RU2294934C2 - Substituted imidazopyridines - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the formula (I):

wherein X means alkylene group; Y means -CO-, -CS- or -SO₂-group; Z represents a simple bond or -NR₅-group; R₁ represents unsubstituted phenyl or phenyl substituted with halogen atom. (C₁-C₂₀)-alkyl group; R₂ is chosen from -alkyl, -alkyl-O-alkyl; R₃ and R₄ represent alkyl; R₅ represents hydrogen atom or (C₁-C₁₀)-alkyl group; Also, invention describes intermediate compounds - derivatives of imidazopyridine-4-amine, 2-phenoxypyridine and 4-phenoxypyridine. Proposed compounds and pharmaceutical compositions are able to stimulate biosynthesis of different cytokines and can be used in treatment of viral and tumor diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

32 cl, 1 tbl, 9 ex

Description

This invention relates to imidazopyridine compounds that have a substituted amino group at position 1, as well as to pharmaceutical compositions containing such compounds. In addition, this invention relates to the use of these compounds as immunomodulators for stimulating cytokine biosynthesis in an animal, as well as for treating various diseases, including viral and tumor diseases.

The first reliable data on the 1H-imidazo [4,5-s] quinoline ring system are given by Buckman et al., J. Org. Chem., 15, 1278-1284 (1950), which reported the synthesis of 1- (6-methoxy-8-quinolinyl) -2-methyl-1H-imidazo [4,5-c] quinoline for its possible use as an antimalarial facilities. Subsequently, reports appeared on the synthesis of various substituted 1H-imidazo [4,5-c] quinolines. For example, Jain et al., J. Med. Chem., 11, pp. 87-92 (1968), synthesized 1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline as a possible anticonvulsant and cardiovascular agent. In addition, Baranov et al., Chem. Abs., 85, 94362 (1976), reported the synthesis of several 2-oxoimidazo [4,5-s] quinolines. Berenie et al., J. Heterocvclic Chem., 18, 1537-1540 (1981), also reported the synthesis of several 2-oxoimidazo [4,5-c] quinolines.

It was later found that certain 1H-imidazo [4,5-c] quinolin-4-amines and their 1- and 2-substituted derivatives can be used as antiviral agents, bronchodilators and immunomodulators. These compounds are described, inter alia, in US Pat. Nos. 4,689,338, 4,698,348, 4,929,624, 5,037,986, 5,268,376, 5,346,905 and 5,389,640; all of these patents are incorporated herein by reference.

Substituted compounds of 1H-imidazopyridin-4-amine, which are effective modifiers of the immune response, are described in US Patent Nos. 5,446,153; 5,494,916 and 5,644,063. The compounds described in these patents, however, do not contain a substituted amino group at position 1. Certain 1H-imidazo [4,5-c] quinolin-4-amines containing the amide, sulfonamide and urethane groups at position 1 are described in PCT Publications WO 00/76505, WO 00/76518 and WO 00/76519.

Despite the recent emergence of compounds that are modifiers of the immune response, there remains a need for compounds with the ability to modulate the immune response by stimulating cytokine biosynthesis or using other mechanisms.

Summary of the invention

A new class of compounds has been found that can stimulate the cytokine biosynthesis in animals. Accordingly, the present invention provides imidazopyridin-4-amine compounds that have a substituted amino group having a substituent at the 1-position. Compounds capable of stimulating cytokine biosynthesis according to IR spectroscopy have the formula (I) below

The nature of the substituents X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 is} described below.

Compounds having the formula (I) are useful modifiers of the immune response due to their ability to initiate cytokine biosynthesis or otherwise modulate the immune response when introduced into animals. This makes such compounds useful in the treatment of various diseases, in particular viral and tumor diseases, which are sensitive to such changes in the immune response.

The invention also provides pharmaceutical compositions containing compounds that alter the immune response, and provides methods for stimulating cytokine biosynthesis in an animal and treating a viral infection and / or tumor in an animal by administering compounds of formula I to the animal.

In addition, methods for the synthesis of compounds of the invention, as well as intermediates used in the synthesis of these compounds, are provided.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, we found some compounds that stimulate the cytokine biosynthesis and modify the immune response in animals. Such compounds have the formula (I) shown below

where X is alkylene or alkenylene group;

Y is —CO—, —CS— or —SO ₂ —groups;

Z represents a single bond or groups —O—, —S— or —NR ₅ -;

R ₁ represents an aryl, heteroaryl, heterocyclyl, C _1-20 alkyl or C _2-20 alkenyl group, each of these groups may be unsubstituted or contain one or more substituents independently selected from the group consisting of

alkyl;

alkenyl;

aryl;

heteroaryl;

heterocyclyl;

-substituted cycloalkyl;

-O-alkyl;

-O- (alkyl) _0-1 aryl;

-O- (alkyl) _0-1- heteroaryl;

-O- (alkyl) _0-1- 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- heteroaryl;

-S (O) _0-2 - (alkyl) _0-1- heterocyclyl;

- (alkyl) _0-1 —N (R ₅ ) ₂ ;

- (alkyl) _0-1 -NR ₅ -CO-O-alkyl;

- (alkyl) _0-1 -NR ₅ -CO-alkyl;

- (alkyl) _0-1 -NR ₅ -CO-aryl;

- (alkyl) _0-1 -NR ₅ -CO-heteroaryl;

-N ₃ ;

a halogen atom;

haloalkyl;

haloalkoxyl;

-CO-haloalkyl;

-CO-haloalkoxyl;

-NO ₂ ;

-CN;

-IT;

-SH; and in the case of alkyl, alkenyl and heterocyclyl groups, also an oxo group;

Deputy R ₂ selected from the group including

a hydrogen atom;

alkyl;

alkenyl;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

- alkyl or alkenyl containing one or more

substituents selected from the group including

-OH;

-halogen

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C _1-10 alkyl;

-NR ₅ -CS-C _1-10 alkyl;

-NR ₅ -SO ₂ -C _1-10 alkyl;

-CO-C _1-10 alkyl;

-CO-OC _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and

each R ₅ substituent independently represents a hydrogen atom or a C _1-10 alkyl group;

or a pharmaceutical grade salt based on these groups.

Getting connections

The compounds of the invention can be prepared according to Reaction Scheme I, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, Y, and Z are as defined above, Bn is a benzyl group, and R 'is represents an alkyl group containing from one to four carbon atoms, or a perfluoroalkyl group containing from one to four carbon atoms. As the substituent R ', a phenyl group or a phenyl group containing as a substituent a halogen atom or an alkyl group having from 1 to 4 carbon atoms can also be used.

At the stage (1) of the process (reaction scheme I), a reaction is carried out between 3-nitropyridine-2,4-disulfonate (formula X) and an amine of the formula R ₁ -ZYN (R ₅ ) -X-NH ₂ , as a result of which 3- nitro-4-aminopyridin-2-sulfonate of the formula XI. The presence of two sulfonate groups, which, in principle, can be substituted, determines the fact that the reaction can form a mixture of products, which, however, can be easily separated using conventional methods, such as preparative chromatography. The reaction is preferably carried out by adding an amine to a solution of the compound of formula X in a suitable solvent, such as dichloromethane, in the presence of a tertiary amine, for example triethylamine. Since the sulfonate group is relatively labile, the reaction can be carried out at a reduced temperature (0 ° C). This helps to reduce the amount of unwanted by-products of 2-aminated and 2,4-diaminated products formed. 3-Nitropyridine-2,4-disulfonates are well known products and can be easily obtained using known synthetic methods, see, for example, Lindstrom et al., US Patent No. 5,446,153, and cited in this patent by reference.

In process step (2) (Reaction Scheme I), a 1-nitro-4-aminopyridin-2-sulfonate of the formula XI is treated with dibenzylamine, whereby a 2-dibenzylamino-3-nitropyridin-4-amine of the formula XII is obtained. To carry out the reaction, a compound of formula XI, dibenzylamine and a tertiary amine such as triethylamine are dissolved in an inert solvent such as benzene, toluene or xylene, and the resulting mixture is heated.

At the stage (3) of the process (reaction scheme 1), the nitro group of 2-dibenzylamino-3-nitropyridin-4-amine (compound of formula XII) is reduced to the amino group. The reduction is preferably carried out under the action of NiB ₂ , which is formed in situ from a solution of sodium borohydride and nickel chloride hydrate in methanol. The reaction is preferably carried out at ambient temperature.

In process step (4) (Reaction Scheme I), 2-dibenzylaminopiperidin-3,4-diamine (compound of formula XIII) is treated with carboxylic acid or its equivalent to obtain 4-dibenzylamino-1H-imidazo [4,5-c] pyridine having formula XV. Suitable carboxylic acid equivalents are orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or its equivalent is chosen so that they ensure the introduction of the necessary substituent R ₂ in the compound of formula XV. For example, when using triethyl orthoformate, a compound will be obtained in which R ₂ represents a hydrogen atom, and when using triethyl orthoacetate, R ₂ = CH ₃ . The reaction can be carried out in the absence of a solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to ensure removal of any alcohol or water formed as by-products during this reaction. If desired, a catalyst such as pyridine hydrochloride may be used in the reaction.

Alternatively, a compound of formula XV can be obtained in two stages by (a) reacting compound XIII with an acyl halide of formula R ₂ C (O) Cl or R ₂ C (O) Br, in which a compound of formula XIV is formed, and (b) subsequent cyclization received product. In step (4a), the acyl halide is added to a solution of diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at room temperature. In step (4b), the product obtained in step (4a) is heated in an alcohol solvent in the presence of a base. Preferably, the product obtained in step (4a) is boiled in ethanol in the presence of an excess of triethylamine or heated in the presence of a methanol solution of ammonia. Another option for carrying out stage (4b) is to heat the product obtained in stage (4a) in pyridine. If step (4a) is carried out in pyridine, step (4b) can be carried out by heating the reaction mixture, after, according to the analysis, step (4a) is completed.

At the stage (5) of the process (reaction scheme I), 4-dibenzylamino-1H-imidazo [4,5-c] pyridine of the formula XV is reduced to 4-amino-1H-imidazo [4,5-c] pyridine ( a compound of formula I). Preferably, the compound of formula XV is heated in formic acid in the presence of palladium hydroxide supported on activated carbon. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

Reaction Scheme I

The compounds of the invention can be prepared according to reaction scheme II in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as defined above, Bn is a benzyl group, BOC is a tert-butoxycarbonyl group, and W is atoms O or S.

In step (1) of the process (reaction scheme II), the protective amino groups of 1H-imidazo [4,5-c] pyridine in the compound of formula XVI are removed and 1H-imidazo [4,5-c] pyridine of formula II is obtained. Preferably, a solution of compound XVI in a suitable solvent, such as dichloromethane, is treated at room temperature with trifluoromethane acetic acid. The compounds of formula XVI can be obtained using the synthesis method used to obtain products in accordance with scheme I of the reaction. In step (1), a 2,4-disulfonate of formula X is treated with an amine of formula BOC-NR ₅ -X-NH ₂ . Then, steps (2) to (4) are carried out as described above to obtain a compound of formula XVI, which is a derivative of compound XV.

In process step (2a) (Reaction Scheme II), a reaction is carried out between 1H-imidazo [4,5-c] pyridine of formula II and an acid chloride of formula R ₁ -C (O) Cl or an acid anhydride of formula R ₁ -C (O) OC (O) -R ₁ and get 1H-imidazo [4,5-c] pyridin-1-yl-amide of the formula XVII, which is a derivative of compound I. The reaction is preferably carried out in the presence of a base such as triethylamine, adding acid chloride or acid anhydride to a solution of a compound of formula II in a suitable solvent, such as dichloromethane or acetonitrile. The reaction can proceed at a reduced temperature (0 ° C) or at room temperature. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

In process step (2b) (Reaction Scheme II), 1H-imidazo [4,5-c] pyridine of formula II is treated with an isocyanate of formula R ₁ -N = C = O or an isothiocyanate of formula R ₁ -N = C = S and as a result, 1H-imidazo [4,5-c] pyridin-1-yl-urea or thiourea of formula XVIII, which is a derivative of the compound of formula I. The reaction is preferably carried out at a reduced temperature (0 ° C) by adding isocyanate or isothiocyanate to a solution of the compound of formula II in a suitable solvent, such as dichloromethane. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

In process step (2c) (reaction scheme II), 1H-imidazo [4,5-c] pyridine of formula II is treated with a sulfonic acid chloride of the formula R ₁ -S (O) ₂ Cl or a sulfonic acid anhydride R ₁ -S (O) ₂ OS (O) ₂ -R ₁ . The result is 1H-imidazo [4,5-c] pyridin-1-yl-sulfonamide of formula XIX, which is a derivative of the compound of formula I. The reaction is preferably carried out by adding sulfonic acid chloride or sulfonic acid anhydride to a solution of the compound of formula II in an appropriate solvent such as dichloromethane in the presence of a base, for example triethylamine. The reaction can proceed both at low (0 ° С) and at room temperature. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

Reaction Scheme II

The compounds of the invention can be prepared according to reaction scheme III, in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as defined above.

At the stage (1) of the process (reaction scheme III), 1H-imidazo [4,5-s] pyridine of the formula II reacts with sulfamoyl chloride R ₁ -N (R ₅ ) S (O) ₂ Cl to form 1H-imidazo [4,5 -c] pyridin-1-yl-sulfamide of the formula XXI, which is a derivative of the compound of the formula I. Preferably, sulfamoyl chloride is added to a solution of the compound of the formula II in a suitable solvent, such as 1,2-dichloroethane, in the presence of a base, for example triethylamine. The reaction can be carried out at elevated temperature. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

Alternatively, the compound of formula XXI can be obtained in two stages as a result of (a) the reaction of 1H-imidazo [4,5-c] pyridine of formula II with sulfuryl chloride, resulting in the formation of in situ sulfamoyl chloride of formula XX, and (b) the subsequent interaction of sulfamoyl chloride with an amine of the formula R ₁ —N (R ₅ ) H. In step (1a), the reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of the compound of formula II in the presence of 1 equivalent of 4- (dimethylamino) pyridine. Preferably, the reaction is carried out at a reduced temperature (-78 ° C). In some cases, upon completion of the addition of components, the reaction mixture can be warmed to room temperature. In step (1b), a solution containing 2 equivalents of R ₁ —N (R ₅ ) H and 2 equivalents of triethylamine in dichloromethane is added to the reaction mixture resulting from step (1a). The reaction is preferably carried out at a reduced temperature (-78 ° C). A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

Reaction Scheme III

The compounds of the invention can be prepared according to Reaction Scheme IV, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as defined above and BOC means a tert-butoxycarbonyl group.

In step (1) of the process (Reaction Scheme IV), chlorinated 2,4-dihydroxy-3-nitropyridine of formula XXII is chlorinated using conventional chlorinating agents, resulting in 2,4-dichloro-3-nitropyridine of formula XXIII. Preferably, the compound of formula XXII is treated with phosphorus oxychloride by heating. Many 2,4-dihydroxy-3-nitropyridines of the formula XXII are known. Other such compounds can be easily obtained using known synthetic methods, see, for example, Lindstom et al., US Patent No. 5,446,153, and cited in this patent by reference.

In process step (2) (Reaction Scheme IV), 2,4-dichloro-3-nitropyridine of formula XXIII is treated with an amine of formula BOC-NR ₅ -X-NH ₂ , whereby 2-chloro-3-nitropyridine of formula XXIV is obtained. The reaction is preferably carried out by adding an amine to a solution of the compound of formula XXIII in a suitable solvent, such as N, N-dimethylformamide, in the presence of a tertiary amine, for example triethylamine.

In process step (3) (Reaction Scheme IV), a reaction is carried out between 2-chloro-3-nitropyridine of the formula XXIV and phenol, resulting in the production of 3-nitro-2-phenoxypyridine of the formula XXV. Phenol is reacted with sodium hydride in a suitable solvent, such as diglyme, to form phenoxide. Phenoxide, in turn, reacts at elevated temperatures with a compound of formula XXIV.

At the stage (4) of the process (reaction scheme IV), 3-nitro-2-phenoxypyridine of formula XXV is reduced to 3-amino-2-phenoxypyridine of formula XXVI. The reduction is preferably carried out using conventional heterogeneous hydrogenation catalysts, such as, for example, platinum or palladium supported on activated carbon. The reaction is preferably carried out in a Parr apparatus in a suitable solvent, such as isopropyl alcohol or toluene.

In process step (5) (Reaction Scheme IV), 3-amino-2-phenoxypyridine (compound of formula XXVI) is treated with a carboxylic acid or its equivalent to obtain 4-phenoxy-1H-imidazo [4,5-c] quinoline having the formula IV . Suitable carboxylic acid equivalents are orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or its equivalent is chosen so that they ensure the introduction of the necessary substituent R ₂ in the compound of formula IV. For example, using triethylorthoformate, a compound will be obtained in which R ₂ represents a hydrogen atom, and when using trimethylorthovaleriate R ₂ = C ₄ H ₉ . The reaction can be carried out in the absence of a solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to ensure removal of any alcohol or water formed as by-products during this reaction. If desired, a catalyst such as pyridine hydrochloride may be used in the reaction.

Alternatively, step (5) can be carried out by (i) reacting a compound of formula XXVI with an acyl halide of formula R ₂ C (O) Cl or R ₂ C (O) Br and (ii) subsequent cyclization of the resulting product. In step (i), the acyl halide is added to a solution of the compound of formula XXV in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. In step (ii), the product obtained in step (i) is heated in pyridine.

In process step (6) (Reaction Scheme IV), BOC groups are cleaved from the compound of formula IV to give 4-phenoxy-1H-imidazo [4,5-c] quinoline of formula V. Preferably, a solution of compound IV in a suitable solvent, such as dichloromethane, is treated at reduced temperature with trifluoroacetic acid or hydrochloric acid.

In process step (7) (Reaction Scheme IV), 4-phenoxy-1H-imidazo [4,5-s] quinoline of formula V is converted to 4-phenoxy-1H-imidazo [4,5-s] quinolin-1-yl- sulfonamide of the formula VI. This process is carried out in the same manner as stage (2c) in reaction scheme II.

In process step (8) (Reaction Scheme IV), 4-phenoxy-1H-imidazo [4,5-s] quinolin-1-yl-sulfonamide of formula VI is aminated to give 4-amino-1H-imidazo [4,5- c] quinolin-1-yl-sulfonamide of the formula XIX, which is a derivative of the compound of the formula I. The reaction can be carried out by adding ammonium acetate to the compound of the formula VI and heating the resulting mixture in a sealed ampoule at a temperature of about 150 ° C. A product or pharmaceutical grade salt based thereon can be isolated using conventional methods.

Reaction Scheme IV

The invention also reports on the synthesis of new compounds of interest as intermediates necessary for the preparation of compounds of formula I. These intermediates have structural formulas II-VI, described in detail below.

One class of intermediates has the formula (II)

where X is an alkylene or alkenylene group;

Deputy R ₂ selected from the group including

a hydrogen atom;

alkyl;

alkenyl;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

- alkyl or alkenyl containing one or more substituents selected from the groups including

-IT;

-halogen

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C _1-10 alkyl;

-NR ₅ -CS-C _1-10 alkyl;

-NR ₅ -SO ₂ -C _1-10 alkyl;

-CO-C _1-10 alkyl;

-CO-OC _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R ₅ is independently a hydrogen atom or

A C _1-10 alkyl group;

or a pharmaceutical grade salt based on these groups.

Another class of intermediates has the formula III

where Q represents NO ₂ or NH ₂ groups;

X is an alkylene or alkenylene group;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and each R ₅ is independently either a hydrogen atom or C _1-10 an alkyl group;

or a pharmaceutical grade salt based on these groups.

Another class of intermediates has the formula (IV)

where X is an alkylene or alkenylene group;

Deputy R ₂ selected from the group including

a hydrogen atom;

alkyl;

alkenyl;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

- alkyl or alkenyl containing one or more substituents selected from the group including

-IT;

-halogen

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C _1-10 alkyl;

-NR ₅ -CS-C _1-10 alkyl;

-NR ₅ -SO ₂ -C _1-10 alkyl;

-CO-C _1-10 alkyl;

-CO-OC _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and

each R ₅ substituent independently represents a hydrogen atom or a C _1-10 alkyl group;

or a pharmaceutical grade salt based on these groups.

Another class of intermediates has the formula (V)

where X is an alkylene or alkenylene group;

Deputy R ₂ selected from the group including

a hydrogen atom;

alkyl;

alkenyl;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

- alkyl or alkenyl containing one or more

substituents selected from the group including

-IT;

-halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C _1-10 alkyl;

-NR ₅ -CS-C _1-10 alkyl;

-NR ₅ -SO ₂ -C _1-10 alkyl;

-CO-C _1-10 alkyl;

-CO-O-C _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and

each R ₅ substituent is independently either a hydrogen atom or a C _1-10 alkyl group;

or a pharmaceutical grade salt based on these groups.

And finally, the last class of intermediates provided in the present invention has the formula (VI)

in which X is an alkylene or alkenylene group;

R ₁ represents an aryl, heteroaryl, heterocyclyl, C _1-20 alkyl or C _2-20 alkenyl group, each of these groups may be unsubstituted or contain one or more substituents independently selected from the group consisting of

alkyl;

alkenyl;

aryl;

heteroaryl;

heterocyclyl;

- substituted cycloalkyl;

-O-alkyl;

-O- (alkyl) _0-1 aryl;

-O- (alkyl) _0-1- heteroaryl;

-O- (alkyl) _0-1- 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- heteroaryl;

-S (O) _0-2 - (alkyl) _0-1- heterocyclyl;

- (alkyl) _0-1 —N (R ₅ ) ₂ ;

- (alkyl) _0-1 -NR ₅ -CO-O-alkyl;

- (alkyl) _0-1 -NR ₅ -CO-alkyl;

- (alkyl) _0-1 -NR ₅ -CO-aryl;

- (alkyl) _0-1 -NR ₅ -CO-heteroaryl;

-N ₃ ;

a halogen atom;

haloalkyl;

haloalkoxyl;

-CO-haloalkyl;

-CO-haloalkoxyl;

-NO ₂ ;

-CN;

-IT;

-SH, and in the case of alkyl, alkenyl and heterocyclyl groups, also an oxo group;

R _{2 is} selected from the group consisting of: a hydrogen atom;

alkyl;

alkenyl;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

- alkyl or alkenyl containing one or more substituents selected from the group including

-IT;

-halogen

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C _1-10 alkyl;

-NR ₅ -CS-C _1-10 alkyl;

-NR ₅ -SO ₂ -C _1-10 alkyl;

-CO-C _1-10 alkyl;

-CO-OC _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl;

the substituents R ₃ and R _{4 are} independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R ₅ represents a hydrogen atom or a C _1-10 alkyl group;

or a pharmaceutical grade salt based on these groups.

As used herein, the terms “alkyl”, “alkenyl” and the prefix “alk—” include both linear and branched chain groups, as well as cyclic groups, for example cycloalkyl and cycloalkenyl groups. Unless otherwise indicated, these groups contain from 1 to 20 carbon atoms, and alkenyl groups from 2 to 20 carbon atoms. Preferably, these groups contain up to 10 carbon atoms. The cyclic groups can be either monocyclic or polycyclic and preferably contain from 3 to 10 carbon atoms in the cycle. Examples of cyclic groups are cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl and adamantyl groups.

The term “haloalkyl” includes groups which, as a substituent, have one or more halogen atoms, including perfluorinated groups. This definition also applies to groups that include the prefix "halo". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

The term “aryl”, as used herein, includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl groups. The term “heteroaryl” refers to aromatic rings or cyclic systems containing in the ring at least one heteroatom (for example, O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolyl, isoquinolyl, indolyl, isoindolyl, triazole, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazole, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl and similar groups.

The composition of "heterocyclyl" compounds includes non-aromatic rings or cyclic systems containing in the ring at least one heteroatom (for example, O, S, N). These compounds include all fully saturated and partially unsaturated derivatives of the above heteroaryl groups. Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl and imidazolidinyl groups.

Aryl, heteroaryl and heterocyclyl groups can be either unsubstituted or containing one or more substituents independently selected from the group consisting of alkyl, alkoxyl, alkylthionyl, haloalkyl, haloalkoxyl, haloalkylthionyl groups, halogen atom, nitrile, hydroxy, hydroxy, hydroxy carboxyl, formyl, aryl, aryloxy, arylthionyl, arylalkoxyl, arylalkylthionyl, heteroaryl, heteroaryloxy, heteroarylthionyl, heteroarylalkoxyl hydrochloric, geteroarilalkiltionilnuyu, amino, alkylamino, dialkylamino, heterocyclyl, geterotsikpoalkilnuyu, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, galoalkilkarbonilnuyu, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, geteroariloksikarbonilnuyu, ariltiokarbonilnuyu, geteroariltiokarbonilnuyu, alkanoyloxy, alkanoiltionilnuyu, arilkarboniloksilnuyu, arilkarboniltionilnuyu, arylcarbonylamino -, alkylaminosulfonyl, alkylsulfonyl w, arylsulfonyl, heteroarylsulfonyl, arildiazinilnuyu, alkylsulfonylamino, arylsulfonylamino, arilalkilsulfonilamino-, alkylcarbonylamino, alkenilkarbonilamino-, arylcarbonylamino, arilalkilkarbonilamino-, geteroarilkarbonilamino-, geteroarilalkilkarbonilamino-, alkylsulfonylamino, alkenilsulfonilamino-, arylsulfonylamino, arilalkilsulfonilamino-, geteroarilsulfonilamino-, geteroarilalkilsulfonilamino -, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbon lamino-, geteroarilaminokarbonilamino-, geteroarilalkilkarbonilaminogruppy; in addition, in the case of heterocyclyl groups, oxo groups. In the event that any other groups are identified as “substituted” or “sometimes substituted”, these groups may also have one or more of the above groups as a substituent.

Generally, only certain substituents are preferred. For example, as preferred groups Y use —CO— and —SO ₂ - groups; preferred Z groups are a single bond or a group —NR ₅ -; preferred R ₁ substituents are a C _1-4 alkyl, aryl or substituted aryl group. Preferred R ₂ groups include alkyl groups containing from 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl groups), methoxymethyl, ethoxymethyl and cyclopropylmethyl groups. A preferred substituent of R ₃ and R ₄ is a methyl group. One or more of these preferred substituents, if any, may be present in any combination of the compounds of the invention.

The invention includes the compounds described above in any pharmaceutically acceptable form thereof, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphic forms and the like. In particular, if the compound is optically active, the invention describes each enantiomer of this compound, as well as a racemic mixture of enantiomers.

Pharmaceutical Formulations and Biological Activity

The pharmaceutical compositions of the invention comprise therapeutically effective amounts of the compounds described above in combination with a pharmaceutically acceptable carrier.

As used herein, the term “therapeutically effective amount” means an amount of a compound sufficient to provide a therapeutic effect, such as stimulating the formation of a cytokine, an antitumor effect and / or an antiviral effect. Although the exact amount of the active substance used in the pharmaceutical composition of the invention varies widely depending on various factors, such as the physical and chemical nature of the substance, as well as the nature of the carrier and the intended dose, it is believed that the compositions of the invention will contain a sufficient amount active ingredient to provide a dose in the range of from about 100 ng / kg to about 50 mg / kg, preferably from about 10 μg / kg to about 5 mg of compound tions per 1 kg of patient weight. The compositions can be used in any conventional dosage forms, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, various kinds of plasters, and the like.

The compounds of the invention can be administered into the body as a single prescribed therapeutic agent or in combination with one or more other active agents, such as additional immune response modifiers, antiviral drugs, antibiotics, and the like.

It was found that the compounds of the invention stimulate the formation of certain cytokines in experiments performed in accordance with the following test methods. These results show that the compounds of the invention are useful modifiers of the immune response, i.e. they are able to modulate the immune response in various ways, thereby helping to treat various diseases.

The cytokines generated by the administration of the compounds of the invention typically include interferon-α (IFN-α) and / or tumor necrosis factor-α (TNF-α), as well as certain interleukins (IL). In particular, these compounds cause the formation of IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, as well as various other cytokines. In addition to other effects, cytokines slow down the growth of viruses and the growth of tumor cells, which makes the proposed compounds useful in the treatment of tumors and viral diseases. Thus, the present invention provides a method for stimulating the cytokine biosynthesis by administering to the animal an effective amount of a compound or compositions of the invention.

It was found that certain compounds of the invention predominantly stimulate the participation of IFN-α in changing the number of hematopoietic cells, such as PBMC (mononuclear cells of peripheral blood), containing pDC2 cells (precursors of dendritic cells of type 2), without causing significant inflammatory cytokinesis.

In addition to their inherent ability to stimulate the formation of cytokines, these compounds also affect other aspects of the innate immune response. For example, the natural activity of the killer cell may be stimulated, and this effect may be due to the formation of a cytokine. The compounds can also activate macrophages, which in turn stimulate the secretion of nitric oxide and the formation of additional cytokines. In addition, these compounds can cause proliferation and differentiation of B-lymphocytes.

The compounds of the invention also affect the acquired immune response. For example, although it is believed that the compounds do not directly affect T-lymphocytes or the formation of T-lymphocyte cytokines, these compounds have an indirect effect on the formation of the IFN-γ cytokine from the type 1 helper phage T-lymphocyte (Th1), and the formation Th2 cytokines IL-4, IL-5 and IL-13 are slowed by the administration of the compounds. These results indicate that the compounds of the invention provide assistance in the treatment of diseases in which an increase in Th1 and / or a decrease in Th2 is required. Given the ability of a compound to slow down the response of a type 2 T-phage helper, it can be expected that these compounds will be useful in treating allergic diseases such as atopic dermatitis, asthma, allergies, allergic rhinitis, systemic lupus erythematosus, and as an adjuvant vaccine to increase immunity, and, possibly, for the treatment of relapses of fungal diseases and chlamydia.

The modifying effect of the compounds on the immune response makes them useful in the treatment of a large number of different diseases. Due to their ability to stimulate the formation of cytokines, such as IFN-α and / or TNF-α, the compounds of this invention are particularly useful in the treatment of viral diseases and tumors. This immunomodulatory effect suggests that the compounds of the invention may be useful in the treatment of diseases (inter alia) such as viral diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex type I and type II, molluscum contagiosum, smallpox, especially smallpox, HIV, cytomegalovirus, varicella-zoster virus, rhinovirus, adenovirus, coronavirus, influenza and parainfluenza, intraepithelial neoplasia, such as cervical intraepithelium flax neoplasia, human viral papilloma and associated tumors; fungal diseases, for example candidiasis, aspergillosis, cryptococcal meningitis; diseases associated with the appearance of neoplasms, such as basal cell carcinoma, hairy cell leukemia, renal epithelial cell cancer, squamous cell epithelial cancer, myelopoiesis leukemia, Kaposi’s sarcoma, multiple myeloma, melanoma, non-Hodgkin’s lymphoma, skin lymphoma and other types of cancer; parasitic diseases, for example pneumocystosis, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosomal infection, leishmaniasis; bacterial infections, such as tuberculosis and mycobacterium avium. Using the proposed compounds, it is also possible to treat senile keratosis, eczema, eosinophilia, essential thrombocythemia, leprosy, multiple sclerosis, Ommen's syndrome, lupus erythematosus, Bowen's disease and bowenoid papulosis, baldness, inhibition of the formation of keloid sutures after other surgical operations and scars. In addition, these compounds can stimulate wound healing, including chronic wounds. They can also be useful for the treatment of opportunistic infections and tumors that appear after suppression of immunity, for example, in cancer and HIV patients, as well as after organ transplant operations.

An effective amount of the administered compound, which is intended to stimulate the biosynthesis of cytokines, is that amount which is sufficient to induce one or more types of cells, such as monocytes, macrophages, dendritic cells and B cells, to form one or more cytokines, such as, for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, in an amount exceeding the background level of such cytokines. The exact amount of the compound will vary widely depending on various factors, but it is expected that the dose of this compound will be in the range of about 100 ng / kg to about 50 mg / kg, preferably in the range of about 10 μg / kg to about 5 mg / kg The invention also provides a method for treating a viral infection and cancer in an animal by introducing into the animal body an effective amount of a compound or compositions based on the invention. An effective amount of a compound for treating or suppressing a viral infection is that amount which will cause a decrease in one or more symptoms of the viral infection, such as viral lesions, viral load, virus formation rate and mortality compared to the situation observed for control animals, not taking these compounds. The exact amount of the compound will vary widely depending on various factors, but it is expected that the dose of this compound should be in the range from about 100 ng / kg to about 50 mg / kg, preferably in the range between about 10 μg / kg to about 5 mg / kg An effective amount of a compound for the treatment of cancer is that amount which will cause a decrease in the size of the tumor or the number of tumors. And in this case, the exact amount of the compound will vary widely depending on various factors, but it is expected that the dose of this compound should be in the range from about 100 ng / kg to about 50 mg / kg, preferably in the range between about 10 μg / kg to about 5 mg / kg.

The invention is illustrated below by various examples. These examples are provided for illustration only and in no way limit the general scope of the invention.

Example 1

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide

Part a

To a suspension of 4-hydroxy-5,6-dimethyl-3-nitro-2 (1H) -pyridone (7.6 g, 41.2 mmol) in 200 ml of dichloromethane was added 16.8 ml of triethylamine (123.8 mmol). The resulting mixture was cooled in an ice bath, 13.7 ml (82.5 mmol) of trifluoromethane acetic acid was added to it, and stirred for 30 minutes. Thereafter, 7.6 g (41.2 mmol) of mono-tert-butylcarbonyl-1,4-butylamine were added to the mixture in one portion and allowed to warm to room temperature. The reaction is continued for 1 hour, and then the mixture is washed twice with a 1% aqueous sodium carbonate solution (in 100 ml portions), dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane and the solution was poured into a column filled with silica gel. Silica gel is eluted first with dichloromethane to remove some impurities from the product, and then with a 2-5% solution of ethyl acetate in dichloromethane to isolate the desired product. Fractions containing the desired product are collected together and concentrated under reduced pressure to obtain 12 g of 4 - ({4 - [(tert-butylcarbonyl) amino] butyl} amino) -5,6-dimethyl-3-nitropyridin-2-yl- trifluoromethanesulfonate as a pale yellow oily product.

Part B

The product obtained in Part A was mixed with 2.5 g (24.7 mmol) of triethylamine, 4.8 g (24.7 mmol) of dibenzylamine and 150 ml of toluene, and then refluxed for 4 hours. After that, the reaction mixture was washed with a 1% aqueous solution of sodium carbonate and concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane and the solution was poured into a chromatographic column filled with silica gel. Silica gel is eluted with a 2-20% solution of ethyl acetate in dichloromethane. The product containing fractions were collected together and concentrated under reduced pressure to obtain about 13 g of tert-butyl-4 - {[2- (dibenzylamino) -5,6-dimethyl-3-nitropyridin-4-yl] amino} butylcarbamate.

Part C

To a solution of nickel chloride hydrate (2.9 g, 12.3 mmol) in methanol, 1.4 g (36 mmol) of sodium borohydride are slowly added and the mixture is stirred for 30 minutes. After that, a methanol solution of the product obtained in part B was added to the mixture in one portion. Sodium borohydride was slowly added to the mixture until the resulting foam became colorless. The mixture was filtered and the filtrate was concentrated under reduced pressure. Dichloromethane was added to the obtained residue, and the resulting salt was removed from the solution by filtration. The filtrate was concentrated under reduced pressure to obtain about 12 g of tert-butyl-4 - {[3-amino-2- (dibenzylamino) -5,6-dimethylpyridin-4-yl] amino} butylcarbamate.

Part D

To a solution of the product obtained in Part C in 200 ml of acetonitrile was added 3 ml (24.7 mmol) of valerianic acid chloride and the reaction mixture was stirred at ambient temperature. After a certain time, the reaction mixture was concentrated under reduced pressure, and ethanol and 5 g (49 mmol) of triethylamine were added to the residue. This reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting product is mixed with dichloromethane and water, while the product is redistributed between the aqueous and organic phases. The dichloromethane layer was separated and loaded onto a silica gel chromatography column. To wash the target product from the chromatographic column, a 9: 90: 1 mixture of ethyl acetate: dichloromethane: methanol was used as an eluent. The fractions containing the desired product were collected and concentrated under reduced pressure to give 6.5 g of an oily tert-butyl-4- [2-butyl-4- (dibenzylamino) -6,7-dimethyl-1H-imidazo [4.5 -c] pyridin-1-yl] butyl carbamate.

Part E

Trifluoromethane acetic acid (16 g, 107 mmol) was added to a solution of the product (6.5 g, 11.4 mmol) obtained in Part D in 250 ml of dichloromethane. The mixture was stirred overnight, after which 50 ml of ammonium hydroxide and 100 ml of water were added and stirring was continued for another 30 minutes. After that, the aqueous and organic layers are separated and the aqueous layer is extracted with 100 ml of dichloromethane. The organic fractions are combined, washed with a 1% aqueous solution of sodium carbonate, brine and concentrated under reduced pressure. 30 ml of methanol was added to the residue, and the mixture was stirred for 30 minutes, after which it was filtered. The filtrate was concentrated under reduced pressure, a 1% aqueous solution of sodium carbonate was added to the residue, and stirred again. The mixture was extracted with hexane to remove organic impurities. The aqueous layer contained insoluble oil, which was extracted with dichloromethane. The organic fractions were combined, magnesium sulfate was added to them, stirred for 5 minutes and filtered. The filtrate was concentrated under reduced pressure to obtain a solid product, after recrystallization of which 1 g of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4- was obtained from toluene amine.

Part F

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in 150 ml of dichloromethane was added 0 , 07 ml (0.5 mmol) of triethylamine. The reaction mixture was cooled in an ice bath and 0.07 ml (0.5 mmol) of benzyl chloride was added to it, after which the cooling bath was removed. The mixture was washed twice with water and concentrated under reduced pressure. The remaining residue was purified by flash chromatography using a 10% solution of methanol in dichloromethane as an eluent. The result is an oily brown product. This product is dissolved in a minimal amount of isopropanol, and then 55 mg (0.5 mmol) of ethanesulfonic acid are added to the solution with stirring. The reaction mixture is stirred at ambient temperature for approximately 1 hour and then subjected to short-term heating in a sand bath until a homogeneous system is obtained. The resulting solution was allowed to cool to ambient temperature and then cooled in an ice bath. The precipitate formed is filtered off and 111 mg of crystalline N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide is obtained. The melting point of this product is 127.8-128.8 ° C.

Analysis. Calculated for C ₂₃ H ₃₁ N ₅ O,%: C 70.20; H 7.94; N, 17.80. Found,%: C 69.82; H, 7.70; N, 17.68.

Example 2

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in 160 ml of dichloromethane was added 0 , 07 ml (0.5 mmol) of triethylamine and the reaction mixture is cooled in an ice bath. To the reaction mixture was added 90 mg (0.5 mmol) of methanesulfonic anhydride and the mixture was removed from the ice bath, after which the reaction mixture was stirred for 35 minutes. After this, the mixture was washed three times with water, concentrated under reduced pressure, and a minimal amount of methyl acetate was added to the residue. The resulting solid crystalline precipitate was filtered off and then dried in an Abderhalden apparatus. The result is 94 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methane sulfonamide, the melting point of which makes 130-130,5 ° C.

Analysis. Calculated for C ₁₇ H ₂₉ N ₅ O ₂ S,%: C 55.56; H 7.95; N, 19.06. Found,%: C 55.37; H 7.89; N, 18.03.

Example 3

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-fluorobenzenesulfonamide hydrate

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in 150 ml of dichloromethane was added 0 , 07 ml (0.5 mmol) of triethylamine and the reaction mixture is cooled in an ice bath. To the reaction mixture was added 113 mg (0.5 mmol of fluorobenzenesulfonic acid chloride and the mixture was removed from an ice bath. After this, the reaction mixture was stirred at ambient temperature for 48 hours. After stirring, the mixture was washed twice with water (150 ml each) and concentrated under reduced pressure, the resulting residue was recrystallized from methyl acetate and then dried in an Abderhalden apparatus to give 50 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5- c] pyridin-1-yl) butyl] -4-fluorobenzenesul phonamide in the form of a white crystalline substance, the melting point of which is 133.1-133.7 ° C.

Analysis. Calculated for C ₂₂ H ₃₀ FN ₅ O ₂ S,%: C 56.75; H 6.93; N, 15.04. Found,%: C 56.99; H 6.58; N, 15.24.

Example 4

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in 150 cooled in an ice bath ml of dichloromethane add 0.056 ml (0.5 mmol) of phenyl isocyanate. The ice bath is removed, 5 minutes after this a white precipitate forms. The reaction mixture was stirred for another 30 minutes and then concentrated under reduced pressure to obtain an off-white crystalline solid. This product is separated on a filter using small amounts of diethyl ether to transfer the product to the filter, and then dried in an Abderhalden apparatus. The result is 185 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea, temperature melting which is 195.8-196.8 ° C.

Analysis. Calculated for C ₂₃ H ₃₂ N ₆ O,%: C 67.62; H 7.89; N, 20.57. Found,%: C 66.84; H 7.71; N, 20.54.

Example 5

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylthiourea hydrate

Using the procedure used in example 4, the reaction 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-s] pyridin-4-amine (100 mg, 0.35 mmol) with phenylisothiocyanate (0.041 ml, 0.35 mmol), resulting in 97 mg of a white solid crystalline hydrate N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) butyl] -N'-phenylthiourea, the melting point of which is 160.0-160.8 ° C.

Analysis. Calculated for C ₂₃ H ₃₂ N ₆ SH ₂ O,%: C 62.41; H 7.74; N, 18.99. Found,%: C 62.39; H 7.47; N, 18.52.

Example 6

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N, N-dimethyl sulfamide

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (67 mg, 0.23 mmol) in 45 ml of dichloromethane was added 0.031 ml (0.23 mmol) of triethylamine. The reaction mixture is cooled in an ice bath and 0.025 ml (0.23 mmol) of dimethyl sulfamoyl chloride is added to it. The ice bath was removed and the reaction mixture was stirred at room temperature for approximately 113 hours. According to high performance liquid chromatography, the reaction after this is not yet 100% complete. Dichloromethane was removed under reduced pressure. Thereafter, 50 ml of 1,2-dichloroethane was added to the residue, and the mixture was heated to 60 ° C. After 3 hours, an additional amount (2.5 μl) of dimethyl sulfamoyl chloride was added and heating was continued. After 22 hours, the temperature of the reaction mixture was brought to a boil, and the mixture was refluxed for 100 hours. The mixture is extracted twice with water. The aqueous fractions are combined and concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate to give 10 mg of an off-white crystalline substance N '- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl ] -N, N-dimethyl sulfamide. The melting point of this product is 129.5-131 ° C. M / Z = 397.1 (M + H) ⁺ .

Example 7

N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide

Part a

A mixture of 5,6-dimethyl-3-nitropyridin-2,4-diol (60.0 g, 326 mmol) and 600 ml of phosphorus oxychloride is refluxed for 2 hours, and then concentrated under reduced pressure. 300 ml of ethyl acetate was added to the residue, and the mixture was filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate, the aqueous layer was separated and extracted twice with ethyl acetate. The organic fractions were combined together, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown solid. This material was chromatographed (silica gel; 60/40 ethyl acetate / hexanes as eluent). The result is 55 g of 2,4-dichloro-5,6-dimethyl-3-nitropyridine.

Part B

To a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol), anhydrous N, N-dimethylformamide (500 ml) and triethylamine (50 ml, 339 mmol) slowly add 60 g (339 mmol) of tert-butyl-4-aminobutylcarbamate. The reaction mixture was stirred overnight and then concentrated under reduced pressure to an oily product. This product was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a dark oily product. This product was chromatographed (silica gel; 40/60 ethyl acetate / hexanes as eluent). The result is 64.5 g of tert-butyl-4- (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl) butyl carbamate in the form of a bright orange oily product. When aged, this product hardens.

Part C

A solution of phenol (18.50 g, 196 mmol) in 50 ml of diglyme is slowly added dropwise to a 60% suspension in mineral oil cooled to 0 ° C. (8.28 g, 207 mmol) in 50 ml of diglyme. 1 hour after the end of the addition of reagents, the cessation of gas evolution during the process was observed. After this, a solution of tert-butyl-4- (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl) butylcarbamate (68.95 g, 185 mmol) in 200 ml of diglyme is slowly added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture was refluxed for 4 hours, after which it was concentrated under reduced pressure to obtain a black oily product. The oil is dissolved in ethyl acetate and then extracted with 1N. sodium hydroxide solution to remove excess phenol. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified on a chromatographic column (silica gel; 30/70 ethyl acetate / hexanes as eluent). The result is 40.67 g of tert-butyl-4 - [(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)] butyl carbamate as an orange oily product.

Part D

A mixture of tert-butyl-4 - [(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl) amino] butyl carbamate (9.17 g, 21.3 mmol), toluene (50 ml), isopropanol ( 5 ml) and platinum (7.0 g) deposited on activated carbon (platinum content 5%), incubated overnight in a Parr apparatus in an atmosphere of hydrogen (3.5 kg / cm ² ). After that, the catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The resulting brown oil was dried in vacuo to give 7.47 g of tert-butyl-4 - [(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butylcarbamate.

Part E

A mixture of the product obtained in Part D, together with triethylorthoacetate (3.59 ml, 19.58 mmol), anhydrous toluene (75 ml) and pyridine hydrochloride (0.75 g) was refluxed for 1 hour and then concentrated at reduced pressure to obtain a brown oily product. The oil is dissolved in ethyl acetate and washed twice with water, then brine, dried over magnesium sulfate and then concentrated under reduced pressure. The result is 6.74 g of tert-butyl-4 - [(2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl carbamate, which is a brown oily product .

Part F

A solution of tert-butyl-4 - [(2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butylcarbamate (6.70 g, 15.8 mmol) in 50 ml of dichloromethane is slowly added to a mixture of trifluoroacetic acid (60 ml) and dichloromethane (100 ml) cooled to 0 ° C. The reaction mixture is heated to ambient temperature and maintained at this temperature overnight. After that, the resulting mixture was concentrated under reduced pressure to a brown oil. This oil is dissolved in dichloromethane and the solution is made alkaline (adjusted to pH 14) by adding a 5% aqueous solution of sodium hydroxide to it. The aqueous and organic layers were separated and the aqueous layer was extracted with dichloromethane. The organic fractions were combined together, dried over magnesium sulfate and then concentrated under reduced pressure. The result is 4.50 g of 4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butylamine as a brown oil.

Part g

A mixture of the product obtained in Part F, together with triethylamine (2.0 ml, 14.6 mmol) and anhydrous acetonitrile (450 ml), is heated until a homogeneous solution is obtained. After that, 2.54 g (14.6 mmol) of methanesulfonic anhydride are slowly added to the reaction mixture. The reaction proceeds quantitatively within 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain a brown oily product. This product is dissolved in dichloromethane and washed with a 5% aqueous solution of sodium hydroxide. The aqueous layer was separated and extracted with dichloromethane. The organic fractions were combined together, dried over magnesium sulfate and then concentrated under reduced pressure to obtain a brown solid. After purification of this substance by chromatographic method (silica gel; a 95/5 dichloromethane / methanol mixture is used as eluent), 4.49 g of a light brown solid is obtained, which is N- [4- (2,6,7-trimethyl-4- phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide.

Part H

N- [4- (2,6,7-Trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide (4.20 g, 10.4 mmol) was mixed with ammonium acetate (42 g) and the mixture is heated in a sealed ampoule at 150 ° C for 36 hours. After that, the reaction mixture is cooled and dissolved in chloroform. The resulting solution was extracted with a 10% aqueous sodium hydroxide solution. The aqueous layer was separated and extracted several times with chloroform. The organic fractions were combined together, dried over magnesium sulfate and then concentrated under reduced pressure to obtain a yellow oil. This oil is dissolved in methanol, combined with a 1 M solution of hydrogen chloride in diethyl ether (10.4 ml). The precipitate formed at this stage of the reaction is filtered off and dried, then it is dissolved in water and, adding solid sodium carbonate, the pH of the solution is adjusted to 10. The resulting white precipitate is filtered off, washed with diethyl ether and dried in a vacuum oven at 80 ° C. The result is 2.00 g of the desired product N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide, the melting point of which makes 228-230 ° C.

Analysis. Calculated for C ₁₄ H ₂₃ N ₅ O ₂ S,%: C 51.67; H, 7.12; N, 21.52. Found,%: C 51.48; H 6.95; N, 21.51.

Example 8

N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide

Part a

Triethylamine (3.3 ml, 23.7 mmol) is added to a mixture of tert-butyl-4 - [(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butyl carbamate (cooled to 0 ° C) 8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 ml). Then, 2.76 g (22.5 mmol) of ethoxyacetyl chloride are added to the mixture, the mixture is kept for 1 hour, warmed to room temperature and then stirred at this temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain tert-butyl-4 - ({3 - [(ethoxyacetyl) amino] -5,6-dimethyl-2-phenoxypyridin-4-yl} amino) butyl carbamate as a brown oily product. To this oil was added 130 ml of pyridine, and the mixture was refluxed overnight, and then concentrated to a brown oily product. This product is dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in diethyl ether and concentrated again under reduced pressure. The result is 8.21 g of tert-butyl-4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl] butylcarbamate.

Part B

Using the procedure used in part F of example 7, the material obtained in part a of this example is hydrolyzed to give 5.76 g of 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H -imidazo [4,5-c] pyridin-1-yl] butan-1-amine as a brown oil.

Part C

Using the procedure used in Part G of Example 7, 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl] butan-1-amine (5.52 g, 15.0 mmol) is treated with methanesulfonic anhydride (2.74 g, 15.7 mmol) to give 6.26 g of N-4- [2- (ethoxymethyl) -6,7-dimethyl -4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide as a brown solid.

Part D

Using the procedure used in Part H of Example 7, the amination of N- {4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl] is carried out butyl} methanesulfonamide (5.86 g, 13.1 mmol), resulting in 1.58 g of white solid N- {4- (4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide The melting point of this product is 165-167 ° C.

Analysis. Calculated for C ₁₆ H ₂₇ N ₅ O ₃ S,%: C 52.01; H 7.37; N, 18.95. Found,%: C 51.83; H 7.39; N, 18.88.

Example 9

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide

Part a

4- (2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butan-1-amine (122 mg, 0.33 mmol) in a nitrogen atmosphere dissolved in dichloromethane in the presence of triethylamine (0.093 ml, 0.67 mmol). The solution was cooled in an ice bath and a solution / suspension of 4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzoyl chloride (106 mg, 0.33 mmol) in dichloromethane was added dropwise to it. The ice bath was removed and the reaction mixture was stirred for 16 hours, after which it was poured into a 10% aqueous solution of sodium carbonate. The aqueous and organic phases are separated and the aqueous phase is extracted with dichloromethane. The organic fractions are combined together, washed with water and brine, dried over sodium sulfate, decanted and evaporated to give a yellow oily product. Purification of this product by flash chromatography (silica gel, eluent gradient from 92: 8 dichloromethane / methanol to 95: 5 dichloromethane / methanol) gives 101 mg of pale yellow solid N- [4- (2-butyl-6,7-dimethyl- 4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide. According to high performance liquid chromatography, the purity of this product exceeds 97%.

MS (Cl): 648 (M + H).

Part B

N- [4- (2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) are placed in a vial with a stirrer, designed to operate at high pressure. The ampoule is sealed and heated for 16 hours at a temperature of 150 ° C. The reaction mixture was cooled to room temperature and diluted with water. The resulting turbid aqueous mixture was made alkaline with a 10% aqueous hydroxide solution and extracted with three portions of chloroform (25 ml each). The combined organic fractions were washed first with water and then with brine, dried over sodium sulfate, decanted and evaporated to give a yellow oily product. Purification of this product by flash chromatography (silica gel, eluent gradient from 95: 5 dichloromethane / methanol to 9: 1 dichloromethane / methanol and final elution with 94: 5: 1 dichloromethane / methanol / triethylamine) gives 14 mg of a yellow oily N- [ 4- (4-amino-2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy ] (phenyl) methyl] benzamide.

¹ H NMR (500 MHz, DMSO-d ₆ ), δ 8.41 (triplet, J = 5.5 Hz, 1H); 7.76 (doublet, J = 8.3 Hz, 2H); 7.43 (doublet, J = 8.3 Hz, 2H); 7.37-7.31 (m, 4H); 7.26 - 7.22 (m, 1H); 5.84 (broad singlet, 2H); 5.52 (singlet, 1H); 4.22 (triplet, J = 7.7 Hz, 2H); 3.49 (triplet, J = 5.8 Hz, 2H); 3.29 (doublet of doublets, J = 6.4, 12.4 Hz, 2H); 2.76 (triplet, J = 7.7 Hz, 2H); 2.58 (triplet, J = 5.7 Hz, 2H); 2.32 (singlet, 3H); 2.27 (singlet, 3H); 2.22 (singlet, 6H); 1.73-1.65 (m, 4H); 1.61-1.55 (multiplet, 2H); 1.35 (sextet, J = 7.4 Hz, 2H); 0.86 (triplet, J = 7.4 Hz, 3H).

¹³ C NMR (125 MHz, DMSO-d ₆ ): δ 165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29, 3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2.

HRMS (Cl): m / e 571.3763 (M + H), (571.3761 calculated for C ₃₄ H ₄₇ N ₆ O ₂ , M + H).

EDUCATION OF CYTOKINE IN HUMAN CELLS

The determination of the activity of the compounds of the invention for stimulating the formation of a cytokine was carried out using human cells in vitro. The activity was evaluated based on the amount of interferon (α) and tumor necrosis factor (α) (IFN and TNF, respectively), determined by the method described in the article by Testerman et al. “Induction of kinin using immuniquodulators Imiquimod and S-27609” published in Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Blood Cell Culture Preparation

Whole blood was collected by venipuncture from healthy donors into special vacuum containers complying with ETDA requirements. Peripheral blood mononuclear cells (PBMCs) were separated from whole blood using a gradient centrifugation method using a Histopaque®-1077 apparatus. PBMCs were washed twice with a solution of balanced Hank salts and then suspended in RPMI medium. The concentration of blood cells in such a suspension was (3-4) × 10 ⁶ cells per 1 ml of suspension. The PBMC suspension was placed in 48 flat-bottomed sterile cells (supplied by Costar, Cambridge, Mass., Or Becton Dickinson Labware, Lincoln Park, New Jersey), in which equal volumes of RPMI medium containing the test compound were located.

Connection Preparation

Compounds were solubilized in dimethyl sulfoxide (DMSO). The final concentration of DMSO in the prepared samples used for testing should not exceed 1%. Typically, compounds were used for testing at concentrations ranging from 0.12 to 30 μmol / L.

Incubation

First, a solution of the compound used for testing was added to the cell in which the RPMI medium was located at a concentration of 60 μmol / L, and then the necessary three-fold dilution was carried out. After that, a suspension of PBMC was added in such an amount that the concentration of the test substance was within the specified limits (from 0.12 to 30 μmol / L). The final concentration of the PBMC suspension was (1.5-2) × 10 ⁶ cells / ml. The cells were closed with sterile plastic covers, the samples were gently mixed and kept for 18-24 hours at 37 ° C in an atmosphere containing 5% carbon dioxide.

Branch

After the incubation period, the samples were centrifuged for 5-10 minutes at a centrifuge rotation speed of 1000 rpm (approximately 200) and a temperature of 4 ° C. The purified solution containing no culture cells was removed using a sterile polypropylene pipette and transferred to a sterile polypropylene ampoule. Samples were stored at -30 to -70 ° C until analysis. Samples were analyzed for interferon-α and tumor necrosis factor-α using an ELISA method.

Analysis of interferon (α) and tumor necrosis factor-α by ELISA (enzyme-linked immunosorbent assay)

Interferon concentration (α) was determined by ELISA using a set of human multiparticles obtained at the PBL Biomedical Laboratory, New Brunswick, NJ. This analysis method allows you to determine the content of interferon in units of picograms / ml

Tumor necrosis factor-α concentration was determined using an ELISA kit supplied by Genzyme, Cambridge, Mass.; RandD Systems, Minneapolis, Minnesota; or Pharmingen, San Diego, California. This analysis method allows you to determine the content of interferon in units of picograms / ml

The table below shows the minimum concentrations of compounds at which the formation of interferon and tumor necrosis factor is observed. The sign "*" means that at any investigated concentration of the added compound, the formation of interferon and tumor necrosis factor was not observed.

The formation of cytokines in human cells Sample Numbers Lowest effective concentration (μmol / L) Interferon Tumor Necrosis Factor one 0.12 1,11 2 0.0046 0.01 3 0.01 0.37 four 0.12 0.37 5 0.01 0.12 6 0.01 0.01 7 0.37 * 8 0.04 10

The above is a description of only a few areas of application of the present invention. A detailed description of the invention and examples are provided here only to achieve complete clarity in understanding the essence of the invention and its fields of application. It is obvious to those skilled in the art that the fields of application of the invention may vary with the spirit and letter of the invention. However, this invention is not limited to the exact details given of the compositions and structures, but encompasses all aspects set forth in the following claims.

Claims (32)

1. The compound of formula (I)

where X is an alkylene group; Y is —CO—, —CS— or —SO ₂ —group; Z represents a single bond or an —NR ₅ group; R ₁ represents phenyl unsubstituted or substituted by a halogen atom, a C _1-20 alkyl group, R _{2 is} selected from the group consisting of alkyl; alkyl-O-alkyl; the substituents R ₃ and R ₄ represent alkyl; each substituent R ₅ represents a hydrogen atom or a C _1-10 alkyl group; or a pharmaceutical grade salt based on these groups. 2. The compound or salt according to claim 1, characterized in that Y represents a group -CO-. 3. The compound or salt according to claim 1, characterized in that Y is a —CO— group, and Z is a single bond. 4. The compound or salt according to claim 1, characterized in that Y represents a group-CS-. 5. The compound or salt according to claim 1, characterized in that Y represents a —CS— group and Z represents a —NR ₅ - group. 6. The compound or salt according to claim 5, characterized in that the substituent R ₅ represents a hydrogen atom, and the substituent R ₁ represents phenyl, unsubstituted or substituted by a halogen atom. 7. The compound or salt according to claim 1, characterized in that Y represents a group -SO ₂ -. 8. The compound or salt according to claim 1, characterized in that Y represents a group -SO ₂ -, and Z is a simple bond. 9. The compound or salt of claim 8, wherein the substituent R ₁ represents a C _1-20 alkyl group. 10. The compound or salt according to claim 1, characterized in that Y represents a group —SO ₂ -, and Z - —NR ₅ -. 11. The compound or salt of claim 10, wherein the substituent R ₅ is a C _1-20 alkyl group and the substituent R _{1 is} also a C _1-20 alkyl group. 12. The compound or salt according to claim 1, characterized in that the substituent R ₂ represents an alkyl or alkyl-O-alkyl group. 13. The compound or salt according to claim 1, characterized in that X represents a - (CH ₂ ) _2-4 - group. 14. The compound or salt according to claim 1, characterized in that the substituents R ₃ and R ₄ independently of each other are methyl. 15. A compound selected from the group consisting of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4-fluorobenzenesulfonamide monohydrate; N - [- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylthiourea monohydrate; N '- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N, N-dimethyl sulfamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N'-phenylurea; N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide and N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide, or salts of pharmaceutical quality based on them. 16. A pharmaceutical composition for inducing cytokine biosynthesis comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 17. A pharmaceutical composition for inducing cytokine biosynthesis comprising a therapeutically effective amount of a compound of claim 8 in combination with a pharmaceutically acceptable carrier. 18. A pharmaceutical composition for inducing cytokine biosynthesis comprising a therapeutically effective amount of a compound according to claim 15 in combination with a pharmaceutically acceptable carrier. 19. A method of stimulating the biosynthesis of cytokine in the animal’s body, which consists in introducing into the animal’s body a therapeutically effective amount of a compound according to claim 1. 20. A method of treating a viral disease in animals, comprising administering to the animal an organism a therapeutically effective amount of a compound according to claim 1. 21. A method of treating a tumorous disease in animals, which method comprises administering to the animal's body a therapeutically effective amount of a compound according to claim 1. 22. A method of stimulating the biosynthesis of cytokine in the animal’s body, which consists in introducing into the animal’s body a therapeutically effective amount of a compound according to claim 8. 23. A method of treating a viral disease in animals, comprising administering to the animal an organism a therapeutically effective amount of a compound of claim 8. 24. A method of treating a tumorous disease in animals, which comprises administering to the animal's body a therapeutically effective amount of a compound of claim 8. 25. A method of stimulating the cytokine biosynthesis in an animal organism, which comprises introducing into the animal organism a therapeutically effective amount of a compound according to claim 15. 26. A method of treating a viral disease in animals, comprising administering to the animal an organism a therapeutically effective amount of a compound according to claim 15. 27. A method of treating a tumorous disease in animals, which comprises administering to the animal's body a therapeutically effective amount of a compound according to claim 15. 28. The compound representing imidazopyridin-4-amine of the formula (II)

where X is an alkylene group; R _{2 is} selected from the group consisting of alkyl and alkyl-O-alkyl; the substituents R ₃ and R _{4 are} independently selected from the group consisting of an alkyl group, and each substituent R ₅ is independently a hydrogen atom or a C _1-10 alkyl group, or a pharmaceutical grade salt based on these groups. 29. 2-Phenoxypyridine compound of the formula (III)

in which Q represents NO ₂ or NH ₂ groups; X is an alkylene group; the substituents R ₃ and R _{4 are} independently selected from an alkyl group; the substituent R ₅ represents a hydrogen atom or a C _1-10 alkyl group; BOC is a tert-butoxycarbonyl group;  or a pharmaceutically acceptable salt. 30. 4-phenoxypyridine compound of the formula (IV)

where X is an alkylene group; R _{2 is} selected from the group consisting of alkyl and alkyl-O-alkyl; the substituents R ₃ and R _{4 are} independently selected from the group consisting of an alkyl group; each substituent R ₅ represents a hydrogen atom and a C _1-10 alkyl group; BOC is a tert-butoxycarbonyl group; or a pharmaceutically acceptable salt. 31. 4-Phenoxypyridine compound of the formula (V):

in which X is an alkylene group; R _{2 is} selected from the group consisting of alkyl and alkyl-O-alkyl; the substituents R ₃ and R _{4 are} independently selected from the group consisting of an alkyl group, each R ₅ substituent independently represents a hydrogen atom or a C _1-10 alkyl group; or a pharmaceutical grade salt based on these groups. 32. 4-phenoxypyridine compound of the formula (VI)

in which X is an alkylene group; R ₁ represents a C _1-20 alkyl, phenyl group, or phenyl substituted with a halogen atom; R _{2 is} selected from the group consisting of alkyl and alkyl-O-alkyl; the substituents R ₃ and R _{4 are} independently selected from the group consisting of an alkyl group; each substituent R ₅ represents a hydrogen atom or a C _1-10 alkyl group; or a pharmaceutical grade salt based on these groups.