Urea-substituted imidazoquinolines, pharmaceutical preparation and method for induction of cytokine biosynthesis based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

 

The technical field to which the present invention

The present invention relates to imidazoquinolines compounds containing urea, timesaving, allocating or sulfonylurea functional group in position 1, to pharmaceutical preparations containing these compounds, and to pharmaceutical preparations containing imidazoquinolines connection with urethane functional group in position 1. In addition, the present invention relates to the use of these compounds as immunomodulators, inducing the biosynthesis of cytokines in animals, and for the treatment of various pathologies, including viral and neoplasticeskih diseases.

Prerequisites to the creation of inventions

In the first authoritative message cyclical 1H-imidazo[4,5-C]quinoline, Bachman and others (Backman et al., J.Orq.Chem. 15,1278-1284 (1950)) describe the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline for possible use as antimalarials. Were later described the synthesis of various substituted 1H-imidazo[4,5-C]quinoline. For example, Jane and others (Jain et al., J.Med.Chem. 11, pp.87-92 (1988)) was synthesized compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline for use as an anticonvulsant and cardiovascular tools. Baranov and others (Baranov et al., Chem.Abs. 85, 94362 (1976)) t is the train reported several 2-accomidate[4,5-C]quinoline, and Bereni and others (Berenyi et al.,J. Heterocyclic Chem.18,1537-1540 (1981)has described some of accomidate[4,5-C]quinoline.

It was later revealed that some of 1H-imidazo[4,5-C]quinoline-4-amines and their substituted in positions 1 and 2 derivatives can be used as an anti-virus tools, bronchodilators and immunomodulators. They are described, including, in U.S. patents№№4689338, 4698348,4929624, 5037986, 5268376, 5346905 and 5389640, which are all incorporated in the present invention by reference.

Interest in cyclic imidazoquinolines systems is maintained. For example, in EP 894797 describes the connection imidazoquinolines type having aminosteroid the substituent in position 1. In this patent it is shown that the active compounds of this series must have a terminal amine Deputy, which may be included in a heterocyclic ring. Another example is WO 00/09506 which describes imidazopyridine and imidazopyridine compounds that may have amido - or michelinstarred the substituent in position 1. Those compounds, which according to this publication can be of practical use, contain a substituent in position 1, in which the amide or urea nitrogen is part of a heterocyclic ring. Despite these efforts to identify compounds that can be used as immunome is Ostrov, remains a need for compounds capable of modulating the immune response, inducing the biosynthesis of cytokines or activates other mechanisms.

A brief formulation of the invention

We have discovered a new class of compounds that can be used for induction in animals biosynthesis of cytokines. Accordingly, the present invention presents imidazoquinolines and tetrahydroisoquinoline the compounds of Formula (I):

where R1, R2and R is defined below. The present invention is also pharmaceutical preparations containing the compounds of formula (Ia); moreover, these compounds have the General structural formula as the above compounds (I).

Compounds of Formulas I and Ia can be used as immunomodulators because of their ability to induce the biosynthesis of cytokines or otherwise modulate the immune response when administered to animals. This allows the use of these compounds for the treatment of various pathologies, such as viral diseases and tumors that are sensitive to such changes in the immune response.

In addition, the present invention is a pharmaceutical preparation containing a therapeutically effective amount of the compounds of Formula (I) or (Ia), and methods induction of the biosynthesis of citoc the new animals the treatment of viral infection and/or treatment neoplasticeskih pathologies in animals by injecting the animal a compound of Formula (I) or (Ia).

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

Detailed description of the invention

As mentioned above, we found that some compounds induce the biosynthesis of cytokines in animals. Such compounds are represented by the following Formulas (I) and (Ia).

In the present invention is represented by compounds of Formula (I):

where

R1is-alkyne-NR3-CY-NR5-X-R4or-alkenyl-NR3CY-NR5-X-R4; where

Y is=O or=S;

X is a bond, -CO - or-S02-;

R4is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

alkenyl;

- aryl;

- heteroaryl;

- heterocyclyl;

- substituted aryl;

- substituted heteroaryl;

- substituted heterocyclyl;

-O-alkyl;

-O-(alkyl)0-1-aryl;

-O-(alkyl)0-1-substituted aryl;

-O-(alkyl)0-1-heteroaryl;

-O-(alkyl)0-1-substituted heteroaryl;

-O-(alkyl)0-1-heterocyclyl;

-O-(alkyl)0-1-alseny heterocyclyl;

-COOH;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-S(O)0-2-(alkyl)0-1-aryl;

-S(O)0-2-(alkyl)0-1-zameshannye;

-S(O)0-2-(alkyl)0-1-heteroaryl;

-S(O)0-2-(alkyl)0-1-substituted heteroaryl;

-S(O)0-2-(alkyl)0-1-heterocyclyl;

-S(O)0-2-(alkyl)0-1-substituted heterocyclyl;

-(alkyl)0-1-NR3R3;

-(alkyl)0-1-NR3CO-O-alkyl;

-(alkyl)0-1-NR3CO-alkyl;

-(alkyl)0-1-NR3CO-aryl;

-(alkyl)0-1-NR3CO-substituted aryl;

-(alkyl)0-1-NR3CO-heteroaryl;

-(alkyl)0-1-NR3CO-substituted heteroaryl;

-N3;

- halogen;

- halogenated;

- halogenoalkanes;

-CO-halogenoalkanes;

-NO2;

-CN;

-HE; and

-SH; and in the case of alkyl, alkenyl or heterocyclyl, ketogroup;

with the proviso that if X is a bond, R4can also be hydrogen.

R2is selected from the group which consists of:

is hydrogen;

- alkyl;

alkenyl;

- aryl;

- substituted aryl

- heteroaryl;

- substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group which consists of:

-HE;

- halogen;

-N(R3)2;

-CO-N(R )2;

-CO-alkyl (C1-10;

-CO-O-alkyl, C1-10;

-N3;

- aryl;

- substituted aryl;

- heteroaryl;

- substituted heteroaryl;

- heterocyclyl;

- substituted heterocyclyl;

-CO-aryl;

-CO-(substituted aryl);

-CO-heteroaryl; and

-CO-(substituted heteroaryl);

each of R3independently selected from the group comprising hydrogen and alkyl, C1-10;

R5selected from the group comprising hydrogen and alkyl, C1-10; or R4and R5together may form a 3-7-membered heterocyclic or substituted heterocyclic ring;

n is a number from 0 to 4, and each R is independently selected from the group comprising alkyl, C1-10alkoxyl C1-10, halogen and trifluoromethyl, or its pharmaceutically acceptable salt.

The present invention is also a pharmaceutical preparation containing a therapeutically effective amount of the compounds of Formula (Ia):

where

R1is-alkyl-NR3-CO-O-R4or-alkenyl-NR3-CO-O-R4;

R4is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

alkenyl;

- aryl;

- heteroaryl

- heterocyclyl;

- substituted aryl;

- substituted heteroaryl;

- substituted heterocyclyl;

-O-alkyl;

-O-(alkyl)0-1-aryl;

-O-(alkyl)0-1-substituted aryl;

-O-(alkyl)0-1-heteroaryl;

-O-(alkyl)0-1-substituted heteroaryl;

-O-(alkyl)0-1-heterocyclyl;

-O-(alkyl)0-1-substituted heterocyclyl;

-COOH;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-S(O)0-2-(alkyl)0-1-aryl;

-S(O)0-2-(alkyl)0-1-zameshannye;

-S(O)0-2-(alkyl)0-1-heteroaryl;

-S(O)0-2-(alkyl)0-1-substituted heteroaryl;

-S(O)0-2-(alkyl)0-1-heterocyclyl;

-S(O)0-2-(alkyl)0-1-substituted heteroalkyl;

-(alkyl)0-1-NR3R3;

-(alkyl)0-1-NR3-CO-O-alkyl;

-(alkyl)0-1-NR3-CO-alkyl;

-(alkyl)0-1-NR3-CO-aryl;

-(alkyl)0-1-NR3-CO-zameshannye;

-(alkyl)0-1-NR3-CO-heteroaryl;

-(alkyl)0-1-NR3-CO-substituted heteroaryl;

-N3;

- halogen;

- halogenated;

- halogenoalkanes;

-CO-halogenoalkanes;

-NO2;

-CN;

HE: and

-SH; and in the case of alkyl, alkenyl or heterocyclyl, ketogroup;

R2is selected from the group which consists of:

is hydrogen;

- alkyl;

alkenyl;

- aryl;

- Thames the config aryl

- heteroaryl;

- substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

- alkyl or alkenyl substituted by one or more substituents selected from the group which consists of:

-HE;

- halogen;

-N(R3)2;

-CO-N(R3)2;

-CO-alkyl (C1-10;

-CO-O-alkyl, C1-10;

-N3;

- aryl;

- substituted aryl;

- heteroaryl;

- substituted heteroaryl;

- heterocyclyl;

- substituted heterocyclyl;

-CO-aryl;

-CO-(substituted aryl);

-CO-heteroaryl; and

-CO-(substituted heteroaryl);

each of R3independently selected from the group comprising hydrogen and alkyl, C1-10;

n is a number from 0 to 4, and each R is independently selected from the group comprising alkyl With1-10alkoxyl C1-10, halogen and trifluoromethyl, or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier.

Getting connections

Imidazoquinolines of the present invention can be obtained in accordance with reaction Scheme 1, in which R, R1, R2and n are defined above.

At the stage (1) of reaction Scheme 14-chloro-3-nitroquinoline Formula II interacts with the amine of formula R1NH2in which R1defined above, to form a 3-nitroanilin-4-amine of Formula III. The reaction can be performed by adding the amine to a solution of connection is of Formula II in a suitable solvent, such as chloroform or dichloromethane, with the possible heat. Many of the quinoline of the Formula II are known compounds (see, for example, U.S. patent No. 4689338 and references therein).

At stage (2) of reaction Scheme I 3-nitroanilin-4-amine of Formula III is restored to a quinoline-3,4-diamine of Formula IV. Restoration should be undertaken on a conventional heterogeneous hydrogenation catalyst such as platinum on coal or palladium on coal. The reaction is conveniently carried out in the Parr apparatus in a suitable solvent, such as isopropyl alcohol or toluene.

At stage (3) of reaction Scheme I, a quinoline-3,4-diamine of Formula IV interacts with the carboxylic acid or equivalent with the formation of 1H-imidazo[4,5-C]quinoline of Formula V. the equivalent of the carboxylic acid may serve as the halides, simple orthoepy and 1,1-diakoniekrankenhaus. Carboxylic acid or equivalent is chosen in such a way as to provide the desired substituent R2in the Formula V. for Example, triethylorthoformate will allow you to obtain a compound in which R2is hydrogen, and when using triethylorthoformate produces compound in which R2is methyl. The reaction may proceed in the absence of solvent, and in such an inert solvent like toluene. The reaction is carried out at considerable heating in order to remove any alcohol and the water, formed as by-products of the reaction.

At stage (4) of reaction Scheme I 1H-imidazo[4,5-C]quinoline of Formula V under the action of a conventional oxidizing agent capable of forming N-oxides, oxidized to 1H-imidazo[4,5-C]quinoline-5N-oxide of Formula VI. The reaction is preferably conducted by means of the interaction of a solution of the compounds of Formula V in chloroform with 3-chloroperoxybenzoic acid at room conditions.

At stage (5) of reaction Scheme I 1H-imidazo[4,5-C]quinoline-5N-oxide of Formula VI miniroot with the formation of 1H-imidazo[4,5-C]quinoline-4-amine of Formula VII, which is one of the variants of the Formula I. stage (5) includes (i) the interaction of the compounds of Formula VI with allermuir agent, and then (ii) interaction of the product of this reaction with aminimum agent. Part (i) stage (5) includes the interaction of the N-oxide of Formula VI with allermuir agent. As alleluya agents to use the appropriate alkyl - or arylsulfonate (for example, benzosulphochloride, methanesulfonate, p-toluensulfonate). Arylsulfonamides preferred. The most preferred para-toluensulfonate. Part (ii) stage (5) includes the interaction of the product from part (i) with excess amineralo agent. As mineralsa agents should be used with ammonia (e.g. ammonium hydroxide) is whether ammonium salts (for example, ammonium carbonate, ammonium bicarbonate, ammonium phosphate). The ammonium hydroxide is preferred. The reaction preferably takes place by dissolving the N-oxide of Formula VI in an inert solvent, such as dichloromethane, adding to the solution allerease agent, and then slowly adding miniraise agent. The product or its pharmaceutically acceptable salt can be distinguished in the usual way.

Different stage (5) can be done through (i) interaction of the N-oxide of Formula VI with isocyanate followed (ii) by hydrolysis of the resulting product. Part (i) includes the interaction of the N-oxide with an isocyanate in which the isocyanate group attached to a carbonyl group. For your preferred isocyanates include trichloroacetonitrile and abolitionary, for example, benzoylation. The interaction of the isocyanate with N-oxide proceeds in anhydrous conditions by adding the isocyanate to a solution of N-oxide in such an inert solvent as chloroform or dichloromethane. Part (ii) involves the hydrolysis of the product obtained in part (i). The hydrolysis can be accomplished by conventional methods such as heating in the presence of water or a lower alcohol or in the presence of such a catalyst as hydroxide of alkali metal or lower alcoholate.

Compounds of the present invention, is that the substituent R 1contains urea or thiourea can also be obtained in accordance with reaction Scheme II, where R, R2, R4and n are defined above, Y is O or S, a m is an integer from 1 to 20.

According to reaction Scheme II aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with the isocyanate or thioisocyanate Formula IX with the formation of the compounds of Formula X, which is a variant of Formula I. the Reaction can be conducted by adding a solution of (thio)isocyanate in a suitable solvent, such as dichloromethane, to the solution of the compounds of Formula VIII may at low temperature. Many 1H-imidazo[4,5-C]quinoline-4-amines is known compounds, see, for example, U.S. patent No. 6069149 (Nanba (Nanba)); other easily obtained well-known synthetic methods. Many isocyanates and thioisocyanate Formula IX are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

Compounds of the present invention, in which the substituent R1contains urea, can also be obtained in accordance with reaction Scheme III, where R1, R2, R4, R5and n are defined above, a m is an integer from 1 to 20.

According to reaction Scheme III aminoil alsamixergui 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with carbamoylation Formula XI to form compounds of Formula XII, which is one of the variants of the Formula I. the Reaction can be conducted by adding a solution of carbamoylated in a suitable solvent, such as pyridine, to a solution of the compounds of Formula VIII at room temperature. Some carbamylcholine Formula XI are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

Compounds of the present invention, in which the substituent R1contains carbamate, can also be obtained according to reaction Scheme IV, where R, R2, R4n and m are defined above.

According to reaction Scheme IV, aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with chloroformiate Formula XIII with the formation of compounds of Formula XIV, which is one of the variants of the Formula Ia. The reaction can be conducted by adding a solution of chloroformate in a suitable solvent such as dichloromethane or pyridine, to a solution of the compounds of Formula VIII may at low temperature. Many chloroformiate Formula XIII are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

Compounds of the present invention, in which the substituent R1contains allocatio, can be obtained according to reaction Scheme V, where R1, R2, R4n and m are defined above.

According to reaction Scheme V, aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with arylisocyanates Formula XV with the formation of compounds of Formula XVI, which is one of the variants of the Formula I. the Reaction can be conducted by adding a solution arylisocyanate in a suitable solvent, such as dichloromethane, to the solution of the compounds of Formula VIII at low temperature. Some arylisocyanate Formula XV are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

Compounds of the present invention, in which the substituent R1contains a sulfonylurea, can be obtained according to reaction Scheme V, where R, R2, R3n and m are defined above.

According to the reaction Scheme V aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula VIII interacts with sulforidazine Formula XVII with the formation of compounds of Formula XVIII, which is one of the variants of the Formula I. the Reaction can be carried out, when is avlee solution sulfonylation in a suitable solvent, such as dichloromethane, to the solution of the compounds of Formula VIII may at low temperature. Some sulfonylation Formula XVII are industrial products; other easily obtained well-known synthetic methods. The product or its pharmaceutically acceptable salt produce using conventional methods.

Tetrahydroisoquinoline of the present invention can be synthesized according to reaction Scheme VII, where R2, R3, R4, R5X, Y and m are defined above.

At the stage (1) of reaction Scheme VI aminoalkylsilanes 1H-imidazo[4,5-C]quinoline-4-amine of Formula XIX is restored to aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of Formula XX. The reduction is preferably conducted by means of the suspension or dissolution of the compounds of Formula XIX in triperoxonane acid, adding a catalytic amount of platinum oxide (IV) and placing the reaction mixture under hydrogen pressure. The reaction is conveniently carried out in a Parr apparatus. The product or its salt can be distinguished by conventional methods.

Stage (2) of reaction Scheme VII can be performed using the methods described in the Schemes of reactions II, III, IV, V and VI to form compounds of Formula XXI, which is a variant of Formula I.

Then it is carbonated shall romization of the present invention can also be synthesized in accordance with reaction Scheme VIII, where R1, R2, R3, R4, R5X, Y, n and m are defined above.

At the stage (1) of reaction Scheme VIII 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]chinoline-tert-BUTYLCARBAMATE Formula XXII is hydrolyzed to aminoalkylsilanes 6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine of Formula XXIII. The reaction can be performed by dissolving the compounds of Formula XXII in a mixture triperoxonane acid and acetonitrile and stirring at room temperature. In addition, the compound of Formula XXII can be mixed with diluted hydrochloric acid and heat on a steam bath. Tetrahydro-1H-imidazo[4,5-C]chinoline-tert-BUTYLCARBAMATE Formula XX can be obtained by the synthetic method described in U.S. patent No. 5352784 (Nikolaidis (Nikolaides)). The product or its salt to produce by conventional methods.

Stage (2) of reaction Scheme VIII can be performed using the methods described in the Schemes of reactions II, III, IV, V and VI to form compounds of Formula XXIV, which is a variant of Formula I.

Some compounds of Formula 1 can be easily obtained from other compounds of Formula I. for Example, compounds in which R4 contains choralcelo group can interact with the amine with the formation of the substituent R4substituted secondary or tertiary amino group; compounds in which the substituent R4sod is RIT the nitrogroup, can recover to compounds in which the substituent R4contains a primary amine.

In the framework of the present invention, the terms "alkyl", "alkenyl", "quinil" and the prefix "-Ala" refers to both linear and branched, and cyclic groups, i.e. cycloalkyl and cycloalkenyl group. Unless otherwise noted, these groups contain from 1 to 20 carbon atoms, whereas alkeneamine and alkyline groups contain from 2 to 20 carbon atoms. Preferred groups containing up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably contain from 3 to 10 carbon atoms included in the cycles. Examples of cyclic groups can be cyclopropyl, cyclopentyl, cyclohexyl and substituted.

The term "halogenated" refers to groups substituted by one or more halogen atoms, including groups in which all of the available hydrogen atoms are replaced by halogen atoms. This also applies to groups whose name contains the prefix "halogenic-". Examples of acceptable halogenating groups can serve as chloromethyl, trifluoromethyl, etc.

In the framework of the present invention, the term "aryl" refers to aromatic rings and cyclic systems. Examples of aryl groups can be phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteros is aryl" refers to aromatic rings and cyclic system, containing in the ring at least one heteroatom (e.g., O, S, N). To an acceptable heteroaryl groups include furyl, thienyl, pyridyl, chinoline, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl etc.

The term "heterocyclyl" refers to nonaromatic rings and cyclic system containing in the ring at least one heteroatom (e.g., O, S, N). Examples of heterocyclic groups can be pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidine, piperazinil, diazolidinyl, imidazolines etc.

Unless otherwise indicated, the terms "substituted cycloalkyl", "substituted aryl", "substituted heteroaryl" and "substituted heterocyclyl" imply that the ring or cyclic system optionally substituted by one or more substituents independently selected from the group comprising alkyl, alkoxyl, alkylthio, hydroxyl, halogen, halogenated, halogenoalkanes, halogenoalkanes (for example, trifloromethyl), a nitrogroup, alkylsulphonyl, alkenylboronic, arylcarbamoyl, heteroarylboronic, aryl, arylalkyl, heteroaryl, heteroaromatic, heterocyclic, heteroseksualci, nitrile, alkoxycarbonyl, alkanoyloxy, alkanity and if cycloalkyl and heterocyclyl, ketogroup.

In the structural formula representing the compounds of the present invention, some tie is depicted by dashed lines. These lines indicate that the relationship depicted by the dashed line can be present or absent. Accordingly, the Formula 1 can be described as imidazoquinolines connection and tetrahydroisoquinoline connection.

The present invention includes the described compounds in any of their pharmaceutically acceptable forms, including isomers, like the diastereomers, the enantiomers, salts, solvate, polymorph, etc.

Pharmaceutical preparations and biological activity

The pharmaceutical preparations of the present invention contain a therapeutically effective amount of the compounds of Formula I in combination with a pharmaceutically acceptable carrier.

In the framework of the present invention, the term "therapeutically effective amount" means an amount of compound sufficient for the manifestation of such a therapeutic effect, as the induction of cytokines, antitumor activity and/or antiviral activity. Although the exact number of active compounds in the pharmaceutical preparation of the present invention may vary depending on such well-known specialists in this field factors as the physical and chemical nature of the compound and the nature of the media, as well as the regimen of the drug, it should be understood that the preparations of the present invention should in order to keep the active ingredient is enough to so that the body received a dose of a compound from 100 ng/kg to 50 mg/kg, and preferably from 10 μg/kg to 5 mg/kg May be used any conventional dosage forms such as tablets, pellets, parenteral preparations, syrups, creams, ointments, aerosol medications, ceremonie patches, the patches on the mucous etc.

Compounds of the present invention can be entered as a single drug in the treatment process, or compounds of the present invention can be introduced in combination with another or with other active means, including additional immunomodulators, antiviral agents, antibiotics, etc.

In experiments carried out by methods described below, it has been shown that the compounds of the present invention induce the synthesis of some cytokines. These results indicate that such compounds can be used as immunomodulators capable of several different ways to modify the immune response, allowing their use for the treatment of various disorders.

The cytokines that can be induced due to the introduction of the compounds of the present invention generally include interferon (IFN) and/or α-tumor necrosis factor (αa (TNF-a), as well as certain interleukins (IL). Cytokines, the biosynthesis of which can induce connections n the standing of the invention, include α-IFN, αTNF, IL-1, 6,10 and 12, and various other cytokines. Among other effects, cytokines inhibit the multiplication of viruses and tumor cell growth, which makes them an effective tool for the treatment of viral diseases and tumors.

In addition to the induction of cytokine synthesis, the compounds of the present invention have an impact on other aspects of the innate immune response. For example, under the action of the produced cytokines, most likely, increased cell activity of natural killer cells. These compounds can also activate macrophages that, in turn, stimulates the secretion of nitric oxide and the production of additional cytokines. In addition, these compounds can promote the proliferation and differentiation of b-lymphocytes.

Compounds of the present invention can also affect the acquired immune response. For example, although it is believed that there is no effect on T-lymphocytes or direct induction of cytokines by T-lymphocytes, the introduction of these compounds indirectly induces the production of cytokines γ-IFN T-helper 1 type (Th-1) and inhibits the production of cytokines IL-4, IL-5 and IL-13 T-helper 2-type (Th-2). Such activity indicates that these compounds are effective in the treatment of such diseases where activation of Th-1 response and/or the inhibition is of a Th-2 response. Having in mind the ability of the compounds of Formula Ia suppress the immune Th-2 response, it is expected that these compounds will be useful in the treatment of pathologies associated with excessive stimulation of Th-2 responses, for example, atopic diseases such as atopic dermatitis, asthma and allergic rhinitis, as systemic lupus erythematosus; and as adjuvant vaccine for cell mediated immunity; and possibly for the treatment of recurrent fungal infections and chlamydia.

The ability of these compounds to modify the immune response makes them useful in treating a wide spectrum of abnormalities. Because of their ability to induce the production of cytokines such as α-IFN and/or αTNF, and IL-12, these compounds are especially effective in the treatment of viral diseases and tumors. This immunomodulating activity suggests that the compounds of the present invention is effective in the treatment of these and not only of diseases such as viral diseases, which include genital warts; common warts; plantar warts; hepatitis b, hepatitis C, herpes simplex virus type I and type II; contagiously clam; HIV; CMV; varicella zoster virus; intraepithelial neoplasia, such as cervical intraepithelial neoplasia, human papillomavirus (HPV) and related n is aplasia; fungal diseases such as Candida, Aspergillus and cryptococcal meningitis; neoplasticheskii pathology, for example, basal cell carcinoma; leukemia retikulez, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-jackinsky lakoma, cutaneous T-cell lymphoma, other cancers; parasitic diseases such as pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, Trypanosoma infection, leishmaniasis; and bacterial infections, such as tuberculosis, mycobacterium avium. In addition, by using compounds of the present invention it is possible to treat diseases such as eczema; eosinophilia; congenital thrombocythemia; leprosy; multiple sclerosis; syndrome Omena; Bowen's disease; Baranovichy papules. These compounds also contribute to the healing of wounds, including chronic ulcers and stimulate it.

Thus, the present invention provides a method of induction of the biosynthesis of cytokines in the body of an animal by introducing an effective amount of the compounds of Formula Ia. The number of compounds effective for the induction of the biosynthesis of cytokines, is a quantity sufficient for one or more types of cells, such as monocytes, macrophages, dendritic cells and b-cells, steel producerof is one or more of these cytokines, as, for example α-IFN, αTNF, IL-1, 6, 10 and 12, which would exceed the base level of these cytokines. The exact number may vary depending on factors known to the experts in this field, however, this will most likely be the dose of 100 ng/kg to 50 mg/kg, and preferably from 10 μg/kg to 5 mg/kg of the Present invention also provides a method of treatment of viral infections in animals and treatment neoplasticeskih conditions of animals that includes the introduction into the organism an effective amount of the compounds of Formula Ia. The amount effective for the treatment or suppression of viral diseases, it is the number that causes the weakening of one or more signs of infection, such as viral infection, the viral load, the level of production of the virus and mortality, compared with control animals not exposed to the compound. The exact number may vary depending on factors known to the experts in this field, however, it can be assumed that the dose will be from 100 ng/kg to 50 mg/kg, and preferably from 10 μg/kg to 5 mg/kg Number of compounds effective for the treatment neoplasticeskih state, it is the quantity that results in reduction in tumor size or number of lesions tumors. Again, the exact number may vary depending on f is tori, well-known experts in this field, however, it can be assumed that the dose will be from 100 ng/kg to 50 mg/kg, and preferably from 10 μg/kg to 5 mg/kg

Further, the present invention is described by way of examples, which are intended only for illustration and not for limitation.

Example 1

tert-Butyl N-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]carbamate

Part a

The triethylamine (66,8 g, 0.33 mol) was added to a solution of tert-butyl N-(2-amino-ethyl)carbamate (55,0 g, 0.34 mol) in anhydrous dichloromethane (500 ml). Slowly added 4-chloro-3-nitroquinoline (68,2 g, 0.33 mol), and starts an exothermic reaction. The reaction mixture is left overnight to mix at room temperature. The formed precipitate is filtered off and produce a solid yellow color. The filtrate is washed with water, dried over magnesium sulfate and concentrate under vacuum. The resulting residue is suspended in hexane and filtered to form additional solid yellow color. After the unification of the two portions is obtained 101 g of yellow solid of tert-butyl N-[2-(3-nitroanilin-4-yl)aminomethyl]carbamate with a melting point 157-158°C.

Part B

To a suspension of tert-butyl N-[2-(3-nitroanilin-4-yl)aminomethyl]carbamate (100 g, 0.30 mol) in toluene (500 ml) was added platinum on coal (1 g, 10%) and sulfate is the atrium (2 g). The mixture overnight placed in an atmosphere of hydrogen under a pressure of 50 psig (3,4×104PA) in a Parr apparatus at room temperature. The reaction mixture is filtered. After evaporation of the filtrate obtained 73 g of tert-butyl N-[2-(3-aminoquinoline-4-yl)aminomethyl]carbamate in the form of a dark yellow oily liquid.

Part b

To a solution of tert-butyl N-[2-(3-aminoquinoline-4-yl)aminomethyl]carbamate (21 g, to 69.4 mmol) in anhydrous toluene (250 ml) was added triethylorthoformate (11.3 g, 73.4 mmol). The reaction mixture is refluxed for 5 hours and then allow to cool down slowly to room temperature. The formed precipitate is filtered off and dried. Yield: 17.6 g of solid light brown tert-butyl-N-[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethyl]carbamate with a melting point 154-155°C.

Part G

To a solution of tert-butyl N-[2-(1H-imidazo[4,5-C]quinoline-1-yl)ethyl]carbamate (17,2 g, with 55.1 mmol) in chloroform (250 ml) was added in small portions 3-chloroperoxybenzoic acid (13,4 g, to 60.6 mmol). The reaction mixture is left overnight at room temperature, and then stop the reaction, 5%sodium carbonate solution. The layers are separated. The organic layer is dried over magnesium sulfate, and then concentrated under vacuum. Obtained 15.0 g of solid grayish-white 1 -[2-(tert-butylcarbamoyl)ethyl]-1H-imidazo[4,5-C]quinoline-5N-about the sid with a melting point 213-215° C.

Part D

To a solution of 1-[2-(tert-butylcarbamoyl)ethyl]-1H-imidazo[4,5-C]quinoline-5N-oxide (15.0 g, of 45.7 mmol) in chloroform (200 ml) under stirring slowly added trichloroacetonitrile (9.5 g, a 50.2 mmol). After 2 hours the reaction is stopped concentrated ammonium hydroxide (100 ml). Add water (100 ml) and separate the layers. The aqueous layer was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate, and then concentrated under vacuum. Obtained a white solid substance. This material is suspended in a warm acetate, and then filtered. Yield: 15 g of white solid of tert-butyl N-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]carbamate with a melting point 215°C. NMR1H (500 MHz, DMSO-D6) δ 8,13 (triplet, J=8.0 Hz, 1H), 8,03 (S., 1H). to 7.61 (doublet, J=8.0 Hz, 1H), 7,44 (triplet, J=8.0 Hz, 1H), 7.23 percent (triplet, J=8.0 Hz, 1H), 7,06 (triplet, J=6.0 Hz, 1H), 6,56 (Shir. S., 2H), 4,63 (triplet, J=7,0 Hz, 2H), 3.43 points (quadruplet, J=6.0 Hz, 2H), 1,32 (C., N); Mass spectrometry (electron impact) m/e 327,1696 (327,1695 calculated for C17H21N502).

Example 2

tert-Butyl N-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

Part a

In accordance with the General method described in part a of Example 1, tert-butyl-N-(2-aminobutyl)carbamate (254 g, 1.35 mol) reacts with 4-chloro-3-nitroquinoline hydrochloride (331 is, 1.35 mol) with the formation of 486 g of a yellow solid of tert-butyl N-(4-[(3-nitroanilin-4-yl)amino]butyl)carbamate. Elemental analysis: theoretical. for C18H24N4O4: %59,99; %N Of 6.71; %N 15,55; exp.: %59,68; %N 6,59; %N 15,74.

Part B

In accordance with the General method described in Part B of Example 1, tert-butyl-N-(4-[(3-nitroanilin-4-yl)amino]butyl)carbamate (162,6 g, 0,451 mol) hydronaut education 149 g dark Golden rubbery tert-butyl-N-(4-[(3-aminoquinoline-4-yl)amino]butyl)carbamate.

Part b

In accordance with the General method described in Part b of Example 1, tert-butyl-N-(4-[(3-aminoquinoline-4-yl)amino]butyl)carbamate (149 g, 0,451 mol) interacts with triethylorthoformate with the formation of crude product. This material is recrystallized from isopropyl alcohol and obtain 84 g of crystalline tert-butyl-N-[4-(1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate.

Part G

In accordance with the General method described in Part G of Example 1, the oxidation of tert-butyl N-[4-(1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate (84 g, 0,247 mol) get to 87.9 g of greenish-yellow frothy 1-[4-(tert-butylcarbamoyl)butyl]-1H-imidazo[4,5-C]quinoline-5N-oxide.

Part D

To a solution of 1-[4-(tert-butylcarbamoyl)butyl]-1H-imidazo[4,5-C]quinoline-5N-oxide (87,9 g, 0,247 mol) in dichloromethane (750 ml) with rapid stirring in small portions was added concentrated annoy ammonium hydroxide (250 ml). Then within 30 minutes in small portions add taillored (47,0 g, 0,247 mol). The reaction mixture is left overnight to mix at room temperature, and then it is filtered yellow-brown precipitate. The layers of the filtrate are separated. The aqueous layer was extracted with dichloromethane (4 x 50 ml). Dichloromethane fractions are combined, dried over sodium sulfate, and then concentrated under vacuum and get a light brown solid. After recrystallization of this material from isopropyl alcohol get to 75.7 g of solid light yellow tert-butyl-N-[2-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 171-173°C. NMR1H (500 MHz, CDCl3) δ 8,19 (S., 1H), 8,03 (doublet, J=8.0 Hz, 1H), 7,26 (doublet, J=8.0 Hz, 1H), 6,83 (triplet, J=6.0 Hz, 1H), 6,60 (Shir. S., 2H), 4,59 (triplet, J=7,0 Hz, 2H), 2.95 and (quadruplet, J=6.0 Hz, 2H)and 1.83 (quintet, J=7,0 Hz, 2H), 1,42 (quintet, J=7,0 Hz, 2H), 1,33 (C., N); Mass spectrometry (electron impact) m/e 335,2001 (335,2008 calculated for C19H25N5O2).

Example 3

Phenyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (9.3 mg, 36 μmol) in 10 ml of dichloromethane is cooled to -5°and, for better mixing barbotine argon, was added a solution of phenylcarbamate (7 mg, 45 μmol) in 1.5 ml dig armeana. Then, within 10 minutes with a vortex stirring mixture is allowed to warm to room temperature. In order to repay the excess chloroformate, add aminomethyl-polystyrene (approximately 80 mg, 1 mEq/g, 100-200 mesh, Bachem), and within a few hours boil the mixture under reflux with vortex mixing. After chromatography was carried out of the mixture through a short plug of silica gel with a mixture of dichloromethane-methanol 10:1 as additionally separated by produce a solid product. NMR1H (500 MHz, DMSO-D6) δ 8,28 (S., 1H), 8,06 (doublet, J=7,6 Hz, 1H), 7,76 (triplet, J=5.6 Hz, 1H), 7,63 (doublet, J=8,2 Hz, 1H), 7,45 (triplet, J=7 Hz, 1H), 7,34 (triplet, J=8,2 Hz, 2H), 7,18 (triplet, J=7,3 Hz, 1H). 7,00 (doublet, J=8.6 Hz. 2H), 6,65 (width, C., 2N), with 4.64 (triplet, J=7 Hz, 2H), 3,10 (quadruplet, J=6 Hz, 2H), with 1.92 (quintet, J=7 Hz, 2H), of 1.52 (quintet, J=7 Hz, 2H); Mass spectrometry (head) m/e 376,15 (M+H).

Example 4

N-9-Fluorenylmethyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

To a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (9.3 mg, 36 μmol) in 10 ml of dichloromethane at room temperature was added solid 9-fluorenylmethoxycarbonyl (8 mg, 30 µmol). Approximately 1 minute vortex mixing at room temperature it is slightly turbid. In order to repay the excess chloroformate, add aminomethyl-polystyrene (approximately 90 mg 0.64 mg-EQ/year 100-200 mesh, Bachem), after a few minutes, filter the mixture through a short plug of silica gel with a mixture of dichloromethane-methanol 10:1 as additionally separated by and produce a solid product. NMR1H (500 MHz, DMSO-D6) δ 8,27 (S., 1H), 8,08 (doublet, J=8,1 Hz, 1H), 7,87 (doublet, J=7,6 Hz, 1H), 7,65 (cf., 1H), 7,50 (triplet, J=7,6 Hz, 1H), 7.40 (triplet, J=7,3 Hz, 1H), and 7.3 (cf., 4H), 7,15 (Shir. S., 2H), 4,62 (triplet, J=7 Hz, 2H). 4,27 (doublet, J=7 Hz, 2H), 4,17 (triplet, J=7 Hz, 1H), 3,03 (quadruplet, J=7 Hz, 2H), of 1.84 (quintet, J=7 Hz, 2H), 1,45 (quintet, J=7 Hz, 2H); Mass spectrometry (head) m/e 478,28 (M+H).

Example 5

N4-[4-(4-Amino-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-4-morpholinylcarbonyl

To a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (0.3 g, 1.2 mmol) in pyridine (70 ml) with stirring was added 4-morpholinylcarbonyl (0.15 ml, 1.3 mmol). The reaction mixture is left overnight at room temperature. The solvent is removed under vacuum and the residue is purified column chromatography under pressure (silica gel, 9:1 dichloromethane/methanol). The fractions containing the product are combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filter, concentrate, and get 0,86 g of yellow-brown powder N4-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-4-morpholinylcarbonyl with a melting point 177,0-179,5°C. NMR1H (300 MHz, DMSO-D6) δ by 8.22 (C., 1H), 8,04 (doublet, J=7,1 Hz, 1H), to 7.64 (doublet, J=7.5 Hz, 1H), 7,47 (triplet, J=7,1 Hz, 1H), 7,28 (triplet, J=7,1 Hz, 1H), 6,72 (Shir. S., 2H), 6,52 (triplet, J=5.4 Hz, 1H), br4.61 (triplet, J=6,9 Hz, 2H), 3,48 (triplet, J=4.6 Hz, 4H), 3,18 (triplet, J=4.6 Hz, 4H), 3,05 (cf., 2H), 1,84 (cf., 4H), 1,44 (cf., 4H); Mass spectrometry (electron impact) m/e 368,1966 (368,1961 calculated for C19H24N602).

Example 6

N1-[4-(4-Amino-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-N-methyl-N-prilocaine

In accordance with the General procedure described in Example 5,1-(4-aminobutyl)-11-1-imidazo[4,5-C]quinoline-4-amine interacts with N-methyl-N-phenylcarbamoyl with the formation of a yellowish-brown powder N1-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N-methyl-N-prilocaine with a melting point of 87.0-88,0°C. NMR1H (300 MHz, DMSO-D6) δ 8,19 (s, 1H), 8,04 (doublet, J=8,1 Hz, 1H), 7,63 (double doublet, J=8,1,1,2 Hz, 1H), 7,45 (double triplet, J=8,1 1.2 Hz, 1H), 7,31-7,24 (cf., 3H), 7.18 in-7,09 (cf., 3H), 6,62 (S. 2N). 5,95 (width, S., 1H), 4,59 (triplet, J=6,9 Hz, 2H), 3,07 (C., 3H), 3,03 (cf., 2H). is 1.82 (quintet, J=7.2 Hz, 2H), 1,42 (quintet, J=7.2 Hz, 2H); Mass spectrometry (electron impact) m/e 388,2023 (388,2012 calculated for C22H24N6O).

Example 7

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-N-[3-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

To a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[45-a]quinoline-4-amine (0,80 g, 3.14 mmol) in pyridine (200 ml) was added dropwise with stirring (-)-methylchloroform (0,675 ml of 3.15 mmol). The reaction mixture is left overnight at room temperature. The solvent is removed under vacuum and the residue is purified column chromatography under pressure (silica gel, 95:5 dichloromethane/methanol). The fractions containing the product are combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, concentrated and obtain 0.32 g of a yellow-brown powder (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-N-[3-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point of 84.0-86,0°C. NMR13C (75 MHz, DMSO-D6) δ 156,5, 152,5, 145,3, 143,1, 131,9, 128,5, 127,0, 126,5, 121,5, 120,8, 115,2, 73,0, 47,2, 46,5, 41,7, 34,1 31,2, 27,5, 26,8, 26,1, 23,4, 22,3, 20,8, 16,6; Mass spectrometry (electron impact) m/e 437,2797 (437,2791 calculated for C25H35N5O2).

Example 8

2-Naphthyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

In accordance with the General procedure described in Example 7,1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine interacts with 2-naftilos ether Harborview acid with the formation of white powder 2-naphthyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 154,0-155,0°C. NMR1H (300 MHz, DMSO-D6) δ 8,23 (S., 1H), 8,08 (doublet, J=7,4 Hz, 1H), 7,94-7,86(cf., 4H). to 7.64 (double doublet, J=8,3, 1.0 Hz, 1H), 7,56-7,43 (cf., 4H), 7,30 (cf., 1H), 7,20 (double doublet, J=8,8, 2.3 Hz, 1H), 6,61 (width, C., 2N)and 4.65 (triplet, J=6,9 Hz, 2H), 3,14 (quadruplet, J=6,4 Hz, 2H), 1,94 (cf., 2H), and 1.56 (cf., 2H); Mass spectrometry (electron impact) m/e 426,1927 (426, 1930 calculated for C25H23N5O2).

Example 9

1-Naphthyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

In accordance with the General procedure described in Example 7,1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine interacts with 1-naftilos ether Harborview acid with the formation of yellow-brown powder 1-naphthyl-N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 89,0-92,0°C. NMR1H (300 MHz, DMSO-D6) δ 8,25 (S., 1H), 8,10 (doublet, J=7,4 Hz, 1H), 8,05 (triplet, J=5.8 Hz, 1H), of 7.96 (doublet, J=7,6 Hz, 1H), 7,79 (doublet, J=8,2 Hz, 1H), 7,66 was 7.45 (cf., 6N), 7,30 (cf., 1H), 7,19 (doublet, J=7.5 Hz, 1H), 6,72 (width, S., 2H), 4.67 (triplet, J=6,9 Hz, 2H), 3,17 (quadruplet, J=6.3 Hz, 2H), 1,96 (cf., 2H), 1,59 (cf., 2H); Mass spectrometry (electron impact) m/e 426,1929 (426, 1930 calculated for C25H23N502).

Example 10

N-{4-[4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}urea

Part a

In accordance with the General methods described in Parts D and e of Example 1 from tert-butyl N-{4-[2-(4-methoxybenzyl)-1H-imidazo[4,5-C]x is the nolin-1-yl]butyl}carbamate get a solid tert-butyl-N-aminocarbonyl-N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}carbamate. NMR1H (300 MHz, DMSO-D6) δ 7,93 (doublet, J=8,1 Hz, 1H), 7,86 (width, S., 1H), to 7.61 (double doublet, J=8,3,1,1 Hz, 1H), 7,41 (cf., 1H), 7.24 to 7,17 (cf., 1H), 6.87 in (doublet, J=8.7 Hz, 1H), 6,55 (width, S., 2H), 4,45 (width, S., 2H), 4,32 (S., 2H), 3,71 (C., 3H), 3,49 (cf., 2H), 1,49 (cf., 4H), 1,31 (C., N).

Part B

tert-Butylcarbamoyl group is removed from tert-butyl N-aminocarbonyl-N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}carbamate by heating this compound in a solution of HCl and ethanol. After neutralization of the reaction mixture (NH4OH) get a grayish-white solid of N-{4-[4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}urea with a melting point 196°C (decomp.). NMR1H (300 MHz, DMSO-D6) δ of 7.96 (doublet, J=7.9 Hz, 1H), to 7.61 (doublet, J=8,3 Hz, 1H), 7,43 (triplet, J=7,6 Hz, 1H), 7,25 (cf., 3H), 6.89 in (doublet, J=8.6 Hz, 2H), 6,58 (Shir. C., 2N), of 5.92 (Shir. S., 1H), are 5.36 (Shir. C., 2N), to 4.41 (cf., 2H), 4,32 (S., 2H), 3.72 points S., 2H), 2,93 (doublet, J=5.8 Hz, 2H), 1,48 (cf., 4H); Mass spectrometry (HEE) m/e 419.

Example 11

N4-{4-[4-Amino-2-(2-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-morpholinylcarbonyl

In accordance with the General procedure described in Example 5,1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-4-amine interacts with 4-morpholinylcarbonyl with the formation of N4-{4-[4-amino-2-(2-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-Martinkevich the amide. NMR1H (500 MHz, CDCl3) δ a 7.85-7,81 (cf., 2H), 7,50 (cf., 1H), 7,30 (cf., 2H), 7,17 (doublet, J=8.6 Hz, 2H), 6,86 (doublet, J=8.6 Hz, 2H), 5,62 (Shir. S., 2H), 4,36 (cf., 2H), or 4.31 (SD, 2H), 3,78 (C., 3H), 3,64 (triplet, J=4.9 Hz, 4H), 3,25 (triplet, J=4.9 Hz, 4H), 3,18 (cf., 2H), 1,70 (cf., 2H), and 1.54 (cf., 2H); Mass spectrometry (electron impact) m/e 488,2533 (488,2536 calculated for C27H32N6About3).

Example 12

tert-Butyl N-[2-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate

Part a

A solution of benzoyl chloride (5.3g, of 37.7 mmol) in dichloromethane (100 ml) at room temperature is slowly added to a solution of tertbutyl-N-{4-[(3-aminoquinoline-4-yl)amino]butyl}carbamate (12.5 g, of 37.7 mmol) in dichloromethane (250 ml). The reaction mixture is left overnight at room temperature. The formed precipitate is filtered off and dried, yielding of 11.0 g of white solid of tert-butyl N-(4-{[3-(benzoylamine)quinoline-4-yl]amino}butyl)carbamate hydrochloride.

Part B

The triethylamine (7,26 g of 71.7 mmol) was added to a solution of material from part a in ethanol (200 ml) and refluxed for 2 days. The reaction mixture was concentrated and get the orange syrup. According to HPLC/MS syrup contains both the desired product and starting material. The syrup is transferred in dichloromethane (100 ml)and then cooled in an ice bath. Added triethylamine (5 ml) and benzoylchloride is (1.9 ml). After keeping the reaction mixture at room temperature for 2 days HPLC shows that the reaction is not completed. The reaction mixture is concentrated under vacuum. The residue is transferred in isopropyl alcohol (150 ml). Added triethylamine (5 ml) and the reaction mixture is stored overnight to boil under reflux. The reaction mixture is concentrated under vacuum. The residue is purified column chromatography under pressure (silica gel, elution with a mixture of 10% methanol in dichloromethane). The fractions containing the product are combined and concentrated under vacuum. After recrystallization of the residue from acetonitrile obtain 6.7 g of a solid of tert-butyl N-[4-(2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 158-159°C.

Part b

3-Chloroperoxybenzoic acid (1.05 equivalent of 65%) is slowly added in small portions to a solution of tert-butyl N-[4-(2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)Boticaria (6,56 g of 15.75 mmol) in dichloromethane (120 ml). After 3 hours the reaction is stopped with 1%aqueous solution of sodium bicarbonate (200 ml). Separate the layers. The aqueous layer was extracted with dichloromethane (2 times 50 ml). The organic fractions are combined, dried over magnesium sulfate, then concentrated under vacuum and receive light orange syrup. After grinding syrup with diethyl ether to obtain 6.8 g of a light brown t is ejogo 1-[4-(tert-butylcarbamoyl)butyl]-2-phenyl-1H-imidazo[4,5-C]quinoline-5N-oxide with a melting point 178-181° C.

Part G

A solution of 1-[4-(tert-butylcarbamoyl)butyl]-2-phenyl-1H-imidazo[4,5-C]quinoline-5N-oxide (6.8 g, of 15.75 mmol) in dichloromethane (100 ml) cooled in an ice bath. Add concentrated ammonium hydroxide (30 ml). Within 30 minutes in small portions add taillored (3.0 g, of 15.75 mmol). The reaction mixture is left overnight to warm to room temperature. The reaction is stopped by the water (350 ml). The layers are separated. The aqueous layer was extracted with dichloromethane. The organic fractions are combined, dried over magnesium sulfate, then concentrated under vacuum and receives a yellow-brown solid. This material is purified column chromatography under pressure (silica gel, elution with a mixture of 10% methanol in dichloromethane) and obtain 4.8 g of the product. A small portion is recrystallized from toluene and get a solid tert-butyl-N-[2-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate with a melting point 182-183°C. Elemental analysis: theory. for C25H29N5O2: %69,58; %N 6,77; %N 16,22; exp.: %69,86; %N, 6.95; %N 15,80.

Example 13

N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-propylthiophene

Part a

tert-Butyl N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]carbamate (4.3 g, 10.0 mmol) dissolved in methanol (15 ml) and 1N-hydrochloric acid (100 ml), and C is the 2 hours and refluxed. The reaction mixture was concentrated under vacuum to a volume of about 50 ml After addition of concentrated ammonium hydroxide to pH 12 residue does not fall out. Using 1N hydrochloric acid, the pH is brought to 7. The mixture is extracted with dichloromethane and then ethyl acetate. The aqueous layer was evaporated to dryness. The residue is dissolved in water (50 ml), and then within 36 hours continuously extracted with boiling chloroform under reflux. The chloroform extract was concentrated under vacuum and get a light brown solid. After recrystallization of this material from acetonitrile obtain 2.5 g of grayish-white solid 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine with a melting point of 175-177°C. Elemental analysis: theory. for C20H21N5: %72,48; %N 6,39; %N 21,13; exp.: %72,72; %N 6,32; %N 20,71.

Part B

The solution propositionthe (0,78 g, 7,72 mmol) in chloroform (5 ml) at room temperature was added to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine (0,256 g, 7,72 mmol) in a mixture chloroform (25 ml) and pyridine (5 ml). The reaction mixture is left for the weekend at room temperature. The reaction mixture was quenched with ethanol, and then concentrated under vacuum and receive light orange syrup. This material is purified column chromatography under pressure (silica gel, elution with a mixture of 10% metanol dichloromethane). Pure fractions are combined, concentrated under vacuum and get to 0.22 g of white solid N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-proportionately with a melting point 113-116°C. Mass spectrometry: M+1=433,2.

Example 14

N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(3-pyridyl)thiourea

A solution of pyridine-3-isothiocyanate (0,136 g, 1.0 mmol) in chloroform (5 ml) at room temperature was added to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine (0,331 g, 1.0 mmol) in a mixture of chloroform (25 ml) and pyridine (5 ml). The reaction mixture is left for the weekend at room temperature. The reaction mixture was quenched with ethanol, and then concentrated under vacuum and get a grayish-white solid. This material is purified column chromatography under pressure (silica gel, elution with a mixture of 10% methanol in dichloromethane). Pure fractions are combined, concentrated under vacuum and obtain 0.2 g of white solid N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(3-pyridyl)thiourea with a melting point 118-120°C. Mass spectrometry: M+1=468,3. Elemental analysis: theoretical. for C26H25N7S: %66,79; %N 5,39; %N 20,97; exp.: %64,29; %N 5,46; %N GRADE OF 20.06.

Example 15

N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(4-forfinal)urea

A solution of 4-perteneciente (0,137 g, 1.0 mmol) in chloroform (5 ml) at room temperature was added to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-C]quinoline-4-amine (0,331 g, 1.0 mmol) in a mixture of chloroform (25 ml) and pyridine (5 ml). The reaction mixture is left for the weekend at room temperature. The reaction is stopped by ethanol. The resulting light yellow precipitate (identified as bis-adduct) is separated by filtration. The filtrate is concentrated under vacuum and get a grayish-white solid. This material is purified column chromatography under pressure (silica gel, elution with a mixture of 10% methanol in dichloromethane). Pure fractions are combined, concentrated under vacuum and get to 0.22 g of white solid N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(4-forfinal)urea with a melting point 145-150°C. Mass spectrometry: M+1=469,2. Elemental analysis: theoretical. for C27H28FN6O: %C 69,21; %lower than the 5.37 N; %N 17,94; exp.: %C 66,70; %N 5,33; %N 17,03.

Examples 16-52

The compounds shown below in Table 1 are in accordance with the General method of synthesis described above in reaction Scheme II.

A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-C]quinoline-4-amine (36 μmol) in 10 ml dichloromethane in a test tube with screw cap cooled to -5°C. In the form of a 0.3 M solution in dichloromethane was added isocyanate (45 mmol is). During the addition and for a further 15 seconds after graduation through the mixture bubbled argon and leave the mixture overnight at -5°C. To this mixture is added approximately 90 mg aminomethyl-polystyrene resin (of 0.62 mEq/g, 100-200 mesh), the mixture is heated to boiling under reflux and shaken for 3 hours at 600 rpm in order To remove the resin, the mixture is filtered through a column of Poly-Prep (Bio-Rad No. 731-1550). Use three different cleaning method. According to the Method And the filtrate is loaded into a column of silica gel. Column elute with a mixture of dichloromethane/methanol 10:1, and the fractions containing the product are combined and dried under vacuum. According to the Method of the filtrate is dried under vacuum and purified prepreparation HPLC on a system of Gilson (column Rainin Microsorb C18, 21,4×250 mm, particle size 8 μm, the pores 60 And 10 ml/min, gradient elution from 2 to 95% B over 25 minutes, 5 minute delay at 95% B, where B=0,1% triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS, the desired fraction lyophilized and get trifenatate salts of the respective compounds. In accordance with the Method, a connection is first purified by the Method, and then to allocate a free on the article, trifenatate salt is dissolved in 3-5 ml of a mixture of dichloromethane/methanol 2:1, within 1-2 hours shaken from about 80 mg (300 μmol) diisopropylaminomethyl-polystyrene resin (Argonaut PS-DIEA, 3,86 mmol/g)and then filtered and dried under vacuum. Connections usually are amorphous solids.

Examples 53-66

The compounds shown below in Table 2 are in accordance with the methods of synthesis described above in reaction Scheme II, using the following General method. 1-(2-amino-ethyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (50 mg), dichloromethane (2 ml) and the isocyanate is placed in a vial on 2 drachmas (7,4 ml). For about 2-16 hours ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 min is t, 2-minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired urea.

Table 2
Example No.The structure of the free baseMolecular weight
53461.2
54495.1

Example No.The structure of the free baseMolecular weight
55417.1
56369.2
57355
58369.2
59 383.3

Example No.The structure of the free baseMolecular weight
60403.2
417.2
62417.2
63417.2

Example No.The structure of the free baseMolecular weight
64428.2
65431.2
66431.2

Examples 67-69

The compounds shown below in Table 3 are in accordance with the following method of synthesis. 1-(2-amino-ethyl)-2-ethoxymethyl-1H-imidazo[4,5-C]quinoline-4-amine hydrochloride (50 mg), dichloromethane (2 ml) and Diisopropylamine (1.2 equivalent) was placed in a vial on 2 drachmas (7,4 ml). About 1 hour ampoule is placed in the shaker at room temperature. Add the appropriate diisocyanate,and shake the vial at room temperature for approximately 4 hours. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired thiourea.

Table 3
Example No.The structure of the free baseMolecular weight
67371.1
68405.1
69427.1

Examples 70-99

The compounds shown below in Table 4 are in accordance with the method of synthesis, the description above in reaction Scheme II, by reacting 1-(4-am is Novotel)-2-butyl-1H-imidazo [4,5-c]quinoline-4-amine with the appropriate isocyanate in accordance with the General method described above in the Examples 53-66.

Table 4
Example No.The structure of the free baseMolecular weight
70395.2
71397.3
72411.3
73431.2

table:4
Example No.The structure of the free baseMolecular weight
74437.3
75445.2
76445.20
77445.2

table:4
Example No.The structure of the free baseMolecular weight
78 449.2
79449.2
80456.2
81459.3

table:4
Example No.The structure of the free baseMolecular weight
82459.3
83459.3
84459.3
85461.3

table:4
Example No.The structure of the free baseMolecular weight
86465.2
87467.3
88471.3
89 475.3

table:4
Example No.The structure of the free baseMolecular weight
90476.2
91476.2
92479.2
93499.2

table:4
Example No.The structure of the free baseMolecular weight
94499.2
95499.2, 501.1
96499.2, 501.1
97509, 511.1

table:4
Example No.The structure of the free baseMolecular weight
9 509, 511.1
99509, 511.1

Examples 100-119

The compounds shown below in Table 5 are in accordance with the methods of synthesis described above in reaction Scheme II, by reacting 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine with the appropriate isocyanate in accordance with the General method described above in Examples 53-66.

Table:5
Example No.The structure of the free baseMolecular weight
100491.3

table:5
Example No.The structure of the free baseMolecular weight
101385.2
102399.2
103413.2
104433.2

table:5
Example No.The structure of the free baseMolecular weight
105439.2
106447.2
107451.1
108458.2

table:5
Example No.The structure of the free baseMolecular weight
109458.2
110461.2
111461.2
112467.1

table:5
Example No.The structure of the free baseMolecular weight
113467.1
114/td> 478.1
115478.1
116501.2

table:5
Example No.The structure of the free baseMolecular weight
117501.2
118501.0, 503.1
119511, 513.1

Examples 120-122

The compounds shown below in Table 6 are in accordance with the methods of synthesis described above in reaction Scheme III, using the following General method. 1-(2-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (50 mg), diisopropylethylamine (34 ml), dichloromethane (2 ml) and carbonylchloride (1.1 equivalent) was placed in a vial on 2 drachmas (7,4 ml). About 2 hours ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue is purified of polypipe is exploring HPLC (column Capcell Cancer C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired urea.

Table:6
Example No.The structure of the free baseMolecular weight
120447.3
121427.2
122411.3

Example 123-124

The compounds shown below in Table 7 are in accordance with the methods of synthesis described above in reaction Scheme II, by reacting 1-(4-aminobutyl)-2-(4-methoxyphenethyl)-1H-imidazo[4,5-c]quinoline-4-amine with the appropriate isocyanate in accordance with the General method described above in Examples 53-66.

Table:7.
Example No.The structure of the free baseMolecular weight
123461.3
124495.3

Examples 125-131

The compounds shown below in Table 8 are in accordance with the methods of synthesis described above in reaction Scheme II, using the following General method. 1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (50 mg), dichloromethane (2 ml) and thioisocyanate (1.1 equivalent) was placed in a vial on 2 drachmas (7,4 ml). Approximately 30-60 minutes the vial was placed in a shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate f the shares are combined and lyophilized. Formed trifurcata salt of the desired thiourea.

Table:8
Example No.The structure of the free baseMolecular weight
125450.1
126542.1
127415.1
128449.1

Table:8
Example No.The structure of the free baseMolecular weight
129413.1
130429.2
131499.2

Examples 132-137

The compounds shown below in Table 9 are in accordance with the General method of synthesis described above in reaction Scheme VII.

Part a

Source tetrahydroquinoline obtained as follows.

A catalytic amount of platinum oxide is (IV) was added to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-C]quinoline-4-amine (2.2 g, 7,06 mmol) in triperoxonane acid (200 ml). Within 6 days the reaction mixture hydronaut in the Parr apparatus under a pressure of 50 pounds per square inch (3,44×105PA). In order to remove the catalyst, the mixture is filtered, and the filtrate concentrated under vacuum. The residue is combined with 1N hydrochloric acid (100 ml) and heated for 2 hours on the steam bath. The mixture is cooled, alkalinized with ammonium hydroxide, and then extracted with dichloromethane. The extract was concentrated under vacuum and get a solid 1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-4-amine with a melting point 63-67°C.

A catalytic amount of platinum oxide (IV) was added to a solution of 1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-C]quinoline-4-amine (7.7 g, 24.5 mmol) in triperoxonane acid (250 ml). The reaction mixture hydronaut in the Parr apparatus under a pressure of 50 psi (3,44×105PA). Over the course of the reaction is monitored by gas chromatography-mass-spectrometer. Through 7,11 and 17 days after start of the reaction add a further quantity of catalyst. After 25 days, the reaction is finished. In order to remove the catalyst, the mixture is filtered through a layer of accelerator filtering celite (Celite®), and the filtrate concentrated under vacuum. The residue is combined with 1N hydrochloric acid (100 ml) and left overnight to mix. The mixture is alkalinized hydroxide, shumilkin) is up to pH 11, and then extracted with dichloromethane (3 x 300 ml). The extracts are combined and concentrated under vacuum. Yield: 3.5 g of solid 1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo[4,5-C]quinoline-4-amine.

Part B

Using the methods described for examples 53-66, tetrahydroisoquinoline part of And interact with the appropriate isocyanate or sulfonylation with the formation of the desired urea or sulfonylureas.

Table 9
1 Example No.The structure of the free baseMolecular weight
132493.20
133449.2
134389.2
135431.2

table:9
Example No.The structure of the free baseMolecular weight
136437.2
137 499.1

Examples 138-140

The compounds shown below in Table 10 are in accordance with the methods of synthesis described above in reaction Scheme VI, using the following General method. 1H-Imidazo[4,5-C]quinoline-4-amine (50 mg), dichloromethane (2 ml) and sulfonylation (1.3 equivalent) was placed in a vial on 2 drachmas (7,4 ml). The ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column Capcell Cancer C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the desired sulfonylurea.

Table 10
Example No.The structure of the free baseMolecular weight
138 495.2
139485.0
140501.0, 503.0

Example 141

N1-{4-[4-Amino-2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-yl]butyl}-N3-benzoylacetone triptorelin

This connection receive in accordance with the General procedure described above in reaction Scheme V. 1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (50 mg), dichloromethane (2 ml) and benzoylisothiocyanate (1.1 equivalent) was placed in a vial on 2 drachmas (7,4 ml). About 2 hours ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm ×20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions connecting the t and lyophilized. Formed trifurcata salt of the target compound. Mass spectrometry: (head) m/e 461.2 (M+H).

Example 142

N1-{4-[4-Amino-2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-yl]butyl}-carbamate triptorelin

This connection receive in accordance with the General procedure described above in reaction Scheme IV. 1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-4-amine (50 mg), diisopropylethylamine (1.2 equivalent), dichloromethane (2 ml) and benzylchloride (1.1 equivalent) was placed in a vial on 2 drachmas (7,4 ml). 2 hours ampoule is placed in the shaker at room temperature. In order to confirm the formation of the desired product, the reaction mixture was analyzed by gas chromatography-mass spectrometer. The solvent is removed and the residue purified prepreparation HPLC (column, Capcell Pak C18, 35 mm x 20 mm, particle size 5 μm, 20 ml/min, gradient elution from 5% to 95% B over 10 minutes, 2 minute delay at 95% B, where A=0.1% of triperoxonane acid in water and B=0.1% of triperoxonane acid in acetonitrile, enable the collection of fractions detected by peak 254 nm). Fractions obtained prepreparation liquid chromatography, and analyzed by gas chromatography-mass spectrometer LC-head/MS and the appropriate fractions are combined and lyophilized. Formed trifurcata salt of the target compound. Mass spectrometry: (head) m/ 448.2 (M+H).

INDUCTION of CYTOKINES IN HUMAN CELLS

To study the induction of cytokines, compounds of the present invention was used, the system of human blood cells in vitro. The method is based on measuring the level (α) interferon and tumor necrosis factor (IFN and TNF, respectively)secreted into the culture medium, as described by Testerman, etc (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 for culture

Whole blood taken from a vein of a healthy person and placed in a test tube. Mononuclear cells from peripheral blood (MCPC) was isolated from whole blood in the density gradient by centrifugation with the use of device Histipaque®-1077 (F. Sigma Chemicals, St. Louis, MO). Mononuclear cells peripheral blood are suspended at a concentration of 3-4×106Katok/ml in RPMI1640 medium containing 10% fetal bovine serum, 2 mm L-glutamine and 1% of a mixture of penicillin and streptomycin (complete RPMI medium). Suspension MCPC make a 48-hole flat-bottomed sterile tablets for tissue culture (F. Costar, Cambridge, MA, or F. Becton Dickinson Labware, Lincoln Park, NJ), in which there are an equal volume of complete RPMI medium containing the test drug.

Preparation

The drug solubilizer in dimethyl sulfoxide (DMSO). The final concentration of DMSO to add in cultural the s wells should not exceed 1%.

Incubation

The solution of the test drug at a concentration of 60 μm contribute to the first well containing complete RPMI medium, then do a series of serial dilutions (3 - or 10-fold). Suspension MCPC then added to the wells in equal volumes, allowing to achieve the desired range of concentrations of the test drug. The final concentration of the suspension MCPC is 1.5-2×106cells/ml Dies closed sterile plastic covers and subjected to careful mixing and then incubated for 18-24 hours at 37 ° °C in an atmosphere with 5%carbon dioxide.

Selection

After incubation, the plates centrifuged for 5-10 minutes in mode 1000 rpm (˜200 g) at a temperature of 4°C. the Supernatant is extracted from a cell culture sterile polypropylene pipette and transferred to sterile polypropylene tubes. The received samples are stored until analysis at a temperature of from -30 to -70°C. Then the samples are tested for content α-interferon and α-tumor necrosis factor by the method of enzyme-linked immunosorbent assay (ELISA) [ELISA].

The analysis of TYPHUS (ELISA) for maintenance α-interferon and αtumor necrosis factor.

Method of TYPHOID allows to determine the concentration of α-interferon using a set of Human Multi-Species kit (F. PBL Biomedical Laboratories, New Brunswic, NJ).

The concentration of tumor necrosis factor is determined using a set of TYPHOID from F. Genzyme, Cambridge, MA; F. R&D Systems, Minneapolis, MN; or F. Phamnigen, San Diego, CA).

Table 11 below shows found the lowest concentration of each drug for the induction of tumor necrosis factor. "**" -reflects the lack of induction in any of the tested concentrations(0,12, 0,37, 1,11, 3,33, 10 and 30 µm); "***" - reflects the lack of induction in any of the tested concentrations (0.0001, 0,001, 0,01, 0,1,1, and 10 μm).

Table 11
Induction of cytokines in human cells
Number exampleThe lowest effective concentration (µm)
InterferonThe tumor necrosis factor
20,373,33
161,1110
20,373,33
4****
17**30
191,1130
201,1130
21****
22**10
23 **10
24****
253,33**
2610**
27****
281,113,33
29**10
303,3330
31**10
321010
33****
34****
351,1110
361,1110
371,1110
38****
391,1110
400,373,33
411,1110
42****
43****
441,1110
453,33**
461,113,33
13,3330
4 3,3310
480,373,33
493,333,33
50****
513030
521,1110
60,37**
53,33**
67110
690,11
6811
137110
1320,011
1330,110
53***10
54***10
5511
5611
139******
14010***
1000,00110
1250,000110
1260,00011
1270,00011
1200,00010,01
1210,0110
1220,0011
710,0011
810,011
820,010,1
830,11
840,11
850,0010,1
860,11
871***
880,11
890,110
1010,011
1020,0011
1030,00010,1
1040,00011
1050,0011
1060,00011
1070,00011
1080,00010,0001
1090,00010,1
141***10
1100,0011
1110,0011
1120,0001 0,1
1130,00011
1140,00010,01
1150,00011
1160,00011
1171010
1181010
1191010
1420,00010,1
1340,0011
1350,0110
1360,00011

In the description of the present invention discussed some examples of its implementation. The above detailed description and examples presented here only for clarity of understanding and they do not follow any restrictions. Specialists in this field it is clear that there are numerous changes in the described embodiments, without changing the nature and scope of the present invention. Thus, the scope of the present invention is limited not by the specific details described herein compositions and structures, but only the language of the following claims.

1. The compound of formula (I)

where connection indicated by the dotted line can p the be, and no,

R1is-alkyl-NR3-CY-NR5-X-R4,

Y is =O or =S;

X is a bond, -CO - or-SO2-;

R4is phenyl, naphthyl, pyridyl, alkyl or alkenyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

-O-alkyl;

-O-(alkyl)0-1is phenyl;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-(alkyl)0-1-NR3R3;

- halogen;

- halogenated;

- halogenoalkanes;

-CO-halogenoalkanes;

-NO2;

-CN;

provided that when X is a bond, R4can also be hydrogen;

R2is selected from the group which consists of:

is hydrogen;

- alkyl;

is phenyl;

-alkyl-O-alkyl and

- alkyl, substituted by one or more substituents selected from the group which consists of:

is phenyl;

is phenyl, substituted by alkoxyl;

-O-phenyl;

each of R3is hydrogen;

R5selected from the group comprising hydrogen and alkyl, C1-10; or R4and R5together may form a ring of the research or pyrrolidine;

n is the number 0,

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein X is a bond, a Y is =O.

3. The compound according to claim 2, wherein R1is -(CH2)2-4-NR3-CO-NR5-R4.

4. The compound according to claim 2, wherein R2is selected from the group comprising hydrogen, alkyl, alkyl-O-alkyl, (alkyl)0-1phenyl, and alkyl-(phenyl, substituted alkoxyl).

5. The compound according to claim 2, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; alkyl (C1-4-O-alkyl, C1-4.

6. The compound according to claim 2, wherein R4is selected from the group comprising alkyl, phenyl or pyridyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

-O-alkyl;

-O-(alkyl)0-1is phenyl;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-(alkyl)0-1-NR3R3;

- halogen;

- halogenated;

- halogenoalkanes;

-NO2and

-CN.

7. The compound according to claim 2, wherein R4is phenyl, unsubstituted or substituted by one or more substituents selected from the group comprising methyl, methoxy, halogen,nitrile, the nitro-group, and trifluoromethyl.

8. The compound according to claim 2, wherein R4and R5together constitute pyrolidine or morpholino ring.

9. The compound according to claim 1, wherein X is a bond, a Y it =S.

10. The connection according to claim 9, wherein R1is -(CH2)2-4-NR3-CS-NR5-R4.

11. The connection according to claim 9, wherein R2is selected from the group comprising hydrogen, alkyl, alkyl-O-alkyl, (alkyl)0-1phenyl and alkyl-(phenyl, substituted alkoxyl).

12. The connection according to claim 9, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; alkyl (C1-4-O-alkyl, C1-4.

13. The connection according to claim 9, wherein R4is selected from the group comprising alkyl, phenyl or pyridyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

-O-alkyl;

-O-(alkyl)0-1is phenyl;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-(alkyl)0-1-NR3R3;

- halogen;

- halogenated;

- halogenoalkanes;

-NO2and

-CN.

14. The connection according to claim 9, wherein R4is phenyl, unsubstituted or is ewenny one or more substituents, selected from the group comprising methyl, methoxy, halogen, nitrile, nitro-group and trifluoromethyl.

15. The connection according to claim 9, wherein R4and R5together constitute pyrolidine or morpholino ring.

16. The connection section 12, characterized in that X is a bond, a R4is hydrogen.

17. The connection section 12, characterized in that Y is =O and X is-CO-.

18. The connection 17, wherein R1is -(CH2)2-4-NR3-CO-NR5-CO-R4.

19. The connection 17, wherein R2is selected from the group comprising hydrogen, alkyl, alkyl-O-alkyl, (alkyl)0-1-phenyl, alkyl-(phenyl, substituted alkoxyl).

20. The connection 17, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; alkyl (C1-4-O-alkyl, C1-4.

21. The connection 17, wherein R4is selected from the group comprising alkyl, phenyl or pyridyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

-O-alkyl;

-O-(alkyl)0-1is phenyl;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-(alkyl)0-1-NR3R3;

- halogen;

- halo is aralkyl;

- halogenoalkanes;

- NO2;

- CN.

22. The connection 17, wherein R4is phenyl, unsubstituted or substituted by one or more substituents selected from the group comprising methyl, methoxy, halogen, nitrile, nitro-group and trifluoromethyl.

23. The connection 17, wherein R4and R5together constitute pyrolidine or morpholino ring.

24. The compound according to claim 1, characterized in that Y is =O and X is-SO2-.

25. The connection point 24, wherein R1is -(CH2)2-4-NR3-CO-NR5-SO2-R4.

26. The connection point 24, wherein R2is selected from the group comprising hydrogen, alkyl, alkyl-O-alkyl, (alkyl)0-1-phenyl, alkyl-(phenyl, substituted alkoxyl).

27. The connection point 24, wherein R2is selected from the group comprising hydrogen; alkyl (C1-4; (alkyl C1-4)-O-(alkyl C1-4).

28. The connection point 24, wherein R4is selected from the group comprising alkyl or phenyl, each of which can be unsubstituted or substituted by one or more substituents selected from the group which consists of:

- alkyl;

is phenyl;

-O-alkyl;

-O-(alkyl)0-1is phenyl;

-CO-O-alkyl;

-CO-alkyl;

-S(O)0-2-alkyl;

-(alkyl)0-1-NR3R3;

- halogen;

- halogenated;

- halogenoalkanes;

-NO2and

-CN.

29. The connection point 24, wherein R4is phenyl, unsubstituted or substituted by one or more substituents selected from the group comprising methyl, methoxy, halogen, nitrile, nitro-group, a trifluoromethyl.

30. The connection point 24, wherein R4and R5together constitute pyrolidine or morpholino ring.

31. The compound according to claim 1, characterized in that the dashed connection missing.

32. The compound according to claim 2, characterized in that the dashed connection missing.

33. The connection according to claim 9, characterized in that the dashed connection missing.

34. The connection 17, characterized in that the dashed connection missing.

35. The connection point 24, characterized in that the dashed connection missing.

36. Compound selected from the group which consists of:

N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-benzyladenine;

N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-mutilation;

N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(2-ethylphenyl)urea;

N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-cyclohexyloxy the ina;

N'-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N-methyl-N-phenylacetone;

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

N-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-N'-(4-phenoxyphenyl)urea;

N-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-N'-benzyladenine;

N-[2-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)ethyl]-N'-proprotein;

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

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

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

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

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

N-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-proprotein;

N-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-[(1S)-1-phenylethyl]urea;

N-[4-(4-amino-2-butyl-1H-imidazo(4,5-C]quinoline-1-yl)butyl]-N'-[(1R)-1-phenylethyl]urea;

N-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]-N'-(2-methoxyphenyl) urea;

N-(4-acetylphenyl)N'-[4-(4-amino-2-butyl-1H-imidazo[4,5-C]quinoline-1-yl)butyl]urea;

N-[4-(4-amino-2-butyl-1H-and is idazo[4,5-c]quinoline-1-yl)butyl]-N'-[4-(dimethylamino)phenyl]urea;

N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinoline-1-yl)butyl]-N'-(4-methoxybenzyl)urea;

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

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(3-were)urea;

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(3-forfinal)urea;

N4-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-4-morpholinylcarbonyl;

N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-proprotein;

N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-phenylacetone; and

N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinoline-1-yl]butyl}-N'-(3-pyridyl)urea;

37. Compound selected from the group which consists of:

N-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-benzyladenine;

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

N4-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-4-morpholinylcarbonyl; and

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

38. Compound selected from the group which consists of:

N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-C]hin the Lin-1-yl]ethyl}-N'-cyclohexyldiamine;

N-[4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-cyclohexyldiamine;

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(3-pyridyl)urea;

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(4-(dimethylamino)-1-naphthyl)thiourea;

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

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

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

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

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

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(1-naphthyl)thiourea;

N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}-N'-(tert-butyl)thiourea; and

N-allyl-N'-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-C]quinoline-1-yl]butyl}thiourea.

39. Compound selected from the group which consists of:

4-amino-2-butyl-1-[4-({[(phenylsulfonyl)amino]carbonyl}amino)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-[4-({[(phenylsulfonyl)amino]carbonyl}am the but)butyl]-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-{4-[({[(4-forfinal)sulfonyl]amino}carbonyl)amino]butyl}-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-{4-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]butyl}-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-{4-[({[(4-ethylphenyl)sulfonyl]amino}carbonyl)amino]butyl}-1H-imidazo[4,5-C]quinoline;

4-amino-2-(2-methoxyethyl)-1-{4-[({[(4-were)sulfonyl]amino}carbonyl)amino]butyl}-1H-imidazo[4,5-C]quinoline;

4-amino-2-(2-methoxyethyl)-1-[4-({[(phenylsulfonyl)amino]carbonyl}amino)butyl]-1H-imidazo[4,5-C]quinoline;

4-amino-2-(ethoxymethyl)-1-[4-({[(phenylsulfonyl)amino]carbonyl}amino)ethyl]-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-{4-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-1H-imidazo[4,5-C]quinoline;

4-amino-2-butyl-1-{4-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}-1H-imidazo[4,5-C]quinoline.

40. Pharmaceutical drug, as immunomodulator initiating the biosynthesis of cytokines containing a therapeutically effective amount of compounds of formula Ia

where communication is depicted by the dashed line, can be present or absent;

R1is-alkyl-NR3-CO-O-R4;

R4is aryl or alkyl, and alkyl substituted with aryl;

R2is selected from the group, in which the th includes:

is hydrogen or

is phenyl;

-alkyl-O-alkyl;

each of R3selected from the group comprising hydrogen and alkyl, C1-10;

n is a number equal to 0

R is independently selected from the group comprising alkyl, C1-10alkoxyl C1-10, halogen and trifluoromethyl,

or its pharmaceutically acceptable salt.

41. Pharmaceutical compound, causing the induction of interferon-α or factor-α tumor necrosis comprising a therapeutically effective amount of a compound according to claim 1 or 2, or 17, or 24, in combination with a pharmaceutically acceptable carrier.

42. Method of induction of the biosynthesis of cytokines in animals, including the introduction of the animal a therapeutically effective amount of a compound according to claim 1 or 2, or 17 or 24.

43. A method of treating viral diseases in animals, including the introduction of the animal a therapeutically effective amount of a compound according to claim 1 or 2, or 17 or 24.

44. The method of treatment neoplasticeskih pathologies in animals, including the introduction of the animal a therapeutically effective amount of a compound according to claim 1 or 2, or 17 or 24.

45. Method of induction of the biosynthesis of cytokines in animals, including the introduction of the animal a therapeutically effective amount of the drug on p.

46. The method of treatment of viral diseases is any animals includes introduction to the animal a therapeutically effective amount of the drug on p.

47. The method of treatment neoplasticeskih pathologies in animals, including the introduction of the animal a therapeutically effective amount of the drug on p.

Priority points and features:

10.06.1999 in respect of claims 1 to 30, 40-44 about signs: R2comprising hydrogen, phenyl; p regarding sign: N-[4-(4-amino-1H-imidazo[4,5-C]quinoline-1-yl)butyl-N1-benzyladenine;

07.06.2000 in respect of all claims.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

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

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

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

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with applying birch bark extract at betulin content in it being above 70% for the purpose to prevent viral hepatitis C and, moreover, manufacture medicinal preparation for preventing viral hepatitis C.

EFFECT: higher efficiency of prophylaxis.

2 cl, 1 tbl

FIELD: biotechnology, immunology.

SUBSTANCE: invention proposes preparation that comprises the immunoelectrophoretically pure secretory immunoglobulin A isolated from whey milk and/or colostrum of immunized ungulate animals and pharmaceutically acceptable vehicles. The base preparation (substance) comprises 6-12% of secretory immunoglobulin A at pH 4-8, an anti-complementary activity at least 10 mg of protein, not activating 2 CH50, protects in >70% against corresponding infections (in infection macroorganism in doses ≥10 ID50), shows areactogenic property in intravenous administration, can comprise stabilizing additives in the total concentration 4%, not above. The preparation possesses high purity, low anti-complementary activity, stable in storage, useful for oral, parenteral and topical using and possesses therapeutic activity with respect to microorganisms and viruses against which humans and animals immunization have been carried out. Invention can be used in treatment and prophylaxis of immunodeficiency states, bacterial and viral infections in humans and animals.

EFFECT: valuable medicinal and veterinary properties of preparation.

9 cl, 1 tbl, 10 ex

FIELD: medicine, biopharmacology, immunology.

SUBSTANCE: invention relates to manufacturing curative-prophylactic preparations based on leukocyte interferon and natural cytokines. The preparation based on complex of natural cytokines is prepared by induction of human leukocytes with Newcastle disease virus of strain "H". Indicated complex of natural cytokines is prepared by at least two treatments of leukocytes before induction stage with virus with the same natural complex of cytokines prepared in previous stage of induction. Complex is purified from foreign proteins of inductor and comprises 104 IU of antiviral activity of human interferon-alpha in one ampoule, not less, and cellular cytokines, phosphate buffer for maintaining pH 6.9-7.5, sodium chloride and mannitol. The end product is lyophilized for preparing the injection preparation. Invention provides increasing activity of the preparation and to retain the natural complex of cytokines.

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

3 cl, 2 ex

FIELD: biotechnology, immunology, veterinary science.

SUBSTANCE: invention proposes the preparation that represents 9,0-11.0% immunoglobulins solution of horse blood serum with pH value from 7.0 to 7.5. The content of γ-globulin fraction in this preparation is 90.0%, not less, of the total protein amount. The preparation comprises albumin, α- and β-globulin fractions as nonspecific impurities in the amount 10.0%, not above, and residual ethyl alcohol in the amount 4.0%, not above. The preparation is apyrogenic, non-toxic and sterile.

EFFECT: valuable properties of preparation.

1 tbl, 1 ex

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to new synthetic biologically active derivatives of pyrimidine, namely to 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine potassium, sodium or ammonium salt of the general formula: wherein X is taken among the group: Na+, K+, NH+4. The claimed substance shows expressed antibacterial activity directed mainly against different fungi, bacteria, protozoan and viruses.

EFFECT: valuable biological properties of compounds.

13 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: veterinary medicine.

SUBSTANCE: vaccine has avirulent antigen material produced from O№112-DEP strain homological virus, protection medium and adjuvant taken in effective proportions. The strain is deposited in micro-organism VGNKI collection under registry number of O№112-DEP. The O№112-DEP strain virus is reproduceable in 9-11 days old SPF-hen embryos having infectious activity of at least 6.9 lg EID50/cm3. The vaccine comprises ethylene imine dimer in 0.1% concentration as inactivation agent. The antigen material is mixed with protection medium after activation and subjected to lyophilization. Before being used, the dried antigen material is solved in adjuvant containing aerosyl, saponin, glycerol and phosphate buffer solution taken in effective proportions. The vaccine is intramuscularly introduced for immunizing clinically healthy 25-30 days old birds in the amount of 0.5 cm3. Immunity comes to a vaccinated bird at the fourteenth-twenty first day after vaccination.

EFFECT: high antigenic and immunogenic activity; no adverse side effects.

8 cl, 5 tbl

FIELD: veterinary medicine.

SUBSTANCE: vaccine has antigenic material produced from La-Sota strain reproduced in 9-10 days old SPF-hen embryos having infectious activity of at least 9.7 lg EID50/cm3 and hemagglutination activity equal to at least 1:512, protective medium and adjuvant of thymogen taken in effective proportions. The protective medium comprises 20% lactalbumin hydrolyzate solution and degreased milk in 1:5 proportion. The vaccine is produced by mixing its ingredients and with following preparation lyophilization. Ready vaccine is dry porous mass of light yellow color. The vaccine is applicable for carrying out specific prophylaxis. The vaccine is introduced as spray at a dose of 1 cm3/head.

EFFECT: high antigenic and immunogenic activity; no adverse side effects.

7 cl, 8 tbl

FIELD: medicine.

SUBSTANCE: method involves treating hepatitis C virus infection or hepatitis B virus infection by introducing carboxamidine of formula 1 or its pharmaceutically permissible salt at a dose of 0.1-40.0 mg/kg of body mass. Α-interferon is also introduced. Compound of formula 1 is in D-configuration.

EFFECT: enhanced effectiveness of treatment.

7 cl, 5 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

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