulfates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, polyphosphates, diphosphate stearates, sulfates, succinates, tartrates, tosylates, valerates and other salts commonly used for medical purposes.

The hydrates of the compounds of the invention or their salts are stoichiometric compositions of these compounds with water, for example hemihydrates, monohydrates or dihydrates.

Solvates of the compounds of the invention or their salts are stoichiometric compositions of these compounds with solvents.

The present invention includes both individual enantiomers or diastereomers, and the corresponding racemates or mixtures of diastereomers of the compounds of the invention and their salts. In addition to this, the scope of the claims of the present invention includes all possible tautomeric forms of the above compounds. Diastereomeric mixtures can be separated into individual isomers using chromatographic processes. Racemates can be resolved into the corresponding enantiomers both by chromatographic processes on the chiral phases and by conventional resolution methods.

In the context of the present invention, substituents, unless otherwise indicated, generally have the following meaning.

The alkyl group in the General case is a hydrocarbon radical with a linear or branched chain with the number of carbon atoms from one to six, preferably from one to four carbon atoms. Examples that cannot be used to limit the scope of the claims include a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl group. The same applies to substituents such as an alkoxy group, an alkylamino group, an alkoxycarbonyl group and an alkoxycarbonylamino group.

An alkoxy group is exemplified and preferably represented by a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a tert-butoxy group, an n-pentoxy group, and an n-hexoxy group.

An alkylcarbonyl group is generally a straight or branched chain hydrocarbon radical with one to six carbon atoms, preferably one to four carbon atoms, which is attached via a carbonyl group. Examples that cannot be used to limit the scope of the claims include the formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, n-hexanoyl groups.

An alkoxycarbonyl group is exemplified and preferably represented by a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxy-carbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl group.

An alkylamino group is an alkylamine radical with one or two (independently selected) alkyl substituents, as an example and preferably it is represented by a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, a tert-butylamino group, an n-pentylamino group, an n-hexylamino group N-dimethylamino, N, N-diethylamino, N-methyl-N-ethylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N- ethyl nn pentylamine uppoy and N-n-hexyl-N-methylamino.

The alkylaminocarbonyl group is an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, as an example and preferably it is methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-pentylaminocarbonyl, n-pentylaminocarbonyl, n-pentylamine , N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-iso ropil-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl group.

An alkylsulfonyl group is generally a straight or branched chain hydrocarbon residue with one to six carbon atoms, preferably one to four carbon atoms, which is attached via a sulfonyl group. Examples that cannot be used to limit the scope of the claims include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl group.

The cycloalkyl group in the General case is a cyclic saturated hydrocarbon residue with the number of carbon atoms from three to eight, preferably from three to six carbon atoms. Examples that cannot be used to limit the scope of the claims include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

The aryl group itself and in the arylcarbonyl group is a mono-, di- or tricyclic aromatic carbocyclic residue with the number of carbon atoms in the general case from six to fourteen, as an example, and preferably it is represented by a phenyl, naphthyl or phenanthrenyl group. An arylcarbonyl group is an example and is preferably represented by a benzoyl and naphthoyl group.

The heteroaryl group itself and in the heteroarylcarbonyl group is an aromatic mono- or dicyclic residue with the number of atoms in the cycle generally from five to ten, preferably from five to six, and with the number of heteroatoms to five, in the preferred case up to four, selected from the group consisting of sulfur, oxygen and nitrogen atoms, as an example, and preferably it is thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, oxadiazolyl, thiadiazo yl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benztiofenilnoy, benztiazolilnoy, quinolinyl, isoquinolinyl group. Heteroarylcarbonyl group as an example and represented preferably thienylcarbonyl, furylcarbonyl, pirrolilkarbonilnoy, thiazolylcarbonyl, oksazolilkarbonilnoy, imidazolilkarbonilnoy, pyridylcarbonyl, pirimidilkarbonilnoy, piridazinilkarbonilnoy, indolilkarbonilnoy, indazolilkarbonilnoy, benzofuranilkarbonilnoy, benztiofenilkarbonilnoy, hinolinilkarbonilnoy, izohinolinilkarbonilnoy group.

The heterocyclyl group by itself and also in the heterocyclylcarbonyl group is a non-aromatic heterocyclic radical with the number of rings from one to several, preferably from one to two, and with the number of atoms in the rings in general from four to ten, in the preferred case of five to eight, and with the number of heteroatoms and / or hetero groups up to three, preferably up to two, selected from the group consisting of nitrogen, oxygen, sulfur, SO and SO ₂ groups. Heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to monocyclic saturated heterocinlyl residues with a number of members from five to eight and with the number of heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, to two, as an example, and preferably they are tetrahydrofuran-2-yl, pyrrolidine -1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl groups.

The heterocyclylcarbonyl group is exemplified and preferably represented by a tetrahydrofuran-2-carbonyl, pyrrolidin-1-carbonyl, pyrrolidin-2-carbonyl, pyrrolidin-3-carbonyl, pyrrolincarbonyl, piperidinecarbonyl, morpholincarbonyl, perhydroazepine carbonyl group.

Halogen is fluoro, chloro, bromo and iodo.

If indicated that Y ¹ , Y ² . Y ³ , Y ⁴ and Y ⁵ mean a CH group or a nitrogen atom, this means that instead of the CH group in the cycle there may also be a carbon atom which is substituted with a substituent R ³ or R ⁷ .

The * symbol next to a bond indicates the place by which it is attached to the molecule.

In another embodiment, the present invention relates to compounds of General formula (I), where

A means an aryl or heteroaryl ring,

R ¹ , R ² and R ³ independently from each other mean a hydrogen atom, halogen, nitro group, cyano group, an alkyl group with the number of carbon atoms from one to six, a hydroxyl group or an alkoxy group with the number of carbon atoms from one to six, and the alkyl group with the number of carbon atoms from one to six and the alkoxy group with the number of carbon atoms from one to six can also be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group and an alkoxy group py with the number of carbon atoms from one to four,

R ⁴ means an alkylcarbonyl group with one to six carbon atoms in the alkyl radical, an alkoxycarbonyl group with one to six alkoxy carbonyl radicals, an alkoxycarbonyl group with one to six carbon atoms in the alkenyl radical, hydroxycarbonyl, aminocarbonyl group, a mono- or dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an arylaminocarbonyl group with the number of carbon atoms in the aryl residue from from ten to ten, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl group or cyano group, the alkylcarbonyl group having one to six carbon atoms in the alkyl radical, the alkoxycarbonyl group having one to six carbon atoms in the alkoxy radical, mono- and dialkylaminocarbonyl groups the number of carbon atoms in each of the alkyl residues from one to four can also be substituted one to three times by the same or different substituents selected from the group consisting of a cycloalkyl group with three to eight carbon atoms, a hydroxyl group, an alkoxy group with one to four carbon atoms, an alkoxycarbonyl group with one to four carbon atoms in the alkoxy group, a hydroxycarbonyl, aminocarbonyl group, a mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an alkylcarbonylamino group with the number of carbon atoms in the alkyl residue from one to four, an amino group, mono and di lkilaminogruppy carbon atoms in each alkyl radicals of one to four, heteroaryl, heterocyclyl groups, and trialkylsilyl groups having the number of carbon atoms in each alkyl radicals of one to six,

R ⁵ means an alkyl group with one to four carbon atoms, which may be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group, an alkoxy group with one to six carbon atoms, alkenoxy groups with one to six carbon atoms, an alkylthiol group with one to six carbon atoms, an amino group, a mono and dialkylamino group with one to six carbon atoms in each of the alkyl residues, ar laminogruppy, hydroxycarbonyl groups, alkoxycarbonyl groups having the number of carbon atoms in the alkoxy radical of one to six and an alkoxyalkoxy group having a carbon number in each of the alkoxy radicals of one to four,

or

R ⁵ means an amino group,

R ⁶ means a hydrogen atom, an alkyl group with one to six carbon atoms, a formyl, aminocarbonyl group, a mono- or dialkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, a cycloalkyl carbonyl group with the number of carbon atoms in the cycloalkyl radical from three to eight, an alkylcarbonyl group with one to six carbon atoms in the alkyl residue, an alkoxycarbonyl group with one to six carbon atoms in alkoxy residue, N-alkylsul an onyl-substituted aminocarbonyl group with one to four carbon atoms in the alkyl residue, an N-alkylsulfonyl substituted N-alkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, a heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclyl carbonyl group, carbon atoms from one to six, mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, alkylcarbonyl the group with the number of carbon atoms in the alkyl residue from one to six, the alkoxycarbonyl group with the number of carbon atoms in the alkoxy residue from one to six, the heteroaryl and heterocyclyl group can be substituted one to three times by the same or different substituents selected from the group consisting of from an aryl, heteroaryl, hydroxyl group, an alkoxy group with one to four carbon atoms, a hydroxycarbonyl group, an alkoxycarbonyl group with the number of carbon atoms in the alkoxy radical from one to six, an aminocarbonyl, mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an amino group, a mono- and dialkylamino group with the number of carbon atoms in each of the alkyl residues from one to four, an alkylcarbonylamino group with the number carbon atoms in the alkyl residue from one to four, a trialkylsilyl group with the number of carbon atoms in each of the alkyl residues from one to six, a cyano group, an N-alkylaminoalkyl substituted aminocarbonyl group and N, N- a dialkylaminoalkyl substituted aminocarbonyl group with one to four carbon atoms in each of the alkyl residues; an N-alk-hydroxyalkyl substituted aminocarbonyl group with one to four carbon atoms in each of the alkyl residues and halogen atoms,

or

R ⁶ means a structural unit of the formula

,

или

,

or

Where

R ^{6A is} selected from the group consisting of a hydrogen atom or an alkyl group with one to six carbon atoms, and n is an integer of 1 or 2,

R ⁷ means a halogen atom, a nitro group, a cyano group, an alkyl group with the number of carbon atoms from one to six, a hydroxyl group or an alkoxy group with the number of carbon atoms from one to six, and an alkyl group with the number of carbon atoms from one to six and an alkoxy group with the number of atoms carbon from one to six can also be substituted one to three times by the same or different substituents selected from the group consisting of halogen atoms, a hydroxyl group and an alkoxy group with one to one carbon atoms tyreh,

and

Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another mean a CH group or a nitrogen atom, and the cycle may include 0, 1 or 2 nitrogen atoms.

In another embodiment, the present invention relates to compounds of General formula (I), where

A means phenyl, naphthyl or pyridyl cycle,

R ¹ , R ² and R ³ independently from each other mean a hydrogen atom, fluorine, chlorine, bromine, nitro group, cyano group, methyl, ethyl, trifluoromethyl group or trifluoromethoxy group,

R ⁴ means an alkylcarbonyl group with one to six carbon atoms in the alkyl residue, an alkoxycarbonyl group with one to six carbon atoms, a hydroxycarbonyl, aminocarbonyl group, a monoalkylaminocarbonyl group with one to four carbon atoms in the alkyl residue, or a cyano group, wherein the alkylcarbonyl group with the number of carbon atoms in the alkyl residue is from one to six, the alkoxycarbonyl group with the number of carbon atoms in the alkoxy residue of about up to six and a monoalkylaminocarbonyl group with one to four carbon atoms in the alkyl radical may also be substituted one to three times by the same or different substituents selected from the group consisting of a cycloalkyl group with three to eight carbon atoms, a hydroxyl group , alkoxy groups with the number of carbon atoms from one to four, alkoxycarbonyl group with the number of carbon atoms in the alkoxy residue of one to four, amino group, mono - or dialkylamino group with the number of atom in carbon in each of the alkyl residues from one to four, heteroaryl and heterocyclyl groups,

R ⁵ means a methyl or ethyl group,

R ⁶ means a hydrogen atom, an alkyl group with one to six carbon atoms, a mono- or dialkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, an alkyl carbonyl group with one to six carbon atoms in the alkyl radical, an alkoxycarbonyl group with one to six carbon atoms in the alkoxyl radical or a heterocyclylcarbonyl group, an alkyl group with one to six carbon atoms and an alkoxycarbonyl group carbon in the alkoxyl radical of one to six can be substituted one to three times by the same or different substituents selected from the group consisting of a heteroaryl, hydroxyl group, an alkoxy group with one to four carbon atoms, a hydroxycarbonyl group, an alkoxycarbonyl group with the number of atoms carbon in the alkoxyl radical of one to six, aminocarbonyl, mono- and dialkylaminocarbonyl groups with the number of carbon atoms in each of the alkyl radicals of one to four, cyano , amino groups, mono - and dialkylamino groups with the number of carbon atoms in each of the alkyl residues from one to four,

or

R ⁶ means a structural unit of the formula

,

или

,

or

Where

R ^{6A is} selected from the group consisting of a hydrogen atom and an alkyl group with one to four carbon atoms, and

n is an integer of 1 or 2,

R ⁷ means a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, a methyl or ethyl group

and

Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each, means a CH group.

In another embodiment, the present invention relates to compounds of General formula (I), where

A means phenyl or pyridyl cycle,

R ¹ and R ³ each mean a hydrogen atom,

R ² means a fluorine atom, chlorine, bromine, nitro group or cyano group,

R ⁴ means a cyano group, an alkylcarbonyl group with one to four carbon atoms in the alkyl radical, or an alkoxycarbonyl group with one to four carbon atoms in the alkoxy radical, the alkoxycarbonyl group with one to four carbon atoms in the alkoxy radical may also be substituted by a substituent selected from the group consisting of a hydroxyl group, an alkoxy group with one to four carbon atoms, an alkoxycarbonyl group with the number of carbon atoms in alkoxy nom radical of one to four, mono- and dialkylamino with the number of carbon atoms in each alkyl radicals of one to four, heteroaryl and heterocyclyl group,

R ⁵ means a methyl group,

R ⁶ means a hydrogen atom, an alkyl group with one to four carbon atoms, a mono- or dialkylaminocarbonyl group with one to four carbon atoms in each of the alkyl radicals, an alkylcarbonyl group with one to four carbon atoms in the alkyl radical, or an alkoxycarbonyl group with one to four carbon atoms in the alkoxy residue, the alkyl group having one to four carbon atoms and an alkoxycarbonyl group with the number of carbon atoms in the alkoxy the residue from one to four may be substituted by a substituent selected from the group consisting of a heteroaryl, hydroxyl group, an alkoxy group with one to four carbon atoms, a hydroxycarbonyl group, an aminocarbonyl, mono- and dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an amino group, a mono- and dialkylamino group with the number of carbon atoms in each of the alkyl residues from one to four,

or

R ⁶ means a structural unit of the formula

или

or

Where

R ^{6A is} selected from the group consisting of a hydrogen atom and a methyl group,

R ⁷ means trifluoromethyl group or nitro group

and

Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each, means a CH group.

In yet another embodiment, the present invention relates to compounds corresponding to the General formula (I), where A represents a phenyl or pyridyl group.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R ¹ means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds according to the general formula (I), wherein R ² is a cyano group, in particular when A is a phenyl or pyridyl group and R ² is a cyano group attached to the para position with respect to the central dihydropyrimidinone ring.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R ³ means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R ⁴ means an alkoxycarbonyl group with the number of carbon atoms in the alkoxyl radical of one to four, which may be substituted by a hydroxyl group, in particular, it may be 2- hydroxyethoxy-carbonyl group, or where R ⁴ means an alkylcarbonyl group with the number of carbon atoms in the alkyl residue from one to four, in particular, means a methylcarbonyl group.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R ⁵ means a methyl group.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R ⁶ means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds according to the general formula (I), wherein R ⁷ is a trifluoromethyl group or nitro group, in particular when R ⁷ is a trifluoromethyl group attached to the meta position with respect to the central dihydropyrimidinone ring.

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

,

,

Where

Z is a CH group or nitrogen atom and

R ¹ , R ³ , R ⁴ and R ⁶ are as defined above.

Compounds corresponding to the present invention in which R is a hydrogen atom can be enolized into the corresponding hydroxyamidines:

Compounds of general formula (I) can be synthesized by condensation of compounds of general formula (II)

,

,

where A, R ¹ and R ² have the above meanings,

with compounds of the general formula (III)

,

,

Where

R ⁴ and R ⁵ have the above meanings,

and with compounds of general formula (IV)

,

,

Where

R ³ , R ⁷ and fragments from Y ¹ to Y ⁵ have the above meanings,

in the presence of acid as a result of a one-step three-component reaction or in a sequential conversion to form compounds of the general formula (IB)

,

,

Where

A, substituents from R ¹ to R ⁵ , R ⁷ and fragments from Y ¹ to Y ⁵ have the above meanings,

wherein the compounds of general formula (IB) can then react with compounds of general formula (V)

,

,

Where

R ^{6 *} has the meaning given above for R ⁶ , but does not mean a hydrogen atom, and

X means a leaving group, for example, a halogen atom, a tosylate, mesylate or sulfate group,

in the presence of a base.

Compounds of general formula (I), where R ⁴ is a cyano group, R ⁵ is an amino group and R ⁶ is a hydrogen atom, can be obtained in an alternative way by condensation of compounds of general formula (II) with compounds of general formula (IV) and with a compound of formula ( VI)

in the presence of acid during a three-way, one-step reaction or during a sequential conversion.

Suitable solvents for the process (II) + (III) / (VI) + (IV) → (IB) are generally conventional organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, as well as ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide or alcohols such as methanol, ethanol, n-propanol, isopropanol , n-butanol or tert-butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. Mixtures of the above solvents may also be used. Preference is given to carrying out the process in tetrahydrofuran.

Suitable acids for the process (II) + (III) / (VI) + (IV) → (IB) are generally inorganic or organic acids. In a preferred case, their list includes carboxylic acids such as, for example, acetic acid or trifluoroacetic acid, sulfonic acids such as methanesulfonic acid or n-toluenesulfonic acid, hydrochloric acid, or phosphoric acids such as polyphosphoric acid. Polyphosphoric acid ethyl ester is preferred. The acid is used in an amount of from 0.25 moles to 100 moles based on one mole of the compound of general formula III.

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

In general, the process is carried out at normal pressure. However, it is possible that it can be carried out at elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

Suitable solvents for the process (IB) + (V) → (I) are generally conventional organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, as well as ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. Mixtures of the above solvents may also be used. Preference is given to carrying out the process in tetrahydrofuran.

Suitable bases for carrying out the process (IB) + (V) → (I) are generally inorganic or organic bases. In a preferred case, these include cyclic amines such as, for example, piperidine or 4-N, N-dimethylaminopyridine, or trialkylamines with one to four carbon atoms in each of the alkyl radicals, for example, triethylamine or diisopropylethylamine, or hydrides such as sodium hydride. Sodium hydride is preferred. The base is used in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 3 mol, based on 1 mol of the compound of general formula (V).

In the General case, the process is carried out in the temperature range from 0 ° C to + 150 ° C, in the preferred case from + 20 ° C to + 80 ° C, in particular at room temperature. In general, the process is carried out at normal pressure. However, it is possible that it can be carried out at elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

Compounds of the general formulas (II), (III), (IV), (V) and (VI) are known per se or they can be prepared by known methods.

The above method can be illustrated by the following diagram:

The compounds of the invention exhibit a useful spectrum of pharmacological and pharmacokinetic activity, which could not have been foreseen. Therefore, they are suitable for use as medicines for the treatment and / or for the prevention of disease in humans or animals.

It was unexpectedly found that the compounds of the present invention exhibit inhibitory activity against human neutrophil elastase, whereby they can be used for the manufacture of medicaments for the treatment of diseases associated with human neutrophil elastase activity. They can be an effective treatment for acute and chronic inflammatory processes, for example, rheumatoid arthritis, atherosclerosis, and in particular acute and chronic lung diseases such as pulmonary fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome, in particular pulmonary emphysema, including smoker's emphysema, and chronic obstructive pulmonary disease, chronic bronchitis and bronchiectasis. Compounds of the present invention may also be effective agents for the treatment of ischemic cardiovascular diseases such as acute coronary syndrome, acute myocardial infarction, intermittent and persistent angina pectoris, consequences of arterial-coronary artery bypass grafting and progressive heart failure, for the treatment of atherosclerosis, mitral valve disease , atrial septal defects, consequences of percutaneous transluminal coronary angioplasty, inflammation after perazim open heart and pulmonary hypertension. They can also be useful for the effective treatment of rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, Churi-Strauss syndrome, acute and chronic allergic dermatitis, psoriasis, systemic erythematous lupus erythematosus, pemphigus, sepsis, alcoholic hepatitis liver fibrosis, Behcet’s disease, allergic fungal sinusitis, allergic sinusitis, Crohn’s disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal disease her, chronic purulent otitis media of the middle ear, chronic venous varicose veins of the legs, inflammatory diseases of the digestive tract, bacterial and viral infections, brain injuries, stroke and other conditions in which neutrophils are noted.

The present invention also relates to medicines containing at least one compound corresponding to the present invention, preferably together with one or more pharmacologically safe diluents or carriers, and also to their use for the above purposes. The active component may have local and / or systemic effects. To this end, it is administered in an appropriate manner, for example, through the mouth, parenterally, through the lungs, nasally, under the tongue, lingually, buccally, rectally, transdermally, through the conjunctiva, into the ear or as an implant.

For these methods of use, the active component may be administered in the form of appropriate dosage forms.

Suitable oral dosage forms include dosage forms that release the active component rapidly and / or in modified form, for example, tablets (uncoated tablets or coated tablets, for example, coated for the small intestine), capsules, coated tablets sugar, granules, pills, powders, emulsions, suspensions, solutions and aerosols.

Parenteral dosage forms can be used for administration, bypassing the stage of absorption (intravenously, intraarterially, intracardially, intraspinally or in the lumbar region), or including the stage of absorption (intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable dosage forms for parenteral administration include compositions for injection and for infusion in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

Dosage forms used for other routes of administration are, for example, inhaled pharmaceutical forms (including powder inhalers, spray), nasal drops / solutions, aerosols, tablets or capsules on the tongue, under the tongue or cheek (buccal), suppositories, ear and ophthalmic dosage forms, vaginal capsules, aqueous suspensions (lotions, medicines to be shaken), lipophilic suspensions, ointments, creams, milk, pastes, powders for dusting or implants.

The active components can be converted into the named dosage forms by methods that are well known. For this, inert, non-toxic, pharmaceutically acceptable carriers are used. These include, among others, carriers (e.g., microcrystalline cellulose), solvents (e.g., liquid polyethylene glycols), emulsifiers (e.g., sodium dodecyl sulfate), dispersants (e.g., polyvinylpyrrolidone), synthetic and natural biopolymers (e.g., albumin), stabilizers ( for example, antioxidants such as ascorbic acid), colored substances (for example, inorganic pigments such as iron oxide), or means for correcting taste and / or smell.

When used by people, when administered by mouth, it is recommended to administer doses from 0.001 to 50 mg / kg, preferably from 0.01 mg / kg to 20 mg / kg. With parenteral administration, for example, when administered intravenously or through the mucous membranes nasally, buccally or by inhalation, it is recommended to use doses from 0.001 mg / kg to 0.5 mg / kg

However, in certain circumstances, it may be necessary to deviate from the indicated amounts, namely, depending on body weight, route of administration, individual characteristics with respect to the active component, type of dosage form and time or interval in which the dosage form is taken. In certain cases, for example, it may be sufficient to use a lesser amount than the above, while in other cases the above upper limit should be exceeded. In the case of the introduction of increased dosages, it is possible to recommend crushing them into several individual doses distributed throughout the day.

Percentages in the following experiments and examples, unless otherwise indicated, relate to mass ratios, parts also relate to mass units. Solvent ratios, dilutions, and concentrations relating to liquid-in-liquid solutions are in all cases based on volumes.

A. Determination of physiological activity

The ability of the compounds of the invention to inhibit the activity of neutrophilic elastase can be demonstrated, for example, using the following experiments.

I. In vitro enzymatic experiments on human neutrophil elastase

Description of experience

The buffer used in the experiment: 0.1 mol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid with sodium hydroxide, pH 7.4, buffer 0.5, 0.5 mol / L sodium chloride, 0.1% (mass by volume) bovine serum albumin.

The corresponding concentration (see below) of human neutrophilic elastase (18 units per mg, as lyophilisate, # 20927.01, SERVA Electrophoresis GmbH, Handelberg, Germany) in the buffer used for the experiment.

The appropriate concentration (see below) of the substrate in the buffer used for the experiment.

The corresponding concentration of the test compounds diluted with the buffer used for the experiment was obtained from a stock solution in dimethyl sulfoxide with a concentration of 10 mmol / L.

Example A

In vitro inhibition of human neutrophil elastase using a fluorogenic peptide substrate (continuous reading of a signal in 384 MTP format)

In the course of this experiment, an elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC (# 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) was used. The test solution is prepared by mixing 10 μl of a dilute solution of the test substance, 20 μl of a diluted human neutrophil elastase enzyme solution (final concentration from 8 to 0.4 μU / ml, under standard conditions 2.1 μU / ml) and 20 μl of a diluted substrate solution ( final concentration from 1 mmol / l to 1 μmol / l, under standard conditions 20 μmol / l), respectively. The solution is incubated for 0-2 hours at 37 ° C (under standard conditions for 1 hour). The fluorescence of AMS released as a result of the enzymatic reaction is measured at 37 ° C (TECAN spectra fluor plus plate reader). The rate of amplification of fluorescence (excitation 395 nm, radiation 460 nm) is proportional to the activity of elastase. IC ₅₀ values are determined by RFU- [I] plot. The values of K _m and K _{m (obs.)} Are determined according to the Lineweaver-Burke plot and are converted to K _i values according to the Dixon coordinates.

In this experiment, the prepared samples had IC ₅₀ values ranging from 5 nmol / L to 5 μmol / L. Representative examples are shown in table 1.

Table 1. Example No. IC ₅₀ [nmol / L] one 8 9 40 fourteen 5 fifteen 8 16 10 twenty 700 24 13 26 10 28 fifty 58 1100 60 5 72 6 73 60 74 twenty 103 60 109 fifteen 110 fifty

Example B

In vitro inhibition of human neutrophilic elastase using a fluorogenic insoluble elastin substrate (periodic reading of a signal in 96 MTR format)

In the course of this experiment, an elastin-fluorescein substrate of elastase is used (# 100620, ICN Biomedicals GmbH, Eschwege, Germany). The test solution is prepared by mixing 3 μl of a dilute solution of the test substance, 77 μl of a diluted human neutrophil elastase enzyme solution (final concentration from 0.22 U / ml to 2.2 U / ml, under standard conditions 21.7 μU / ml) and 80 μl of a suspension of substrate (final concentration of 2 mg / ml). The suspension is incubated for 0-16 hours at 37 ° C (under standard conditions for 4 hours), gently shaking it. To stop the enzymatic reaction, 160 μl of decimolar acetic acid (final concentration of 50 mmol / L) is added to the test solution. Polymer elastin-fluorescein is precipitated by centrifugation (Eppendorf 5804 centrifuge, 3000 rpm, 10 minutes). The supernatant is transferred to a new MTP and the fluorescence of the peptide fluorescein released as a result of the enzymatic reaction (BMG Fluostar plate reader) is determined. The rate of amplification of fluorescence (excitation 490 nm, radiation 520 nm) is proportional to the activity of elastase. IC ₅₀ values are determined by RFU- [I] plot.

II. In vitro experiments on human neutrophils

Example A

In vitro experiment on elastolytic activity on polymorphonuclear cells

This experience is used to determine the elastolytic ability of human polymorphonuclear cells and assess the degree of degradation associated with neutrophilic elastase [see also Z.W.She et al., Am. J. Respir. Cell. Mol. Biol. 9, 386-392 (1993)].

Tritium-labeled elastin in suspension is applied to a 96-well plate at 10 μg per well. The test substance, the reference substance [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), international patent application No. 95/21855), and an α1 protease inhibitor (приб) are added to the wells at appropriate concentrations. α1PI)]. Human polymorphonuclear cells are separated from the peripheral venous blood of healthy donors and resuspended in the culture medium. Neutrophils are added to wells coated with elastin in concentrations ranging from 1 × 10 ⁶ to 1 × 10 ⁵ cells per well. In the positive control, pork pancreatic elastase (1.3 μmol / L) is used for the experiment, while α1PI (1.2 μmol / L) is used as a positive inhibitor of neutrophilic elastase. Control cells are polymorphonuclear cells without adding substances for each corresponding cell density. Cells with added compounds are incubated in a humidification incubator at 37 ° C. for 4 hours. The plates are centrifuged in order to be able to select only the supernatant over the cells. A 75 μl supernatant was transferred to the corresponding wells of a 96-well Lumaplate ™ plate (plates containing a solid scintillant). The tablets are dried until there is no visible liquid in the wells and counted in a beta counter for 3 minutes per well.

Lysis of ³ H-elastin leads to an increase in the counter reading in the supernatant. Inhibition of such elastolysis leads to a decrease in the tritium content in the supernatant compared to the cell control. With α1PI, inhibition is obtained at 83.46 ± 3.97% (± means a statistically significant confidence interval) at 1.2 μmol / L (for three different data sources at 3.6 × 10 ⁵ cells per well). The IC ₂₀ values obtained for the reference substance ZD-0892 correspond to 45.50 ± 7.75 nmol / L (± means a statistically significant confidence interval) (for two different data sources at 3.6 × 10 ⁵ cells per well).

If we take into account that ZD-0892 is a selective elastase inhibitor of polymorphonuclear leukocytes and take into account the data on inhibition with α1PI, these results indicate that the main degradation of elastin by polymorphonuclear leukocytes is associated with the release of neutrophilic elastase, and not with other elastolytic enzymes , for example, with matrix metalloproteases. The compounds of the present invention showed inhibitory activity in this neutrophil dependent human elastase model experiment on elastin lysis by neutrophils.

Example B

In vitro Inhibition of Membrane Associated Elastase

Determination of elastase inhibition associated with a neutrophil membrane is carried out in experiments using human neutrophils. Neutrophils are stimulated with LPS at 37 ° C for 35 minutes and then centrifuged at 1600 rpm. After that, the membrane-bound elastase is fixed on neutrophils with 3% paraformaldehyde and 0.25% glutaraldehyde for 3 minutes at 4 ° C. After this, neutrophils are centrifuged and the carrier and test compound are added, then the substrate MeOSuc-Ala-Ala-Pro-Val-AMC (# 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) with a concentration of 200 μmol / l is added. After incubation for 25 minutes at 37 ° C, the reaction is stopped with phenylmethanesulfonyl fluoride and the fluorescence is determined by excitation with 400 nm light to radiation at 505 nm. IC ₅₀ values are determined by graphically interpolating the relative fluorescence data as a function of inhibitor concentration.

III. In vivo model experiments

Example A

In vivo model of acute rat lung injury

Instillation of a neutrophilic human elastase in the lung of a rat causes acute damage. The development of this damage can be assessed by measuring pulmonary hemorrhage.

Rats are anesthetized with Hypnorm / Hypnovel / water and are installed with human neutrophil elastase or saline into the lungs via a micropulverizer. The test compounds are administered by intravenous injection, orally or inhaled at the prescribed time before the administration of human neutrophil elastase. Sixty minutes after the administration of elastase, the animals were euthanized with an overdose of anesthetic (pentabarbitone sodium) and the lungs were washed with two milliliters of phosphate-buffered saline supplemented with heparin. The volume of bronchoalveolar lavage is recorded and samples are placed in ice. Each bronchoalveolar lavage sample was centrifuged at 900 rpm for 10 minutes at 4-10 ° C. The supernatant is discarded, and the pelleted cells are resuspended in phosphate buffered saline and centrifuged again. The supernatant is discarded again, and the pelleted cells are resuspended in 1 ml of phosphate-buffered saline containing 0.1% cetyltrimethylammonium bromide to lyse the cells. Before determining the blood content, the samples are frozen. Before analysis for hemorrhage, the samples are thawed and mixed. 100 μl of each sample is added to individual wells of a 96-well flat base plate. All samples are analyzed twice. In a blank experiment, 100 μl of phosphate-buffered saline with heparin containing 0.1% cetyltrimethylammonium bromide was taken. Absorption in the wells is determined using a spectrophotometer at 415 nm. A standard curve is constructed from optical density measurements at 415 nm at various blood concentrations in phosphate buffered saline containing 0.1% cetyltrimethylammonium bromide. The values of the blood content are calculated according to the results of comparison with the standard curve (it is built for each tablet) and lead them to the obtained volume of liquid bronchoalveolar lavage.

In this model, rat hemorrhage induced by human neutrophilic elastase in rats, the inhibitory activity of the compounds of the invention was studied by intravenous, oral and inhalation.

Example B

Model experiment in rats with acute myocardial infarction in vivo

Elastase inhibitors are tested in an experiment on a rat-simulated infarcted ligation. Male Wistar rats (weighing more than 300 g) receive 10 mg / kg of aspirin 30 minutes before surgery. They are anesthetized with isoflurane and artificial ventilation is performed during the entire operation (120-130 beats per minute, single volume 200-250 μl, MiniVent Type 845, Hugo Sachs Elektronik, Germany). After opening the chest on the left side in the fourth intercostal space, the pericardium is opened and the heart is removed for a short time. A loop is applied around the left coronary artery without closing it. A tourniquet is passed under the skin to the back of the animal. The chest is closed and the animal is allowed to recover for four days. On the fifth day, the rats are anesthetized with ether for three minutes, the loop is tightened, closing the left coronary artery, controlling the process by electrocardiogram. The test compounds are administered before occlusion of the left coronary artery or after that orally, intraperitoneally or intravenously (injection or continuous infusion). 1 hour after occlusion, the constriction is opened, restoring blood flow. The hearts are removed and after 48 hours the sizes of the heart attacks are determined by staining the hearts after repeated occlusion with Evans blue dye, followed by staining of triphenyltetrazolium chloride with 2 mm heart sections. Areas with normal oxygenation (tissue not affected by occlusion) are colored blue, ischemic zones (affected by occlusion but not dead) are colored red, and necrotic zones (tissue that has died as a result of occlusion) remain white. Each tissue section is scanned and infarct sizes are determined using computer planimetry.

B. Examples

Abbreviations:

aq. water conc. concentrated DMF N, N-dimethylformamide Dmso dimethyl sulfoxide Ei electron impact ionization (mass spectrometry) ESI electrospray ionization (for mass spectrometry) Hlpc high performance liquid chromatography (HPLC) LC-MS liquid chromatography combined with mass spectrometry Mr melting temperature Ms mass spectrometry NMR nuclear magnetic resonance spectroscopy (NMR) of. th. from theory (output) R _t retention time (with HPLC) Thf Tetrahydrofuran

General techniques

All reactions are carried out in an argon atmosphere, unless otherwise indicated. Solvents are used as received from Aldrich without further purification. The term “silica gel” or “silica” refers to silica gel grade 60 (0.040 mm-0.063 mm) from Merck KGaA. Melting points are determined on a Biichi 512 instrument or on a similar instrument for determining the melting point; they are not corrected.

Compounds purified by preparative HPLC were purified on an RP18 column using acetonitrile with water as an eluent, gradient from 1: 9 to 9: 1.

Liquid chromatography mass spectrometry and HPLC

Liquid chromatomass spectrometry, method 1

Instrument Type: Micromass Quattro LCZ, HP 1100; column: Uptisphere HDO, 50 mm × 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; thermostat: 55 ° C; flow rate: 0.8 ml / min; UV detector: 208-400 nm.

Liquid chromatography mass spectrometry, method 2

Device: Waters Alliance 2790 LC; column: Symmetry C18, 50 mm × 2.1 mm, 3.5 μm; eluent A: water + 0.1% formic acid; eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0 minutes 5% B → 5.0 minutes 10% B → 6.0 minutes 10% B; temperature 50 ° C; flow rate: 1.0 ml / min; UV detector: 210 nm.

Liquid chromatomass spectrometry, method 3

Device: Micromass Platform LCZ, HP1100; column: Aquasil C-18, 50 mm × 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; thermostat: 55 ° C; flow rate: 0.8 ml / min; UV detector: 208-400 nm.

Liquid chromatomass spectrometry, method 4

Device: HP 1100 with a digital diode array detector; column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; eluent: A = 5 ml of HClO ₄ per 1 liter of water, B = acetonitrile; gradient: 0 minutes 2% B, 0.5 minutes 2% B, 4.5 minutes 90% B, 6.5 minutes 90% B; flow rate: 0.75 ml / min; temperature: 30 ° C; UV detector: 210 nm.

Liquid chromatomass spectrometry, method 5

Device: Micromass TOF-MUX-Interface, 4x parallel input, with Waters 600 HPLC; column: Uptisphere HDO, 50 mm × 2.0 mm, 3.0 μm; eluent A: 1 l of water + 1 ml of 50% formic acid; eluent B: 11 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 → 4.6 minutes 100% A → 6.5 minutes 100% A; thermostat: room temperature; flow rate: 0.8 ml / min; UV detector: 210 nm.

Liquid chromatomass spectrometry, method 6

Instrument: Micromass Platform LCZ with Agilent Serie 1100 HPLC; column: Grom-SIL120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; eluent A: 1 l of water + 1 ml of 50% formic acid; eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 minutes 100% A → 0.2 minutes 100% A → 2.9 minutes 30% A → 3.1 minutes 10% A → 4.5 minutes 10% A; thermostat: 55 ° C; flow rate: 0.8 ml / min; UV detector: 208-400 nm.

Liquid chromatomass spectrometry, method 7

Instrument: Micromass Quattro LCZ with Agilent Serie 1100 HPLC; column: Uptisphere HDO, 50 mm × 2.0 mm, 3 μm; eluent A: 1 l of water + 1 ml of 50% formic acid; eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 minutes 100% A → 0.2 minutes 100% A → 2.9 minutes 30% A → 3.1 minutes 10% A → 4.5 minutes 10% A; thermostat: 55 ° C; flow rate: 0.8 ml / min; UV detector: 208-400 nm.

Source products

Example 1A

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

In a round-bottom flask equipped with a reflux condenser and a Dean-Stark trap, 6-bromo-3-pyridinecarbaldehyde (500 mg, 2.7 mmol) and 1,2-ethanediol (200 mg, 3.2 mmol) are dissolved in toluene (50 ml) ) together with Amberlyst 15 resin (100 mg). The solution was left overnight under reflux and stirring, then cooled to room temperature, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel with cyclohexane and ethyl acetate as the eluent to give the title compound as a colorless oil.

Yield 0.489 g (79% of theory).

HPLC (method 4): 3.46 minutes.

Mass spectrum (electrospray ionization, positive ions): m / z = 231 (M + H) ⁺ .

¹ H-NMR (300 MHz, deuterochloroform): δ = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) ppm.

Example 2A

5- (1,3-dioxolan-2-yl) -2-pyridinecarbonitrile

The substance of Example 1A (2.8 g, 12.5 mmol), zinc cyanide (1.6 g, 13.8 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.4 g, 1.3 mmol) are dissolved in dimethylformamide (100 ml) and left overnight (for 18 hours) with stirring at 80 ° C. More tetrakis (triphenylphosphine) palladium (0) (0.1 g) was added and again left overnight (for 18 hours) with stirring at 80 ° C, then left for 2 days (48 hours) at room temperature. The solvent was removed in vacuo, water (100 ml) was added to the residue, and the product was extracted with ethyl acetate (1 L). The organic phase is washed with a solution of sodium chloride (200 ml), dried with magnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel with cyclohexane and ethyl acetate as the eluent to give the title compound as a white amorphous solid.

Yield 0.94 g (42% of theory).

HPLC (method 4): 3.21 minutes.

Mass spectrum (electrospray ionization, positive ions): m / z = 177 (M + H) ⁺ .

¹ H-NMR (400 MHz, d ₆ -dimethyl sulfoxide): δ = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4.13- 3.94 (m, 4H) ppm.

Example 3A

5-Formyl-2-pyridinecarbonitrile

Method a)

The synthesis is carried out by analogy with the methods of Dodd, D. and others [J. Org. Chem. 1992, 57, 7226-7234]. To a stirred solution of 5- (1,3-dioxolan-2-yl) -2-pyridinecarbonitrile (as in Example 2A, 850 mg, 4.8 mmol) in acetone with water 85:15 (59.5 ml) was added n-toluene -sulfonic acid (102 mg, 0.59 mmol). The reaction mixture was left overnight (for 18 hours) under reflux and with stirring, then additional n-toluenesulfonic acid (50 mg) and water (5 ml) were added. The reaction mixture was stirred at the boil under reflux for another 48 hours. The solution was cooled to room temperature and a saturated sodium bicarbonate solution was added. The product is extracted with ethyl acetate (3 times 100 ml), dried over magnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC to give a pale yellow solid.

Yield 0.66 g (93% of theory).

Mp 80-82 ° C.

HPLC (method 4): 2.13 minutes.

Mass spectrum (electrospray ionization, positive ions): m / z = 133 (M + H) ⁺ .

¹ H-NMR (400 MHz, d ₆ -dimethyl sulfoxide): δ = 10.18 (s, 1H), 9.21 (m, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm

Method b)

1.04 g (8.2 mmol) of oxalyl chloride are dissolved in 8 ml of dichloromethane. At −78 ° C., 1.28 g (16.4 mmol) of dimethyl sulfoxide are added dropwise. The solution was stirred at -78 ° C for 20 minutes, then 1 g (7.46 mmol) of the substance of Example 5A was added as a solution in 7 ml of dichloromethane, stirring was continued at -78 ° C for another 2 hours, then was added dropwise 3.4 g (33.6 mmol) of triethylamine and, after warming to room temperature, the mixture is purified by column chromatography (silica, eluent: from cyclohexane to cyclohexane with ethyl acetate 2: 1).

Yield 0.76 g (77% of theory).

Analytical data is given above.

Example 4A

5-methyl-2-pyridinecarbonitrile

In 500 ml of dimethylformamide, 36 g (209 mmol) of 2-bromo-5-methylpyridine and 37.5 g (418 mmol) of copper cyanide are refluxed for two hours. After cooling to 50 ° C., 10% aqueous ammonia solution (500 ml) is added with stirring. The product was extracted with dichloromethane, the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The product is purified by column chromatography (silica, eluent cyclohexane with ethyl acetate 9: 1).

Yield 18 g (73% of theory).

¹ H-NMR (300 MHz, deuterochloroform): δ = 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm.

Example 5A

The compound of Example 4A (13 g, 110 mmol) was dissolved in 400 ml of carbon tetrachloride and 29.4 g (165 mmol) of N-bromosuccinimide and 0.4 g (1.6 mmol) of dibenzoyl peroxide were added. The reaction mixture was refluxed for three hours, cooled to room temperature and filtered. The solution was washed with aqueous sodium thiosulfate, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was dissolved in 200 ml of dioxane and 200 ml of water, calcium carbonate (44 g, 440 mmol) was added and the mixture was heated at reflux for 2 hours with stirring. After cooling to room temperature, the mixture was filtered and dichloromethane was added. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent cyclohexane with ethyl acetate 2: 1).

Yield 5.2 g (35% of theory).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 4.7 (d, 2H), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 ( s., 1H) ppm.

Production Examples

Example 1

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

7.0 g (34.29 mmol) of N- [3-trifluoromethyl) phenyl] urea, 8.99 g (68.58 mmol) of 4-cyanobenzaldehyde, 8.92 g (68.58 mmol) are suspended in 250 ml of tetrahydrofuran. 3-ketobutanoic acid ethyl ester; and 20 g polyphosphoric acid ethyl ester. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 13.4 g (91%).

¹ H-NMR (200 MHz, d ₆ -dimethylsulfoxoxy): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.4 (d, 1H) ppm.

Example 2

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

265 mg (1.3 mmol) of N- [3- [3- (trifluoromethyl) phenyl] urea, 131 mg (1.0 mmol) of 4-cyanobenzaldehyde and 100 mg (1.0 mmol) are suspended in 2 ml of tetrahydrofuran 2, 4-pentanedione and a catalytic amount of concentrated hydrochloric acid is added. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 29 mg (7%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 2.0 (s, 3H); 2.2 (s, 3H); 5.5 (d, 1H); 7.5 (m, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H); 8.5 (d, 1H) ppm.

Example 3

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

In 2 ml of tetrahydrofuran, 204 mg (1.0 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 142 mg (0.77 mmol) of 4-bromobenzaldehyde and 100 mg (0.77 mmol) of 3-ketobutane ethyl ester are suspended. acids, a catalytic amount of concentrated hydrochloric acid is added. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 23 mg (6%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.4 (m, 2H); 7.6 (m, 3H); 7.7 (m, 3H); 8.3 (d, 1H) ppm.

Example 4

6-Methyl-2-oxo-1- (4-fluorophenyl) -4- (4-cyanophenyl) -1,2,3,4-tetra-hydro-5-pyrimidinecarboxylic acid ethyl ester

154 mg (1.0 mmol) of N- (4-fluorophenyl) urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of 3-ketobutanoic acid ethyl ester are suspended in 2 ml of tetrahydrofuran; a catalytic amount of concentrated hydrochloric acid. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 40 mg (14%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.3 (m, 4H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm.

Example 5

6-methyl-2-oxo-1- (3-chlorophenyl) -4- (4-cyanophenyl) -1,2,3,4-tetra-hydro-5-pyrimidinecarboxylic acid ethyl ester

170 mg (1.0 mmol) of N- (3-chlorophenyl) urea, 100 g (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of 3-ketobutanoic acid ethyl ester are suspended in 2 ml of tetrahydrofuran, and 3-ketobutanoic acid ethyl ester is added. a catalytic amount of concentrated hydrochloric acid. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 13 mg (4%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.2 (m, 1H); 7.4 (m, 3H); 7.5 (m, 2H); 7.9 (m, 2H); 8.3 (d, 1H) ppm.

Example 6

(1S) -1-Methyl-2-methoxy-2-oxoethyl ether 6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4 -tetrahydro-5-pyrimidinecarboxylic acid

200 mg (0.98 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 129 mg (0.98 mmol) of 4-cyanobenzaldehyde, 92 mg (0.49 mmol) of (1S) -1 are suspended in 3 ml of tetrahydrofuran. 3-ketobutanoic acid methyl 2-methoxy-2-oxoethyl ester; and polyphosphoric acid ethyl ester 295 mg. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent. A mixture of diastereomers is obtained.

Yield 96 mg (40%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.3 (d, 3H); 1.4 (d, 3H); 2.0 (s, 3H + 3H); 3.6 (s, 3H); 3.6 (s, 3H); 5.0 (m, 1H + 1H); 5.4 (m, 1H + 1H); 7.6-7.9 (m, 8H + 8H); 8.4 (m, 1H + 1H) ppm.

Example 7

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

150 mg (0.73 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 96 mg (0.73 mmol) of 4-cyanobenzaldehyde, 63 mg (0.37 mmol) of 4- (4-) are suspended in 3 ml of tetrahydrofuran. morpholinyl) -4-keto-2-butanone and 220 mg polyphosphoric acid ethyl ester. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with dichloromethane and methanol as eluent.

Yield 28 mg (16%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.5 (s, 3H); 3.1 (m, 4H); 3.6 (m, 4H); 5.3 (br s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (br.s, 1H) ppm.

Example 8

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

200 mg (0.98 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 128 mg (0.98 mmol) of 4-cyanobenzaldehyde, 77 mg (0.49 mmol) of 4- (4-) are suspended in 3 ml of tetrahydrofuran. di-ethylamino) -4-keto-2-butanone and 295 mg of polyphosphoric acid ethyl ester. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with dichloromethane and methanol as eluent.

Yield 106 mg (47%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 0.9 (m, 6H); 3.1 (m, 4H); 5.2 (br s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H); 8.0 (br.s, 1H) ppm.

Example 9

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

400 mg (1.97 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 199 mg (1.51 mmol) of 4-cyanobenzaldehyde and 100 mg (1.51 mmol) of malononitrile are suspended in 2 ml of tetrahydrofuran and a catalytic amount is added concentrated hydrochloric acid. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with dichloromethane and methanol as eluent.

Yield 4 mg (1%).

¹ H-NMR (400 MHz, d ₆ -dimethyl sulfoxide): δ = 5.2 (d, 1H); 6.0 (s, 2H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.4 (d, 1H) ppm.

Example 10

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -3-formyl-4- (4-cyano-phenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester acid

100 mg (0.23 mmol) of the compound of Example 1 are dissolved in 1 ml of dimethylformamide and 35.7 mg (0.23 mmol) of phosphoryl chloride are added. The reaction mixture is stirred for 2 hours at 70 ° C. After cooling to room temperature, the product was isolated by preparative HPLC.

Yield 43 mg (41%).

¹ H-NMR (300 MHz, d ₆ dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.1 (s, 3H); 4.1 (q, 2H); 6.4 (s, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 4H); 9.2 (s, 1H) ppm.

Example 11

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

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

Yield 1.27 g (45%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.0 (s, 3H); 5.4 (d, 1H); 7.6 (m, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm.

Example 12

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

40 mg (0.1 mmol) of the compound of Example 11 are dissolved in 2 ml of dimethylformamide, 7 mg (0.11 mmol) of n-propylamine, 15 mg (0.11 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 12 mg are added (0.1 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred at 0 ° C and 21 mg (0.11 mmol) of 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride are added. The reaction mixture was stirred at room temperature for 18 hours, then water and ethyl acetate were added. The organic phase is washed with saturated aqueous potassium bisulfate, water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 29 mg (66%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 0.7 (t, 3H); 1.3 (sext., 2H); 1.7 (s, 3H); 3.0 (q, 2H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, 1H); 8.1 (d, 1H) ppm.

Example 13

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

48 mg (0.12 mmol) of the compound of Example 11 are dissolved in 2 ml of dimethylformamide, 10 mg (0.13 mmol) of 2-methoxyethylamine, 18 mg (0.13 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 15 mg are added. (0.12 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred at 0 ° C and 25 mg (0.13 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added. The reaction mixture was stirred at room temperature for 18 hours, then water and ethyl acetate were added. The organic phase is washed with saturated aqueous potassium bisulfate, water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 22 mg (40%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.7 (s, 3H); 3.2 (s, 3H); 3.3 (m, 4H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 3H); 7.9 (m, 2H); 8.1 (m, 1H) ppm.

Example 14

3,6-Dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

To a suspension of 12.4 mg (0.31 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 89 mg (0.21 mmol) of the compound of Example 1. The mixture was stirred at room temperature for 2 hours. Then 26 mg (0.21 mmol) of dimethyl sulfate are added and the mixture is stirred at room temperature for another 2 hours. After that, water and ethyl acetate are added and the organic phase is washed with water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 85 mg (93%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (q, 2H); 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.

Example 15

3-Acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyano-phenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

To a suspension of 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0.23 mmol) of the compound of Example 1. The mixture was stirred at room temperature for 2 hours. Then 91 mg (1.16 mmol) of acetyl chloride are added and the mixture is stirred at room temperature for another 2 hours. After that, water and ethyl acetate are added and the organic phase is washed with water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 93 mg (85%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.2 (t, 3H); 2.1 (s, 3H); 2.5 (s, 3H); 4.2 (m, 2H); 6.7 (s, 1H); 7.4 (m, 1H); 7.5 (m, 2H); 7.6 (m, 1H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) ppm.

Example 16

4-Methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -6- (4-cyanophenyl) -3,6-dihydro-1,5 (2H) -pyrimidinedicarboxylic acid diethyl ester

To a suspension of 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0.23 mmol) of the compound of Example 1. The mixture was stirred at room temperature for 2 hours. Then 126 mg (1.16 mmol) of ethyl chlorocarbonate are added and the mixture is stirred at room temperature for another 2 hours. After that, water and ethyl acetate are added and the organic phase is washed with water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 92 mg (79%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.2 (t, 3H; t, 3H); 2.1 (s, 3H); 4.2 (m, 2H); 4.3 (q, 2H); 6.4 (s, 1H); 7.4 (m, 1H); 7.5 (m, 3H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 2H) ppm.

Example 17

6-methyl-1- [3- (methyl) phenyl] -2-oxo-4- (4-cyanophenyl) -1,2,3,4-tetra-hydro-5-pyrimidinecarboxylic acid ethyl ester

150 mg (1.0 mmol) of N- (3-methylphenyl) urea, 101 mg (0.77 mmol) of 4-cyanobenzaldehyde and 100 mg (0.77 mmol) of 3-ketobutanoic acid ethyl ester are suspended in 2 ml of tetrahydrofuran and a catalytic amount of concentrated hydrochloric acid is added. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 8 mg (3%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.0 (m, 2H); 7.2 (m, 1H); 7.3 (m, 1H); 7.6 (m, 2H); 7.9 (m, 2H); 8.2 (d, 1H) ppm.

Example 18

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-chlorophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

204 mg (1.0 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 108 mg (0.77 mmol) of 4-chlorobenzaldehyde and 100 mg (0.77 mmol) of 3- ethyl ester are suspended in 2 ml of tetrahydrofuran. ketobutanoic acid and a catalytic amount of concentrated hydrochloric acid is added. The mixture was refluxed for 18 hours with stirring. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 29 mg (9%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.3 (d, 1H); 7.5 (m, 5H); 7.6 (m, 1H); 7.7 (m, 2H); 8.3 (d, 1H) ppm.

Example 19

6-Bromomethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

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

Yield 3.2 g (90%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 4.0 (q, 2H, d, 1H); 4.6 (bd, 1H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.6 (d, 1H) ppm.

Example 20

6 - [(diethylamino) methyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

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

Yield 15 mg (75%).

¹ H-NMR (300 MHz, d ₆ dimethyl sulfoxide): δ = 0.6 (t, 6H); 1.1 (t, 3H); 2.0 (m, 2H); 2.2 (m, 2H); 3.1 (bd, 1H); 3.9 (bd, 1H); 4.1 (q, 2H); 5.4 (d, 1H); 7.5 (m, 1H); 7.6 (m, 4H); 7.7 (m, 1H); 7.9 (m, 2H) ppm.

Example 21

6- (Anilino) methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

50 mg (0.1 mmol) of the compound of Example 19 are dissolved in 2 ml of acetone and 18 mg (0.20 mmol) of aniline are added. The mixture was stirred at room temperature for 18 hours, then the solvent was removed in vacuo. The residue was purified by preparative HPLC.

Yield 28 mg (55%).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 3.6 (dd, 1H); 4.1 (q, 2H); 4.4 (dd, 1H); 5.4 (m, 2H); 6.2 (m, 2H); 6.5 (m, 1H); 6.9 (m, 2H); 7.6 (m, 6H); 7.9 (m, 2H); 8.4 (d, 1H) ppm.

Example 22

(+) - 6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

The enantiomers of the compound of Example 1 are separated by preparative HPLC on a chiral phase: 100 mg of the compound is dissolved in 1.5 ml of ethyl acetate, column KBD 8361 (chiral silica gel selector based on N-methacryloyl-L-leucine-1-methylamide monomer, see application European patent No. A-379917) 250 mm × 20 mm, ethyl acetate as eluent, flow rate 25 ml / min, temperature 23 ° C., injection volume 2500 μl, detector 254 nm.

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 4.0 (q, 2H); 5.4 (d, 1H); 7.6 (m, 3H); 7.7 (m, 2H); 7.8 (m, 1H); 7.9 (m, 2H); 8.4 (d, 1H) ppm.

[α] ²⁰ = + 3.3 ° (λ = 589 nm, dichloromethane, c = 535.0 mg per 100 ml).

Example 23

(-) - 3,6-Dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

To a suspension of 14 mg (0.35 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0.23 mmol) of the compound of Example 22. The mixture was stirred at room temperature for 2 hours. Then 29 mg (0.23 mmol) of dimethyl sulfate are added and the mixture is stirred at room temperature for another 2 hours. After that, water and ethyl acetate are added and the organic phase is washed with water and a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness in vacuo. The product was purified by silica gel column chromatography with cyclohexane and ethyl acetate as eluent.

Yield 76 mg (74%).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 2.8 (s, 3H); 4.0 (q, 2H); 5.5 (s, 1H); 7.6 (m, 3H); 7.7 (m, 1H); 7.8 (m, 2H); 7.9 (m, 2H) ppm.

[α] ²⁰ = -18.1 ° (λ = 589 nm, dichloromethane, c = 530.0 mg per 100 ml).

Example 24

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (6-cyano-3-pyridinyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

To a solution of the compound of Example 3A (76 mg, 0.58 mmol) in tetrahydrofuran (5 ml), 3-ketobutanoic acid ethyl ester (75 mg, 0.58 mmol), N- [3- (trifluoromethyl) phenyl] was added with stirring urea (118 mg, 0.58 mmol) and polyphosphoric acid ethyl ester (200 mg, freshly prepared according to the method of Cava and others, J. Org. Chem. 1969, 34, 2665). The reaction mixture was refluxed for two days (48 hours), after which the solution was diluted with dimethyl sulfoxide (2 ml) and purified using preparative HPLC. The product fractions were concentrated in vacuo and again chromatographed on silica with cyclohexane and ethyl acetate as eluent.

Yield 92 mg (35% of theory).

Mass spectrum (electrospray ionization, positive ions): m / z = 431 (M + H) ⁺ .

HPLC (method 4) = 4.63 minutes.

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 8.76 (s, 1H), 8.36 (d, 1H), 8.16-8.00 (m, 2H), 7.83-7.74 (m, 2H), 7.75-7.58 (m, 2H), 5.47 (d, 1H), 4.03 (q, 2H), 2, 06 (s, 3H), 1.08 (t, 3H) ppm.

Example 25

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

To a solution of 501 mg (1.25 mmol) of the compound of Example 11 in 5 ml of dry dimethylformamide, 567 mg (3.5 mmol) of N, N-carbonyldiimidazole are added. The reaction mixture was left overnight, after which the solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate and washed with water and a solution of sodium chloride. It is then dried with magnesium sulfate and the solvent is distilled off in vacuo. Yield 500 mg (88.6% of theory).

Mass spectrum (electron impact ionization): m / z = 452 (M + H) ⁺ .

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.40 (d, 3H), 5.5 (d, 1H), 7.0 (s, 1H), 7.55- 8.0 (m, 9H), 8.4 (s, 1H), 8.45 (d, 1H) ppm.

Example 26

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-hydroxyethyl ester

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of ethylene glycol. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (Agilent Zorbax Extend C18 column 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B:

water + 0.1% concentrated ammonia; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength 220 nm; the input volume of about 500 μl, the number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 22 mg (49.4% of theory).

Mass spectrum (electron impact ionization): m / z = 446 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): S = 2.05 (d, 3H), 3.5 (q, 2H), 3.95-4.15 (m, 2H), 4.75 (t, 1H), 5.45 (d, 1H), 7.55-7.75 (m, 5H), 7.75 (d, 1H), 7.85 (d. , 2H); 8.35 (d, 1H) ppm.

Example 27

6- Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2- (dimethylamino) ethyl ester

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 2- (dimethylamino) ethanol. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (Agilent Zorbax Extend C 18 column 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength 220 nm; injected volume of about 500 μl, number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 24 mg (50.8% of theory).

Mass spectrum (electron impact ionization): m / z = 473 (M + H) ⁺ .

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

Example 28

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

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 2- (4-pyridinyl) ethanol. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (Agilent Zorbax Extend C 18 column 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength 220 nm; injected volume of about 500 μl, number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 17 mg (33.5% of theory).

Mass spectrum (electron impact ionization): m / z = 507 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.0 (d, 3H), 2.9 (t, 2H), 4.3 (t, 2H), 5.25 ( d, 1H), 7.15 (d, 2H). 7.45 (d, 2H), 7.5 (d, 1H), 7.65 (t, 2H), 7.8 (m, 3H), 8.35 (d, 1H). 8.4 (d, 2H) ppm.

Example 29

6- methyl-2-oxo-1- [3- (trifluoro-methyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5- 2- (2-pyridinyl) ethyl ether pyrimidine carboxylic acid

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 2- (2-pyridinyl) ethanol. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (Agilent Zorbax Extend C 18 column 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength 220 nm; injected volume of about 500 μl, number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 22 mg (43.4% of theory).

Mass spectrum (electron impact ionization): m / z = 507 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.0 (d, 3H), 3.0 (t, 2H), 4.4 (t, 2H), 5.25 ( d, 1H), 7.15-7.25 (m, 2H), 7.4 (d, 2H), 7.5 (d, 1H), 7.6-7.75 (m, 3H) ), 7.8 (m, 3H), 8.3 (d, 1H), 8.45 (d, 1H) ppm.

Example 30

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

45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml of 1- (2-hydroxyethyl) -2-pyrrolidinone. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (Agilent Zorbax Extend CIS column 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength 220 nm; injected volume of about 500 μl, number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 25 mg (48.8% of theory).

Mass spectrum (electron impact ionization): m / z = 513 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.8 (quin., 2H), 2.0 (d, 3H), 2.1 (t, 2H), 3.2 ( t, 2H), 3.4 (t, 2H), 4.0-4.2 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7, 6 (d, 2H), 7.7 (t, 2H), 7.8 (d, 1H), 7.9 (d, 2H), 8.4 (d, 1H) ppm .

The following compounds were obtained by analogy with the methods of examples 14-16.

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 31

The compound of example 1, ethyl bromo acetate 85 4.01 (1) 516 32

The compound of example 1, cyclopropane-carbonyl chloride 79 4.09 (1) 498 33

The compound of example 1, bromoethane fifteen 4.28 (2) 458 34

The compound of example 1, 4-morpholine-carbonyl chloride 97 3.97 (2) 543

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 35

The compound of example 1, dimethylcarbamoyl chloride 98 4.00 (2) 523
[M + Na] ⁺ 36

The compound of example 1, methylchlorocarbonate 96 4.10 (2) 488 37

The compound of example 1, benzyl bromide 58 4.59 (2) 520 38

The compound of example 1, propanoyl chloride 43 4.42 (2) 486

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 39

The compound of example 1, 2-methoxy-ethylchloro-carbonate 95 4.12 (2) 532 40

The compound of example 1, isopropyl chlorocarbonate 67 4.55 (2) 500 41

The compound of example 1, diethylcarbamoyl chloride eighteen 4.25 (2) 529 42

The compound of example 1, methyl (methyl-sulfonyl) -carbamoyl chloride 40 4.10 (2) 565

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 43

The compound of example 1, 2-bromoacetamide, 2.5 equivalents of sodium hydride 54 3.7 (3) 487 44

The compound of example 1, 2-bromoacetic acid, 2.5 equivalents of sodium hydride 67 3.8 (3) 488 45

The compound of example 1, 2-bromoethane-amine hydrobromide, 2.5 equivalents of sodium hydride 28 2.9 (2) 473 46

The compound of example 1, 2- (chloromethyl) -pyridine hydrochloride, 2.5 equivalents of sodium hydride 37 4.0 (3) 521

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 47

The compound of Example 1, H- (2-bromo-ethyl) -N, N-diethylamine hydrobromide, 2.5 equivalents of sodium hydride 82 2.98 (2) 529 48

The compound of example 1, 2-bromo-N-methylacetamide, 2.5 equivalents of sodium hydride 65 3.70 (2) 501 49

The compound of example 1, 3- (chloromethyl) -pyridine hydrochloride, 2.5 equivalents of sodium hydride fifteen 3.68 (2) 521 fifty

The compound of example 1, 4- (chloromethyl) -pyridine hydrochloride, 2.5 equivalents of sodium hydride 21 3.47 (2) 521

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 51

The compound of example 1, 2- (bromomethyl) -1H-imidazole hydrobromide, 2.5 equivalents of sodium hydride 6 2.97 (2) 510 52

The compound of example 1, 3- (chloromethyl) -1,2,4-oxadiazole 37 4.0 (3) 469 53

The compound of example 1, 2-bromo-N- (2-methoxyethyl) -acetamide 91 3.77 (2) 545

The following compounds were obtained by analogy with the methods of examples 6-8.

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 54

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, 3-ketobutanoic acid methyl ester 79 3.68 (2) 416 55

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, 3-ketobutanoic acid cyclopropyl methyl ether 58 4.09 (2) 456 56

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, 3-ketobutanoic acid isopropyl ester 85 4.03 (2) 444 57

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, (1R) -2-methoxy-1-methyl-2-oxoethyl ester of 3-ketobutanoic acid 73 3.2 (2) 488

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 58

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, N, N-dimethylamide 3-ketobutanoic acid 9 3.2 (2) 429

Example 59

6-methyl-3- [2- (4-morpholinyl) -2-oxoethyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3 ethyl ester , 4-tetrahydro-5-pyrimidinecarboxylic acid

80 mg (0.16 mmol) of the compound of Example 44 are dissolved in 2 ml of dimethylformamide, 16 mg (0.18 mmol) of morpholine, 24 mg (0.18 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 20 mg (0) are added. , 16 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred at 0 ° C and then 35 mg (0.18 mmol) of 1- (3-di-methylaminopropyl) -3-ethylcarbodiimide hydrochloride are added. The reaction mixture was stirred at room temperature for 18 hours, then water and ethyl acetate were added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. If necessary, the product is further purified by column chromatography or preparative HPLC.

Yield 78 mg (85%).

¹ H-NMR (300 MHz, d ₆ dimethyl sulfoxide): δ = 1.1 (t, 3H); 2.0 (s, 3H); 3.4 (m, 4H); 3.6 (m, 4H); 3.7 (d, 1H); 4.1 (m, 2H); 4.5 (d, 1H); 5.5 (s, 1H); 7.6 (m, 5H); 7.8 (m, 1H); 7.9 (m, 2H) ppm.

By analogy with the method of example 59 receive the following compounds.

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 60

The compound of example 44, N-methyl-piperazine 90 2.93 (2) 570 61

The compound of example 44, N- (2-amino-ethyl) -N, N-dimethylamine 87 2.93 (2) 558 62

The compound of example 44, dimethylamine (2 mol / l in tetrahydrofuran) 83 3.84 (2) 515

By analogy with the methods of examples 6-8 receive the following compounds.

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 63

N- [3- (trifluoromethyl) phenyl] urea, 4-cyano-benzaldehyde, 1- (3-methyl-1,2,4-oxadiazol-5-yl) acetone 23 3.80 (3) 440 64

N- [3- (trifluoromethyl) phenyl] urea, 4-cyano-benzaldehyde, 1- (1,3-benztriazol-2-yl) acetone 23 4.42 (2) 491 65

N- [3- (trifluoromethyl) phenyl] urea, 4-cyano-benzaldehyde, 5-methyl-2,4-hexanedione 33 4.3 (1) 428 66

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

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 67

N- [3- (trifluoromethyl) phenyl] urea, 4-cyanobenzaldehyde, 1- (2-furyl) -1,3-butanedione 13 3.70 (2) 452 68

N- [3- (trifluoromethyl) phenyl] urea, 4-cyano-benzaldehyde, 1-phenyl-1,3-butanedione fourteen 4.03 (2) 462 69

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

Example 70

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

200 mg (0.5 mmol) of the compound of Example 11 are dissolved in 5 ml of tetrahydrofuran and 6 mg (0.05 mmol) of 4-N, N-dimethylaminopyridine, 77 mg (0.6 mmol) of N, N-diisopropylethylamine and 115 are added. mg (0.6 mmol) of benztriazol-1-yl-hydroxy-tris (pyrrolidino) phosphonium hexafluorophosphate. The reaction mixture was stirred for 15 minutes at room temperature, then 5 ml of ammonia solution (2.5 mmol as a solution in dioxane with a concentration of 0.5 mol / l) was added. The reaction mixture was stirred for 1 hour at room temperature, then water and ethyl acetate were added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The product is further purified by preparative HPLC.

Yield 55 mg (28% of theory).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 1.8 (s, 3H); 5.4 (d, 1H); 7.2 (br.s, 1H); 7.4 (br.s, 1H); 7.6 (m, 5H); 7.7 (m, 1H); 7.9 (m, 2H); 8.1 (d, 1H) ppm.

Example 71

(+) - 6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

The enantiomers of the compound of Example 11 were separated by preparative HPLC on a chiral phase [column KBD 8361 (chiral silica gel selector based on N-methacryloyl-L-leucine-1-methylamide monomer, see also European Patent Application No. A-379917), 250 mm × 20 mm, eluent: ethyl acetate → methanol → ethyl acetate, flow rate 25 ml / min, temperature 23 ° C, detector 254 nm].

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.0 (s, 3H); 5.4 (d, 1H); 7.6 (m, 1H); 7.6 (m, 2H); 7.7 (m, 1H); 7.8 (m, 1H); 7.9 (m, 3H); 8.3 (d, 1H); 12.5 (s, 1H) ppm.

[α] ²⁰ = + 2.5 ° (λ = 589 nm, methanol, s = 505 mg / 100 ml).

Example 72

(+) - 6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-hydroxyethyl ester

In an argon atmosphere, 1560 mg (3.89 mmol) of the compound of Example 71 are added to 19.6 ml of dimethylformamide. After the addition of 1.095 ml (7.86 mmol) of triethylamine and 1.11 ml (15.7 mmol) of 2-bromoethanol, the reaction is stirred mixture at a temperature of about 70 ° C for 8 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. After drying with magnesium sulfate, the organic phase is evaporated in vacuo. The residue was dissolved in 8 ml of methanol and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus, 20 × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.3% formic acid; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl ; number of entries: 18). The fractions containing the product are combined and lyophilized.

Yield 1290 mg (74.5% of theory).

Mass spectrum (electron impact ionization): m / z: 446 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.05 (d, 3H); 3.5 (q, 2H); 3.95-4.15 (m, 2H); 4.75 (t, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 8.35 (d, 1H) ppm.

[α] ²⁰ = + 14.3 ° (λ = 589 nm, methanol, s = 455 mg / 100 ml).

Example 73

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

To a solution of the compound of Example 3A (75 mg, 0.57 mmol) in tetrahydrofuran (5 ml), 2,4-pentanedione (57 mg, 0.57 mmol), N- [3- (trifluoromethyl) phenyl] urea is added with stirring (116 mg, 0.57 mmol) and polyphosphoric acid ethyl ester (200 mg, freshly prepared according to the method of Cava and others, J. Org. Chem. 1969, 34, 2665).

The reaction mixture was refluxed for 24 hours, after which time the solution was diluted with dimethyl sulfoxide (2 ml) and purified using preparative HPLC.

Yield 101 mg (44% of theory).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 2.02 (s, 3H); 2.24 (s, 3H); 5.54 (d, 1H); 7.52-7.90 (m, 4H); 8.08 (d, 2H); 8.50 (d, 1H); 8.81 (s, 1H) ppm.

Example 74

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

The enantiomers of the compound of Example 73 were separated by preparative HPLC on a chiral phase [column KBD 8361 (chiral silica gel selector based on N-methacryloyl-L-leucine-1-methylamide monomer, see also European Patent Application No. A-379917), 250 mm × 20 mm, eluent: ethyl acetate → methanol → ethyl acetate, flow rate 25 ml / min, temperature 23 ° C, detector 254 nm].

¹ H-NMR (300 MHz, deuterochloroform): δ = 2.06 (s, 3H); 2.35 (s, 3H); 5.69 (d, 1H); 6.02 (d, 1H); 7.29-7.50 (m, 2H); 7.57-7.75 (m, 3H); 7.83 (dd, 1H); 8.74 (d, 1H) ppm.

[α] ²⁰ = + 25.1 ° (λ = 589 nm, methanol, s = 505 mg / 100 ml).

Example 75

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

To a solution of 40.1 mg (0.1 mmol) of the compound of Example 11 in 0.4 ml of dry dimethylformamide was added 48.6 mg (0.3 mmol) of N, N-carbonyldiimidazole. The reaction mixture was left for one hour, after which the reaction mixture was diluted with water and extracted with dichloromethane. After drying with magnesium sulfate, the solvent is distilled off in vacuo. 0.5 ml of (2-pyridinyl) methanol is added to the residue. The reaction mixture is stirred for 1 hour at a temperature of about 100 ° C. After cooling, the reaction mixture was purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 minutes 10 % A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injected volume : about 550 μl; number of injections: 1). The fractions containing the product are combined and evaporated in vacuo.

Yield 17 mg (34.5% of theory).

Mass spectrum (electron impact ionization): m / z = 493 (M + H) ⁺ .

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 2.1 (d, 3H); 5.15 (dd, 2H); 5.45 (d, 1H); 7.05 (d, 1H); 7.3 (dd, 1H); 7.5-7.85 (m, 9H); 8.35 (d, 1H); 8.5 (d, 2H) ppm.

Example 76

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

To a solution of 60.2 mg (0.15 mmol) of the compound of Example 11 in 0.57 ml of dry dimethylformamide, 72.9 mg (0.45 mmol) of N, N-carbonyldiimidazole are added. The reaction mixture was left for one hour, after which the reaction mixture was diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is distilled off in vacuo. 185 mg (1.5 mmol) of 2- (3-pyridinyl) ethanol and 20 μl (0.27 mmol) of triethylamine are added to the residue. The reaction mixture is stirred for 1 hour at 100 ° C. After this, the reaction mixture was diluted by adding 0.4 ml of methanol, filtered and purified using preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0, 1% formic acid; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injected volume: about 550 μl; number of injections: 1). The fractions containing the product are combined and evaporated in vacuo.

Yield 44 mg (57.9% of theory).

Liquid chromatography-mass spectrometry (electron impact ionization, method 5): m / z = 507 (M + H) ⁺ , retention time 3.19 minutes.

Example 77

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

4.1 g (9.25 mmol) of the compound of Example 14 are dissolved in 100 ml of ethanol. 6.2 ml (27.6 mmol) of a solution of potassium hydroxide in water (25 wt.%) Are added to this solution. The reaction mixture is left for 18 hours at room temperature. Then add another 12.4 ml (55.2 mmol) of a solution of potassium hydroxide in water (25 wt.%) And the reaction mixture is stirred for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The aqueous phase is acidified with 1 N. hydrochloric acid and extracted with ethyl acetate. This latter extract is dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica with cyclohexane and ethyl acetate as eluent.

Yield 1.5 g (39% of theory).

Mass spectrum (electron impact ionization): m / z = 416 (M + H) ⁺ .

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

By analogy with the procedure of example 76 receive the following compounds.

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 78

The compound of example 11, 3-pyridinyl-methanol 56.9 3.45 (5) 493 79

The compound of example 11, 2-hydroxy-acetamide ¹⁾ 61.1 3.38 (5) 459 80

The compound of example 11, 2-hydroxy-ethyl (methyl) -formamide 80.9 3.5 (5) 487 81

The compound of example 11, 2-hydroxy-ethylacetamide 56.2 3.44 (5) 487

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 82

The compound of example 11, (1-methyl-1H-imidazol-5-yl) -methanol ¹⁾ 45.8 2.87 (5) 496 83

The compound of example 11, 2- (1H-pyrazol-1-yl) ethanol 60.6 3.7 (5) 496 84

The compound of example 11, 2- (1H-1,2,4-triazol-1-yl) -ethanol ¹⁾ 67.1 3.48 (5) 497 85

The compound of example 11, 2-hydroxy-ethyl acetate 56.1 3.98 (5) 488

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 86

The compound of example 11, 2- (dimethyl-amino) -2-methyl-1-propanol 34.6 2.9 (5) 502 87

The compound of example 11, 3- (dimethyl-amino) -propanol 54.8 2.86 (5) 487 88

The compound of example 11, 2- (1-pyrrole-dinyl) ethanol 56.2 2.86 (5) 500 89

The compound of example 77 2- (3-pyridinyl) ethanol 58.9 3.36 (5) 522

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 90

The compound of example 77, (3-pyridinyl) methanol 61.9 3.64 (5) 507 91

The compound of example 77, 2-hydroxy-acetamide ¹⁾ 53.6 3.54 (5) 473 92

The compound of example 77, 2-hydroxy-ethyl (methyl) -formamide 54.6 3.68 (5) 501 93

The compound of example 77, 2-hydroxy-ethylacetamide 66.6 3.59 (5) 501

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 94

The compound of example 77, (1-methyl-1 H-imidazol-5-yl) methanol ¹⁾ 34.0 3.02 (5) 510 95

The compound of example 77, 2- (1H-pyrazol-1-yl) ethanol 61.5 3.91 (5) 510 96

The compound of example 77, 2- (1H-1,2,4-triazol-1-yl) -ethanol ¹⁾ 71.8 3.64 (5) 511 97

The compound of example 77, 2-hydroxy-ethyl acetate 53,2 4.12 (5) 502

Example No. Formula Source products Exit [%] R _t [min] (method) Weight [M + H] ⁺ 98

The compound of example 77, 2- (dimethyl-amino) -2-methyl-1-propanol 25.9 3.02 (5) 516 99

The compound of example 77, 3- (dimethyl-amino) propanol 54.6 2.98 (5) 502 one hundred

The compound of example 77, 2- (1-pyrroli-dinyl) ethanol 55.9 2.98 (5) 514 101

The compound of example 77, (2-pyridinyl) methanol 67.1 3.91 (5) 507 1) In this case, the alcohol used is a solid and the reaction is carried out in the presence of 0.4 ml of dimethylformamide.

Example 102

1- (3,5-Dichlorophenyl) -6-methyl-2-oxo-4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

In an argon atmosphere in 0.5 ml of dioxane, 30.8 mg (0.15 mmol) of N- (3,5-dichlorophenyl) urea are stirred at 80 ° C for 4 hours together with 39.3 mg (0.3 mmol) of 4- formyl benzonitrile, 39 mg (0.3 mmol) of 3-ketobutanoic acid ethyl ester and 90 mg of trimethylsilyl polyphosphate. After adding a small amount of dimethyl sulfoxide, the reaction mixture was filtered and purified using preparative HPLC (column: Agilent Zorbax Extend C 18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; 0 minutes 10% A, 2 minutes 10% A, b minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injection volume: about 500 μl; number of injections: 1). The fractions containing the product are combined and evaporated in vacuo.

Yield 38.1 mg (59% of theory).

Liquid chromatography-mass spectrometry (electron impact ionization, method 7): m / z = 431 (M + H) ⁺ , retention time 4.14 minutes.

Example 103

6-Methyl-4- (3-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid ethyl ester

30.6 mg (0.15 mmol) of N- [3- (trifluoromethyl) phenyl] urea are shaken in 0.5 ml of dioxane and 0.1 ml of dimethylformamide at a temperature of 80 ° C for 18 hours together with 45.3 mg (0, 3 mmol) of 3-nitrobenzaldehyde, 39 mg (3 mmol) of ethyl ester of 3-ketobutanoic acid and 90 mg of ethyl ester of polyphosphoric acid (freshly prepared according to the method of Cava and others, J. Org. Chem. 1969, 34, 2665). After adding 200 μl of dimethylformamide, the reaction mixture was filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 minutes 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injected volume: about 800 μl; number of inputs: 1). The fractions containing the product are combined and evaporated in vacuo.

Yield 34 mg (50.4% of theory).

Liquid chromatography-mass spectrometry (electron impact ionization, method b): m / z = 450 (M + H) ⁺ , retention time 3.94 minutes.

By analogy with the procedure of example 102 receive the following compounds.

Example No. Formula Source products Exit [%] R _t [min (method) Weight [M + H] ⁺ 104

N- (3-nitrophenyl) urea, 4-chlorobenzaldehyde, 3-ketobutanoic acid ethyl ester 70.5 3.65 (6) 417 105

N- (3-nitrophenyl) urea, 3-nitrobenzaldehyde, 3-ketobutanoic acid ethyl ester 81.3 3.61 (6) 427 106

N- (3-nitrophenyl) urea, 4-fluorobenzaldehyde, 3-ketobutanoic acid ethyl ester 56.8 3.63 (6) 400 107

N- (3-nitrophenyl) urea, 4-bromobenzaldehyde, 3-ketobutanoic acid ethyl ester 69.5 4.02 (5) 461

Example 108

6-Methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -4- (4-cyanophenyl) -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid 2-cyanoethyl ester

9.87 g (48.3 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 12.68 g (96.68 mmol) of 4-cyanobenzaldehyde, 15 g (96.68 mmol) are suspended in 250 ml of tetrahydrofuran. 3-ketobutanoic acid 2-cyanoethyl ester and polyphosphoric acid ethyl ester. The mixture is stirred for 18 hours at the boil under reflux. After cooling to room temperature, the solvent was distilled off in vacuo and the residue was purified by silica gel chromatography with cyclohexane and ethyl acetate as an eluent.

Yield 25 g (100% of theory).

¹ H-NMR (200 MHz, d ₆ -dimethyl sulfoxide): δ = 2.1 (s, 3H); 2.8 (m, 2H); 4.2 (m, 2H); 5.4 (d, 1H); 7.6 (m, 4H); 7.7 (m, 2H); 7.9 (m, 2H); 8.5 (d, 1H) ppm.

Example 109

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

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

Yield 249 mg (43% of theory).

¹ H-NMR (300 MHz, d ₆ -dimethyl sulfoxide): δ = 1.8 (s, 3H); 5.4 (d, 1H); 7.7 (m, 4H); 7.8 (m, 2H); 8.0 (m, 2H), 8.4 (d, 1H) ppm.

Example 110

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

In 100 ml of tetrahydrofuran, 7.84 g (38.4 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 5.81 g (38.4 mmol) of 4-nitrobenzaldehyde are suspended, 5.0 g (38.4 mmol) of ethyl ester of 3-ketobutanoic acid and 15 g of ethyl ester of polyphosphoric acid. The mixture is stirred for 18 hours at the boil under reflux. After cooling to room temperature, the solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography with toluene and ethyl acetate as an eluent.

Yield 8.75 g (51% of theory).

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

Example 111

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

0.407 g (2.0 mmol) of N- [3- (trifluoromethyl) phenyl] urea, 0.302 g (2.0 mmol) of 4-nitrobenzaldehyde, 0.2 g (2.0 mmol) of 2 are suspended in 20 ml of tetrahydrofuran. 4-pentanedione and 0.4 g of polyphosphoric acid ethyl ester. The mixture is stirred for 18 hours at the boil under reflux. After cooling to room temperature, the solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography with cyclohexane and ethyl acetate as an eluent.

Yield 0.302 g (36% of theory).

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

B. Examples of production methods related to pharmaceutical compositions

Compounds of the invention may be converted into pharmaceutical preparations by the following methods.

Tablet

Structure:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (unmodified), 10 mg of polyvinylpyrrolidone (PVP 25) (manufactured by BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

The weight of the tablet is 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production method

A mixture of the active component, lactose and starch is granulated with a 5% solution (wt.%) Of polyvinylpyrrolidone in water. After drying, the granules are mixed with magnesium stearate for 5 minutes. From this mixture, tablets are compressed using a conventional tablet press (tablet format shown above). The pressing force is typically 15 kN.

Suspension for oral administration

Structure:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of rhodigel (xanthan gum arabic produced by FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention is contained in 10 ml of an oral suspension.

Production method

Rodigel is suspended in ethanol and the active component is added to the suspension. With stirring, water is added. Stirring is continued for approximately 6 hours until the process of swelling of the rodigel is completed.

Claims (8)

1. Compounds of General Formula (I)

,
where A represents a phenyl or pyridyl ring,
R ¹ and R ³ each means a hydrogen atom,
R ² means a fluorine atom, chlorine, bromine, nitro group or cyano group,
R ⁴ means a cyano group, an alkylcarbonyl group with one to four carbon atoms in the alkyl radical, or an alkoxycarbonyl group with one to four alkoxy carbon atoms, the alkoxycarbonyl group having one to four carbon atoms in the alkoxy radical is substituted by a substituent selected from the group consisting of a hydroxyl group, an alkoxy group with one to four carbon atoms, an alkoxycarbonyl group with the number of carbon atoms in the alkoxyl group attack from one to four, mono- or dialkylamino groups with the number of carbon atoms in each of the alkyl residues from one to four, 5-6-membered heteroaryl groups containing from 1 to 4 heteroatoms in the heteroaryl ring selected from nitrogen, oxygen or sulfur, possibly substituted alkyl group containing from 1 to 4 carbon atoms and possibly condensed with a benzene ring, and 5-8 membered heterocyclyl group containing from 1 to 3 heteroatoms from the group of nitrogen, oxygen or sulfur, or SO, SO ₂ , possibly substituted by a keto group ,
R ⁵ means a methyl group,
R ⁶ means a hydrogen atom, an alkyl group with the number of carbon atoms from one to four, a mono- or dialkylaminocarbonyl group with the number of carbon atoms in each of the alkyl residues from one to four, an alkylcarbonyl group with the number of carbon atoms in the alkyl residue from one to four, or an alkoxycarbonyl group with the number of carbon atoms in the alkoxy radical of one to four, the alkyl group with the number of carbon atoms from one to four and an alkoxycarbonyl group with the number of carbon atoms in the alkoxy the residue from one to four may be substituted by a substituent selected from the group consisting of a 5-6 membered heteroaryl group containing from 1 to 4 heteroatoms in the ring selected from nitrogen, oxygen or sulfur, a hydroxyl group, an alkoxy group with carbon atoms from one to four, hydroxycarbonyl group, aminocarbonyl, mono- and dialkylaminocarbonyl groups with the number of carbon atoms in each of the alkyl residues from one to four, amino groups, mono- and dialkylamino groups with the number of carbon atoms in each of alk one to four residues, or
R ⁶ means a structural unit of the formula

, or

where R ^{6A is} selected from the group consisting of a hydrogen atom and a methyl group,
R ⁷ means a trifluoromethyl group or a nitro group, and
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each means a CH group, as well as their pharmaceutically acceptable salts, hydrates and / or solvates. 2. The compounds of General formula (I) according to claim 1, where R ² means a cyano group. 3. The compounds of General formula (I) according to claim 1 or 2, where R ⁴ means an alkoxycarbonyl group with the number of carbon atoms in the alkoxy residue of one to four, which may be substituted by a hydroxyl group, or where R ⁴ means an alkylcarbonyl group with the number carbon atoms in the alkyl residue from one to four. 4. The compounds of general formula (I) according to any one of claims 1 to 3, where R ⁶ means a hydrogen atom. 5. The compounds of General formula (I) according to claim 1, where the remainder

means

where Z is a CH group or a nitrogen atom and
R ¹ has the values given in claim 1,
R ³ , R ⁴ and R ⁶ are as defined in claim 1, R ⁵ is methyl, Y ¹ -Y ⁴ is CH, each, and R ⁷ is trifluoromethyl at position 3 of the phenyl moiety. 6. The compound of general formula (I) according to claim 1, which is a compound 5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4- tetrahydro-4-pyrimidinyl} -2-pyridinecarbonitrile. 7. The compound of general formula (I) according to claim 1, which is a compound (+) - 5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2, 3,4-tetrahydro-4-pyrimidinyl} -2-pyridinecarbonitrile. 8. A pharmaceutical composition having the properties of a human neutrophilic elastase inhibitor, comprising at least one compound of general formula (I) according to claims 1 to 5, and a pharmaceutically acceptable diluent.