Urea-substituted imidazoquinoline ethers

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel urea-substituted imidazoquinoline ethers depicted by general formula I: (1), in which X represents -CHR5- or -CHR5-alkyl group; R1 is selected from radicals: -R4-NR8-CR3-NR5-Z-R6-Alk, -R4-NR8-CR3-NR5-Z-R6-Ph, -R4-NR8-CR3-NR5-Z-R6-furanyl, -R4-NR8-CR3-NR5R-7, phenyl being optionally substituted by one or more substituents selected from methyl, methoxy, methylthio, cyano, hydrogen, dimethylamino, and acetyl; R2 is selected from hydrogen, alkyl, and alkyl-Y-alkyl; R3 represents =O or =S; R4 represents alkyl optionally substituted by one or several O-groups; each of R5 represents C1-C10-alkyl; R6 represents ordinary bond or alkyl; R7 forms cycle together with R5; R4 represents hydrogen, C1-C10-alkyl, or forms morpholine ring together with R8; Y represents -O-; Z ordinary bond, -CO-, or -SO2-; n=0; each of R is independently selected from C1-C10-alkyl, C1-C10-alkoxy, hydroxy, halogen, and trifluoromethyl; or pharmaceutically acceptable salt of forgoing compounds. Described are further compounds of general formula II, intermediates of compounds of general formulae III and IV, pharmaceutical compositions based on compounds I and II, which are immunomodulators for synthesis of cytokines based on compounds I and II, methods of treating viral diseases utilizing compounds I and II, and methods of treating tumor diseases utilizing compounds I and II.

EFFECT: expanded synthetic possibilities in quinoline series and increased choice of therapeutically useful compounds.

25 cl, 4 tbl, 44 ex

 

The present invention relates to imidazopyridine compounds having ether and urea groups in position 1, and pharmaceutical compositions containing such compounds. Another aspect of the present invention involves the application of these compounds as immunomodulators to stimulate the biosynthesis of cytokines in animals and for the treatment of diseases including viral diseases and neoplastic diseases.

The first reliable report on cyclical 1H-imidazo[4,5-C]quinoline (Bachman and others, J. Orq. Chem. 15, 1278-1284 (1950)describes the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline for possible use as antimalarials. Further, it was reported the synthesis of various substituted 1H-imidazo[4,5-C]quinoline. So, for example, was synthesized compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline (Jane and others, J. Med. Chem. 11, p.87-92 (1968)) as a supposed anti-seizure drugs and cardiovascular drugs. There were also reports of some 2-accomidate[4,5-C]quinoline (Baranov and others, Chem. Abs. 85, 94362 (1976), Bereni etc., J. Heterocyclic Chem. 18, 1537-1540 (1981)).

It was later discovered that some of 1H-imidazo[4,5-C]quinoline-4-amines and their 1 - and 2-substituted derivatives can be used as antiviral agents, bronchodilators, and immunomodulators. Proxypolicy can be referenced U.S. patent No. 4689338, 4698348, 4929624, 5037986, 5268376, 5346905 and 5389640; all of these patents are hereby incorporated as references.

Continues to generate interest cyclic system imidazoquinolines.

Known to some 1H-imidazo[4,5-C]naphthiridine-4-amines and 1H-imidazo[4,5-C]pyridine-4-amines and 1H-imidazo[4,5-C]quinoline-4-amines having a Deputy with a simple ester group in position 1. They are described in U.S. patent No. 5268376, 5389640 and 5494916 and in the international application WO 99/29693.

Despite these attempts to identify compounds that are useful as immune response modifiers, there is still a need for compounds that have the ability to modulate the immune response by stimulating the biosynthesis of cytokines or under the action of other mechanisms.

A brief description of the invention

The authors discovered a new class of compounds able to stimulate the biosynthesis of cytokines in animals. The present invention therefore relates to compounds of imidazoquinolines-4-amine and tetrahydroisoquinoline-4-amine, having the Deputy with simple ether and urea groups in position 1. These compounds may be described by the formulas (I) and (II); the details of their structure are below. General structural formula of these compounds is as follows:

Thus X, R1, R2and R is defined for each class travel is, having formula (I) and (II).

Compounds represented by formulas (I) and (II), can be used as immune response modifiers due to their ability to stimulate the biosynthesis of cytokines and other ways to modulate the immune response when introduced into the animal organism. These properties make these compounds useful for the treatment of several diseases, such as viral diseases and tumors that respond to changes in the immune response.

The present invention relates to pharmaceutical compositions containing compounds of modifying an immune response, and methods for the stimulation of the biosynthesis of cytokines in animals, the treatment of viral infections in animals and / or treatment of neoplastic diseases in animals by injecting the animals with compounds of formula (I) or (II).

In addition, the present invention concerns the synthesis methods of the compounds represented in it, and intermediates used in the synthesis of these compounds.

Detailed description of the invention

As mentioned above, found some compounds that stimulate the biosynthesis of cytokines and modifying immune reactions in animals. Such compounds represented by formulae (I) and (II)below.

Imidazoquinolines compounds forming the subject of the invention and having a single ether and ochevidnuyu group in position 1, represented by formula (I):

Where X represents-CHR5-, -CHR5-alkyl or-CHR5-alkenylphenol group;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6alkenyl;

-R4-NR8-CR3-NR5-Z-R6-aryl;

-R4-NR8-CR3-NR5-Z-R6-heteroaryl;

-R4-NR8-CR3-NR5-Z-R6-heterocyclyl;

-R4-NR8-CR3-NR5R7;

-R4-NR8-CR3-NR9-Z-R6-alkyl;

-R4-NR8-CR3-NR9-Z-R6alkenyl;

-R4-NR8-CR3-NR9-Z-R6-aryl;

-R4-NR8-CR3-NR9-Z-R6-heteroaryl;

-R4-NR8-CR3-NR9-Z-R6-heterocyclyl;

R2selected from the group consisting of radicals:

is hydrogen;

-alkyl;

alkenyl;

-aryl;

-heteroaryl;

-heterocyclyl;

-alkyl-Y-alkyl;

-alkyl-Y-alkenyl;

-alkyl-Y-aryl; and

-alkyl or alkenyl, with one or more substituents selected from the group consisting of radicals:

-HE;

-halogen;

-N(R5)2;

-CO-N(R5)2;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

p> -aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

each R3represents =O or =S;

each R4represents independently alkyl or alkenyl, which may include one or more-O-groups;

each R5represents independently N or C1-10alkyl;

R6is a bond or alkyl or alkenyl, which may be interrupted by one or more-O-groups;

R7represents N or C1-10alkyl, which may contain heteroatom, or R7and R5can be connected, forming a loop;

R8represents H, C1-10alkyl or arylalkyl or R4and R8can be connected, forming a loop;

R9represents a C1-10alkyl, which can connect with R8with the formation of the loop;

each Y is independently-O - or-S(O)0-2-;

Z represents a bond, -CO - or-SO2-;

n can have a value from 0 to 4;

each R is selected independently from the group consisting of the radicals C1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

The present invention also includes tetrahydroisoquinoline compounds bearing ether group and Deputy containing urea, in position 1. Such tetrahydroisoquinoline compounds represented by formula (II):

Where X represents-CHR5-, -CHR5-alkyl or-CHR5-alkenylphenol group;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6alkenyl;

-R4-NR8-CR3-NR5-Z-R6-aryl;

-R4-NR8-CR3-NR5-Z-R6-heteroaryl

-R4-NR8-CR3-NR5-Z-R6-heterocyclyl

-R4-NR8-CR3-NR5R7

-R4-NR8-CR3-NR9-Z-R6-aryl

-R4-NR8-CR3-NR9-Z-R6alkenyl;

-R4-NR8-CR3-NR9-Z-R6-aryl;

-R4-NR8-CR3-NR9-Z-R6-heteroaryl; and

-R4-NR8-CR3-NR9-Z-R6-heterocyclyl;

R2selected from the group consisting of radicals:

is hydrogen;

-alkyl;

alkenyl;

-aryl;

-heteroaryl;

-heterocyclyl;

-alkyl-Y-alkyl;

-alkyl-Y-alkenyl;

-alkyl-Y-aryl; and

-alkyl or alkenyl, with one or more substituents selected from the group consisting of radicals:

-HE;

-halogen;

-N(R5)2;

-CO-N(R5)2

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

each R3represents =O or =S;

each R4represents independently alkyl or alkenyl, which may include one or more-O-groups;

each R5represents independently N or C1-10alkyl;

R6is a bond or alkyl or alkenyl, which may be interrupted by one or more-O-groups;

R7represents N or C1-10alkyl, which may contain heteroatom, or R5and R7can be connected, forming a loop;

R8represents H, C1-10alkyl or arylalkyl or R4and R8can be connected, forming a loop;

R9represents a C1-10alkyl, which can connect with R8forming a loop;

each Y is independently-O - or-S(O)0-2-;

Z represents a bond, -CO - or-SO2-;

n can have a value from 0 to 4;

each R is selected independently from the group consisting of the radicals C1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

Getting connections

Compounds which are the subject this is the first invention, can be obtained by the reaction scheme I where R, R2, R3, R4, R5, R8, X and n are defined above, BOC represents a tert-butoxycarbonyl, a R11it-Z-R6-alkyl, -Z-R6alkenyl, -Z-R6-aryl, -Z-R6-heteroaryl, -Z-R6-heterocyclyl or R11is an R7moreover , the values of R6, R7and Z is defined above.

At the stage (1) process (scheme I, reaction of the amino group of amerosport formula X protected tert-butoxycarbonyl group. The solution amerosport in tetrahydrofuran is treated with di-tert-BUTYLCARBAMATE in the presence of a base, e.g. sodium hydroxide. Many of the aminoalcohols of formula X are commercially available; others can be obtained using known methods of synthesis.

At stage (2) process (scheme I, reaction) protected amerosport formula XI is transformed into iodide (formula XII). Iodine is injected into a solution of triphenylphosphine and imidazole in dichloromethane; then add a solution of the protected amerosport formula XI in dichloromethane. The reaction is carried out at ambient temperature.

At stage (3) process (scheme I, reaction) 1H-imidazo[4,5-C]quinoline-1-silt alcohol of formula XIII alkylate iodide of formula XII with obtaining 1H-imidazo[4,5-C]quinoline-1-silt simple ester of the formula XIV. The alcohol of formula XIII is treated with sodium hydride in an appropriate solvent, the ACOM as N,N-dimethylformamide to form the alkoxide. When ambient temperature to a solution of alkoxide type specified iodide. Upon completion of addition the reaction mixture is stirred at elevated temperature (approx. 100°). There are many known compounds of formula XIII; see, for example, U.S. patent 4689338 (Gerster). Other compounds can be obtained easily by known synthesis methods, see, for example, U.S. patent No. 5605899 (Gerster and others) and 5175296 (Gerster).

At stage (4) process (scheme I, reaction) 1H-imidazo[4,5-C]quinoline-1-silt ether of the formula XIV to oxidize 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XV using commonly used oxidizing agent capable of forming N-oxides. It is preferable to oxidize the solution of the compounds of formula XIV in chloroform 3-chloroperoxybenzoic acid at ambient temperature.

At stage (5) process (scheme I, reaction) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XV miniroot obtaining 1H-imidazo[4,5-C]quinoline-4-amine of formula XVI. In stage (5) comprises the following parts: (i) reaction of the compound of formula XV with allermuir substance and (ii) reaction of the resulting product with aminimum substance. Part (I) stage (5) is reacted N-oxide of formula XV with allermuir substance. Among the suitable alleluya substances include alkyl - or arylsulfonate (for example, benzosulphochloride, methanesulfonate, p-toluensulfonate). P is epostane given to arylsulfonamides. The most applicable n-toluensulfonate. Part (ii) stage (5) includes the interaction of the product of part (i) with excess amineralo substances. Among the suitable mineralsa substances include ammonia (e.g. ammonium hydroxide) and ammonium salts (e.g. ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Preference is given to ammonium hydroxide. The reaction is preferably conducted by dissolving the N-oxide of formula XV in an inert solvent (such as dichloromethane or 1,2-dichloroethane) when heated, if necessary, add amineralo substances to the solution and slow introduction Alliluyeva substances. Alternatively, it is possible to conduct the reaction in an autoclave at elevated temperature (85-100°).

At stage (6) process (scheme I, reaction of the protective group is removed by hydrolysis in acidic conditions, receiving 1H-imidazo[4,5-C]quinoline-4-amine of formula XVII. It is preferable to process the compound of formula XVI hydrochloric acid with ethanol at ambient temperature or with gentle heating.

At stage (7) process (scheme I, reaction) 1H-imidazo[4,5-C]quinoline-4-amine of formula XVII is transformed into a derivative of urea or thiourea of formula XVIII using known methods of synthesis. For example, the compound of formula XVII can be treated with the isocyanate of formula R12-N=C=O where R12this R 6-alkyl, -R6alkenyl, -R6-aryl, R6-heteroaryl or-R6-heterocyclyl. The reaction can be conducted by adding a solution of isocyanate in an appropriate solvent, such as dichloromethane or 1-methyl-2-pyrrolidinone, to a solution of the compounds of formula XVII at ambient temperature. Alternatively, you can process the compound of formula XVII thioisocyanate formula R12-N=C=S, arylisocyanate formula R12-C(O)-N=C=O, sulforidazine formula R12-S(O2)-N=C=O or carbamoylation formula R13-N-C(O)Cl, where R13this R12or R7. The product or its salt, pharmaceutical quality can be identified according to standard methods.

Scheme I, reaction

Compounds which are the subject of the present invention, can be obtained in accordance with reaction scheme II, where R, R2, R3, R4, R5, R8, X and n are defined above and BOC represents tert-butoxycarbonyl.

At the stage (1) process (reaction scheme II) the amino amerosport formula XIX protected tert-butoxycarbonyl group. The solution amerosport in tetrahydrofuran is treated with di-tert-BUTYLCARBAMATE in the presence of a base, for example sodium hydroxide. Many of the aminoalcohols of formula XIX commercially available; others can be obtained with approx the application of well known methods of synthesis.

At stage (2) process (reaction scheme II) protected amerosport formula XX is converted into the methanesulfonate (formula XXI). A solution of the compounds of formula XX in an appropriate solvent, such as dichloromethane, is treated with methanesulfonamide in the presence of a base, such as triethylamine. The reaction can be conducted at low temperature (0°).

On stage (3A) of the process (reaction scheme II) methanesulfonate of formula XXI is transformed into azide of formula XXII. To a solution of the compounds of formula XXI in a suitable solvent such as N,N-dimethylformamide, add sodium azide. The reaction can be conducted at elevated temperatures (80-100°).

On stage (3b) of the process (reaction scheme II), the compound of formula XXII alkylate a halide of formula Hal-R8getting the compounds of formula XXIII. For compounds in which R8represents hydrogen, skip this step. Conduct the reaction between the compound of formula XXII and sodium hydride in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran, with the formation of the anion, followed by interaction with the halide. The reaction can be conducted at ambient temperature.

At stage (4) process (reaction scheme II) azide of formula XXII or XXIII reduced to an amine of formula XXIV. It is preferable to carry out the restoration with the use of ordinary heterog the spent hydrogenation catalyst, such as palladium on carbon. The reaction is conveniently run in a Parr apparatus in an appropriate solvent, such as methanol or isopropanol.

At stage (5) process (reaction scheme II) 4-chloro-3-nitroquinoline formula XXV is reacted with an amine of formula XXIV, forming a 3-nitroquinoline formula XXVI. The reaction can be performed by adding the amine of formula XXIV to a solution of the compounds of formula XXV in an appropriate solvent, such as dichloromethane, in the presence of a base, such as triethylamine. There are many quinoline of formula XXV; such quinoline can also be obtained using known methods (see, for example, U.S. patent 4689338 (Gerster) and the data it references.

At stage (6) process (reaction scheme II) 3-nitroquinoline formula XXVI reduced to 3-aminoquinoline formula XXVII. It is preferable to carry out the restoration of the conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The reaction is conveniently run in a Parr apparatus in an appropriate solvent, such as toluene.

At stage (7) process (reaction scheme II), the compound of formula XXVII is reacted with carboxylic acid or its equivalent, forming 1H-imidazo[4,5-finalin formula XIV. In a number of suitable equivalents of carboxylic acid are difficult orthoepy and 1,1-diakoniekrankenhaus. Carboxylic acid or equivalent is chosen is so, to the composition of the compounds of formula XIV was part of the desired substituent R2. So, for example, with the introduction of triethylorthoformate produces compound in which R2represents hydrogen; in the presence of triethylorthoformate R2represents butyl. The reaction can be carried out in the absence of solvent or in an inert solvent, such as toluene. The reaction proceeds with heat, sufficient for any alcohol or water formed as by-products, vanished. Alternatively, you can enter a catalytic amount of pyridinecarboxamide.

Alternatively, you can run stage (7) through (i) the reaction between a compound of formula XXVII and allelochemical formula R2C(O)Cl and (ii) cyclization. In part (i) allalone added to a solution of the compounds of formula XXVII in an inert solvent, such as acetonitrile or dichloromethane. This reaction can be carried out at ambient temperature or low temperature. In part (ii) the product of part (i) is heated in ethanol solution in the presence of a base. It is preferable to heat the ethanol solution of the product of part (i) in the presence of excess triethylamine under reflux or heat in a methanolic ammonia solution.

Stage(8), (9), (10) and (11) are the same as stage(4), (5), (6) and (7) process (scheme I R the shares).

Scheme II reactions

Compounds which are the subject of the present invention, can be obtained by the reaction scheme III, where R, R2, R3, R4, R5, R8, R11, X and n are defined above.

At the stage (1) process (scheme III reactions) 1H-imidazo[4,5-C]quinoline-4-amine of formula XVII to restore 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of formula XXVIII. Preferably the recovery by suspension or dissolution of the compounds of formula XVII in triperoxonane acid, adding a catalytic amount of platinum oxide (IV) and subsequent hydrogenation. The reaction is conveniently run in a Parr apparatus.

Stage (2) are the same as stage (7) process (scheme I, reaction) receiving 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of formula XXIX. The product or its salt, pharmaceutical quality can be identified according to standard methods.

Reaction scheme III

Compounds which are the subject of the present invention can be obtained in accordance with scheme IV reactions, where R, R2, X and n are defined above.

At the stage (1) process (scheme IV reaction) 4-chloro-3-nitroquinoline formula XXV is reacted with an amine of formula R1-O-X-NH2forming a 3-nitroanilin-4-amine of formula XXX. The reaction can be conducted through doba is of amine to a solution of the compounds of formula XXV in a suitable solvent, such as chloroform or dichloromethane, with the possible heat. Many quinoline of formula XXV is well known: see, for example U.S. patent 4689338 (Gerster) and in the references.

At stage (2) process (scheme IV reaction) 3-nitroanilin-4-amine of formula XXX restore using the method described for stage (6) process (reaction scheme II), receiving a quinoline-3,4-diamine of formula XXXI.

At stage (3) process (scheme IV reaction) quinoline-3,4-diamine of formula XXXI is subjected to cyclization according to the method described for stage (7) process (reaction scheme II), receiving 1H-imidazo[4,5-C]quinoline of formula XXXII.

At stage (4) process (scheme IV reaction) 1H-imidazo[4,5-C]quinoline of formula XXXII are oxidized according to the method described for stage (4) process (scheme I reaction), receiving 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXIII.

At stage (5) process (scheme IV reaction) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXIII miniroot according to the method described for stage (5) process (scheme I, reaction) to give 1H-imidazo[4,5-C]quinoline-4-amine of formula I. the Product or its salt, pharmaceutical quality can be identified according to standard methods.

Scheme IV reactions

Compounds which are the subject of the present invention, can be obtained according to scheme V the reaction, where R, R2, R3, R4, R5, R8, R11, X and n ODA is defined above.

At the stage (1) process (scheme V reaction) group VOS remove from compounds of formula XIV using the method described for stage (6) process (scheme I reaction), with 1H-imidazo[4,5-C]quinoline of formula XXXIV.

At stage (2) process (scheme V reaction) 1H-imidazo[4,5-C]quinoline of formula XXXIV in turn a derivative of urea or thiourea of formula XXXV, using the method described for stage (7) process (scheme I reaction).

At stage (3) process (scheme V reaction) 1H-imidazo[4,5-C]quinoline of formula XXXV are oxidized according to the method described for stage (4) process (scheme I reaction), with 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXVI.

At stage (4) process (scheme V reaction) 1H-imidazo[4,5-C]quinoline-5N-oxide of formula XXXVI are oxidized according to the method described for stage (5) process (scheme I reaction), with 1H-imidazo[4,5-C]quinoline-4-amine of formula XVIII. The product or its salt, pharmaceutical quality can be identified according to standard methods.

Scheme V reaction

The present invention also includes novel compounds used as intermediates for the synthesis of compounds of formulas (I) and (II). These intermediate compounds are characterized by structural formulas (III) and (IV) and described in detail below.

One class of intermediate compounds has the formula (III):

Where X represents-CHR5-, -CHR5-alkyl or-CHR5-alkenylphenol group;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6alkenyl;

-R4-NR8-CR3-NR5-Z-R6-aryl;

-R4-NR8-CR3-NR5-Z-R6-heteroaryl;

-R4-NR8-CR3-NR5-Z-R6-heterocyclyl; and

-R4-NR8-CR3-NR5R7;

-R4-NR8-CR3-NR9-Z-R6-alkyl;

-R4-NR8-CR3-NR9-Z-R6alkenyl;

-R4-NR8-CR3-NR9-Z-R6-aryl;

-R4-NR8-CR3-NR9-Z-R6-heterocyclyl; and

-R4-NR8-CR3-NR9-Z-R6-heterocyclyl;

R2selected from the group consisting of radicals:

is hydrogen;

-alkyl;

alkenyl;

-aryl;

-heteroaryl;

-heterocyclyl;

-alkyl-Y-alkyl;

-alkyl-Y-alkenyl;

-alkyl-Y-aryl; and

-alkyl or alkenyl, with one or more substituents selected from the group consisting of radicals:

-HE;

-halogen;

-N(R5)2;

-CO-N(R5)2;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocy is poured;

-CO-aryl; and

-CO-heteroaryl;

each R3represents =O or =S;

each R4represents independently alkyl or alkenyl, which may include one or more-O-groups;

each R5represents independently N or C1-10alkyl;

R6is a bond or alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R7represents N or C1-10alkyl, which may contain heteroatom, or R7and R5can be connected, forming a loop;

R8represents H, C1-10alkyl, or arylalkyl; or R4and R8can be connected, forming a loop;

R9represents a C1-10alkyl, which can connect with R8with the formation of the loop;

each Y is independently-O - or-S(O)0-2-;

Z represents a bond, -CO - or-SO2-;

n can have a value from 0 to 4;

each R is selected independently from the group consisting of the radicals C1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

The present invention also includes compounds of imidazoquinolines-N-oxide of formula (IV):

Where X represents-CHR5-, -CHR5 -alkylenes or-CHR5-alkenylamine group;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6alkenyl;

-R4-NR8-CR3-NR5-Z-R6-aryl;

-R4-NR8-CR3-NR5-Z-R6-heteroaryl;

-R4-NR8-CR3-NR5-Z-R6-heterocyclyl;

-R4-NR8-CR3-NR5R7;

-R4-NR8-CR3-NR9-Z-R6-alkyl;

-R4-NR8-CR3-NR9-Z-R6alkenyl;

-R4-NR8-CR3-NR9-Z-R6-aryl;

-R4-NR8-CR3-NR9-Z-R6-heteroaryl; and

-R4-NR8-CR3-NR9-Z-R6-heterocyclyl;

each Y is independently-O - or-S(O)0-2-;

Z represents a bond, -CO - or-SO2-;

each R4represents independently alkyl or alkenyl, which may include one or more-O-groups;

each R5represents independently N or C1-10alkyl;

R6is a bond or alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R7represents N or C1-10alkyl, which may contain heteroatom, or R7and R5 can be connected, forming a loop;

R8represents H, C1-10alkyl, or arylalkyl; or R4and R6can be connected, forming a loop;

R9represents a C1-10alkyl, which can connect with R8with the formation of the loop;

n can have a value from 0 to 4;

each R is selected independently from the group consisting of the radicals C1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

Used in the text, the terms "alkyl", "alkenyl" and the prefix "ALK-" include both groups with straight and branched chain and cyclic groups, i.e. cycloalkyl and cycloalkenyl residues. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, and alkeneamine groups contain from 2 to 20 carbon atoms. The total number of carbon atoms in groups, which are preferred, up to 10. Cyclic groups can contain one cycle or several cycles; the preferred number of carbon atoms in the cycle from 3 to 10. Among examples of such residues, as cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, and substituted.

You should also add that the alkyl and Alchemilla part-X groups may have substituents or contain will replace the if (one or more); these substituents selected from the group comprising alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroallyl and geterotsiklicheskikh.

The term "halogenated" includes groups substituted by one or more halogen atoms, including perfluorinated group. This statement is true for groups in whose name includes the prefix "halo". Examples of acceptable halogenating groups are CHLOROTHALONIL, triptorelin and similar residues.

Used here, the term "aryl" refers to carbocyclic aromatic cycles or systems cycles. Examples of aryl groups can be called phenyl, naphthyl, diphenyl, forfinal and indenyl. The term "heteroaryl" refers to aromatic cycles cycles or systems containing at least one heteroatom (e.g., O, S, N) in a loop. In the number of heteroaryl groups include furyl, thienyl, pyridyl, chinoline, ethenolysis, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophene, carbazole, benzoxazole, pyrimidinyl, benzimidazolyl, honokalani, benzothiazolyl, naphthyridine, isoxazolyl, isothiazolin, purinol, hintline etc.

The term "heterocyclyl" includes non-aromatic cycles or system cycles containing at least one of heteroatom (for example, O, S, N) in a loop. This includes all of the fully saturated and partially unsaturated derivatives of the above-mentioned heteroaryl groups. Examples of heterocyclic groups can be called pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidine, piperazinil, diazolidinyl, imidazolidinyl, isothiazolinones, etc.

Aryl, heteroaryl and heterocyclyl groups can be unsubstituted or substituted; in the latter case, they may contain one Deputy or more substituents independently selected from the group consisting of such radicals as alkyl, alkoxy, alkylthio, halogenated, halogenoalkane, allogeneically, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, aaltio, Allakaket, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroaromatics, heteroaromatic, amino, alkylamino, dialkylamino, heterocyclyl, heteroseksualci, alkylsulphonyl, alkenylboronic, alkoxycarbonyl, halogenoalkanes, gelegenheitsarbeit alkylthiomethyl, arylcarbamoyl, heteroarylboronic, aryloxyalkyl, heteroarylboronic, aristochromis, heteroarylboronic, alkanoyloxy, alkanity, alkanolamine, arylcarboxylic, arylcarboxylic, alkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, aroldis the Nile, alkylsulfonamides, arylsulfonamides, arylalkylamine, alkylcarboxylic, alkenylamine, arylcarboxamide, arylalkylamine, heteroarylboronic, heteroarylboronic, alkylsulfonyl, alkanesulfonyl, arylsulfonamides, arylalkylamine, heteroarylboronic, heteroarylboronic, alkylaminocarbonyl, alkynylaminopyrazoles, arylenecarborane, arylalkylamines, heteroarylboronic, heteroarylboronic and, in the case heterocyclyl balance, oxo. If any other groups say they are "substituted" or "possibly substituted, these groups can also contain one or more of the aforementioned substituents.

In General, some of the substituents given preference. So, for example, preferred R1groups are R4-NR8-CR3-NR5-Z-R6-alkyl and R4-NR8-CR3-NR5-Z-R6-aryl, where alkyl and aryl groups may contain substituents or contain them; preferably, R4was ethylene or n-butylene or R4and R8can be connected, forming a loop. Preferably the absence of R-substituents, i.e. n=0. Among the preferred groups R2are hydrogen, alkyl the s group with 1-4 carbon atoms (it is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and cyclopropylmethyl), methoxyethyl and ethoxymethyl. For the substituted groups, such as substituted alkyl or substituted aryl residues, preferred substituents include halogen, nitrile, methoxy, methylthio, trifluoromethyl, triptoreline. One or more of these preferred substituents when present may be in the composition of the compounds that are the subject of the present invention, in any combination.

The present invention includes compounds described herein in any pharmaceutically accessible form, including isomers (e.g., diastereomers and enantiomers), salt, solvate, polymorph options, etc. In particular, if a compound is optically active, the present invention includes each of the enantiomers of the compounds, as well as racemic mixtures of enantiomers.

Pharmaceutical formulations and biological activity

Pharmaceutical compositions that are the subject of the present invention contain a therapeutically effective amount of the above compounds in combination with a pharmaceutically available carrier.

The term "therapeutically effective amount" means that amount of compound which is sufficient to achieve a therapeutic effect, such as encouraging the synth is for cytokines, manifestation of anti-tumor activity and / or expression of antiviral activity. Although the exact number of active compounds used in the pharmaceutical composition, which is the subject of the present invention may vary depending on factors known to those who are expert in this field (for example, physical and chemical nature of the compound, the nature of the medium and the intended dosing regimen), it is assumed that the compositions of the subject of the present invention will contain sufficient active ingredient to create the dose of the compound from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg per body weight patient. Can be used any known dosage forms such as tablets, lozenges, parenteral preparations, syrups, creams, ointments, aerosol medications, transcutaneous patches, the patches on the mucous membrane, etc.

Compounds that are the subject of the present invention can be used as the sole therapeutic agent in the treatment regimen or data connections can be used in combination with one another or with other active substances, including additional modifiers of the immune response, antiviral substances, Antibes is otice etc.

It was shown that the compounds that are the subject of the present invention, stimulate the synthesis of certain cytokines in the experiments performed in accordance with the test conditions described below. The test results show that these compounds are used as modifiers of the immune response; they can modify the immune response in different ways, which makes these compounds useful in the treatment of various diseases.

Among the cytokines, the synthesis of which can be stimulated by the use of compounds that are the subject of the present invention generally include interferon-α (ifαand / or tumor necrosis factor-α (TNF-α), as well as certain interleukins (IL). The group of cytokines, the biosynthesis of which can be stimulated by compounds that are the subject of the present invention, includes IGF-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and some other cytokines. Among other effects, these and other cytokines can inhibit the multiplication of viruses and tumor cell growth, making these compounds useful in the treatment of viral diseases and tumors. In connection with the foregoing, the present invention relates to a method of stimulating the biosynthesis of cytokines in the body of the animal by injecting an effective amount of the compound which is the subject n the standing of the invention, or composition in the body of the animal.

It was found that some compounds that are the subject of the present invention, to a greater extent stimulate the expression of IGF-α in a population of hematopoietic cells, such as okbc (mononuclear cells peripheral blood) and pDC2 cells (dendritic precursor cells type 2) without concomitant synthesis of large amounts of cytokines, accompanying inflammation.

In addition to the ability to stimulate the synthesis of cytokines, compounds that are the subject of the present invention, impact on other aspects of the innate immune response. So, for example, possible stimulation of the activity of natural killer cells, probably due to stimulation of cytokines. These compounds can also activate macrophages, which in turn stimulates the secretion of nitric oxide and synthesis of additional quantities of cytokines. In addition, these compounds can induce proliferation and differentiation of b-lymphocytes.

Compounds that are the subject of the present invention, also affect the acquired immune response. For example, although not believe that they have a direct effect on T cells or directly induce cytokines T cells, cytokine synthesis of if-γ T helper type 1 (T×1) is stimulated indirectly, and the synthesis of cytokines IL-4, IL-5 and the L-13 T-helper type 2 (T× 2) inhibited after administration of these compounds. This activity means that these compounds are applicable for the treatment of diseases which require increasing regulation of T×1-response and (or) decreasing regulation of T×2-answer. Due to the ability of these compounds to inhibit T×2 immune response, it can be expected that they are applicable in the treatment of atopic diseases such as atopic dermatitis, asthma, Allergy, allergic rhinitis, systemic lupus erythematosus; they can also be used as adjuvants in vaccines for the development of cell-mediated immunity. Possible use for the treatment of recurrent diseases caused by microscopic fungi, and chlamydia.

Effects associated with the modification of the immune response of these compounds make possible their use in the treatment of a wide range of diseases. Due to its ability to stimulate the synthesis of cytokines, such as if-α and / or TNF-α, these compounds are particularly applicable in the treatment of viral diseases and tumors. Immunomodulating activity of these compounds suggests that the compounds that are the subject of the present invention may find application in the treatment of diseases such as virus, including genital warts, common warts, plantar Borodavko is, hepatitis b, hepatitis C, a disease caused by herpes simplex virus type I and type II, molluscum contagiosum, variola, especially black smallpox, diseases caused by HIV, CMV, varicella zoster virus, diseases caused by rhinovirus, adenovirus, influenza virus and parainfluenza virus (these lists are not exhaustive). Possible use of these compounds in the case of intraepithelial neoplasms, such as cervical intraepithelial neoplasia. Possible impact on disease caused by the human papillomavirus and related neoplasms; diseases caused by microscopic fungi (Candida, Aspergillus), including cryptococcal meningitis. These compounds may find application in the treatment of such neoplastic diseases such as basal cell carcinoma, leukemia reticuloendotheliosis, Kaposi's sarcoma, renal cell cancer, squamous cell carcinoma, myeloid leukemia, multiple myeloma, melanoma, nahodkinskaja lymphoma, cutaneous T-cell lymphoma and other cancers. Possible use in the treatment of parasitic diseases: pneumocystosis, caused by the microorganism Pneumocystis canriii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomiasis, leishmaniasis, bacterial infections, such as tuberculosis and diseases caused microorganism the Mycobacterium avium. Other diseases that can be treated with compounds that are the subject of the present invention, includes radiation keratosis, eczema, eosinophilia, essential thrombocythemia, leprosy, multiple sclerosis, syndrome Omena, discoid lupus erythematosus, Bowen's disease, papules Bowen, alopecia areata, inhibition of the formation of keloids and other scars. It should be added that these compounds may increase or stimulate the healing of wounds, including chronic damage. These compounds may be used for the treatment of diseases caused by opportunistic microorganisms and tumors arising after the suppression of cell-mediated immunity, such as patients after organ transplantation, cancer patients and HIV-positive.

The number of compounds effective in the stimulation of the biosynthesis of cytokines, is a mass sufficient to stimulate one cell type or a few types of cells, such as monocytes, macrophages, dendritic cells and b-cells, the production of a certain number of one or more cytokines, such as if-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, exceeding the background level. The exact number depends on factors known to specialists in this area, but it is assumed that the dose will be faced the ü from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg of the Present invention also involves a method of treating viral infections in animals and a method of treatment of neoplastic diseases in animals by applying an effective amount of a compound or composition which is the subject of the present invention. The mass of a substance effective in the treatment or inhibition of viral infection, is a number, causing a decrease in the intensity of one or more manifestations of viral infections, such as viral lesions, viral load, speed of reproduction of viruses and mortality, compared with control animals that have not undergone treatment. The exact number depends on factors known to specialists in this area, but it is assumed that the dose will be from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg/kg Weight compounds effective in the treatment of neoplastic diseases, is the amount that causes reduction of tumor size or number of disease outbreaks. The exact number depends on factors known to specialists in this area, but it is assumed that the dose will be from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg up to approx the tion of 5 mg/kg

Further description of the present invention is illustrated by the following examples; the examples in no way limit the General scope of the invention.

In the following examples of some compounds were subjected to cleaning by way prepreparation HPLC. Use automatic cleaning system Waters Fraction Lynx. Fractions obtained by the method prepreparation HPLC, and analyzed by gas chromatography instrument Micromass LC-TOFMS; the corresponding fractions were combined and dried in a centrifuge, getting trifenatate salt necessary connections. Structures of compounds were confirmed by way of1H NMR.

Column: Phenomenex Luna C18(2), 10×50 mm, particle size 5 µm, pore size 100 Å. Flow rate 25 ml/min Gradient elution: 5-65% component b for 4 min, 65-95% of a component b for 0.1 min, exposure at the 95% level component In for 0.4 minutes And is a 0,05%mixture triperoxonane acid and water, is a 0,05%mixture triperoxonane acid and acetonitrile. Collection of the fractions is carried out by mass-selective signal.

Example 1

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-prilocaine

Part a

In an atmosphere of nitrogen was cooled solution of 2-2(2-aminoethoxy)ethanol (29.0 g, 0,276 mol) in 180 ml of tetrahydrofuran THF) to a temperature of 0° And was treated with 140 ml of 2N NaOH solution. Next was added dropwise over 1 hour a solution of di-tert-BUTYLCARBAMATE (60,2 g, 0,276 mol) in 180 ml of THF with rapid stirring. The reaction mixture is left to heat up to room temperature and stirred for 18 hours. Then THF was removed under reduced pressure, and the pH of the remaining aqueous slurry is brought to 3 by adding 150 ml of a 1M solution of H2SO4. The product was extracted with ethyl acetate (300 ml, 100 ml)and the combined organic layers were washed with water (2×) and brine. The organic portion was dried over Na2SO4and concentrated, obtaining tert-butyl-2-(2-hydroxyethoxy)ethylcarbamate in the form of a colorless oily liquid (47,1 g).

Part b

In an atmosphere of nitrogen cooled rapidly stirred solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47,1 g, 0,230 mol) in 1 l of anhydrous CH2Cl2to a temperature of 0°C and treated with triethylamine (48,0 ml, 0,345 mol). Next was added dropwise methanesulfonanilide (19.6 ml, 0,253 mol) over 30 minutes, the Reaction mixture is left to heat up to room temperature and stirred for 22 hours. The reaction was stopped by adding 500 ml of a saturated solution of NaHCO3; the organic layer was separated. The organic phase is washed with water (3×500 ml) and brine. The organic portion was dried over Na2SO 4and concentrated, obtaining 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethylmethanesulfonate in the form of a brown oily liquid color (63,5 g).

The part With

Mix a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethylmethanesulfonate (63.5 g, 0,224 mol) in 400 ml of N,N-dimethylformamide (DMF) was treated with NaN3(16.1 g, 0,247 mol)and the reaction mixture was heated to 90°C in nitrogen atmosphere. After 5 hours the solution was cooled to room temperature and treated with 500 ml of cold water. Next, the reaction mixture was extracted with Et2O (3×300 ml). The combined organic extracts were washed with water (4×100 ml) and brine (2×100 ml). The organic portion was dried over MgSO4and focused, getting 52,0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate in the form of an oily liquid light brown color.

Part D

A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47,0 g, 0,204 mol) in Meon was treated with 4 g of Pd (10%on carbon was shaken in an atmosphere of hydrogen (3 bar) for 24 hours. The solution was filtered through a layer of celite (Celite) and concentrated, getting to 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate in the form of a colorless liquid which was used without further purification.

Part E.

In nitrogen atmosphere stir a solution of 4-chloro-3-nitroquinoline (of 31.4 g, 0,151 mol) in 500 ml anhydrous CH2Cl2about amityvale by triethylamine (43 ml, 0,308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0,151 mol). After stirring over night the reaction mixture was washed with water (2×300 ml) and brine (300 ml). The organic portion was dried over Na2SO4and concentrated, having a solid bright yellow. Upon recrystallization from a mixture of ethyl acetate-hexane received by 43.6 g of tert-butyl 2-{2-[(3-nitroanilin-4-yl)amino]ethoxy}ethylcarbamate in the form of crystals of a bright yellow color.

Part F

A solution of tert-butyl 2-{2-[(3-nitroanilin-4-yl)amino]ethoxy}ethylcarbamate (7,52 g, 20,0 mmole) in toluene was treated with 1.5 g of Pt (5%) on carbon was shaken in an atmosphere of hydrogen (3 bar) for 24 hours. The solution was filtered through a layer of celite and concentrated, obtaining 6,92 g of crude tert-butyl 2-{2-[(3-aminoquinoline-4-yl)amino]ethoxy}ethylcarbamate in the form of a syrupy liquid yellow color.

Part G

A solution of tert-butyl 2-{2-[(3-nitroanilin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, to 29.5 mmole) in 250 ml anhydrous CH2Cl2cooled to a temperature of 0°and treated with triethylamine (4,18 ml of 30.0 mmole). Next was added dropwise methoxypropionitrile (3,30 ml of 30.3 mmole) within 5 min. the Reaction mixture was heated to room temperature and continued stirring for another 1 hour. Then the reaction mixture was concentrated under reduced pressure with the floor is in solid orange. This product was dissolved in 250 ml EtOH and added to 12.5 ml of triethylamine. The mixture was heated under reflux with stirring in nitrogen atmosphere overnight, then the mixture was concentrated to dryness under reduced pressure and treated with 300 ml of Et2O. the Mixture was filtered and the filtrate was concentrated under reduced pressure to obtain solid brown color. The substance was dissolved in 200 ml of hot Meon and treated with activated charcoal. The hot solution was filtered and concentrated, obtaining 11.1 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate in the form of a syrupy liquid yellow color.

Part N

A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate (10,22 g, 24.7 mmole) in 250 ml of CHCl3was treated with 3-chloroperoxybenzoic acid (77%, 9,12 g and 40.8 mmole). After stirring for 30 min the reaction mixture was washed with 1%solution of Na2CO3(2×75 ml) and brine. The organic layer was dried over Na2SO4and concentrated, obtaining 10.6 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate in the form of an orange foam. This product was used without further purification.

Part I

A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate is a (10.6 g, of 24.6 mmole) in 100 ml of 1,2-dichloroethane was heated to 60°and treated with 10 ml of concentrated solution of NH4HE. With rapid stirring, was added solid n-toluensulfonate (7,05 g, 37,0 mmol) for 10 minutes, the Reaction mixture was treated with an additional quantity of concentrated solution of NH4OH (1 ml) and placed in the autoclave; heating was continued for another 2 hours. The reaction mixture is cooled and treated with 100 ml of CHCl2. Next, the reaction mixture was washed with water, 1%solution of Na2CO3(2×) and brine. The organic portion was dried over Na2SO4and concentrated, obtaining 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate in the form of a brown foam.

Part J

Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethylcarbamate (10.6 g, of 24.6 mmole) was treated with 75 ml of 2M HCl solution in EtOH; the mixture was heated under reflux with stirring. After 1.5 hours the reaction mixture is cooled and filtered to obtain a solid resinous substance. This solid is washed EtOH and Et2O, dried in vacuum and received hydrochloric acid salt in the form of a solid light brown color. The free base was obtained by dissolving the salt in 50 ml of water and processing of 10%NaOH solution. Next, the aqueous suspension to the centered dryness, and the residue was treated with CHCl3. The salts were removed by filtration; the filtrate was concentrated and received 3,82 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine in the form of a powder, yellowish-brown.

The data of mass spectrometry MS: 330 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ 8,10 (d, J=8,1 Hz, 1H); 7,66 (d, J=8,2 Hz, 1H); 7,40 (m, 1H); 7,25 (m, 1H); 6,88 (MS, 2H); 4,78 (t, J=5.4 Hz, 2H); to 3.89 (t, J=4,8 Hz, 2H); of 3.84 (t, J=6.9 Hz, 2H); of 3.54 (t, J=5.4 Hz, 2H); 3,31 (s, 3H); 3,23 (t, J=6.6 Hz, 2H); is 2.88 (t, J=5.3 Hz, 2H).

Part of It

1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (750 mg, 2,28 mmole) was dissolved in 30 ml anhydrous CH2Cl2and cooled to 0°C in nitrogen atmosphere. To the reaction mass added phenylisocyanate (247 μl, 2.28 mmol) and Et3N (of 0.64 ml, 4,56 mmol) and gave the system to slowly warm to room temperature. After 2-hour stirring, the reaction mixture was concentrated under reduced pressure and the obtained solid yellow color. This substance was dissolved in minimum amount of CH2Cl2after which was added EtOAc until the turbidity of the solution. This mixture is put in the freezer over night; in the formed white crystals. The crystals were separated by filtration and dried under vacuum; received 126 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-FeNi is urea. Melting point 171,0-174,0°C.

The data of mass spectrometry MS: 449 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ and 8.50 (s, 1H); with 8.05 (d, J=7.7 Hz, 1H); a 7.62 (d, J=8,8 Hz, 1H); 7,44-to 7.18 (m, 3H); 7,27-to 7.18 (m, 3H); to 6.88 (t, J=7,3 Hz, 1H); is 6.54 (s, 2H); 6,12 (t, J=5.5 Hz, 2H); was 4.76 (t, J=4,8 Hz, 2H); 3,88 (t, J=5.3 Hz, 2H); 3,81 (t, J=6,7 Hz, 2H); 3.40 in (t, J=6.0 Hz, 2H); or 3.28 (s, 3H); 3.25 to 3,14 (m, 4H).

Data13With NMR (75 MHz, DMSO-d6): δ 155,5; 152,0; 144,9; 140,8; 132,7; 129,0; 126,8; 126,5; 121,5; 121,4; 120,5; 117,9; 115,1; 70,5; 69,4; 58,4; 45,5; 27,6.

The data of elemental analysis: Calculated for C24H28N6About3.0,21 N2ABOUT: WITH 63,73%, N 6,33%, N 18,58%. Found: 63,33%, N 6,28%, N 18,67%.

Example 2

N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-prilocaine

Part a

1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (10.0 g, 27,3 mmol) was dissolved in 50 ml triperoxonane acid and processed PtO2(1.0 g). The reaction mixture was shaken in an atmosphere of hydrogen (3 bar). After 4 days, the added amount of PtO2(0.5 g) and continued to hydrogenation for 3 days. The reaction mixture was filtered through celite and concentrated under reduced pressure, obtaining an oily brown liquid. The liquid was dissolved in 200 ml of water and gave the solution of the basic reaction (pH˜11) by adding 10%RA the creators of NaOH. After extraction with CHCl3(5×75 ml) the combined organic layers were dried over Na2SO4and concentrated, obtaining of 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine in the form of a solid, yellowish-brown.

The data of mass spectrometry MS: 334 (M+N)+.

Data1H NMR (300 MHz, CDCl3): δ 5,19 (s, 2H); of 4.49 (t, J=5.4 Hz, 2H); of 3.84 (t, J=6.6 Hz, 2H); 3,71 (t, J=5.4 Hz, 2H); to 3.36 (t, J=5,2 Hz, 2H); 3,51 (s, 3H); 3.15 in (t, J=6.6 Hz, 2H); 2.95 and (m, 2H); 2,82 (m, 2H); was 2.76 (t, J=a 5.1 Hz, 2H); of 1.84 (m, 4H); 1,47 (CL, 2H).

Part b

1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine (919 mg, was 2.76 mmole) was dissolved in 30 ml anhydrous CH2Cl2and cooled to 0°C in nitrogen atmosphere. Later in the reaction mixture is added phenylisocyanate (300 μl, was 2.76 mmole) and Et3N (of 0.77 ml, 5,51 mmole); the mixture gave to slowly warm to room temperature. After mixing, which lasted all night, the reaction was stopped by adding a saturated solution of NaHCO3(30 ml). The organic layer was separated and washed with water and brine, dried over Na2SO4and concentrated under reduced pressure to obtain solid yellow color. This substance is rubbed with Et2O (30 ml)to which was added a few drops of the Meon. The solid product was separated by filtration and dried under vacuum, the floor is Yves 460 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-prilocaine in the form of a white powder. Melting point 180-182°C.

The data of mass spectrometry MS: 453 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ 8,51 (s, 1H); 7,37 (d, J=7.7 Hz, 2H); 7,19 (t, J=8,2 Hz, 2H); 6,86 (t, J=7.7 Hz, 1H); 6,11 (t, J=5.5 Hz, 2H); 5,70 (s, 2H); 4,43 (t, J=5,1 Hz, 2H); 3,78 at 3.69 (m, 4H); 3,39 (t, J=5.6 Hz, 2H); of 3.25 (s, 3H); 3,19 (m, 2H); 3,10 (t, J=6,8 Hz, 2H); 2.91 in (m, 2H); of 2.64 (m, 2H); 1,72 (m, 4H).

Data13With NMR (75 MHz, DMSO-d6): δ 155,5; 151,3; 149,3; 146,3; 140,8; 138,5; 129,0; 125,0; 121,4; 118,0; 105,6; 70,6; 70,5; 70,4; 58,4; 44,6; 39,2; 32,7; 27,6; 23,8; 23,1; 23,0.

The data of elemental analysis: Calculated for C24H32N6About3: 63,70%, N 7,13%, N A 18.57%. Found: 63,33%, H 7.16 Percent, N 18,66%.

Example 3

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methyl-N'-prilocaine

Part a

Sodium hydride (60%dispersion in oil, 9,1 g, 228 mmol) was placed in a round bottom flask and washed with hexane (3×) in nitrogen atmosphere. Dried sodium hydride was dissolved in 800 ml of anhydrous THF. To a stirred solution of sodium hydride was added over 40 minutes a solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (41,9 g, 182 mmol). Upon completion of addition the reaction mixture was stirred for 20 min, then added methyliodide (to 13.6 ml, 218 mmol). After mixing, which lasted all night, the reaction was stopped by adding 300 ml of a saturated solution of NaHCO3. Later in reactio the ing the mixture is brought to 200 ml of water and 1 l Et 2O. the Organic phase was separated and washed with water and brine. The organic portion was dried over MgSO4and concentrated under reduced pressure, obtaining a 41.9 g of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate in the form of a yellow liquid.

Part b

A solution of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41,9 g, 170 mmol) in 600 ml Meon was treated with 2.5 g of Pd (10%on carbon, shaking in an atmosphere of hydrogen (3 bar) for 24 hours. Then, the solution was filtered through celite and concentrated to obtain 37,2 crude tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate in the form of liquid light yellow color.

The part With

In a nitrogen atmosphere to a solution of 4-chloro-3-nitroquinoline (32,3 g, 155 mmol) in 400 ml of anhydrous CH2Cl2added with stirring triethylamine (43,1 ml, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37,2 g, 171 mmol). After stirring over night the reaction mixture was washed with water (2×300 ml) and brine (300 ml). The organic portion was dried over Na2SO4and concentrated, obtaining an oily brown liquid. After cleaning method chromatography on a column (SiO2, elution with a mixture of ethyl acetate-hexane from 33 to 67%) got to 46.7 g of tert-butylmethyl(2-{2-[(3-nitroanilin-4-yl)amino]ethoxy}ethyl)carbamate in the form of a solid yellow color.

Part D

The solution t is et-butylmethyl(2-{2-[(3-nitroanilin-4-yl)amino]ethoxy}ethyl)carbamate (6,56 g, is 16.8 mmole) in 75 ml of toluene was treated with 0.5 g of Pt (5%) on carbon, shaking in an atmosphere of hydrogen (3 bar) for 24 hours. The solution was filtered through celite and concentrated, obtaining the crude tert-butyl 2-{2-[(3-aminoquinoline-4-yl)amino]ethoxy}ethyl(methyl)carbamate in the form of a syrupy liquid orange. The product was used without further purification.

Part E.

A solution of tert-butyl 2-{2-[(3-aminoquinoline-4-yl)amino]ethoxy}ethyl(methyl)carbamate (6,05 g, a 16.8 mmole) in 200 ml anhydrous CH2Cl2was cooled to 0°C and treated with triethylamine (of 2.40 ml, 17.2 mmole). Next was added dropwise methoxypropionitrile (1,72 ml, 17.2 mmole) within 5 min. the Reaction mixture was heated to room temperature and stirring continued for another 3 hours. Next, the reaction mixture was concentrated under reduced pressure to obtain solid orange color. This substance was dissolved in 200 ml EtoH and added to 7.2 ml of triethylamine. The mixture was heated under reflux with stirring overnight under nitrogen atmosphere. Then the reaction mixture was concentrated to dryness under reduced pressure and treated with 300 ml of Et2O. the mixture was filtered; the filtrate was concentrated under reduced pressure to obtain solid brown color. This substance was dissolved in 300 ml of CH2Cl2ipromise water and brine. The organic portion was dried over Na2SO4and concentrated, obtaining an oily brown liquid. This liquid was dissolved in 100 ml of hot Meon and treated with activated charcoal. The hot solution was filtered and concentrated, obtaining 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate in the form of a syrupy liquid yellow color.

Part F

A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate (7.20 g, a 16.8 mmole) in 200 ml of CH2Cl2was treated with 3-chloroperoxybenzoic acid (77%, 4,32 g, and 19.3 mmole). After stirring for 6 hours the reaction mixture was treated with saturated solution of NaHCO3and he divided the formed layers. The organic portion was washed with water and brine, dried over Na2SO4and concentrated, obtaining 7,05 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate in the form of a solid light brown color.

Part G

A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate (7,05 g, 15.9 mmole) in 100 ml of 1,2-dichloroethane was heated to 80°and treated with 5 ml of concentrated solution of NH4OH. With rapid stirring, to the solution was added solid n-toluensulfonate (3.33 g, 17,mmol) for 10 minutes Next, to the reaction mixture was added an additional amount of concentrated solution of NH4OH (5 ml) and placed the mixture in the autoclave; the heating is continued for 4 hours. Next, the reaction mixture is cooled and treated with 100 ml of CH2Cl2. After the reaction mixture was washed with water, 1%solution of Na2CO3(3×) and brine. The organic portion was dried over Na2SO4and concentrated, obtaining 6.50 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate in the form of an oily liquid brown.

Part N

Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl(methyl)carbamate (6.50 g, 14.7 mmole) was dissolved in 100 ml EtOH and treated with 20 ml of 2M HCl solution in EtOH; the mixture was heated under reflux with stirring. After 6 hours the reaction mixture is cooled and filtered, obtaining a resinous substance. This substance is washed EtOH and Et2O and dried under vacuum, obtaining hydrochloric acid salt in the form of powder light brown. The free base was obtained by dissolving the salt in 50 ml of water and the treatment of 5 ml of concentrated NH4OH. The aqueous suspension was extracted with CH2Cl2(5×50 ml). The combined organic layers were dried over Na2SO4and concentrated, obtaining 3,93 g 2-(2-methoxy what Teal)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine in the form of powder light brown color.

The data of mass spectrometry MS: 344 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ 8,07 (d, J=7.7 Hz, 1H); a 7.62 (DD, J=1,0; 8,3 Hz, 1H);7,42(DDD, J=1,0; 7,1;8,2 Hz, 1 H); 7,22 (DDD, J=1,1; 7,1; 8,2 Hz, 1H); of 6.49 (s, 2H); 4.75 V (t, J=5,1 Hz, 2H); 3,83 (t, J=6,8 Hz, 4H); 3,35 (t, J=5.6 Hz, 2H); 3,30 (s, 3H); is 3.21 (t, J=6.9 Hz, 2H); of 2.45 (t, J=5.6 Hz, 2H); 2,12 (s, 3H).

Part I

2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-finalen-4-amine (929 mg, 2,71 mmole) was dissolved in 30 ml anhydrous CH2Cl2and was treated with phenylisocyanate (300 μl, was 2.76 mmole). After stirring overnight under nitrogen atmosphere the reaction mixture was concentrated under reduced pressure. When cleaning method chromatography on a column (SiO2, eluent 3%solution Meon in CHCl3saturated aqueous solution of NH4OH) received the product in a solid white color. Crystallization from a mixture of N2O-Meon received 610 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl-N-methyl-N'-prilocaine as white scaly crystals. Melting point 184,8-185,8°C.

The data of mass spectrometry MS: 463 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ is 8.16 (s, 1H); of 8.06 (d, J=7.7 Hz, 1H); to 7.61 (DD, J=1,0; 8,3 Hz, 1H); 7,43-7,38 (m, 3H); 7,25-7,17 (m, 3H); 6,91 (t, J=7,3 Hz, 1H); 6,47 (s, 2H); was 4.76 (t, J=5.0 Hz, 2H); 3,88 (t, J=5,1 Hz, 2H); of 3.78 (t, J=6,8 Hz, 2H); of 3.48(t, J=5,2 Hz, 2H); 3,39 (t, J=5.4 Hz, 2H); with 3.27 (s, 3H); 3,20 (t, J=6,8 Hz, 2H); 2.82 from (s, 3H).

Data 13With NMR (75 MHz, DMSO-d6): δ 155,6; 152,0; 151,9; 145,1; 140,9; 132,7; 128,5; 126,7; 126,6; 122,0; 121,4; 120,5; 120,1; 115,1; 70,5; 69,6; 69,4; 58,4; 47,7; 45,5; 35,4; 27,6.

The data of elemental analysis: Calculated for C25H30N6O3.0,12 H2O 64,62%, N 6,56%, N 18,08%. Found: 64,69%, N Of 6.65%, N 18,09%.

Example 4

N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methyl-N'-prilocaine

Part a

2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine (4,22 g, 12.3 mmole) was dissolved in 25 ml triperoxonane acid and processed PtO2(0.5 g). The reaction mixture was shaken in an atmosphere of hydrogen (3 bar). After 4 days added an additional amount of PtO3(0.5 g) and continued to hydrogenation for 3 days. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain oily liquid yellow. This liquid was dissolved in 50 ml of water and was Proektirovanie 50 ml CHCl3. The organic portion was separated and discarded. Water part gave the basic reaction (pH approx. 12), adding 10%NaOH solution. Then spent the extraction CHCl3(6×50 ml) and the combined organic layers were dried over Na2SO4and concentrated, obtaining an oily brown liquid. This liquid was dissolved in 100 ml of hot MeO and was treated with 1 g of activated charcoal. The hot solution was filtered through celite and concentrated to dryness. The obtained resinous substance was planted several times from Et2O; product 2-(2-methoxyethyl)-1-{2-[2- (methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine(3,19 g) in the form of a powder almost white.

The data of mass spectrometry MS: 348 (M+N)+.

Data1H NMR (300 MHz, CDCl3): δ 4,84 (s, 2 H); 4,48 (t, J=5.7 Hz, 2 H); a-3.84 (t, J=6,7 Hz, 2H); 3,70 (t, J=5.7 Hz, 2H); 3.46 in (t, J=5,1 Hz, 2H); to 3.36 (s, 3H); 3,14 (t, J=6,7 Hz, 2H); 2,96 (m, 2H); and 2.83 (m, 2H); to 2.65 (t, J=5,1 Hz, 2H); of 2.36 (s, 3H); of 1.85 (m, 4H).

Part b

2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine (750 mg, of 2.16 mmole) was dissolved in 30 ml anhydrous CH2Cl2and was treated with phenylisocyanate (239 μl, of 2.20 mmole). After stirring overnight under nitrogen atmosphere the reaction mixture was concentrated under reduced pressure. Crystallization from a mixture of EtOAc-CH2Cl2got 170 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl-N-methyl-N'-prilocaine as white fluffy crystals. Melting point 167,7-170,0°C.

The data of mass spectrometry MS: 467 (M+N)+.

Data1H NMR (300 MHz, DMSO-d6): δ 8,17 (s, 1H); the 7.43 (d, J=7,6 Hz, 2H); 7,21 (t, J=7.9 Hz, 2H); 6,91 (t, J=7,3 Hz, 1H); the 5.65 (s, 2H); 4,43 (t, J=5.0 Hz, 2H); and 3.72 (t, J=7,0 Hz, 2H); 3,70 (t, J=5,2 Hz, 2H); 3.46 in-to 3.41 (m, 4H); 3,24, 3H); of 3.07(t, J=6.9 Hz, 2H); 2,92 (m, 2H); 2,85 (s, 3H); of 2.64 (m, 2H); 1,72 (m, 4H).

Data13With NMR (75 MHz, DMSO-d6): δ 155,6; 151,2; 149,3; 146,3; 140,9; 138,4; 128,5; 124,9; 122,0; 120,1; 105,5; 70,7; 70,5; 69,5; 58,4; 48,0; 44,6; 35,5; 32,8; 27,6; 23,8; 23,1; 23,0.

The data of elemental analysis: Calculated for C25H34N6About3: 64,36%, N 7,35%, N TO 18.01%. Found: 64,04%, N 7,38%, N 18,02%.

Example 5

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)morpholine-4-carboxamide

In nitrogen atmosphere 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (0.75 g, 2.3 mmole) was dissolved in dichloromethane (30 ml) and triethylamine (of 0.64 ml, 4.6 mmole) with gentle heating and vigorous stirring. The solution was cooled in a bath of ice water, after which the solution dropwise introduced 4-morpholinylcarbonyl (0,27 ml, 2.3 mmole). The cooling bath was removed and continued stirring for another 4 hours. The reaction was stopped by adding a saturated solution of sodium bicarbonate (25 ml). After phase separation the organic layer was washed with water (3×25 ml) and brine (25 ml), dried over Na2SO4was filtered and concentrated, obtaining a yellow foam. Product recrystallization from a mixture of dichloromethane and ethyl acetate. Crystals of the product triturated with ether (2×5 ml) to remove residual amounts of solvent. After drying in vacuum the furnace Oh has received 200 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)morpholine-4-carboxamide in the form of a crystalline substance of a yellowish-brown color.

Data1H NMR (300 MHz, DMSO-d6): δ of 8.06 (d, J=8,1 Hz, 1H); to 7.61 (d, J=7,3 Hz, 1H); 7,42 (t, J=7.2 Hz, 1H); 7.23 percent (t, J=7.8 Hz, 1H); 6,51 (s, 2H); 6,33 (t, J=5.0 Hz, 1H); 4,74 (t, J=4.3 Hz, 2H); 3,85-3,81 (m, 4H); 3.49 points (t, J=the 4.3 Hz, 4H); to 3.33 (t, J=5,9 Hz, 2H); 3,30 (s, 3H); is 3.21 (t, J=6,8 Hz, 2H); 3,14 (t, J=4.5 Hz, 4H); is 3.08 (t, J=6.0 Hz, 2H).

Data13With NMR (75 MHz, DMSO-d6): δ 157,8; 151,9; 145,0; 132,7; 126,7; 126,6; 121,4; 120,5; 115,1; 70,4; 70,2; 69,2; 58,4; 45,5; 44,0; 27,6.

The data of elemental analysis: Calculated for C22H30N6O4: 59,71%, N 6.83 per cent, N 18.99%. Found: 59,71%, N 6.80 Per Cent, N 18,78%.

The data of mass spectrometry MS: 443 (M+H).

Example 6

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-M-methylmorpholin-4-carboxamid

In nitrogen atmosphere 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-C]quinoline-4-amine (802 mg, of 2.34 mmole) was dissolved in 30 ml anhydrous CH2Cl2and cooled to 0°C. With stirring was added Et3N (0,65 ml, and 4.68 mmol) and morpholinylcarbonyl (273 μl, of 2.34 mmole); the reaction mixture is left overnight to warm up to room temperature. The reaction was stopped by adding a saturated solution of NaHCO3(30 ml) and CH2Cl2(30 ml). The organic layer after separation was washed with water and brine, dried over Na2SO4and concentrated under reduced pressure. When cleaning method chromatography on a column (SiO2e is went 2-5%solution Meon in CHCl 3saturated aqueous solution of NH4OH) received the product as a colourless foam. Crystallization from EtOAc received 640 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl-N-methylmorpholin-4-carboxamide as white crystals. The melting temperature level of 121.8-122,3°C.

The data of mass spectrometry MS: 457 (M+N)+.

Data1H NMR (500 MHz, DMSO-d6): δ of 8.06 (DD, J=0,9; 8,3 Hz, 1H); to 7.61 (DD, J=1,1; 8,3 Hz, 1H); 7,41 (DDD, J=1,2; 7,0; 8,3 Hz, 1H); 7,22 (DDD, J=1,3; 7,0; 8,1 Hz, 1H); 6,44 (s, 2H); 4,74 (t, J=5,2 Hz, 2H); of 3.84 (t, J=5,2 Hz, 2H); 3,82 (t, J=6,9 Hz, 2H); 3,50-of 3.43 (m, 6N); 3,30 (s, 3H); 3,20 (t, J=6.9 Hz, 2H); and 3.16 (t, J=5.5 Hz, 2H); is 2.88 (t, J=4,7 Hz, 4H); at 2.59 (s, 3H).

Data13With NMR (75 MHz, DMSO-d6): δ 163,8; 152,0; 151,8; 145,2; 132,7; 126,7; 121,3; 120,6; 115,1; 70,4; 69,4; 68,9; 66,1; 58,5; 49,1; 47,3; 45,5; 36,9; 27,7.

The data of elemental analysis: Calculated for C23H32N6O4: 60,51%, N 7,07%, N 18,41%. Found: 60,56%, N 6,85%, N 18,19%.

Examples 7-21

Part a

A solution of tert-butyl 2-{2-[(3-aminoquinoline-4-yl)amino]ethoxy}ethylcarbamate (of 3.46 g, 10.0 mmole) in 50 ml of toluene was treated with triethylorthoformate (2.5 ml, 14.5 mmole) and the reaction mixture were heated under reflux. Further added 25 mg of pyridinecarboxamide and the reflux continued for another 4 h, the Reaction mixture was concentrated to dryness under reduced pressure. The product was dissolved in 50 ml of CH2Cl2and washed the feast upon the s ' solution of NaHCO 3, water and brine. The organic portion was dried over Na2SO4and concentrated, obtaining oily liquid green. This liquid was dissolved in 50 ml of hot Meon and treated with activated charcoal. The hot solution was filtered and concentrated, obtaining 4.12 g of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate in the form of an oily liquid yellow color.

Part b

A solution of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 ml of CH2Cl2processed 3-chloroperoxybenzoic acid (77%, 2.5 g, 11.2 mmole). After stirring for 5 hours the reaction mixture was treated with saturated solution of NaHCO3and separated the layers. The organic portion was washed with water and brine, dried over NaSO4and concentrated, obtaining 3,68 g of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate foam light brown color.

The part With

A solution of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (3,68 g, 8.60 mmol) in 100 ml of 1,2-dichloroethane was heated to 80°and treated with 10 ml of concentrated solution of NH4OH. With rapid stirring solution was added solid n-toluensulfonate (1,87 g, 9,81 mmole) for 10 minutes, the Reaction mixture was placed in an autoclave and heating was continued is still within 2 hours. After that, the reaction mixture is cooled and treated with 100 ml of CH2Cl2. Next, the reaction mixture was washed with water, 1%solution of Na2CO2(3×) and brine. The organic portion was dried over Na2SO4and concentrated, obtaining 3,68 g of tert-butyl 2-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate foam light brown color.

Part D

Tert-butyl 2-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (3,68 g, 8.60 mmol) suspended in 20 ml of 2M HCl solution in EtOH and the suspension was heated under reflux with stirring. After 3 hours the reaction mixture was concentrated, obtaining a solid residue. The residue is triturated with hot EtOH (50 ml) and filtered, obtaining 2,90 g of the product in the form of muriate. The free base was obtained by dissolving the salt in 50 ml of water and the treatment of 5 ml of concentrated NH2HE. This aqueous suspension was extracted with CH2Cl2(3×50 ml). The combined organic layers were dried over Na2SO4and concentrated, obtaining 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine in the form of a powder, yellowish-brown.

The data of mass spectrometry MS: 328 (M+N)+.

Data1H NMR (300 MHz, CDCl3): δ to 7.95 (d, J=8,3 Hz, 1H); 7,83 (d, J=8,4 Hz, 1H); to 7.50 (m, 1H); 7,30 (m, 1H); 5,41 (s, 2H); 4,69 (t, J=5.6 Hz, 2H); 3,93 (t, J=5.6 Hz, 2H); 3,39 (who, J=5,1 Hz, 2H); of 2.97 (t, J=7.9 Hz, 2H); was 2.76 (t, J=5,1 Hz, 2H); 1,89 (m, 2H); of 1.52 (m, 2H); 1.26 in (MS, 2H); of 1.01 (t, J=7,3 Hz, 3H).

Part E.

The compounds listed in the following table 1 were prepared in stage (7) process (scheme 1 reaction) (see above) with the following General principles.

Isocyanate (84 mmol) was introduced into a test tube with a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (25 mg, 76 mcmole) in dichloromethane (5 ml). The tube was closed and placed in the apparatus for shaking at ambient temperature; the shaking continued for 20 hours. The solvent was removed by vacuum centrifugation. The residue was purified by way prepreparation HPLC; details of the procedures described above. The table below shows the structure of the free base and data on observed exact mass (M+H).

Table 1
Number exampleThe structure of the free baseExact mass (observed)
7413.2644
8427.2841
9427.2823
10447.2496

Number exampleThe structure of the free baseExact mass (observed)
11441.2638
12453.2980
13472.2457
14477.2611

Number exampleThe structure of the free baseExact mass (observed)
15487.2804
16490.2919
17493.2386
18207.2741

Number exampleThe structure of the free baseExact mass (observed)
19511.2120
20 525.2280
21545.1758

Examples 22-36

Part a

Taking into account common method described in part a for Examples 7-21, spent the reaction between 4-piperidinemethanol (10 g, 77.4 mmol) and di-tert-BUTYLCARBAMATE (17,7 g, 81,3 mmole)gain of 13.1 g of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate in the form of transparent oily liquid.

Part b

To a solution of imidazole (3,89 g, 57,1 mmole) and triphenylphosphine (14,98 g, 57,1 mmole) in dichloromethane (350 ml) was added iodine (of 7.97 g) in three portions. After 5 min was introduced a solution of the product obtained in part a, in dichloromethane (70 ml). The reaction mixture was stirred at ambient temperature overnight. Further added an additional amount of iodine (7,97 g) and stirring at ambient temperature was continued for 1 hour. The reaction mixture was washed with saturated solution of sodium thiosulfate (2×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, obtaining an oily residue. The residue was purified by way of chromatography on a column (silica gel, eluent 20%solution of ethyl acetate in hexane)with 15,52 g of tert-butyl 4-(2-codetel)piperidine-1-carboxylate in the form of an oily liquid light yellow color.

The part With

p> In nitrogen atmosphere 2-(1H-imidazo[4,5-C]quinoline-1-yl)butane-1-ol (6.5 g, 26.9 mmole) was added in three portions to a suspension of sodium hydride (1.4 g, 60%, 35,0 mmol) in anhydrous N,N-dimethylformamide. The reaction mass was stirred for 45 min; by the end of this period, the evolution of gas has ended. Dropwise added tert-butyl 4-(2-codetel)piperidine-1-carboxylate (of 10.05 g of 29.6 mmole) for 15 minutes the Reaction mixture was stirred at ambient temperature for 2.5 hours; next, the mass was heated to 100°and left under stirring overnight. The analysis method HPLC showed that the reaction was completed by approximately 35%. In the mixture introduced a saturated solution of ammonium chloride and the resulting mixture was stirred for 20 min, and then held the extraction with ethyl acetate (2×). The obtained extracts were washed with water (2×) and brine, combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure, obtaining an oily brown liquid. This liquid was purified by the method chromatography on a column (silica gel; was suirable consistently 30%solution of ethyl acetate in hexane, 50%solution of ethyl acetate in hexane and ethyl acetate), obtaining 2.2 g of tert-butyl 4-{2-[2-(1H-imidazo[4,5-C]quinoline-1-yl)butoxy]ethyl}piperidine-1-carboxylate.

Part D

Taking into account common method described in H is STI N for Examples 7-21, oxidized product of Part C, having tert-butyl 4-{2-[2-(5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)butoxy]ethyl}piperidine-1-carboxylate in the form of an oily liquid.

Part E.

The ammonium hydroxide solution (20 ml) was added to a solution of the product of Part D in dichloromethane (20 ml). Further added a solution of tosylchloramide (0,99 g, 5.2 mmole) in dichloromethane (10 ml) for 5 min Obtained two-phase reaction mixture is left overnight under stirring. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution. After separation of the layers the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure, obtaining a glassy mass of brown. This mass was purified by the method chromatography on a column (silica gel; was suirable consistently 50%solution of ethyl acetate in hexane and ethyl acetate), obtaining 1.0 g of tert-butyl 4-{2-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butoxy]ethyl}piperidine-1-carboxylate in the form of a glassy foam yellow color.

Part F

In nitrogen atmosphere tert-butyl 4-{2-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1,00 g, 2.1 mmole) was mixed with 2 N hydrochloric acid solution in ethanol (10 ml, 20 mmol); the solution was stirred at ambient temperature for 14 hours. The solvent was removed under vacuum and the resulting solid in the form of yellowish-brown color dissolved in water. Next was added a saturated aqueous solution of sodium carbonate to achieve a pH of 10. After extraction with dichloromethane (3×) the organic fractions were combined, washed with brine, dried (Na2SO4), filtered, and removed a large part of the solvent by vacuum processing. Further added hexane, which led to the formation of a precipitate. After vacuum filtering received 0.5 g of 1-{1-[(2-piperidine-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine in the form of a powder, yellowish-brown.

Data1H NMR (300 MHz, DMSO-d6): δ a 8.34 (SHS, 1H); 8,19 (d, J=8,49 Hz, 1H); to 7.61 (DD, J=8,31; 1.13 Hz, 1H); 7,45-7,39 (m, 1H); 7,25-7,19 (m, 1H); 6,55 (s, 2H); 5.25 to further 5.15 (m, 1H); 4,00-of 3.80 (m, 2H); 3,5-3,3 (m, 2H); 2,8-of 2.64 (m, 2H); 2,22-2,11 (m, 2H); 2,09 of 1.99 (m, 2H); 1,8-1,63 (SHS, 1H); 1,37-1,0 (m, 5H); 0,95-0,7 (m, 5H).

Data13With NMR (75 MHz, DMSO-d6): (152,8; 145,8; 140,6; 133,0; 127,8; 127,0; 126,9; 121,3; 121,0; 115,5; 71,8; 68,1; 58,4; 46,1; 36,3; 33,1; 32,7; 24,5; 9,9.

The data of mass spectrometry MS(CI): m/e 368,2459 (368,2450 in the calculation for C21H30N50).

Part G

The compounds listed in the following table 2, were prepared in accordance with stage (7) process (scheme I, reaction) (see above) with the following General principles.

Isocyanate or isothiocyanate (75 mcmole) was introduced into a test tube with a solution of 1-{1-[(2-piperidine-4-ylethoxy)methyl]propyl}-1H-imidazo[4,5-C]quinoline-4-amine (25 mg, 68 μmol) in dichloromethane (5 ml). The tube was closed and placed the in the machine shaking when the ambient temperature; the shaking continued for 20 hours. The solvent was removed by vacuum centrifugation. The residue was purified by way prepreparation HPLC; details of the procedures described above. The table below shows the structure of the free base and data on observed exact mass (M+H).

Table 2
Number exampleThe structure of the free baseExact mass (observed)
22453.2983
23467.3138
24487.2787
25481.2930

Number exampleThe structure of the free baseExact mass (observed)
26493.3270
27512.2757
28517.2907
29 527.3112

Number exampleThe structure of the free baseExact mass (observed)
30529.2911
31533.2704
32547.3032
33565.2641

Number exampleThe structure of the free baseExact mass (observed)
34585.2056
35521.2297
36503.2589

Examples 37-44

Part a

A solution of tert-butyl 2-{2-[(3-aminoquinoline-4-yl)amino]ethoxy}ethylcarbamate (6,92 g, 20.0 mmol) in 100 ml of toluene was treated with triethylorthoformate (4,65 ml of 28.0 mmol)and the reaction mixture were heated under reflux. Next added 100 mg of pyridinecarboxamide and the reflux continued for another 2 h the owls. The reaction mixture was concentrated to dryness under reduced pressure. The product was dissolved in 200 ml of CH2Cl2and washed with saturated solution of NaHCO3, water and brine. The organic portion was dried over Na2SO4and concentrated, obtaining oily liquid green. This liquid was dissolved in 200 ml of hot Meon and treated with activated charcoal (10 g). The hot solution was filtered and concentrated, obtaining a 5.25 g of tert-butyl 2-[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate in the form of an oily liquid light yellow color.

Part b

A solution of tert-butyl 2-[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (5,25 g, 14.7 mmol) in 200 ml of CH2Cl2processed 3-chloroperoxybenzoic acid (77%, 3,63 g, 16.3 mmole). After stirring over night the reaction mixture was treated with saturated solution of NaHCO3and separated the layers. The organic portion was washed with water and brine, dried over Na2SO4and concentrated, obtaining 4,60 g of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate foam light brown color.

The part With

A solution of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (4,60 g, 12.4 mmole) in 150 ml of 1,2-dichloroethane was heated to 80°and treated with 10 ml of concentrated solution of NH4OH. With rapid stirring to relax is whether solid p-toluensulfonate (2,71 g, 14.2 mmole) for 10 minutes, the Reaction mixture was treated with an additional amount (2 ml) of concentrated solution of NH4OH, and placed in the autoclave; heating was continued for another 3 hours. After that, the reaction mixture is cooled and treated with 100 ml of CH2Cl2. Next, the reaction mixture was washed with water, 1%solution of Na2CO3(3×) and brine. The organic portion was dried over Na2SO4and concentrated, obtaining 4,56 g of tert-butyl 2-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate foam light brown color.

Part D

Tert-butyl 2-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethoxy]ethylcarbamate (4,56 g, 12.3 mmol) was dissolved in 100 ml EtOH and treated with 30 ml of a 2 M solution of HCl in EtOH. The mixture was heated under reflux with stirring. After 3 hours the reaction mixture was concentrated, obtaining a solid residue. The residue is triturated with hot EtOH (100 ml) and filtered, after getting the product in the form of muriate. The free base was obtained by dissolving the salt in 50 ml of water and the treatment of 5 ml of concentrated NH4OH. This aqueous suspension was extracted with CH2Cl2(5×50 ml). The combined organic layers were dried over Na2SO4and concentrated, obtaining 1.35 g of 1-[2-(2-aminoethoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine in the form of a powder, yellowish-brown.

The data of mass spectrometry MS: 272 (M+N)+.

Data1H NMR (300 MHz, CDCl3): δ 7,98 (d, J=8,2 Hz, 1H); 7,88 (d, J=8,4 Hz, 1H); to 7.84 (d, J=8,4 Hz, 1H); rate of 7.54 (m, 1 H); 7,32 (m, 1 H); 5,43 (s, 2 H); 4,74 (t, J=5,2 Hz, 2 H); of 3.97 (t, J=5,2 Hz, 2 H); 3.42 points (t, J=5,1 Hz, 2 H); 2,78 (t, J=5,1 Hz, 2H); 1,10 (CL, 2H).

Part E.

The compounds listed in the following table 3 were prepared in accordance with stage (7) process (scheme 1 reaction) (see above) with the following General principles.

1-[2-(2-Aminoethoxy)ethyl]-1H-imidazo[4,5-C]quinoline-4-amine (20 mg, 74 mcmole) mixed in vitro with 1-methyl-2-pyrrolidone (5 ml) and prepared a solution by ultrasonic irradiation during heating. Next was added the isocyanate (81 mcmole), the tube was closed and placed in the apparatus for shaking at ambient temperature; the shaking continued for 20 hours. The solvent was removed by vacuum centrifugation. The residue was purified by way prepreparation HPLC; details of the procedures described above. The table below shows the structure of the free base and data on observed exact mass (M+H).

Table 3.
Number exampleThe structure of the free baseExact mass (observed)
37371.2204
38391.1884
39397.2373
40416.1844

Number exampleThe structure of the free baseExact mass (observed)
41421.1946
42431.2206
43451.2115
44455.1513

STIMULATION of CYTOKINE SYNTHESIS IN HUMAN CELLS

To assess the kinetics of stimulation of cytokine synthesis using in-vitro with human blood cells. The synthesis activity is measured by the number of interferon and tumor necrosis factor (α) (if and TNF, respectively)secreted into the culture medium, as described by Testerman and others (Testerman et al., Cytokine Induction by the Immunomodulators Imiquimod and S-27609, Journal of Leukocyte Biology, 58, 365-372, September, 1995).

Preparation of blood cells to grow in culture medium

Whole blood taken from a healthy donor is in from Vienna, placed in evacuated tubes containing EDTU. Mononuclear cells from peripheral blood (OKC) are separated from whole blood by centrifugation in a density gradient using reagent Histopaque®-1077. OKC washed twice with balanced salt solution Hank and then suspended in number (3-4)×106cells/ml in complete RPMI medium. Suspension OKC contribute on a flat sterile tablets for tissue culture with 48 wells (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ); in the wells contained an equal volume of complete RPMI medium containing the analyzed connection.

The preparation of the compounds

Connection solubilizer in dimethyl sulfoxide (DMSO). The concentration of DMSO should not exceed the final value (1%) adding in the hole.

Incubation

A solution of the compound injected into the first well containing complete RPMI medium, and the remaining holes are conducting serial dilution. Next, add the suspension OKC in equal volumes, receiving the desired range of concentrations of the investigated compounds. The final concentration of the suspension OKC is (1,5-2)×106cells/ml Tablet cover with a sterile plastic lids, gently mixed and incubated for 18-24 hours at 37 ° °C in an atmosphere containing 5% carbon dioxide.

Division

After the Incubus is the tablets centrifuged for 5-10 min at a speed of 1000 rpm -1(approx. 200 g) and a temperature of 4°C. the Supernatant, containing no cells were removed with a sterile polypropylene pipette and transferred to sterile polypropylene tubes. Samples stored until analysis at a temperature of from -30 to -70°C. Perform tests on interferon (α) and tumor necrosis factor (α) by the way ELIZA.

Analyses on interferon (α) and tumor necrosis factor (α) by the way ELIZA

The concentration of interferon (α) was determined using a set of ELIZA called Human Multi-Species Kit manufactured by PBL Biomedical Laboratories, New Brunswick, NJ. The results were expressed in PG/ml.

The concentration of tumor necrosis factor (α) (TNF) was determined using sets ELIZA production companies Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; Pharmingen, San Diego, CA. The results were expressed in PG/ml.

The following table 4 gives the lowest concentration that has been found to stimulate the synthesis of interferon and stimulate the synthesis of tumor necrosis factor for each connection. The asterisk * means that the stimulation was not observed at any concentration of the studied compounds. In General, the highest investigated concentration was 10-30 microns.

Table 4.

The induction of cytokine synthesis in human cells
Number exampleThe lowest effective concentration, µm
InterferonThe tumor necrosis factor
30,010,37
70,000110
80,000110
90,00011
100,000110
110,00010,1
120,00011
130,00011
140,000110
150,00010,1
160,000110
17*10
181*
190,110
200,0110
21110
220,11
2311
240,11
250,11
260,11
270,1 1
280,11
290,11
3011
31110
320,11
33110
34110
3511
360,1*
371010
381010
391010
401010
411010
4210*
431010
44**

1. The compound of formula (I):

X represents-CHR5-, -CHR5is an alkyl group, R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6is phenyl;

-R4-NR8-CR3-NR5-Z-R6-furanyl;

-R4-NR8-CR3-NR 5R7;

however phenyl substituted or not substituted with one or more substituents selected from the group consisting of methyl; methoxyl; methylthio; cyano; hydrogen; amine and acetyl;

R2selected from the group consisting of radicals:

is hydrogen;

-alkyl; and

-alkyl-Y-alkyl;

R3represents =O or=S;

R4represents alkyl, which may include one or more-O-groups; each R5represents N or C1-10alkyl;

R6is a bond or alkyl;

R7connect with R5forming morpholino ring;

R8represents H, C1-10alkyl, or R4and R8can be connected, forming a loop;

Y represents-O-;

Z represents a bond, -CO - or-SO2-;

n has a value of 0;

each R is selected independently from the group consisting of radicals With1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

2. The compound or salt according to claim 1, characterized in that X represents-CH(alkyl)(alkyl)-, and the alkyl groups can be identical or different.

3. The compound or salt according to claim 1, characterized in that's submitted is a-CH 2-CH2-.

4. The compound or salt according to claim 1, characterized in that X represents-CH(C2H5)(CH2)-.

5. The compound or salt according to claim 1, wherein R2represents N.

6. The compound or salt according to claim 1, wherein R2represents alkyl.

7. The compound or salt according to claim 1, wherein R2represents an alkyl-O-alkyl.

8. A compound selected from the group consisting of the following substances:

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-phenylacetone;

N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N'-phenylacetone;

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylacetone;

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methylmorpholin-4-carboxamide;

N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylacetone;

N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]ethoxy}ethyl)-N-methyl-N'-phenylacetone;

and its salt, pharmaceutical quality.

9. The compound of formula (II):

X represents-CHR5-, -CHR5-alkyl;

R1selected from the group content is soup:

-R4-NR8-CR3-NR5-Z-R6is phenyl;

R2selected from the group consisting of:

is hydrogen;

-alkyl; and

-alkyl-Y-alkyl;

R3represents =O;

R4represents alkyl;

R5represents N;

R6represents a bond;

R8represents H, C1-10alkyl;

Y represents-O-;

Z represents a bond;

n has a value of 0;

each R is selected independently from the group consisting of radicals With1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

10. The compound or salt according to claim 9, wherein R2represents H or alkyl.

11. The compound or salt according to claim 9, wherein R2represents an alkyl-O-alkyl.

12. Pharmaceutical composition, which is an immunomodulator for the biosynthesis of cytokines containing a therapeutically effective amount of a compound or salt according to claim 1 and pharmaceutically available carrier.

13. Way to stimulate the biosynthesis of cytokines in the animal organism, which consists in the introduction of a therapeutically effective amount of a compound or salt according to claim 1 in the body of the animal.

14. The method according to the .13, wherein said cytokine is an if-α.

15. A method of treating a viral disease in an animal, which consists in the introduction of a therapeutic effective amount of a compound or salt according to claim 1 in the body of the animal.

16. A method of treating neoplastic disease in an animal, which consists in the introduction of a therapeutic effective amount of a compound or salt according to claim 1 in the body of the animal.

17. The compound of formula (III)

X represents-CHR5-, -CHR5-alkyl;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6is phenyl;

-R4-NR8-CR3-NR5-Z-R6-furanyl;

-R4-NR8-CR3-NR5R7;

however phenyl substituted or not substituted with one or more substituents selected from the group consisting of methyl; methoxyl; methylthio; cyano; hydrogen; amine and acetyl;

R2selected from the group consisting of radicals:

is hydrogen;

-alkyl; and

-alkyl-Y-alkyl;

R3represents =O or =S;

R4represents alkyl, which may include one or more-O-groups;

each R 5represents independently N or C1-10alkyl;

R6is a bond or alkyl;

R7connect with R5forming morpholino ring;

R8represents N or C1-10alkyl and can connect with R4forming a loop;

Y represents-O-;

Z represents a bond, -CO - or-SO2-;

n has a value of 0;

each R is selected independently from the group consisting of radicals With1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

18. The compound of formula (IV)

X represents-CHR5-, -CHR5-alkylen;

R1selected from the group consisting of radicals:

-R4-NR8-CR3-NR5-Z-R6-alkyl;

-R4-NR8-CR3-NR5-Z-R6is phenyl;

-R4-NR8-CR3-NR5-Z-R6-furanyl;

-R4-NR8-CR3-NR5R7;

however phenyl substituted or not substituted with one or more substituents selected from the group consisting of methyl; methoxyl; methylthio; cyano; hydrogen; amine and acetyl;

Y represents-O-;

Z represents a Saint is z, -CO - or SO2-;

R4represents alkyl, which may include one or more-O-groups;

each R5represents independently N or C1-10alkyl;

R6is a bond or alkyl;

R7connect with R5forming morpholino ring;

R8represents H, C1-10alkyl, or R4and R8can be connected, forming a loop;

n has a value of 0;

each R is selected independently from the group consisting of radicals With1-10alkyl, C1-10alkoxy, hydroxy, halogen and trifluoromethyl;

or salt of the pharmaceutical quality of these connections.

19. Pharmaceutical composition for the induction of the biosynthesis of cytokines containing a therapeutically effective amount of a compound or salt according to claim 1 and pharmaceutically available carrier.

20. Way to stimulate the biosynthesis of cytokines in the animal organism, which consists in the introduction of a therapeutically effective amount of a compound or salt according to claim 9 in the body of the animal.

21. The method according to claim 20, wherein the cytokine is an if-α.

22. A method of treating a viral disease in an animal, which consists in the introduction of a therapeutic effective amount of a compound or salt according to claim 9 in the body of the animal.

23. With whom persons treatment of neoplastic disease in an animal, which consists in the introduction of a therapeutic effective amount of a compound or salt according to claim 9 in the body of the animal.



 

Same patents:

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

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

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

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

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

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

35 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes derivatives of pyrido[2,1-a]isoquinoline of the formula (I): wherein R1 means (lower)-alkyl, unsubstituted phenyl, phenyl mono-, di- or tri-substituted with (lower)-alkyl or (lower)-alkoxy-group, pyrrolyl, pyridynyl or (lower)-alkyl substituted with cycloalkyl or phenyl; each among R2, R and R4 means independently hydrogen, halogen atom, hydroxy-, (lower)-alkoxy-group or (lower)-alkenyl wherein (lower)-alkoxy-group and (lower)-alkenyl are optionally substituted with groups: (lower)-alkoxycarbonyl, unsubstituted phenyl, phenyl substituted with di-(lower)-alkylamine or cyano-group, thiazolyl substituted with (lower)-alkyl, pyridinyl or morpholino-group; R5 means hydrogen atom, (lower)-alkyl or phenyl optionally substituted with halogen atom, (lower)-alkoxy- or hydroxy-group; R6 means hydrogen atom, (lower)-alkyl or hydroxy-(lower)-alkyl; or R and R6 in common with carbon atoms to which they are bound form phenanthridine; R7 means hydrogen atom or (lower)-alkyl. Also, invention describes a method for synthesis of compounds of the formula (I) and preparing a pharmaceutical composition. Proposed compounds are used in treatment or prophylaxis of diseases associated with enzyme DPP-IV, i. e. dipeptidyl peptidase IV, such as diabetes mellitus and firstly non-insulin dependent diabetes mellitus and disturbed tolerance to glucose.

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

21 cl, 1 tbl, 107 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 8-methoxy[1,2,4]triazolo[1,5-a]pyridine of the general formula (I): wherein R1 means unsubstituted phenyl or phenyl substituted with one substitute chosen from group including halogen atom, trifluoromethyl, (lower)-alkyl, (lower)-alkoxy-, acetylamino-group, acetyl, (lower)-alkenyl, -C(O)O-(lower)-alkyl or thio(lower)-alkyl, or thiophenyl possibly substituted with halogen atom, or indolyl; R2 means unsubstituted phenyl or phenyl substituted with a single substitute chosen from group including halogen atom, (lower)-alkyl, halogen-(lower)-alkyl or (lower)-alkoxy-group, or thiophenyl possibly substituted with (lower)-alkyl, their pharmaceutically acceptable salts, and pharmaceutical preparation based on thereof. Novel compounds possess antagonistic effect on adenosine A2A-receptors and can be used in medicine for stimulation of the central nervous system activity and as enhancers of cognitive ability.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

10 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of naphthyridine of the formula (I): or their salts wherein R1 means phenyl or phenyl substituted with one or two substitutes chosen from group including cyano-group, halogen atom, carboxyl, aminocarbonyl group and others; R2 means (C3-C8)-cycloalkyl substituted with carboxyl or (C1-C8)-alkoxycarbonyl. Compounds of the formula (I) and their salts possess inhibitory effect with respect to activity of phosphodiesterase isozyme 4 (PDE4) and can be used for preparing a medicinal agent in treatment of obstructive or inflammatory disease of respiratory ways.

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

8 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-amino-[1,2,4]triazolo-[1,5-a]pyridine-6-carboxylic acid amide of the formula (I): wherein R1 means -NR'R'' wherein R'1 and R'' represent independently of one another lower alkyl, -(CH2)n-C(O)NRaRb, -(CH2)n-pyridinyl, -(CH2)n-phenyl, -(CH2)n-CN, -(CH2)n-O-lower alkyl or -(CH2)n-(C3-C8)-cycloalkyl; or R' and R'' form in common with nitrogen atom (N) 5- or 6-membered nonaromatic ring system wherein the latter can comprise additionally one heteroatom - oxygen (O) or sulfur (S) atom and wherein indicated ring system can be unsubstituted or substituted with one or two substitutes chosen from group consisting of lower alkyl, -C(O)NRaRb or group -(CH2)n-O-lower alkyl; each Ra and Rb represents independently hydrogen atom or lower alkyl; R2 means phenyl or heteroaryl representing pyridinyl, furanyl substituted possibly with halogen atom, or lower alkyl, thiophenyl substituted possibly with lower alkyl, or thiazolyl radical, and its pharmaceutically acceptable salts also. Compounds can be used in treatment of disease associated with adenosine A2-receptors.

EFFECT: valuable medicinal properties of compounds.

12 cl, 1 tbl, 108 ex

FIELD: organic synthesis.

SUBSTANCE: 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinolines (including their cis- and trans-isomers) are depicted by following general formulae: (1) and (2), in which R1, R2, and R4 independently represent cyclic system substituents selected from hydrogen atom and alkyl; R3 is amino group selected from alkyl, cycloalkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, alkoxy, amino, alkylamino, and dialkylamino; R5 and R6 independently represent amino group substituents selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamino, dialkylamino, or arylalkylamino; or R5 and R6, together with nitrogen atom to which they are linked, form optionally substituted aza-heterocycle. Method of preparing compounds 1 consists in reaction of corresponding indol-3-ylmethylamines with homophthalic anhydrides in an organic solvent. Compounds 2 are prepared by treating compounds 1 with thionyl chloride or 1,1'-carbonyldiimidazole to form corresponding derivatives, which are reacted with corresponding amines in an organic solvent. Compounds of invention exhibit proteinkinase inhibiting activities. Combinatory and focused libraries are also provided to reveal leading compounds.

EFFECT: expanded synthetic possibilities in quinoline series and increased choice of proteinkinase inhibitors.

3 cl, 3 tbl, 3 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

FIELD: medicine, oncology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition and its using in cancer treatment. Invention relates to polyphenol-containing pharmaceutical compositions wherein the concentration of polyphenols provides the effectiveness in cancer treatment. Proposed compositions are used as an agent for prophylaxis and treatment of cancer, and these compositions comprise ascorbic acid, lysine, proline and at least one polyphenolic compound chosen from group consisting of epigallocatechin gallate, epicatechin gallate, epigallocatechin, epicatechin and catechin. The claimed polyphenol-base pharmaceutical compositions are able to block proliferation of cancer cells and metastazing process effectively.

EFFECT: valuable medicinal properties of composition.

19 cl, 14 dwg, 10 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves applying alternating sinusoid magnetic field for 8 days in interrupted mode with sending and pause duration equal to 2 s, inductance of 60 mTesla units and frequency of 50 Hz during 5-10 min. Antitumor chemopreparations combined with autoblood are introduced at the first and eighth treatment day in intravenous and drip feed mode. Blood is taken from peripheral vein into two bottles containing blood preservative in the amount of 100 ml in each. 30 mg/m2 of Doxorubicine is introduced into the first bottle, 500 mg/m2 of 5-fluorouracyl and 600 mg/m2 of cyclophosphane into the second one. Then both bottles are incubated and the contents of the first bottle is injected, and then the content of the second one. Surgical removal of relapse is carried out two weeks later after the last antitumor preparation introduction.

EFFECT: avoided adverse toxic side effects; no additional medical preparations consumption; completely eliminated lesion focus.

2 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing bio-organic animal preparation in advance during 4 days at daily intramuscular dose of 0.3 per 100 g of animal mass, before introducing cancerogenic agent. Then, the cancerogenic agent injections are started and continued during 30 days.

EFFECT: increased tissular resistance, antitumor immunity and phagocytic macrophage activity.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-yl)pyrimidine-2-ylamino)phenyl]benzamide of formula I or its pharmaceutically permissible salt for preparing pharmaceutical compositions for treating CD117-positive non-operable and/or metastatic malignant gastrointestinal stromal tumors.

EFFECT: enhanced effectiveness of treatment.

6 cl, 1 tbl

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention elates to a novel polymorphous form © of crystalline irinotecan hydrochloride of the formula: This form is characterized by X-ray diffraction picture on a powder with values of angle 2θ about 9.15; about 10.00; about 11.80; about 12.20; about 13.00 and about 13.40 and showing infrared spectrum comprising peaks at 1757, 1712 and 1667 cm-1. The novel polymorphous form © is used in treatment of cancer diseases but as distinct from the known polymorphous form (b) it possesses significantly greater solubility in water that allows its using both oral and parenteral administration.

EFFECT: improved and valuable properties of drug.

19 cl, 2 dwg, 4 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves introducing photosensitizer, recording level of its accumulation in tumors, carrying out photodynamic therapy. Pyrogenal is introduced at a dose of 40-1000 mkg/csm2 before introducing photosensitizer into the tumor base with tumor temperature being recorded until stable tumor tissue hyperemia being achieved for 12-24 h. Then, the tumor is smeared with composition containing 3-10 mg of photosensitizer, gel "Ultramix" and 20-200 mcg of Pyrogenal. Treatment with ultrasound is applied with intensity 0.2-0.4 W/cm2, in labile continuous mode within 5-8 min. The composition is left on skin for 1-2 h. Then, photodynamic therapy session is uniformly carried out over the whole tumor area, with total number of 3-5 procedures per treatment course.

EFFECT: enhanced effectiveness of treatment; prolonged optimum photosensitizer dose being supported in tumor, sufficient for effective photodynamic therapy action.

FIELD: medicine, oncology, biochemistry, antibiotics.

SUBSTANCE: invention relates to variants used in treatment of cancer. Method involves administration in a patient needing with such treatment of the effective dose of 9-amino-6-deoxy-5-hydroxytetracycline or its salt, or 9-nitro-6-deoxy-5-hydroxytetracycline or its salt for aims in treatment of breast cancer, melanoma, myeloma and prostate gland cancer. Invention provides anti-tumor, anti-metastatic effect and the elevating viability index based on inhibition of matrix-destructing metalloproteinase by indicated derivatives of tetracycline and without significant body weight loss.

EFFECT: valuable medicinal properties of derivatives, enhanced effectiveness of treatment.

4 cl, 5 tbl

FIELD: medicine, immunology.

SUBSTANCE: the present innovation deals with specific prophylaxis of smallpox and viral hepatitis B. The kit contains two tablets each contains stabilizing additives, a filler and lyophilized alive viral material worked out based upon recombinant VOV strain at typical VOV properties expressing proteins preS2-S and HBs virus of hepatitis B virus, the first immunizing dosage corresponds to minimal quantity of viral material being sufficient to obtain weak immune response in the body in case of insignificant at insignificant reactogenicity, and immunizing dosage of the second - maximal quantity of viral material that causes pronounced and prolong immune response in the body at no negative side action. The technique of applying the kit of bivaccine tablets, first, one should use the 1st tablet at minimal dosage of bivaccine, as for the 2nd tablet - with maximal dosage of bivaccine it should be taken till the moment of developing humoral answer (in 7-14 d) after injecting the 1st tablet at minimal immunizing dosage of bivaccine. The innovation enables to create stable immunity.

EFFECT: higher efficiency.

4 cl, 5 ex, 6 tbl

Up!