Derivatives of n-heterocyclic compounds, pharmaceutical composition based on thereof and method for treatment

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

 

The technical field

The invention relates to a series of N-heterocyclic compounds and their derivatives for use as inhibitors synthase nitric oxide (NOS) and to methods of treatment of various diseases with the use of these compounds.

The level of technology

The nitric monoxide (NO) is involved in various physiological processes, including the relaxation of smooth muscle, inhibition of blood clotting, transmission of nerve impulses, regulation of the immune response and an erection. Nitric oxide is produced in different conditions all mammalian cells that have a nucleus. Anomalies in the production of NO is associated a number of pathological conditions, including stroke, insulin-dependent diabetes, hypotension, caused by septic shock, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in biological tissues by enzyme-synthase nitric oxide (NOS), which uses NADPH and molecular oxygen for the oxidation of L-arginine to citrulline and nitric oxide.

Synthase nitric oxide (NOS) there are at least three isoforms, which belong to two primary groups (enzymes): constitutive and inducible. Identified two constitutive isoforms that are dependent on calcium and calmoduline, and one of the inducible isoform. Constitutive isoforms are (1) isoform nervous t is Ani, NOS-1 or nNOS, which is found in the brain and skeletal muscle, and (2) the endothelial isoform, NOS-3 or eNOS, which is expressed in the endothelium of blood vessels, epithelium of the bronchi and in the brain tissue. These constitutive forms are not the target of NOS inhibitors according to the present invention.

The inducible isoform (NOS2 or iNOS) is expressed in all mammalian cells that have a nucleus after exposure (to them) inflammatory cytokines or lipopolysaccharide. First of all, noteworthy is the presence of this form in macrophages and epithelial cells of the lung. The inducible isoform is not stimulated by calcium and is not blocked by antagonists of calmoduline. It contains several strongly related cofactors, including FMN, FAD, and tetrahydrobiopterin.

The nitric oxide generated by inducible form of NOS is involved in the pathogenesis of inflammatory processes. In experimental animals hypotension induced by lipopolysaccharide or tumor necrosis factor and may be withdrawn by NOS inhibitors. Conditions that lead to hypotension induced by cytokines include septic shock, hemodialysis and therapy with interleukin in cancer patients. It is assumed that the iNOS inhibitor will be effective in the treatment of cytokine-induced hypotension. In addition, recent studies have shown the b the involvement of NO in the pathogenesis of the inflammatory process, and, therefore, the NOS inhibitors may have a therapeutic effect in inflammatory bowel disease, cerebral ischemia and arthritis. In addition, the NOS inhibitors can find application in the treatment of respiratory distress syndrome (ARDS) in adults and myocarditis and can be used as adjuvants for short-term immunosuppression in transplant therapy. Due to the variety and wide range of functions of NO in physiology therapeutic effect on the processes associated with NO, is of undoubted interest. Since the production of endogenous NO is the result of close but different isoenzymes, selective inhibition of NOS isoenzymes allows for more targeted therapies with negligible side effects.

Brief description of the invention

The first aspect of the invention is a compound of formula (Yc):

where

n and m each independently denote an integer from 1 to 4

And means-C(O)OR1or-C(O)N(R1R2;

W stands for CH;

R1means hydrogen or C1-C8alkyl;

R2independently means hydrogen, C1-C8alkyl, -(CH2)n-N(R1)2,

geterotsiklicheskikh selected from the group including pyridinyl, morpholinyl, benzodioxolyl benzodioxolyl, if m is 1; if m means 2-4, R4can optionally indicate hydroxy, -N(R1R2where R1and R2independently mean hydrogen, C1and C8alkyl or benzylation, -N(R1)-C(O)-R1, -N(R1)-C(O)OR1, -N(R1)-S(O)t-R1where R1means hydrogen or C1-C8alkyl, -N(R1)-C(O)-N(R1)2where R1means hydrogen,

R5means1-C8alkyl;

t means 2,

in the form of an individual stereoisomer or a mixture thereof, or their pharmaceutically acceptable salts.

Another aspect of the invention are the compounds of formula (IV)

where

AA denotes an amino acid,

X, Y and Z independently of one another denote N or C(R19),

U represents N or C(R5), provided that U mean N only when X is N and Z and Y denote C(R19);

W stands for N or CH;

R1and R2independently from each other selected from the group comprising hydrogen, optionally substituted C1-C20alkyl, optionally substituted cycloalkyl, -[C0-C8alkyl]-R9, -[C2-C8alkenyl]-R9, -[C2-C8quinil]-R9, -[C2-C8alkyl]-R10(optionally substituted by hydroxy group), -[C1-C8]-R11(optional Zam is on the group hydroxy), and optionally substituted heterocyclyl;

or R1and R2together with the nitrogen atom to which they are attached represent optionally substituted N-heterocyclyl;

R5selected from the group comprising hydrogen, halogen, alkyl, halogenated, optionally substituted aralkyl, optionally substituted aryl, -OR16, -S(O)t-R16, -N(R16R21, -N(R16)C(O)N(R1R16, -N(R16)C(O)OR16, -N(R16)C(O)R16, -[C0-C8alkyl]-C(O)OR16, -[C0-C8alkyl]-C(H)[C(O)OR16]2and -[C0-C8alkyl]-C(O)N(R1R16,

each R9independently from each other selected from the group including halogenated, cycloalkyl (optionally substituted with halogen, cyano, alkyl or alkoxy), carbocyclic (optionally substituted by one or more substituents selected from the group comprising halogen, alkyl and alkoxy), and heterocyclyl (optionally substituted by alkyl, aralkyl or alkoxy);

each R10independently from each other selected from the group comprising halogen, alkoxy, optionally substituted, aryloxy, optionally substituted, Alcoxy, optionally substituted-S(O)t-R22acylamino, amino, monoalkylamines, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamides;

each R11independently from each other selected from the group, including the non cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamines and dialkylaminoalkyl;

each R16independently of one another denotes hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl;

R19means hydrogen, alkyl (optionally substituted by hydroxy group), cyclopropyl, halogen or halogenated;

each R21means hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, -C(O)R22or-SO2R22;

or R21together with R1and the nitrogen atom to which they are attached represent optionally substituted N-heterocyclyl;

or R21together with R16and the nitrogen atom to which they are attached represent optionally substituted N-heterocyclyl;

each R22independently mean alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and

t is 0, 1 or 2;

in the form of an individual stereoisomer or a mixture thereof, or their pharmaceutically acceptable salts.

Another aspect of the invention are pharmaceutical compositions comprising a compound of formula (Ya), formula (Yb) and formula (Yc)described above, and a pharmaceutically acceptable carrier.

Another aspect of the invention are methods of treatment, wismann the th anomaly in the production of nitric oxide, which include the introduction of the mammal with a condition caused by an abnormality in the production of nitric oxide, a therapeutically effective amount of the above compounds of formula (Ya), formula (Yb) and formula (Yc).

Detailed description of the invention

Definition of terms

Unless otherwise stated, the following terms used in this text and the claims, have the following meanings.

"Alkyl" means a radical with a straight or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing no unsaturated bonds, having from one to eight carbon atoms and is attached to the remainder of the molecule by a simple relationship, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl) and the like, Alkyl radicals having more than eight carbon atoms are denoted in the text of the application by the symbol "[Sx-Cyalkyl], where x and y indicate the number of people present carbon atoms. The alkyl radical may be optionally substituted by one or more substituents independently selected from the group comprising halogen, hydroxy, alkoxy, carboxy, cyano, carbonyl, alkoxycarbonyl, amino, monoalkylamines, dialkylamino, nitro, alkylthio, amidino, aryl, heterocyclyl, aryloxy, Alcoxy, acylamino, aminocarbonyl, monoalkylamines dialkylaminoalkyl.

"Alkenyl" means a monovalent or divalent radical with a straight or branched chain consisting solely of carbon atoms and hydrogen, containing at least one double bond and having from one to eight carbon atoms, for example, ethynyl, prop-1-enyl, but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl etc.

"Quinil" means a monovalent or divalent radical with a straight or branched chain consisting solely of carbon atoms and hydrogen, containing at least one triple bond and having from one to eight carbon atoms, for example, ethinyl, prop-1-inyl, but-1-inyl, Penta-1-inyl, Penta-3-inyl etc.

"Alkoxy" means a radical of the formula-ORawhere Rameans an alkyl radical, with the values specified above, for example, methoxy, ethoxy, propoxy, etc.

"Alkoxycarbonyl" means a radical of the formula-C(O)ORawhere Rameans an alkyl radical, with the values specified above, for example, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl etc.

"Alkoxycarbonyl" means a radical of the formula-Ra-C(O)ORawhere each Raindependently mean alkyl radical having values above, for example, 2-(methoxycarbonyl)ethyl, 3-(etoxycarbonyl)propyl, 4-(n-propoxycarbonyl)butyl, etc.

"Alkylsulfonyl" means a radical of the formula-N(H)S(O)2- awhere Rameans an alkyl radical, with the values specified above, for example, methylsulfonylamino, ethylsulfonyl and other

"Alkylsulfonyl" means a radical of the formula-S(O)2-Rawhere Rameans an alkyl radical, with the values specified above, for example, methylsulphonyl, ethylsulfonyl etc.

"Alkylthio" means a radical of the formula-S-Rawhere Rameans an alkyl radical, with the values specified above, for example, methylthio, ethylthio, n-propylthio etc.

"Amidino" means a radical of the formula-C(NH)-NH2.

"Amino" means a radical of the formula-NH2.

"Aminocarbonyl" means a radical of the formula-C(O)NH2.

"Aminosulfonyl" means a radical of the formula-S(O)2NH2.

"Aryl" means a phenyl radical or naphthyl. The aryl radical may be optionally substituted by one or more substituents selected from the group comprising hydroxy, mercapto, halogen, alkyl, alkenyl, quinil, phenyl, phenylalkyl, phenylalkyl, alkoxy, phenoxy, funeralcare, halogenated, halogenoalkane, formyl, nitro, cyano, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenoxyethyl, generalkonsulat, amidino, ureido, alkoxycarbonyl, amino, monoalkylamines, dialkylamines, monophenyltin, monovinylacetylene, sulfonylamino, alkylsulfonyl, aminoalkyl, monoalkylamines the sludge, dialkylaminoalkyl, monofilaments, monovinylacetylene, acyl, carboxylic, alkoxycarbonylmethyl, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, aminocarbonyl, monoalkylammonium and dialkylaminoalkyl, as indicated in the context of the application.

"Aralkyl" means a radical of the formula-RaRbwhere Rameans alkyl radical having values above a Rbmeans aryl radical, with the values specified above, for example, benzyl and the like, the Aryl radical may be optionally substituted as described above.

"Aryloxy" means a radical of the formula-ORbwhere Rbmeans aryl radical, with the values specified above, for example, phenoxy, naphthoxy etc. Aryl radical may be optionally substituted as described above.

"Aryloxyalkyl" means a radical of the formula-C(O)ORbwhere Rbmeans aryl radical, with the values specified above, for example, phenoxycarbonyl.

"Arakaki" means a radical of the formula-ORcwhere Rcmeans Uralkaliy radical having values above, for example, benzyloxy, etc. Uralkaliy radical may be optionally substituted as described above.

"Arelaxation" means a radical of the formula-C(O)ORcwhere Rcmeans Uralkaliy radical, they shall store the values above, for example, benzyloxycarbonyl etc. Uralkaliy radical may be optionally substituted as described above.

"Allumination" means a radical of the formula-C(O)N(Rb)H, where Rbmeans aryl radical, with the values specified above, for example, phenylenecarbonyl etc. Aryl radical may be optionally substituted as described above.

"Arylamination" means a radical of the formula-S(O)2N(Rb)H, where Rbmeans aryl radical, with the values specified above, for example, phenylenesulfonyl etc. Aryl radical may be optionally substituted as described above.

"Arylsulfonyl" means a radical of the formula-S(O)2-Rbwhere Rbmeans aryl radical, with the values specified above, for example, phenylsulfonyl etc. Aryl radical may be optionally substituted as described above.

"Arylsulfonamides" means a radical of the formula-C(O)N(H)S(O)2Rbwhere Rbmeans aryl radical, with the values specified above, for example, vinylsulfonylacetamido etc. Aryl radical may be optionally substituted as described above.

"Acyl" means a radical of the formula-C(O)-Raand-C(O)-Rbwhere Rameans alkyl radical having values above and Rbmeans aryl radical, there is a first value, above, for example, acetyl, propionyl, benzoyl, etc.

"Acylamino" means a radical of the formula-N(H)-C(O)-Raand-N(H)-C(O)-Rbwhere Rameans alkyl radical having values above and Rbmeans aryl radical, with the values specified above, for example, acetylamino, benzoylamine etc.

"Alkylene" means the divalent radical with a straight or branched chain consisting solely of carbon atoms and hydrogen, containing no unsaturated communication and having from one to eight carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. Radical alkylene may be optionally substituted by one or more substituents selected from the group comprising alkyl, hydroxy, -N(R16R21or-C(O)N(R1R16where R1, R16and R21have the meanings specified above in the Brief description of the invention.

"Cycloalkyl" means stable 3-10-membered monocyclic or bicyclic saturated moiety, consisting of only carbon atoms and hydrogen, for example, cyclopropyl, cyclobutyl, cyclohexyl, decaline etc. If the bid is not specifically stated otherwise, it should be assumed that the term "cycloalkyl" includes radicals cycloalkyl, optionally substituted by one or more substituents independently selected from the group comprising alkyl, halogen, guide is hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

"Carboxy" means a radical of the formula-C(O)HE.

"Carboxylic" means a radical of the formula-Ra-C(O)OH, where Rameans an alkyl radical, with the values specified above, for example, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl etc.

"Di(alkoxy)alkyl" means a radical of the formula-Ra(ORa)2where each Raindependently mean alkyl radical having values above and where-ORagroups can be linked to any carbon atom in the group Rafor example, 3,3-dimethoxypropane, 2,3-dimethoxypropane etc.

"Dialkylamino" means a radical of the formula-N(RaRawhere each Raindependently mean alkyl radical having values above, for example, dimethylamino, diethylamino, (methyl)(ethyl)amino, etc.

"Dialkylaminoalkyl" means a radical of the formula-C(O)N(RaRawhere each Raindependently mean alkyl radical having values above, for example, dimethylaminoethyl, methylaminomethyl, diethylaminoethyl, dipropylthiocarbamate, ethylpropylamine etc.

"Dialkylaminoalkyl" means a radical of the formula-S(O)2N(RaRawhere each Raindependently mean alkyl radical having values above voltage is emer, dimethylaminomethyl, methylaminomethyl, diethylaminosulfur, dipropyleneglycol, ethylpropylamine-sulfonyl etc.

"Halogen" means bromine, chlorine, iodine or fluorine.

"Halogenated" means an alkyl radical having values above, substituted by one or more halogen radicals, having the values specified above, for example, trifluoromethyl, deformity, trichloromethyl, 2,2,2-triptorelin, 1-vermeil-2-foretel, 3-bromo-2-forproper, 1-methyl bromide-2-bromacil etc.

"Halogenoalkane" means a radical of the formula-ORdwhere Rdmeans radical halogenated with the values specified above, for example, triptoreline, deformedarse, trichlormethane, 2,2,2-triptoreline, 1-vermeil-2-floratone, 3-bromo-2-forproperty, 1-methyl bromide-2-bromoethoxy etc.

"Heterocyclyl" means stable 3-15 membered cyclic radical comprising carbon atoms and from one to five heteroatoms selected from the group comprising atoms of nitrogen, oxygen and sulfur. For the purposes of the present invention the radical heterocyclyl may be monocyclic, bicyclic and tricyclic system, which may include kondensirovannye or bridged cyclic system, and the atoms of nitrogen, carbon or sulfur radical heterocyclyl may not necessarily be in the oxidized form, the nitrogen atom may not affect Iwate Quaternary ammonium base, and radical heterocyclyl may be partially or fully saturated or aromatic.

Radical heterocyclyl can be attached to the main fragment at any heteroatom or carbon atom which provides the formation of a stable connection. Examples of the radical heterocyclyl include, but are not limited to, azepine, azetidinol, acridines, benzimidazolyl, benzodioxolyl, benzodioxane, benzothiazolyl, benzoxazolyl, benzopyranyl, benzofuranyl, benzothiazol, carbazolyl, cinnoline, decahydroquinoline, DIOXOLANYL, furyl, isothiazolin, hinokitiol, imidazolyl, imidazolyl, imidazolidinyl, isothiazolinones, indolyl, isoindolyl, indolinyl, isoindolyl, indolizinyl, isoxazolyl, isoxazolidine, morpholine, naphthyridine, oxadiazole, octahedrally, activitiesunder, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, oxazolyl, oxazolidinyl, peligrosamente, piperidinyl, piperazinil, 4-piperidinyl, phenazines, phenothiazines, phenoxazines, phthalazine, pteridine, purinol, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidine, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, hintline, honokalani, chinoline, hinokitiol, ethenolysis, thiazolyl, diazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, tetrahydropyranyl, tetrahedrite INAIL, thienyl, thiomorpholine, dimorpholinyldiethyl and thiomorpholine. Radical heterocyclyl may be optionally substituted by R6with the value specified in the Brief description of the invention, or may be optionally substituted by one or more substituents selected from the group comprising hydroxy, mercapto, halogen, alkyl, alkenyl, quinil, phenyl, phenylalkyl, phenylalkyl, alkoxy, phenoxy, funeralcare, halogenated, halogenoalkane, formyl, nitro, cyano, amidino, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenoxyethyl, generalkonsulat, amidino, ureido, alkoxycarbonyl, amino, monoalkylamines, dialkylamines, monophenyltin, monovinylacetylene, aminoalkyl, monoalkylamines, dialkylaminoalkyl, monofilaments, monovinylacetylene, alkylsulphonyl, carboxyethyl alkoxycarbonylmethyl, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl and imidazolyl, as indicated in the context of the application.

"Geterotsiklicheskikh" means a radical of the formula-Ra-Rewhere Rameans alkyl radical having values above a Remeans radical heterocyclyl with the values specified above, for example, 2-(1,3-benzodioxol-5-yl)ethyl and 3-(1,4-benzodioxan-6-yl)propyl, etc.

"MES is alkylamino" means a radical of the formula-N(H)R awhere Rameans an alkyl radical, with the values specified above, for example, methylamino, ethylamino, propylamino etc.

"Monoalkylamines" means a radical of the formula-C(O)N(H)Rawhere Rameans an alkyl radical, with the values specified above, for example, methylaminomethyl, ethylaminomethyl, propylaminoethyl etc.

"Monoalkylbenzenes" means a radical of the formula-S(O)2N(H)Rawhere Rameans an alkyl radical, with the values specified above, for example, methylaminomethyl, ethylaminomethyl, propylaminosulfonyl etc.

"N-heterocyclyl" means the radical heterocyclyl that have values as described above, containing at least one nitrogen atom and attached to the main portion through the nitrogen atom. The radical N-heterocyclyl can contain up to three additional heteroatoms. Examples of the radical N-heterocyclyl include piperidinyl, piperazinil, pyrrolidinyl, morpholinyl, thiomorpholine, azetidine, indolyl, pyrrolyl, imidazolyl, tetrahydroisoquinoline, peligrosamente, tetrazolyl, triazolyl, oxazinyl, etc. that may not necessarily be substituted as described above for the radicals heterocyclyl. In addition to the optional substitution of the substituents listed above for the radical heterocyclyl, the radical N-heterocyclyl may be optional is tion substituted R 6as described above in the Brief description of the invention.

"Phenylalkyl" means an alkyl radical, having a value, as indicated above, the substituted phenyl radical, for example, benzyl, etc.

"Optional" or "optionally" means that the following event or circumstances may occur or may not occur, and the description includes examples in which the above-mentioned event or circumstance occurs and instances in which they occur. For example, "optionally substituted aryl" means aryl radical may be substituted or unsubstituted, and the description is included as a substituted aryl radicals, and radicals having no substituents. The term "-[S2-C8alkyl]-R10(optionally substituted by hydroxy group)" means that the alkyl is optionally substituted. The same applies to the term "-[S1-C8alkyl]-R11(optionally substituted by hydroxy group)". The term "optionally substituted-S(O)tR22" means that all the substituents R22are optionally substituted.

"Phenylalkyl" means a radical of alkenyl having values, as indicated above, the substituted phenyl radical.

The term "pharmaceutically acceptable salts" means salts derived from pharmaceutically acceptable non-toxic acids or bases including ka is inorganic acids and bases, and organic acids and bases. If the compounds of the present invention are bases, salts obtained using pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention include salts of acetic acid, benzosulfimide (besylate), benzoic, camphorsulfonic, lemon, atenololbuy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate (2-hydroxyethanesulfonic), lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, para-toluensulfonate acids, etc. If the compounds contain acidic side chain, suitable pharmaceutically acceptable basic additive salts of the compounds of the present invention include metal salts, such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts using lysine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine.

"Therapeutically effective amount" means such amount of the compounds according to the invention that, when introduced into the body to be cured is Yu, sufficient for delivery of therapeutic action, as listed below, with conditions caused by abnormal production of nitric oxide. The number of compounds according to the invention, which constitutes a "therapeutically effective amount"will vary depending on the connection status and the severity of the disease, age of the patient to be treated, and may be determined by the person skilled in the art based on their own experiences and descriptions of the present invention.

The term "treatment" or "therapy"used in this text includes therapy of human diseases caused by abnormal production of nitric oxide, which includes:

(I) the prevention of the state, primarily in people predisposed to the disease, which has not yet been diagnosed;

(II) the suppression of disturbances, i.e. preventing the development of disease;

(III) the weakening of the disease, i.e. stimulation of the regression of the disease.

The output of each reaction described in the proposal, expressed as a percentage of theoretical yield.

Most of the compounds described in the proposal, have one or more asymmetric centers and therefore can form enantiomers, diastereomers, and other stereoisomeric forms that may be marked approved terms of absolute stereochemistry of (R)- or (S)-, or (D)- or (L)-, Kakinada to denote amino acids. It is assumed that the present invention includes all the possible isomers, as well as their racemic and optically pure forms. Optically active (R)- and (S)-, or (D)and (L)-isomers may be obtained using chiral synthons or chiral reagents, or may be separated by known methods. If the connection is described in the text of the application, contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is understood that the compounds include E and Z geometric isomers. Similarly, it is understood that the compounds include all tautomeric forms.

The nomenclature used in the text of the application is a modified form of the nomenclature of the IUPAC system, where the compounds according to the invention are named as derivatives of the amide. For example, the following compound according to the invention

in the text of the application is called 2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl] [2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide. If not specified, it is assumed that the names of the compounds include any individual stereoisomer, enantiomer, racemate, or a mixture.

The scope of the compounds according to the invention

The nitric oxide formed by the inducible form synthase nitric oxide (i-NOS), is involved in the pathogenesis of a number of vospalitelnye autoimmune diseases and diseases that are not normally considered to be inflammatory, but nevertheless may be held with the participation of cytokines, which stimulate i-NOS at the local level. Therefore, the compounds according to the invention, alone or in combination with other pharmaceutical agents that are suitable for the treatment of mammals, preferably humans, in the condition caused by an abnormality in the production of nitric oxide. Such conditions include (but are not limited to):

Multiple sclerosis (J.F. Parkinson and others, J. Mol. Med. (1997), t, str-186), stroke or cerebral ischemia (Iadecola C., and others, J. Neurosci. (1997), V.17, str-9164), Alzheimer's disease (Smith M.A. and others, J. Neurosci. (1997), V.17, str-2657; Wallace M.N., etc., Exp. Neurol. (1997), t, str-272), HIV-associated dementia (Adamson D.C. and others, Science. (1996), t, str-1921), Parkinson's disease (Hunot S., and others, Neuroscience (1996), t, str-363), meningitis (Koedel U., and others, Ann. Neurol. (1995), v.37, str-323), extensive cardiomyopathy and congestive heart failure (Satoh, M. and others, J. Am. Coll. Cardiol. (1997), t, str-724), atherosclerosis (J.N. Wilcox and others, Arterioscler. Thromb. Vasc. Biol. (1997), V.17, str-2488), restenosis or stenosis of the implant, septic shock and hypotension (Petros A. and others, Cardiovasc. Res. (1994), V.28, p.34-39), hemorrhagic shock (Thiemermann C. and others, Proc. Natl. Acad. Sci. (1993), t, SCR-271), asthma (Barnes P.J., Ann. Med, (1995), v.27, str-393; Flak T.A. and others, Am. J. Respir. Crit. Care Med. (1996), t, .S202-S206), respiratory distress C the drôme adults lung damage by smoke or particulate matter (Ischiropoulos H., and others, Am. J. Respir. Crit. Care Med. (1994), t, str-341; Van Dyke K., Agents Actions (1994), v.41, p.44-49), pneumonia caused by pathogenic microorganisms (H. Adler and others, J. Exp. Med. (1997), t, str-1540), injury of various etiologies (Thomae K.R. and others, Surgery (1996), t, p.61-66), rheumatoid arthritis and osteoarthritis (Grabowski P.S., and others, Br. J. Rheumatol. (1997), T.36, str-655), glomerulonephritis (Weinberg J.B., and others, J. Exp. Med. (1994), t, str-660), systemic lupus erythematosus (Belmont H.M. and others, Arthritis Rheum. (1997), t, str-1816), inflammatory bowel disease such as ulcerative colitis and Crohn's disease (Godkin AJ and others, Eur. J. Clin. Invest. (1996), t, str-872; Singer I.I. and others, Gastroenterology (1996), t, 871-885), insulin-dependent diabetes mellitus (M.L. McDaniel and others, Proc. Soc. Exp. Biol. Med. (1996), t, p.24-32), diabetic neuropathy or nephropathy (Sugimoto K., Yagihashi S., Microvasc. Res. (1997), t, p.105-112; A. Amore, etc., Kidney Int. (1997), t, p.27-35), acute and chronic rejection of the transplanted organ (Worrall N.K. and others, Transplantation (1997), t, str-1101), a disorder of vessels of the graft (M.E. Russell and others, (1995), t, str-464), homologous disease (graft versus host) (Kichian K., and others, J. Immunol. (1996), t, str-2856), psoriasis and other inflammatory skin disorders (Bruch-Gerharz d, etc., J. Exp. Med. (1996), I. 184, str-2012) and cancer (Thomsen L.L. and others, Cancer Res. (1997), t, str-3304).

Compounds of the present invention can be also use the s in the treatment of male and female reproductive functions, if they are used alone or in combination with other drugs, usually prescribed for similar indications. Examples include (not limited to): inhibition of fertilization, uterine receptivity and implantation (alone or in combination with an antagonist of progesterone), postcoital contraception (alone or in combination with an antagonist of progesterone), stimulation of abortion (in combination with antiprogestins, and then combined with prostaglandin), control and management of labour and delivery, treatment of cervical insufficiency (alone or in combination with progesterone or a progestin), therapy of endometriosis (alone or in combination with other lekarstvennymi means, including agonists/antagonists RFLG (releasing factor, luteinizing hormone), antiprogestin or progestins in sequential or concomitant introduction). See, for example, the following articles: Chwalisz, K., and others, J. Soc. Gynecol. Invest. (1997), V. 4, No. 1 (Supplement), Stra discussing the suppression of fertilization, uterine receptivity and implantation, or postcoital contraception, when used alone or in combination with an antagonist of progesterone; Chwalisz, K., and others, Prenat. Neonat. Med. (1996), vol. 1, str-329 discussing stimulation of abortion, when used in combination with antiprogestins, and then combined with the question what eglantina, and the control and management of labour and delivery; and Chwalisz, K., and others, Hum. Reprod. (1997), vol.12, p.101-109, discussing the treatment of cervical insufficiency, when applied alone or in combination with progesterone or a progestin.

To a person skilled in the art it is also evident that the compounds of the present invention include 1-substituted imidazoles. This class of compounds has previously been described as a heme-binding inhibitors of enzymes of the family of cytochrome P450 (Maurice M. and others, FASEB J. (1992), V.6, str-758)involved in the mechanism of action in addition to the synthesis of nitric oxide (Chabin R.N.M., etc., Biochemistry (1996), t.35, str-9575). Thus, the compounds of the present invention can be used as inhibitors of individual members of the family of cytochrome P450, representing therapeutic interest, including, but not limited to, the P450 enzymes involved in the biosynthesis of steroids and retinoids (Masamura and others, Breast Cancer Res. Treat. (1995), v.33, p.19-26; Swart, R., and others, J. Clin. Endocrinol. Metab. (...), t, p.98-102; Docks R. and others, Br. J. Dermatol. (1995), t, str-432) and in the biosynthesis of cholesterol (Burton P.M. and others, Biochem. Pharmacol. (1995), t, str-544; and Swinney D.C. and others, Biochemistry (1994), v.33, str-4713). Compounds with imidazole may also have antifungal activity (Aoyama, Y. and others, Biochem. Pharmacol. (1992), t, str-1705). Inhibitory activity of the compounds according to the invention in which Oseni P450 can be defined through the use of appropriate systems analysis, specific test P450 isoforms. Such analyses are included in the above article. Another example isoforms of cytochrome P450 mammals, which can be ingibirovany compounds of the present invention, is a cytochrome P450 3A4, which may be identified in a manner analogous to the method described in the article Yamazaki and others, Carcinogenesis (1995), t.16., str-2170.

The test compounds according to the invention

Synthase nitric oxide is a complex of enzymes that catilium the conversion of L-arginine into nitric oxide (NO) and citrulline. The process of catalysis passes through two successive stages of oxidation of guanidinium moiety of arginine.

For analysis of the compounds according to the invention uses a method for determining the activity of the synthase nitric oxide using cells, which is based on the measurement of nitrite, which is the oxidation product of nitric oxide in air-conditioned environment of the cell culture. Reliably established that the murine macrophage cell line RAW 264.7 and J774 have the ability to produce >10 μm nitrite in response to immunostimulation.

Induction of iNOS in cell lines of mouse RAW 264.7

The cell line of mouse macrophages RAW 264.7 was obtained from ATS (Rockville, Marylend) and maintained in RPMI medium 1640 containing 10% fetal calf serum (FBS), 5000 units/ml of panic line and streptomycin, and 2 mm glutamine (supportive environment). The NOS activity was measured by fluorescence analysis of the oxidation product of nitric oxide, nitrite (see Diamani, etc., Talanta (1986), v.33, str-652). The induction of iNOS (inducible synthase nitric oxide) stimulate treatment of the cells with lipopolysaccharide and γ-interferon. The method of analysis described below.

Cells were collected, diluted supporting medium to a concentration of 500,000 cells/ml and inoculated in 96-well tablets 100 ál to well. The plates were incubated at 37°during the night in an atmosphere containing 5% CO2. Then the medium was replaced with 90 μl of environment TOGETHER with 10% FBS, 100 units/ml penicillin, 100 μl streptomycin, 2 mm glutamine, 100 units/ml of interferon-γ and 2 µg/ml of lipopolysaccharide. Four wells were added N-guanidinate-L-arginine (negative control) to a final concentration of 200 μm using a 10 μl 2 mm solution in 100 mm HEPES, pH of 7.3+0.1% of DMSO, and four wells were added only buffer solution, 100 mm HEPES/0.1% DMSO (positive control). Analyzed transferred to the wells of the 96-well plate. The plates were incubated at 37°C for 17 h in an atmosphere containing 5% CO2. Formed in the culture medium nitrite was determined by the following procedure: in each well was added 15 μl of a solution of 2,3-diaminonaphthalene (10 μg/ml of 0.75 M HCl) and incubated at room temperature for 10 mindball 15 μl of 1N. NaOH and when the wave excitation 365 nm was measured by fluorescence emission at 405 nm. Enzymatic activity in the wells with enzyme was calculated in percentage compared with the control wells using positive and negative control. In this method, analysis of the ratio of signal intensity to noise was >10. When testing this method, compounds of the invention demonstrated the ability to inhibit the production of nitric oxide.

For compounds according to the invention is defined values IC50. The experiments were conducted with different cell lines, for example, A, which are a cell line of human astrocytomas, and with various stimulants used to induce NO such as gamma-interferon, interleukin-1-beta and alpha-factor tumor necrosis. All reported samples of the compounds are active at micromolar quantities, namely below 1 μm in the in vitro experiments.

Fourth from the list of compounds, namely 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide (value IC501.3 nm) was studied in experiments in vivo model study of the effects on arthritis in rats.

At the dose of 10 mg/kg and 4.2 figure was 7.7 and 4.2 at the dose of 30 mg/kg on the 29th day despite the fact that this indicator is theoretically 4 for each konechnostey comparison metric for the media is 10.5, and for untreated limbs - 10 on the 29th day.

To determine the ability of compounds according to the invention to treat a condition caused by an abnormal production of nitric oxide, such as arthritis, can be used different ways of in vivo tests. Below is a description of the tests using rats.

The action of the compounds according to the invention for arthritis in rats induced by adjuvant

The male Lewis rats were injected intradermally (proximal quarter of the tail with 0.1 ml of Mycobacterium butyricum in incomplete adjuvant Freud (10 mg/ml). The solvent (acidified saline, 1 ml/kg) or the compound of the invention (3, 10 or 30 mg/kg) was administered subcutaneously (b.i.d.), starting from the next day after immunization adjuvant, and continued introduction before the end of the experiment (N=10 rats in each group). Clinical indicators (see below) was assessed on all limbs three times a week throughout the experiment. Rats were scored by the method of euthanasia through 34-35 days after immunization. At the time of euthanasia was performed radiological assessment (see below) of the hind legs, took blood samples for clinical analysis and determination of the content of the medicinal product (only the group receiving the high dose after 6 or 12 h after receiving the last dose)were cut liver to determine possible toxicity, and conservera is whether hindquarters for histopathological analysis.

Clinical indicators on each limb was evaluated according to the following scale: no signs of inflammation, moderate red, the first signs of swelling, flexible joint, moderate redness, mild swelling, flexible joint, redness, significant swelling and curvature of legs, the first signs of ankylosis of the joint, 4 redness, significant swelling, shear legs, complete fusion of the joint.

Radiological indicators on each hind limb was evaluated on a scale of 0-3 for each of the following indications: soft-tissue swelling, loss of cartilage, erosion, heterotropia ossification.

When tested by this method of connection Sobranie showed the ability to cure arthritis observed in the experimental rats.

To a person skilled in the art it is evident that there are many ways of determining the activity of isoforms of NOS (iNOS, nNOS and eNOS), which can be used to determine the biological activity of the compounds of the present invention. These methods include analysis of native isoforms of NOS in tissues ex vivo (Mitchell and others, Br. J. Pharmacol. (1991), t, str-291; Szabo and others, Br. J. Pharmacol. (1993), t, str-792; Joly and others, Br. J. Pharmacol. (1995), t, str-497), as well as in primary cell cultures and cell lines (Forstermann and others, Eur. J. Pharmacol. (1992), t, str-165; Radmoski and others, Cardiovasc. Res. 1993), v.27, str-1382; Wang and others, J. Pharmacol. Exp. Ther. (1994), t, str-557). To a person skilled in the art it is clear that recombinant NOS enzymes can be expressed in heterologous cells using cDNA NOS at the time of transfection (Karlsen and others, Diabetes (1995), t, str-758), when stable transfection (McMillan and others, Proc. Natl. Acad. Sci.(1992), t, str-11145; Sessa, etc., J. Biol. Chem. (1995), t, str-17644) or by transfection lytic virus (Busconi & Michel, Mol. Pharmacol. (1995), t, str-659; List and others, Biochem. J. (1996), t, p.57-63). Heterologous expression can be carried out in mammalian cells (McMillan and others, Proc. Natl. Acad. Sci.(1992), t, str-11145), insect cells (Busconi & Michel, Mol. Pharmacol. (1995), t, str-659; List and others, Biochem. J. (1996), t, p.57-63), yeast (Sari and others, Biochemistry (1996), t.35, str-7213) or bacteria (Roman and others, Proc. Natl. Acad. Sci.(1995), t, str-8432; Martasek, etc., Biochem. Biophys. Res. Commun. (1996), t,; page 359-365). Any of these heterologous systems can be used to develop a systems analysis of iNOS, nNOS and eNOS, suitable for determination of biological activity of the compounds of the present invention.

Introduction compounds according to the invention

To ensure patient an effective dose of a compound according to the invention can be any suitable type of introduction.

For example, can be used for oral, rectal, parenteral (subcutaneous, in timesexy, intravenous), transdermal, and other ways. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, patches, etc.

The pharmaceutical compositions of the present invention include compounds according to the invention as an active ingredient, and may also include pharmaceutically acceptable carrier or optionally other therapeutic ingredients. Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, sizing, binders, dezintegriruetsja tools, etc. that are suitable in the case of solid preparations (such as powders, capsules and tablets), for oral administration, and solid preparations in this case, the preferred liquid forms. The methods of preparation of such drugs are known in the art.

Due to the simplicity of taking tablets and capsules represent the most preferred form of standard doses for oral administration, in which use solid pharmaceutical carriers. If necessary, the tablets may be coated according to standard methods in aqueous or non-aqueous environment. In addition to the usual above-described dosage forms, the compounds of the present invention can also be entered in the form with constant isopropanolamine release and in the form of delivery systems.

The pharmaceutical compositions of the present invention for oral administration may represent a discrete forms, such as capsules, sachets (wafers), or tablets, each of which contains a certain amount of the active ingredient, as well as a powder or granules, or a solution or suspension in water, non-aqueous medium, emulsion oil-in-water"or in liquid emulsion water in oil. Such compositions can be prepared by any method known in the pharmacy, but all methods include the stage of introduction of the active ingredient in contact with the media, which consists of one or more necessary ingredients. Typically, the compositions are prepared uniform and thorough mixing of the active ingredient with liquid carriers or finely powdered solid carriers, or both with one and another, and then, if necessary, processing into a desired shape.

Preferred embodiments of the inventions

A preferred group of compounds of formula (Yc)described above are compounds of the formula (Yc), where n is 1, m is 2 or 3, a represents-C(O)OR1or-C(O)N(R1R2each W means SN, R1means hydrogen or alkyl, R2means hydrogen, alkyl, optionally substituted geterotsiklicheskikh or optionally substituted phenyls1-C4alkyl.

Among this subgroup of compounds, a preferred class are those compounds where R4means-N(R1R2where R1means hydrogen or alkyl, and R2means geterotsiklicheskikh selected from the group comprising (1,3-benzodioxol-5-yl)methyl or (1,4-benzodioxan-6-yl)methyl.

Among this class of compounds, preferred compounds are selected from the group including:

ethyl ester of 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-(2-dimethylaminoethyl)ndimethylacetamide,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetamide", she

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide,

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethyl-cetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide and

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide.

A preferred subgroup of compounds are compounds in which R4means heterocyclyl.

In this class of compounds, preferred compounds are selected from the group including:

2-[[pyridine-3-ylmethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][(1,3-benzodioxol-5-yl)methyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide and

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][2-(morpholine-4-yl)ethyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide.

In this subgroup of compounds, another preferred class of compounds are compounds in which R4means hydroxy, cyano, -N(R1R2, -N(R1)-C(O)-R1, -N(R1)-C(O)OR1, -N(R1)-S(O)t-R1or-N(R1)-C(O)-N(R1)2where each R1and each R2independently of one another denote hydrogen, alkyl or aralkyl.

In this class of compounds, preferred compounds are selected from the group including:

2-[[3-hydroxypropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[2-cyanoethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-the l)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(di(phenylmethyl)amino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin the-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide and

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide.

Obtaining the compounds of the present invention

In schemes 1-4 presents methods for obtaining compounds of formula (Yc). Similarly can be obtained the compounds of formula (Ya) and formula (Yc).

Scheme 1

Compounds of formula (Y1), (Y2), (Y4) and (Y5) are commercial products or can be obtained by the techniques described in the text of the application, or by methods known to experts in this field of technology. Each of R1, R2m and n independently has a value described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc), a R5and W have the values described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc).

The above synthesis can be performed as follows:

To Adilov the mu ether, N-cyanoethylene (15.9 g, 102 mmole) (compound of formula (Y2))dissolved in DMSO (70 ml), was added 4-chloro-6-methyl-2-methylsulfonylamino (18.5 g, 91 mmol) (a compound of the formula (Y1)) and diisopropylethylamine (18 ml, 100 mmol). After stirring for 16 h the temperature of the reaction mixture was raised to 70°and added imidazole (26,5 g to 0.39 mol). After stirring for 1 day, the reaction mixture was cooled to ambient temperature and poured into ice-cold water. The resulting solid precipitate was filtered under vacuum and collected on filter paper, were given to 9.9 g of ethyl ester of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (compound of formula (Yc1)).

To the ethyl ether of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (4,51 g, 14.4 mmole)dissolved in THF (250 ml), was added LiOH (0,91 g, and 21.7 mmole) and water (30 ml). After stirring for 18 h the bulk of the solvent was removed in vacuo and added to 1N. HCl (21,7 ml of 21.7 mmole). The resulting solid precipitate was filtered under vacuum and collected on filter paper, were received 3,17 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (compound of formula (Yc2)).

To 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (1,53 g, 5.3 mmole)suspended in DMF (25 ml), EXT is ulali carbonyldiimidazole (0.87 g, 5.4 mmole). After stirring for 2 h was added diethylamine (1.0 ml, 9.7 mmole) (compound of formula (Y4)). After stirring for 18 h the reaction mixture was distributed between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and the solvent was removed in vacuum, thus received of 0.91 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide (compound of formula (Yc3)).

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Yc3) and their derivatives:

2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide,

2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide.

Through a solution of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide (0,22 g, 0.65 mmole) in Meon (25 ml) was passed ammonia gas. Then was added Raney Nickel (0.8 g) and the mixture was stirred in nitrogen atmosphere at a pressure of 50 psi. After completion of the reaction according to TLC, the reaction mixture was filtered under vacuum through celite and the solvent was removed in vacuum. To the residue dissolved in Meon (10 ml), was added piperonal (0,29 g, 1.9 mmole) and NaBH(OAc)3(0.40 g, 1.9 mmole). After stirring for 18 h the solvent is evaporated and the residue was distributed between those who acetate and an aqueous solution of bicarbonate. The organic layer was separated, dried (Na2SO4) and the solvent was removed in vacuum. After chromatography on silica gel in acetonitrile/ammonium hydroxide (19:1) was obtained 2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide (compound of formula (Yc4)); NMR (CDCl3): 8,4 (s, 1), the 7.65 (s, 1), 7,0 (s, 1), 6,85 (s, 1), to 6.75 (d, 1), and 6.5 (d, 1), 6,05 (user., 1), to 5.85 (s, 2), a 4.3 (s, 2), 3,85 (s, 2), 3,65 (user., 2), and 3.4 (m, 4), 2,95 (t, 2), 2,3 (s, 3), 2,2 (m, 2), 1,25 (t, 3), 1,1 (t, 3) ppm million

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Yc4) and their derivatives:

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), and 7.1 (s, 1), to 6.75 (m, 3), and 6.25 (user., 1), 4,25 (s, 4), 4,15 (user., 2), and 3.7 (s, 2), and 3.6 (s, 2), and 2.8 (d, 3), a 2.75 (m, 2), and 2.4 (s, 3), 1, 85 (m, 2) ppm million;

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide; NMR (DMSO-d6): 8,4 (s, 1), and 8.0 (m, 1), and 7.8 (s, 1), 7,05 (s, 1)and 6.9 (s, 1), 6,8 (m, 2), of 6.65 (s, 1), and 6.3 (user., 1), 5,95 (s, 2), 4,1 (user., 2), and 3.6 (s, 2), 3,55 (user., 2), 3,3 (user., 3), and 2.6 (m, 2), 2,3 (s, 3), a 1.75 (m, 2) ppm million;

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide; NMR (CDCl3): 8,4 (s, 1), and 7.7 (s, 1), 7,05 (s, 1), 6,85 (s, 1), and 6.6 (m, 2), and 6.3 (user., 1), and 4.4 (s, 2), 4,25 (s, 4), and 3.7 (s, 2), 3,6 (m, 2), 3,4 (q, 4), and 2.7 (t, 2), to 2.35 (s, 3), and 1.9 (m, 2), 1,35 t, 3)and 1.15 (t, 3) ppm million;

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methyl-pyrimidine-4-yl]amino]ndimethylacetamide; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), and 7.1 (s, 1), to 6.75 (m, 3), and 6.3 (user., 1), 6,0 (user.,1)and 4.2 (s, 4), is 4.15 (s, 2), the 3.65 (m, 4), a 2.75 (m, 2), and 2.4 (s, 3), of 1.85 (m, 2) ppm million;

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide; NMR (CDCl3): 8,5 (s, 1), of 7.75 (s, 1), 7,05 (s, 1), to 6.75 (m, 3), and 6.3 (user., 1), 5,95 (s, 2), 5,4 (user., 1), is 4.15 (s, 2), 3,7 (user., 2), and 3.6 (s, 2), a 2.75 (t, 2), and 2.4 (s, 3), of 1.85 (m, 2) ppm million

The compounds of formula (Y4), where R2means of 2-(1,4-benzodioxan-6-yl)ethyl, can be obtained in the following way, and entered into reaction with the compound of the formula (Yc2) to obtain compounds of formula (Yc3), which can then be introduced into the reaction as described above to form compounds of formula (Yc4):

To 1,4-benzodioxan-6-carboxaldehyde (10.0 g, 60 mmol) in acetic acid (50 ml) was added nitromethane (6.3 ml, 1.9 EQ.) and ammonium acetate (5.1 g, 1.1 EQ.). After heating at 110°C for 4 h the mixture was cooled to ambient temperature, was added water and the solid precipitate was collected by filtration. The solid was led from methylene chloride/hexane (1:1, 45 ml), were obtained 7.6 g (61%) of 6-(2-nitroethanol)-1,4-benzodioxane. To portions of a solid (3.58 g), dissolved in MeOH/EtOH/AcOEt (1:1:1, 450 ml)was added 10% Pd/C (1.7 g) and conc. HCl (3.3 ml, 2.3 EQ.). PEFC is shaking in Parr apparatus for hydrogenation at 45 psi for 5 h the catalyst was removed by filtration through celite and washed with methanol. After evaporation of the filtrate received 3,59 g (96%) of the hydrochloride 1,4-benzodioxan-6-ethanamine.

In another embodiment, the compounds of formula (Y3) can react as described below to form compounds of formula (Yc3), where R1and R2both signify hydrogen, and these compounds can then react with the compound of the formula (Y5) to form compounds of formula (Yc4).

Through a suspension of ethyl ester of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (2.3 g, 7.3 mmole) in Meon (50 ml), cooled in a bath of dry ice/acetone, missed NH3. The reactor was tightly closed and heated on an oil bath at 65°C for 2 days. The reaction mixture was cooled in a bath of dry ice/acetone and the reactor was opened. A solid substance was separated by filtration under vacuum, it was obtained 1.7 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide.

Figure 2 illustrates another method of preparing compounds of the formula (Yc). Similarly can be obtained the compounds of formula (Ya) and formula (Yb).

Scheme 2

Compounds of formula (Y1), (Y6), (Y7), (Y9) and (Y5) are commercial prapratno or they can be obtained by the techniques described in the text of the application, or by methods known to experts in this field, t is the transport. Each of R1, R2m and n independently have the meanings as indicated above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc)and R4, R5and W have the values opisanie above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc).

The above synthesis can be performed as follows.

The hydrochloride homopiperazine (2.14 g, 10.6 mmole) (compound of formula (Y7)) in CH2Cl2(20 ml), cooled in an ice bath, was added triethylamine (3.1 ml, 21 mmol) and chlorocatechol of 0.85 ml, 10 mmol) (a compound of the formula (Y6)). After warming to ambient temperature and stirring for 16 h the reaction mixture was added 1N. HCl. The organic layer was separated, washed with aqueous bicarbonate, dried (Na2SO4) and the solvent was removed in vacuum, were obtained 1.8 g of 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Y8)).

To 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (0.45 g, 1.9 mmole) in ethanol (10 ml) was added 3-aminopropanol (to 0.72 ml, 9.4 mmole) (compound of formula (Y9)). After heating the reaction mixture on an oil bath at 60°within 1 day, the reaction mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SOsub> 4) and the solvent was removed in vacuum, thus received of 0.44 g of 2-[(3-hydroxypropyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Y10)).

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Y10):

2-[(3-pyridinylmethyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[2-(4-morpholinyl)ethyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[(1,3-benzodioxol-5-ylmethyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide.

To 2-[(3-hydroxypropyl)amino]-N-(1,3-benzodioxol-5-ylmethyl)ndimethylacetamide (of 0.44 g, 1.6 mmole), dissolved in DMSO (5 ml), was added 4-chloro-6-methyl-2-methylsulfonylamino (0.31 g, 1.5 mmole) (compound of formula (Y1)) and diisopropylethylamine (0,55 ml, 3.1 mmole). After stirring for 16 h the temperature of the reaction mixture was raised to 70°and added imidazole (0,47 g of 6.9 mol). After stirring for 1 day, the reaction mixture was cooled to ambient temperature and distributed between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and the solvent was removed in vacuum. After chromatography on silica gel in CH2Cl2/MeOH was obtained 2-[[3-hydroxypropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Yc5)).

In a similar way and the correspondingly substituted starting materials were obtained the following compounds of formula (Yc5) and their derivatives:

2-[[pyridine-3-ylmethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,6 (s, 1), to 8.45 (s, 2), 8,15 (t, 1), and 7.8 (s, 1), and 7.7 (d, 1), 7,35 (user., 1), 7,05 (s, 1), 6,8 (user., 2), 6,6 (user., 2), 6,0 (s, 2), and 4.8 (m, 2), 4,2 (m, 2), and 3.3 (m, 2), and 2.6 (m, 2), 2,3 (s, 3) ppm million;

2-[[2-cyanoethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), and 7.1 (s, 1), and 6.6 (d, 1), 6,55 (d, 1), and 6.3 (t, 1)and 6.2 (s, 1)and 5.9 (s, 2)and 4.2 (s, 2), 3,9 (t, 2), 3,55 (t, 2), 2.8 (t, 2), a 2.75 (t, 2), a 2.45 (s, 3) frequent./million;

ethyl ester of 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), 7,05 (s, 1), 6,85 (s, 1), to 6.75 (m, 2), 6,4 (user., 1)and 5.9 (s, 2), 4,2 (m, 4), and 3.6 (m, 2), and 3.4 (s, 2), 2,4 (t, 2), to 2.35 (s, 3), 2,2 (s, 3), and 1.9 (t, 3), and 1.2 (t, 3) ppm million;

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][2-(morpholine-4-yl)ethyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), and 7.1 (s, 1), and 6.5 (d, 1), and 6.3 (user., 1), x 6.15 (s, 2), 5,7 (user., 2), to 4.0 (m, 4), of 3.45 (m, 8), and 2.6 (m, 2), and 2.4 (s, 3), to 2.35 (m, 4) ppm million; and

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][(1,3-benzodioxol-5-yl)methyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3) is 8.75 (s, 1), 8,15 (t, 1), and 7.8 (s, 1), to 7.15 (s, 1), to 6.75 (d, 1), 6,7 (m, 2), 6,55 (d, 1), 6,4 (m, 2), 6,2 (user., 1), 6,0 (s, 2)and 5.9 (s, 2)and 4.65 (user., 2), 4,1 (user, 2), 3,4 (m, 2), 2,3 (s, 3) ppm million

In another embodiment, the compounds of formula (Y10) and their derivatives were obtained as follows:

Ana is ogino to as described above for compounds of formula (Yc3), 2-[(2-cyanoethyl)(dimethylethoxysilane)amino]acetic acid (8,3 g, 39 mmol)dissolved in CH2Cl2(100 ml)was added carbonyldiimidazole (6.2 g, 38 mmol). After stirring for 30 min was added the hydrochloride homopiperazine (8.0 g, 41 mmol) and diisopropylethylamine (7.5 ml, 43 mmole). After stirring for 18 h the bulk of the solvent was removed in vacuum and the residue was distributed between ethyl acetate and 1N. HCl. The organic layer was separated, washed with aqueous bicarbonate and brine, dried (Na2SO4) and the solvent was removed in vacuum, were obtained 13 g of 2-[(2-cyanoethyl)(dimethylethoxysilane)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide.

To 2-[(2-cyanoethyl)(dimethylethoxysilane)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (14 g, 37 mmol) in CH2Cl2(75 ml), cooled in an ice bath, was added triperoxonane acid (50 ml). After stirring for 1 h the ice bath was removed and the solvent was removed in vacuum. The residue is triturated with ether, formed a solid residue. The solid is collected by filtration, were obtained 12 g of triptoreline 2-[(2-cyanoethyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide, the compound of formula (Y10).

In another embodiment, the compounds of formula (Y10) and their derivative is received as follows:

To N-methyl-β-alaninate (50 g, mmol) in acetonitrile was added piperonylic (50 g, mmol). After stirring for 18 h the solvent was removed in vacuum. The residue was dissolved in CH2Cl2off , washed with water carbonate solution, dried (MgSO4) and the solvent was removed in vacuum. The residue was dissolved in methanol saturated with ammonia (600 ml)was added Raney Nickel (10 g). After shaking in a hydrogen atmosphere at 20 psi for 6 h, the reaction mixture was filtered through celite and the solvent was removed in vacuum, when it received 65 g of N-(1,3-benzodioxol-5-ylmethyl)-N-methyl-1,3-propandiamine.

To N-(1,3-benzodioxol-5-ylmethyl)-N-methyl-1,3-propandiamine (33 g, and 0.15 mol) in CH2Cl2(500 ml) was added ethylglycol (30 ml of 50%solution in toluene, and 0.15 mol) and triacetoxyborohydride sodium (40 g, to 0.19 mol). After stirring for 4 h the reaction mixture was washed with an aqueous solution of potassium carbonate and the solvent was removed in vacuum. After chromatography on silica gel in CH2Cl2/Meon/ammonium hydroxide was obtained 14 g of ethyl ester of 2-[[3-[(1,3-benzodioxol-5-ylmethyl)amino]propyl]amino]acetic acid (compound of formula (Y10)).

Figure 3 presents another method of preparing compounds of the formula (Yc).

In a similar way from the correspondingly substituted starting materials can be p the obtained compounds of formula (Ya) and formula (Yb).

Scheme 3

The compounds of formula (Yc3) was obtained according to the methods described in the proposal. Each of R1, R2m and n independently has a value described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc), a R5and W have the values described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc).

The above synthesis can be performed as follows:

Through a solution of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (2.5 g, 5.8 mmole) (compound of formula (Yc3)) in the Meon (50 ml) missed ammonia. Added Raney Nickel (1.0 g of a 50%suspension) and the reaction mixture was loaded into a Parr apparatus for hydrogenation at 50 psi. After shaking for 16 h, the pressure was reduced to normal and the reaction mixture was filtered under vacuum through celite. The solvent was removed in vacuo and the residue was chromatographically on silica gel (CH3CN/NH4OH 9:1), was obtained 2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Yc6)) in the form of a solid white; NMR (DMSO-d6, 90° (C): 8,4 (s, 1), and 7.8 (s, 1), 7,0 (s, 1), to 6.75 (d, 1), 6,7 (s, 1), and 6.6 (d, 1)and 5.9 (s, 2), 4,1 (s, 2), 3,6 (user., 2), and 3.3 (m, 2), a 2.75 (t, 2), and 2.6 (t, 2), 2,3 (s, 3), and 1.8 (m, 2) castle

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Yc6) and their derivatives:

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (DMSO-d6, 90° (C): 8,4 (s, 1), and 7.8 (s, 1), 7,05 (m, 3), 6.75 (d, 2), of 6.45 (s, 1), 4,1 (s, 2), and 3.7 (s, 3), 3,55 (t, 2), and 3.3 (m, 2), 3,2 (s, 2), 3,6 (m, 4), 2,3 (s, 3) ppm million;

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (DMSO-d6): 8,42 (user., 1), 8,08 (user., 1), 7,80 (user., 1), 7,02 (s, 1), of 6.65 (m, 4), 4,16 (m, 6), 4,05 (user., 1), 3,65 (user., 1), 3,45 (user., 2), 3,15 (user., 2), at 2.59 (m, 4), to 2.35 (s, 3), of 1.62 (m, 2) ppm million and

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,46 (s, 1), of 7.75 (s, 1), 7,06 (s, 1), to 6.80 (s, 1), 6,70 (d, 1), 6.52 (d, 1), 6,18 (user., 1), to 4.46 (t, 2), 4,06 (user., 2), 3,60 (user., 2), of 3.45 (m, 2), 3,05 (m, 2), 2,78 (user., 2), to 2.65 (m, 2), 2,39 (s, 3), 1,70 (user., 4) frequent./million

The compounds of formula (Yc6) can be used to obtain compounds of formula (Yc6)), (Yc7), (Yc8) and (Yc9), as described below:

To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (0.3 g, 0.7 mmole) (compound of formula (Yc6)), dissolved in Meon (10 ml), was added formaldehyde (0.15 ml, 2.0 mmole) and triacetoxyborohydride sodium (from 0.37 g, 1.7 mmole). After stirring for 16 h the solvent was removed in vacuo the E. The residue was distributed between ethyl acetate and an aqueous solution of bicarbonate. The organic layer was separated, washed with brine, dried (Na2SO4) and the solvent was removed in vacuum. After chromatography on silica gel in acetonitrile/ammonium hydroxide was obtained 0.14 g of 2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Yc8)); NMR (CDCl3): 8,5 (s, 1). of 7.8 (s, 1), and 7.1 (s, 1), and 6.5 (d, 1), 6.45 (s, 2), 6,4 (d, 1)and 6.2 (m, 1)and 5.9 (s, 2), is 4.15 (s, 2), 3,55 (m, 2), and 3.5 (q, 2), and 2.6 (t, 2), and 2.4 (s, 3), 2,3 (t, 2 in), 2.25 (s, 6), 1,7 (m, 2) ppm million

To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (50 mg, of 0.11 mmole) (compound of formula (Yc6)) in methanol (2 ml) was added benzaldehyde (0.2 M solution in methanol, 68 μl, of 0.14 mmole). After stirring for 15 min was added bropirimine complex (0.2 M solution in methanol, of 0.14 mmole). After 2 h, the solution evaporated. The residue was distributed between water and ethyl acetate. The aqueous layer was twice extracted with ethyl acetate. Combined fractions in ethyl acetate was washed with saline, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane, 2:1), was obtained 2-[[3-(phenylethylamine)-propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide compound of formula (Yc8)) in the form of a solid white; NMR (CDCl3): 8,65 (s, 1), and 7.7 (s, 1), 7,2 (user., 5), and 7.1 (s, 1), and 6.6 (d, 1), 6,55 (s, 1), and 6.5 (d, 1), 6,1 (user., 2)and 5.9 (s, 2), 3,95 (user., 2), 3,5 (user., 6), and 2.7 (m, 3), to 2.35 (s, 6) ppm million

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Yc8) and their derivatives:

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), 7,2 (user., 5), 7,05 (s, 1)and 6.9 (d, 2), of 6.65 (d, 2), 6,4 (user., 1), 4,1 (s, 2 in), 3.75 (s, 2), and 3.7 (s, 3), 3,6 (user., 2), of 3.45 (dd, 2), and 2.7 (m, 4), to 2.35 (s, 3), and 1.8 (s, 2) ppm million;

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), 7,05 (s, 1), 6,85 (d, 2), and 6.6 (d, 2), and 6.3 (user., 1), and 6.25 (user., 1), 4,1 (s, 2), and 3.7 (s, 3), and 3.5 (m, 4), and 2.7 (t, 2), and 2.4 (s, 3), 2,3 (t, 2), 2,2 (s, 6), a 1.75 (m, 2) ppm million;

2-[[3-(di(phenylmethyl)amino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.70 (s, 1), 7,35 (m, 10),? 7.04 baby mortality (s, 1), 6,62 (d, 1), of 6.45 (s, 1), 6,40 (d, 1), 6,06 (user., 1), 5,96 (user., 1), 4,15 (user., 4), 3,92 (user., 2), of 3.60 (s, 4), of 3.45 (m, 4), 2,62 (t, 2), 2,50 (t, 2), is 2.30 (s, 3), 1,72 (m, 2) ppm million;

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), 7,25 (m, 6), 7,05 (s, 1), 6,60 (d, 1), of 6.45 (s, 1), 6,40 (d, 1), 6,20 (user., 1), 4,10 (m, 6), 3,70 (user., 4), 3,40 (m, 2), to 2.65 (t, 2), 2,60 (t, 2), is 2.40 (s, 3), 1,90 (user., 1), to 1.76 (m, 2) ppm million;

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), 7,05 (s, 1), of 6.65 (d, 1), 6.50 (s, 1), 6.42 per (s, 1), 6,30 (t, 1), 6,16 (user., 1), of 4.12 (m, 6), to 3.50 (m, 4), a 2.75 (m, 2), 2,62 (t, 2), of 2.56 (s, 6), is 2.40 (s, 3), 2,10 (m, 2) ppm million;

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,46 (s, 1), of 7.75 (s, 1), 7,30 (m, 6), 7,10 (s, 1), PC 6.82 (s, 1), of 6.68 (d, 1), is 6.54 (d, 1), and 6.25 (user., 1), to 4.46 (t, 2), 4,10 (user., 2), 3,70 (user., 2), 3,62 (user., 2), of 3.45 (m, 2), 3,05 (t, 2), to 2.65 (m, 4), is 2.40 (s, 3), of 1.78 (m, 2) ppm million and

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), 7,76 (s, 1), 7,06 (s, 1), 6,85 (s, 1), 6,70 (d, 1), 6,50 (d, 1), 6,16 (user., 2), 4,50 (t, 2), 4,10 (s, 2), 3,52 (m, 4), was 3.05 (t, 2), was 2.76 (m, 2), 2,68 (m, 2), 2,62 (s, 6), 2,42 (s, 3), 2,10 (m, 2) ppm million

To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-5-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (0.3 g, 0.7 mmole) (compound of formula (Yc6), dissolved in pyridine (5 ml), was added acetic anhydride (0.10 ml, 1.0 mmol). After stirring for 16 h the reaction mixture was distributed between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuum. After chromatography on silica gel in CH2Cl2was obtained 0.14 g of 2-[[3-(acetylen the but)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide (compound of formula (Yc7)); NMR (DMSO-d6): 8,4 (s, 1), with 8.05 (t, 2), a 7.85 (t, 1), and 7.8 (s, 1), 7,05 (s, 1), 6,7 (m, 2), and 6.6 (m, 1)and 6.2 (s, 1)and 5.9 (s, 2), 4,1 (m, 2), 3-3,6 (m, 6), and 2.6 (m, 2), 2,3 (m, 3), and 1.8 (s, 3), of 1.65 (m, 2) ppm million

In a similar way from the correspondingly substituted starting materials were obtained the following compounds of formula (Yc7) and their derivatives:

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), the 7.65 (s, 1), 7,0 (s, 1), 6,55 (m, 2), and 6.5 (s, 1), of 6.45 (d, 1), x 6.15 (user., 1), 5,95 (user., 1), to 5.85 (s, 2), 4,1 (s, 2), 3,65 (user., 2), of 3.45 (m, 2), and 3.2 (dd, 2), 2,9 (s, 3), to 2.65 (t, 2), to 2.35 (s, 3), and 1.9 (m, 2) ppm million;

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), and 7.7 (s, 1), and 7.1 (s, 1), 6,55 (d, 1), and 6.5 (s, 1), of 6.45 (d, 1), and 6.3 (user., 1)and 6.1 (user., 1)and 5.9 (s, 2), 4,1 (s, 2), and 3.7 (s, 3), and 3.5 (m, 2), and 3.2 (dd, 2), and 2.7 (t, 2), and 2.4 (s, 3), of 1.85 (m, 4) ppm million;

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), and 7.1 (s, 1), to 6.95 (d, 2), 6,7 (d, 2), and 6.25 (user., 1), 6,15 (user., 1), 4,1 (s, 2 in), 3.75 (s, 3), 3,6 (user., 2), and 3.5 (m, 2), and 3.2 (dd, 2), 2,95 (s, 3), and 2.7 (t, 2), and 2.4 (s, 3), of 1.85 (m, 2) ppm million;

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), of 7.75 (s, 1), and 7.1 (s, 1)and 6.9 (d, 2), 6,7 (d, 2), 6,2 (user., 1)and 6.1 (user., 1), of 4.05 (s, 2 in), 3.75 (s, 3), the 3.65 (s, 2), and 3.5 (s, 3), 3,2 (m, 2), and 2.7 (t, 2), and 2.4 (s, 3), and 1.8 (m, 4) h is Art. per million;

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide; NMR (CDCl3): to 8.45 (s, 1), and 7.7 (s, 1), 7,05 (s, 1)and 6.9 (d, 2), of 6.65 (d, 2), 6,4 (user., 1)and 6.1 (s, 1), of 4.05 (s, 2), and 3.7 (s, 3), and 3.5 (m, 4), of 3.25 (dd, 2), and 2.7 (t, 2), and 2.4 (s, 3), and 1.9 (s, 3), and 1.8 (m, 2) ppm million;

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): at 8.60 (s, 1), 7,78 (s, 1), was 7.08 (s, 1), only 6.64 (d, 1), of 6.45 (s, 1), 6,44 (d, 1), and 6.25 (user., 1), x 6.15 (s, 1), of 5.05 (user., 1), of 4.12 (m, 6), the 3.65 (s, 3), of 3.45 (m, 4), 3,20 (m, 2). to 2.65 (t, 2), is 2.40 (s, 3), of 1.80 (m, 2) ppm million;

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): and 8.50 (s, 1), of 7.75 (s, 1), 7,06 (s, 1), 6,62 (d, 1), 6,58 (user., 1), of 6.45 (s, 1), 6.42 per (d, 1), x 6.15 (s, 1), 4,10 (m, 6), 3,55 (m, 4), 3,30 (m, 2), 2,64 (t, 2), is 2.40 (s, 3), with 1.92 (s, 3), equal to 1.82 (m, 2) ppm million;

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,46 (s, 1), 7,76 (s, 1), 7,03 (s, 1), of 6.65 (d, 1), 6,50 (s, 1), 6.42 per (d, 1), 6,18 (user., 1), 5,80 (user., 1), 4,20 (m, 6), 3,65 (user., 2), of 3.48 (m, 2), 3,20 (m, 2), of 2.92 (s, 3), to 2.65 (m, 2), is 2.40 (s, 3), 1,90 (m, 2) ppm million;

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,46 (s, 1), 7,76 (s, 1), 7,05 (s, 1), 6,86 (s, 1), 6,72 (d, 1), 6,55 (d, 1), 6,45 (user., 2), 6,13 (s, 1), 4,50 (t, 2), 4,08 (s, 2), 3,55 (m, 4), 3,30 (q, 2), 3,06 (t, 2), of 2.66 (t, 2), is 2.40 (s, 3), of 1.93 (s, 3), of 1.85 (m, 2) ppm million;

2-[[3-(methoxy is ebonyline)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,46 (s, 1), 7,76 (s, 1), 7,05 (s, 1), at 6.84 (s, 1), 6,70 (d, 1), is 6.54 (d, 1), 6,26 (user., 2), 6,10 (s, 1), 5,08 (user., 1), 4,50 (t, 2), 4,06 (s, 2), the 3.65 (s, 3), a 3.50 (m, 4), up 3.22 (q, 2), 3.04 from (t, 2), of 2.66 (t, 2), 2,42 (s, 3), of 1.80 (m, 2) frequent. /million and

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (CDCl3): 8,44 (s, 1), 7,74 (s, 1), 7,02 (s, 1), 6,86 (s, 1), 6,72 (.d, 1), of 6.52 (m, 2), to 6.19 (s, 2), 5,80 (user, 1), 4,50 (t, 2), 4,10 (s, 2), 3,62 (user., 2), of 3.46 (q, 2), 3,20 (q, 2), 3,06 (t, 2), 2,95 (s, 3), of 2.66 (t, 2), of 2.38 (s, 3), to 1.86 (m, 2) ppm million

To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide (135 mg, of 0.32 mmole) (compound of formula (Yc6)) in pyridine (1.5 ml) was added a solution of potassium cyanate (64 mg, from 0.76 mmole) in water (1.5 ml). The mixture was stirred and heated on an oil bath at 80°With during the night. The mixture was poured into water and was extracted with ethyl acetate (3×20 ml). Combined fractions in ethyl acetate was washed with saline, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (CH3CN/NH4OH, 9:1), was obtained 2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]ndimethylacetamide (compound of formula (Yc9)) in the form of a solid white; NMR (DMSO-d6, 90° (C): 8,4 (s, 1), and 7.8 (s, 1), 7,05 (d, 2), 7,0 (s, 1), to 6.75 (d, 2), to 6.4 (s, 1), 4,1 (s, 2), and 3.7 (s, 3), and 3.5 (m, 2), of 3.25 (m, 2), 3,05 (m, 2), to 2.65 (t, 2), 2,3 (s, 3), of 1.7 (m, 2) ppm million

Similar is cnym way of correspondingly substituted starting materials were obtained the following compounds of formula (Yc9) and their derivatives:

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide; NMR (DMSO-d6): 8,42 (user., 1), 8,08 (t, 1), 7,80 (user., 1), 7,05 (s, 1), 6,60 (m, 3), 6,03 (user., 1), the 5.45 (user., 1), 4,18 (user., 6), 3,40 (m, 6), of 3.00 (m, 2), to 2.55 (m, 2), 2,35 (user., 3), and 1.7 (m, 2) ppm million and

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide; NMR (DMSO-d6): 8,45 (user., 1), 8,12 (user, 1), 7,80 (user., 1), of 7.00 (m, 2), PC 6.82 (m, 1), 6,60 (user., 1), 6,10 (user., 1), 5,42 (user, 1), 4,42 (t, 2), 4,14 (m, 2), 3,00-of 3.60 (m, 10), 2.60 (m, 2), is 2.30 (s, 3), by 1.68 (m, 2) ppm million

Figure 4 presents another method of preparing compounds of the formula (Yc). Similarly can be obtained the compounds of formula (Ya) and formula (Yb).

Scheme 4

The compounds of formula (Yc10) was obtained according to the methods described in the proposal. Each of R1, R2m and n independently has a value described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc), a R5and W have the values described above in the Brief description of the invention for compounds of formula (Ya), formula (Yb) and formula (Yc).

The above synthesis can be performed as follows:

To ethyl ether, 2-[[3-[(1,3-benzodioxol-5-ylmethyl)amino]methyl)-propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (2.2 g, 4.6 mmole) (connection forms the crystals (Yc10), dissolved in THF (50 ml), was added LiOH (0.34 g, 8.1 mmole) and water (10 ml). After stirring for 16 h the solvent was removed in vacuo and added to 1N. HCl (8.1 ml, 8.1 mmole). The solvent was removed in vacuum, while the received 2-[[3-[(1,3-benzodioxol-5-ylmethyl)(methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (compound of formula (Yc11)).

To 2-[[3-[(1,3-benzodioxol-5-ylmethyl)(methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid (0.35 g, 0.8 mmole) (compound of formula (Yc11), suspended in DMF (5 ml), was added carbonyldiimidazole (0.14 g, 0.8 mmole). After stirring for 20 min was added diethylamine (0.25 ml, 2.4 mmole). After stirring for 18 h the reaction mixture was distributed between ethyl acetate and water.

The organic layer was separated, washed with water, dried (Na2SO4) and the solvent was removed in vacuum, thus received of 0.91 g of the desired product. After chromatography on silica gel in CH2Cl2/MeOH was obtained 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide; NMR (CDCl3): 8,4 (s, 1), a 7.85 (s, 1), and 7.1 (m, 1), 6,85 (s, 1), to 6.75 (m, 2), 6,4 (user, 1), 5,95 (s, 2), 4,4 (user., 2), 3,6 (user., 2), 3,4 (m, 6), a 2.45 (t, 2), to 2.35 (s, 3), 2,2 (s, 3), and 1.9 (m, 2)and 1.3 (t, 3)and 1.15 (t, 3) ppm million

Similarly received the following compounds of formula (Yc12) and carried the items:

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-(2-dimethylaminoethyl)ndimethylacetamide; NMR (CDCl3): 8,5 (s, 1), and 7.8 (s, 1), and 7.1 (s, 1), 6,8 (s, 1), to 6.75 (m, 2), and 6.25 (user., 1), 5,95 (s, 2), 4,15 (user., 2), 3,6 (user., 2), and 3.4 (s, 2), the 3.35 (m, 2), 2,4 (t, 2), and 2.4 (s, 3), to 2.35 (t, 2), 2,2 (s, 3), 2,0 (user., 6), and 1.8 (m, 2), and 1.6 (m, 2) ppm million and

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide; NMR (DMSO-d6): 8,4 (s, 1), and 7.8 (s, 1), and 7.5 (s, 1), and 7.1 (m, 2), 6,8 (m, 3), and 6.3 (user., 1), 6,0 (s, 2), 5,4 (user., 1), 4,1 (m, 2), 3,4 (m, 4), 2,4 (t, 2), 2,3 (s, 3), 2,1 (s, 3), a 1.75 (m, 2) ppm million

Although the present invention is described with reference to specific embodiments of the invention, those skilled in the art it is evident that within the essence and scope of the invention various modifications and equivalent replacements. In addition, taking into account the particular situation, material, composition of matter, method, stage or stages of the method, the possible modification of the object, nature and scope of the present invention. It is assumed that all such modifications are within the scope of the claims.

1. Derivatives of N-heterocyclic compounds of the formula (Yc)

where n and m denote an integer from 1 to 4;

W stands for CH;

And means-C(O)OR1or-C(O)N(R1, R 2where

R1means hydrogen or C1-C8alkyl;

R2means hydrogen, C1-C8alkyl, geterotsiklicheskikh selected from the group comprising benzodioxolyl-, benzodioxolyl or dihydrobenzofuranyl, and containing C1-C4carbon atoms in the alkyl part, or panels1-C4alkyl, possibly substituted C1-C4alkoxy,

R4means cyano or heterocyclyl selected from the group including pyridinyl, morpholinyl, benzodioxolyl or benzodioxolyl, if m is 1; if m means 2 to 4, R4can optionally indicate hydroxy, NR1R2where R1and R2independently mean hydrogen, C1-C8alkyl or benzylation, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1where R1means hydrogen or C1-C8alkyl, -N(R1)-C(O)-N(R1)2where R1means hydrogen;

R5means (C1-C8)alkyl;

t means 2;

in the form of a single stereoisomer, or mixtures thereof, or their pharmaceutically acceptable salts.

2. The compound according to claim 1, where

n is 1, m is 2 or 3,

And means-C(O)OR1or-C(O)N(R1R2,

W stands for CH,

R1means hydrogen or C1 -C8alkyl and

R2means hydrogen, C1-C8alkyl, geterotsiklicheskikh as specified in claim 1, or a possibly substituted phenyls1-C4alkyl.

3. The compound according to claim 2, where R4means-N(R1R2where R1means hydrogen or C1-C8alkyl, and R2means geterotsiklicheskikh selected from the group comprising (1,3-benzodioxol-5-yl)methyl or (1,4-benzodioxan-6-yl)methyl.

4. The compound according to claim 3, selected from the group including

ethyl ester of 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetic acid,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-(2-dimethylaminoethyl)ndimethylacetamide,

2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]acetamide", she

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide,

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-methylacetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]the Mino]-N-methylacetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N,N-diethylacetamide,

2-[[3-[(1,4-benzodioxan-6-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide and

2-[[3-[(1,3-benzodioxol-5-yl)methyl]aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide.

5. The compound according to claim 4, representing 2-[[3-[[(1,3-benzodioxol-5-yl)methyl](methyl)amino]propyl][2-(1H-imide-azole-1-yl)-6-methylpyrimidin-4-yl]amino]ndimethylacetamide.

6. The compound according to claim 2, where R4means heterocyclyl.

7. The connection according to claim 6, selected from the group including

2-[[pyridine-3-ylmethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][(1,3-benzodioxol-5-yl)methyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide and

2-[[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl][2-(morpholine-4-yl)ethyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]ndimethylacetamide.

8. The compound according to claim 2, where R4means hydroxy, cyano, -N(R1R2, -N(R1)-C(O)-R1, -N(R1)-C(O)OR1, -N(R1)-S(O)t-R1or-N(R1)-C(O)-N(R1)2where R1and R2have the meanings indicated in claim 1.

9. The compound of claim 8 selected from the group including

2-[[3-hydroxypropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin the-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[2-cyanoethyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,3-benzodioxol-5 yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(acetylamino)the PCC is l][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(di(phenylmethyl)amino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(dimethylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]acetamide", she

2-[[3-(phenylethylamine)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-aminopropyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(l is methylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(methoxycarbonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(methylsulfonylamino)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]acetamide", she

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(1,4-benzodioxan-6-yl)ethyl]ndimethylacetamide and

2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]amino]-N-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]ndimethylacetamide.

10. Pharmaceutical composition having inhibitory activity against synthase nitric oxide, comprising the compound of formula (IC) according to claim 1 and a pharmaceutically acceptable carrier.

11. The method of treatment of a condition caused by an abnormality in the production of nitric oxide, which includes an introduction to a mammal in need of such treatment, a therapeutically effective amount of the compounds of formula (IC) according to claim 1.

12. The method according to claim 11, where the above condition caused by an abnormality in the production of nitric oxide, is rheumatoid arthritis.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 7 tbl, 7 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds and preparations.

7 cl, 3 tbl, 19 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 4,6-bis-(diethylamino)-2-[(2'-tetrazol-(2'H)-5'yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance shows the enhanced effectiveness in increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry and can find application in medicine

The invention relates to new selective antagonists1b-adrenergic receptors of the formula :

where a is a 2-tetrahydrofuryl, 2-furyl, substituted linear or branched alkyl containing from 1 to 5 carbon atoms, benzyloxy group or phenoxyalkanoic group, a substituted linear or branched alkyl containing from 1 to 5 carbon atoms and/or alkoxy group containing from 1 to 4 carbon atoms, or an enantiomer, diastereoisomer or pharmaceutically acceptable salt of such compounds, and to pharmaceutical compositions based on these compounds, which are able to improve the condition associated with sexual dysfunction

The invention relates to pharmaceutical industry and AA derivatives of N-(aryloxyalkyl)-heteroarylboronic and-heteroarylboronic General formula (I) used to obtain drugs with antipsychotic or analgesic activity, and a method of treating psychoses by using these derivatives

The invention relates to a derivative of erythromycin formulas (I)

in which Y denotes a hydrogen atom or fluorine; n denotes an integer from 1 to 8; Z represents a hydrogen atom or a residue of carboxylic acid, and in which pyrazol cycle substituted heteroaryl radical, which contains one nitrogen atom; and their salt adducts with tilotama

FIELD: medicine.

SUBSTANCE: method involves introducing oxygen gas is introduced into knee joint cavity on the background of traditional complex therapy at a dose of 40-150 ml in progressive mode with 3-4 days long pauses in a course of 5-6 procedures.

EFFECT: enhanced effectiveness in rapid cicatrix tissue involution; increased movement amplitude.

1 dwg

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