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

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

 

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

Fibrous protein elastin, which in percentage terms is a substantial fraction of all proteins in some tissues, such as arteries, in some connective tissues, the tissues of the lungs and heart, may be hydrolysed or otherwise destroyed by a special group of enzymes classified as elastase. Leukocyte elastase person (class 3.4.21.37), also known as neutrophil elastase person, is a heavily glycosylated basic serine protease, which is azurophilic granules polymorphically of human leukocytes. Neutrophil elastase person is released from activated polymorphically leukocytes, she may participate in the pathogenesis of acute and chronic inflammatory diseases. Neutrophil elastase person causes the degradation of a wide range of matrix proteins, including elastin and collagen, in addition to this action on connective tissue neutrophil elastase person exhibits a broad spectrum of vocal the positive activity, including the activation of gene expression of IL-8, the formation of edema, hyperplasia of mucous glands and mucus hypersecretion. It also performs the role of mediator in the damaged tissue as a result of hydrolysis of the collagen structures, for example, in the heart after acute myocardial infarction or in the process of development of heart failure, thus damaging the cells of the endothelium, promoting extravasation of neutrophils adjacent to the endothelium, and influencing the process of adhesion.

Pulmonary disease, in which, as is plays the role of neutrophil elastase include pulmonary fibrosis, pneumonia, acute respiratory disease, emphysema of the lungs, including emphysema caused by Smoking, chronic obstructive pulmonary disease and cystic fibrosis. In cardiovascular diseases neutrophil elastase person involved in the development of ischemic tissue damage with subsequent disruption of the functioning of the heart muscle after acute myocardial infarction and reduction processes occurring in progressive heart failure. Neutrophil elastase person may also participate in the course of rheumatoid arthritis, atherosclerosis, brain trauma, cancer and in similar conditions, with the participation of neutrophils.

In line with this, inhibitory activity of neutrophil elastase 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 the activity of neutrophil elastase person can be also used for the treatment of acute miocardio syndrome, intermittent angina, acute myocardial infarction and arterial-coronary bypass surgery [..Tiefen-bacher and others, Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, S563-S570 (1997); Dinerman and others, 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 and others, Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy, Cardiov. Res. 34. S377-S383 (1997)] and atherosclerosis [Dollery and others, Neutrophil elastase in human atherosclerotic plaque. Circulation 107, 2829-2836 (2003)].

Synthesis of 5-etoxycarbonyl-1-phenyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-it is described in J. Heterocyclic Chem. 38, 1051 (2001). Data on the pharmacological activity of this compound are not available.

The present invention relates to compounds of General formula (I)

where

A represents aryl or heteroaryl cycle

R1, R2and R3independently from each other mean a hydrogen atom, halogen, a nitro-group, a cyano, alkyl group with carbon atoms of from one to six hydroxyl group and the and alkoxygroup with the number of carbon atoms of from one to six, moreover, an alkyl group with the number of carbon atoms of from one to six and alkoxygroup with the number of carbon atoms of from one to six can be from one to three times substituted by identical or different substituents selected from the group consisting of halogen atoms, hydroxyl groups and alkoxygroup with the number of carbon atoms one to four,

R4means triftormetilfullerenov, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, allenxlenalee group with the number of carbon atoms in Alchemilla the balance from one to six, hydroxycarbonyl, aminocarbonyl group, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, arylaminomethylene group with the number of carbon atoms in the aryl residue from six to ten, arylcarbamoyl, heteroarylboronic, geterotsiklicheskikh, heteroaryl, heterocyclyl group, or cyano, and acylcarnitine group the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, mono - and dialkylaminoalkyl g is the SCP with the number of carbon atoms in each alkyl residue of from one to four can be from one to three times substituted by identical or different substituents, selected from the group consisting of cycloalkyl group with the number of carbon atoms from three to eight hydroxyl groups, alkoxygroup with the number of carbon atoms one to four, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, hydroxycarbonyl, aminocarbonyl group, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic with the number of carbon atoms in the alkyl residue of from one to four, allylcarbamate alkylamino with the number of carbon atoms in each alkyl residue of from one to four, ceanography, amino mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl, heterocyclyl group and trialkylsilyl group with the number of carbon atoms in each alkyl residue of from one to six, and where heteroarylboronic, heterocyclyl-carbonyl, and heteroaryl heterocyclyl group may also be substituted by alkyl groups with carbon atoms of from one to four,

R5means alkyl group with the number of carbon atoms one to four, which can be from one to three times substituted by identical or different substituents which, selected from the group consisting of halogen atoms, hydroxyl group, alkoxygroup with the number of carbon atoms of from one to six, allinoneruby with the number of carbon atoms of from one to six, alkylthiol group with the number of carbon atoms of from one to six, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to six, killingray, hydroxycarbonyl group, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six and alkoxyalkyl group with the number of carbon atoms in each of CNS residues from one to four,

or

R5means an amino group,

R6means a hydrogen atom, alkyl group with carbon atoms of from one to six, formyl, aminocarbonyl group, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, cycloalkylcarbonyl group with the number of carbon atoms in cycloalkyl the remainder from three to eight, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, N-alkylsulfonamides aminocarbonyl group with the number of carbon atoms in alkylen the m residue from one to four, N-alkylsulfonamides N-alkylaminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl, heterocyclyl, heteroarylboronic or geterotsiklicheskikh group, with the alkyl group with the number of carbon atoms of from one to six, mono - and dialkyl aminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, heteroaryl and heterocyclyl group can be from one to three times substituted by identical or different substituents selected from the group consisting of aryl, heteroaryl, hydroxyl group, alkoxygroup with the number of carbon atoms one to four, hydroxycarbonyl group, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, aminocarbonyl, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic with the number of atoms of plastics technology : turning & the Yes in the alkyl residue one to four, trialkylsilyl group with the number of carbon atoms in each alkyl residue of from one to six, ceanography, N-alkylamineacetate aminocarbonyl group and N,N-dialkylaminoalkyl aminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four, N-alkoxysilanes aminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four halogen atoms,

or

R6means a structural unit of the formula

,or

where

R6Aselected from the group consisting of hydrogen atom and alkyl groups with carbon atoms of from one to six, and

n means an integer of 1 or 2,

R7means a halogen atom, a nitro-group, a cyano, alkyl group with carbon atoms of from one to six hydroxyl group, or alkoxygroup with the number of carbon atoms of from one to six, with an alkyl group with the number of carbon atoms of from one to six and alkoxygroup with the number of carbon atoms of from one to six can be from one to three times substituted by identical or different substituents selected from the group consisting of halogen atoms, hydroxyl groups and alkoxygroup with the number of atoms ug is erode from one to four,

and

Y1, Y2, Y3, Y4and Y5independently from each other mean a CH group or a nitrogen atom, and the cycle may include 0, 1 or 2 nitrogen atom.

Relevant to the present invention compounds may also be presented in the form of their salts, hydrates and/or solvate.

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

In accordance with the invention, the term physiologically acceptable salts refers to non-toxic salts, which in General case can be obtained by the reaction of compounds (I) with inorganic or organic base or an inorganic or organic acid, are commonly used for these purposes. Examples of pharmaceutically acceptable salts of compounds (I), which may not be used to limit the scope of the claims, include salts with alkali metals such as lithium, potassium and sodium salts, such salts with alkaline earth metals such as magnesium and calcium salts including Quaternary ammonium salts, such as, for example, triethylammonium salts, acetates, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borates, bromides, carbonates, chlorides, citrates, dihydrochloride, fumarate, gluconate, glutamate, hexylresorcinol, hydrobromide, hydrochloride, hydro is xinafoate, the iodides, isothionate, lactate, laurate, malate, maleate, salt almond acid, mesylates, methylbromide, methylnitrate, methylsulfate, nitrates, oleates, oxalates, palmitate, Pantothenate, phosphates, diphosphate, polygalacturonate, salicylates, stearates, sulfates, succinate, tartratami, tozilaty, valerate and other salts commonly used in medical purposes.

Hydrates relevant to the invention compounds or their salts are stoichiometric compositions of these compounds with water, for example, this polyhydrate, monohydrate or dihydrate.

A corresponding solvate of the invention compounds or their salts are stoichiometric compositions of these compounds with solvents.

The present invention includes both the individual enantiomers or diastereoisomers, and the corresponding racemates or mixtures of diastereoisomers corresponding to the invention of compounds and their corresponding salts. In addition, the scope of claims of the present invention includes all possible tautomeric forms of the above compounds. Diastereomeric mixtures can be separated into individual isomers by chromatographic processes. The racemates can be separated into the corresponding enantiomers as by chromatographic processes on chiral phases, and regular sposobamiraboty.

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

The alkyl group in General represents a hydrocarbon radical with a linear or branched chain with the number of carbon atoms of from one to six, in the preferred case, from one to four carbon atoms. Examples that may not be used to limit the scope of the claims, include metal, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, hexeline, isohexyl group. The same applies to such substituents as CNS group, alkylamino, alkoxycarbonyl group and alkoxycarbonylmethyl.

Alkoxygroup as an example and preferably presents a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, tert-butoxypropyl, n-phenoxypropane and n-hexachrome.

Acylcarnitine group in General represents a hydrocarbon radical with a linear or branched chain with the number of carbon atoms of from one to six, in the preferred case, with the number of carbon atoms one to four, which is attached via a carbonyl group. Examples that may not be used to limit the volume is and claims, include formyl, acetyl, n-propionyl, n-butyryloxy, isobutyryloxy, pivaloyloxy, n-hexanoyl group.

Alkoxycarbonyl group as an example and preferably presents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxy-carbonyl, tert-butoxycarbonyl, n-phenoxycarbonyl and n-hexoxyethanol group.

Alkylamino is alkylamine radical with one or two (independently selected from each other) alkyl substituents, as an example, and preferably it is represented by methylaminopropane, arylaminopoly, n-propylamino, isopropylamino, tert-butylamino, n-intellimorph, n-hexylamino, N,N-dimethylaminopropyl, N,N-diethylaminopropyl, N-methyl-N-arylaminopoly, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylaminopropane, N-ethyl-N-n-intellimorph and N-n-hexyl-N-methylaminopropane.

Alkylaminocarbonyl group is alkylaminocarbonyl radical with one or two (independently selected from each other) alkyl substituents, as an example, and preferably it presents methylaminoethanol, ethylaminoethanol, n-propylenecarbonate, isopropylaminocarbonyl, tert-is ethylaminoethanol, n-intramyocardially, n-hexylaniline, N,N-dimethylaminocarbonylmethyl, N,N-diethylaminocarbonylmethyl, N-methyl-N-ethylaminomethyl, N-methyl-N-n-propylaminosulfonyl, N-ISO-propyl-N-n-propylaminosulfonyl, N-tert-butyl-N-methylaminoethanol, N-ethyl-N-n-intramyocardially and N-n-hexyl-N-methylaminomethyl group.

Alkylsulfonyl group in General represents a hydrocarbon residue with a linear or branched chain with the number of carbon atoms of from one to six, in the preferred case, from one to four carbon atoms attached through sulfonyloxy group. Examples that may not be used to limit the scope of the claims include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylaniline, n-butylsulfonyl, tert-butylsulfonyl group.

Cycloalkyl group in General is a cyclic saturated hydrocarbon residue with the number of carbon atoms from three to eight, in the preferred case from three to six carbon atoms. Examples that may not be used to limit the scope of the claims include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo and cycloheptyl group.

Aryl group itself and in arylcarbamoyl the Noah 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 presents phenyl, naftilos or phenanthroline group. Arylcarbamoyl group as an example and preferably presents bentilee and naftolin group.

Heteroaryl group itself and in heteroarylboronic group represents an aromatic mono - or disilicate balance with the number of atoms in the cycle in General from five to ten, in the preferred case from five to six, and with up to five heteroatoms, in the preferred case, up to four, selected from the group consisting of sulfur atoms, oxygen, and nitrogen, as an example, and preferably it presents thienyl, furillo, pyrrolidino, thiazolidine, oxazolidine, imidazolidine, oxadiazolidine, thiadiazolidine, peredelnoj, pyrimidines, pyridazinyl, indolines, indazolinone, benzofuranyl, bestoftulsacgi, benzthiazoles, hyalinella, ethanolamines group. Heteroarylboronic group as an example and preferably presents taylorsville, fuelleborni, pyrrolidinones, thiazolecarboxamide, oxazolidinones, imidazoledicarbonitrile, pirimicarb the ilen, pyrimidinecarbonitrile, pyridinecarboxylic, indolocarbazoles, indotricarbocyanine, benzofurazanyl, bestoverture.info, chinainternational, izohinolinove group.

Heterocyclyl group itself and in heterocalixarenes group represents a non-aromatic heterocyclic residue with the number of cycles from one to several, in the preferred case, from one to two, and with the number of atoms in cycles in General from four to ten, in the preferred case from five to eight, and the number of heteroatoms and/or heterogroup to three, in the preferred case, up to two selected from the group consisting of nitrogen atoms, oxygen, sulfur, a group SO and SO2. Heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to monocyclic saturated heterocyclyl balances with the number of members from five to eight and the number of heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, up to two, as an example, and preferably they are presented tetrahydrofuran-2-ilen, pyrrole-DIN-1-ilen, pyrrolidin-2-ilen, pyrrolidin-3-ilen, pyrrolidine, piperidinyl, morpholinyl, peligrosamente group.

Geterotsiklicheskikh group as an example and preferably redstavlena tetrahydrofuran-2-carbonyl, pyrrolidin-1-carbonyl, pyrrolidin-2-carbonyl, pyrrolidin-3-carbonyl, pyrrolidinecarbonyl, piperidinecarbonitrile, morpholinylcarbonyl, perhydroanthracene group.

Halogen represents fluorine, chlorine, bromine and iodine.

If you specify that Y1, Y2. Y3, Y4and Y5mean CH group or a nitrogen atom, then this means that instead of the CH-groups in the cycle may also be a carbon atom, which is substituted by substituent R3or R7.

The * symbol next to the link means the place to which it is attached to the molecule.

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

A represents aryl or heteroaryl cycle

R1, R2and R3independently from each other mean a hydrogen atom, halogen, a nitro-group, a cyano, alkyl group with carbon atoms of from one to six hydroxyl group, or alkoxygroup with the number of carbon atoms of from one to six, with an alkyl group with the number of carbon atoms of from one to six and alkoxygroup with the number of carbon atoms of from one to six can be from one to three times substituted by identical or different substituents selected from the group consisting of halogen atoms, hydroxyl groups and alkoxygroup with the number of carbon atoms from the real is up to four,

R4means alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, allenxlenalee group with the number of carbon atoms in Alchemilla the balance from one to six, hydroxycarbonyl, aminocarbonyl group, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, arylaminomethylene group with the number of carbon atoms in the aryl residue from six to ten, heteroarylboronic, geterotsiklicheskikh, heteroaryl, heterocyclyl group, or cyano, and acylcarnitine group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four can be from one to three times substituted by identical or different substituents selected from the group consisting of cycloalkyl group with the number of carbon atoms from three to eight hydroxyl groups, alkoxygroup with the number of carbon atoms one to four, alkoxycarbonyl group with the number of atoms in the of Lerida in CNS residue from one to four, hydroxycarbonyl, aminocarbonyl group, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic with the number of carbon atoms in the alkyl residue of from one to four, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl, heterocyclyl group and trialkylsilyl group with the number of carbon atoms in each alkyl residue of from one to six,

R5means alkyl group with the number of carbon atoms one to four, which can be from one to three times substituted by identical or different substituents selected from the group consisting of halogen atoms, hydroxyl group, alkoxygroup with the number of carbon atoms of from one to six, allinoneruby with the number of carbon atoms of from one to six, alkylthiol group with the number of carbon atoms of from one to six, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to six, killingray, hydroxycarbonyl group, alkoxycarbonyl group with the number of carbon atoms in the CNS the balance from one to six and alkoxyalkyl group with the number of carbon atoms in each of CNS Ostashkovo one to four,

or

R5means an amino group,

R6means a hydrogen atom, alkyl group with carbon atoms of from one to six, formyl, aminocarbonyl group, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, cycloalkylcarbonyl group with the number of carbon atoms in cycloalkyl the remainder from three to eight, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, N-alkylsulfonamides aminocarbonyl group with the number of carbon atoms in the alkyl residue of from one to four, N-alkylsulfonamides N-alkylaminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl, heterocyclyl, heteroarylboronic or geterotsiklicheskikh group, with the alkyl group with the number of carbon atoms of from one to six, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS the remainder of the one on the six, heteroaryl and heterocyclyl group can be from one to three times substituted by identical or different substituents selected from the group consisting of aryl, heteroaryl, hydroxyl group, alkoxygroup with the number of carbon atoms one to four, hydroxycarbonyl group, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, aminocarbonyl, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, with alkylcarboxylic the number of carbon atoms in the alkyl residue of from one to four, trialkylsilyl group with the number of carbon atoms in each alkyl residue of from one to six, ceanography, N-alkylamineacetate aminocarbonyl group and N,N-dialkylaminoalkyl aminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four, N-ALK-oxyalkylene aminocarbonyl group with the number of carbon atoms in each alkyl residue of from one to four halogen atoms,

or

R6means a structural unit of the formula

, or

where

R6Aselected from the group consisting of a hydrogen atom or alkyl group with carbon atoms of from one to six, and n means an integer of 1 or 2,

R7means a halogen atom, a nitro-group, a cyano, alkyl group with carbon atoms of from one to six hydroxyl group, or alkoxygroup with the number of carbon atoms of from one to six, with an alkyl group with the number of carbon atoms of from one to six and alkoxygroup with the number of carbon atoms of from one to six can be from one to three times substituted by identical or different substituents selected from the group consisting of halogen atoms, hydroxyl groups and alkoxygroup with the number of carbon atoms one to four,

and

Y1, Y2, Y3, Y4and Y5independently from each other mean a CH group or a nitrogen atom, and the cycle may include 0, 1 or 2 nitrogen atom.

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

A represents phenyl, nattily or peredelnyj cycle

R1, R2and R3independently from each other mean a hydrogen atom, fluorine, chlorine, bromine, a nitro-group, a cyano, metal, ethyl, triptorelin group or cryptometer,

R4means alkitab the strong group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six, hydroxycarbonyl, aminocarbonyl group, monoacylglycerols group with the number of carbon atoms in the alkyl residue of from one to four or cyano, and acylcarnitine group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six and monoacylglycerols group with the number of carbon atoms in the alkyl residue of from one to four can be from one to three times substituted by identical or different substituents selected from the group consisting of cycloalkyl group the number of carbon atoms from three to eight hydroxyl groups, alkoxygroup with the number of carbon atoms one to four, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, amino, mono - or dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl and heterocyclyl group,

R5means metal or ethyl group,

R6means a hydrogen atom, alkyl group with carbon atoms of from one to six, mono - or dialkylaminoalkyl group with the number of atoms ug is erode in each of the alkyl residues from one to four, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to six, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six or geterotsiklicheskikh group, with the alkyl group with the number of carbon atoms of from one to six and alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to six can be from one to three times substituted by identical or different substituents selected from the group consisting of heteroaryl, hydroxyl group, alkoxygroup with the number of carbon atoms one to four, hydroxycarbonyl group, alkoxycarbonyl group with the number of carbon atoms in CNS residue from one to six, aminocarbonyl, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, ceanography, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four,

or

R6means a structural unit of the formula

,or

where

R6Aselected from the group consisting of hydrogen atom and alkyl group with the number of carbon atoms one to four, and

n means aleecia 1 or 2,

R7means a halogen atom, a nitro-group, a cyano, triptorelin group, cryptometer, methyl or ethyl group

and

Y1, Y2, Y3, Y4and Y5every means CH-group.

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

And means phenyl or peredelnyj cycle

R1and R3each mean a hydrogen atom,

R2means fluorine atom, chlorine, bromine, nitro-group or a cyano,

R4means cyano, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to four or alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, and alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four may also be substituted by the Deputy selected from the group consisting of hydroxyl group, alkoxygroup with the number of carbon atoms one to four, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, heteroaryl and heterocyclyl group,

R5means metal group,

R6means atom bodoro is a, alkyl group with the number of carbon atoms one to four, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to four or alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, and an alkyl group with the number of carbon atoms one to four and alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four can be replaced by Deputy selected from the group consisting of heteroaryl, hydroxyl group, alkoxygroup with the number of carbon atoms one to four, hydroxycarbonyl group, aminocarbonyl, mono - and dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four,

or

R6means a structural unit of the formula

or

where

R6Aselected from the group consisting of a hydrogen atom and a metal of the group,

R7means triptorelin group or a nitro-group

and

Y1, Y2Y 3, Y4and Y5every means CH-group.

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

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R1means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R2means cyano, in particular, when a represents phenyl or pyridyloxy group, and R2means cyano, attached to parapolitica with respect to the Central dihydropyrimidinase cycle.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R3means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R4means alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, which can be substituted by a hydroxyl group, in particular, it can be 2-hydroxyethoxy-carbonyl group, or where R4means alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to four, in particular, oznacza the t methylcarbamyl group.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R5means methyl group.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R6means a hydrogen atom.

In yet another embodiment, the present invention relates to compounds corresponding to General formula (I), where R7means triptorelin group or a nitro-group, in particular, when R7means triptorelin group attached to metabologia with respect to the Central dihydropyrimidinase cycle.

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

,

where

Z denotes CH-group or a nitrogen atom, and

R1, R3, R4and R6have the above value.

Relevant to the present invention compounds in which R means a hydrogen atom, can analizowalismy in the relevant hydroxyamide:

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

,

where A, R1and R2have the above values,

with compounds of General formula (III)

,

where

R4and R5have the above values,

and with compounds of General formula (IV)

,

where

R3, R7and fragments from the Y1to Y5have the above values,

in the presence of acid in the single-stage three-component reaction or in successive transformation with the formation of compounds of General formula (IB)

,

where

And, the substituents from R1to R5, R7and fragments from the Y1to Y5have the above values,

thus compounds of General formula (IB) can then react with compounds of General formula (V)

,

where

R6*has the meaning given above for R6but does not mean a hydrogen atom, and

X denotes a leaving group, for example, halogen atom, tosylate, mesilato or sulphate group,

in the presence of a base.

Compounds of General formula (I), where R4means cyano, R5means an amino group and R6means a hydrogen atom, can be obtained in an alternative way by condensation of compounds of General formula (II) with compounds of General formula (IV) with a compound of formula (VI)

in the presence of acid in the course of a three-component one-step is eacli or during sequential transformation.

Suitable solvents for the process (II)+(III)/(VI)+(IV)→(IB) are in General organic solvents which do not change in the reaction conditions. These include such ethers like diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, and ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, 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 halogen-substituted hydrocarbons like dichloromethane, dichloroethane, trichloromethane or chlorobenzene. You can also use mixtures of the abovementioned solvents. Preference is given to carrying out the process in tetrahydrofurane.

Suitable acids for the process (II)+(III)/(VI)+(IV)→(IB) are in General inorganic or organic acids. In the preferred case, the list includes such carboxylic acids, such as acetic acid or triperoxonane acid, sulfonic acids such as, for example, methanesulfonate or n-toluensulfonate, hydrochloric acid or phosphoric acid, as polyphosphoric acid. Preference is given to ethyl ether polyphosphoric acid. The acid is used in amounts of from 0.25 mole is to 100 moles based on one mole of the compounds 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 up to +100°C.

In General the process is carried out at normal pressure. However, it is not excluded the possibility of holding it at an 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 in General organic solvents which do not change in the reaction conditions. These include such ethers like diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, and ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogen-substituted hydrocarbons like dichloromethane, dichloroethane, trichloromethane or chlorobenzene. You can also use mixtures of the abovementioned solvents. Preference is given to carrying out the process in tetrahydrofuran.

Suitable bases for carrying out process (IB)+(V)→(I) in General are inorganic or organic bases. In the preferred case, including such cyclic amines, such as piperidine or 4-N,N-dimethylaminopyridine, or trialkylamine with the number of carbon atoms in which each of the alkyl residues from one to four, such as triethylamine or diisopropylethylamine, or hydrides such as sodium hydride. Preference is given to sodium hydride. The base is used in amounts of from 0.1 mole to 10 moles, in the preferred case from 1 mole to 3 moles, based on 1 mol of the compounds of General formula (V).

In General 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 not excluded the possibility of holding it at an elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

Compounds of General formula (II), (III), (IV), (V) and (VI) by themselves are known or they can be obtained by known methods.

The above method can be illustrated by the following scheme:

Corresponding to the invention compounds exhibit useful spectrum of pharmacological and pharmacokinetic activity that was not anticipated in advance. Therefore, they are suitable for use as medicaments for treatment and/or prevention of disease symptoms in humans or animals.

It was unexpectedly found that the appropriate present invention compounds exhibit inhibitory activity on Rel is increased neutrophil elastase person, so they can be used for the manufacture of medicaments for the treatment of diseases associated with the activity of neutrophil elastase person. They can be an effective tool for the treatment of acute and chronic inflammatory processes such as rheumatoid arthritis, atherosclerosis and, in particular, such acute and chronic diseases of the lungs as pulmonary fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome, in particular pulmonary emphysema, including the smoker emphysema, and chronic obstructive pulmonary diseases, chronic bronchitis and bronchiectasis. Relevant to the present invention compounds can also be an effective means for the treatment of ischemic cardiovascular disease, acute coronary syndrome, acute myocardial infarction, intermittent and persistent angina, the consequences of arterial coronary artery bypass surgery and progressive heart failure for the treatment of atherosclerosis, diseases of the mitral valve defects of the atrial septum, the effects of percutaneous transluminal coronary angioplasty, inflammation after open-heart surgery and pulmonary hypertension. They can also be useful for the effective treatment of rheumatoid arthri is a, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, syndrome Cure-Strauss, acute and chronic allergic dermatitis, psoriasis, systemic lupus erythematous, bladderworts, sepsis, alcoholic hepatitis, liver fibrosis, disease behceta, allergic fungal sinusitis, allergic sinusitis, Crohn's disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal disease, chronic suppurative otitis of the middle ear, chronic venous varicose veins of the legs, inflammatory diseases of the digestive tract, bacterial and viral infections, brain injury, stroke and other conditions, with the participation neutrophils.

The present invention also relates to medicaments containing at least one relevant to the present invention the connection, in the preferred case, together with one or more pharmacologically safe diluents or carriers, as well as to use them for the above purposes. The active component may have a local and/or systemic action. To this end it is injected in the appropriate manner, for example, orally, parenterally, through the lungs, nasal, under the tongue, lingual, buccal, rectal, transdermal, through the conjunctiva, in the ear and is in the form of the implant.

For these methods of application of the active component can be entered in the appropriate dosage forms.

Appropriate dosage forms for administration through the mouth include dosage forms which release the active component quickly and/or in modified form, for example, tablets (uncoated tablets or coated tablets, for example, by coating the small intestine), capsules, pills, coated with sugar, granules, pills, powders, emulsions, suspensions, solutions or aerosols.

Parenteral dosage forms can be used for injection, bypassing the stage of absorption (intravenously, intraarterially, intracardiac, intraspinal or in the lumbar region), or including the stage of absorption (intramuscularly, subcutaneously, intradermal, transdermal, or intraperitoneally). Appropriate dosage forms for parenteral administration include formulations for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow and sterile powders.

Dosage forms for other routes of administration, presented, for example, inhalation of pharmaceutical forms (including powder inhalers, sprays), nasal drops/solutions, sprays, tablets or capsules on the tongue, under the tongue or cheek (buccal), suppositories, ear and CH the EIT dosage forms, vaginal capsules, aqueous suspensions (lotions, potions, which must shake), lipophilic suspensions, ointments, creams, milk, pastes, powders for dusting or implants.

The active ingredients can be converted into the mentioned dosage forms by methods that are well known. This is an inert, non-toxic, pharmaceutically acceptable carriers. These include, along with other carriers (for example microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulphate), dispersants (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colored substances (for example, such inorganic pigments such as iron oxide) or funds for the correction of taste and/or smell.

When using people, in case of introduction through the mouth, it is recommended to introduce a dose of from 0.001 to 50 mg/kg, in the preferred case from 0.01 mg/kg to 20 mg/kg When administered parenterally, for example, when administered intravenously or through the mucous membranes of the nasal, buccal or inhalation, the recommended dose of 0.001 mg/kg to 0.5 mg/kg

However, in certain circumstances, it may be necessary to deviate from the shown quantities namely depending on the body weight, route of administration, individual characteristics in relation to the active component, type of dosage form and the time or interval at which the reception of the dosage form. In certain cases, for example, it may be sufficient to use smaller compared to the above amount, whereas in other cases, you may exceed the above upper limit. In the case of the introduction of increased dosages can recommend splitting them into several individual doses distributed throughout the day.

The percentages in the following experiments and examples, unless otherwise stated, refer to ratios of the masses, part also apply to units of mass. The ratio of solvents, dilution and concentration, related to the solutions of the liquid in the liquid, in all cases based on the volume.

A. Determination of physiological activity

The ability of the relevant invention compounds to inhibit the activity of neutrophil elastase can be demonstrated, for example, in the following experiments.

I. Enzymatic in vitro experiments on neutrophil elastase person

Description experience

Used in the experience buffer: 0.1 mol/l 4-(2-hydroxyethyl)-1-piperazineethanesulfonic with sodium hydroxide, pH of 7.4 buffer, 0.5 mol/is sodium chloride, 0,1% (weight to volume) albumin bovine serum.

The appropriate concentration (see below) neutrophil elastase person (18 units per mg, in the form of a lyophilisate, #20927.01, SERVA Electrophoresis GmbH, Heidelberg, Germany) used for the experiment the buffer.

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

The corresponding concentration of the studied compounds, diluted used for the experiment, the buffer received from the base solution in dimethyl sulfoxide to a concentration of 10 mmol/L.

Example

Inhibition of in vitro neutrophil elastase person using fluorogenic peptide substrate (constant readout of the signal in the format of 384 MTP)

During this experience using the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany). The test solution is prepared by mixing 10 μl of the dilute solution of the analyte, 20 ál of diluted enzyme solution neutrophil elastase person (the final concentration of from 8 to 0.4 mked/ml under standard conditions 2.1 mked/ml) and 20 μl of diluted substrate solution (final concentration 1 mmol/l to 1 μmol/l under standard conditions of 20 µmol/l), respectively. The solution is incubated for 0-2 hours at 37°C (under standard conditions within 1 hour). The fluorescence emitted from the enzymatic reaction of AMC was measured at 37°C (TECAN spectra fluor plus plate reader). The rate of amplification of fluorescence (excitation 395 nm, emission 460 nm) is proportional to the activity of elastase. The values of the IC50define schedule RFU-[I]. Values of Kmand Km(OBS.)determine schedule of Leinweber-Burke and translate them into values of Kicoordinates Dixon.

In this experiment, the prepared samples had values IC50within 5 nmol/l to 5 mmol/l Typical examples are shown in table 1.

Table 1.
Example No.IC50[nmol/l]
18
940
145
158
1610
20700
2413
2610
2850
581100
605
726
7360
7420
10360
10915
11050

Example B

Inhibition of in vitro neutrophil elastase person using fluorogenic insoluble elastin substrate (periodic readout of the signal in the format of a 96 MTP)

During this experience using elastin-fluoresceine substrate elastase (#100620, ICN Biomedicals GmbH, Eschwege, Germany). The test solution is prepared by mixing 3 μl of the dilute solution of the analyte, 77 μl of diluted enzyme solution neutrophil elastase person (the final concentration of 0.22 U/ml to 2.2 U/ml, in the standard conditions of 21.7 MK U/ml) and 80 μl of the suspension substrate (final concentration 2 mg/ml). The suspension is incubated for 0-16 hours at 37°C (under standard conditions for 4 hours), slightly shaking her. To stop the enzymatic reaction to the investigated solution add 160 ál of decimal the nuclear biological chemical (NBC acetic acid (final concentration of 50 mmol/l). Polymer elastin-fluorescein precipitated by centrifugation (Eppendorf centrifuge 5804, 3000 rpm, 10 minutes). The supernatant transferred to a new inventory and determine the fluorescence emitted from the enzymatic reaction of the peptide fluorescein (BMG Fluostar plate reader). The rate of amplification of fluorescence (excitation 490 nm, emission 520 nm) is proportional to the activity of elastase. The values of the IC50define schedule RFU-[I].

II. The in vitro experiments on human neutrophils

Example

Experience an in vitro alactolyticus activity on polymorphing cells

This experience is used to determine alactolyticus ability polymorphically human cells and to assess the degree of degradation related to neutrophil elastase [see also Z.W.She and others, Am. J. Respir. Cell. Mol. Biol. 9, 386-392 (1993)].

Tritium-labeled elastin in the form of suspension applied to 96-well plates at 10 μg per well. In the respective concentrations in the wells add the test substance, the substance comparison [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), application of international patent No. 95/21855), and inhibitor α1 protease (α1PI)]. Polymorphically human cells separated from peripheral venous blood of healthy donors and again suspended in culture medium. In wells coated with elastin add neutrophils at concentrations lying in the range from 1×106up to 1×105tile is to the hole. In positive control for the experiment using pig to pancreatic elastase (1.3 µmol/l), whereas α1PI (1.2 µmol/l) used as a positive inhibitor of neutrophil elastase. Control cells are polymorphically cells without the addition of substances for each corresponding density of cells. Cells with the added compounds are incubated in an incubator with humidity at 37°C for 4 hours. Tablets centrifuged in order to have the possibility of selecting only the supernatant above the cell. The supernatant volume of 75 μl is transferred into the corresponding wells of 96-hole tablet Lumaplate™ (tablets containing solid scintillant). The tablets are dried to zero in the holes visible fluid and conduct the counting in a beta counter for 3 minutes per well.

Lysis3H-elastin increases the counter in the supernatant. Inhibition of such elastolysis leads to a decrease in the content of tritium in the supernatant compared to cellular control. With α1PI receive inhibition on 83,46±3,97% (± indicates a statistically significant confidence interval) at 1.2 µmol/l (for three different data sources 3.6×105cells per well). The values of the IC20received for matter of comparison ZD-0892 correspond 45,50±7,75 nmol/l (± indicates statistically significant to retelny interval) (for two different data sources 3.6×10 5cells per well).

If we take into account that ZD-0892 is a selective inhibitor of elastase polymorphically leukocytes, and take into account data on inhibition with α1PI, these results suggest that the main degradation of elastin polymorphisim by leukocytes is associated with the release neutrophil elastase, but not with other elastoliticescoy enzymes, for example, with a matrix metalloprotease. Relevant to the present invention compounds showed inhibitory activity is dependent neutrophil elastase human modeling experience in lysis elastin neutrophils.

Example B

Inhibition of in vitro elastase associated with membrane

Determination of the inhibition of elastase associated with the membrane of neutrophils, conduct experiments, using human neutrophils. Neutrophils stimulated with LPS at 37°C for 35 minutes and then centrifuged at 1600 rpm then associated with the membranes of the elastase fixed on neutrophils with 3%paraformaldehyde and 0.25%glutaraldehyde for 3 minutes at 4°C. After that, the neutrophils centrifuged and added to the media and investigated the connection, then add the substrate MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) with a concentration of 200 µmol/l After incubation for 2 minutes at 37°C. stop the reaction by phenylmethanesulfonyl and determine fluorescence when excited with light of 400 nm on the emission at 505 nm. The values of the IC50define graphical interpolation of data on the relative fluorescence depending on the concentration of the inhibitor.

III. Model experiments in vivo

Example

Model of acute lung damage in rats in vivo

Instillation neutrophil elastase person in rat lung induces severe damage. The development of this damage can be assessed by measurement of pulmonary hemorrhage.

Rats anaesthetize with Hypnorm/Hypnovel/water and install neutrophile Lactasoy person or saline into the lungs through micropulverized. The compounds are administered intravenously by injection, ingestion or inhalation at a set time before the introduction of neutrophil elastase person. Sixty minutes after administration of elastase animals are euthanized by an overdose of anesthetic (pentobarbitone-sodium) and washed with light two milliliters of phosphate saline buffer with the addition of heparin. Volume bronchoalveolar lavage register and establish patterns in the ice. Each sample bronchoalveolar lavage centrifuged at 900 rpm for 10 minutes at 4-10°C. the Supernatant discarded, and the precipitated cells are again suspended in phosphate buffered saline and again centrifuged. Again, discard the supernatant and the precipitated cells resuspended in 1 ml SOLEV the th phosphate saline buffer, containing 0.1% bromide, cetyltrimethylammonium for lizirovania cells. To determine the content of blood samples frozen. Before analysis haemorrhage samples thawed and mixed. In separate wells of 96-well plate with flat base make 100 ál of each sample. All samples analyzed twice. No experience take 100 ál of phosphate saline buffer with heparin containing 0.1% bromide, cetyltrimethylammonium. The absorbance in the wells is determined using a spectrophotometer at 415 nm. A standard curve is built by measuring the optical density at 415 nm at different concentrations of blood in phosphate buffered saline containing 0.1% bromide, cetyltrimethylammonium. Values of blood calculated by comparison with a standard curve (it is built for each plate) and lead them to the resulting volume of liquid bronchoalveolar lavage.

This model induced neutrophilic Lactasoy person hemorrhage in rats inhibiting activity relevant to the invention compounds was studied by intravenous, oral and inhalation administration.

Example B

Model experience on rats with acute myocardial infarction in vivo

Inhibitors of elastase examined in the experiment on simulated using the ligation of the heart in rats. Male Wistar rats (weighing bol is e 300 g) receive 10 mg/kg of aspirin 30 minutes before surgery. Their anaesthetize with isoflurane and during all operations are performed artificial ventilation (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 to expose the pericardium and for a short time remove the heart. The noose put around the left coronary artery, without closing it. Harness is passed under the skin to the neck of the animal. Breast close and allow the animal to recover for four days. On the fifth day, rats in three minutes anaesthetize ether, loop delay, closing the left coronary artery, controlling the process on the electrocardiogram. The compounds injected before occlusion of the left coronary artery or after oral, intraperitoneal or intravenous injection or continuous infusion). Within 1 hour after occlusion of the waist opening, restoring blood flow. Heart extract and 48 hours determines the size of the infarct staining of hearts after re-occlusion of the dye Evans blue, followed by staining with chloride of triphenyltetrazolium 2 mm slices of the heart. Areas with normal oxygenation (tissue not affected by occlusion) are colored in blue, the ischemic zone (affected by occlusion, but not lost) are colored in red, and the necrotic zone (dead is the result of occlusion of the fabric) are white. Each tissue section scan and computerized planimetry determines the size of heart attacks.

B. Examples

Abbreviations:

aq.water
conc.concentrated
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EIionization by electronic impact (in mass spectrometry)
ESIelectrospray ionization (mass spectrometry)
HLPChigh-performance liquid chromatography (HPLC)
LC-MSliquid chromatography combined with mass spectrometry
Mr.melting point
MSmass spectrometry
NMRspectroscopy nuclear magnetic resonance (NMR)
of. th.from theory (output)
Rtretention time (HPLC)
THFTetrahydrofuran

General methods

All reactions carried out in an argon atmosphere, unless otherwise noted. The solvents used in the form in which they were received from Aldrich without further purification. The term “silica” or “silica ' refers to silica gel grade 60 (0,040 mm 0,063 mm) Merck KGaA. The melting temperature is determined at the device Biichi 512, or similar device for determining the melting temperature, they are not fixed.

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

Liquid / mass spectrometry and HPLC

Liquid / mass 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% of formic acid, eluent B: acetonitrile +0.05% of formic acid; gradient: 0.0 to min 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 / mass spectrometry, method 2

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

Liquid / mass spectrometry, method 3

Instrument: Micromass Platform LCZ, HP1100; column: Aquasil C-18, 50 mm ×2.0 mm, 3 μm; eluent A: water+0.05% of formic acid, eluent B: acetonitrile +0.05% of formic acid; gradient: 0.0 to min 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 / mass spectrometry, method 4

Instrument: HP 1100 with digital diode matrix detector; column: Kromasil RP-18, 60 mm ×2 mm, 3.5 µm; eluent: A=5 ml HClO4on 1 l of water, B = acetonitrile; gradient: 0 min 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 detection: 210 nm.

Liquid / mass spectrometry, method 5

Instrument: Micromass TOF-MUX-Interface, 4-fold parallel input with HPLC Waters 600; column: Uptisphere HDO, 50 mm ×2.0 mm, 3.0 mm; eluent A: 1 l water +1 ml 50%formic acid, eluent B: 11 acetonitrile +1 ml 50%formic acid; gradient: 0.0 to min 100% A→0.2 minutes 100% A→2.9 minutes 30% A→3.1 minutes 10% A→4.5 minutes 10% A→4.6 100 minutes% A→6.5 minutes, 100% A; thermostat: room temperature; flow rate: 0.8 ml/min; UV detection: 210 nm.

Liquid / mass spectrometry, method 6

Instrument: Micromass Platform LCZ with HPLC Agilent Serie 1100; a number of the NCA: Grom-SIL120 ODS-4 HE, 50 mm ×2.0 mm, 3 μm; eluent A: 1 l water +1 ml 50%formic acid, eluent B: 1 l of acetonitrile +1 ml 50%formic acid; gradient: 0.0 to min 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 / mass spectrometry, method 7

Instrument: Micromass Quattro LCZ with HPLC Agilent Serie 1100; column: Uptisphere HDO, 50 mm ×2.0 mm, 3 μm; eluent A: 1 l water +1 ml 50%formic acid, eluent B: 1 l of acetonitrile +1 ml 50%formic acid; gradient: 0.0 to min 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.

Original products

Primera

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

In a round bottom flask, equipped with a reflux condenser and a trap Dean-stark in toluene (50 ml) was dissolved 6-bromo-3-pyridinecarboxamide (500 mg, 2.7 mmole) and 1,2-ethanediol (200 mg, 3.2 mmole) together with the resin Amberlyst 15 (100 mg). The solution is kept overnight while boiling under reflux and stirring, then cooled to room temperature, filtered and concentrated in vacuo. The crude product chromatographic on silica gel with cyclohexane and ethyl acetate as eluent and obtain the target compound as a colourless oil.

Output 0,489 g (79% of theory).

HPLC (JV the property 4): 3.46 in minutes.

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

1H-NMR (300 MHz, deuterochloroform): δ=8,46 (D., 1H), to 7.64 (m, 1H), 7,49 (m, 1H), 4,15-4,00 (m, 4H) ppm

Example 2A

5-(1,3-Dioxolane-2-yl)-2-pyridylcarbonyl

The substance according to example 1A (2.8 g, 12.5 mmole), cyanide zinc (1.6 g, of 13.8 mmole) and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.3 mmole) was dissolved in dimethylformamide (100 ml) and left overnight (18 hours) under stirring at 80°C. Add another tetrakis(triphenylphosphine)palladium(0) (0.1 g) and then left overnight (18 hours) under stirring at 80°C, then leave for 2 days (48 hours) at room temperature. The solvent is removed in vacuo, to the residue was added water (100 ml) and extracted the product with ethyl acetate (1 liter). The organic phase is washed with sodium chloride solution (200 ml), dried monohydrate magnesium sulfate, filtered and concentrated in vacuo. The crude product chromatographic on silica gel with cyclohexane and ethyl acetate as eluent and get the target compound in the form of a solid amorphous substance of white color.

The output of 0.94 g (42% of theory).

HPLC (method 4): 3,21 minutes.

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

1H-NMR (400 MHz, d6-sulfoxide): δ=8,81 (S., 1H), 8,09 (S., 2H), 5,95 (S., 1H), 4,13-3,4 (m, 4H) ppm

Example 3A

5-Formyl-2-pyridylcarbonyl

Method (a)

Synthesis of lead by analogy with the method Dodd, D. and others [J. Org. Chem. 1992, 57, 7226-7234]. To a stirred solution of 5-(1,3-dioxolane-2-yl)-2-pyridinecarboxamide (example 2A, 850 mg, 4.8 mmole) in acetone with water 85:15 (59,5 ml) was added n-toluene-acid (102 mg, of 0.59 mmole). The reaction mixture was left overnight (18 hours) while boiling under reflux and under stirring, then add an additional amount of n-toluenesulfonic acid (50 mg) and water (5 ml). The reaction mixture is stirred at the boil under reflux for 48 hours. The solution is cooled to room temperature and add a saturated solution of sodium bicarbonate. The product is extracted with ethyl acetate (3 x 100 ml), dried over monohydrate magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified using preparative HPLC, get a solid light yellow color.

Yield 0.66 g (93% of theory).

TPL 80-82°C.

HPLC (method 4): 2.13 minutes.

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

1H-NMR (400 MHz, d6-sulfoxide): δ=10.18 (s, 1H), of 9.21 (m, 1H), 8,49 (m, 1H), 8,27 (m, 1H) ppm

Method b)

In 8 ml of dichloromethane is dissolved 1.04 g (8.2 mmole) of oxalicacid. At -78°C was added Kaplan,28 g (to 16.4 mmole) of dimethyl sulfoxide. The solution was stirred at -78°C for 20 minutes, then add 1 g (7,46 mmole) of the compound of example 5A in the form of a solution in 7 ml of dichloromethane, continue stirring at -78°C for another 2 hours, then added dropwise 3.4 g (a 33.6 mmole) of triethylamine and, after heating to room temperature purify the mixture with column chromatography (silica, eluent: cyclohexane to cyclohexane with ethyl acetate 2:1).

Output 0,76 g (77% of theory).

Analytical data given above.

Example 4A

5-Methyl-2-pyridylcarbonyl

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

Yield 18 g (73% of theory).

1H-NMR (300 MHz, deuterochloroform): δ=2,4 (C., 3H), 7,6 (m, 2H), 8,6 (S., 1H) ppm

Example 5A

The compound from example 4A (13 g, 110 mmol) is dissolved in 400 ml of carbon tetrachloride and add to 29.4 g (165 mmol) of N-bromosuccinimide and 0.4 g (1.6 mmole) of dibenzoylperoxide. P is a promotional mix for three hours, refluxed, cooled to room temperature and filtered. The solution was washed with aqueous sodium thiosulfate, dried over magnesium sulfate and remove the solvent in vacuo. The residue is dissolved in 200 ml of dioxane and 200 ml of water, add calcium carbonate (44 g, 440 mmol) and 2 hour boil the mixture under reflux with stirring. After cooling to room temperature the mixture is filtered and added dichloromethane. After phase separation the organic phase is dried over magnesium sulfate and remove the solvent in vacuo. The product was then purified via chromatography (silica, eluent cyclohexane to ethyl acetate 2:1).

The output of 5.2 g (35% of theory).

1H-NMR (300 MHz, d6-sulfoxide): δ=4,7 (D., 2H), 5,6 (t, 1H), 8.0 a (m, 2H), 8,7 (S., 1H) ppm

Examples retrieve

Example 1

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

In 250 ml of tetrahydrofuran suspended 7.0 g (34,29 mmole) of N-[3-trifluoromethyl)phenyl]urea, 8,99 g (68,58 mmole) of 4-cyanobenzaldehyde, of 8.92 g (68,58 mmole) ethyl ester 3-clobutinol acid and 20 g of ethyl ester of polyphosphoric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on Colo is ke on silica with cyclohexane and ethyl acetate as eluent.

The output of 13.4 g (91%).

1H-NMR (200 MHz, d6-dimethylsulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 4.0 (with square, 2H); 5,4 (D., 1H); to 7.6 (m, 3H), and 7.7 (m, 3H); to 7.9 (m, 2H); 8.4V (D., 1H) ppm

Example 2

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

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

Yield 29 mg (7%).

1H-NMR (200 MHz, d6-sulfoxide): δ=2,0 (C., 3H); 2,2 (C., 3H); 5,5 (D., 1H); 7.5 (a m, 1H); to 7.6 (m, 3H), and 7.7 (m, 1H); 7,8 (m, 1H); to 7.9 (m, 2H); 8,5 (D., 1H) ppm

Example 3

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

In 2 ml of tetrahydrofuran suspended 204 mg (1.0 mmol) N-[3-(trifluoromethyl)phenyl]urea, 142 mg (0.77 mmole) of 4-bromobenzaldehyde and 100 mg (0.77 mmole) of ethyl ester of 3-clobutinol acid, was added a catalytic quantity is STV concentrated hydrochloric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 23 mg (6%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 4.0 (with square, 2H); 5,3 (D., 1H); to 7.4 (m, 2H); to 7.6 (m, 3H), and 7.7 (m, 3H); 8.3 (the doctor, 1H) ppm

Example 4

Ethyl ester 6-methyl-2-oxo-1-(4-forfinal)-4-(4-cyanophenyl)-1,2,3,4-Tetra-hydro-5-pyrimidinecarboxylic acid

In 2 ml of tetrahydrofuran suspended 154 mg (1.0 mmol) of N-(4-forfinal)urea, 101 mg (0.77 mmole) of 4-cyanobenzaldehyde and 100 mg (0.77 mmole) of ethyl ester of 3-clobutinol acid, was added a catalytic amount of concentrated hydrochloric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 40 mg (14%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 4.0 (with square, 2H); 5,3 (D., 1H); and 7.3 (m, 4H); 7,5 (m, 2H); to 7.9 (m, 2H); 8.3 (the doctor, 1H) ppm

Example 5

Ethyl ester 6-methyl-2-oxo-1-(3-chlorophenyl)-4-(4-cyanophenyl)-1,2,3,4-Tetra-hydro-5-PI is midinterval acid

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

Yield 13 mg (4%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,1 (C., 3H); 4.0 (with square, 2H); 5,3 (D., 1H); to 7.2 (m, 1H); to 7.4 (m, 3H); 7,5 (m, 2H); to 7.9 (m, 2H); 8.3 (the doctor, 1H) ppm

Example 6

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

In 3 ml of tetrahydrofuran is suspended 200 mg (0,98 mmole) of N-[3-(trifluoromethyl)phenyl]urea, 129 mg (0,98 mmole) of 4-cyanobenzaldehyde, 92 mg (0,49 mmole) of (1S)-1-methyl-2-methoxy-2-xoetrope ester 3-clobutinol acid and 295 mg of ethyl ester of polyphosphoric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue chromatography what Finance on a column of silica with cyclohexane and ethyl acetate as eluent. Get a mixture of diastereomers.

Yield 96 mg (40%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,3 (D., 3H); 1,4 (D., 3H); 2,0 (C., 3H+3H); 3,6 (C., 3H); 3,6 (C., 3H); 5.0 (m, 1H+1H); to 5.4 (m, 1H+1H); of 7.6 to 7.9 (m, 8H+8H); and 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

In 3 ml of tetrahydrofuran is suspended 150 mg (0.73 mmole) of N-[3-(trifluoromethyl)phenyl]urea, 96 mg (0.73 mmole) of 4-cyanobenzaldehyde, 63 mg (0.37 mmole) of 4-(4-morpholinyl)-4-keto-2-butanone and 220 mg of ethyl ester of polyphosphoric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with dichloromethane and methanol as eluent.

Yield 28 mg (16%).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,5 (C., 3H); 3,1 (m, 4H); 3,6 (m, 4H); 5,3 (Sh.S., 1H); 7,6 (m, 2H), and 7.7 (m, 1H); 7,8 (m, 2H); to 7.9 (m, 2H); 8.0 a (Sh.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-pyrimidinecarboxylic

In 3 ml of tetrahydrofuran is suspended 200 mg (0,98 mmole) of N-[3-(trifluoromethyl)phenyl]urea, 128 mg (0,98 mmole) of 4-cyanobenzaldehyde, 77 mg (0,49 mmole) of 4-(4-di ethylamino)-4-keto-2-butanone and 295 mg this is a new air of polyphosphoric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with dichloromethane and methanol as eluent.

Yield 106 mg (47%).

1H-NMR (300 MHz, d6-sulfoxide): δ=0,9 (m, 6N); 3,1 (m, 4H); 5,2 (Sh.S., 1H); 7,6 (m, 2H), and 7.7 (m, 1H); 7,8 (m, 2H); to 7.9 (m, 2H); 8.0 a (Sh.S., 1H) ppm

Example 9

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

In 2 ml of tetrahydrofuran suspended 400 mg (1.97 mmole) of N-[3-(trifluoromethyl)phenyl]urea, 199 mg (1,51 mmole) of 4-cyanobenzaldehyde and 100 mg (1,51 mmole) of malononitrile and added a catalytic amount of concentrated hydrochloric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with dichloromethane and methanol as eluent.

Yield 4 mg (1%).

1H-NMR (400 MHz, d6-sulfoxide): δ=5,2 (D., 1H); 6,0 (S., 2H); to 7.6 (m, 3H), and 7.7 (m, 2H); 7,8 (m, 1H); to 7.9 (m, 2H); 8.4V (D., 1H) ppm

Example 10

Ethyl ester 6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-3-formyl-4-(4-cyano-phenyl)-1,2,3,4-tetr ahydro-5-pyrimidinecarbonitrile

In 1 ml of dimethylformamide was dissolved 100 mg (0,23 mmole) of the compound of example 1 and added to 35.7 mg (0,23 mmole) of phosphorylchloride. The reaction mixture is stirred for 2 hours at 70°C. After cooling to room temperature the product emit using preparative HPLC.

Yield 43 mg (41%).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,1 (s, 3H); 4,1 (square, 2H); 6,4 (S., 1H); 7,6 (m, 2H), and 7.7 (m, 1H); 7,8 (m, 1H); to 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-pyrimidinecarbonitrile acid

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

Yield 1.27 g (45%).

1H-NMR (300 MHz, d6-sulfoxide): δ=2,0 (C., 3H); 5,4 (D., 1H); 7,6 (m, 1H); 7,6 (m, 2H), and 7.7 (m, 1H); 7,8 (m, 1H); to 7.9 (m, 3H); 8.3 (the doctor, 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-pyrimidinecarboxylic

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

Yield 29 mg (66%).

1H-NMR (300 MHz, d6-sulfoxide): δ=0,7 (t, 3H); 1,3 (Sextus., 2H); 1,7 (C., 3H); 3,0 (square, 2H); 5,4 (D., 1H); to 7.6 (m, 3H), and 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-pyrimidinecarboxylic

In 2 ml of dimethylformamide is dissolved 48 mg (0.12 mmole) of the compound from example 11, was added 10 mg (of 0.13 mmole) of 2-methoxyethylamine, 18 mg (0,13 mmole) hydrate (1-hydroxy-1H-benzotriazole and 15 mg (0.12 mmole) of 4-dimethylaminopyridine. The reaction mixture was stirred at 0°C and added 25 mg (of 0.13 mmole) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture is stirred for 18 hours at room temperature, for the eat added water and ethyl acetate. The organic phase is washed with saturated aqueous potassium bisulfate, water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum to dryness. If necessary, the product is optionally purified by column chromatography or preparative HPLC.

Yield 22 mg (40%).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,7 (C., 3H); 3,2 (C., 3H); 3,3 (m, 4H); 5,4 (D., 1H); to 7.6 (m, 3H), and 7.7 (m, 3H); to 7.9 (m, 2H); 8,1 (m, 1H) ppm

Example 14

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

To a suspension of 12.4 mg (0.31 in mmole) of 60%sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 89 mg (0,21 mmole) of the compound of example 1. The mixture is stirred for 2 hours at room temperature. Then added 26 mg (0,21 mmole) dimethylsulfate and stirred the mixture at room temperature for another 2 hours. Then add water and ethyl acetate and the organic phase is washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum to dryness. If necessary, the product is optionally purified by column chromatography or preparative HPLC.

Yield 85 mg (93%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2.0 (C., 3H); 2,8 (C., 3H); 4.0 (square, 2H); 5,5 (S., 1H); to 7.6 (m, 3H), and 7.7 (m, 1H); 7,8 (m, 2H); to 7.9 (m, 2H) m is.

Example 15

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

To a suspension of 12 mg (0,28 mmole) of 60%sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0,23 mmole) of the compound of example 1. The mixture is stirred for 2 hours at room temperature. Then give 91 mg (1.16 mmole) acetylchloride and stirred the mixture at room temperature for another 2 hours. Then add water and ethyl acetate and the organic phase is washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum to dryness. If necessary, the product is optionally purified by column chromatography or preparative HPLC.

Yield 93 mg (85%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,2 (t, 3H); 2,1 (C., 3H); 2,5 (C., 3H); 4,2 (m, 2H); 6,7 (S., 1H); to 7.4 (m, 1H); 7.5 (a m, 2H); 7,6 (m, 1H), and 7.7 (m, 1H); 7,8 (m, 1H); to 7.9 (m, 2H) ppm

Example 16

Diethyl ether 4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-6-(4-cyanophenyl)-3,6-dihydro-1,5(2H)-pyrimidinecarboxylic acid

To a suspension of 12 mg (0,28 mmole) of 60%sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0,23 mmole) of the compound of example 1. The mixture is stirred for 2 hours at room temperature. Then added 126 mg (1,16 the mole) of atilglukuronida and stirred the mixture at room temperature for another 2 hours. Then add water and ethyl acetate and the organic phase is washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum to dryness. If necessary, the product is optionally purified by column chromatography or preparative HPLC.

Yield 92 mg (79%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,2 (t, 3H; so, 3H); 2,1 (C., 3H); 4,2 (m, 2H); 4,3 (square, 2H); 6,4 (S., 1H); to 7.4 (m, 1H); 7.5 (a m, 3H), and 7.7 (m, 1H); 7,8 (m, 1H); to 7.9 (m, 2H) ppm

Example 17

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

In 2 ml of tetrahydrofuran is suspended 150 mg (1.0 mmol) of N-(3-were)-urea, 101 mg (0.77 mmole) of 4-cyanobenzaldehyde and 100 mg (0.77 mmole) of ethyl ester of 3-clobutinol acid and added a catalytic amount of concentrated hydrochloric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 8 mg (3%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 2,3 (C., 3H); 4.0 (with square, 2H); 5,3 (D., 1H); 7,0 (m, 2H); to 7.2 (m, 1H); and 7.3 (m, 1H); 7,6 (m, 2H); to 7.9 (m, 2H); 8,2 (D., 1H) ppm

Example 18

Atila the initial ester 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

In 2 ml of tetrahydrofuran suspended 204 mg (1.0 mmol) N-[3-(trifluoromethyl)-phenyl]urea, 108 mg (0.77 mmole) of 4-chlorobenzaldehyde and 100 mg (0.77 mmole) of ethyl ester of 3-clobutinol acid and added a catalytic amount of concentrated hydrochloric acid. The mixture is boiled for 18 hours under reflux with stirring. After cooling to room temperature, remove the solvent in vacuo and purify the residue by chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 29 mg (9%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 4.0 (with square, 2H); 5,3 (D., 1H); 7.5 (a m, 5H); 7,6 (m, 1H); 7.7 (m, 2H); 8.3 (the doctor, 1H) ppm

Example 19

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

In 100 ml of chloroform was dissolved 3 g (7 mmol) of the compound of example 1. At 0°C was added dropwise 558 mg (3,48 mmole) of bromine. The mixture is stirred for two hours at room temperature, then remove the solvent in vacuo. The residue is distilled chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 3.2 g (90%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 4.0 (with square, 2H, D., 1H); 4,6 (SD, 1H); 5,4 (DV, N); to 7.6 (m, 3H), and 7.7 (m, 2H); 7,8 (m, 1H); to 7.9 (m, 2H); 8,6 (D., 1H) ppm

Example 20

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

In 2 ml of acetone was dissolved 20 mg (0.04 mmole) of the compound from example 19 and added 8 mg (0.10 mmole) of diethylamine. The mixture is stirred for 18 hours at room temperature, then remove the solvent in vacuo. The residue is purified using preparative HPLC.

Yield 15 mg (75%).

1H-NMR (300 MHz, d6-sulfoxide): δ=0,6 (so, 6N); 1,1 (t, 3H); 2,0 (m, 2H); 2,2 (m, 2H); 3,1 (SD, 1H); 3,9 (SD, 1H); 4,1 (square, 2H); 5,4 (D., 1H); 7.5 (a m, 1H); to 7.6 (m, 4H), and 7.7 (m, 1H); to 7.9 (m, 2H) ppm

Example 21

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

In 2 ml of acetone dissolve 50 mg (0.1 mmole) of the compound from example 19 was added 18 mg (0,20 mmole) of aniline. The mixture is stirred for 18 hours at room temperature, then remove the solvent in vacuo. The residue is purified using preparative HPLC.

Yield 28 mg (55%).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 3,6 (Shostakovich, 1H); 4,1 (square, 2H); 4,4 (Shostakovich, 1H); to 5.4 (m, 2H); 6,2 (m, 2H); 6.5 in (m, 1H); to 6.9 (m, 2H); 7,6 (m, 6N); to 7.9 (m, 2H); 8.4V (D., 1H) ppm

Example 22

(+)-Ethyl ester 6-methyl-2-oxo-1-[3-(trifluoromethyl)the dryer is l]-4-(4-cyanophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

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

1H-NMR (300 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 4.0 (with square, 2H); 5,4 (D., 1H); to 7.6 (m, 3H), and 7.7 (m, 2H); 7,8 (m, 1H); to 7.9 (m, 2H); 8.4V (D., 1H) ppm

[α]20=+3,3° (λ=589 nm, dichloromethane,=535,0 mg per 100 ml).

Example 23

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

To a suspension of 14 mg (0.35 mmole) of 60%sodium hydride (in mineral oil) in 2 ml of tetrahydrofuran was added 100 mg (0,23 mmole) of the compound from example 22. The mixture is stirred for 2 hours at room temperature. Then added 29 mg (0,23 mmole) dimethylsulfate and stirred the mixture at room temperature for another 2 hours. Then add water and ethyl acetate and the organic phase is washed with water and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum to dryness. The product cleans the chromatography was carried out is on the column on silica gel with cyclohexane and ethyl acetate as eluent.

Yield 76 mg (74%).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 2.8 (C., 3H); 4.0 (with square, 2H); 5,5 (S., 1H); to 7.6 (m, 3H), and 7.7 (m, 1H); 7,8 (m, 2H); to 7.9 (m, 2H) ppm

[α]20=-18,1° (λ=589 nm, dichloromethane,=530,0 mg per 100 ml).

Example 24

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

To a solution of the compound from example 3A (76 mg, of 0.58 mmole) in tetrahydrofuran (5 ml) under stirring was added ethyl ester 3-clobutinol acid (75 mg, of 0.58 mmole), N-[3-(trifluoromethyl)phenyl]urea (118 mg, of 0.58 mmole) and ethyl ester of polyphosphoric acid (200 mg, freshly prepared by the method of Cava and others, J. Org. Chem. 1969, 34, 2665). The reaction mixture is two days (48 hours) is refluxed, after which the solution was diluted with dimethylsulfoxide (2 ml) and purified using preparative HPLC. The fractions with the product was concentrated in vacuo and again chromatographic 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+N)+.

HPLC (method 4) = 4,63 minutes.

1H-NMR (300 MHz, d6-sulfoxide): δ=8,76 (S., 1H), at 8.36 (D., 1H), 8,16-of 8.00 (m, 2H), 7,83-7,74 (m, 2H), 7,75-7,58 (m, 2H), 5,47 (D., 1H), 4,03 (square, 2H), 2.06 to (C., 3H), of 1.08 (t, 3H) ppm

Example 25

4-{5-(1H-AND idazole-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 mmole) of the compound from example 11 in 5 ml of dry dimethylformamide is added 567 mg (3.5 mmole) of N,N-carbonyldiimidazole. The reaction mixture was left overnight, then evaporated in vacuum solvent. The residue is dissolved in ethyl acetate and washed with water and sodium chloride solution. Then dried with magnesium sulfate and the solvent is distilled off in vacuum. The yield 500 mg (88,6% of theory).

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

1H-NMR (200 MHz, d6-sulfoxide): δ=1,40 (D., 3H), 5,5 (D., 1H), 7,0 (S., 1H), 7,55 to 8.0 (m, N), and 8.4 (SD, 1H), 8,45 (D., 1H) ppm

Example 26

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

To 0.5 ml of ethylene glycol was added 45,1 mg (0.1 mmole) of the compound from example 25. The reaction mixture is 1 hour and stirred at a temperature of about 100°C. After cooling, the reaction mixture was purified using preparative HPLC (column Agilent Bond Extend C18, 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B:

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

Yield 22 mg (49,4% of theory).

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

1H-NMR (300 MHz, d6-dimethylsulfoxide): S=2,05 (D., 3H), 3,5 (square, 2H), 3.95 to to 4.15 (m, 2H), 4.75 V (t, 1H), 5,45 (D., 1H), 7,55 to 7.75 (m, 5H), 7,75 (D., 1H), 7,85 (D., 2H), 8,35 (D., 1H) ppm

Example 27

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

To 0.5 ml of 2-(dimethylamino)ethanol was added 45,1 mg (0.1 mmole) of the compound from example 25. The reaction mixture is 1 hour and stirred at a temperature of about 100°C. After cooling, the reaction mixture was purified using preparative HPLC (column Agilent Bond Extend From 18 to 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of concentrated ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 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 (ionization by electron impact): m/z=473 (M+N)+.

1H-NMR (300 MHz, d6-sulfoxide): δ=2,05 (D., 3H), 2,1 (C., 6N), 2,4 (m, 2H), 4,1 (m, 2H), 5,35 (D., 1H), 7,55 (D., 1H), 7,6 (D., 2H), and 7.7 (m, 2H), 7,8 (D., 1H), 7,85 (D., 2H), 8,35 (D., 1H) ppm

Example 28

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

To 0.5 ml of 2-(4-pyridinyl)ethanol was added 45,1 mg (0.1 mmole) of the compound from example 25. The reaction mixture is 1 hour and stirred at a temperature of about 100°C. After cooling, the reaction mixture was purified using preparative HPLC (column Agilent Bond Extend From 18 to 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of concentrated ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 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 (ionization by electron impact): m/z=507 (M+N)+.

1H-NMR (300 MHz, d6-sulfoxide): δ=2,0 (D., 3H), 2,9 (t, 2H), 4,3 (t, 2H), 5.25-inch (D., 1H), 7,15 (D., 2H). 7,45 (D., 2H), 7.5 (a doctor, 1H), 7,65 (t, 2H), 7.8 (m, 3H), 8,35 (D., 1H). 8,4 (D.,2H) ppm

Example 29

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

To 0.5 ml of 2-(2-pyridinyl)ethanol was added 45,1 mg (0.1 mmole) of the compound from example 25. The reaction mixture is 1 hour and stirred at a temperature of about 100°C. After cooling, the reaction mixture was purified using preparative HPLC (column Agilent Bond Extend From 18 to 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent is B: water +0.1% of concentrated ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; wavelength 220 nm; injected volume of about 500 μl, the number of inlets: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 22 mg (43,4% of theory).

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

1H-NMR (300 MHz, d6-sulfoxide): δ=2,0 (D., 3H), 3,0 (t, 2H), 4,4 (t, 2H), 5.25-inch (D., 1H), 7,15-7,25 (m, 2H), 7.4 (D., 2H), 7.5 (a doctor, 1H), 7,6 to 7.75 (m, 3H), and 7.8 (m, 3H), 8.3 (the doctor, 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

To 0.5 ml of 1-(2-hydroxyethyl)-2-pyrrolidinone add 45,1 mg (0.1 mmole) of the compound from example 25. The reaction mixture is 1 hour and stirred at a temperature of about 100°C. After cooling, the reaction mixture was purified using preparative HPLC (column Agilent Bond Extend CIS 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of concentrated ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; wavelength 220 nm; injected volume of about 500 μl, the number of inputs: 1). The fractions containing the product are combined and concentrated in vacuo.

Yield 25 mg (48.8% of theory).

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

1H-NMR (300 MHz, d6-sulfoxide): δ=1,8 (the Queen., 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), and 7.7 (t, 2H), 7,8 (D., 1H), 7,9 (D., 2H), 8.4V (D., 1H) ppm

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

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
31The compound of example 1, ativam-acetate854,01 (1)516
32The compound of example 1, cyclopropane-carbonyl-chloride794.09 to (1)498
33The compound of example 1, bromatan154,28 (2)458
34The compound of example 1, 4-morpholine-carbonyl-chloride973,97 (2)543

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
35The compound of example 1, dimetilan-bataillone984,00 (2)523
[M+Na]+
36The compound of example 1, methylcarbonate964,10 (2)488
37The compound of example 1, benzylbromide584,59 (2)520
38The compound of example 1, propanol-chloride434,42 (2)486

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
39Connection example 1 2-methoxy-atilhan-carbonate954,12 (2)532
40The compound of example 1, isopropyl-chlorocarbonate674,55 (2)500
41The compound of example 1, diethylcarbamoyl184,25 (2)529
42The compound of example 1, methyl(methyl-sulfonyl)-carbamoylated404,10 (2)565

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
43The compound of example 1, 2-bromoacetamide, 2.5 equivalents of sodium hydride543,7 (3)487
44The compound of example 1, 2-brooksyne acid, 2.5 equivalents of sodium hydride673,8 (3)488
45The compound of example 1, the hydrobromide of 2-bromatan-amine, 2.5 equivalents of sodium hydride 282,9 (2)473
46The compound of example 1, the hydrochloride of 2-(chloromethyl)-pyridine, 2.5 equivalents of sodium hydride374,0 (3)521

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
47The compound of example 1, the hydrobromide of N-(2-bromo-ethyl)-N,N-diethylamine, 2.5 equivalents of sodium hydride822,98 (2)529
48The compound of example 1, 2-bromo-N-methylacetamide, 2.5 equivalents of sodium hydride653.70 (2)501
49 The compound of example 1, the hydrochloride of 3-(chloromethyl)-pyridine, 2.5 equivalents of sodium hydride153,68 (2)521
50The compound of example 1, the hydrochloride of 4-(chloromethyl)-pyridine, 2.5 equivalents of sodium hydride213,47 (2)521

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
51The compound of example 1, the hydrobromide of 2-(methyl bromide)-1H-imidazole, 2.5 equivalents of sodium hydride62,97 (2)510
52The compound of example 1, 3-(chloromethyl)-1,2,4-oxadiazol 374,0 (3)469
53The compound of example 1, 2-bromo-N-(2-methoxyethyl)-ndimethylacetamide91of 3.77 (2)545

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

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
54N-[3-(trifluoromethyl)phenyl] urea, 4-cyanobenzaldehyde, methyl ester 3-clobutinol acid793,68 (2)416
55N-[3-(trifluoromethyl)-phenyl]urea, 4-cyanobenzaldehyde, cyclopropylmethyl ether 3-clobutinol acid584.09 to (2) 456
56N-[3-(trifluoromethyl)-phenyl]urea, 4-cyanobenzaldehyde, isopropyl ester 3-clobutinol acid854,03 (2)444
57N-[3-(trifluoromethyl)-phenyl]urea, 4-tzianabos-aldehyde, (1R)-2-methoxy-1-methyl-2-oksietilnye ether 3-clobutinol acid733,2 (2)488

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
58N-[3-(trifluoromethyl)-phenyl]urea, 4-cyanobenzaldehyde, N,N-dimethylamide 3-clobutinol acid93,2 (2)429

Example 59

Ethyl ester 6-methyl-3-[2-(4-morpholinyl)-2-oxoe the yl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-4-(4-cyanophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

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

Yield 78 mg (85%).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,0 (C., 3H); 3,4 (m, 4H); 3,6 (m, 4H); 3,7 (D., 1H); to 4.1 (m, 2H); 4,5 (D., 1H); 5,5 (S., 1H); to 7.6 (m, 5H); 7,8 (m, 1H); to 7.9 (m, 2H) ppm

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

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
60 Connection example 44 N-methyl-piperazine902,93 (2)570
61Connection example 44 N-(2-amino-ethyl)-N,N-dimethylamine872,93 (2)558
62Connection example 44, dimethylamine (2 mol/l in tetrahydrofuran)833,84 (2)515

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

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
63N-[3-(trifluoromethyl)phenyl]urea, 4-cyano-benzaldehyde, 1-(3-methyl-1,2,4-oxadiazol-5-yl)acetone23 3.80 (3)440
64N-[3-(trifluoromethyl)phenyl] urea, 4-cyano-benzaldehyde, 1-(1,3-benzotriazol-2-yl)acetone234,42 (2)491
65N-[3-(trifluoromethyl)phenyl]urea, 4-cyano-benzaldehyde, 5-methyl-2,4-hexandione334,3 (1)428
66N-[3-(trifluoromethyl)phenyl] urea, 4-cyano-benzaldehyde, 1-methoxy-2,4-pentandiol33,47 (2)430

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
67 N-[3-(trifluoromethyl)phenyl]urea, 4-tzianabos-aldehyde, 1-(2-furyl)-1,3-butandiol133,70 (2)452
68N-[3-(trifluoromethyl)phenyl]urea, 4-cyano-benzaldehyde, 1-phenyl-1,3-butandione144.03 (2)462
69N-[3-(trifluoromethyl)-phenyl]urea, 4-cyano-benzaldehyde, 1,1,1-Cryptor-2,4-pentandiol53,9 (3)454

Example 70

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

In 5 ml of tetrahydrofuran was dissolved 200 mg (0.5 mmole) of the compound from example 11 and added 6 mg (0.05 mmole) of 4-N,N-dimethylaminopyridine, 77 mg (0.6 mmole) of N,N-diisopropylethylamine and 115 mg (0.6 mmole) of hexaflurophosphate benzotriazol-1-yl-oxy-Tris(pyrrolidino)phosphonium. The reaction mixture is stirred for 15 minutes at room temperature, then add 5 ml of ammonia solution (2.5 mmole in the form of a solution in dioxane with a concentration of 0.5 mol/l). The reaction is ionic mixture of 1 hour and stirred at room temperature then add water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in vacuum to dryness. The product is optionally purified using preparative HPLC.

Yield 55 mg (28% of theory).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,8 (C., 3H); 5,4 (D., 1H); 7,2 (Sh.S., 1H); 7,4 (Sh.S., 1H); to 7.6 (m, 5H), and 7.7 (m, 1H); to 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-pyrimidinecarbonitrile acid

The enantiomers of the compounds according to example 11 separated using preparative HPLC on a chiral phase [column KBD 8361 (chiral silica gel selector based on monomer N-methacryloyl-L-leucine-1-methylamide, see also the application for the European patent No.-379917), 250 mm ×20 mm, eluent: ethyl acetate→methanol→ethyl acetate, flow rate 25 ml/min, 23°C, detector at 254 nm].

1H-NMR (300 MHz, d6-sulfoxide): δ=2,0 (C., 3H); 5,4 (D., 1H); 7,6 (m, 1H); 7,6 (m, 2H), and 7.7 (m, 1H); 7,8 (m, 1H); to 7.9 (m, 3H); 8.3 (the doctor, 1H); 12,5 (S., 1H) ppm

[α]20=+2,5° (λ=589 nm, methanol, C=505 mg/100 ml).

Example 72

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

In an argon atmosphere to a 19.6 ml of dimethylformamide is added 1560 mg (with 3.89 mmole) of the compound from example 71. After primav the value 1,095 ml (7,86 mmole) of triethylamine and of 1.11 ml (15.7 mmole) of 2-bromoethanol stirred the reaction mixture at a temperature of about 70°C for 8 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate and washed with water. After drying with magnesium sulfate the organic phase is evaporated in vacuum. The residue is dissolved in 8 ml of methanol and purified using preparative HPLC (column: Nucleosil 100-5 18 Nautilus, 20×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.3% of formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; wavelength: 220 nm; amount: 500 μl; number of entries: 18). The fractions containing the product are combined and lyophilized.

Output 1290 mg (74.5% of theory).

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

1H-NMR (300 MHz, d6-sulfoxide): δ=2,05 (D., 3H); 3,5 (square, 2H); 3.95 to to 4.15 (m, 2H); 4.75 V (t, 1H); 5,45 (D., 1H); 7,55 to 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, C=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-pyridylcarbonyl

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

Reactionary see the camping 24 hours refluxed, after this time the solution was diluted with dimethylsulfoxide (2 ml) and purified using preparative HPLC.

Yield 101 mg (44% of theory).

1H-NMR (200 MHz, d6-sulfoxide): δ=2,02 (C., 3H); 2,24 (C., 3H); 5,54 (D., 1H); 7,52-of 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-pyridylcarbonyl

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

1H-NMR (300 MHz, deuterochloroform): δ=2.06 to (C., 3H); 2,35 (C., 3H); 5,69 (D., 1H); 6,02 (D., 1H); 7.29 trend is 7.50 (m, 2H); EUR 7.57 to 7.75 (m, 3H); 7,83 (DD, 1H); total of 8.74 (D., 1H) ppm

[α]20=+25,1° (λ=589 nm, methanol, C=505 mg/100 ml).

Example 75

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

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

Yield 17 mg (34.5% of theory).

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

1H-NMR (300 MHz, d6-sulfoxide): δ=2.1 a (doctor, 3H); further 5.15 (DD, 2H); 5,45 (D., 1H); 7,05 (D., 1H); 7,3 (Shostakovich, 1H); 7.5 to a 7.85 (m, N); 8,35 (D., 1H); 8,5 (D., 2H) ppm

Example 76

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

To a solution of 60.2 mg (0.15 mmole) of the compound from example 11 in 0,57 ml of dry dimethylformamide was added to 72.9 mg (0.45 mmole) of N,N-carbonyldiimidazole. The reaction mixture is left for one hour, after which dilute the reaction mixture with water and extracted with ethyl acetate. After drying with magnesium sulfate the solvent is distilled in in the cosmology vacuum. To the residue was added 185 mg (1.5 mmole) of 2-(3-pyridinyl)ethanol and 20 μl (or 0.27 mmole) of triethylamine. The reaction mixture is 1 hour and stirred at 100°C. After that the reaction mixture is diluted by adding 0.4 ml of methanol, filtered and purified using preparative HPLC (column: Nucleosil 100-5 18 Nautilus 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; flow rate 25 ml/min; wavelength: 220 nm; injected volume: about 550 ál; number of inputs: 1). The fractions containing the product are combined and evaporated in vacuum.

Yield 44 mg (57,9% of theory).

Liquid / mass spectrometry (ionization by electron impact, method 5): m/z=507 (M+N)+the retention time 3,19 minutes.

Example 77

3,6-Dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-4-(4-cyanophenyl)-1,2,3,4-Tetra-hydro-5-pyrimidinecarbonitrile acid

In 100 ml of ethanol is dissolved 4.1 g (a 9.25 mmole) of the compound from example 14. To this solution was added 6.2 ml (27.6 mmole) of potassium hydroxide solution in water (25 wt.%). The reaction mixture is left for 18 hours at room temperature. Then add more of 12.4 ml (55,2 mmole) of potassium hydroxide solution in water (25 wt.%) and stirred the reaction mixture for 2 hours. The reaction mixture was diluted with water and three times extragear the Ute with ethyl acetate. The aqueous phase is acidified with 1 N. hydrochloric acid and extracted with ethyl acetate. This last extract is dried over magnesium sulfate and evaporated in vacuum. The residue is distilled chromatographytandem on a column of silica with cyclohexane and ethyl acetate as eluent.

Yield 1.5 g (39% of theory).

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

1H-NMR (300 MHz, d6-sulfoxide): δ=2,0 (C., 3H); 2,8 (C., 3H); 5,5 (D., 1H); 7,6-7,8 (m, 6N); 7,9 (D., 2H); 12,6 (S., 1H) ppm

By analogy with the method of example 76 receive the following connections.

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
78Connection example 11, 3-pyridinyl-methanol56,93,45 (5)493
79Connection example 11, 2-hydroxy-ndimethylacetamide1)61,1 3,38 (5)459
80Connection example 11, 2-hydroxy-ethyl(methyl)-formamide80,93,5 (5)487
81Connection example 11, 2-hydroxy-ethylacetamide56,23,44 (5)487

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
82Connection example 11, (1-methyl-1H-imidazol-5-yl)-methanol1)45,82,87 (5)496
83Connection example 11, 2-(1H-pyrazole-1-yl)ethanol 60,63,7 (5)496
84Connection example 11, 2-(1H-1,2,4-triazole-1-yl)-ethanol1)67,13.48 (5)497
85Connection example 11, 2-hydroxy-ethyl acetate56,13,98 (5)488

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
86Connection example 11, 2-(dimethyl-amino)-2-methyl-1-propanol34,62,9 (5)502
87Connection example 11, 3-(dimethyl-what Mino)-propanol of 54.82,86 (5)487
88Connection example 11, 2-(1-pyrrole-dinyl)ethanol56,22,86 (5)500
89Connection example 77 2-(3-pyridi-nil)ethanolof 58.93.36 (5)522

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
90Connection example 77, (3-pyridinyl)methanol61,93,64 (5)507
91Connection example 77 2-hydroxyacetamido 1)53,63,54 (5)473
92Connection example 77, 2-hydroxy-ethyl(methyl)-formamide54,63,68 (5)501
93Connection example 77, 2-hydroxy-ethylacetamide66,63,59 (5)501

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
94Connection example 77, (1-methyl-1 H-imidazol-5-yl)-methanol1)34,0to 3.02 (5)510
95 Connection example 77, 2-(1H-pyrazole-1-yl)ethanol61,53,91 (5)510
96Connection example 77, 2-(1H-1,2,4-triazole-1-yl)-ethanol1)71,83,64 (5)511
97Connection example 77, 2-hydroxy-ethyl acetate53,24,12 (5)502

Example No.FormulaOriginal productsOutput [%]Rt[min] (method)Mass [M+H]+
98Connection example 77, 2-(dimethyl-amino)-2-methyl-1-propanol25,9to 3.02 (5)516
99 Connection example 77, 3-(dimethyl-amino)propanol54,62,98 (5)502
100Connection example 77, 2-(1-pyrrole-dinyl)ethanol55,92,98 (5)514
101Connection example 77, (2-pyridi-nil)methanol67,13,91 (5)507
1) In this case used the alcohol is a solid and the reaction is carried out in the presence of 0.4 ml of dimethylformamide.

Example 102

Ethyl ester of 1-(3,5-dichlorophenyl)-6-methyl-2-oxo-4-(4-cyanophenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

In an argon atmosphere in 0.5 ml of dioxane is stirred for 4 hours at 80°From 30.8 mg (0.15 mmole) of N-(3,5-dichlorophenyl)urea together from 39.3 mg (0.3 mmole) of 4-formyl-benzonitrile, 39 mg (0.3 mmole) of ethyl ester of 3-clobutinol acid and 90 mg of trimethylsilyltriflate. After addition of a small amount of dim is tranfixed the reaction mixture was filtered and purified using preparative HPLC (column: Agilent Bond Extend From 18 Nautilus 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of concentrated ammonia; 0 min 10% A, 2 min 10% a, b min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; flow rate 25 ml/min; wavelength: 220 nm; injected volume: 500 μl; number of inputs: 1). The fractions containing the product are combined and evaporated in vacuum.

The output of 38.1 mg (59% of theory).

Liquid / mass spectrometry (ionization by electron impact, method 7): m/z=431 (M+N)+the retention time 4,14 minutes.

Example 103

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

In 0.5 ml of dioxane and 0.1 ml of dimethylformamide at a temperature of 80°C 18 hours shaken out of 30.6 mg (0.15 mmole) of N-[3-(trifluoromethyl)phenyl]urea together with of 45.3 mg (0.3 mmole) of 3-nitrobenzaldehyde, 39 mg (0.3 mmole) of ethyl ester of 3-clobutinol acid and 90 mg of ethyl ester of polyphosphoric acid (freshly prepared by the method of Cava and others, J. Org. Chem. 1969, 34, 2665). After addition of 200 μl of dimethylformamide, the reaction mixture was filtered and purified using preparative HPLC (column: Nucleosil 100-5 18 Nautilus 20 mm ×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water +0.1% of formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 minutes 10% A, 8 min 10% A; flow rate 25 ml/min; wavelength of the s: 220 nm; injected volume: 800 ál; number of inputs: 1). The fractions containing the product are combined and evaporated in vacuum.

Yield 34 mg (50,4% of theory).

Liquid / mass spectrometry (ionization by electron impact, method b): m/z=450 (M+N)+the retention time of 3.94 minutes.

By analogy with the method of example 102 receives the next connection.

Example No.FormulaOriginal productsOutput [%]Rt[min (method)Mass [M+H]+
104N-(3-nitrophenyl)urea, 4-chlorobenzaldehyde, ethyl ester 3-clobutinol acid70,5the 3.65 (6)417
105N-(3-nitrophenyl)urea, 3-nitrobenzaldehyde, ethyl ester 3-clobutinol acid81,33,61 (6)427
106 N-(3-nitrophenyl)urea, 4-fermentology, ethyl ester 3-clobutinol acid56,83,63 (6)400
107N-(3-nitrophenyl)urea, 4-bromobenzaldehyde, ethyl ester 3-clobutinol acid69,5as 4.02 (5)461

Example 108

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

In 250 ml of tetrahydrofuran suspended 9,87 g (48.3 mmole) of N-[3-(trifluoromethyl)-phenyl]urea, 12,68 g (96,68 mmole) of 4-cyanobenzaldehyde, 15 g (96,68 mmole) 2-cyanoethylene ester 3-clobutinol acid and 37.5 g of ethyl ester of polyphosphoric acid. The mixture is stirred for 18 hours while boiling under reflux. After cooling to room temperature the solvent is distilled off in vacuo and purify the residue by chromatographytandem on silica gel with cyclohexane and ethyl acetate as eluent.

The yield 25 g (100% of theory).

1H-NMR (200 MHz, d6-sulfoxide): δ=2.1 a (C., 3H); 2,8 (m, 2H); 4,2 (m, 2H); 5,4 (D., 1H); to 7.6 (m, 4H), and 7.7 (m, 2H); to 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

In 60 ml of tetrahydrofuran is dissolved 0,609 g (1.52 mmole) of the compound from example 70 and added 1.24 g (12,93) mmole (methoxycarbonylamino)-triethylammonium-N-betaine. The reaction mixture is 1 hour and stirred at room temperature, the solvent is distilled off in vacuo and purify the residue by chromatographytandem on a column of silica gel with mixtures of dichloromethane and methanol as eluent.

Exit 249 mg (43% of theory).

1H-NMR (300 MHz, d6-sulfoxide): δ=1,8 (C., 3H); 5,4 (D., 1H), and 7.7 (m, 4H); 7,8 (m, 2H); 8.0 a (m, 2H), 8.4V (D., 1H) ppm

Example 110

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

In 100 ml of tetrahydrofuran is suspended to 7.84 g (of 38.4 mmole) of N-[3-(trifluoromethyl)-phenyl]urea, of 5.81 g (of 38.4 mmole) of 4-nitrobenzaldehyde, 5.0 g (of 38.4 mmole) ethyl ester 3-clobutinol acid and 15 g of ethyl ester of polyphosphoric acid. The mixture is stirred for 18 hours while boiling under reflux. After cooling to room temperature the solvent is distilled off in vacuo and purify the residue by chromatographytandem on a column of silica gel with toluene and ethyl acetate as eluent.

The output of 875 g (51% of theory).

1H-NMR (200 MHz, d6-sulfoxide): δ=1,1 (t, 3H); 2,1 (C., 3H); 4.0 a (m, 2H); 5,4 (D., 1H); 7.5 to about 7.8 (m, 6N); to 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-tetrahydropyrimidin

In 20 ml of tetrahydrofuran is suspended 0,407 g (2.0 mmole) N-[3-(trifluoromethyl)-phenyl]urea, 0,302 g (2.0 mmole) of 4-nitrobenzaldehyde, 0.2 g (2.0 mmole) of 2,4-pentanedione and 0.4 g of ethyl ester of polyphosphoric acid. The mixture is stirred for 18 hours while boiling under reflux. After cooling to room temperature the solvent is distilled off in vacuo and purify the residue by chromatographytandem on a column of silica gel with cyclohexane and ethyl acetate as eluent.

Output 0,302 g (36% of theory).

1H-NMR (200 MHz, d6-sulfoxide): δ=2,0 (C., 3H); 2,2 (C., 3H); 5,5 (D., 1H); 7.5 to about 7.8 (m, 6N); to 8.3 (m, 2H); 8,5 (D., 1H) ppm

C. Examples of methods of obtaining relevant to pharmaceutical compositions

Corresponding compounds of the invention can be converted into pharmaceutical preparations the following ways.

Tablet

Composition:

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) (produced by BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

The mass of the tablet and 212 mg, diameter 8 mm, the radius of curvature of 12 mm

The way to obtain

The mixture of active ingredient, lactose and starch granularit with a 5%solution (wt.%) polyvinylpyrrolidone in water. After drying, mix the granules with magnesium stearate for 5 minutes. From this mixture, compressed tablets using conventional press for tabletting (format tablets above). The pressing force in the normal case, equal to 15 kN.

Suspension for oral administration

Composition:

1000 mg of the compound of example 1, 1000 mg of ethanol (96%), 400 mg of rodies (xanthan gum Arabic production FMC, Pennsylvania, USA) and 99 g of water. Single dose of 100 mg corresponding to the invention of compounds contained in a 10 ml suspension for oral administration.

The way to obtain

Redigel suspended in ethanol and added to suspensions of the active component. While mixing, add water. Stirring is continued for about 6 hours until, until the swelling of rodies.

1. Compounds of General formula (I)
,
where a represents phenyl or peredelnyj cycle,
R1and R3each means a hydrogen atom,
R2means fluorine atom, chlorine, bromine, nitro-group or a cyano,
R4means cyano, alkylcarboxylic group with the number of carbon atoms in the alkyl residue from one of the four, or alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, and alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four can be replaced by a substitute, select the group consisting of hydroxyl group, alkoxygroup with the number of carbon atoms one to four, alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, mono - or dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, 5-6-membered heteroaryl group 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 nitrogen, oxygen or sulfur, or SO, SO2possibly replaced by geography,
R5means methyl group,
R6means a hydrogen atom, alkyl group with the number of carbon atoms one to four, mono - or dialkylaminoalkyl group with the number of carbon atoms in each alkyl residue of from one to four, alkylcarboxylic group with the number of carbon atoms in the alkyl residue of the aqueous to four, or alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, and an alkyl group with the number of carbon atoms one to four and alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four can be replaced by Deputy 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, hydroxyl group, alkoxygroup with the number of carbon atoms one to four, hydroxycarbonyl group, aminocarbonyl, mono - and dialkylaminoalkyl group with the number of atoms carbon in each of the alkyl residues from one to four, amino, mono - and dialkylamino with the number of carbon atoms in each alkyl residue of from one to four, or
R6means a structural unit of the formula
or
where R6Aselected from the group consisting of a hydrogen atom and a methyl group,
R7means triptorelin group or a nitro-group, and
Y1, Y2, Y3, Y4and Y5every means CH-group, and their pharmaceutically acceptable salt, hydrate and/or solvate.

2. Compounds of General formula (I) according to claim 1, where R2means cyano.

3. Compounds of General formula (I) according to claim 1 or 2, where R4means alkoxycarbonyl group with the number of carbon atoms in the CNS residue from one to four, which can be substituted by a hydroxyl group, or where R4means alkylcarboxylic group with the number of carbon atoms in the alkyl residue of from one to four.

4. Compounds of General formula (I) according to any one of claims 1 to 3, where R6means a hydrogen atom.

5. Compounds of General formula (I) according to claim 1, where the rest
means
where Z denotes a CH group or a nitrogen atom, and
R1has given in claim 1 values
R3, R4and R6have specified in claim 1 values, R5means methyl, Y1-Y4means CH-group, each R7means trifluoromethyl in position 3 of the phenyl residue.

6. The compound of General formula (I) according to claim 1, representing a compound 5-{5-acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}-2-pyridylcarbonyl.

7. The compound of General formula (I) according to claim 1, representing a compound (+)-5-{5-acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}-2-pyridylcarbonyl.

8. Pharmaceutical composition having the properties of an inhibitor of neutrophil elastase person, containing at least one soybean is inania General formula (I) according to claims 1 - 5, and a pharmaceutically acceptable diluent.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: described are novel chemical biologically active substances. As substances, educing negative impact of herbicide 2,4-dichlorophenoxyacetic acid on sunflower plant, proposed are 4,6-dimethyl-2-chlor-3-(5-X-1,2,4-oxadiazolyl-3)pyridines of formula 1-3

EFFECT: extension of line of biologically active substances, obtained by synthetic way, for their application in agriculture as antidotes for 2,4-D.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) or to its pharmaceutically acceptable salts or to it solvates, where m is equal 0 to 3, X stands for N, Y stands for -SO2-, each R1 independently stands for halogen, C1-C12alkyl, halogen(C1-C12)alkyl, hydroxy(C1-C6)alkyl, R2 stands for aryl or heteroaryl which represents monocyclic radical containing 5 to 12 atoms in a cycle, including one, two or three nitrogen heteroatoms in a cycle optionally substituted with halogen or cyano, each R3 and R4 independently stands for C1-C12alkyl, or R3 and R4 together with carbon atom whereto they are attached, form the cyclic group containing 3-6 atoms in a cycle, and each R5, R6, R7, R8 and R9 stands for hydrogen. Besides, the invention concerns the pharmaceutical composition.

EFFECT: preparation of the new biologically active compounds with antagonistic action to 5-NT6 receptor.

15 cl, 6 ex, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

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