Hiv inhibiting 5-heterocyclyl pyrimidines

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

 

The present invention relates to pyrimidine derivative having the property of inhibiting the replication of HIV (virus immunodeficita person). Additionally, the invention relates to methods for their preparation and pharmaceutical compositions containing them. The invention also relates to the use of these compounds for the prevention or treatment of HIV infection.

The resistance of the HIV virus to the currently available drugs against HIV remains the leading cause of treatment failure. This has led to the introduction of combination therapy using two or more agents against HIV, usually having different activity profile. Significant progress has been achieved through the introduction of HAART therapy (highly active antiretroviral therapy), which has led to a significant reduction of the complicated course and mortality in groups of HIV patients who were treated with it. HAART consists of various combinations of nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). In these standards for antiretroviral therapy recommended this mode of triple therapy combinations for initial treatment. However, these therapies with many medications do not eliminate HIV completely, and long-term treatment usually leads to resistance to a multitude of the activities of the drugs. In particular, half of the patients receiving combination therapy against HIV, do not respond to treatment in full, mainly due to resistance to one or more of the used drugs. Also it is shown that the resistant virus is transferred to newly infected individuals, which leads to a strictly limited selection of therapy for these patients not receiving the drug.

In this regard continues to exist a need for new combinations of active ingredients effective against HIV. In new types of combination therapy useful new types of highly effective active ingredients against HIV, differing in chemical structure and activity profile. In this regard, the presence of these active ingredients is a very desirable goal to achieve.

The present invention is directed to providing a new series of pyrimidine derivatives having the property of inhibiting HIV replication. In WO 99/50250, WO 00/27825 and WO 01/85700 discloses certain substituted aminopyrimidine and in WO 99/50256 and EP-834507 disclosed aminotriazines having the property of inhibiting HIV replication.

Compounds in accordance with the invention differ from the compounds of the prior art structure, pharmacological activity and/or farmacologicas the th effectiveness. Found that the introduction of heterocyclyl group in position 5 specific substituted pyrimidines leads to compounds acting favorably not only with respect to their ability of inhibiting replication of the virus immunodeficita human (HIV), but also an improved ability to inhibit the replication of mutant strains, including strains that have become resistant to one or more known drugs NNRTIS (drugs non-nucleoside reverse transcriptase inhibitors), such strains are referred to as strains of HIV that are resistant to the drug or multiple drugs.

Thus, in one aspect the present invention relates to compounds of the formula

their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where

-a1=a2-a3=a4- represents a bivalent radical of the formula

-CH=CH-CH=CH-(a-1);
-N=CH-CH=CH-(a-2);
-N=CH-N=CH-(a-3);
-N=CH-CH=N(a-4);
-N=N-CH=CH- (a-5);

-b1=b2-b3=b4- represents a bivalent radical of the formula

-CH=CH-CH=CH-(b-1);
-N=CH-CH=CH-(b-2);
-N=CH-N=CH-(b-3);
-N=CH-CH=N(b-4);
-N=N-CH=CH-(b-5);

n is 0, 1, 2, 3 and if-a1=a2-a3=a4represents (a-1), n may also be equal to 4;

m is 0, 1, 2, 3 and if-b1=b2-b3=b4represents a (b-1), then m may be equal to 4; each R1independently represents hydrogen; aryl; formyl; C1-6alkylsulphonyl; C1-6alkyl, C1-6allyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarboxylic, C1-6allyloxycarbonyl, or C1-6alkylcarboxylic; each R2independently represents hydroxy; halogen; C1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C3-7cycloalkyl; C2-6alkenyl, optionally substituted by one who, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C2-6quinil, optionally substituted one, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C1-6allyloxycarbonyl; carboxyl; cyano; nitro; amino; mono - or di(C1-6alkyl)amino; POLYHALOGENATED; POLYHALOGENATED; -S(=O)pR6; -N-S(=O)pR6; -C(=O)R6; -NHC(=O)H; -C(=O)NHNH2; NHC(=O)R6; C(=NH)R6; R2arepresents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkalosis1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C 1-6the alkyl or R7; C2-6alkenyl substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6quinil substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

X1represents-NR1-, -O-, -C(=O)-, -CH2-, -CHOH-, -S-, -S(=O)p-;

R3represents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkalosis1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently researched the mo is selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6alkenyl substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6quinil substituted one, two or three substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

X3represents-NR1-, -O-, -C(=O)-, -S-, -S(=O)p-;

R4is a halogen; hydroxy; C1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C2-6alkenyl, optionally substituted one, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C2-6quinil, optionally substituted one, two or three substituents, each of which is independently selected from halogen, cyano, or-C(=O)R6; C3-7cycloalkyl; C1-6alkyloxy; cyano; nitro; polyhalogen1-6alkyl; polyhalogen1-6alkyloxy; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl is l; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

R5represents 5 - or 6-membered fully unsaturated cyclic system, where one, two, three or four members of the cycle are heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur, and where the remaining members of the cycle are carbon atoms; and where possible, any nitrogen member of the cycle may be optionally substituted C1-6the alkyl, this cyclic system may be optional annulirovano with benzene cycle; and where any carbon atom in the cycle, including any optional carbon annulirovano benzene cycle may be optional, each independently, substituted by a Deputy selected from halogen, hydroxy, mercapto, cyano, C1-6of alkyl, hydroxys1-4of alkyl, carboxy1-4of alkyl, C1-4alkalosis1-4of alkyl, tsianos1-4of alkyl, di(C1-4alkyl)amino1-4of alkyl, Het-C1-4of alkyl, aryls1-4of alkyl, polyhalogen1-4of alkyl, C3-7cycloalkyl, C2-6alkenyl, arils2-4alkenyl, C1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl, C1-4allyloxycarbonyl is, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, aryl, Het;

where Het represents a pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, chinoline, benzothiazyl, benzofuranyl; each of which may be optionally substituted by one or two C1-4alkalinity radicals;

Q represents hydrogen, C1-6alkyl, halogen, polyhalogen1-6alkyl or

-NR9R10;

R6represents a C1-4alkyl, amino, mono - or di(C1-4alkyl)amino or polyhalogen1-4alkyl;

R7represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, formyl, C1-6alkylsulphonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkit is about, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8), R7a, -X3-R7aor R7a-C1-4of alkyl;

R7arepresents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, formyl, C1-6alkylsulphonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, -CH(=N-OR8);

R8represents hydrogen, C1-4alkyl, aryl or arils1-4alkyl;

R9and R10each independently represents hydrogen, C1-6alkyl, C1-6alkylsulphonyl; C1-6allyloxycarbonyl; amino; mono - or di(C1-6alkyl)aminocarbonyl; -CH(=NR11or R7, where is each of the above C 1-6alkyl groups can be optionally and individually substituted by one or two substituents, each of which is independently selected from hydroxy, C1-6alkyloxy, hydroxys1-6alkyloxy, carboxyl, C1-6allyloxycarbonyl, cyano, amino, imino, mono - or di(C1-4alkyl)amino, POLYHALOGENATED, POLYHALOGENATED, POLYHALOGENATED, -S(=O)pR6, -NH-S(=O)pR6, -C(=O)R6, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R6, -C(=NH)R6, R7; or R9and R10may together form a divalent or trivalent radical of the formula

-CH2-CH2-CH2-CH2-(d-1);
-CH2-CH2-CH2-CH2-CH2-(d-2);
-CH2-CH2-O-CH2-CH2-(d-3);
-CH2-CH2-S-CH2-CH2-(d-4);
-CH2-CH2-NR12-CH2-CH2-(d-5);
-CH2-CH=CH-CH2-(d-6);
=CH-CH=CH-CH=CH-(d-7);

R11represents cyano; C1-4alkyl, optionally substituted C1-4alkyloxy, cyano, amino, mono - or di(C1-4alkyl)amino or aminocarbonyl; C1-4alkylsulphonyl; C1-4allyloxycarbonyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl;

R12represents hydrogen or C1-4alkyl;

R13and R14each independently represents a C1-6alkyl, optionally substituted by cyano or aminocarbonyl, C2-6alkenyl, optionally substituted by cyano or aminocarbonyl, C2-6quinil, optionally substituted by cyano or aminocarbonyl;

R15represents a C1-6alkyl, substituted cyano or aminocarbonyl;

R16represents a C1-6alkyl, optionally substituted by cyano or aminocarbonyl, or R7;

each p is 1 or 2;

each aryl represents phenyl or phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, C1-6alkylsulphonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6Ala is La, polyhalogen1-6alkyloxy, aminocarbonyl, Het or-X3-Het.

The present invention also relates to the use of compounds to obtain drugs for treatment or prevention of HIV infection, where the compound has formula (I)as specified in this application.

Used above or below the context of this invention, C1-4alkyl as a group or part of a group defines such saturated hydrocarbon radicals with a straight or branched chain, having from 1 to 4 carbon atoms, like methyl, ethyl, propyl, 1-methylethyl, butyl; C1-6alkyl as a group or part of a group defines such saturated hydrocarbon radicals with a straight or branched chain, having from 1 to 6 carbon atoms as the group defined for C1-4of alkyl, and pentyl, hexyl, 2-methylbutyl etc.; C2-6alkyl as a group or part of a group defines such saturated hydrocarbon radicals with a straight or branched chain, having from 2 to 6 carbon atoms as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl etc.; C3-7cycloalkyl is a generalization to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C2-6alkenyl determines such hydrocarbon radicals with a straight or branched chain, having from 2 to 6 carbon atoms containing a double bond, such as ethynyl propenyl, butenyl, pentenyl, hexenyl etc.; C2-6quinil determines such hydrocarbon radicals with a straight or branched chain, having from 2 to 6 carbon atoms containing a triple bond, as ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl etc. Among C2-6alkenyl and C2-6the quinil preferred are unsaturated analogs having from 2 to 4 carbon atoms, that is, C2-4alkenyl and C2-4quinil respectively.

In many cases, the radicals C1-6alkyl, C2-6alkenyl, C2-6quinil or C1-6alkalosis1-6the alkyl can be substituted one, two or three substituents. Preferably, these radicals substituted by 2 substituents, more preferably one Deputy.

Monocyclic, bicyclic or tricyclic saturated carbocycle is a cyclic system containing 1, 2 or 3 cycles specified cyclic system consists only of carbon atoms of the cyclic system contains only a single bond; monocyclic, bicyclic or tricyclic partially saturated carbocycle is a cyclic system containing 1, 2 or 3 cycles specified cyclic system consists only of carbon atoms and contains at least one double bond provided that the cyclic system is not si is theme of the aromatic cycle; monocyclic, bicyclic or tricyclic aromatic carbocycle is a system of aromatic cycle consisting of 1, 2 or 3 cycles specified cyclic system consists only of carbon atoms; the term "aromatic" is known to the person skilled in the art and defines a cyclic conjugated system of 4n + 2 electrons, that is with 6, 10, 14, etc. π-electrons (the hückel rule); monocyclic, bicyclic or tricyclic saturated, the heterocycle is a cyclic system containing 1, 2 or 3 cycles and containing at least one heteroatom selected from O, N or S, the specified cyclic system contains only a single bond; monocyclic, bicyclic or tricyclic partially saturated the heterocycle is a cyclic system containing 1, 2 or 3 cycles and containing at least one heteroatom selected from O, N or S, and at least one double bond provided that the cyclic system is not aromatic cycle; monocyclic, bicyclic or tricyclic aromatic heterocycle is an aromatic tsiklicheskuyu system consisting of 1, 2 or 3 cycles and containing, at least one heteroatom selected from O, N or S.

Specific examples of monocyclic, bicyclic or three is Ilichevsky saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,2,0]octenyl, cyclogeranyl, cyclodecane, decahydronaphthalene, tetradecahydrophenanthrene, etc. are Preferred cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; more preferred are cyclopentyl, cyclohexyl, cycloheptyl.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated carbocycle are cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, bicyclo[4,2,0]octenyl, cyclododecyl, cyclodecene, octahydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 1,2,3,4,4A,9,9a,10-octahydronaphthalene etc.

Specific examples of monocyclic, bicyclic or tricyclic aromatic carbocycle are phenyl, naphthalenyl, anthracenes. Preferred is phenyl.

Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, imidazolidinyl, diazolidinyl, tetrahydrothieno, dihydrooxazolo, isothiazolinones, isoxazolidine, oxadiazolidine, diazolidinyl, thiadiazolidine, pyrazolidine, piperidine, hexahydropyridine, hexahydropyrazino, dioxane, morpholinyl, dithienyl, thiomorpholine, piperazinil, ritieni, decahydroquinoline, octahedrally, etc. are Preferred tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, imidazolidinyl, diazolidinyl, dihydrooxazolo, diazolidinyl, piperidinyl, dioxane, morpholinyl, thiomorpholine, piperazinil. Especially preferred are tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, piperidinyl, dioxane, morpholinyl, thiomorpholine, piperazinil.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles are pyrrolidyl, imidazolyl, pyrazolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, indolinyl, etc. are Preferred pyrrolidyl, imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, indolinyl.

Specific examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are ezetil, acetimidoyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, be satyavati, benzotriazolyl, purinol, chinoline, ethenolysis, cinnoline, hemolysins, phthalazine, honokalani, hintline, naphthyridine, pteridine, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolopyridine, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyridine, thienopyridines, properidine, isothiazolinones, triazolopyridazines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, oxadiazolidine, thiadiazolidine, triazolopyridazines, imidazolidinyl, imidazothiazoles, imidazolidinyl, isoxazolidine, isothiazolinones, pyrazoloacridine, oxazolidinyl, diazolidinyl, imidazolidinyl, oxadiazole azinil, thiadiazolidine, triazolopyridazines, carbazolyl, acridines, phenazines, phenothiazines, phenoxazines etc.

Preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles. Interest monocyclic, bicyclic or tricyclic aromatic heterocycle alauda pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolopyridine, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazol pyrimidinyl, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, carbazolyl, acridines, phenothiazinyl, phenoxazines etc.

Of particular interest aromatic heterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline etc.

In the context of the present invention designation (=O) forms a carbonyl group when joining the carbon atom, sulfoxide group when joining a sulfur atom and sulfonyloxy group, when these two symbols are attached to the sulfur atom.

The terms "carboxyl", "carboxy" or "hydroxycarbonyl" refers to the group-COOH.

The term "halogen" is a generalization for fluorine, chlorine, bromine and iodine is and. Used above and hereinafter sense POLYHALOGENATED as a group or part of a group is defined as mono - or polyhalogen methyl, in particular methyl with one or more fluorine atoms, for example deformity or trifluoromethyl; polyhalogen1-4alkyl or polyhalogen1-6alkyl as a group or part of a group is defined as mono - or polyhalogen C1-4alkyl or C1-6alkyl, such as groups defined for halogenmethyl, 1,1-deperately etc. if in the definition of POLYHALOGENATED, polyhalogen1-4the alkyl or polyhalogen1-6the alkyl to an alkyl group attached to more than one halogen atom, they may be the same or different.

R5represents 5 - or 6-membered fully unsaturated cyclic system, as defined in this application. The term "fully unsaturated" as used in this definition means that the cycle contains the maximum number of double bonds. In many cases, a 5 - or 6-membered cyclic system is aromatic. In this regard, particular subgroups of the compounds in accordance with the present invention are groups or subgroups, as defined in this application, where R5represents 5 - or 6-membered ring system of aromatic cycle, as defined in this application. The radical Het, the particular could be any of the heterocycles listed in groups of monociclo, bicyclo or tricycles, noted above, which are included in the General definition of Het, for example pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, chinoline, ethenolysis, cinnoline phthalazine, honokalani, hintline, naphthyridine, benzopyranyl.

Each aryl independently defined above in the definition of compounds of formula (I) whenever it occurs in the definition of compounds of formula (I) or any subgroup noted in this application, or each aryl may have any of the values defined below.

It is assumed that the term "heterocycle" in the definition of R7or R7aincludes all possible isomeric forms of the heterocycles, for example pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl.

"Carbocycle" or "heterocycle" in the definition of R7or R7acan be attached to the rest of the molecule of formula (I) through any podhodjashjaja carbon or heteroatom in the cycle, if not stated otherwise. Thus, for example, when the heterocycle is imidazolyl, it can represent a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc. or when carbocycle is naphthalenyl, it can represent a 1-naphthalenyl, 2-naphthalenyl etc.

When any variable (for example, R7X2) occurs in any component more than once, each definition this variable is independent.

It is assumed that in this application to a group of compounds of formula (I), as well as to any subgroup defined or marked in this application, any applicable limit in the definitions of radicals.

The line depicted from the Deputy inside the ring systems, indicate that the relationship can be attached to any suitable ring atoms.

Salts of compounds of formula (I) for therapeutic use are salts in which the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are not pharmaceutically acceptable may also find use, for example, in obtaining or purification of pharmaceutically acceptable compounds. All salts, such as pharmaceutically acceptable and not included in the scope of the present invention.

It is assumed that the pharmaceutically acceptable salt additive, to the to above, are therapeutically active non-toxic form of the acid additive salts, which are capable of forming compounds of formula (I). The latter can be obtained conveniently by treating the basic form of such appropriate acids as inorganic acids, such as halogen acids, for example chlorodane, bromatology and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroxyestra, 2-hydroxypropionate, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oxybenzone, 4-amino-2-hydroxybenzoic and the like acids. On the other hand, the salt form can be converted to a free basic form by treatment with alkali.

The compounds of formula (I)containing a proton acid, can be converted to therapeutically active additive salt form non-toxic metal or amine by treatment with appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, such as lithium salts, sodium, potassium,magnesium, calcium and the like, salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic amines, as salts of methylamine, ethylamine, Propylamine, Isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, research, trimethylamine, triethylamine, Tripropylamine, hinoklidina, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propane diol, geranamine, and salt amino acids such as, for example, arginine, lysine, etc. on the other hand, the salt form can be converted to the form of the free acid by treatment with acid. The term "additive salt" also includes hydrates and additive forms of the solvent, to form the compounds of formula (I). Examples of such forms are hydrates, alcoholate, etc.

The term "Quaternary amine" used in the above sense, defines the Quaternary ammonium salts which are able to form the compounds of formula (I) by the interaction between the basic nitrogen of compounds of formula (I) and therefore suitable quaternization agent, as, for example, optionally substituted alkylamide, arielgold or arylalkylamine, for example, methyliodide or benzylated. Also can be the used other such reagents with easy atmasamyama groups, as alkylarylsulfonate, alkylarylsulfonate and alkyl p-toluensulfonate. The Quaternary amine contains positively charged nitrogen. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin and acetate. Selected counterion can be introduced using ion-exchange resins.

It is assumed that the N-oxide forms of the present compounds include the compounds of formula (I)wherein one or several tertiary nitrogen atoms oxidized to the so-called N-oxide.

It should be understood that some of the compounds of formula (I) and their N-oxides, additive salts, the Quaternary amines and stereochemical isomeric form can contain one or more centers of chirality and exist in the form of stereochemical isomeric forms.

The term "stereochemical isomeric forms" as used in this application the sense above defines all the possible stereoisomeric forms which can have the compounds of formula (I) and their N-oxides, additive salts, Quaternary amines or physiologically functional derivatives. Unless specified or noted otherwise, the chemical designation of compounds shows a mixture of all possible stereochemical isomeric forms, these mixes contain all diastereoisomers and enantiomers basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salt, solvate or Quaternary amines are mostly clean, that is combined with less than 10%, preferably less than 5%, in particular less than 2%, and most preferably, less than 1% of other isomers. Thus, when the compound of formula (I), for example, is defined as (E), this means that the connection is mostly not contains the isomer (Z). In particular, stereogenic centers may have the R - or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the CIS-or TRANS-configuration. Compounds containing double bonds, can have E (entgegen) or Z (zusammen) -stereochemistry at the specified double bond. The terms "CIS", "trance", "R", "S", "E" and "Z" are well known to the person skilled in the art. It is assumed that the stereochemical isomeric forms of the compounds of formula (I) is included in the scope of this invention.

Some of the compounds of formula (I) can also exist in tautomeric form. It is assumed that such forms are included within the scope of the present invention, although they are not indicated explicitly in the above formula.

It is assumed that each time you use hereinafter the term "compounds of formula (I)also include their N-oxide forms, their salts, their Quaternary amines and their stereochemical isomeric form. Of particular interest are compounds f is rmula (I), which is the stereochemical clean.

Particular subgroups of compounds of formula (I) or any subgroup of compounds of formula (I)defined in this application are naselenie form, salt, N-oxide forms and stereochemical isomeric form. Among them are of interest naselenie forms, salts and stereochemical isomeric form. Used in this application the meaning of the term "nosoleva form" means a form of connection that is not salt, which in most cases is a free basic form.

Whenever you specify above or below that "substituents can be selected each independently from a list of many such definitions, as, for example, for R9and R10"that assumes all possible combinations, which is chemically possible or leading to a chemically stable molecules.

It should be understood that, as expected, any of the subgroups of compounds of formula (I)as defined in the present application contains any of the prodrugs, N-oxides, additive salts, Quaternary amines, metal complexes and stereochemical isomeric forms of such compounds.

Particular subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where-a1=a2-a3=a4- presented yet a-CH=CH-CH=CH- (a-1).

Additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where b1=b2-b3=b4- represents-CH=CH-CH=CH- (b-1).

Additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where (a) n is 0, 1, 2, 3; or where (b) n is 0, 1 or 2; or (c) n is equal to 0.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where (a) m is 0, 1, 2, 3; or where (b) m is 0, 1 or 2; or (c) m is equal to 2.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R1represents hydrogen; formyl; C1-6alkylsulphonyl; C1-6alkyl, C1-6allyloxycarbonyl; or

(b) R1represents hydrogen, C1-6alkyl; or

(c) R1represents hydrogen.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R2represents hydroxy; halogen; C1-66; C3-7cycloalkyl; C2-6alkenyl, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C2-6quinil, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C1-6allyloxycarbonyl; carboxyl; cyano; nitro; amino; mono - or di(C1-6alkyl)amino; POLYHALOGENATED; POLYHALOGENATED; -S(=O)pR6; -NH-S(=O)pR6; -C(=O)R6; -NHC(=O)H; -C(=O)NHNH2; NHC(=O)R6; C(=NH)R6;

(b) R2represents hydroxy; halogen; C1-6alkyl, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C2-6alkenyl, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C2-6quinil, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C1-6allyloxycarbonyl; carboxyl; cyano; nitro; amino; mono - or di(C1-6alkyl)amino; trifluoromethyl;

(c) R2represents halogen, C1-6alkyl, optionally substituted by cyano, C2-6alkenyl, optionally substituted by cyano, C2-6quinil, optionally substituted by cyano, C1-6allyloxycarbonyl, carboxyl, cyano, amino, mono(C1-6 alkyl)amino, di(C1-6alkyl)amino;

(d) R2represents halogen, cyano, aminocarbonyl, C1-6alkyloxy, C1-6alkyl, C1-6alkyl, substituted cyano, or C2-6alkenyl, substituted cyano;

(e) R2represents halogen, cyano, aminocarbonyl, C1-4alkyl, substituted cyano, or C2-4alkenyl, substituted cyano;

(f) R2represents cyano, aminocarbonyl; or

(g) R2represents cyano.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R2arepresents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from GoLoG is on, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6alkenyl substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6quinil substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

(b) R2arepresents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C2-6alkenyl substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C2-6quinil substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10;

(c) R2arepresents halogen, tzia is about, aminocarbonyl, C1-6alkyl, optionally substituted by cyano or aminocarbonyl, C2-6alkenyl, optionally substituted by cyano or aminocarbonyl;

(d) R2arepresents halogen, cyano, aminocarbonyl, C1-6alkyl, substituted cyano or aminocarbonyl, or C2-6alkenyl, substituted by cyano or aminocarbonyl;

(e) R2arepresents cyano, aminocarbonyl, C1-6alkyl, substituted cyano, or C2-6alkenyl, substituted cyano;

(f) R2arepresents cyano, aminocarbonyl, C1-4alkyl, substituted cyano, or C2-4alkenyl, substituted cyano;

(g) R2arepresents cyano, C1-4alkyl, substituted cyano, or C2-4alkenyl, substituted cyano; or (h) R2arepresents cyano.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) X1represents-NR1-, -O-, -S-, -S(=O)p-;

(b) X1represents-NH-, -N(C1-4alkyl)-, -O-, -S-, -S(=O)p-;

(c) X1represents-NH-, -N(CH3)-, -O-, -S-;

(d) X1represents-NH-, -O-, -S-;

(e) X1represents-NH-, -O-; or

(f) X1represents-NH-.

Other subgroups of the compounds of formula (I) are the soedineniya formula (I) or any subgroup of compounds of formula (I), defined in this application, where

(a) R3represents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6alkenyl substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; C2-6quinil substituted by one Deputy, selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7; in particular,

(b) R3represents cyano; aminocarbonyl; amino; C1-6alkyl; halogen; C1-6alkyloxy, where C1-6alkalmazhat be optionally substituted by cyano; Other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C1-6alkyl, substituted hydroxy and a second Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C2-6alkenyl substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10; C2-6quinil substituted by one Deputy, selected from halogen, cyano, -C(=O)-NR9R10;

(c) R3represents halogen, cyano, aminocarbonyl, C1-6alkyl, optionally substituted by cyano or aminocarbonyl, C2-6alkenyl, optionally substituted by cyano or aminocarbonyl;

(d) R3represents halogen, cyano, aminocarbonyl, C1-6alkyl, substituted cyano or aminocarbonyl, or C2-6alkenyl, substituted by cyano or aminocarbonyl;

(e) R3represents cyano, C1-4alkyl, substituted cyano, or C2-4alkenyl, substituted cyano;

(f) R3represents a C1-4alkyl, substituted cyano, or C2-4alkenyl, substituted cyano;

(g) R3represents a C2-4alkyl, C is displaced cyano, or C2-4alkenyl, substituted cyano;

(h) R3represents a C2-4alkenyl, substituted cyano;

(i) R3represents ethynyl, substituted cyano;

(j) R3represents (E)-2-cyanoethyl.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R4is a halogen; hydroxy; C1-6alkyl, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C2-6alkenyl, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C2-6quinil, optionally substituted by one Deputy, selected from halogen, cyano, or-C(=O)R6; C3-7cycloalkyl; C1-6alkyloxy; cyano; nitro; polyhalogen1-6alkyl; polyhalogen1-6alkyloxy; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

(b) R4is a halogen; hydroxy; C1-6alkyl, optionally substituted by one Deputy selected from cyano; C2-6alkenyl, optionally substituted by cyano; C2-6quinil, optionally substituted by cyano; C3-7cycloalkyl; C1-6alkyloxy; cyano; nitro; trifluoromethyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

(c) R4is a halogen; hydroxy; C1-6alkyl, optionally substituted by cyano; C2-6alkenyl, optionally substituted by cyano; C2-6quinil, optionally substituted by cyano; C1-6alkyloxy; cyano; nitro; trifluoromethyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino;

(d) R4represents halogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6quinil, C1-6alkyloxy, cyano, nitro, amino;

(e) R4represents halogen, hydroxy, C1-4alkyl, C1-4alkyloxy, cyano; or

(f) R4represents halogen, C1-4alkyl, C1-4alkyloxy.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R5represents 5 - or 6-membered fully unsaturated cyclic system, where one, two, three or four members of the cycle are heteroatoms, each of to whom that independently selected from the group consisting of nitrogen, oxygen and sulfur, and where the remaining members of the cycle represents the carbon atoms; and where possible, any nitrogen member of the cycle may be optionally substituted C1-6the alkyl, this cyclic system may not necessarily be annulirovano with benzene cycle; and where any carbon atom in the cycle, including any optional carbon annulirovano benzene cycle, may be, each independently, optionally substituted Deputy selected from halogen, hydroxy, mercapto, cyano, C1-6of alkyl, hydroxys1-4of alkyl, carboxy1-4of alkyl, C1-4alkalosis1-4of alkyl, tsianos1-4of alkyl, di(C1-4alkyl)amino1-4of alkyl, Het-C1-4of alkyl, aryls1-4of alkyl, polyhalogen1-4of alkyl, C3-7cycloalkyl, arils2-4alkenyl, C1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl, aryl, Het;

(b) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, tetrazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazyl, benzimidazolyl, Ben is oxazolyl, benzothiazolyl, benzotriazolyl, indolyl, benzothiazolyl, benzofuranyl, benzoxadiazole, indazole, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, cyano, C1-6of alkyl, hydroxys1-4of alkyl, carboxy1-4of alkyl, C1-4alkalosis1-4of alkyl, tsianos1-4of alkyl, di(C1-4alkyl)amino1-4of alkyl, Het-C1-4of alkyl, aryls1-4of alkyl, polyhalogen1-4of alkyl, C3-7cycloalkyl, arils2-4alkenyl, C1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl, C1-4allyloxycarbonyl, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, aryl, Het;

(c) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, triazolyl, tetrazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl, benzothiazolyl, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of whom which is independently selected from halogen, hydroxy, cyano, C1-6of alkyl, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, aryl, Het;

(d) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, isothiazoline, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzofuranyl, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from halogen, hydroxy, cyano, C1-6of alkyl, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, aminocarbonyl, aryl (the latter, in particular, represents phenyl), Het;

(e) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, isothiazoline, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzofuranyl, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from halogen, hydroxy, cyano, C1-6of alkyl, amino, mono - and dis1-4alkylamino, C1-4alkylcarboxylic, aryl (the latter, in particular, represents phenyl), Het;

(f) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, oxadiazolyl, p is ridilla, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, aryl (the latter, in particular, represents phenyl), Het;

(g) R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, thiazolyl, oxadiazolyl, pyridyl, benzofuranyl, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from C1-6of alkyl, amino, aminocarbonyl, phenyl, Het.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) Het represents pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl; each of which may be optionally substituted by one or two C1-4alkyl radicals;

(b) Het is a pyridyl, thienyl, furanyl; each of which may be optionally substituted by one or two C1-4alkyl radicals; or

(c) Het represents pyridyl, thienyl, furanyl;

(d) Het represents pyridyl.

Other additional subgroups of compounds of formula (I) is the tsya the compounds of formula (I) or any subgroup of compounds of formula (I), defined in this application, where

(a) Q represents hydrogen, C1-6alkyl or-NR9R10;

(b) Q represents hydrogen or-NR9R10;

(c) Q represents hydrogen, amino, mono - or dis1-4alkylamino; or

(d) Q represents hydrogen.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R6represents a C1-4alkyl, amino, mono - or di(C1-4alkyl)amino; in particular,

(b) R6represents a C1-4alkyl or amino; or

(c) R6represents a C1-4alkyl.

Other additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R7represents a monocyclic or bicyclic, partially saturated or aromatic carbocycle, or monocyclic or bicyclic partially saturated or aromatic heterocycle, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, Csub> 1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy or aminocarbonyl; in particular,

(b) R7is any of the specific monocyclic or bicyclic, partially saturated or aromatic carbocyclic or monocyclic or bicyclic, partially saturated or aromatic heterocycles specified in this specification, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen-C1-6of alkyl, polyhalogen1-6alkyloxy or aminocarbonyl;

(c) R7arepresents a monocyclic or bicyclic, partially saturated or aromatic carbocycle or monocyclic or bicyclic, partially saturated or aromatic heterocycle, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two or three batch is italiani, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy or aminocarbonyl; in particular,

(d) R7ais any of the specific monocyclic or bicyclic, partially saturated or aromatic carbocyclic or monocyclic or bicyclic, partially saturated or aromatic heterocycles specified in this specification, where each of the said carbocyclic or heterocyclic systems can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy or aminocarbonyl.

Additional subgroups of compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) X3represents-NR1-, -O - or-S-; (b) X represents-NR1- or-O-; (c) X3represents-NH-, -N(C1-4alkyl)-, -O-; (d) X3represents-NH-, -N(CH3)-, -O-; or (e) X3represents-NH-, -O-.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where (a) R represents hydrogen, C1-4alkyl or arils1-4alkyl; or (b) R8represents hydrogen or C1-4alkyl.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R9and R10each independently represents hydrogen, C1-6alkyl, C1-6alkylsulphonyl; C1-6allyloxycarbonyl; mono - or di(C1-6alkyl)aminocarbonyl; -CH(=NR11), where each of the above C1-6alkyl groups may be optionally substituted by one or two substituents, each of which is independently selected from hydroxy, C1-6alkyloxy, hydroxys1-6alkyloxy, carboxyl, C1-6allyloxycarbonyl, cyano, amino, mono - or di(C1-4alkyl)amino, POLYHALOGENATED, POLYHALOGENATED;

(b) R9and R10each independently represents hydrogen, C1-6alkyl, C1-6alkylaryl or C1-6Ala is oxycarbonyl;

(c) R9and R10each independently represents hydrogen or C1-6alkyl;

(d) R9and R10represent hydrogen.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R13and R14each independently represents a C1-6alkyl, optionally substituted by cyano, C2-6alkenyl, optionally substituted by cyano, C2-6quinil, optionally substituted by cyano;

(b) R13and R14each independently represents hydrogen or C1-6alkyl;

(c) R13and R14represent hydrogen.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where R15represents a C1-6alkyl, optionally substituted by cyano.

Other subgroups of the compounds of formula (I) are the compounds of formula (I) or any subgroup of compounds of formula (I), as defined in this application, where

(a) R16represents a C1-6alkyl, optionally substituted by cyano or aminocarbonyl; or where

(b) R16represents a C1-6alkyl, optionally substituted by cyano.

Other subgroups of the compounds of formula (I) are the two who are the compounds of formula (I) or any subgroup of compounds of formula (I), defined in this application, where

(a) aryl represents phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, C1-6alkylsulphonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhalogen1-6of alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, phenyl, tanila or pyridyl;

(b) aryl represents phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyloxy, C1-6allyloxycarbonyl, C1-6alkylthio, cyano, nitro, trifloromethyl, triptoreline, aminocarbonyl, phenyl;

(c) aryl represents phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, hydroxys1-6of alkyl, amino1-6of alkyl, mono - or di(C1-6alkyl)amino1-6of alkyl, C1-6alkylsulphonyl, C1-6alkyla the si, C1-6allyloxycarbonyl, cyano, nitro, trifloromethyl;

(d) aryl represents phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, cyano, nitro, trifloromethyl.

One embodiment of a contains a subgroup of compounds of formula (I)having the formula:

their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where b1=b2-b3=b4-, R1, R2, R2a, R3, R4, R5, m, n and X1defined above in the General definitions of the compounds of formula (I) or their various subgroups.

Another embodiment of belongs to the subgroup of compounds of formula (I)having the formula:

their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where-a1=a2-a3=a4-, R1, R2, R2a, R3, R4, R5, m, n and X1defined above in the General definitions of the compounds of formula (I) or their various subgroups.

Another embodiment of belongs to the subgroup of compounds of formula (I)having the formula:

their N-oxides, Pharm is citiesi acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where R1, R2, R2a, R3, R4, R5, m, n and X1defined above in the General definitions of the compounds of formula (I) or their various subgroups.

An additional embodiment of covers subgroup of compounds of formula (I)having the formula:

their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where R1, R2a, R3, R4, R5and X1defined above in the General definitions of the compounds of formula (I) or their various subgroups.

Also of interest embodiment of covers subgroup of compounds of formula (I)having the formula:

their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines or a stereochemical isomeric forms, where R1, R2, R2a, R3, R5and X1defined above in the General definitions of the compounds of formula (I) or their various subgroups.

The compounds of formula (I) can be obtained by reacting the intermediate compounds of formula (II), where W1is a suitable tsepliaeva group, such as halogen, for example chlorine and the like, with an intermediate compound of formula (III).

The interaction of the pyrimidine derivative (II) with the amine (III) is usually carried out in the presence of a suitable solvent. Suitable solvents are, for example, an alcohol, such as ethanol, 2-propanol; such a dipolar aprotic solvent like acetonitrile, N,N-dimethylformamide; N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone; ether such as tetrahydrofuran, 1,4-dioxane, onomatology ether of propylene glycol. The reaction can be carried out in acidic conditions, which can be obtained by adding various amounts of a suitable acid, for example camphorsulfonic acid, and a suitable solvent, such as tetrahydrofuran or an alcohol, such as 2-propanol, or by using acidified solvents, for example hydrochloric acid, dissolved in such aliphatic alcohol such as 1 - or 2-propanol.

The compounds of formula (I) can also be obtained by forming a connection with X1by interacting or (IV-a) with (V-a)or (IV-b) with (V-b), as noted in the following diagram.

In this reaction scheme W2is a suitable functional group, which, when combined with a group-X1H can be transformed into a relationship with X1. This procedure is most useful for producing compounds of formula (I), where X1 represents a heteroatom such as-NR1-, -O-, -S-.

In particular, the compounds of formula (I), where X1represents NR1these compounds are represented by formula (I-a)can be obtained by reacting the intermediate compounds of formula (IV-c), where W1constitutes a suitable tsepliaeva group, for example chlorine or bromine, with an intermediate compound of formula (V-c). Tsepliaeva band W1may also be entered in situ, for example, by converting the corresponding hydroxypoly in tsepliaeva group, for example, using POCl3. The reaction of (IV-c) with (V-c) is preferably carried out in a suitable solvent in the presence of a base, such as triethylamine. Suitable solvents are, for example, acetonitrile, alcohols such as, for example, ethanol, 2-propanol, ethylene glycol, propylene glycol, such polar aprotic solvents, such as N,N-dimethylformamide; N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, [bmim]PF5; such ethers as 1,4-dioxane, onomatology ether of propylene glycol.

This conversion is also suitable for the case where X1represents-O - or-S-. In particular, the compounds of formula (I), where X1represents O, these compounds are represented by formula (I-b), can be perceived by the s by reacting the intermediate compounds of formula (VI), where W1is a suitable tsepliaeva group, such as halogen, for example chlorine and the like, with an intermediate compound of formula (VII) in the presence of such a suitable base, such as, for example, K2CO3or tert-butyl potassium (KO t-Bu), and a suitable solvent such as, for example, acetone or tetrahydrofuran. In particular the performance of the intermediate compound (VII) is first subjected to a reaction with a suitable metal hydride in an organic solvent with stirring at room temperature. Then add the intermediate compound (VI), where-W1constitutes a suitable tsepliaeva group.

The compounds of formula (I-b) can also be obtained by reacting the intermediate compounds of formula (IV-b), where-X1H represents-OH, these intermediate compounds represented by (IV-d), with an intermediate compound of formula (VII) in the presence of POCl3such a suitable base, such as, for example, K2CO3or tert-butyl potassium (KO t-Bu), and a suitable solvent such as, for example, acetone or tetrahydrofuran.

Thio-compounds (X1represents-S-) can be obtained in a similar way and can be a convenient way converted to the corresponding sulfoxide or su is than using known from the prior art procedures oxidation.

The compounds of formula (I), where X1different heteroatom, can be obtained by reacting (IV-a) with (V-a) or (IV-b) with (V-b), as noted in the above scheme, by choosing the appropriate functional groups-X1H and-W2.

In particular, where X1represents-C(=O)-, source material (V-a) or (IV-b), where the group-X1H represents a group of the Grignard type (-Mg-halogen) or lithium, is subjected to reaction with the starting material (IV-a) or (V-b), where W2is an ester (-Coolkill). The last ester can also be restored to alcohol, for example, using LiAlH4and then oxidized using a moderate oxidant, as MnO2to the corresponding aldehyde, which is then subjected to reaction with a suitable source material, where the group-X1H represents a group of the Grignard type (-Mg-halogen) or lithium. Compounds where X1- represents-C(=O)-, can be converted into analogues-CHOH - through suitable reduction reaction of, for example, with LiAlH4.

In those cases where X1represents-CH2-this link can be entered using the Grignard reaction, for example, by reacting starting material (V-a) or (IV-b), where the group-X1H represents CH2-Mg-halogen, with an intermediate compound (IV-a) or (V-b), where W2predstavljaet a halogen. Methylene group may be oxidized to a group-C(=O)- (X1represents-C(=O)-), for example, selenium dioxide. In turn, the group-C(=O)- can be restored in such a suitable hydride, as LiAlH4to group-CHOH-.

The compounds of formula (I) can also be obtained by reacting the intermediate compound (VIII), where W1is a suitable tsepliaeva group, such as halogen, for example chlorine, bromine, with a heterocyclic compound such special groups as boranova acid (B(OH)2or borate esters (that is,- B(OR)2where R represents an alkyl or alkylene, for example, R represents methyl, ethyl or ethylene). This type of reaction can usually be carried out in the presence of a copper salt, in particular of copper acetate(II), and the reaction mixture can be added such suitable quencher as pyridine. Introduction heterocyclyl group can also be done with other such derivatives of boron as bis(pinacolato)dibor. Debroy ester bis(pinacolato)dibor interacts with heterocyclisation in the presence of palladium catalysts with education geterotsiklicheskikh esters, which are easily converted to heterocyclisation acid, which react with (VIII). This reaction can be conducted is and how agnatically procedure; it can be carried out at mild reaction conditions, for example, in such a bipolar aprotic solvent, such as DMF, or in any other of these solvents.

Intermediate compound (VIII) can be obtained by halogenation of the source material (X), for example, using N-chloro - or N-bromosuccinimide or other chlorides of iodine. Other otsepleniya groups can be introduced by substitution of the halogen with the use of suitable reagents.

The compounds of formula (I), where R is pyrrolyl, can also be obtained by reacting the intermediate compound (IX) with a suitable derivative of 1,2-atendees, for example, such acetaline derived as 2.5-dimethoxytetrahydrofuran.

Intermediate compound (IX) can be obtained by amination of the corresponding starting material (VIII).

Additionally, the compounds of formula (I) can be obtained by converting compounds of the formula (I) into each other in accordance with the known from the prior art reactions of transformation groups.

The compounds of formula (I) can be converted into the corresponding N-oxide forms by implementing known from the prior art procedures for converting the tertiary nitrogen is in its N-oxide form. Essentially, the reaction of N-oxidation may be performed by reacting starting material of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides include, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include hydroperoxides such acids, such as, for example, derbentina acid or derbentina acid, substituted with halogen, such as 3-chloroperbenzoic acid, paracalanidae acid, for example purakayastha acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The compounds of formula (I), where R2, R2a, R3or R4represents a C2-6alkenyl, replaced by aminocarbonyl, can be converted to the compound of formula (I), where R2, R2a, R3or R4represents a C2-6alkenyl, substituted cyano, due to the interaction with POCl3.

The compounds of formula (I), where m is zero, can be converted to connected to the e of the formula (I), where m is non-zero, and R4represents halogen, due to the interaction with such a suitable agent for the introduction of a halogen, such as, for example, N-chlorosuccinimide or N-barsocchini or their combination, in the presence of a suitable solvent such as, for example, acetic acid.

The compounds of formula (I), where R3is a halogen, can be converted to the compound of formula (I), where R3represents a C2-6alkenyl substituted by one or more substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7by interaction with a corresponding C2-6the alkene, substituted by one or more substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7in the presence of such a suitable base, such as N,N-diethylethanamine such a suitable catalyst, such as palladium acetate in the presence of triphenylphosphine, and a suitable solvent such as, for example, N,N-dimethylformamide.

The compounds of formula (I), where R2ais a halogen, can be converted to the compound of formula (I), where R2arepresents a C2-6alkenyl substituted by one or more substituents, each the second of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7by interaction with a corresponding C2-6the alkene, substituted by one or more substituents, each of which is independently selected from halogen, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6the alkyl or R7in the presence of such a suitable base, such as N,N-diethylethanamine such a suitable catalyst, such as palladium acetate in the presence of triphenylphosphine, and a suitable solvent such as, for example, N,N-dimethylformamide.

The compounds of formula (I), where R1represents a C1-6allyloxycarbonyl, can be converted to the compound of formula (I), where R1represents hydrogen, by interacting with such a suitable base, such as hydroxide or sodium methoxide. In those cases where R1represents a tert-butyloxycarbonyl, the corresponding compounds where R1represents hydrogen, can be obtained by processing triperoxonane acid.

Some of the compounds of formula (I) and some of the intermediate compounds in the present invention may contain an asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained put the m applications are known from the prior art procedures. For example, diastereoisomers can be separated by such physical methods as selective crystallization or chromatographic techniques, such as ways to counter current distribution, liquid chromatography and the like, the Enantiomers can be obtained from racemic mixtures by, first, converting these racemic mixtures of such suitable separating agents, such as, for example, chiral acids, mixtures diastereoisomeric salts or compounds; then the physical separation of these mixtures diastereoisomeric salts or compounds, for example, by selective crystallization or chromatographic techniques, such as methods of liquid chromatography and the like; and, finally, conversion of the specified divided diastereoisomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric form can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reactions are stereospecific way.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography, in particular liquid chromatography using a chiral stationary phase.

Some of the tick compounds and starting materials are known compounds and can be commercially available or can be obtained in accordance with known prior art procedures.

Intermediate compounds of formula (II) can be obtained by reacting the intermediate compounds of formula (XI), where W1defined above, with an intermediate compound of formula (XII) in the presence of a suitable solvent such as, for example, tetrahydrofuran, and optionally in the presence of such a suitable base, such as, for example, Na2CO3.

Intermediate compounds of formula (XI) can be obtained in accordance with known prior art procedures.

Intermediate compounds of formula (III), where R1represents hydrogen, these intermediate compounds represented by formula (III-a), or the intermediate compound (V-a-1), which represent the intermediate compound (V-a), where-X1H represents-NH2can be obtained by reacting the intermediate compounds of formula (XIII) or (XIV) with such a suitable reducing agent, as Fe, in the presence of NH4Cl and such a suitable solvent, such as tetrahydrofuran, H2O and alcohol, for example methanol, etc.

Intermediate compounds of formula (III-a) or (V-a-1), where R2aor R3represents a C2-6alkyl, substituted cyano, these intermediate compounds represented by formulas (III-a-1) the (V-a-2), can be obtained by reacting the intermediate compounds of formula (XIII-a) or (XIV-a) with Pd/C in the presence of a suitable solvent such as, for example, alcohol such as ethanol, etc.

Intermediate compounds of formula (III), (V-a) or (VII)where R2aor R3represents halogen, these intermediate compounds represented by formulas (III-b), (V-b) and (VII-a), can be converted to intermediate compounds of the formula (III) or (V) or (VII)where R2aor R3represents a C2-6alkenyl, substituted C(=O)NR9R10specified intermediate compounds represented by formulas (III-c), (V-c) and (VII-b), by reacting the intermediate compounds of formula (XIII) in the presence of Pd(OAc)2, P(o-Tol)3such a suitable base, such as N,N-diethylethanamine, and a suitable solvent such as, for example, CH3-CN.

Intermediate compounds of formula (III-c), (V-c) and (VII-b) can also be obtained by reacting the intermediate compounds of formula (III-f), (V-f) and (VII-c) H-NR9R10in the presence of oxalicacid and in the presence of a suitable solvent such as, for example, N,N-dimethylformamide, CH2Cl2and tet is hydrofuran.

Intermediate compounds of formula (III-d), (V-d) and (VII-c) can be obtained by reacting the intermediate compounds of formula (III-b), (V-b) and (VII-a) H-C2-6alkenyl-C(=O)-OH in the presence of Pd(OAc)2, P(o-Tol)3such a suitable base, such as N,N-diethylethanamine, and a suitable solvent such as, for example, CH3-CN.

Intermediate compounds of formula (III-b), (V-b) and (VII-a) can also be converted to intermediate compounds of the formula (III) or (V) or (VII)where R2aor R3represents a C2-6alkenyl, substituted CN, these intermediate compounds represented by formulas (III-e), (V-e) and (VII-d), by interacting with H-C2-6alkenyl-CN in the presence of Pd(OAc)2, P(o-Tol)3such a suitable base, such as N,N-diethylethanamine, and a suitable solvent such as, for example, CH3-CN.

Intermediate compounds of formula (XV) can be obtained by reacting the intermediate compounds of formula (XVI), where W3is a suitable tsepliaeva group, such as halogen, for example chlorine, with H-NR9R10in the presence of a suitable solvent such as, for example, dieti the new ether and tetrahydrofuran.

Intermediate compounds of formula (XIII) or (XIV), where R2aor R3is cyanovinyl, these intermediate compounds represented by formula (XIII-b) and (XIV-b), can be obtained by reacting the intermediate compounds of formula (XVIII) or (XIX) with citizen.metropolitan in the presence of such a suitable base, such as, for example, NaOCH3and such a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (XIII) or (XIV), where R2aor R3represents-C(CH3)=CH-CN, these intermediate compounds represented by formula (XIII-c) and (XIV-c), can be obtained by reacting the intermediate compounds of formula (XX) or (XXI) with citizen.metropolitan in the presence of such a suitable base, such as, for example, NaOCH3and such a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formulae (XVIII) and (XIX) can be obtained by reacting the intermediate compounds of formula (XXII) or (XXIII) with such a suitable oxidant, such as MnO2in the presence of a suitable solvent such as, for example, ACE is he.

Intermediate compounds of formulae (XXII) and (XXIII) can be obtained by reacting the intermediate compounds of formula (XXIV) or (XXV) with NaBH4in the presence of ethylchloride such a suitable base, such as N,N-diethylethanamine, and a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formulae (XIII) and (XIV), where R2aor R3represents hydroxy, these intermediate compounds represented by formula (XIII-d) or (XIV-d), can be converted into an intermediate compound of formula (XIII) or (XIV), where R2aor R3represents a C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano, given R2aor R3represented by P and the above intermediate compound represented by formula (XIII-e) or (XIV-e), by reacting with an intermediate compound of formula (XXV), where W4is a suitable tsepliaeva group, such as halogen, for example chlorine, etc. in the presence of NaI, such a suitable base, such as, for example, K2CO3and such a suitable solvent, such as acetone.

Intermediate compounds of formulae (XIII) and (XIV) can be obtained by reacting the intermediate compounds of formula (XXVI) or (XXVII) with NaNO3in the presence of CH3SO3H.

Intermediate compounds of formula (IV-d) can be obtained as follows:

Intermediate compounds of formula (XXX) can be converted to intermediate compounds of the formula (IV-e), which are intermediate compounds of formula (IV-d), where R5represents bromine, by interacting with Br2in the presence of such a suitable base, such as N,N-diethylethanamine, and a suitable solvent such as, for example, dimethyl sulfoxide.

Intermediate compounds of formula (IV-e) can be converted to intermediate compounds of the formula (VI), where R5and W2represent chlorine, specified intermediate compound represented by formula (VI-a), by interacting with POCl3.

The compounds of formula (I) have antiretroviral properties (properties of inhibiting reverse transcriptase inhibitors), in particular, against virus immunodeficita human (HIV), which is the etiologic agent of the syndrome of acquired immunodeficiency is (AIDS) in humans. The HIV virus selectively infects T-4-human cells and destroys them or change their normal function, in particular the coordination of the immune system. In the infected patient has a constantly decreasing number of T-4 cells, which, in addition, behave abnormally. Thus, the system of immune protection are unable to resist infections and tumors, and HIV-infected individual usually dies because of such opportunistic infections as pneumonia or cancer. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system characterized by progressive demyelination, leading to dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. Advanced HIV infection has also been associated with peripheral neuropathy, progressive widespread lymphadenopathy (PGL) and AIDS-associated complex (ARC).

These compounds are also active against strains of HIV that are resistant to (multiple) drugs, in particular strains of HIV-1-resistant (plural) drugs, specifically these compounds exhibit activity against HIV strains, especially strains of HIV-1 with acquired resistance to one or more known the figures from the prior art non-nucleoside reverse transcriptase inhibitor. Known from the prior art non-nucleoside reverse transcriptase inhibitors are non-nucleoside reverse transcriptase inhibitors, non of these compounds and are known to the person skilled in the art, in particular commercial non-nucleoside reverse transcriptase inhibitor. These compounds also possess a small or does not have affinity binding to α-1 acid glycoprotein person; α-1 acid glycoprotein person has no effect or little effect on anti-HIV activity of these compounds.

Because antiretroviral properties, particularly anti-HIV properties, especially anti-HIV-1 activity, the compounds of formula (I), their N-oxides, pharmaceutically acceptable additive salts, the Quaternary amines and stereochemical isomeric forms are useful in the treatment of individuals infected with HIV and for the prophylaxis of these infections. Essentially, the compounds in accordance with the present invention may be useful in the treatment of warm-blooded animals infected with viruses, the existence of which is indirect and depends on the enzyme reverse transcriptase. Conditions that can be prevented or can be treated using the compounds in accordance with the present invention, particularly conditions associated with HIV and other pathogenic retrov the Russ, include AIDS, AIDS-associated complex (ARC), progressive disseminated lymphadenopathy (PGL), as well as chronic diseases of the Central nervous system caused by retroviruses, such as dementia, mediated HIV, and multiple sclerosis.

In this regard, the compounds in accordance with the present invention or any subgroup can be used as a drug against the above-described conditions. The specified application as a medicine or method of treatment includes the introduction of HIV-infected individuals amount, effective to withstand the conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1. In particular, the compounds of formula (I) can be used in the production of pharmaceuticals for the treatment or prevention of HIV infections.

Because of the usefulness of the compounds of formula (I) has been provided a method of treating warm-blooded animals, including humans, suffering from viral infections, particularly HIV infections, or a method of preventing warm-blooded animals, including humans. This method consists of the administration, preferably oral administration, of an effective amount of the compounds of formula (I), its N-oxide form, pharmaceutically acceptable additive salts, the Quaternary amine is or a possible stereoisomeric form of warm-blooded animals, including humans.

The present invention also provides compositions for the treatment of viral infections, containing a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds in accordance with the present invention or any subgroup can be obtained in various pharmaceutical forms for administration. As appropriate compositions can be cited all compositions usually used for system administration. To obtain pharmaceutical compositions in accordance with this invention an effective amount of a compound, optionally in the form of a salt additive, as an active ingredient together in the form of a homogeneous mixture with a pharmaceutically acceptable carrier, where the carrier may take a wide variety of forms depending on the form of preparation desired for administration. Preferably the data of the pharmaceutical compositions are in the form of standard dosage forms, suitable in particular for oral, rectal, subcutaneous injection or administration by parenteral injection. For example, in obtaining the compositions in oral dosage form may be used any of such conventional pharmaceutical environments, as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations, as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers, as starches, sugars, kaolin, diluents, lubricants, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. In cases where definitely use solid pharmaceutical carriers, tablets and capsules represent the most preferred standard oral dosage forms because of the simplicity of their introduction. For parenteral compositions, the carrier typically includes at least a significant proportion of sterile water, but may include other ingredients, for example, to facilitate solubility. For example, can be obtained solutions for injection, in which the medium contains saline solution, glucose solution or a mixture of glucose and saline. Can also be obtained suspension for injection, which can be used suitable liquid carriers, suspendresume agents, etc. are Also included preparations in solid form, which is converted into the liquid form shortly before use. In the compositions suitable for percutaneous administration, the carrier optionally contains an agent that enhances the penetration and/or a suitable wetting agent, obazatelno combined with suitable additives of any nature in minor proportions, who does not bring a significant negative impact on the skin. These supplements can facilitate application to the skin and/or may be useful to obtain the desired compositions. Song data can be entered in various ways, for example in the form of a transdermal patch, in the form of drops, in the form of ointment. Compounds in accordance with the present invention can also be entered by inhalation or insufflation through the methods and drugs used in the prior art for the introduction of the given path. Thus, essentially, the compounds in accordance with the present invention can be introduced into the lungs in the form of a solution, suspension or dry powder. For the introduction of these compounds can be any system designed for the delivery of solutions, suspensions or dry powders by oral or nasal inhalation or insufflation.

To facilitate the solubility of the compounds of formula (I) in the composition can be included suitable ingredients, such as cyclodextrins. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers, where one or more hydroxy groups anhydroglucose residual cyclodextrin substituted C1-6the alkyl, in particular the stands, ethyl or isopropyl, e.g. randomly methylated β-CD; hydraxis1-6the alkyl, cha is the surrounding area-hydroxyethyl, the hydroxypropyl or hydroxybutyl; carboxyl1-6the alkyl, in particular carboxymethyl or carboxyethyl; C1-6alkylcarboxylic, in particular acetyl. Especially noteworthy as complexing agents and/or soljubilizatory β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD and, in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term "mixed air" means derivative of cyclodextrin, where at least two of the hydroxy-group of the cyclodextrin tarifitsirovana such different groups, such as hydroxypropyl and hydroxyethyl.

As a measure of the average number of moles of alkoxyamines per mole of anhydroglucose use the average molar substitution (M.S.). The average degree of substitution (D.S.) means the average number of substituted hydroxyl on anhydroglucose balance. The value M.S. and D.S. can be determined using such analytical techniques as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the methodology used can be obtained several different values for a single value of that derivative of cyclodextrin. Preferably, in accordance with the measurement using mass spectrometry, M.S. is in the range from 0125 10 and D.S. is in the range from 0.125 to 3.

Other suitable compositions for oral or rectal injection contain particles consisting of a solid dispersion containing the compound of formula (I) and one or more suitable pharmaceutically acceptable water-soluble polymers.

Used hereinafter, the term "solid dispersion" defines a system in a solid state (as opposed to liquid or gaseous state), containing at least two components, in this case, the compound of formula (I) and water-soluble polymer, where one component is dispersed more or less evenly throughout the other component or components (if included well-known in the prior art such additional pharmaceutically acceptable agents to obtain the drug, as plasticizers, preservatives and the like). When the specified variance of the components is such that the system is chemically and physically uniform or homogenous throughout the volume or consists of one phase, in accordance with the definition in thermodynamics such solid dispersion is called a "solid solution". Solid solutions are preferred physical systems because the components they usually are bioavailable to organisms, which they are administered. Probably, this advantage can be explained laid down the spine, with which these solid solutions can form liquid solutions in contact with such liquid medium, as the gastro-intestinal juices. Ease of dissolution can be explained, at least in part by the fact that the energy required for dissolution of the components of the solid solution, is less than that required for dissolution of the components of the crystalline or microcrystalline solid phase.

The term "solid dispersion" means a dispersion, which are less homogeneous throughout the volume than solid solutions. Such dispersions are not chemically and physically homogeneous throughout the volume or contain more than one phase. For example, the term "solid dispersion" also refers to the system that contains domains or small areas where amorphous, microcrystalline or crystalline compound of formula (I) or amorphous, microcrystalline or crystalline water-soluble polymer, or both are dispersed more or less evenly in the other phase containing water-soluble polymer or the compound of formula (I) or a solid solution containing the compound of formula (I) and water-soluble polymer. These domains represents a region in the solid dispersion, clearly highlighted some physical property, small size and are uniformly and randomly distributed on everything in terms of solid dispersions.

To obtain a solid dispersion there are various techniques including extrusion from the melt, spray drying and evaporation of the solution.

The process of evaporation of a solution includes the following steps:

a) dissolving the compounds of formula (I) and water-soluble polymer in a suitable solvent, optionally at elevated temperatures;

b) heating the solution obtained in step a), optionally in a vacuum to evaporate the solvent. The solution can also be poured on the large surface area for the formation of thin films and evaporation of the solvent from it.

In the method of drying by spraying two component also dissolved in a suitable solvent and then the resulting solution is sprayed through a nozzle spray dryer with subsequent evaporation of the solvent from the resulting droplets at elevated temperatures.

The preferred technique for producing solid dispersions is the process of extrusion from the melt, containing the following steps:

a) mixing the compounds of formula (I) and a suitable water-soluble polymer,

b) optional mixing of the additives with the thus obtained mixture,

c) heating and mixing the thus obtained mixture until then, until a homogeneous melt,

d) forcing the thus obtained melt through one and the and more injectors and

e) cooling the melt prior to solidification.

The terms "melt" and "melting" should be interpreted in a broad sense. These terms not only indicate the change from a solid state to a liquid state, but can also indicate a transition to the glassy state or a rubbery state, and which may include one component of the mixture to another more or less uniformly. In specific cases, one component is melted and the other component (s) dissolved in the melt, thus forming the solution, after cooling, can form a solid solution containing the preferential dissolution properties.

After obtaining a solid dispersion as described above, the resulting products may not necessarily be milled and sifted.

Product solid dispersion can be permalot or comminuted to particles having a size less than 600 microns, preferably less than 400 μm and most preferably less than 125 microns.

Then of particles obtained as described above, conventional techniques can be obtained such pharmaceutical dosage forms like tablets and capsules.

It should be understood that the person skilled in the art can optimize parameters such methods of producing solid dispersions described above, as the most suitable solvent, the working temperature is, the type of the device, the speed of drying by atomization, the rate of passage of material in the extruder.

Water-soluble polymers in the particles are polymers that have an effective viscosity, when dissolved at 20°C in aqueous solution at 2% (wt./vol.), equal 1-5000 MPa·s, more preferably 1-700 MPa·s and most preferably 1-100 MPa·S. for Example, suitable water-soluble polymers include alkylaryl, hydroxyethylcellulose, hydroxyethylmethylcellulose, karboksimetsiltsellyulozy, alkali metal salts and carboxymethylcellulose, carboxylmethylcellulose, esters of karboksimetsiltsellyulozy, starches, pectines, chitin derivatives, such di-, oligo - and polysaccharides such as trehalose, alginic acid or its salts of alkali metals and ammonium, carragenan, galactomannan, tragakant, agar-agar, gum Arabic, guar gum and xanthan gum, polyacrylic acids and their salts, polymethacrylic acid and their salts, copolymers of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, oxides polyalkylene and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are hydroxypropylmethylcellulose.

To obtain the described visicalc as a water-soluble polymer can be used one or more cyclodextrins, as disclosed in WO 97/18839. These cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in the prior art, specifically α-, β - or γ-cyclodextrins or their pharmaceutically acceptable derivatives.

Substituted cyclodextrins that can be used to obtain the above-described particles include polyethers described in U.S. patent 3459731. Additional substituted cyclodextrins are ethers, where the hydrogen of one or more hydroxyl groups of the cyclodextrin substituted C1-6the alkyl, hydroxys1-6the alkyl, carboxy1-6the alkyl or C1-6allyloxycarbonyl1-6the alkyl, or mixed ethers. In particular, such substituted cyclodextrins are ethers, where the hydrogen of one or more hydroxyl groups of the cyclodextrin substituted C1-3the alkyl, hydroxys2-4the alkyl or carboxy1-2the alkyl or more preferably the stands, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

Especially useful are the ethers of β-cyclodextrin, for example, dimethyl-β-cyclodextrin, as described in Drugs of the Future, Vol. 9, No. 8, p. 577-578, M. Nogradi (1984), and polyethers, such as hydroxypropyl-β-cyclodextrin, and hydroxyethyl-β-cyclodextrin. This alkilany question is why the ether may be a dimethyl ether with a degree of substitution of from about 0.125 to 3, for example, approximately 0.3 to 2. This hydroxypropylcellulose, for example, can be formed by the interaction between β-cyclodextrin and propylene oxide and may have a value of MS from about 0.125 to 10, for example from about 0.3 to 3.

Another type of substituted cyclodextrins are sulfosalicylate.

The ratio of the compounds of formula (I) in relation to the water-soluble polymer can be varied within wide limits. For example, can be applied in a ratio of from 1/100 to 100/1. Interest ratio of compounds of formula (I) with respect to the cyclodextrin is in the range from about 1/10 to 10/1. Of great interest ratios are in the range of from about 1/5 to 5/1.

Additionally, it may be convenient to obtain the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface in a quantity sufficient to maintain an effective average particle size of less than 1000 nm. It is assumed that the useful surface modifiers include surface modifiers, which physically adhere to the surface of the compounds of formula (I), but not chemically bound with the specified connection.

Suitable surface modifiers preferably can be you the wounds from known organic and inorganic pharmaceutical inert fillers. Such inert fillers include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting method of obtaining compounds of formula (I) includes a pharmaceutical composition in which the compounds of formula (I) is incorporated in hydrophilic polymers, and the introduction of the mixture as a film sheath covering many small granules, which thus provides a composition that can be done the easy way and which is suitable for producing pharmaceutical dosage forms for oral administration.

These granules contain a Central, rounded or spherical core, a shell in the form of a film of the hydrophilic polymer and the compounds of formula (I) and optional layer of insulating coating.

There are many materials suitable for use as the core of the granules, provided that these materials are pharmaceutically acceptable and have the appropriate size and stiffness. Examples of such materials are polymers, inorganic substances, organic substances and sugars and their derivatives.

Particularly preferably receive the aforementioned pharmaceutical is omposite in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form in the context of the present invention refers to physically separate units, suitable as a standard doses, each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored or coated tablets), capsules, pills, packets of powders, plates, suppositories, injectable solutions or suspensions, etc. and a lot of them in the split view.

Experts in the field of HIV treatment could determine the effective daily amount from the test results presented in this application. Essentially, it is expected that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg of body weight. It may be appropriate introduction of necessary doses of two, three, four or more subds at suitable intervals during the day. These subdata can be obtained in the form of standard doses of medicines, containing, for example, 1-1000 mg and, in particular, 5-200 mg of active ingredient in each standard dosage form.

The exact frequency and dosage of the introduction depends on concr the spas used the compounds of formula (I), the severity of the disease, which is treated, age, weight and General physical condition of the particular patient, and other pharmaceutical agents that can take the individual as known to experts in this field. Moreover, it is clear that the effective daily amount may be reduced or increased depending on the response of the individual, which is subjected to treatment, and/or depending on the evaluation of the physician prescribing the compounds in accordance with the present invention. In this regard, the above-noted ranges effective daily amounts are only recommendations, and assumes that they in no way limit the scope or application of the invention.

These compounds of formula (I) can be used alone or in combination with other therapeutic agents, as anti-viral agents, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They can also be used alone or in combination with other prophylactic methods to prevent viral infections. These compounds may be used in vaccines and methods for protection of individuals against viral infections over a long period of time. These compounds may be used in such in which Kinah or separately, or together with other compounds in accordance with this invention, or in combination with other antiviral agents in a way compatible with the normal use of reverse transcriptase inhibitors in vaccines. Thus, these compounds may be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines, and to be entered in prophylactically effective amounts to protect individuals from HIV infection over a long period of time.

In addition, as a drug may be used in combination of one or more antiretroviral compounds and the compounds of formula (I). Thus, the present invention also relates to a product containing (a) compound of formula (I) and (b) one or more additional antiretroviral compounds in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of HIV. In a single preparation can be combined in various preparations together with pharmaceutically acceptable carriers. These other antiretroviral compounds may represent such well-known antiretroviral compounds as suramin, pentamidine, thymopentin, castanospermine, dextran (textresult), foscarnet the three is (trinacria fastnfurious); nucleoside reverse transcriptase inhibitors such as zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (2',3'-dideoxyinosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (2',3'-dideoxy-3'-thiacytidine, 3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir and the like; non-nucleoside reverse transcriptase inhibitors, as reviparin (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b: 2',3'-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120, TMC-125 and the like; phosphonate inhibitors of reverse transcriptase, such as tenofovir and the like; compounds of the type TIBO (tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepine-2(1H)-he tion), such as (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-tion; connection type α-APA (α-anilinoquinazoline), for example α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic and the like; such inhibitors transactivity proteins as inhibitors of TAT, e.g. RO-5-3335, or inhibitors of REV and the like; protease inhibitors e.g. indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, APV, TMC-126, BMS-232632, VX-175, etc.; fusion inhibitors, such as T-20, T-1249 and the like; the CXCR4 receptor antagonists such as AMD-3100 and the like; inhibitors of viral integrase; nucleotidase reverse transcriptase inhibitors, such as tenofovir and the like; inhibitors ribonucleotidic inhibitors, such as hydroxyurea, etc.

Due to the introduction of compounds in accordance with the present invention with other antiviral agents that act on different events in the viral life cycle can be enhanced therapeutic effect of these compounds. Combined therapy, as described above, exhibit a synergistic effect in the inhibition of HIV replication, because all the components of the combination act on different areas of HIV replication. The use of such combinations can reduce the dosage of this conventional antiretroviral agent, required for the desired therapeutic or prophylactic effect means as compared with the case where the agent was introduced as monotherapy. These combinations can reduce or eliminate the side effects of conventional single antiretroviral therapy without interfering with antiviral agents. These combinations reduce potential resistance to therapy with a single agent, while minimizing any associated toxicity. These combinations can also increase the efficiency of ordinary agent without increasing the conjugate toxicity.

Compounds in accordance with the present invention can also be introduced in combination with immunomodulatory agents such as levamisole, bropirimine, anti-human antibody of alphainterferon, alpha-interferon, interleukin-2, mentionedearlier, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, such as isocyanato of pentamidine etc.; cholinergic agents, such as tacrine, rivastigmine, donepezil, galantamine and the like; blockers of the NMDA channel, for example, memantine, to prevent or combat infection and diseases or symptoms of diseases associated with HIV infections, such as AIDS and ARC, for example dementia. The compound of formula (I) can also be combined with another compound of the formula (I).

Although the present invention focuses on the use of these compounds for the prevention or treatment of HIV infections, these compounds can also be used as inhibitors for other viruses that depend on similar reverse transcriptase inhibitors for the events in their life cycle.

The following examples are intended to illustrate the present invention.

Examples

Further, "DMSO" is defined as dimethylsulfoxide, "TN" is defined as triperoxonane acid, "DMF" is defined as N,N-dimethylformamide and "THF" is defined as tetrahydrofuran.

A. Obtaining intermediates

Example A1: obtain the intermediate compounds2

To the intermediate connection1(0,0327 mol), the receipt of which is described in WO-03/016306, CH3CN (100 ml) was added in parts N-bromosuccinimide (0,0393 mol) at room temperature. The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with CH3CN and dried to obtain 10,08 g of the desired final product. The filtrate is evaporated and was purified by column chromatography (eluent: CH2Cl2100; 35-70 μm). Collected pure fractions, the solvent evaporated and the residue was led out of CH3CN. Yield: 2.4 g of intermediate compounds2. Collected these two fractions. Full output: 12,48 g of intermediate compound2(86%, melting point: >250°C).

Example A2: obtain the intermediate compounds3

To the intermediate connection1(0,000273 mol) in CH3CN (5 ml) was added in parts N-chlorosuccinimide (0,000327 mol) at room temperature. The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with CH3CN and dried. Output: 0,065 g of intermediate compound3(59%, melting point: >250°C).

Example A3: obtain the intermediate compounds4

Used a procedure similar to example A1, starting with a similar split timing is th connection 1(0,000128 mol) with 2-fluoro-6-chlorine and N-bromosuccinimide (0,000154 mol) in CH3CN (5 ml); output: 0,037 g of intermediate compound4(62%, melting point: 236°C).

Example A4: obtain the intermediate compounds5

To a suspension of intermediate compounds1(0,0273 mol) in EtOH (180 ml) was added a suspension of CaCO3(1.64 g) in water (30 ml). Was added dropwise chloride of iodine (ICl) in CH2Cl2(1 BC) (22.5 ml). The mixture was stirred at room temperature for 24 hours, then was cooled to 0°C and filtered. The filtrate was dried in vacuo, then was absorbed EtOH (180 ml), was filtered, washed with EtOH and CH3CN and dried. Output: 8,5, part of the filtrate is evaporated. The residue was led from the hot CH3CN. The precipitate was filtered and dried. Yield: 1.54 g of the intermediate compound5(the total yield 78%).

Example A5: obtain the intermediate compounds6,7and8

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0516 mol) and 4-(2-cyanoethyl)-2,6-dimethylphenylamine (0,0516 mol) was stirred at 140°C in an oil bath for 45 minutes, then was poured into a mixture of water and 10% K2CO3. The precipitate was filtered and the filtrate was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified using column is cromatografia on silica gel (eluent: CH 2Cl2100; 35-70 μm). Collected pure fractions and the solvent evaporated, obtaining 6.0 g of intermediate compounds6(35%, melting point: >250°C).

The intermediate connection7

A mixture of intermediate compound6(0,0182 mol) and 4-cyanoaniline (0,0182 mol) was heated at Association for 5 minutes, then was poured into a mixture of water and 10% K2CO3. Added CH2Cl2and a small amount of MeOH and the precipitate was filtered and dried sludge. Output: 7,4 g of intermediate compound7(95%, melting point: >250°C)

The intermediate connection8

A mixture of intermediate compound7(0,0180 mol) and chloride dihydrate tin(II) (0.125 mol) in ethanol (100 ml) was stirred at 700°C overnight, then was poured into a mixture of water and 10% K2CO3. The precipitate was filtered on celite. Remove the filtrate and the precipitate was washed CH2Cl2and THF. The solvent evaporated. Yield: 6.0 g of intermediate compounds8(87%), melting point: >250°C).

Example A6

Getting 2-fluoro-6-chloraniline analogues of intermediates 6, 7 and 8

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0153 mol) and 4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine (0,0153 mol) was heated at Association for 5 minutes, then was poured into a mixture of water and 10% K2CO3and was extracted with CH2Cl2. Organic is Loy was dried over magnesium sulfate, was filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2100; 35-70 μm). Collected pure fractions and the solvent evaporated. Yield: 1.9 g of 2-chloro-4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidine, intermediate compounds9(35%, melting point: 217°C).

A mixture of intermediate compound9(0,000424 mol) and 4-cyanoaniline (0,000424 mol) was heated at Association for 5 minutes, then was poured into a mixture of water and 10% K2CO3. Added CH2Cl2and a small amount of MeOH and the precipitate was filtered and dried. Output: of 1.34 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidin]amino]benzonitrile, intermediate compounds10(73%, melting point: >250°C)

A mixture of intermediate compound10(0,00306 mol) and chloride dihydrate tin(II) (0,0214 mol) in ethanol (20 ml) was stirred at 70°C overnight, then was poured into a mixture of water and 10% K2CO3. The precipitate was filtered on celite. Remove the filtrate and the precipitate was washed CH2Cl2and THF. The solvent evaporated. Yield: 1.1 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-aminopyrimidine]amino]benzonitrile, intermediate compounds11(89%, melting point: >250°C).

Example A7: obtain the intermediate compounds12

The mixture between the exact connection 2(0,0247 mol), dichlorobis(triphenylphosphine)palladium(II) (0,00494 mol) and triethylamine (0,107 mol) in ethanol (100 ml) was stirred at 100°C for 72 hours at a pressure of 15 bar of carbon monoxide. The mixture was poured into water. The precipitate was filtered, receiving 6 g of intermediate compound12. The filtrate was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH of 99.5/0.5 to; 15-40 μm). Collected pure fractions and the solvent evaporated, obtaining 1.9 g of the intermediate compound12. Two parts of the intermediate connection12United, which gave the total yield 7.9 g (73%, melting point: >250°C).

Example B1: Getting connection1

To the intermediate connection8(0,00524 mol) in acetic acid (5 ml) was added 2,5-dimethoxytetrahydrofuran (0,00157 mol) at room temperature. The mixture was stirred at 90°C for 50 minutes. After cooling, the mixture was poured into water, was added 10% K2CO3and the mixture was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2100; 35-70 μm). Collected clean the fraction and the solvent evaporated, getting 0,145 g (64%, melting point: 163°C) connection1.

Example B2: Connection2

To a solution of tetrakis(triphenylphosphine)palladium(0) (0,0449 mmol) in 1,2-dimethoxyethane was added intermediate connection2(0,449 mmol) at room temperature. Solution was added 1,3-probandooooo cyclic ether pyridine-3-Bronevoy acid (is 0.135 mmol) in methanol (3 ml) at room temperature. The mixture was stirred at 95°C for 20 hours and then poured into ice water, extracted with ethyl acetate. The organic layer was washed with a concentrated salt solution and dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 98/2; 10 μm). Collected pure fractions and the solvent evaporated, getting 0,130 g (65%, melting point: 238°C) connection2.

Example B3: Connection3and22

To a solution of compound3(0,347 mmol) in THF (50 ml) and methanol (30 ml) was added 10% palladium on charcoal (0,069 mmol) in argon. Connection3received in accordance with the procedures of example B2, starting with 1,3-probandooooo cyclic ether furan-2-Voronovo acid. This mixture was introduced into the instrument for hydrogenation under hydrogen pressure (3 bar) and stirred at whom atoi temperature for 1.5 hours. Then the mixture was filtered on celite, washed with THF and the solvent evaporated. The residue was absorbed by ethyl acetate and washed with water and saturated salt solution. Then it was dried over magnesium sulfate, filtered, evaporated and the residue was purified by column chromatography on silica gel (eluent: CH2Cl2/AcOEt 90/10; 35-70 μm). Collected pure fractions and the solvent evaporated. Output: 0,149 g (98%, melting point: 211-212°C) connection22.

Example B4

To the intermediate connection11(0,000246 mol) in acetic acid (3 ml) was added 2,5-dimethoxytetrahydrofuran (0,000739 mol) at room temperature. The mixture was stirred at 90°C for 50 minutes. After cooling, the mixture was poured into water, was added 10% K2CO3and the mixture was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 99/1; 35-70 μm). Collected pure fractions and the solvent evaporated. Output: 0,050 g (45%, melting point: 211°C) connection4.

Example B5

A mixture of intermediate compound12(0,00057 mol), 2-pyridylmethylene (0,00171 mol), 60% sodium hydride (0,00285 mol) in DMF (15 ml) was stirred at 0°C for 15 mi the ut. Then the mixture was made in a microwave (MW) device and irradiated at 300 W for 15 minutes (T=142°C). The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, then dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 99/1; 10 μm, then eluent: MeOH/NH4HCO30,5%/THF: 45/35/20; Hyperprep HS C18 8μm). Collected pure fractions and the solvent evaporated. Output: 0,021 g (7%, melting point: >250°C) connection5.

Example B6

A mixture of intermediate compound5(0.002 mol), PdCl2(dppf) (of 0.0004 mol), bis(pinacolato)Debora (0,0024 mol) and AcOK (0,006 mol) in DMF (10 ml) was stirred at 85°C for 18 hours in a stream of N2. Was added a mixture of 4-amino-3-bromopyridine (0,004 mol), PdCl2(dppf) (of 0.0004 mol) and 2 N. K2CO3(0.01 mol) in DMF (10 ml). The mixture was stirred at 85°C for 3 days. Added H2O. the Mixture was twice extracted with CH2Cl2/THF. The organic layer was washed with saturated NaCl, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by column chromatography on a kromasil (eluent: CH2Cl2/CH3OH/NH4OH from 98/2/0,2 to 90/10/0,1; 5 μm). Collected pure fractions and the solvent evaporated. Yield: 0.075 g (8%) (melting point: 188°C) is soedineniya 6(structure: see table).

Table 1 lists the compounds obtained in accordance with one of the above examples (Example no.).

The connection numberExampleR4R4aR5Physical data and stereochemistry
1B1CH3CH3(E)
163°C
2B2CH3CH3(E)
238°C
3B3CH3CH3(E)
>250°C
4B4F Cl211°C
5B5CH3CH3>250°C
6B6CH3CH3(E)
188°C
7B2CH3CH3(E)
226°C
8B2CH3CH3(E)
>250°C
9B2CH3CH3(E)
250°C
10B2 CH3CH3(E)
245°C
11B2CH3CH3(E)
235°C
12B2CH3CH3(E)
>250°C
13B5CH3CH3(E/Z:40/60)
>250°C
14B5CH3CH3(E)
>250°C
15B5CH3CH3(E)
>250°C
16B5CH3CH3(E)
>250°C
17B5CH3CH3(E)
>250°C
18B6CH3CH3(E)
>250°C
19B6CH3CH3(E)
156°C
20B6CH3CH3(E)
>250°C
21B6CH3CH3 >250°C

Table 2 lists the compounds obtained in accordance with one of the above examples (Example no.).

The connection numberExampleR4R4aR5Physical data and stereochemistry
22B3CH3CH3211-212°C

Examples of drugs

Capsules

The compound of formula (I) is dissolved in such an organic solvent as ethanol, methanol or methylene chloride, preferably in a mixture of ethanol and methylene chloride. Such polymers as copolymers of polyvinylpyrrolidone with vinyl acetate (PVP-VA) or hypromellose (HPMC), usually 5 MPa·s, is dissolved in such organic solvents as ethanol, methanol, methylene chloride. The polymer is preferably dissolved in ethanol. The polymer solutions of the compounds are mixed and then dried by spraying. Sootnoshenie the compound/polymer chosen from 1/1 to 1/6. Intermediate ranges can be 1/1,5 and 1/3. A suitable ratio may be equal to 1/6. Then spray dried powder, solid dispersion fill capsule for introduction. The dose medicines in one pill is between 50 and 100 mg depending on the size of the used capsules.

Tablets film coated

Obtain core tablets

A mixture of 100 g of compound of formula (I), 570 g lactose and 200 g starch is thoroughly mixed and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then it added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All components are thoroughly mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the forming device and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspe the Ziya and all components are homogenized. Core tablets cover the thus obtained mixture in a device for coating.

Antiviral spectrum

Due to the increasing incidence of resistant strains of HIV drugs, these compounds were tested for efficacy against clinically isolated HIV strains bearing multiple mutations. These mutations are associated with resistance to reverse transcriptase inhibitors and lead to the emergence of viruses expressing various degrees of phenotypic cross-resistance to such commercial currently available drugs, such as AZT and delavirdine.

Antiviral activity of compounds in accordance with the present invention was evaluated in the presence of HIV wild-type and mutant HIV carrying mutations in the gene for reverse transcriptase. The activity of compounds was evaluated using cell analysis and the residual activity was expressed in values of pEC50. In columns IIIB and A-G in the table lists the values pEC50in relation to different strains IIIB, A-G.

Strain IIIB is a strain of HIV-LAI wild-type.

The strain contains A mutation Y181C in the reverse transcriptase of HIV.

Strain B contains the K103N mutation in the reverse transcriptase of HIV.

Strain C contains the L100I mutation in the reverse transcriptase of HIV.

Strain D contains the Y188L mutation in bratney the transcriptase of HIV.

Strain E contains mutations L100I and K103N in the reverse transcriptase of HIV.

Strain F contains mutations K103N and Y181C in the reverse transcriptase of HIV.

Strain G contains mutations L100I, K103N, Y181C, V179I, Y181C, E138G, V179I, L2214F, V278V/I and A327A/V in the reverse transcriptase of HIV.

The connection numberIIIBABCDEFG
1989,198,28,48,15,8
29,28,39,28,78,47,97,55,1
39,28,59,19,28,6 8,58,46,2
498,399,17,98,58,55,6
68,06,9---6,36,35,3
78,98,18,68,78,18,185,6
87,87,288,17,17,37,34,6
99,28,59,19,28,5 8,88,65,9
108,57,78,58,47,77,77,74,6
118,16,77,56,56,1-6,54,6
128,97,98,68,17,77,67,84,6
137,87,17,77,87774,6
148,37,17,87,36,76,95,3
157,66,9-6,76,24,66,64,6
168,37,8-8,47,87,78,05,5
177,06,3-6,0the 5.75,05,94,6
188,07,7---7,77,36,1

198,48,1- --8,37,86,2
208,77,9---7,17,0a 4.9
217,56,9---6,26,35,6

1. The compound of the formula

its pharmaceutically acceptable additive salt or a stereochemical isomeric form, where
a1=a2-a3=a4- represents a bivalent radical of the formula
-CH=CH-CH=CH- (a-1);
b1=b2-b3-b4- represents a bivalent radical of the formula
-CH=CH-CH=CH- (b-1);
n is 0, 1, 2, 3,4;
m is 0, 1, 2;
each R1independently represents hydrogen;
each R2represents hydrogen;
R2arepresents cyano;
X1represents-NR1-;
R3represents a C1-6alkyl, substituted cyano;
With2-6 alkenyl, substituted cyano;
R4is a halogen; C1-6alkyl;
R5represents 5 - or 6-membered fully unsaturated cyclic system, where one, two or three members of the cycle are heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur, and where the remaining members of the cycle are carbon atoms; where 6-membered cyclic system may be optional annulirovano with benzene cycle; where any carbon atom in the cycle can be optionally each independently substituted Deputy selected from C1-6of alkyl, amino, mono - and dis1-4alkylamino, aminocarbonyl, mono - and dis1-4alkylcarboxylic, phenyl and Het;
where Het represents a pyridyl, thienyl, furanyl;
Q represents hydrogen.

2. The compound according to claim 1, where R5represents a heterocycle selected from pyrrolyl, furanyl, teinila, thiazolyl, oxadiazolyl, pyridyl, chinoline, said heterocycle optionally substituted on the carbon atoms by one, two or three substituents, each of which is independently selected from C1-6of alkyl, amino, aminocarbonyl, phenyl, Het, where Het is defined in claim 1.

3. Pharmaceutical composition having antiviral activity against HIV, including the pharmaceutically preelimination and as an active ingredient, a therapeutically effective amount of a compound according to claim 1 or 2.

4. The compound according to claim 1 or 2, having the properties of an inhibitor of HIV and intended for use as a drug.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention relates to uniformly tritium-labelled (R)-(+)-[5-methyl-3-(4-morpholinylmethyl)-2,3-dihydro-[1,4]oxazine[2,3,4-hi]-6-indolyl]-1-naphthalinylmethanone acetate of formula I: .

EFFECT: wide range of labelled analogues of physiologically active compounds.

1 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: I, where R1 is selected from group, consisting of ethyl, 2-fluorethyl and isopropyl; R2 is selected from group, consisting of hydrogen, C1-7-alkyl, hydroxy, C1-7-alkoxy, C3-7-cycloalkyl, halogen, -C(O)OR6, where R6 represents C1-7-alkyl, amino, phenyl, phenyl, substituted with 1-3 substituents, selected from group, consisting of halogen, halogen-C1-7-alkyl and halogen-C1-7-alkoxy, pyridyl, imidazolyl, triazolyl and pyrrolyl; R3 is selected from group, consisting of hydrogen, C1-7-alkoxy, amino, -O-benzyl and -o-tetrahydropyranyl; or R2 and R3 are bound to each other with formation of cycle together with carbon atoms to which they are bound, and R2 and R3 together represent -CH=CH-NH-; R4 is selected from group, consisting of hydrogen, halogen, pyridyl and pyrimidyl; R5 and R5' independently on each other are selected from hydrogen or methyl; A is selected from group, consisting of isphenyl; phenyl, substituted with 1-3 substituents, selected from group, consisting of C1-7-alkyl, C3-7-cycloalkyl, C1-7-alkylsulfonyl, -O-C1-7-alkylsulfonyl, hydroxy, C1-7-alkoxy, hydroxy-C1-7-alkyl, hydroxy-C2-7-alkoxy, dihydroxy-C3-7-alkoxy, C1-7-alkylamino, di-C1-7-alkylamino, amino-C2-7-alkoxy, amino-C1-7-alkyl, -C(O)NR10R11, -O-C1-7-alkylene-C(O)NR10R11, -C(O)OR10, -C1-7-alkylene-C(O)OR10, -O-C1-7-alkylene-C(O)OR10, halogen, halogen-C1-7-alkoxy, cyano- C1-7-alkoxy, fluorphenyl, pyridyl, tetrazolyl and tetrazolyl- C1-7-alkoxy; 1,3-benzodioxolyl; naphtyl; pyrimidinyl; pyridyl, substituted with one or two substituents, selected from group, consisting of C1-7-alkyl, C1-7-alkoxy, amino, C1-7-alkylamino, di-C1-7-alkylamino, C3-7-cycloalkylamino, halogen, cyano, morpholinyl, imidazolyl and -NH-C(O)-R9, where R9 represents C1-7-alkyl or C3-7-cycloalkyl, and indolyl; R10 and R11 independently on each other represent hydrogen or C1-7-alkyl; and to their pharmaceutically accdeptable salts. Invention also relates to pharmaceutical compositions.

EFFECT: obtaining novel biologically active compounds, which are antagonists of somatostatin receptor subtype 5 (SSTR5).

26 cl, 266 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

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