Substituted imidazopyridines

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

 

This invention relates to imidazopyridine compounds, which are substituted by the amino group in position 1, as well as to pharmaceutical compositions containing such compounds. In addition, this invention relates to the use of these compounds as immunomodulators to stimulate cytokine biosynthesis in an animal's body, as well as for the treatment of various diseases including viral and neoplastic diseases.

The first reliable data on 1H-imidazo[4,5-C]quinoline cyclic system of the present Bukhmanom etc., J. Org. Chem., 15, 1278-1284 (1950), who reported the synthesis of 1-(6-methoxy-8-chinoline)-2-methyl-1H-imidazo[4,5-C]quinoline for its possible use as an antimalarial remedy. Subsequently there were reports about the synthesis of different substituted 1H-imidazo[4,5-C]quinoline. For example, Jain and others, J. Med. Chem., 11, p.87-92 (1968), synthesized 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-C]quinoline as a possible anti-seizure drugs and cardiovascular drugs. In addition, rams, etc., Chem. Abs., 85, 94362 (1976)reported the synthesis of several 2-accomidate[4,5-C]quinoline. Berani etc., J. Heterocvclic Chem., 18, 1537-1540 (1981)also reported the synthesis of several 2-accomidate[4,5-C]quinoline.

Later it was found that certain 1H-imidazo[4,5-C]quinoline-4-amines and their 1 - and 2-substituted derivatives can be used in quality is ve antiviral agents, bronchodilators and immunomodulators. These compounds are described inter alia in U.S. patents№№4689338, 4698348, 4929624, 5037986, 5268376, 5346905 and 5389640; all of these patents are included in the description by reference.

Substituted compounds 1H-imidazopyridine-4-amine, which is an effective immune response modifiers, described in U.S. Patent No. 5446153; 5494916 and 5644063. Shown in these patents connections, however, do not contain a substituted amino group in position 1. Certain 1H-imidazo[4,5-C]quinoline-4-amines containing amide sulfonamidnuyu and urethane group in position 1, are described in PCT publications WO 00/76505, WO 00/76518 and WO 00/76519.

Despite the emergence in recent times of compounds which are modifiers of the immune response remains a need for compounds which are able to modulate the immune response through stimulation of cytokine biosynthesis or other mechanisms.

Summary of the invention

Found a new class of compounds able to stimulate cytokine biosynthesis in animals. Accordingly, the invention provides compounds of imidazopyridine-4-amine, which are replaced by the amino group containing a substituent in the 1-position. Compounds capable of stimulating cytokine biosynthesis, according to the IR spectroscopy have forms the Lu (I), below

The nature of the substituents X, Y, Z, R1, R2, R3, R4and R5described below.

Compounds having the formula (I)are useful immune response modifiers due to their ability to initiate cytokine biosynthesis or otherwise modulate the immune response when introduced into the animal organism. This makes these compounds useful for the treatment of various diseases including viral and neoplastic diseases that are sensitive to such changes in the immune response.

The invention also provides pharmaceutical compositions containing compounds that modify the immune response, and reports on ways to stimulate cytokine biosynthesis in an animal's body and the treatment of viral infections and/or neoplastic disease in an animal by introducing into the body of the animal compounds of formula I.

Also provides methods of synthesis of compounds that are the subject of the invention, and intermediates used in the synthesis of these compounds.

Detailed description of the invention

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

where X is Allenova or alkenylamine group;

Y is-CO-, -CS - or-SO2group;

Z is a simple bond or a group-O-, -S - or-NR5-;

R1represents aryl, heteroaryl, heterocyclyl, C1-20-alkyl or C2-20-alkenylphenol group, and each of these groups may be unsubstituted or contain one or more substituents independently selected from the group including

-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(R5)2;

-(alkyl)0-1-NR5-CO-O-alkyl;

-(alkyl)0-1-NR5-CO-alkyl;

-(alkyl)0-1-NR5-CO-aryl;

-(alkyl)0-1-NR5-CO-heteroaryl;

-N3;

is a halogen atom;

-haloalkyl;

-haloalkoxy;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO2;

-CN;

-HE;

-SH; and in the case of alkyl, alkenylphenol and heterocyclyl groups also oxoprop;

Deputy R2selected from the group including

is 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 that contains one or more

substituents selected from the group including

-OH;

-halogen

-N(R5)2;

-CO-N(R5)2;

-CS-N(R5)2;

-SO2-N(R5)2;

-NR5-CO-C1-10alkyl;

-NR5-CS-C1-10alkyl;

-NR5-SO2-C1-10alkyl;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl, and

-CO-heteroaryl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R5represents independently a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

Getting connections

Proposed in the invention compounds can be obtained in accordance with scheme I, the reaction in which the values of R1, R2, R3, R4, R5X, Y, and Z are defined above, Bn is benzyl gr is the PAP and the radical R' represents an alkyl group containing from one to four carbon atoms, or performanceline group containing from one to four carbon atoms. As the substituent R' may be used as phenyl group or phenyl group containing as a substituent a halogen atom or an alkyl group having from 1 to 4 carbon atoms.

At the stage (1) process (scheme I, reaction) conduct the reaction between 3-nitropyridine-2,4-disulfonate (formula X) and an amine of formula R1-Z-Y-N(R5)-X-NH2, which formed 3-nitro-4-aminopyridine-2-sulfonate of formula XI. The presence of two sulphonate groups, which, in principle, can be substituted, leads to the fact that the reaction may form a mixture of products, which, however, can easily be separated by conventional methods such as preparative chromatography. The reaction is preferably carried out by adding the amine to a solution of the compounds of formula X in a suitable solvent, such as dichloromethane, in the presence of a tertiary amine such as triethylamine. Because sulphonate group is relatively labile, the reaction can be conducted at low temperature (0°). This reduces the number of generated unwanted side 2-aminirovaniya and 2,4-diaminononane cont the mswb. 3-Nitropyridine-2,4-disulfonate are well-known products and can be easily obtained by known synthetic methods, see, for example, Lindstrom and others, U.S. Patent No. 5446153, and is provided in this patent as a reference.

At stage (2) process (scheme I, reaction of 1-nitro-4-aminopyridine-2-sulfonate of formula XI is treated with dibenzylamine, resulting in a gain of 2 dibenzylamino-3-nitropyridine-4-amine of formula XII. For the reaction of the compound of formula XI, dibenzylamine and tertiary amine, such as triethylamine, dissolved in an inert solvent, such as benzene, toluene or xylene, and heated the mixture.

At stage (3) process (scheme 1 reaction) carry out the restoration of the nitro group of 2-dibenzylamino-3-nitropyridine-4-amine (the compound of formula (XII) to the amino group. Recovery is preferably carried out under a NiB2, which is formed in situ from a solution of sodium borohydride and hydrate Nickel chloride in methanol. The reaction is preferably carried out at ambient temperature.

At stage (4) process (scheme I, reaction) 2-dibenzylpiperazine-3,4-diamine (compound of formula (XIII) is treated with a carboxylic acid or its equivalent to obtain 4-dibenzylamino-1H-imidazo[4,5-C]pyridine having the formula XV. Suitable equivalents of carboxylic acid are complex, the PR shall aafire and 1,1-diakoniekrankenhaus. Carboxylic acid or equivalent is chosen so that they provide an introduction to the compound of formula XV necessary substituent R2. For example, when using triethylorthoformate will be obtained compound in which R2represents a hydrogen atom, and when using triethylorthoformate R2=CH3. The reaction can be carried out in the absence of solvent or in an inert solvent, such as toluene. The reaction is carried out under sufficient heat to ensure the removal of any alcohol or water formed during the reaction as by-products. Optionally, the reaction can be used catalyst, such as hydrochloric acid pyridine.

Alternatively, the compound of formula XV can be obtained in two stages as a result of (a) interaction of compound XIII with allelochemical formula R2C(O)Cl or R2C(O)Br, which yields the compound of formula XIV, and (b) subsequent cyclization of the resulting product. On stage (4A) allalone added to a solution of the diamine in an inert solvent, such as acetonitrile, pyridine or dichloromethane. The reaction can be conducted at room temperature. On stage (4b) the product obtained in stage (4A), is heated in an alcohol solvent in the presence of a base. Preferably the product obtained in stage (4A), boil the t in ethanol in the presence of excess triethylamine or heated in the presence of methanolic solution of ammonia. Another option stage (4b) is the heating of the product obtained at stage (4A), in pyridine. If stage (4A) is carried out in pyridine, stage (4b) can be conducted by heating the reaction mixture, after according to the data analysis stage (4A) will fail.

At stage (5) process (scheme I, reaction) is carried out restoration 4-dibenzylamino-1H-imidazo[4,5-C]pyridine having the formula XV, 4-amino-1H-imidazo[4,5-C]pyridine (compound of formula (I). Preferably the compound of formula XV is heated in formic acid in the presence of palladium hydroxide deposited on activated carbon. The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

Scheme I, reaction

Specified in the invention compounds can be obtained in accordance with reaction scheme II, in which R1, R2, R3, R4, R5and X is defined above, Bn means benzyl group, BOC is tert-butoxycarbonyl group, and W represents the atoms O or S.

At the stage (1) process (reaction scheme II) protective amino 1H-imidazo[4,5-C]pyridine the compound of formula XVI is removed and the result is 1H-imidazo[4,5-C]pyridine of formula II. Preferably a solution of compound XVI in a suitable solvent, such as dichloromethane,is treated at room temperature cryptometrics acid. The compounds of formula XVI can be obtained by the synthesis method used to obtain the products in accordance with scheme I, reaction. At the stage (1) 2,4-disulfonate formula X is treated with an amine of the formula BOC-NR5-X-NH2. Then hold stage (2)-(4)as described above to obtain the compound of formula XVI, which is derived compounds XV.

On stage (2A) of the process (reaction scheme II) conduct the reaction between 1H-imidazo[4,5-C]pyridine of formula II and the acid chloride of the acid of formula R1-C(O)Cl or anhydride of the acid of formula R1-C(O)OC(O)-R1and get 1H-imidazo[4,5-C]pyridin-1-yl-amide of formula XVII, which is derived compound I. the Reaction is preferably carried out in the presence of a base, such as triethylamine, adding the acid chloride of the acid or acid anhydride to a solution of the compounds of formula II in a suitable solvent such as dichloromethane or acetonitrile. The reaction may proceed at a lower temperature (0° (C) or at room temperature. The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

On stage (2b) of the process (reaction scheme II) 1H-imidazo[4,5-C]pyridine of formula II is treated with an isocyanate of formula R1-N=C=O or isothiocyanato formula R1-N=C=S and the result of 1H-imidazo[4,5-C]pyridin-1-yl-urea and the and the thiourea of formula XVIII, which is a derivative of compounds of formula I. the Reaction is preferably carried out at low temperature (0° (C)by adding isocyanate or isothiocyanate to a solution of the compounds of formula II in a suitable solvent such as dichloromethane. The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

On stage (2C) of the process (reaction scheme II) 1H-imidazo[4,5-C]pyridine of formula II is treated with a sulfonic acid chloride of the acid of formula R1-S(O)2Cl or sulfonic acid anhydride R1-S(O)2OS(O)2-R1. The result of 1H-imidazo[4,5-C]pyridin-1-yl-sulfonamide of the formula XIX, which is a derivative of compounds of formula I. the Reaction is preferably carried out by adding the acid chloride sulfonic acid or sulfonic acid anhydride to a solution of the compounds of formula II in an appropriate solvent, such as dichloromethane, in the presence of a base, such as triethylamine. The reaction may occur at low (0° (C)and at room temperature. The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

Scheme II reactions

Specified in the invention compounds can be obtained according to reaction scheme III, in which R1 , R2, R3, R4, R5and X is defined above.

At the stage (1) process (scheme III reactions) 1H-imidazo[4,5-C]pyridine of formula II reacts with sulfhemoglobin R1-N(R5)S(O)2Cl with the formation of 1H-imidazo[4,5-C]pyridin-1-yl-sulphonamide of the formula XXI, which is a derivative of compounds of formula I. Preferably sulfhemoglobin added to a solution of the compounds of formula II in a suitable solvent, such as 1,2-dichloroethane, in the presence of a base, such as triethylamine. The reaction can be conducted at elevated temperatures. The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

Alternatively, the compound of formula XXI can be obtained in two stages as a result of (a) interaction 1H-imidazo[4,5-C]pyridine of formula II with chloride sulfuricum, leading to the formation in situ of sulfhemoglobin formula XX, and (b) subsequent interaction sulfhemoglobin with an amine of formula R1-N(R5)H. On stage (1A), the reaction can be conducted by adding a solution of chloride Sulfuryl in dichloromethane to a solution of the compounds of formula II in the presence of 1 equivalent of 4-(dimethylamino)pyridine. Preferably the reaction is carried out at low temperature (-78°). In some cases, after the components are added, the reaction mixture can be agrevated room temperature. On stage (1b) a solution containing 2 equivalents of R1-N(R5)H and 2 equivalents of triethylamine in dichloromethane, is added to the reaction mixture resulting from stage (1A). The reaction is preferably carried out at low temperature (-78°). The product or salt of the pharmaceutical quality based on it can be isolated using conventional methods.

Scheme III reactions

Specified in the invention compounds can be obtained in accordance with scheme IV reaction, in which R1, R2, R3, R4, R5and X is defined above and BOC means tert-butoxycarbonyl group.

At the stage (1) process (scheme IV reaction) using conventional gloriously agents carry out the chlorination of 2,4-dihydroxy-3-nitropyridine formula XXII, leading to the 2,4-dichloro-3-nitropyridine formula XXIII. Preferably the compound of formula XXII is treated with phosphorus oxychloride when heated. There are many known 2,4-dihydroxy-3-nitropyridine formula XXII. Other similar compounds can be easily obtained by known synthetic methods, see, for example, Lindstom and others, U.S. Patent No. 5446153, and is provided in this patent as a reference.

At stage (2) process (scheme IV reaction) of 2,4-dichloro-3-nitropyridine formula XXIII is treated with an amine of the formula BOC-NR5-X-NH2 , resulting in a gain of 2-chloro-3-nitropyridine formula XXIV. The reaction is preferably carried out by adding the amine to a solution of the compounds of formula XXIII in a suitable solvent such as N,N-dimethylformamide, in the presence of a tertiary amine such as triethylamine.

At stage (3) process (scheme IV reaction) conduct the reaction between 2-chloro-3-nitropyridine formula XXIV and phenol, leading to the 3-nitro-2-phenoxypyridine formula XXV. Phenol interacts with sodium hydride in a suitable solvent, such as diglyme, with the formation of phenoxide. Phenoxide, in turn, reacts at elevated temperatures with a compound of formula XXIV.

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

At stage (5) process (scheme IV reaction of 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. Appropriate, equivalent the AMI carboxylic acids are complex orthoepy and 1,1-diakoniekrankenhaus. Carboxylic acid or equivalent is chosen so that they provide an introduction to the compound of the formula IV required substituent R2. For example, when using triethylorthoformate will be obtained compound in which R2represents a hydrogen atom, and when using triethylorthoformate R2=C4H9. The reaction can be carried out in the absence of solvent or in an inert solvent, such as toluene. The reaction is carried out under sufficient heat to ensure the removal of any alcohol or water formed during the reaction as by-products. Optionally, the reaction can be used catalyst, such as hydrochloric acid pyridine.

Alternatively, stage (5) can be performed by (i) interaction of the compounds of formula XXVI with allelochemical formula R2C(O)Cl or R2C(O)Br and (ii) subsequent cyclization of the resulting product. At stage (i) allalone added to a solution of the compounds of formula XXV in an inert solvent, such as acetonitrile, pyridine or dichloromethane. The reaction can be conducted at ambient temperature. At stage (ii) the product obtained in stage (i), is heated in pyridine.

At stage (6) process (scheme IV reaction) is conducted banding groups VOS of the compounds of formula IV, resulting in a gain of 4 phenoxy-1H-what imidazo[4,5-C]quinoline of formula V. Preferably a solution of compound IV in a suitable solvent, such as dichloromethane, is treated at low temperature triperoxonane acid or hydrochloric acid.

At stage (7) process (scheme IV reaction) 4 phenoxy-1H-imidazo[4,5-C]quinoline of formula V is converted into 4-phenoxy-1H-imidazo[4,5-C]quinoline-1-yl-sulfonamide of the formula VI. This process is carried out in the same manner as stage (2C) in reaction scheme II.

On stage (8) process (scheme IV reaction) 4 phenoxy-1H-imidazo[4,5-C]quinoline-1-yl-sulfonamide of the formula VI is subjected aminating to obtain 4-amino-1H-imidazo[4,5-C]quinoline-1-yl-sulfonamida formula XIX, which is a derivative of compounds of formula I. the Reaction can be conducted by adding to the compound of formula VI ammonium acetate and heating the mixture in a sealed ampoule at a temperature of about 150°C. a Product or salt of the pharmaceutical quality based on it can to be isolated using conventional methods.

Scheme IV reactions

The invention also reported the synthesis of new compounds of interest as intermediate products for preparing compounds of formula I. These intermediate compounds have the structural formula II-VI, described in detail below.

One class of intermediate compounds has the formula (II)

where X is Allenova or alkenylamine group;

Deputy R2selected from the group including

is 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

-HE;

-halogen

-N(R5)2;

-CO-N(R5)2;

-CS-N(R5)2;

-SO2-N(R5)2;

-NR5-CO-C1-10alkyl;

-NR5-CS-C1-10alkyl;

-NR5-SO2-C1-10alkyl;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl, and

-CO-heteroaryl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R5represents independently a hydrogen atom or

C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

Another class of intermediate compounds has the formula III

where Q represents the NO2or NH2group;

X - allenvale alkenylamine group;

the substituents R3and R4independently selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and alkylthiol groups, and each substituent R5represents independently either a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

Another class of intermediate compounds has the formula (IV)

where X is Allenova or alkenylamine group;

Deputy R2selected from the group including

is 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

-HE;

-halogen

-N(R5)2;

-CO-N(R5)2;

-CS-N(R5)2;

-SO2-N(R5)2;

-NR5-CO-C1-10alkyl;

-NR5-CS-C1-10alkyl;

-NR5-SO2-C1-10alkyl;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl, and

-CO-heteroaryl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R5represents independently a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

Another class of intermediate compounds has the formula (V)

where X is Allenova or alkenylamine group;

Deputy R2selected from the group including

is 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 that contains one or more

substituents selected from the group including

-HE;

-halogen;

-N(R5)2;

-CO-N(R5)2;

-CS-N(R5)2;

-SO2-N(R5)2;

-NR5-CO-C1-10alkyl;

-NR5-CS-C1-10alkyl;

-NR5-SO2-C1-10alkyl;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl, and

-CO-heteroaryl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and al is illilnois groups, and

each substituent R5represents independently or atom of hydrogen or C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

And finally, the last class of intermediate compounds presented in this invention has the formula (VI)

in which X - Allenova or alkenylamine group;

R1represents aryl, heteroaryl, heterocyclyl, C1-20-alkyl or C2-20-alkenylphenol group, and each of these groups may be unsubstituted or contain one or more substituents independently selected from the group including

-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(R5)2;

-(alkyl)0-1-NR5-CO-O-alkyl;

-(alkyl)0-1-NR5-CO-alkyl;

-(alkyl)0-1-NR5-CO-aryl;

-(alkyl)0-1-NR5-CO-heteroaryl;

-N3;

atom g is lagena;

-haloalkyl;

-haloalkoxy;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO2;

-CN;

-HE;

-SH, and in the case of alkyl, alkenylphenol and heterocyclyl groups, also oxoprop;

Deputy R2selected from the group comprising: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

-HE;

-halogen

-N(R5)2;

-CO-N(R5)2;

-CS-N(R5)2;

-SO2-N(R5)2;

-NR5-CO-C1-10alkyl;

-NR5-CS-C1-10alkyl;

-NR5-SO2-C1-10alkyl;

-CO-C1-10alkyl;

-CO-O-C1-10alkyl;

-N3;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl, and

-CO-heteroaryl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl, alkenylphenol, halogen, CNS, amino, alkylamino, dialkylamino and alkylthiol groups, and

each substituent R5represents a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

Used herein, the terms "alkyl", "alkenyl" and so the rate of "ALK-" include linear, and branched chain groups and of cyclic groups, for example cycloalkyl and cycloalkenyl group. Unless otherwise noted, these groups contain from 1 to 20 carbon atoms, and alkeneamine group is from 2 to 20 carbon atoms. Preferably these groups contain up to 10 carbon atoms. The cyclic group may be either monocyclic or polycyclic and mainly to keep the cycle from 3 to 10 carbon atoms. Examples of cyclic groups are cyclopropyl, cyclopropylmethyl, cyclopentamine, tsiklogeksilnogo and adamantly group.

The term "keloidalis" includes groups, who as Deputy have one or more halide atoms, including perfluorinated group. This definition applies also to groups that include the prefix "halo". Examples of suitable haloidalkyls groups are chloromethylene, triptoreline and similar groups.

The term "aryl"as used herein includes carbocyclic aromatic cycles or cyclic system. Examples of aryl groups include phenyl, naftalina, biphenylene, fluoroanilino and indenolol group. The term "heteroaryl" refers to aromatic cycles or cyclic systems containing in the ring at least one heteroatom (e.g., O, S, N). Suitably the e heteroaryl groups include follow, thienyl, pyridyloxy, hyalinella, izohinolinove, indolenine, isoindolyl, triazole, pyrrolidino, tetrazolyl, imidazolidinyl, pyrazolidine, oxazolidine, thiazolidine, benzofuranyl, benzothiophene, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazole, khinoksalinona, benzothiazolyl, naphthyridinone, isoxazolidine, isothiazolinone, parinello, chinazolinei and similar groups.

The "heterocyclyl" compounds are non-aromatic cycles or cyclic system containing in the ring at least one heteroatom (e.g., O, S, N). These compounds include all of the fully saturated and partially unsaturated derivatives of the above heteroaryl groups. Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholine, piperidinyl, piperazinilnom, diazolidinylurea and imidazolidinyl group.

Aryl, heteroaryl and heterocyclyl group can be either unsubstituted, and containing one or more substituents independently selected from the group consisting of alkyl, CNS, alkylthio, haloethanol, haloidalkyls, galotolerantnoi group, halogen atom, nitrile, hydroxyl, mercapto - and ceanography, CT is auxillou, formyl, aryl, aryloxyalkyl, reltively, arylalkyl, arylalkylamine, heteroaryl, heteroepitaxial, heteroallyl, heteroarylboronic, heteroarylboronic, amino, alkylamino, dialkylamino-, heterocyclyl, geteroseksualnoe, alkylcarboxylic, alkenylboronic, alkoxycarbonyl, haloalkaliphilic, Gloucestershire, alkyldiethanolamine, arylcarbamoyl, heteroarylboronic, aryloxyalkyl, heteroarylboronic, aristoteleion, heteroarylboronic, alkanoyloxy, alkanolamine, arylcarboxylic, arylcarbamoyl, arylcarboxamide-, alkylaminocarbonyl, alkylsulphonyl, arylsulphonyl, heteroarylboronic, aryldiazonium, alkylsulfonyl, arylsulfonyl, arylalkylamine, alkylcarboxylic, alkenylamine, arylcarboxamide, arylalkylamine-, heteroarylboronic, heteroarylboronic, alkylsulfonyl, alkanesulfonyl, arylsulfonamides, arylalkylamine, heteroarylboronic, heteroarylboronic, alkylaminocarbonyl, alkynylaminopyrazoles, arylenecarborane, arylalkylamines, heteroarylboronic-, g is tetraarylporphyrins; in addition, in the case heterocyclyl group - carbonyl group. In the case when any other group identified as "substituted" or "sometimes substituted, these groups may have as a substituent one or more of the above groups.

Usually only certain substituents are preferred. For example, as the preferred groups Y use-WITH - and-SO2group; preferred groups Z is a simple bond or the group-NR5-; preferred substituents R1are C1-4alkyl, aryl or substituted aryl group. Preferred R2groups include alkyl groups containing from 1 to 4 carbon atoms (i.e., methyl, ethyl, sawn, ISO-propyl, n-bucilina, second-bucilina, isobutylene and tert-bucilina group), methoxymethyl, ethoxymethyl and cyclopropylmethyl group. The preferred substituent R3and R4is a methyl group. One or more of these preferred substituents, if present at all, may be contained in the proposed invention the compounds in any combination.

The invention includes the above-described compounds in any of their pharmaceutically available form, including isomers such as diastereomers and enantiomer is, salt, solvate, polymorph forms, etc. In particular, if a compound is optically active, in the invention described each enantiomer of this compound and the racemic mixture of enantiomers.

Pharmaceutical formulations and biological activity

Proposed in the invention, the pharmaceutical compositions contain a therapeutically effective amount of the above compounds in combination with a pharmaceutically acceptable carrier.

Used herein, the term "therapeutically effective amount" means an amount of compound sufficient to provide a therapeutic effect, such as the stimulation of the formation of the cytokine, anti-tumor effects and/or antiviral activity. Although the exact number of active substances used in the pharmaceutical composition proposed in the invention varies widely depending on various factors such as the physical and chemical nature of the substance and nature of the media and the estimated dose, believe that proposed in the invention compositions will contain sufficient active ingredient to provide a dose in the range from about 100 ng/kg to about 50 mg/kg, preferably from about 10 μg/kg to about 5 mg of the compound per 1 kg of patient's weight. The compositions can use the I in any conventional dosage forms, such as pills, pellets, parenteral formulations, syrups, creams, ointments, aerosol formulations, various plasters, etc.

Proposed in the invention compounds may be introduced into the body in the form of one written in the recipe therapeutic agent or in combination with one or more other active agents, such as additional modifiers of the immune response, antiviral drugs, antibiotics, etc.

It is established that proposed in the invention compounds stimulate the production of certain cytokines in the experiments, carried out in accordance with the following testing methods. These results show that the proposed compounds are useful modifiers of the immune response, i.e. they are able to modulate the immune response in various ways, thereby helping the treatment of various diseases.

Cytokines, resulting in the introduction of this invention compounds generally include interferon-α (IFN-αand/or factor-α tumor necrosis (TNF-α), as well as certain interleukins (IL). In particular, these compounds induce the formation of IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and various other cytokines. In addition to the other effects of cytokines inhibit the multiplication of viruses and tumor cell growth, making the offer with the unity useful in the treatment of tumors and viral diseases. Thus, the present invention provides a method of stimulating cytokine biosynthesis by introducing into the animal an effective quantities of the compounds or compositions proposed in the invention.

Certain proposed in the invention compounds mainly stimulate the participation of IFN-α change in the number of hematopoietic cells, such as RVS (mononuclear cells peripheral blood)containing pDC2 cells (precursors of dendritic cells type 2)without causing significant inflammatory cytokines.

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

Proposed in the invention compounds also have implications for acquired immune response. For example, although, as I believe, the compounds have no direct effect on T cells or the formation of T-limfocitna the cytokines, these compounds have an indirect influence on the formation of the cytokine IFN-γ from phage-helper type 1 T-lymphocyte (Th1), and the formation of Th2 cytokines IL-4, IL-5 and IL-13 is slowed down with the introduction of compounds. These results show that proposed in the present invention compounds assist in the treatment of diseases that require an increase in the number of Th1 and/or reducing the number of Th2. Given the ability of compounds to slow the nominal response of the T-phage-helper type 2, it can be expected that these compounds will be useful for the treatment of allergic diseases such as atopic dermatitis, asthma, Allergy, allergic rhinitis, systemic lupus erythematosus, as well as auxiliary vaccines to increase the immune system, and possibly for the treatment of relapse of fungal diseases and chlamydia.

Modifying effect of compounds on the immune response makes them useful in the treatment of many different diseases. Due to its ability to stimulate the formation of cytokines, such as IFN-α and/or TNF-αas proposed in the present invention compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulatory effect suggests that proposed in the invention compounds may be useful in the treatment of such diseases (OMIM the other), as viral diseases such as genital warts, the common warts, plantar warts, hepatitis b, hepatitis C, herpes simplex type I and type II, molluscum contagiosum, smallpox, especially smallpox, HIV, CMV, the virus stays zoster, rhinovirus, adenovirus, coronavirus, influenza and parainfluenza, intraepithelial neoplasia, such as cervical intraepithelial neoplasia, human papilloma virus and associated tumors, fungal infections, such as candidiasis, aspergillosis, cryptococcal meningitis, diseases associated with the appearance of tumors, such as basal cell carcinoma, leukemia "hairy" cells, cancer of renal epithelial cells, cancer cells simple squamous epithelium, leukemia of myelopoiesis, Kaposi's sarcoma, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous lymphoma, and other cancers; parasitic diseases, such as pneumocystosis, cryptosporidiosis, histoplasmosis, toxoplasmosis, Trypanosoma infection, leishmaniasis; bacterial infections, such as tuberculosis and mycobacterium avium. Using the proposed compounds can, in addition, to treat senile keratosis, eczema, eosinophilia, essential thrombocythaemia, leprosy, multiple sclerosis, Ommen's syndrome, discoid lupus, Bowen's disease and bowenoid papules, alopecia,inhibition of keloid formation seams after surgical operations and other types of surgical scars. In addition, these compounds can stimulate the healing of wounds, including chronic wounds. They can be also useful for the treatment of opportunistic infections and tumors that appear after the suppression of the immune system, for example, in cancer and HIV patients, as well as after organ transplants.

Effective number of established connections, which is intended to stimulate the biosynthesis of cytokines, is a quantity that is sufficient to induce one or more types of cells, such as monocytes, macrophages, dendritic cells and b-cells, to the formation of one or more cytokines, such as IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, in excess of the background level of such cytokines. The exact number of connections will vary widely depending on various factors, but it is expected that the dose of this compound will be in the range from about 100 ng/kg to about 50 mg/kg, preferably between about 10 μg/kg to about 5 mg/kg Invention also provides a method of treating viral infections and cancer in animals by introducing into the animal an effective amount proposed in the invention compounds or compositions based on it. Efficiency the effective amount of the compounds for the treatment or suppression of viral infection is its number, which will result in a decrease one or more symptoms of a viral infection, such as viral lesions, viral load, rate of formation of viruses and their mortality compared with the situation observed for control animals not receiving these connections. The exact number of connections 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 between about 10 μg/kg to about 5 mg/kg Effective amount of the compounds for the treatment of cancer is its number, which will result in a decrease in tumor size or number of tumors. And in this case the exact number of connections 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 between about 10 μg/kg to about 5 mg/kg

The invention is illustrated below various examples. These examples are given only as an illustration and in no way limit the General scope of the invention.

Example 1

N-[4-(4-Amino--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 mmole) in 200 ml dichloromethane added to 16.8 ml of triethylamine (123,8 mmole). The resulting mixture was cooled in an ice bath, add it to 13.7 ml (82,5 mmole) cryptometrics acid and stirred for 30 minutes. Then add to the mixture one portion of 7.6 g (41,2 mmole) of mono-tert-butylcarbamoyl-1,4-butylamine and allow it to warm to room temperature. The reaction continued for 1 hour, and the mixture is then washed twice with 1%aqueous solution of sodium carbonate (100 ml), dried over magnesium sulfate and concentrate under reduced pressure. The crude product is dissolved in dichloromethane and the solution poured into a column Packed with silica gel. Silica gel elute first with dichloromethane to remove from the product of certain impurities, and then 2-5%solution of ethyl acetate in dichloromethane to isolate a target product. The fraction containing the target product, collected together and concentrated under reduced pressure to obtain 12 g of 4-({4-[(tert-butylcarbamoyl)amino]butyl}amino)-5,6-dimethyl-3-nitropyridine-2-yl-triftoratsetata in the form of a light yellow oily product.

Part b

The product obtained in part a, is mixed with 2.5 g (24.7 mmole) of triethylamine, 4.8 g (24.7 mmole) dibenzyl the ins and 150 ml of toluene and then refluxed for 4 hours. Then the reaction mixture was washed with 1%aqueous solution of sodium carbonate and concentrated under reduced pressure. The crude product is dissolved in dichloromethane and the solution poured into a chromatographic column filled with silica gel. Silica gel elute 2-20%solution of ethyl acetate in dichloromethane. The fractions containing the product are collected together and concentrated under reduced pressure to obtain about 13 g of tert-butyl 4-{[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridine-4-yl]amino}BUTYLCARBAMATE.

The part With

To a solution of hydrate Nickel chloride (2.9 g, 12.3 mmole) in methanol is slowly added 1.4 g (36 mmole) of sodium borohydride and stirred the mixture for 30 minutes. Then to the mixture in one portion add a methanol solution of the product obtained in part C. To the mixture is added slowly to borohydride sodium up until the resulting foam becomes colorless. The mixture is filtered and the filtrate concentrated under reduced pressure. To the obtained residue is added dichloromethane and the formed salt is removed from the solution by filtration. The filtrate is concentrated under reduced pressure to obtain 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, 200 ml of acetonitrile add the 3 ml (24.7 mmole) of the acid chloride valerianic acid and the reaction mixture stirred at ambient temperature. After some time the reaction mixture was concentrated under reduced pressure and to the residue is added ethanol and 5 g (49 mmol) of triethylamine. This reaction mixture is refluxed overnight and then concentrated under reduced pressure. The resulting product is mixed with dichloromethane and water, thus there is a redistribution of the product between the aqueous and organic phases. The dichloromethane layer is separated and loaded into a chromatographic column filled with silica gel. To flush the target product from the chromatographic column as eluent a mixture of 9:90:1 ethyl acetate : dichloromethane : methanol. Containing the target product fractions are collected and concentrated under reduced pressure, resulting in a gain of 6.5 g of oily tert-butyl-4-[2-butyl-4-(dibenzylamino)-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl]BUTYLCARBAMATE.

Part E.

Cryptometrics acid (16 g, 107 mmol) are added to a solution of the product (6.5 g, 11.4 mmole)obtained in part D, in 250 ml of dichloromethane. The mixture is stirred over night, then add 50 ml of ammonium hydroxide and 100 ml of water and stirring is continued for another 30 minutes. Then share the aqueous and organic layers and the aqueous layer was extracted with 100 ml dichloromethane. The organic fractions combined, washed with 1%aqueous solution of carbon is sodium, brine and concentrated under reduced pressure. To the residue add 30 ml of methanol and the mixture is stirred for 30 minutes, then filtered. The filtrate is concentrated under reduced pressure, to the residue was added 1%aqueous sodium carbonate solution and again mix. The mixture is extracted with hexane to remove organic impurities. The aqueous layer contained the insoluble oil which is extracted with dichloromethane. The organic fractions were combined, was added magnesium sulfate was stirred for 5 minutes and filtered. The filtrate is concentrated under reduced pressure to obtain a solid product, after recrystallization from toluene receive 1 g of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine.

Part F

To a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine (150 mg, 0.5 mmole) in 150 ml dichloromethane type of 0.07 ml (0.5 mmole) of triethylamine. The reaction mixture was cooled in an ice bath and add to it of 0.07 ml (0.5 mmole) of benzyl chloride, and then removing the cooling bath. The mixture is washed twice with water and concentrated under reduced pressure. The remaining residue is purified by way of flash chromatography using a 10%solution of methanol in dichloromethane as eluent. The result is oily product is brown. This paragraph shall oduct dissolved in a minimum amount of isopropanol and then to the solution was added with stirring to 55 mg (0.5 mmole) econsultancy acid. The reaction mixture was stirred at ambient temperature for approximately 1 hour and then subjected to intermittent heating on a sand bath to obtain a homogeneous system. The resulting solution was let to cool to ambient temperature and then cooled it in an ice bath. The formed precipitate is filtered off and the result is 111 mg of crystalline N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]benzamide. The melting point of this product is 127,8-128,8°C.

Analysis. Calculated for C23H31N5O, %: C 70,20; N 7,94; N 17,80. Found,%: C 69,82; N. Of 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]pyridine-4-amine (150 mg, 0.5 mmole) in 160 ml of dichloromethane type of 0.07 ml (0.5 mmole) of triethylamine and the reaction mixture is cooled in an ice bath. To the reaction mixture are added 90 mg (0.5 mmole) of anhydride methanesulfonic acid and remove the mixture from the ice bath, after which the reaction mixture is stirred for 35 minutes. After that, the mixture is washed three times with water, concentrated under reduced pressure and add to the remainder of the minimum number of acetate. The obtained solid crystalline ocado is filtered off and then dried in the apparatus of Abderhalden. 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-sulfonamida, melting point which is 130-130,5°C.

Analysis. Calculated for C17H29N5O2S, %: 55,56; N. OF 7.95; N 19,06. Found, %: C 55,37; N 7,89; N 18,03.

Example 3

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

To a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine (150 mg, 0.5 mmole) in 150 ml dichloromethane type of 0.07 ml (0.5 mmole) of triethylamine and the reaction mixture is cooled in an ice bath. To the reaction mixture are added 113 mg (0.5 mmole of acid chloride forbindelsesteknologi acid and remove the mixture from the ice bath. Then the reaction mixture was stirred at ambient temperature for 48 hours. After mixing, the mixture is washed twice with water (portions 150 ml) and concentrate under reduced pressure. The obtained residue is recrystallized from methyl acetate and then dried in the apparatus of Abderhalden. The result is 50 mg, hydrate, N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-4-forbindelsesfaneblad in the form of a white crystalline substance, melting point which is 133,1-133,7°C.

Analysis. Calculated for C22H30FN 5O2S, %: 56,75; N 6,93; N 15,04. Found, %: C 56,99; N To 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'-prilocaine

It cooled in an ice bath to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine (150 mg, 0.5 mmole) in 150 ml dichloromethane add 0,056 ml (0.5 mmole) of phenylisocyanate. The ice bath is removed after 5 minutes after that a white precipitate is formed. The reaction mixture is stirred for 30 minutes and then concentrated under reduced pressure to obtain a whitish solid crystalline substances. This product is separated on a filter, using a small amount of diethyl ether, to bring the product on the filter, and then dried in the apparatus of Abderhalden. 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'-phenylacetone, melting point which is 195,8-196,8°C.

Analysis. Calculated for C23H32N6O, %: 67,62; N 7,89; N 20,57. Found, %: C 66,84; N 7,71; N 20,54.

Example 5

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

Using the method used in example 4, hold the reaction of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine (100 mg, 0.35 mmole) with finalist asianata level (0.041 ml, 0.35 mmole), as a result of 97 mg of a white solid crystal, hydrate, N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-N'-phenyltoloxamine, melting point which is 160,0-160,8°C.

Analysis. Calculated for C23H32N6SH2O, %: 62,41; N 7,74; N 18,99. Found, %: C 62,39; N 7,47; N Holds 18.52.

Example 6

N-[4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-N,N-dimethylsulfone

To a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridine-4-amine (67 mg, of 0.23 mmole) in 45 ml of dichloromethane add 0,031 ml (0,23 mmole) of triethylamine. The reaction mixture was cooled in an ice bath and add to it 0,025 ml (0,23 mmole) of dimethylsulfoxide. Remove the ice bath and the reaction mixture was stirred at room temperature for approximately 113 hours. According to high performance liquid chromatography, the reaction after that is not yet 100%complete. Dichloromethane is removed under reduced pressure. Then to the residue are added 50 ml of 1,2-dichloroethane and the mixture is heated to 60°C. After 3 hours, add the additional amount (2,5 ál) dimethylsulfoxide and continue heating. After 22 hours the temperature of the reaction mixture brought to a boil and the mixture is refluxed for 100 hours. A mixture of two the water is extracted with water. The aqueous fractions are combined and concentrated under reduced pressure. The obtained residue is recrystallized from methyl acetate and receive 10 mg whitish crystalline substance N'-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-N,N-dimethylsulfide. The melting point of this product is of 129.5-131°C. M/Z=397,1 (M+N)+.

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-nitropyridine-2,4-diol (60,0 g, 326 mmol) and 600 ml of phosphorus oxychloride is refluxed for 2 hours, then concentrated under reduced pressure. To the residue add 300 ml of ethyl acetate and the mixture filtered. The filtrate is washed with aqueous sodium bicarbonate solution, the aqueous layer was separated and extracted twice its ethyl acetate. The organic fractions are combined together, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown solid. This material is subjected to chromatographic purification (silica gel; eluent - 60/40 ethyl acetate/hexane). 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, mol) slowly add 60 g (339 mmol) of tert-butyl 4-aminobutyrate. The reaction mixture is stirred overnight and then concentrated under reduced pressure to obtain an oily product. This product is dissolved in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain a dark oily product. This product is subjected to chromatographic purification (silica gel; eluent - 40/60 ethyl acetate/hexane). The result of 64.5 g of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridine-4-yl)BUTYLCARBAMATE in the form of an oily product is bright orange. While keeping this product hardens.

The part With

A solution of phenol (18,50 g, 196 mmol) in 50 ml of diglyme slowly added dropwise to a cooled to 0°60%suspension in mineral oil (of 8.28 g, 207 mmol) in 50 ml of diglyme. Within 1 hour after the addition of reagents was observed cessation of gas evolution, formed during the process. Then to the reaction mixture is slowly added dropwise a solution of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridine-4-yl)BUTYLCARBAMATE (68,95 g, 185 mmol) in 200 ml of diglyme. Upon completion of addition the reaction mixture is refluxed for 4 hours, then concentrated under reduced pressure to obtain a black oily product. The oil is dissolved in etelaat the e and then extracted with 1N. the sodium hydroxide solution to remove excess phenol. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified through column chromatography (silica gel; eluent - 30/70 ethyl acetate/hexane). The result 40,67 g of tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridine-4-yl)]BUTYLCARBAMATE in the form of an oily product of orange color.

Part D

A mixture of tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridine-4-yl)amino]BUTYLCARBAMATE (9,17 g, 21.3 mmole), toluene (50 ml), isopropanol (5 ml) and platinum (7.0 g)supported on activated carbon (content of platinum 5%), incubated overnight in a Parr apparatus in an atmosphere of hydrogen (3.5 kg/cm2). Then the catalyst is filtered off and the filtrate evaporated under reduced pressure. The obtained brown oil is dried in vacuum and the result 7.47 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridine-4-yl)amino]BUTYLCARBAMATE.

Part E.

A mixture of the product obtained in part D, together with triethylorthoformate (3,59 ml, 19,58 mmole), anhydrous toluene (75 ml) and hydrochloric acid pyridine (0.75 g) is refluxed for 1 hour and then concentrated under reduced pressure to obtain an oily product brown. The oil is dissolved in ethyl acetate and washed twice with water, C is the brine, dried over magnesium sulfate and then concentrated under reduced pressure. The result 6,74 g of tert-butyl 4-[(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl)BUTYLCARBAMATE representing 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 mmole) in 50 ml of dichloromethane is added slowly to a cooled to 0°With a mixture of triperoxonane acid (60 ml) and dichloromethane (100 ml). The reaction mixture is heated to ambient temperature and kept at this temperature during the night. After concentrating the mixture under reduced pressure to a brown oil. This oil is dissolved in dichloromethane and the solution make alkaline (bring the pH to 14), by adding thereto a 5%aqueous solution of sodium hydroxide. Separate the aqueous and organic layers and the aqueous layer was extracted with dichloromethane. The organic fractions are combined together, dried over magnesium sulfate and then concentrated under reduced pressure. The result 4,50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl)butylamine in the form of a brown oil.

Part G

A mixture of the product obtained in part F, together with triethylamine (2.0 ml, of 14.6 mmole) and anhydrous acetonitrile (450 ml) is heated until then, until you get a homogeneous solution. the donkey to this reaction mixture is added slowly to 2.54 g (a 14.6 mmole) of anhydride methanesulfonic acid. 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 5%aqueous solution of sodium hydroxide. The aqueous layer was separated and extracted with dichloromethane. The organic fractions are combined together, dried over magnesium sulfate and then concentrated under reduced pressure to obtain a brown solid substance. After purification of this substance chromatography (silica gel; eluent a mixture of 95/5 dichloromethane/methanol) get of 4.49 g of light brown solid, which represents the N-[4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl)butyl]methanesulfonamide.

Part N

N-[4-(2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl)butyl]methanesulfonamide (4,20 g of 10.4 mmole) is mixed with ammonium acetate (42 g) and the mixture is heated in a sealed vial at 150°C for 36 hours. After that the reaction mixture is cooled and dissolved in chloroform. The resulting solution was extracted with 10%aqueous solution of sodium hydroxide. The aqueous layer was separated and extracted several times with chloroform. The organic fractions are combined together, dried over magnesium sulfate and then concentrated under reduced pressure to obtain a yellow oil. This is oil is dissolved in methanol, connect with 1 M solution of hydrogen chloride in diethyl ether (10.4 ml). Formed at this stage of the reaction the precipitate is filtered off and dried, then dissolved in water and by adding solid sodium carbonate to bring the pH to 10. The obtained white precipitate is filtered off, washed with diethyl ether and dried in a vacuum oven at 80°C. the result of 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, melting point which is 228-230°C.

Analysis. Calculated for C14H23N5O2S, %51,67; N 7,12; N 21,52. Found, %: C 51,48; N 6,95; 21.51 N.

Example 8

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

Part a

The triethylamine (3.3 ml, 23.7 mmole) is added to cooled to 0°With a mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridine-4-yl)amino]BUTYLCARBAMATE (at 8.60 g, 21.5 mmole) and anhydrous dichloromethane (200 ml). Then to the mixture is added 2.76 g (22.5 mmole) of ethoxyacetylene, stand the mixture for 1 hour, warmed to room temperature and then stirred at this temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and obtain tert-butyl 4-({3-[(ethoxyethyl)amino]-5,6-dimethyl-2-phenoxypyridine-4-yl}amino)butilka is bamat in the form of a brown oily product. To this oil is added 130 ml of pyridine, and the mixture is refluxed overnight, and then concentrated to obtain a brown oily product. This product is dissolved in dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The residue is dissolved in diethyl ether and again concentrated under reduced pressure. The result 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 methodology used in part F of example 7, the material obtained in part a of this example, is subjected to hydrolysis, which receive USD 5.76 g of 4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl]butane-1-amine as a brown oil.

The part With

Using the methodology applied in part G of example 7, 4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl]butane-1-amine (5,52 g, 15.0 mmol) is treated with anhydride methanesulfonic acid (2,74 g, 15.7 mmole) and the result of 6.26 g of N-4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-C]pyridin-1-yl]butyl}methanesulfonamide in a solid brown color.

Part D

Using the methodology applied in part H of example 7, conduct amination of N-{4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-they are the azo[4,5-C]pyridin-1-yl]butyl}methanesulfonamide (5,86 g, 13.1 mmole), which was 1.58 g of a white solid of 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 C16H27N5O3S, %: 52,01; N 7,37; N 18,95. Found, %: C 51,83; N 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)butane-1-amine (122 mg, of 0.33 mmole) under nitrogen atmosphere was dissolved in dichloromethane in presence of triethylamine (0,093 ml, 0.67 mmole). The solution is cooled in an ice bath and added dropwise thereto a solution/suspension of 4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (106 mg, of 0.33 mmole) in dichloromethane. The ice bath removed and the reaction mixture stirred for 16 hours, then poured it in a 10%aqueous solution of sodium carbonate. Separate the aqueous and organic phase 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 obtain a yellow oily product. Purification of this product by way of flash chromatography (silica gel, gradient of eluent from 92:8 dichlormid the n/methanol 95:5 dichloromethane/methanol) to give 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 mmole) and ammonium acetate (1.1 g) was placed in a vial with a stirrer, designed to work at high pressure. The vial is sealed and heated for 16 hours at a temperature of 150°C. the Reaction mixture is cooled to room temperature and diluted with water. The obtained turbid water, the mixture is alkalinized 10%aqueous hydroxide solution and extracted with three portions of chloroform (25 ml each). The combined organic fractions washed first with water and then brine, dried over sodium sulfate, decanted and evaporated to obtain a yellow oily product. Purification of this product by way of flash chromatography (silica gel, gradient eluent 95:5 dichloromethane/methanol 9:1 dichloromethane/methanol and the final elution with a mixture of 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.

1H NMR (500 MHz, DMSO-d6), δ to 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 (multiplet, 4H); 7,26-7,22(multiplet, 1H); of 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 (double doublet, J=6,4, and 12.4 Hz, 2H); was 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, 6N); 1,73-1,65 (multiplet, 4H); 1,61-1.55V (multiplet, 2H); 1.35 (sextet, J=7.4 Hz, 2H); 0,86 (triplet, J=7.4 Hz, 3H).

13With NMR (125 MHz, DMSO-d6): 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 C34H47N6O2, M+N).

EDUCATION CYTOKINE IN HUMAN CELLS

Determination of the activity obtained in the invention compounds to stimulate the formation of cytokines was performed using human cells in vitro. The activity was assessed, based on the number of interferon (α) and factor (α) tumor necrosis (IFN and TNF, respectively), determined by the method specified in article Testerman and other "Induction cenina using immunomodulators Imiquimod and S-27609", published in the journal of Leukocyte Biology", 58, 365-372 (September, 1995).

Preparation of culture on the basis of blood cells

Whole blood was collected by venipuncture from healthy donors in a special vacuum containers that meet the requirements ETDA. Mononuclear cells from peripheral blood (RVMS) were separated from whole blood using the method of gradie the private centrifugation using the apparatus of Histopaque® -1077. RVMS washed twice with a solution of balanced salts Khanka (Hank) and then suspended in RPMI medium. The concentration of blood cells in this suspension was (3-4)×106cells in 1 ml of suspension. Suspension RVMS were placed in 48 flat-bottomed sterile cells (supplied by Costar, Cambridge, strassacker, or Becton Dickinson Labware, Lincoln Park, new Jersey), which was equal volume of RPMI medium containing the analyzed connection.

Preparation connections

The connection was solubilizers in dimethyl sulfoxide (DMSO). The final concentration of DMSO in the prepared samples used for the test should not exceed 1%. Usually for tests used compounds at a concentration in the range from 0.12 to 30 µmol/L.

Incubation

First, in the cell, which was the RPMI medium was added to the solution used for the test compounds at a concentration of 60 mmol/l and then carried out the necessary three-fold dilution. After this was added, the suspension RVMS in such quantity that the concentration of the analyte was within the specified limits (from 0.12 to 30 µmol/l). The final concentration of the suspension RWMS was (1,5-2)×106cells/ml Cells was closed sterile plastic lids, gently mixed samples and kept them within 18-24 hours at 37 C in an atmosphere containing 5% carbon dioxide.

Department

After the end of the incubation period, the samples were subjected to centrifugation for 5 to 10 minutes at a rotation speed of the centrifuge 1000 rpm (approximately 200) and a temperature of 4°C. the Purified solution not containing cell culture was removed with a sterile polypropylene pipette and transferred into a sterile polypropylene vial. Samples prior to analysis was kept at a temperature of from -30 to -70°C. the Samples were analyzed for interferon-α and the factorα tumor necrosis using ELISA method.

Analysis of interferon (α) and factor-α tumor necrosis method ELISA (ELISA test)

The concentration of interferon (α) was determined by ELISA method, using a set of human multicystic obtained in PBL biomedical laboratories, new Brunswick, new Jersey. This method of analysis allows to determine the content of interferon in units of picograms/ml

The concentration of factor-α tumor necrosis was determined with an ELISA kit supplied by the firm Genzyme, Cambridge, strassacker; RandD Systems, Minneapolis, iminnesota, or firm Pharmingen, San Diego, stilborne. This method of analysis allows to determine the content of interferon in units of picograms/ml

The following table shows the minimum stake is entrale compounds, in which there is the formation of interferon and tumor necrosis factor. The sign "*" means that any of the investigated concentrations of added compounds was not observed the formation of interferon and tumor necrosis factor.

Education cytokine in human cells
Non sampleThe lowest effective concentration (µmol/l)
InterferonThe tumor necrosis factor
10,121,11
20,00460,01
30,010,37
40,120,37
50,010,12
60,010,01
70,37*
80,0410

The above description only a few applications of the present invention. Detailed description of the invention and the examples given here only to achieve full clarity in understanding the invention and areas of its application. For professionals in this field is evident that the field of application of the invention can change the I save the letter and spirit of the invention. However, this invention is not limited to the precise details of the compositions and structures, and covers all of the parties listed in the following claims.

1. The compound of formula (I)

where X is Allenova group;

Y is-CO-, -CS - or-SO2- group;

Z is a simple bond or-NR5group;

R1represents phenyl, unsubstituted or substituted by a halogen atom, a C1-20is an alkyl group,

Deputy R2selected from the group comprising alkyl; alkyl-O-alkyl; the substituents R3and R4represent alkyl; each substituent R5represents a hydrogen atom or a C1-10alkyl group; or a salt of the pharmaceutical quality on the basis of 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 represents a group-CO-, a Z - simple connection.

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 group-CS-, and Z is a group-NR5-.

6. The compound or salt according to claim 5, characterized in that the substituent R5represents a hydrogen atom, and the substituent R1 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-SO2-.

8. The compound or salt according to claim 1, characterized in that Y represents a group-SO2-, and Z is a simple bond.

9. The compound or salt of claim 8, characterized in that the substituent R1represents a C1-20is an alkyl group.

10. The compound or salt according to claim 1, characterized in that Y represents a group-SO2-, and Z is-NR5-.

11. The compound or salt of claim 10, characterized in that the substituent R5represents a C1-20is an alkyl group and the substituent R1also a1-20is an alkyl group.

12. The compound or salt according to claim 1, characterized in that the substituent R2represents an alkyl or alkyl-O-alkyl group.

13. The compound or salt according to claim 1, characterized in that X represents -(CH2)2-4group.

14. The compound or salt according to claim 1, characterized in that the substituents R3and R4independently from each other represent 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;

mo is ohydrate N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-4-forbindelsesfaneblad;

monohydrate of N-[-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-C]pyridin-1-yl)butyl]-N'-phenyltoloxamine;

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

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

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 pharmaceutical grade salt based on them.

16. Pharmaceutical composition for inducing cytokine biosynthesis, contains a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

17. Pharmaceutical composition for inducing cytokine biosynthesis, contains a therapeutically effective amount of a compound of claim 8 in combination with a pharmaceutically acceptable carrier.

18. Pharmaceutical composition for inducirovani cytokine biosynthesis, contains a therapeutically effective amount of a compound according to § 15 in combination with a pharmaceutically acceptable carrier.

19. Method of stimulating cytokine biosynthesis in animal organism is th, which consists in introducing into the animal a therapeutically effective amount of a compound according to claim 1.

20. A method of treating viral diseases in animals, which consists in introducing into the animal a therapeutically effective amount of a compound according to claim 1.

21. A method of treating neoplastic disease in animals, which consists in introducing into the animal a therapeutically effective amount of a compound according to claim 1.

22. Method of stimulating cytokine biosynthesis in an animal's body, which consists in introducing into the animal a therapeutically effective amount of a compound of claim 8.

23. A method of treating viral diseases in animals, which consists in introducing into the animal a therapeutically effective amount of a compound of claim 8.

24. A method of treating neoplastic disease in animals, which consists in introducing into the animal a therapeutically effective amount of a compound of claim 8.

25. Method of stimulating cytokine biosynthesis in an animal's body, which consists in introducing into the animal a therapeutically effective amount of the compound according to item 15.

26. A method of treating viral diseases in animals, which consists in introducing into the animal a therapeutically effective amount of the compound according to item 15.

27. The method of treatment SDA is olevaga diseases in animals which consists in introducing into the animal a therapeutically effective amount of the compound according to item 15.

28. The connection that represents imidazopyridine-4-amine of formula (II)

where X is Allenova group;

Deputy R2selected from the group comprising alkyl and alkyl-O-alkyl; the substituents R3and R4independently from each other selected from the group consisting of alkyl group, and each substituent R5represents independently a hydrogen atom or a C1-10alkyl group, or a salt of the pharmaceutical quality on the basis of these groups.

29. 2-Phenoxypyridine compound of formula (III)

in which Q represents NO2or NH2group;

X - Allenova group;

the substituents R3and R4independently selected from alkyl groups;

Deputy R5represents a hydrogen atom or a C1-10alkyl group;

BOC represents a tert-butoxycarbonyl group;

or a pharmaceutically acceptable salt.

30. 4-phenoxypyridine compound of formula (IV)

where X is Allenova group;

Deputy R2selected from the group comprising alkyl and alkyl-O-lkyl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl groups;

each substituent R5represents a hydrogen atom, and C1-10alkyl group;

VOS is tertbutoxycarbonyl group;

or a pharmaceutically acceptable salt.

31. 4-Phenoxypyridine compound of formula (V):

in which X - Allenova group;

Deputy R2selected from the group comprising alkyl and alkyl-O-alkyl; the substituents R3and R4independently from each other selected from the group consisting of alkyl groups,

each substituent R5represents independently a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.

32. 4-phenoxypyridine compound of formula (VI)

in which X - Allenova group;

R1represents a C1-20-alkyl, phenyl groups, or phenyl substituted by a halogen atom;

Deputy R2selected from the group comprising alkyl and alkyl-O-alkyl;

the substituents R3and R4independently from each other selected from the group consisting of alkyl groups;

each mandated the tel R 5represents a hydrogen atom or a C1-10alkyl group;

or salt of the pharmaceutical quality on the basis of these groups.



 

Same patents:

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes a herbicide against weeds resistant to sulfonylurea-base herbicide and comprising compound of the formula (I):

wherein Q represents condensed heterocyclic group of the formula (Q1), (Q3), (Q4) given in the invention description; X represents lower alkyl or lower alkoxyl group; Y represents lower alkoxyl group. Invention describes compound of the formula (II):

wherein R1 represents halogen atom or optionally halogenated lower alkyl group; R2 represents hydrogen atom; R3 represents (C2-C4)-alkyl group or lower cycloalkyl group; X represents lower alkyl group or lower alkoxyl group; Y represents lower alkoxyl group. Also, invention describes herbicides comprising compounds of the formula (II) and a method for control of weeds resistant to sulfonylurea-base herbicide. Method involves applying herbicide comprising compound of the formula (I) or compound of the formula (II). Herbicide is used for control of weeds resistant to sulfonylurea-base herbicide in rice-paddy fields.

EFFECT: valuable properties of herbicides.

10 cl, 8 tbl, 69 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: pharmacology, medicine.

SUBSTANCE: invention relates to new mercaptoacetylamide derivatives, which represents angiotensine converting enzyme and neutral endopeptidase inhibitors and useful in treatment of cardiovascular condition. More particularly invention relates to derivatives of formula I , wherein R1 represents hydrogen or acyl; wherein R2 represents hydrogen or biphenylmethyl; { represents -(CH2)n (n = 1, integer); B1 and B2 are independently hydrogen; or pharmaceutically acceptable salts or stereomers thereof. Method for production of compounds of formula I and formula II, pharmaceutical composition on the base of formula I, method for production thereof and method for treatment of cardiovascular condition.

EFFECT: new derivatives having value biological properties.

14 cl, 3 tbl, 4 ex, 1 dwg

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to derivatives of tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine of the formula (1): , wherein R3 means oxygen atom or absent; R8 is chosen from: (a) hydrogen atom; (b) (C1-C3)-alkyl that can be unsubstituted or substituted with 1-6 fluorine atoms; (c) -O-(C1-C3)-alkyl; (d) fluorine atom, and (e) hydroxy-group, and their pharmaceutically acceptable salts and separate diastereomers. These compounds are modulators of activity of chemokine receptors. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), method for modulation of activity of chemokine receptors in humans and animals and a method for preparing a medicinal agent. Invention provides preparing novel modulators of chemokine receptors activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinoquinoline of the formula (II): or their tautomers, or their pharmaceutically acceptable salts wherein ring A represents ortho-condensed phenyl and monosubstituted with R4 wherein R4 means halogen atom; R1 represents -(CH2)nL wherein n means a whole number from 1 to 6; L is chosen from unsubstituted phenyl or its benzo-derivative, or L is chosen from phenyl or its benzo-derivative and substituted with one or two groups chosen from -CN, -CF3, (C1-C4)-alkyl, or L is chosen from -OH, -OCOR', -SOmR' wherein m means 0, 1 or 2, -NR'R'' under condition that -NR'R'' differs from -NH2, -NR'COR'', or L is chosen from heterocycle or heteroaryl wherein in each abovementioned case any group from R' or R'' is chosen from hydrogen atom, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl, phenyl-(C1-C4)-alkyl and wherein any group from R' or R'' is unsubstituted or substituted 1, 2 or 3 times with phenyl, -OH, O-(C1-C4)-alkyl at carbon atoms wherein in any abovementioned case heterocycle is chosen from five- or six-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) atoms or its condensed benzo-derivative, indicated heterocycle wherein carbon atom is disubstituted to form (C5-C7)-spiro-group and indicated heterocycle wherein carbon atom © is substituted for oxygen atom (O) to form carbonyl group and wherein in any case heteroaryl is chosen from unsubstituted thiophene, furan, imidazole, triazole, tetrazole. Compounds of the formula (II) are antagonists of glycine-receptors and can be used in preparing pharmaceutical agents designated for treatment or prophylaxis of ischemic disease.

EFFECT: valuable medicinal properties of compounds.

5 cl, 8 tbl, 148 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: method involves applying effective doses of epidermis growth factor receptors antagonists being active ingredient in drug for inhibiting various types of resistant human tumors. The epidermis growth factor receptor antagonists are combined with other chemotherapeutic agents like Cisplatin, Irinotecan or ionizing radiation.

EFFECT: enhanced effectiveness of treatment.

50 cl, 2 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with adjuvant chemoradiation therapy of malignant cerebral meningiomas. In postsurgical period it is necessary to carry out lumbar puncture, catheterize subarachnoid space, sample 5 ml liquor, incubate liquor with cisplatin at the quantity of 0.1 mg in vitro at 38°C for 30 min to introduce it through a catheter into subarachnoid space. The procedure should be carried out twice at a 7-d-long interval, since the 2nd d of the beginning of this procedure it is necessary to conduct distance gamma-therapy at the bottom of removed tumor daily for 20 d up to total focal dosage being 60 Gy. The innovation enables to achieve stable remission, decrease toxicity of chemopreparation and frequency of side effects at considerable decrease of its cost price.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to geranyl compounds represented by the following formulas (I-1) , (I-2) or (I-3) wherein R1 means compounds of the following formulas: or R2 means a group remaining after removing all carboxyl groups presenting in carboxylic acid chosen from group consisting of malic acid, citric acid, succinic acid, fumaric acid and others; m = 1, 2 or 3; n = 0, 1 or 2, and m + n represent a number of carboxylic groups presenting in indicated carboxylic acid; R3 means p-hydroxyphenyl or mercapto-group. Also, invention relates to derivatives of mevalonic acid represented by the following formula (I-4): wherein R means -CH2OH or CH3. Also, invention to an antitumor agent comprising as an active component geranyl compound of formulas (I-1), (I-2) or (I-3) or derivative of mevalonic acid of the formula (I-4), and optionally a pharmaceutically acceptable carrier or solvent. Also, invention relates to a method for treatment of liver cancer based on using geranyl compound of formulas (I-1), (I-2) or (I-3), or derivative of mevalonic acid of the formula (I-4) and using proposed compounds in manufacturing an antitumor agent. Invention provides using geranyl compounds or derivatives of mevalonic acid as antitumor agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 17 ex

FIELD: medicine, therapy.

SUBSTANCE: as a sclerotherapeutic preparation one should choose ethoxysclerol to carry out 1-2 courses of therapy at intervals between the courses being 14-21 d. Preparation should be introduced under ultrasound control by introducing 0.5-4%-ethoxysclerol solution at the quantity of 0.5-1 ml/ml nodal volume in case of nodal-type neoplasm. In case of cystic neoplasm - at the quantity of 3-5 ml. Introduction should be fulfilled after liquid aspiration only. One day before the onset of every course of sclerotherapy Movalis 7.5 mg should be prescribed once daily after meals for 5-10 d. The innovation enables to avoid surgical therapy, and, also, increase patients' quality of life due to carrying out sclerosing along with interrupting the pronounced pain syndrome and in some cases heal the disease mentioned.

EFFECT: higher efficiency of therapy.

2 cl, 4 ex

FIELD: chemical-pharmaceutical industry, biochemistry, medicine.

SUBSTANCE: invention relates to a liposome directly effecting on αvβ3-integrin receptors and comprising cationic amphiphilic substance including 1,2-dioleoyloxy-3-(N,N,N-trimethylammonium)propane chloride, neutral lipid, lipid with a direct effect having domain with a direct effect and hydrophobic domain bound with domain of a direct effect, and nucleic acid forming complex with cationic lipid. Cationic lipid presents in the amount from about 1 to about 50 molar % and indicated lipid with a direct effect presents in the amount from about 1 to about 20 molar % wherein molar percents are calculated as measured for the total number of lipid moles in liposome. Domain with a direct effect comprises a nonpeptide antagonist of αvβ3-integrin comprising 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy]-benzoyl-2-(S)-aminoethylsulfonamino-β-alanine (compound 10) bound covalently with hydrophilic domain by amide bond. Also, invention relates to a method for inhibition of angiogenesis and involving administration to a patient needing in inhibition of angiogenesis a liposome in the therapeutically effective dose that directly effects on αvβ3-integrin receptors and comprising nucleic acid that is able to express a protein or peptide suppressing angiogenesis.

EFFECT: valuable properties of system.

27 cl, 2 tbl, 18 dwg, 8 ex

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

SUBSTANCE: invention relates to novel derivative of variolin B of the general formula (I) or their pharmaceutically acceptable salts possessing antitumor activity. In the general formula (I) radical R1 means aromatic group representing aromatic group representing phenyl optionally substituted with nitro-group, amino-group or alkyl-substituted amino-group, or aromatic group represents 5-6-membered heterocycle with two nitrogen atoms or sulfur atom as heteroatoms optionally substituted with (C1-C12)-alkyl, -OH, unsubstituted amino-group or amino-group substituted with (C1-C4)-acyl, phenyl-(C1-C4)-alkyl wherein phenyl group can be substituted with -OR1, or (C1-C12)-alkylthio-group, (C1-C12)-alkyl- or phenylsulfonyl, (C1-C12)-alkyl- or phenylsulfinyl or -OR1 wherein R1 is chosen from (C1-C12)-alkyl or phenyl; R2 represents hydrogen atom; R3 represents oxo-group when a dotted line is between nitrogen atom to which R2 is bound and carbon atom to which R3 is absent, or R2 is absent when R3 represents optionally protected amino-group wherein a substitute is chosen from (C1-C4)-acyl, phenylsulfonyl and (C1-C4)-alkylphenylsulfonyl when a dotted line forms a double bond between nitrogen atom to which R2 is bound and carbon atom to which R2 is bound; R4 represent hydrogen atom. Also, invention relates to a method for synthesis of compounds of the invention and to intermediate substances for their realization. Also, invention relates to a pharmaceutical composition based on variolin B derivatives.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 5 sch, 1 tbl, 50 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel tricyclic compounds, their pharmaceutically acceptable salts and solvates useful for inhibition of activity of farnesyl-protein-transferase. Invention describes compound of the formula (1.0): or its pharmaceutically acceptable salt or solvate wherein one among a, b, c and d means nitrogen atom (N) or -N+O-, and other a, b, c and d mean carbon atom and wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; or all a, b, c and d mean carbon atom wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; broken line (- - -) means optional binds; X means N or -CH when optional bond is absent, and it means carbon atom (C) when optional bond presents; when optional bond between carbon atom 5 and carbon atom 6 presents then only a single substitute A presents bound with carbon atom 5, and only a single substitute B presents bound with carbon atom 6, and A and B fifer from hydrogen atom (H); if optional bind between carbon atom 5 and carbon atom 6 is absent then two substitutes A present bound with carbon atom 5, and two substitutes B bound with carbon atom 6 wherein at least one of two substitutes A or one among two substitutes B mean H and wherein at least one of two substitutes A or one of two substitutes B has value distinct from H, and other radical are described in the invention claim. Also, invention disclosed a pharmaceutical composition comprising such compounds, a method for inhibition of anomalous growth of cells and methods for treatment of proliferative diseases as cancer.

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

52 cl, 2 tbl, 505 ex

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes dipeptide-nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters that are used in therapeutic or prophylaxis treatment of disease of morbid state mediated by cathepsin K.

EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

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

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

FIELD: veterinary virology, biotechnology.

SUBSTANCE: the suggested vaccine contains avirulent and purified antigenic material out of strain A (Georgia) being homologous to infection agent 1999/N1721-DEP obtained in passaged cell culture VNK-21 being the suspension that contains, predominantly, 146S and 75S immunogenic components of foot-and-mouth disease virus, adjuvants aluminum hydroxide with saponin and maintenance medium in efficient ratios. The vaccine is of high immunogenicity and is capable to provide efficient protection against homologous infection agent circulating in Transcaucasian countries and those of Central Asia, Near and Middle East.

EFFECT: higher efficiency.

10 cl, 1 dwg, 4 ex, 10 tbl

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